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Does cD154 on the surface of CD4+CD25+ regulatory T cells contributes to skin transplant tolerance?

It is known that the infusion of whole blood from donors (donor-specific transfusion) into recipients combined with anti-CD154 therapy can prolong allograft survival. It has generally been agreed that the effectiveness of anti-CD154 therapy is caused by the inactivation of alloreactive CD4+ and CD8+ effector T cells. The recent literature has implicated CD4+CD25+ regulatory T cells in the suppression of autoimmunity and graft rejection, and we therefore examined whether CD154 blockade is effective because of its blockade of inflammatory T-cell activation or because of a direct impact on the regulatory T cells. RAG(-/-) mice were adoptively transfused with CD4+ T cells or a subset of the population (CD4+CD25+ or CD4+CD25- T cells) alone or in combination with donor-specific transfusion and anti-CD154 and given an allo-skin transplant. The longevity of the transplant was determined over time. CD154(-/-)CD4+ T cells were used to assess the importance of CD154 in graft rejection and acceptance. CD154 blockade (or loss of CD154) on CD4+CD25+ regulatory T cells enhanced their immunosuppressive activities and was a contributing factor to anti-CD154-induced immune suppression in vivo. In a model of allograft tolerance, suppression was elicited by antigen and anti-CD154 or antigen alone if the CD4+CD25+ regulatory T cells were deficient in CD154 expression.

Neutralizing the function of CD154 on regulatory T cells upon antigen exposure induces heightened levels of suppressive activities and is likely a contributing factor to the long-lived therapeutic effects of anti-CD154 treatment.

Is every labor unique : but `` call when your contractions are 3 minutes apart ''?

To explore women's perceptions of transitioning to the birth facility when in labor. Qualitative. Twenty-four nulliparous women were interviewed following their birth experiences. Pain was identified as the primary reason for transitioning to the hospital. Once arriving at the hospital, women often felt pressure to "get it right" and not make multiple trips. Three themes were identified: (a) Don't trust your body, trust us; (b) This is not right; and (c) This is too labor!

The implications for nursing involve increased recognition of the range of normal experiences and acknowledgment that pain is a primary basis for women coming to the hospital as opposed to cervical dilation. Reevaluating the instruction the healthcare providers give to women is warranted.

Does high-sensitivity troponin level pre-catheterization predict adverse cardiovascular outcomes after primary angioplasty for ST-elevation myocardial infarction?

Cardiac troponins are the preferred biomarkers for diagnosing myocardial infarction (MI). High-sensitivity troponin T (hs-TnT) assays have increased sensitivity and enable more rapid diagnosis of infarction. We assessed the prognostic utility of admission hs-TnT to detect outcomes after primary angioplasty for ST-elevation/new left bundle branch block myocardial infarction (STEMI). Patients admitted to Auckland City Hospital for acute coronary catheterization with a diagnosis of STEMI between October 2010 and September 2011 were identified, and included if hs-TnT levels were measured at admission. Clinical characteristics and major adverse cardiovascular events (MACE: death, myocardial infarction and revascularization) at 30 days and 1 year were collected from national statistics and electronic medical records. Median admission hs-TnT level in the 173 STEMI patients studied was 59 ng/L (interquartile range (IQR) 19-310). Incidences of MACE at 30 days and 1 year were 10% (n=17) and 18% (n=31), respectively. C-statistics and 95% confidence interval (CI) (95% CI) for hs-TnT on admission at detecting MACE at 30 days and 1 year were 0.800 (0.696-0.904) and 0.750 (0.655-0.845) respectively, with the optimal cut-point of 225 ng/L giving sensitivities/specificities of 76.5%/75.6% and 64.5%/78.2% respectively. Admission log(hs-TnT) independently predicted both MACE at 30 days with hazards ratio 5.16, 95% CI (2.25-11.9) and 1 year with hazards ratio 2.88, 95% CI (1.79-4.63), as did age and cardiogenic shock. Age, Maori or Pacific ethnicity and chronic respiratory disease were independent predictors of hs-TnT>225 ng/L.

Admission hs-TnT measured in primary angioplasty is strongly prognostic of MACE at 30 days and 1 year, even following adjustment for potential confounding variables.

Does esomeprazole reduce gastroesophageal reflux after beer consumption in healthy volunteers?

Patients with gastroesophageal reflux disease (GERD) are advised to avoid alcoholic beverages since alcohol consumption induces gastroesophageal reflux in healthy volunteers and increases it in patients with GERD. Proton-pump inhibitors (PPIs) are frequently administered for reflux symptoms but their effect on gastroesophageal reflux after alcohol consumption has not yet been fully studied. The aim of the present study was therefore to investigate the effect of esomeprazole, an S-enantiomer of omeprazole, on gastroesophageal reflux after beer consumption. In this placebo-controlled, double-blind, crossover study, 16 healthy male volunteers received 20 mg esomeprazole daily for one week. On day 7, in an acute experiment, the subjects then consumed 500 ml beer within 5 min. Subsequently, gastroesophageal reflux was monitored by pH-metry over a period of 3 h. In addition, gastric emptying was measured by ultrasonography and blood concentrations of ethanol, cholecystokinin and gastrin were determined. Gastroesophageal reflux was significantly (p=0.001) reduced by 93% after treatment with esomeprazole (0.2%, median percentage of time pH<4) as compared to placebo (2.6%), but gastric emptying, blood ethanol and cholecystokinin concentrations were not significantly different after esomeprazole treatment. Plasma gastrin levels were significantly (p=0.0003) higher after esomeprazole (98.6+/-19.7 pg/ml) than after placebo (22.7+/-3.8 pg/ml) before beer consumption. However, there was no difference in the increase in plasma gastrin after beer consumption between the esomeprazole treatment and placebo.

Esomeprazole significantly reduces gastroesophageal reflux after beer consumption in healthy volunteers. Gastric emptying of beer is not prolonged after treatment with esomeprazole, although compared with placebo, this PPI induced significantly higher plasma gastrin concentrations. Moderate alcohol consumption does not worsen gastroesophageal reflux when a PPI is administered.

Is right portal vein ligation as efficient as portal vein embolization to induce hypertrophy of the left liver remnant?

Aim of this retrospective study was to compare induction of left liver hypertrophy after right portal vein ligation (PVL) and right portal vein embolization (PVE) before right hepatectomy for liver metastases. Between 1998 and 2005, 18 patients underwent a PVE, whereas 17 patients underwent a PVL during a first stage laparotomy. There was no complication related to PVE or PVL. After a similar interval time (7 +/- 3 vs 8 +/- 3 weeks), the increase of the left liver volume was similar between the two groups (35 +/- 38 vs 38 +/- 26%). After PVE and PVL, right hepatectomy was performed in 12 and 14 patients, respectively. Technical difficulties during the right hepatectomy were similar according to duration of procedure (6.4 +/- 1 vs 6.7 +/- 1 h, p = 0.7) and transfusion rates (33 vs 28%, p = 0.7). Mortality was nil in both groups, and morbidity rates were respectively 58% for the PVE group and 36% for the PVL group (p = 0.6).

Right PVL and PVE result in a comparable hypertrophy of the left liver. During the first laparotomy of a two-step liver resection, PVL can be efficiently and safely performed.

CT of hypervascular hepatic tumors: are unenhanced scans necessary for diagnosis?

In most institutions, a combination of unenhanced and contrast-enhanced CT is used to screen patients for suspected hypervascular hepatic neoplasms. Elimination of the unenhanced examination could save time and expense and reduce the patient's exposure to radiation. We compared unenhanced and incremental bolus dynamic contrast-enhanced CT for detection of hypervascular hepatic neoplasms and evaluated the need for preliminary unenhanced hepatic CT. We prospectively examined 101 consecutive patients with hypervascular primary hepatic malignant tumors or suspected hypervascular metastases. Primary hepatic neoplasms included hepatocellular carcinoma (seven), sarcoma (two), and hemangioendothelioma (one); extrahepatic primary tumors included breast (37) and renal cell (24) carcinoma, melanoma (15), carcinoid (nine), and endocrine and other tumors (six). All patients had both unenhanced and bolus dynamic contrast-enhanced CT with 5-mm collimated sections at 8-mm intervals. For contrast-enhanced CT, 150-180 ml of IV contrast material, a mechanical power injector, and a scanning protocol that allowed completion of liver imaging within 2 min were used. Both unenhanced and contrast-enhanced CT scans were compared for detection and conspicuousness of hepatic lesions. Hepatic lesions were found in 34 patients. In 21 patients, all hepatic lesions seen on unenhanced scans also were apparent on contrast-enhanced scans. However, in 12 (57%) of 21 patients, lesions were more conspicuous and better defined on contrast-enhanced scans. The absolute number of lesions detected with each method of scanning differed in 12 patients. In four patients, the contrast-enhanced scan showed more lesions; in five patients, the unenhanced scan showed more lesions; and in three patients, administration of contrast material obscured some lesions shown on unenhanced scans and made others more conspicuous. If only a contrast-enhanced CT scan had been obtained, the presence of malignant hepatic neoplasm would have been missed in only one case (a patient with a single 2.8-cm metastasis from renal cell carcinoma).

Bolus dynamic contrast-enhanced CT alone correctly showed the presence or absence of primary or metastatic hypervascular hepatic tumors in 100 of 101 cases. If the goal of CT examination is detection of hypervascular hepatic lesions, use of contrast-enhanced CT alone may be adequate and the addition of unenhanced scans is not cost-effective.

Do baseline psychological stress and ovarian norepinephrine levels negatively affect the outcome of in vitro fertilisation?

We determined the effect of baseline psychological stress and norepinephrine (NE) levels in the follicular fluid on the outcome of in vitro fertilisation (IVF). One hundred seven women with tubal factor infertility were evaluated before and during their first IVF treatment. On the first day of down-regulation, their psychological state was measured using the Zung Self-rating Anxiety (SAS) and Depression Scales (SDS), and defined as baseline psychological stress. On oocyte retrieval day, NE levels in the follicular fluid and peripheral plasma were measured by high-performance liquid chromatography. On the first day of down-regulation, nearly 10% of the women with tubal factor infertility reported that they were experiencing both anxiety and depression. This baseline psychological stress was lower in pregnant (3.7%) than in non-pregnant women (15.7%, p<0.05). On oocyte retrieval day, the NE levels in follicular fluid were almost twice the amount seen in peripheral plasma, but did not differ in pregnant and non-pregnant women (p>0.05). NE levels in follicular fluid were negatively associated with the percentage of good quality embryos (r= -0.62, p<0.05).

Baseline psychological stress (both anxiety and depression) may negatively influence the clinical pregnancy rate of IVF treatment in women with tubal factor infertility. Furthermore, follicular NE levels are negatively associated with the percentage of good quality embryos.

Is the pituitary-adrenocortical system involved in the sex difference in passive avoidance?

The hypothesis that sex differences in passive avoidance are related to the sex difference in the pituitary-adrenocortical system was studied. A high dose of dexamethasone (500 microg/kg body weight) was injected in male and female rats in order to suppress the activity of the pituitary-adrenocortical system. Dexamethasone treated animals and controls were tested for retention of passive avoidance at one of 4 different intervals after punishment. The percentage of females re-entering the compartment in which they were previously shocked was significantly higher than the percentage of males, after a retention interval of 60 minutes, but not after an interval of 0 minutes or 15 minutes (Experiment 1). Dexamethasone did not affect this pattern of sex differences. The same sex difference was found after an interval of 24 hours (Experiment 2), and again dexamethasone had no effect on it. However, in males a state-dependent effect of dexamethasone treatment was found in Experiment 2 when animals were given two injections of either dexamethasone or saline, one before the learning trial and one before the retention trial. Within the groups of males given two different injections (Dex-Sal and Sal-Dex) a higher percentage re-entered the shock compartment, when compared with the groups of males given the same injection twice (Sal-Sal and Dex-Dex).

(1) A sex difference in passive avoidance apparently occurs after a certain interval during which the animals are not disturbed. (2) This sex difference does not depend on the integrity of the pituitary-adrenocortical system. (3) State-dependency was observed in males only, indicating that changes in the pituitary-adrenocortical system, as a consequence of dexamethasone treatment, may have a more important stimulus value in males.

Does pET imaging in extratemporal epilepsy require consideration of electroclinical findings?

The study aimed to assess the relevance of interictal temporal glucose hypometabolism in patients with extratemporal epilepsy (ETE) by analyzing its association with a seizure semiology suggestive for temporal seizure involvement and the presence of temporal interictal epileptiform discharges (IEDs). We retrospectively reviewed the database of our epilepsy monitoring unit for patients with ETE, in whom long-term EEG-video-monitoring and [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) had been performed. The localization of IEDs and the glucose hypometabolism were compared. Almost half (46%) of the 63 ETE patients had IEDs localized in the temporal lobe. Most patients (87.5%; 7/8) with temporal IEDs and an ipsitemporal hypometabolism showed seizure semiology suggestive of temporal or limbic system involvement in contrast to only 31.0% (9/29, p=0.01) in patients without temporal IEDs nor temporal hypometabolism. Those patients also showed an ictal seizure pattern spread into the ipsitemporal lobe, compared with 75.9% (22/29, n.s.) in patients without temporal IEDs nor temporal hypometabolism. Both, extratemporal (ipsilateral in 82.1%; 23/28 patients) and temporal (ipsilateral in 78.6%; 11/14 patients) hypometabolism significantly (p<0.05) lateralized to the epileptogenic hemisphere.

The common temporal glucose hypometabolism in ETE patients reflects a remote epileptic dysfunction arising from extratemporal epileptogenic zones. Thus, interpretation of interictal FDG-PET results requires consideration of EEG results and seizure semiology to avoid false localization particularly in non-lesional epilepsy.

Does porphyromonas gingivalis decrease osteoblast proliferation through IL-6-RANKL/OPG and MMP-9/TIMPs pathways?

Porphyromonas gingivalis, an important periodontal pathogen, is closely associated with inflammatory alveolar bone resorption. This bacterium exerts its pathogenic effect indirectly through multiple virulence factors, such as lipopolysaccharides, fimbriae, and proteases. Another possible pathogenic path may be through a direct interaction with the host's soft and hard tissues (e.g., alveolar bone), which could lead to periodontitis. The aim of the present study was to investigate the direct effect of live and heat-inactivated P gingivalis on bone resorption, using an in vitro osteoblast culture model. Optical microscopy and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide MTT assay revealed that live P gingivalis induced osteoblast detachment and reduced their proliferation. This effect was specific to live bacteria and was dependent on their concentration. Live P gingivalis increased IL-6 mRNA expression and protein production and downregulated RANKL and OPG mRNA expression. The effect of live P gingivalis on bone resorption was strengthened by an increase in MMP-9 expression and its activity. This increase was accompanied by an increase in TIMP-1 and TIMP-2 mRNA expression and protein production by osteoblasts infected with live P gingivalis.

Overall, the results suggest that direct contact of P gingivalis with osteoblasts induces bone resorption through an inflammatory pathway that involves IL-6, RANKL/OPG, and MMP-9/TIMPs.

Does mitogen-activated protein kinase signaling cause malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival?

Intrinsic and acquired resistance to drug therapies remains a challenge for malignant melanoma patients. Intratumoral heterogeneities within the tumor microenvironment contribute additional complexity to the determinants of drug efficacy and acquired resistance. We use 3D biomimetic platforms to understand dynamics in extracellular matrix (ECM) biogenesis following pharmaceutical intervention against mitogen-activated protein kinases (MAPK) signaling. We further determined temporal evolution of secreted ECM components by isogenic melanoma cell clones. We found that the cell clones differentially secrete and assemble a myriad of ECM molecules into dense fibrillar and globular networks. We show that cells can modulate their ECM biosynthesis in response to external insults. Fibronectin (FN) is one of the key architectural components, modulating the efficacy of a broad spectrum of drug therapies. Stable cell lines engineered to secrete minimal levels of FN showed a concomitant increase in secretion of Tenascin-C and became sensitive to BRAF(V600E) and ERK inhibition as clonally- derived 3D tumor aggregates. These cells failed to assemble exogenous FN despite maintaining the integrin machinery to facilitate cell- ECM cross-talk. We determined that only clones that increased FN production via p38 MAPK and β1 integrin survived drug treatment.

These data suggest that tumor cells engineer drug resistance by altering their ECM biosynthesis. Therefore, drug treatment may induce ECM biosynthesis, contributing to de novo resistance.

Do how Australian and New Zealand schools of optometry prepare students for culturally competent practice?

This study is an investigation of how Australian and New Zealand schools of optometry prepare students for culturally competent practice. The aims are: (1) to review how optometric courses and educators teach and prepare their students to work with culturally diverse patients; and (2) to determine the demographic characteristics of current optometric students and obtain their views on cultural diversity. All Australian and New Zealand schools of optometry were invited to participate in the study. Data were collected with two surveys: a curriculum survey about the content of the optometric courses in relation to cultural competency issues and a survey for second year optometry students containing questions in relation to cultural awareness, cultural sensitivity and attitudes to cultural diversity. Four schools of optometry participated in the curriculum survey (Deakin University, Flinders University, University of Melbourne and University of New South Wales). Sixty-three students (22.3 per cent) from these four schools as well as the University of Auckland participated in the student survey. Cultural competency training was reported to be included in the curriculum of some schools, to varying degrees in terms of structure, content, teaching method and hours of teaching. Among second year optometry students across Australia and New Zealand, training in cultural diversity issues was the strongest predictor of cultural awareness and sensitivity after adjusting for school, age, gender, country of birth and language other than English.

This study provides some evidence that previous cultural competency-related training is associated with better cultural awareness and sensitivity among optometric students. The variable approaches to cultural competency training reported by the schools of optometry participating in the study suggest that there may be opportunity for further development in all schools to consider best practice training in cultural competency.

Does variable number of tandem repeats of the insulin gene determine susceptibility to latent autoimmune diabetes in adults?

The different clinical presentations of latent autoimmune diabetes in adults (LADA) and type 1 diabetes mellitus may be the result of susceptibility genes in determining the mode of onset. We analyzed the 5' polymorphisms of the insulin mini-satellite region (INS), a variable number of tandem repeats (VNTR) [repeat units; RU]. We evaluated the association of the different INS-VNTR alleles in patient susceptibility to LADA autoimmune diabetes. To our knowledge, this constitutes the first study of this kind performed in a Caucasian population. From an group of 160 Argentinean patients previously characterized as having LADA, we selected 44 patients who presented with humoral autoimmunity for genotyping and compared them to 88 patients with type 1 diabetes and 138 healthy individuals. The INS-VNTR allele classes were determined by Southern blotting (class I: 21-44RU; class III: 138-159RU). Subjects with class I alleles were further studied using PCR amplification to determine the exact length of the alleles (short 1S: 22-37RU; medium 1M: 38-41RU; large 1L: 42-43RU). Allelic and genotype frequencies were estimated by chi(2) tests for independence with 2 x 2 contingency tables and the relative risks (RR) were determined using GraphPad InStat software. We observed differential associations among the class I alleles when comparing patients with LADA (80.6%) and type 1 diabetes (81.3%) with the controls (70%; p < 0.005). This increase was largely due to the high frequency of the 1S/S genotype (63.6% LADA vs 37% controls, with a p-value of 0.0019 [p1]; 53.4% type 1 diabetes vs 37% controls, with a p-value of 0.0149 [p2]). Remarkably, all LADA patients genotyped as class I homozygous had the shorter (S) class I allele (100%). Differences in the overall 1S distribution were observed: in LADA the 94.4% of the alleles were equal to or smaller than 35RU, while in patients with type 1 diabetes it was 78.3% and in controls 74.1%. Moreover, the relative risks associated with the 1S/S genotype for patients with LADA showed a substantial increase with respect to those with type 1 diabetes (52%) when we compare them to the controls (1S/S LADA/control, 2.282 [RR1] vs type 1 diabetes/control, 1.497 [RR2]).

The presence of the 1S allele could be considered a risk factor in LADA patients, as previously reported for type 1 diabetes. The class I INS-VNTR allele in LADA increases genetic susceptibility to disease development.

Does non-high-density lipoprotein cholesterol independently predict new onset of non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular disease (CVD) risk. Non-high-density lipoprotein cholesterol (non-HDL-C), i.e. total cholesterol minus HDL, is a well-established risk factor for CVD; however, its association with NAFLD development has not been established. Our aim was to test whether non-HDL-C is an independent predictor of new onset of NAFLD. A prospective cohort study of 213 subjects from the general population, without liver disease, was studied. Evaluation of medical history, dietary and physical activity habits, fasting blood tests and ultrasonographic evidence of NAFLD was performed at baseline and after a 7-year follow-up by identical protocols. From 147 patients that did not have NAFLD at baseline, 28 (19%) developed NAFLD at the 7-year follow-up. The baseline levels of non-HDL-C were higher among subjects who developed NAFLD (179.5 ± 37.1 vs. 157.3 ± 35.1 mg/dl, P = 0.003). Non-HDL-C independently predicted new onset of NAFLD adjusting for age, gender, BMI or waist circumference, lifestyle and serum insulin (OR = 1.02 for every mg/dl increment, 1.01-1.04 95% CI, P = 0.008). Non-HDL-C was a stronger predictor for NAFLD than total cholesterol, low-density lipoprotein cholesterol, triglycerides and HDL. No patients with non-HDL-C < 130 mg/dl developed NAFLD, whereas 20.8% of those with values between 130 to 160 and 24.6% of those with values >160 mg/dl developed NAFLD (P for trend = 0.015).

Non-HDL-C is an independent predictor for NAFLD and a stronger predictor than other lipoproteins. This association may stem from the combined hepato-toxic effect of non-HDL-C and may explain the association between NAFLD and CVD.

Do [ Experimental study on establishment of a simple model of rats crush injury-crush syndrome ]?

To establish a repeatable, simple, and effective model of rat crush injury and crush syndrome. A total of 42 female Sprague Dawley rats (2-month-old, (CS) so as to lay a foundation for further study on CS. weighing 160-180 g) were divided randomly into the control group (n=6) and experimental group (n=36). The rats of the experimental group were used to establish the crush injury and CS model in both lower limbs by self-made crush injury mould. The survival rate and hematuria rate were observed after decompression. The biochemical indexes of blood were measured at 2, 4, 8, 12, 24, and 48 hours after decompression. The samples of muscle, kidney, and heart were harvested for morphological observation. There was no treatment in the control group, and the same tests were performed. Seven rats died and 15 rats had hematuria during compression in the experimental group. Swelling of the lower limb and muscle tissue was observed in the survival rats after reperfusion. The liver function test results showed that the levels of alanine transaminase and aspartate aminotransferase in the experimental group were significantly higher than those in the control group (P < 0.05). The renal function test results showed that blood urea nitrogen level increased significantly after 2 hours of decompression in the experimental group, showing significant difference when compared with that in the control group at 12, 24, and 48 hours after decompression (P < 0.05); the creatinine level of the experimental group was higher than that of the control group at 4, 8, 12, and 24 hours, showing significant difference at 8, 12, and 24 hours (P < 0.05). The serum K+ concentration of the experimental group was higher than that of the control group at all time, showing significant difference at the other time (P < 0.05) except at 2 hours. The creatine kinase level showed an increasing tendency in the experimental group, showing significant difference when compared with the level of the control group at 4, 8, 12, and 24 hours (P < 0.05). The histological examination of the experimental group showed that obvious edema and necrosis of the muscle were observed at different time points; glomeruli congestion and swelling, renal tubular epithelial cell degeneration, edema, necrosis, and myoglobin tube type were found in the kidneys; and myocardial structure had no obvious changes.

The method of the crush injury and CS model by self-made crush injury mould is a simple and effective procedure and the experimental result is stable. It is a simple method to establish an effective model of rats crush injury and CS.

Is genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms strongly associated with depression and anxiety in Japanese employees?

Although alcohol-related disorders (ARD) have been shown to be accompanied by comorbid depressive and anxiety disorders, and alcohol metabolic enzyme genes, ADH1B and ALDH2 polymorphisms, have been associated with an increased risk of ARD, no studies have been conducted to evaluate the associations between these genetic polymorphisms and anxiety or depression. A total of 1944 Japanese workers were interviewed regarding their depressive and anxiety disorders, including suicidality, by a brief psychiatric structured interview (MINI). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphism combinations with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and anxiety/depressive disorders, adjusting for sex, age, and job rank. The degree of alcohol sensitivity was classified into five groups according to the combination of two enzyme genotypes (Group I-V, in order from the lowest alcohol sensitivity). Those with ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1 were likely to be at an increased risk of depressive and anxiety disorders as well as ARD. This tendency was more apparent among non-drinkers (OR 9.20, 95% CI 1.66-50.89). No adverse effects of ALDH2 or ADH1B alone were observed with mental disorder risks. Likewise, analyses conducted combining job rank and genetic alcohol sensitivity showed no material associations with such risks.

Genetic alcohol sensitivity, especially that with the genotype combination of ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1, was significantly associated with an increased risk of depressive and anxiety disorders as well as ARD.

Early PET/CT after radiofrequency ablation in colorectal cancer liver metastases: is it useful?

Morphologic imaging after radiofrequency ablation (RFA) of liver metastases is hampered by an inflammatory response in the ablation margin, making the identification of local tumor progression (LTP) difficult. The aim of this study was to evaluate the efficacy of early (18)F-FDG PET/CT scanning to monitor the effectiveness of RFA in colorectal liver metastases. Twelve patients with 20 metastases were treated with RFA for colorectal liver metastases. They underwent PET/CT within 2 weeks before RFA and within 24 hours after RFA (so termed "early PET/CT"). PET/CT was repeated at 1, 3, and 6 months, and then every 6 months after ablation. The standard of reference was based on available clinical and radiological follow-up data. Early PET/CT revealed total photopenia in 16 RFA-treated metastases, which were found to be without residual tumor on the final PET/CT scan. Three RFA-treated metastases with focal uptake were identified as local tumor progression, which necessitated further treatment. One RFA-treated metastasis with rim-shaped uptake was regarded as inflammation. The results of the early PET/CT scanning were consistent with the findings of the final follow-up.

PET/CT performed within 24 hours after RFA can effectively detect whether residual tumor exists for colorectal cancer liver metastases. The results can guide further treatment, and may improve the efficacy of RFA.

Does liver stiffness predict clinical outcome in human immunodeficiency virus/hepatitis C virus-coinfected patients with compensated liver cirrhosis?

Our aim was to assess the predictive value of liver stiffness (LS), measured by transient elastography (TE), for clinical outcome in human immunodeficiency virus / hepatitis C virus (HIV/HCV)-coinfected patients with compensated liver cirrhosis. This was a prospective cohort study of 239 consecutive HIV/HCV-coinfected patients with a new diagnosis of cirrhosis, done by TE, and no previous decompensation of liver disease. The time from diagnosis to the first liver decompensation and death from liver disease, as well as the predictors of these outcomes, were evaluated. After a median (Q1-Q3) follow-up of 20 (9-34) months, 31 (13%, 95% confidence interval [CI]: 9%-17%) patients developed a decompensation. The incidence of decompensation was 6.7 cases per 100 person-years (95% CI, 4.7-9-6). Fourteen (8%) out of 181 patients with a baseline LS < 40 kPa developed a decompensation versus 17 (29%) out of 58 with LS ≥ 40 kPa (P = 0.001). Factors independently associated with decompensation were Child-Turcotte-Pugh (CTP) class B versus A (hazard ratio [HR] 7.7; 95% CI 3.3-18.5; P < 0.0001), log-plasma HCV RNA load (HR 2.1; 95% CI 1.2-3.6; P = 0.01), hepatitis B virus coinfection (HR, 10.3; 95% CI, 2.1-50.4; P = 0.004) and baseline LS (HR 1.03; 95% CI 1.01-1.05; P = 0.02). Fifteen (6%, 95% CI: 3.5%-9.9%) patients died, 10 of them due to liver disease, and one underwent liver transplantation. CTP class B (HR 16.5; 95% CI 3.4-68.2; P < 0.0001) and previous exposure to HCV therapy (HR 7.4; 95% CI 1.7-32.4, P = 0.007) were independently associated with liver-related death; baseline LS (HR 1.03; 95% CI 0.98-1.07; P = 0.08) was of borderline significance.

LS predicts the development of hepatic decompensations and liver-related mortality in HIV/HCV-coinfection with compensated cirrhosis and provides additional prognostic information to that provided by the CTP score.

Does smoke exposure interact with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness?

ADAM33 is the first identified asthma gene by positional cloning, especially asthma combined with bronchial hyperresponsiveness (BHR). Moreover, ADAM33 is associated with early-life lung function and decline of forced expiratory volume in 1 s (FEV(1)) in the general population. In utero and postnatal cigarette smoke exposure (CSE) are associated with reduced lung function, and development of BHR and asthma. We hypothesized that this may occur via interaction with ADAM33. To replicate the role of ADAM33 in childhood lung function and development of BHR and asthma. Furthermore, we investigated gene-environment interaction of ADAM33 with in utero and postnatal CSE in the Dutch PIAMA cohort. Six ADAM33 single-nucleotide polymorphisms (SNPs) were genotyped. Rint was measured at age 4 and 8 years, FEV(1) and BHR at age 8 years; asthma was based on questionnaire data at age 8. In the total cohort, the rs511898 A, rs528557 C, and rs2280090 A alleles increased the risk to develop asthma (+BHR). There existed interaction between in utero but not postnatal CSE and the rs528557 and rs3918396 SNPs with respect to development of BHR, the rs3918396 SNP with Rint at age 8 and the rs528557 SNP with FEV(1)% predicted.

We confirm associations between ADAM33 and the development of asthma (+BHR). This is the first study suggesting that interaction of in utero CSE with ADAM33 results in reduced lung function and the development of BHR, which needs further confirmation.

Are hyperinsulinemia during oral glucose tolerance test and high normal serum cortisol associated with increased secretion of calcitonin in normal subjects?

Previous studies showed that insulin stimulated directly calcitonin (Ct) secretion in the pig thyroid, while dexamethasone stimulated the production of Ct and Ct mRNA in medullary thyroid carcinoma (MTC) cell lines. The objective of this study was to investigate if hyperinsulinemia during the oral glucose tolerance test (GTT) stimulates Ct secretion in normal subjects as well as to examine the relationship between serum cortisol and Ct. In 26 normal subjects (9 men and 17 women) with detectable basal serum Ct, aged 22-70 yr [51.5±14.6 (mean±SD), median 55.5], we measured serum or plasma Ct, cortisol, ACTH, insulin, and blood glucose before (0 min) and at 30, 60, 90, and 120 min after ingestion of 75 g glucose. During GTT mean serum cortisol increased slightly by 9.3% at 30 min, whereas mean serum insulin increased 9.4-fold, reaching a peak value at 60 min. Median serum Ct increased by 51% (p<0.001) in normal subjects (by 27% in men, p=0.004, and by 44% in women, p<0.001) at 30 min and remained significantly higher thereafter (up to 120 min) when compared to median baseline level. Regression analysis showed that basal serum cortisol, but not basal serum insulin, was correlated with basal serum Ct (p=0.01). Peak concentrations of Ct were also correlated with peak concentrations of cortisol at 30 min (p<0.001) but not at later time points. Serum insulin was correlated with serum Ct at the serum insulin peak level (60 min), and at later time points (90 and 120 min) (p=0.001). Multiple and simple regression analysis showed that calcitonin-AUC (Area Under Curve) values correlated with insulin-AUC (p=0.003), and also with cortisol-AUC (p=0.02) values, the standardized effect of insulin-AUC on Calcitonin-AUC being greater than that of cortisol-AUC.

These findings suggest that acute hyperinsulinemia during GTT is very likely associated with increased Ct secretion in normal subjects. Serum cortisol within the physiological range was also correlated with serum Ct under basal conditions, as well as during GTT.

Is transesophageal Echocardiographic Measurement of Cardiac Index by the Prosthetic Mitral Valve Method Similar to the Continuous Thermodilution Method Via a Pulmonary Artery Catheter?

To compare the agreement of cardiac index measurements between transesophageal echocardiography across the prosthetic mitral valve and the continuous thermodilution method through a pulmonary artery catheter (PAC-TD) in patients undergoing double-valve replacement. Observational prospective study. University hospital. Twenty-five patients undergoing double-valve replacement (12 men and 13 women, age 25-78 years, ASA III-IV, NYHA II-III, LVEF≥45%). Patients were grouped according to their prosthesis (mechanical prosthesis v bioprosthesis). All patients underwent cardiac index assessment during double-valve replacement. Cardiac index across the prosthetic mitral valve was measured simultaneously using transesophageal echocardiography (CI(MV)) and PAC-TD (CI(PAC)) at 15, 30, 45, and 60 minutes after weaning from cardiopulmonary bypass, and at 0, 15, and 30 minutes after incision closure. A correlation was present between CI(MV) and CI(PAC) in both groups (mechanical prosthesis: r = 0.47, p<0.01; bioprosthesis: r = 0.60, p<0.01). In the mechanical prosthesis group, the bias between techniques (CI(PAC) v CI(MV)) was-0.5 L/min/m(2) (95% CI:-1.97 to 0.97), and error was 55%. In the bioprosthesis group, the bias between both techniques was-1.3 L/min/m(2) (95% CI:-3.1 to 0.5), and error was 56%.

A relatively weak correlation and lack of agreement between values of CI(PAC) and CI(MV) were observed in patients undergoing double-valve replacement. Therefore, transesophageal echocardiography might not be interchangeable with PAC-TD for measuring cardiac output or cardiac index. A regression equation is needed to correct the probable value of CI(PAC). CI(MV) might be useful as a quantitative or semi-quantitative cardiac output measurement.

Do the impact of limited English proficiency on asthma action plan use?

The goal of this study was to compare rates of asthma action plan use by limited English proficiency (LEP) caregivers to English proficient (EP) caregivers. A cross-sectional bilingual survey was distributed at an urban, academic, pediatric emergency department (PED). Surveys were completed by adult caregivers of children with asthma who sought PED care for asthma related chief complaints. LEP was defined as caregiver ability to speak English less than "very well". Data were analyzed using Fisher's exact test and odds ratios (OR). One hundred seven surveys were completed and analyzed. Fifty-one surveys (48%) were completed by LEP caregivers and 56 (52%) by EP caregivers. A 25% difference (p = .01) in action plan use rates between LEP caregivers (39%) and EP caregivers (64%) was observed. EP alone was associated with action plan use (OR 2.8 [95% CI 1.3-6.1]). Variables not associated with plan use included mother acting as caregiver (OR 2.1 [95% CI 0.7-7.0]), age of child >7 years (OR 1.0 [95% CI 0.5-2.4]), caregiver education  ≥  associate degree (OR 1.4 [95% CI 0.6-3.0]), private insurance (OR 0.7 [95% CI 0.3-1.8]), White race (OR 0.7 [95% CI 0.2-2.2]), Latino ethnicity (OR 0.5 [95% CI 0.2-1.3]) and a federally qualified health center (OR 0.8 [95% CI 0.3-2.0]). The main caregiver reasons for plan use were feeling that a plan works/gets results, helps with symptom management and appreciation towards physician attentiveness when a plan is prescribed. The main caregiver reasons for non plan use were they were not informed/given an action plan or perceived the child's asthma as mild/well controlled.

Compared with EP caregivers, those with LEP experience disparate rates of asthma action plan use.

Chest pain evaluation in the emergency department: can MDCT provide a comprehensive evaluation?

The purpose of our study was to determine whether MDCT can provide a comprehensive assessment of cardiac and noncardiac causes of chest pain in stable emergency department patients. Patients with chest pain who presented to the emergency department without definitive findings of acute myocardial infarction based on history, physical examination, and ECG were recruited immediately after the initial clinical assessment. For each patient, the emergency department physician was asked whether a CT scan would normally have been ordered on clinical grounds (e.g., to exclude pulmonary embolism). Each consenting patient underwent enhanced ECG-gated 16-MDCT. Ten cardiac phases were reconstructed. The images were evaluated for cardiac (coronary calcium and stenosis, ejection fraction, and wall motion and perfusion) and significant noncardiac (pulmonary embolism, dissection, pneumonia, and so forth) causes of chest pain. Correlation was made between the presence of significant cardiac and noncardiac findings on CT and the final clinical diagnosis based on history, examination, and any subsequent cardiac workup at the 1-month follow-up by a consensus of three physicians. Sixty-nine patients met all criteria for enrollment in the study, of whom 45 (65%) would not otherwise have undergone CT. Fifty-two patients (75%) had no significant CT findings and a final diagnosis of clinically insignificant chest pain. Thirteen patients (19%) had significant CT findings (cardiac, 10; noncardiac, 3) concordant with the final diagnosis. CT failed to suggest a diagnosis in two patients (3%), both of whom proved to have clinically significant coronary artery stenoses. In two patients (3%), CT overdiagnosed a coronary stenosis. Sensitivity and specificity for the establishment of a cardiac cause of chest pain were 83% and 96%, respectively. Overall sensitivity and specificity for all other cardiac and noncardiac causes were 87% and 96%, respectively.

ECG-gated MDCT appears to be logistically feasible and shows promise as a comprehensive method for evaluating cardiac and noncardiac chest pain in stable emergency department patients. Further hardware and software improvements will be necessary for adoption of this paradigm in clinical practice.

Does liposomal quercetin efficiently suppress growth of solid tumors in murine models?

Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro. Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues. Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis.

Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.

Are host sanctions in Panamanian Ficus likely based on selective resource allocation?

Fig trees and their pollinators, fig wasps, present a powerful model system for studying mutualism stability: both partners depend on each other for reproduction, cooperation levels can be manipulated, and the resulting field-based fitness quantified. Previous work has shown that fig trees can severely reduce the fitness of wasps that do not pollinate by aborting unpollinated figs or reducing the number and size of wasp offspring. Here we evaluated four hypotheses regarding the mechanism of sanctions in four Panamanian fig species. We examined wasp and fig samples from field experiments with manipulated levels of pollination. In unpollinated figs, the fig wall and the wasp offspring had a lower dry mass. Unpollinated figs had as many initiated wasp galls as pollinated figs but fewer galls that successfully produced live wasp offspring. Across three experimentally increasing levels of pollination, we found nonlinear increases in fig wall mass, the proportion of wasp galls that develop, and wasp mass.

Our data did not support the hypotheses that lack of pollination prevents gall formation or that fertilized endosperm is required for wasp development. While our data are potentially consistent with the hypothesis that trees produce a wasp-specific toxin in response to lack of pollination, we found the hypothesis that sanctions are a consequence of trees allocating more resources to better-pollinated figs more parsimonious with the aggregate data. Our findings are completely analogous to the selective resource allocation to more beneficial tissues documented in other mutualistic systems.

Does pPARgamma deficiency result in reduced lung elastic recoil and abnormalities in airspace distribution?

Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear hormone receptor that regulates gene expression, cell proliferation and differentiation. We previously described airway epithelial cell PPARgamma deficient mice that develop airspace enlargement with decreased tissue resistance and increased lung volumes. We sought to understand the impact of airspace enlargement in conditionally targeted mice upon the physio-mechanical properties of the lung. We measured elastic recoil and its determinants, including tissue structure and surface forces. We measured alveolar number using radial alveolar counts, and airspace sizes and their distribution using computer-assisted morphometry. Air vs. saline-filled pressure volume profiles demonstrated loss of lung elastic recoil in targeted mice that was contributed by both tissue components and surface tension, but was proportional to lung volume. There were no significant differences in surfactant quantity/function nor in elastin and collagen content between targeted animals and littermate controls. Importantly, radial alveolar counts were significantly reduced in the targeted animals and at 8 weeks of age there were 18% fewer alveoli with 32% more alveolar ducts. Additionally, the alveolar ducts were 19% larger in the targeted animals.

Our data suggest that the functional abnormalities, including loss of recoil are secondary to altered force transmission due to differences in the structure of alveolar ducts, rather than changes in surfactant function or elastin or collagen content. These data further define the nature of abnormal lung maturation in the absence of airway epithelial cell PPARgamma and identify a putative genetic determinant of dysanapsis, which may serve as a precursor to chronic lung disease.

Are elevated levels of the steroidogenic factor 1 associated with over-expression of CYP19 in an oestrogen-producing testicular Leydig cell tumour?

Testicular Leydig cell tumours (LCTs) are rare, steroid-secreting tumours. Elevated levels of aromatase (CYP19 or CYP19A1) mRNA have been previously described in LCTs; however, little is known about the mechanism(s) causing CYP19 over-expression. We report an LCT in a 29-year-old male with elevated plasma oestradiol caused by enhanced CYP19 transcription. First, we measured the intra-tumour expression of CYP19 and determined the use of CYP19 promoters by qPCR. Secondly, we explored CYP19 and promoter II (PII) for gene amplifications and activating mutations in PII by sequencing. Thirdly, we analysed intra-tumour expression of steroidogenic factor 1 (SF-1 (NR5A1)), liver receptor homologue-1 (LRH-1 (NR5A2)) and cyclooxygenase-2 (COX2 (PTGS2)). Finally, we analysed SF-1 for promoter mutations and gene amplifications. Similar to what has been recorded in normal Leydig cells, we first found the bulk of tumour CYP19 transcripts to be PII derived, excluding promoter shift as a cause of enhanced transcription. Secondly, we excluded CYP19 and PII gene amplifications, and activating mutations in PII, as causes of elevated CYP19 mRNA. We found SF-1 mRNA to be up-regulated in the tumour, while LRH-1 and COX2 were down-regulated. The finding of elevated SF-1 levels in the tumour was confirmed by immunohistochemistry. The elevated level of SF-1 was not due to promoter mutations or amplifications of the SF-1 gene.

Our results strongly suggest that the elevated levels of SF-1 have induced PII-regulated CYP19 transcription in this tumour. These findings are of relevance to the understanding of CYP19 up-regulation in general, which may occur in several tissues, including breast cancer.

Is eP3-2 receptor mRNA expression reduced and EP3-6 receptor mRNA expression is increased in gravid human myometrium?

To assess relative expression levels of mRNA for EP3 isoforms EP3-2, EP3-3, and EP3-6 in human myometrium in various physiologic states. Using semiquantitative reverse transcriptase-polymerase chain reaction, we analyzed myometrial samples from 46 women (ten menopausal, ten nongravid premenopausal, 19 gravidas, seven premenopausal misoprostol-treated nongravid women) for the specific expression of mRNA messages for the EP3 receptor isoforms EP3-2, EP3-3, and EP3-6. We found that the expression of EP3-2 was significantly lower in gravid than nongravid myometrium (P < .0001). Levels of the EP3-6 message were higher in gravid samples than in nongravid specimens (P < .02). EP3-3 mRNA was present in higher levels in menopausal samples compared with the other groups.

The selective fluctuation of mRNA expression of the different EP3 isoforms suggests the possibility of an important regulatory role for these receptors in myometrial contractility. Additional studies are necessary to evaluate the exact mechanism of action of EP3 receptor isoforms in human myometrium.

Is nelfinavir effective in inhibiting the multiplication and aspartic peptidase activity of Leishmania species , including strains obtained from HIV-positive patients?

There is a general lack of effective and non-toxic chemotherapeutic agents for leishmaniasis and there is as yet no study about the effect of HIV peptidase inhibitors (HIV PIs) on Leishmania/HIV-coinfected patients. In the present work, we performed a comparative analysis of the spectrum of action of HIV PIs on different Leishmania spp., including strains obtained from HIV-positive patients receiving or not receiving antiretroviral treatment. The effects of nelfinavir and saquinavir on Leishmania proliferation were assessed by means of a colorimetric assay (MTT). Subsequently, the effect of nelfinavir on aspartic peptidase activity from Leishmania spp. was assessed by following the degradation of the fluorogenic substrate MCA-G-K-P-I-L-F-F-R-L-K-DNP-Arg-NH(2). Nelfinavir was capable of significantly reducing the multiplication of many Leishmania reference strains and isolates obtained from HIV-positive patients receiving or not receiving antiretroviral treatment. Leishmania major growth was inhibited by ≈ 50%, while all other flagellates were strongly inhibited (at least 94%), except for a Leishmania chagasi strain obtained from an HIV-positive patient under treatment with highly active antiretroviral therapy (HAART). Culture of this isolate in the presence of nelfinavir induced a considerable reduction in the aspartic peptidase activity. In addition, nelfinavir was also capable of inhibiting the aspartic peptidase activity of all Leishmania strains tested.

The present data contribute to the study of the effect of HIV PIs on Leishmania infection and add new insights into the possibility of exploiting aspartic peptidases as promising targets in order to generate novel medications to treat leishmaniasis.

Is proliferation of Ewing sarcoma cell lines suppressed by the receptor tyrosine kinase inhibitors gefitinib and vandetanib?

Tyrosine kinase inhibitors (TKIs) have gained much attention in recent years as targeted agents for the treatment of a wide range of human cancers. We have investigated the effect of the TKIs gefitinib and vandetanib on tumor cell lines derived from Ewing sarcoma, a highly malignant tumor affecting bone and soft tissue in children and young adults. Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase activity (EGFR) and vandetanib selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2) with additional activity against VEGFR-3, EGFR and RET kinase receptors. Two Ewing sarcoma cell lines investigated showed high levels of nuclear EGFR expression as well as moderate expression in plasma membrane and cytoplasm. When treated with concentrations of 5 muM and more of either gefitinib or vandetanib, we observed a significant decrease in cell proliferation. However, there were no detectable changes in p44/42 MAPK and Akt-1 phosphorylation, or in the expression of cyclin D1 or c-Myc following gefitinib or vandetanib treatment.

We conclude that Ewing sarcoma tumor cell proliferation is not highly sensitive to inhibition of EGFR signaling alone or the simultaneous inhibition of VEGFR receptors, EGFR and RET kinase. Decreased tumor cell proliferation could be achieved with gefitinib and vandetanib, but only at higher doses where non-specific effects of the compounds may be overriding. As Ewing tumor cells do not seem to depend on EGFR and VEGFR pathways for survival, other key factors in the cellular signaling of Ewing sarcoma should be targeted in order to obtain a potent therapeutic response.

Do genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B?

Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta  = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta  = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta  = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta  = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71)  ≤ Pmeta  ≤ 9.92 × 10(-7) ).

Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.

Is sleep apnea associated with bronchial inflammation and continuous positive airway pressure-induced airway hyperresponsiveness?

Obstructive sleep apnea syndrome (OSA) is associated with systemic and upper airway inflammation. Pharyngeal inflammation has a potential role in upper airway collapse, whereas systemic inflammation relates to cardiovascular morbidity. However, the presence of an inflammatory involvement of lower airway has been poorly investigated. The aim of the study was to demonstrate an inflammatory process at the bronchial level in patients with OSA and to analyze effects of continuous positive airway pressure (CPAP) application and humidification on bronchial mucosa. The study was conducted by using sequential induced sputum for cell analysis and IL-8 production, nitric oxide exhalation measurement, and methacholine challenge before and after CPAP. Bronchial neutrophilia and a high IL-8 concentration were observed in untreated OSA compared with controls (75% +/- 20% vs 43% +/- 12%, P < .05; and 25.02 +/- 9.43 ng/mL vs 8.6 +/- 3.7 ng/mL, P < .001, respectively). IL-8 in sputum supernatant was correlated to apnea hypopnea index (P < .01; r = 0.81). After 1 month of CPAP, this inflammatory pattern remained unchanged, and an increase in airway hyperresponsiveness (AHR) was observed (P < .001).

Obstructive sleep apnea syndrome is associated with bronchial inflammation. Our data demonstrate CPAP effect on the development of AHR, possibly facilitated by the pre-existing inflammation. Both issues should be evaluated during long-term CPAP use.

Is full length Bid sufficient to induce apoptosis of cultured rat hippocampal neurons?

Bcl-2 homology domain (BH) 3-only proteins are pro-apoptotic proteins of the Bcl-2 family that couple stress signals to the mitochondrial cell death pathways. The BH3-only protein Bid can be activated in response to death receptor activation via caspase 8-mediated cleavage into a truncated protein (tBid), which subsequently translocates to mitochondria and induces the release of cytochrome-C. Using a single-cell imaging approach of Bid cleavage and translocation during apoptosis, we have recently demonstrated that, in contrast to death receptor-induced apoptosis, caspase-independent excitotoxic apoptosis involves a translocation of full length Bid (FL-Bid) from the cytosol to mitochondria. We induced a delayed excitotoxic cell death in cultured rat hippocampal neurons by a 5-min exposure to the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 300 microM). Western blot experiments confirmed a translocation of FL-Bid to the mitochondria during excitotoxic apoptosis that was associated with the release of cytochrome-C from mitochondria. These results were confirmed by immunofluorescence analysis of Bid translocation during excitotoxic cell death using an antibody raised against the amino acids 1-58 of mouse Bid that is not able to detect tBid. Finally, inducible overexpression of FL-Bid or a Bid mutant that can not be cleaved by caspase-8 was sufficient to induce apoptosis in the hippocampal neuron cultures.

Our data suggest that translocation of FL-Bid is sufficient for the activation of mitochondrial cell death pathways in response to glutamate receptor overactivation.

Is cA 19-9 nonproduction associated with poor survival after resection of pancreatic adenocarcinoma?

Carbohydrate antigen (CA) 19-9 is the most common serum biomarker used in pancreatic adenocarcinoma (PC). Elevated preoperative levels have been shown to correlate with more advanced stage, greater risk of unresectability, and overall worse survival. The prognostic value of CA 19-9 nonproduction, which is present in an estimated 5% to 15% of the population, is unclear. We sought to determine whether CA 19-9 nonproduction was associated with worse survival after PC resection. We retrospectively reviewed our institution's prospective pancreatic database for all PC patients with documented preoperative CA 19-9 values who underwent resection with curative intent from March 1992 to August 2009. After excluding 10 perioperative deaths, 200 patients remained for analysis. Mean and median follow-up was 23.3 and 16.1 months, respectively. Median survival in months for patients with preoperative CA 19-9 levels in U/mL by category was as follows: normal (5.1 to 36.9): 32, nonproduction (≤ 5): 21, mildly elevated (37 to 99.9): 35, highly elevated (100+): 16. Factors significantly associated with worse overall survival were: nonwhite race, nonproduction or highly elevated preoperative CA 19-9 (≥ 100 U/mL), estimated blood loss ≥ 1 L, tumor size (≥ 2 cm), lymph node-positivity, and advanced (3/4) histologic grade. On multivariate analysis, only CA 19-9 nonproduction or highly elevated production, estimated blood loss ≥ 1 L, advanced histologic grade, and node positivity remained significant in the final model.

CA 19-9 nonproduction is not associated with improved survival after pancreatic cancer resection, as has previously been asserted, when compared with patients with normal and elevated levels.

Does over-expression of mitochondrial antiviral signaling protein inhibit coxsackievirus B3 infection by enhancing type-I interferons production?

Recent studies have revealed that Mitochondrial Antiviral Signaling (MAVS) protein plays an essential role in the inhibition of viral infection through type I interferon (IFN) pathway. It has been shown that 3C (pro) cysteine protease of coxsackievirus B3 (CVB3) cleaves MAVS to inhibit type I IFNs induction. Other workers also found that MAVS knock-out mice suffered CVB3 susceptibility and severe histopathological change. Accordingly,our experiments were designed to explore the protection of over-expressing MAVS against CVB3 infection and the possible mechanism. In this study, HeLa cells (transfected with MAVS constructs pre- or post- exposure to CVB3) were used to analyze the function of exogenous MAVS on CVB3 infection. The results revealed that though CVB3 infection induced production of type I IFNs, viral replication and cell death were not effectively inhibited. Similarly, exogenous MAVS increased type I IFNs moderately. Morever, we observed robust production of type I IFNs in CVB3 post-infected HeLa cells thereby successfully inhibiting CVB3 infection, as well formation of cytopathic effect (CPE) and cell death. Finally, introduction of exogenous MAVS into CVB3 pre-infected cells also restricted viral infection efficiently by greatly up-regulating IFNs.

In summary, exogenous MAVS effectively prevents and controls CVB3 infection by modulating and promoting the production of type I IFNs. The IFNs level in MAVS over-expressing cells is still tightly regulated by CVB3 infection. Thus, the factors that up-regulate MAVS might be an alternative prescription in CVB3-related syndromes by enhancing IFNs production.

Does renal resistive index in addition to low-grade albuminuria complement screening for target organ damage in therapy-resistant hypertension?

We examined the value of renal resistive index (RRI) for prevalence of cardiovascular target organ damage in therapy-resistant hypertension in comparison to low-grade albuminuria. Eighty-four patients with therapy-resistant hypertension (age 59.7 +/- 8.1 years) were screened for cardiovascular target organ damage with coronary computed tomography, cardiac magnetic resonance imaging (MRI), Doppler sonography for the assessment of carotid intima media thickness and, RRI, pulse wave velocity and for low-grade albuminuria of at least 10 mg/day in men and 15 mg/day in women, respectively. In patients with RRI greater than 0.7 pulse wave velocity (11.6 +/- 3.7 vs. 9.8 +/- 2.2 m/s; P = 0.02) intima media thickness (0.85 +/- 0.09 vs. 0.76 +/- 0.1 mm; P = 0.007) and Agatston score of coronary calcification (640 +/- 915 vs. 129 +/- 256; P = 0.05) were increased, whereas left ventricular mass (127 +/- 24.5 vs. 125 +/- 15.0 g; P = 0.70) was similar between the two groups. When patients were categorized according to low-grade albuminuria left ventricular mass was significantly higher in those with low-grade albuminuria (123 +/- 25.8 vs. 135 +/- 15.7 g; P = 0.01), whereas vascular parameters (intima media thickness, Agatston score, pulse wave velocity) did not differ between the two groups.

In patients with therapy-resistant hypertension RRI reflects functional and structural vascular parameters, whereas low-grade albuminuria is related to cardiac structural changes. Thus, measurement of RRI in addition to low-grade albuminuria complements screening for target organ damage in therapy-resistant hypertension.

Are lipoprotein concentration , particle number , size and cholesterol efflux capacity associated with mitochondrial oxidative stress and function in an HIV positive cohort?

Association of lipoprotein particle size/number and HDL function with mitochondrial oxidative stress and function may underlie the excess cardiovascular (CVD) risk in HIV. Among HIV infected individuals on stable highly active antiretroviral therapy, we related standard and novel lipid measures [plasma total cholesterol, triglycerides, HDL-C, LDL-C, lipoprotein particle (-P) subclass size and number and HDL function (via cholesterol-efflux capacity)] with oxidative stress [peripheral blood mononuclear cell's mitochondrial-specific 8-oxo-deoxyguanine (8-oxo-dG)] and function markers [oxidative phosphorylation (OXPHOS) NADH dehydrogenase (Complex I) and cytochrome c oxidase (Complex IV) enzyme activities]. Multivariable-adjusted logistic and linear regression analyses were employed adjusting for age, gender, CD4 nadir, viral load, smoking, diabetes, HOMA-IR, hypertension and lipid medications. Among 150 HIV-infected persons (mean age 52 years, 12% women, median CD4 count 524 cell/mm3), low HDL-C and high total cholesterol/HDL-C ratio were related to PBMC 8-oxo-deoxyguanine (p = 0.01 and 0.02 respectively). Large HDL-P and HDL-P size were inversely related to PBMC 8-oxo-deoxyguanine (p = 0.04). Small LDL-P (p = 0.01) and total LDL-P (p = 0.01) were related to decreased OXPHOS Complex I activity. LDL-P was related to decreased OXPHOS Complex IV activity (p = 0.02). Cholesterol efflux capacity was associated with increased OXPHOS Complex IV activity.

HDL concentration and particle size and number are related to decreased PBMC mitochondrial oxidative stress whereas HDL function is positively related to mitochondrial oxidative function. The association we find between atherogenic lipoprotein profile and increased oxidative stress and function suggests these pathways may be important in the pathogenesis of cardiometabolic disease in HIV disease.

Is the nuclear pore complex protein Elys required for genome stability in mouse intestinal epithelial progenitor cells?

Elys is a conserved protein that directs nuclear pore complex (NPC) assembly in mammalian cell lines and developing worms and zebrafish. Related studies in these systems indicate a role for Elys in DNA replication and repair. Intestinal epithelial progenitors of zebrafish elys mutants undergo apoptosis early in development. However, it is not known whether loss of Elys has a similar effect in the mammalian intestine or whether the NPC and DNA repair defects each contribute to the overall phenotype. We developed mice in which a conditional Elys allele was inactivated in the developing intestinal epithelium and during preimplantation development. Phenotypes of conditional mutant mice were determined using immunohistochemical analysis for nuclear pore proteins, electron microscopy, and immunoblot analysis of DNA replication and repair proteins. Conditional inactivation of the Elys locus in the developing mouse intestinal epithelium led to a reversible delay in growth in juvenile mice that was associated with epithelial architecture distortion and crypt cell apoptosis. The phenotype was reduced in adult mutant mice, which were otherwise indistinguishable from wild-type mice. All mice had activated DNA damage responses but no evidence of NPC assembly defects.

In mice, Elys maintains genome stability in intestinal epithelial progenitor cells, independent of its role in NPC assembly in zebrafish.

Are 5-HT1A receptors involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats?

Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa which induces anxiolytic- and antipsychotic-like effects in rodents. These effects could be mediated by facilitation of the endocannabinoid system or by the activation of 5-HT(1A) receptors. As either of these mechanisms could promote adaptation to inescapable stress, the aim of the present work was to test the hypothesis that CBD would attenuate the autonomic and behavioural consequences of restraint stress (RS). We also investigated if the responses to CBD depended on activation of 5-HT(1A) receptors. Male Wistar rats received i.p. injections of vehicle or CBD (1, 10 or 20 mg kg(-1)) and 30 min later were submitted to 60 min of restraint where their cardiovascular responses were recorded. The protocol of the second experiment was similar to the first one except that animals received i.p. injections of the 5-HT(1A) receptor antagonist WAY100635 (0.1 mg kg(-1)) before CBD treatment and exposure to restraint. 24 h later they were also tested in the elevated plus-maze (EPM), an animal model of anxiety. Exposure to RS increased blood pressure and heart rate and induced an anxiogenic response in the EPM 24 h later. These effects were attenuated by CBD. WAY100635 by itself did not change the cardiovascular and anxiogenic response to RS, but blocked the effects of CBD.

The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT(1A) receptor-mediated neurotransmission.

Does omental transposition decrease ischemic brain damage examined in a new ischemia model?

The aim of this study was to determine whether omental transposition at the time of focal cerebral ischemia can decrease ischemic brain damage produced in dogs, in a new ischemia model, which had been described by us. In group 1 (n = 5), the left internal carotid artery and arterial circle of the brain (posterior communicating artery in humans) were occluded permanently. In group 2 (n = 5), additionally to this ischemia model, omental transposition was performed simultaneously. In the postoperative early period (first 24 h), single photon emission computed tomography (SPECT) and in the late period (72-96 h) SPECT and magnetic resonance imaging (MRI) of the brain were performed. Mann-Whitney U, paired t and Wilcoxon signed rank tests were used for statistical analyses, and p < 0.05 was considered significant. The dogs had a neurological score (NS) of 3.6 +/- 0.5 and 3.4 +/-0.5 in groups 1 and 2, respectively, in the early period (p > 0.05). In the late period, the dogs had an NS of 4.4 +/- 0.5 and 5.6 +/- 0.5 in groups 1 and 2, respectively (p < 0.05). The NS of each group differed significantly between the early and late period (p < 0.05). Early SPECT imaging showed 50 +/- 7.0% and 52 +/- 8.4% hypoperfusion corresponding to the left middle cerebral artery territory in groups 1 and 2, respectively (p > 0.05). In the late period, the degree of hypoperfusion decreased to 34 +/- 5.5% and 12 +/- 4.8% in groups 1 and 2, respectively (p < 0.05). The degree of hypoperfusion in both groups changed significantly between the early and late period (p < 0.05). In T(1)- and T(2)-weighted MRI images, the volume of the lesion in group 1 was significantly greater than in group 2 (p < 0.001).

In our new ischemia model, simultaneous omental transposition is helpful in reversing the neurologic deficit and cerebral ischemic damage.

Does endoscopic retrograde cholangiopancreaticography prior to explorative laparotomy avoid unnecessary surgery in patients suspected for biliary atresia?

Timely diagnosis of biliary atresia (BA) requires key investigations that are less invasive but as accurate as possible. Non-invasive imaging preselects patients before explorative laparotomy is performed. The purpose of this prospective study was to evaluate the accuracy of endoscopic retrograde cholangiopancreaticography (ERCP) in these patients and to discuss its relevance to future diagnostic guidelines in neonatal jaundice. Over a 7-year period, ERCP was routinely performed in cholestatic patients less than 6 months of age suspected for an extrahepatic origin of cholestasis, most likely BA. Endoscopic diagnosis was correlated with intraoperative findings. In 140 consecutive patients (mean age: 60 days; weight: 4 kg), ERCP excluded BA in 34 (25%) but failed in 18 newborns (13%) for technical reasons. The average procedure time was 23 min, and no severe complications occurred. Explorative laparotomy was performed in 106 patients and revealed BA in 80 cases. In this series, the sensitivity of ERCP for diagnosing biliary atresia was 92% and specificity was 73%.

In preselected patients, ERCP is not an alternative to non-invasive imaging, but it avoids unnecessary surgical procedures in almost 25% of the cases. Hence, ERCP is recommended prior to explorative laparotomy in all patients suspected for BA.

Does estradiol cause a dose-dependent stimulation of prostate growth in castrated beagle dogs?

Previous studies have shown that chronic treatment of castrate dogs with androgen and estrogen results in significant prostate growth. Estrogen treatment of castrate dogs in the absence of androgen has resulted in conflicting data as reported by several authors. The purpose of this experiment was to evaluate the effect of a physiological dose of estradiol on prostate growth in dogs, using ultrasound to study size changes over time. Dogs (n = 25) were randomly divided into groups (n = 5) and treated as follows: castration alone (CC), castration plus low dose estradiol (E(2) low), castration plus high estradiol (E(2) high), castration plus estradiol and androstanediol (E(2)A), or no treatment (normal controls, NC). Silastic implants containing 5alpha-androstan-3alpha-17beta-diol (3alphadiol), and/or 17beta-estradiol were used for continous delivery of steroids. Prostate volume was measured by transrectal ultrasonography, and blood was drawn for hormone and sex hormone binding globulin (SHBG) determinations. Results show that serum estradiol and SHBG levels were fairly constant over 12 weeks in all groups. Estradiol-treated groups had mean serum estradiol values of approximately 40 and 60 pg/ml, respectively. Initially, all groups had similar prostate volumes. Over 12 weeks the castrate dogs had a decline in prostate volume, whereas the intact dogs and those treated with E(2) and 3alpha-diol maintained a constant prostate volume. Estradiol treatment caused a large, late onset (week 7), dose-dependent increase in prostate volume relative to the intact group (P < 0.01). At 12 weeks, animals were euthanized and prostates weighed. The mean prostate weights in each group were: NC 14.8 +/- 2. 9, CC 2.4 +/- 0.5, E(2)A 9.7 +/- 2.0, E(2) low 21.7 +/- 4.3, and E(2) high 63.6 +/- 12.6 g (geometric mean +/- SEM). Histologically, prostates of estrogen-treated dogs showed metaplastic squamous epithelium.

These results demonstrate that estradiol causes marked dose-dependent stimulation of prostate growth in the castrate dog.

Does the mean mean as much anymore : finding sub-groups for tailored therapeutics?

The genomics revolution is still in its infancy, and there is much to learn about how to transform biological knowledge into useful medicines to further public health. At the bedside, we are asking how and why individual patients respond to different drug treatments in different ways. In addition to genetic mechanisms, there are many clinical markers (e.g. medical history, disease severity) as well as social/environmental factors (e.g. smoking habits) that can be used to identify who may or may not respond to treatment. This issue has some considerable statistical complexity, and different approaches to the analysis of clinical trials may yield more interesting insights into the problem. Novel applications of statistical methods will be discussed, and examples will be used to demonstrate sub-group identification. In order to evaluate many potential predictors of response, we use recursive partitioning methods to identify predictor variables and their cut-off values to define sub-groups of patients with differential treatment response. Validation of this variable/model selection approach was done using independent data from other clinical trials. In one example, a classification tree was developed using baseline measures to define important sub-groups of patients that responded much better than the overall mean response in the study. In a second example, a classification tree was built based on measures of response early in treatment to predict longer-term responders and nonresponders. Limitation Classification algorithms can be prone to over-fitting, and validation of results is an important consideration. Obviously, analyses are limited by the available predictor variables.

Using classification trees proved to be very useful in evaluating large numbers of potential predictors to find sub-groups of patients with exceptional response. The method is easy to use, and clinicians can easily interpret and implement results. This approach can be helpful in tailoring treatments to individual patients.

Are endogenous Na , K pump ligands differentially regulated during acute NaCl loading of Dahl rats?

Two mammalian digitalis-like factors, an ouabain-like compound (OLC) and marinobufagenin (MBG), exhibit specificity to alpha-3 and alpha-1 Na(+),K(+)-ATPase isoforms, respectively. We compared regulation of MBG and OLC by acute NaCl loading in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. An intraperitoneal NaCl load (0.8 g/kg) was given to adult male rats (24 DS and 24 DR). Diuresis, natriuresis, renal excretion, and tissue levels of MBG and OLC were measured. Inhibition of renal Na(+),K(+)-ATPase by MBG and ouabain was compared in DS, DR, and Wistar rats. DS (versus DR) exhibited a smaller peak (2 hours) natriuretic response (1.34+/-0.10 versus 2.08+/-0.14 mmol. kg(-)(1). h(-)(1); P:<0.01), despite a greater plasma Na(+) (153+/-2 versus 145+/-1 mmol/L; P:<0.01). In DS and DR, pituitary, adrenal, and plasma OLC exhibited transient 2-fold to 3-fold increases, followed by a decrease to baseline levels. Plasma and adrenal MBG doubled in both strains within 1 hour of NaCl loading and remained elevated. Eight-hour MBG excretion in DS was 4-fold greater than in DR (15. 8+/-0.8 versus 3.6+/-0.4 pmol; P:<0.01), whereas OLC excretion in DS was only 30% greater than in DR (16.1+/-1.1 and 11.9+/-0.8 pmol; P:<0.05). Kidney Na(+),K(+)-ATPase (alpha-1 isoform) from Wistar rats and DS exhibited greater sensitivity to MBG than to ouabain.

NaCl loading of DS causes transient increase in OLC but sustained increases in MBG tissue levels and excretion. We hypothesize that increased MBG production occurs in an attempt to compensate for genetically impaired pressure-natriuresis mechanisms.

Does the calculation of baseline serum creatinine overestimate the diagnosis of acute kidney injury in patients undergoing cardiac surgery?

The current definition and classification of acute kidney injury is based on consensus criteria (RIFLE and AKIN systems). Creatinine is the most commonly used of the recommended parameters (creatinine, glomerular filtration rate and diuresis). If the baseline value is not known, it can be calculated based on the simplified MDRD equation, assuming a filtration rate of 75 ml/min/1.73 m2 for the calculation. The aim of this study was to evaluate the diagnostic impact of using estimated baseline creatinine compared to the actual value measured in patients undergoing cardiac surgery. Analysis of patients undergoing major cardiac surgery, who were prospectively included in a database. The maximum RIFLE stage reached was calculated for each patient using the measured and estimated baseline creatinine levels. The impact on the diagnosis was analysed using intraclass correlation coefficients, concordance analysis and Bland-Altman plots. The incidence of postoperative acute kidney injury in 2103 cases between 2002 and 2007 was 29.1%, according to estimated creatinine (14.3% with the measure). This represents an overestimation of 104%, with an intraclass correlation of 0.12. By excluding patients with known chronic kidney disease (glomerular filtration rate [<60 ml/min/1.73 m2), both the overestimation (2.4%) and the correlation (0.57) improved.

The calculation of baseline creatinine using the MDRD equation overestimates the incidence of acute kidney injury after cardiac surgery, and is an inadequate method for detection when the baseline value is unknown.

Does endoglin selectively modulate transient receptor potential channel expression in left and right heart failure?

Transient receptor potential (TRP) channels are broadly expressed cation channels that mediate diverse physiological stimuli and include canonical (TRPC), melastatin (TRPM), and vanilloid (TRPV) subtypes. Recent studies have implicated a role for TRPC6 channels as an important component of signaling via the cytokine, transforming growth factor beta 1 (TGFβ1) in right (RV) or left ventricular (LV) failure. Endoglin (Eng) is a transmembrane glycoprotein that promotes TRPC6 expression and TGFβ1 activity. No studies have defined biventricular expression of all TRP channel family members in heart failure. We hypothesized that heart failure is associated with distinct patterns of TRP channel expression in the LV and RV. Paired viable LV and RV free wall tissue was obtained from human subjects with end-stage heart failure (n=12) referred for cardiac transplantation or biventricular assist device implantation. Paired LV and RV samples from human subjects without heart failure served as controls (n=3). To explore a functional role for Eng as a regulator of TRP expression in response to RV or LV pressure overload, wild-type (Eng Compared to nonfailing human LV and RV samples, mRNA levels of TRPC1, 3, 4, 6, and TRPV-2 were increased and TRPM2, 3, and 8 were decreased in failing LV and RV samples. TRPC1 and 6 levels were higher in failing RV compared to failing LV samples. After TAC, murine LV levels of TPRC1 and 6 were increased in both Eng

This is the first study to demonstrate that TRP channels exhibit distinct profiles of expression in the LV and RV of patients with heart failure and in murine models of univentricular pressure overload. We further introduce that the TGFβ1 coreceptor Eng selectively regulates expression of multiple TRP channels in the setting of LV or RV pressure overload.

Is helicobacter pylori urease activity influenced by ferric uptake regulator?

The role of the Ferric Uptake Regulator (FUR) in the acid resistance of Helicobacter pylori (H. pylori) has been thought to be independent of urease. However, we demonstrated in this study that Fur influences urease activity. A fur knockout mutant of H. pylori was constructed by replacing the Fur gene with a kanamycin resistant marker gene. The wild-type H. pylori and fur mutant were compared for survival. The integrity of the inner membrane of the bacteria was evaluated by confocal microscopy using membrane-permeant and -impermeant fluorescent DNA probes. Urease activity of intact H. pylori was measured between pH 3 and 8. Real time PCR of both strains was performed for urease genes including ureI, ureE, ureF, ureG, and ureH. The fur deletion affected the survival of H. pylori at pH 4. The urease activity curve of the intact fur mutant showed the same shape as the wild-type but was 3-fold lower than the wild-type at a pH of less than 5. Real time PCR revealed that the expression of all genes was consistently down-regulated in the fur mutant.

The results of this study showed that fur appears to be involved in acid resistant H. pylori urease activity.

Expression of the 17-1A antigen in gastric and gastro-oesophageal junction adenocarcinomas: a potential immunotherapeutic target?

A murine monoclonal antibody against the 17-1A epithelial antigen has been shown to be a useful adjuvant therapy in colorectal cancer. Its clinical use could be extended to patients with upper gastrointestinal adenocarcinoma.AIM: To determine the distribution of the antigen in gastric and oesophageal adenocarcinoma. The activity of two monoclonal antibodies active against 17-1A epithelial antigen was studied in gastric and gastro-oesophageal junction adenocarcinomas: fresh frozen tissue from both the carcinoma and adjacent mucosa was stained using immunocytochemistry with a murine monoclonal antibody (17-1A edrecolomab, Glaxo Wellcome); paraffin embedded tissue was stained using the humanised monoclonal antibody 3622W94 (Glaxo Wellcome). 29 of 33 cancers (88%) stained with the murine antibody and 39 of 40 (98%) with the humanised antibody. The degree of staining was greater in well differentiated and moderately differentiated tumours. There was no staining of the normal background gastric or oesophageal mucosa, but areas of intestinal metaplasia stained intensely. The humanised monoclonal 3622W94 antibody produced more intense staining than the murine antibody.

The high incidence of expression of the 17-1A antigen in patients with gastric and gastro-oesophageal junction adenocarcinomas suggests a potential role for these antibodies as an adjuvant treatment for these common cancers.

Is panniculitis a common unrecognized histopathological feature of cutaneous leishmaniasis?

Cutaneous leishmaniasis (CL) is a parasitic cutaneous infection caused by Leishmania parasite. The histopathology is usually granulomatous in nature. The aim of the present study is to elucidate the histology of CL and evaluate the presence and the frequency of panniculitis among the affected patients. Case series interventional study. Thirty-five patients with CL were diagnosed clinically between December-2012 and May-2013. Diagnostic confirmation established by smears, culture, and polymerase chain reaction (PCR). The histopathological assessment was carried out to study the general pathology and to look for the presence of panniculitis. Simple statistics utilized via SPSS version 16.0 (SPSS, Inc., Chicago, USA). Eighteen women and 17 men with CL were enrolled in the present work with a mean duration of their disease was 3 months. The results of the diagnostic tests were as follow: The smear was positive in 21 (60%) of cases, Leishman-Donovan (LD) bodies were seen in 7 (20%) patients, culture was positive in 24 (68%), and PCR was positive in 32 (91.4%) patients. The epidermal changes included acanthosis, pseudoepitheliomatous hyperplasia, ulceration, focal spongiosis, and interface dermatitis while the dermal changes were dependent on the spectrum of the disease, so in the ulcerative lesions there was lymphohistiocytic infiltration with foci of plasma cells and sometimes aggregate of LD bodies, whereas in the dry lesions the pathology is mainly of epithelioid granuloma. Panniculitis was seen in 16 (46%) cases as a diffuse lymphohistiocytic infiltration of both the septum and lobules of the subcutaneous layer of the skin.

Panniculitis is an important feature of CL that must be differentiated from other diseases that can simulate CL such as chronic skin infections, Discoid lupus erythematosus, and cutaneous lymphoma.

Does [ Association between limited joint mobility syndrome and risk of accidental fall in diabetic patients ]?

Limited joint mobility syndrome (LJMS) appears exclusively in both type 1 and type 2 diabetic patients. It is characterized by a limited range of digital motion, with involvement of small joints of the hands. It initially affects the proximal interphalangeal joints, followed by wrists, elbows, shoulders, knees, and axial skeleton. The diagnosis can be made by the simple "prayer sign" test. The objective was to study the prevalence of diabetic patients with LJMS, and to evaluate the association between LJMS and metabolic control, and the risk of accidental falls. A cross-sectional study was conducted in the San Fernando II Health Centre, Madrid (suburbs). The sample consisted of 184 patients with a diagnosis of diabetes of over 5 years from November to March, 2013. The prayer sign was used to define which patients had LJMS. Fall risk was determined using the Timed Up & Go test. A total of 99 patients (53.8%) (95% CI 46.6 to 61) had a positive prayer sign. No statistically significant relationship was found with HbA1c, but there was an association with the Timed Up & Go test (P<.001) (95% CI 1.173 to 1.611). The patients with LJMS had a moderate risk of falls compared with those without LJMS, which was of low risk.

The prevalence of LJMS is high. This is the first study that shows a relationship between LJMS and the risk of falls in diabetic patients.

Does expression of amphiregulin predict poor outcome in patients with pancreatic ductal adenocarcinoma?

The validation of novel diagnostic, prognostic and predictive biomarkers in cancer is crucial for optimizing the choice and efficacy of personalized therapies. The aim of this study was to determine the epidermal growth factor receptor (EGFR), epidermal growth factor receptor variant III (EGFRvIII) and amphiregulin (AREG) protein expression levels and to evaluate the prognostic significance of EGFR, EGFRvIII and AREG in pancreatic ductal adenocarcinoma (PDAC). The EGFR, EGFRvIII and AREG protein levels in PDAC (n = 92) were examined by using immunohistochemistry. The associations between EGFRvIII expression, AREG expression, AREG/EGFR co-expression and clinicopathological factors were assessed, the correlation between AREG and EGFR expression was analyzed and the survival analyses were performed. Among the lesions of PDAC, 12 (13 %) stained positive for EGFRvIII, 49 (53.3 %) stained positive for AREG and 22(23.9 %) stained double positive for AREG/EGFR. The relationships between each protein expression level and the clinicopathologic factors were examined, only AREG/EGFR co-expression was significantly related to tumor differentiation (P = 0.032). The correlation between AREG and EGFR expression was statistically insignificant (P = 0.709). Univariate survival analysis proved that high tumor-node-metastasis (TNM) stage, poor tumor differentiation and AREG expression were significant poor prognostic factors for disease-free survival (DFS) and overall survival (OS). By multivariate survival analysis, tumor differentiation was an independent poor prognostic factor for DFS (HR = 1.785, P < 0.05), whereas high TNM stage (HR = 2.25, P < 0.05), poor tumor differentiation (HR = 2.125, P < 0.01), positive resection margins (HR = 1.84, P < 0.05), and AREG expression (HR = 1.822, P < 0.05) were all independent poor prognostic factors for OS.

In conclusion, our data indicate that AREG expression is an important prognostic biomarker in PDAC .

Are estimation of prostate cancer probability by logistic regression : free and total prostate-specific antigen , digital rectal examination , and heredity significant variables?

Despite low specificity, serum prostate-specific antigen (PSA) is widely used in screening for prostate cancer. Specificity can be improved by measuring free and total PSA and by combining these results with clinical findings. Methods such as neural networks and logistic regression are alternatives to multistep algorithms for clinical use of the combined findings. We compared multilayer perceptron (MLP) and logistic regression (LR) analysis for predicting prostate cancer in a screening population of 974 men, ages 55-66 years. The study sample comprised men with PSA values >3 microg/L. Explanatory variables considered were age, free and total PSA and their ratio, digital rectal examination (DRE), transrectal ultrasonography, and a family history of prostate cancer. When at least 90% sensitivity in the training sets was required, the mean sensitivity and specificity obtained were 87% and 41% with LR and 85% and 26% with MLP, respectively. The cancer specificity of an LR model comprising the proportion of free to total PSA, DRE, and heredity as explanatory variables was significantly better than that of total PSA and the proportion of free to total PSA (P <0.01, McNemar test). The proportion of free to total PSA, DRE, and heredity were used to prepare cancer probability curves.

The probability calculated by logistic regression provides better diagnostic accuracy for prostate cancer than the presently used multistep algorithms for estimation of the need to perform biopsy.

Advertisements promoting human papillomavirus vaccine for adolescent boys: does source matter?

Many parents recall hearing of human papillomavirus (HPV) vaccine through drug company advertisements. This study sought to examine whether parents accurately recall the source (ie, sponsor) of advertisements promoting HPV vaccine and the impact of drug company advertisements. A U.S. national sample of 544 parents of adolescent boys aged 11-17 participated in an online between-subjects experiment. Parents viewed an advertisement encouraging HPV vaccination for boys with a logo from a randomly assigned source. Parents rated trust, likability and motivation for vaccination while viewing the advertisement and later indicated who they believed sponsored it. Nearly half (43%) of parents who viewed a hypothetical advertisement containing a logo incorrectly identified the advertisement source. More parents correctly identified the source of drug company advertisements than advertisement from other sources (62% vs. 25%, OR 4.93, 95% CI 3.26 to 7.46). The majority of parents who saw a logo-free advertisement believed a drug company created it (60%). Among parents who correctly identified the advertisement source, drug company advertisements decreased motivation to vaccinate their sons, an association mediated by reduced liking of and trust in the advertisements.

Parents were more accurate in identifying drug company advertisements, primarily because they tended to assume any advertisement was from a drug company. Public health organisations may need to take special measures to ensure their messages are not perceived as sponsored by drug companies.

Does pain dominate measurements of elbow function and health status?

Elbow function can be quantified with use of physician-based elbow-rating systems and health status questionnaires. Our hypothesis was that pain has a strong influence on these scores, which overwhelms the influence of objective factors such as motion. One hundred and four patients were evaluated, at a minimum of six months (average, forty-six months) after the latest surgery for an intra-articular fracture of the elbow, with use of three physician-based evaluation instruments (Mayo Elbow Performance Index [MEPI], Broberg and Morrey rating system, and American Shoulder and Elbow Surgeons Elbow Evaluation Instrument [ASES]), an upper-extremity-specific health status questionnaire (Disabilities of the Arm, Shoulder and Hand [DASH]), and a general health status questionnaire (Short Form-36 [SF-36]). Multivariate analysis of variance and regression modeling were used to identify the factors that account for the variability in scores derived with these measures-in other words, which factors have the strongest influence on the final score. Pain alone accounted for 66% of the variability in the MEPI scores, 59% of the variability in the Broberg and Morrey scores, and 57% of the variability in the ASES scores. Models that included other factors accounted for only slightly more variability (73%, 79%, and 79%, respectively), and those that did not include pain accounted for only 22%, 41%, and 41% of the variability. Thirty-six percent of the variability in the DASH scores could be accounted for by pain alone, and 45% could be accounted for by pain and range of motion. Models not including pain accounted for only 17% of the variability in the DASH scores.

Pain has a very strong influence on both physician-rated and patient-rated quantitative measures of elbow function. Consequently, these measures may be strongly influenced by the psychosocial aspects of illness that have a strong relationship with pain, and objective measures of elbow function such as mobility may be undervalued. It may be advisable to evaluate pain separately from objective measures of elbow function in physician-based elbow ratings.

Does implementation of a protocol facilitate evidence-based physiotherapy practice in intensive care units?

To compare the physiotherapy service provided when therapists' decisions are guided by an evidence-based protocol with usual care (i.e. patient management based on therapists' clinical decisions). Exploratory, controlled, pragmatic sequential time block clinical trial. Level 3 surgical unit in a tertiary hospital in South Africa. All patients admitted consecutively to the surgical unit over a 3-month period were allocated to usual or protocol care based on date of admission. Usual care was provided by clinicians from the hospital department, and non-specialised physiotherapists were appointed as locum tenens to provide evidence-based protocol care. Patient waiting time, frequency of treatment sessions, tasks performed and adverse events. During protocol-care periods, treatment sessions were provided more frequently (P<0.001) and with a shorter waiting period (P<0.001). It was more likely for a rehabilitation management option to be included in a treatment session during protocol-care periods (odds ratio 2.34, 95% confidence interval 1.66 to 3.43; P<0.001). No difference in the risk of an adverse event was found between protocol-care and usual-care periods (P=0.34).

Physiotherapy services provided in intensive care units (ICUs) when the decisions of non-specialised therapists are guided by an evidence-based protocol are safe, differ from usual care, and reflect international consensus on current best evidence for physiotherapy in ICUs. Non-specialised therapists can use this protocol to provide evidence-based physiotherapy services to their patients. Future trials are needed to establish whether or not this will improve patient outcome.

Does balloon pump-induced pulsatile perfusion during cardiopulmonary bypass improve brain oxygenation?

Whether pulsatile flow offers substantial advantages for brain protection during cardiopulmonary bypass is controversial. The purpose of this study is to determine whether differences exist between pulsatile and nonpulsatile bypass concerning the effects on internal jugular venous saturation and on the state of regional cerebral oxygenation during normothermia. Twenty-two patients undergoing elective coronary artery bypass grafting were randomly divided into 2 groups: group 1 (n = 11) received nonpulsatile perfusion during cardiopulmonary bypass and group 2 (n = 11) received pulsatile perfusion during bypass. We used an intra-aortic balloon pump to generate pulsatility. A spectrophotometric probe (INVOS 3100R, Somanetics, Troy, Mich) was used to assess the state of regional cerebral oxygenation. A 4F fiberoptic oximetry oxygen saturation catheter was inserted into the right jugular bulb to monitor jugular venous oxygen saturation. Hemodynamic variables, arterial and jugular venous blood gases, and regional cerebral oxygenation were measured at 7 times points. In both groups, jugular venous oxygen saturation decreased at the early stage of the cardiopulmonary bypass (P =.03). Five patients in group 1 and 6 in group 2 had a jugular venous oxygen saturation of less than 50%. In both groups, the regional cerebral oxygenation value decreased during cardiopulmonary bypass (P =.04).

The present results showed that pulsatility generated through the use of intra-aortic balloon pumping did not produce any beneficial effects on jugular venous oxygen saturation and regional cerebral oxygenation at normothermia.

Does early citalopram treatment increase mortality due to left ventricular rupture in mice after myocardial infarction?

Both anxiety and depression are common and independent outcome predictors in patients after myocardial infarction (MI). However, it is unclear whether and how anti-depressants influence remodeling after MI. Thus, we studied cardiac remodeling in mice after experimental MI under treatment with citalopram, a selective serotonin reuptake inhibitor widely used as antidepressant. Treatment with citalopram versus saline was applied via osmotic pump after coronary artery ligation. Two different groups were studied: early treatment during the healing phase (starting immediately after surgery), or late treatment in the remodeling phase (starting 7days after surgery). Late treatment did not change mortality or left ventricular remodeling after MI over the period of 6weeks. However, in the early treatment group mortality was increased in citalopram-treated mice predominantly due to left ventricle rupture without differences in infarct size. Remodeling 4weeks after MI was not altered by the treatment. Neither infiltration of inflammatory cells, as determined by FACS analysis of myocardial tissue, nor mRNA-expression of inflammatory cytokines changed 3days after MI in the early treatment group. However, extracellular matrix functioning was altered: There was a significant increase of MMP13 in citalopram treated animals after MI. Pretreatment with the MMP inhibitor PD 166793 prevented left ventricular ruptures and demonstrated a tendency to improved survival after citalopram treatment.

Treatment with antidepressant citalopram in the acute but not in the late phase after MI significantly increased mortality in mice by disturbing early healing. Pharmacological MMP inhibition partially reversed the deleterious effects of citalopram.

Does blockade of muscarinic acetylcholine receptors in the ventral tegmental area prevent acquisition of food-rewarded operant responding in rats?

We recently found that muscarinic receptor (mAChR) stimulation in the ventral tegmental area (VTA) is involved in the acquisition of a feeding task. To investigate the involvement of VTA mAChR and nicotinic receptors (nAChR) in the acquisition and performance of a food-rewarded lever-pressing task. In experiment 1 (N=54), rats were trained under a fixed ratio 1 schedule of reinforcement and received bilateral intra-VTA microinjections of scopolamine (0, 2.5 or 5 microg/0.5 microl) or mecamylamine (0, 5 or 10 microg/0.5 microl) before each of the first four sessions. Before session 10, all rats that initially received a dose of either compound now received the vehicle and vice versa. In experiment 2 (N=14), rats were tested with scopolamine or mecamylamine while lever pressing under a progressive ratio schedule of reinforcement. In experiment 1, lever pressing by rats initially treated with any mecamylamine dose or the scopolamine vehicle rose to and stayed at maximal levels for the remaining sessions. Responding by rats initially treated with the 2.5- or 5-microg dose of scopolamine remained low, even after the cessation of scopolamine treatment, and gradually rose to maximal levels by the final sessions. Injections of scopolamine 1 to 2 mm dorsal to the VTA had no significant effect on responding. In experiment 2, neither of the compounds significantly affected break points.

Stimulation of VTA mAChR, but not of nAChR, is necessary for the acquisition of a food-rewarded lever-pressing task and neither is necessary for the performance of the task.

Does follicle-stimulating hormone directly regulate bone mass in human beings : evidence from nature?

To evaluate the effect of FSH levels in the development of human osteoporosis. Case-series study. Gynecology department in a teaching hospital. A total of 8 women diagnosed with Kallman syndrome (KS) were compared with 11 with Turner syndrome and 11 with pure gonadal dysgenesia (GD, karyotype 46,XX). We assessed the pituitary-gonadal axis, bone turnover markers, bone mass, and patient characteristics. Bone mineral density as assessed by dual-energy X-ray absorptiometry, plasma FSH, LH, E(2), osteocalcin (BGP), and urinary type I collagen cross-linked N-telopeptide. Other biochemical markers included 25-hydroxyvitamin D, as well as parathyroid hormone and urine concentration of calcium and creatinine. In girls with Turner syndrome and GD, FSH (64.03 +/- 29.2 and 90.08 +/- 22.41 mIU/mL, respectively) and LH (45.29 +/- 11.90 and 48.83 +/- 12.44 mIU/mL, respectively) levels were significantly higher compared with those observed in girls with KS (FSH: 1.87 +/- 0.64 and LH: 1.02 +/- 0.57), whereas no differences were detected in E(2) or bone marker levels. Bone mineral density correlated positively with FSH levels but not with E(2); however, after adjusting for previous growth-hormone therapy, these differences were not found. In addition, bone mineral density in spine and total hip was significantly lower in patients with KS.

Follicle-stimulating hormone does not appear to have a major role in the development of bone loss in young women with primary amenorrhea.

Is combined modality therapy necessary for advanced Hodgkin's disease?

To determine whether single-modality therapy is optimal management for patients with Stage III-IV Hodgkin's disease. All patients with advanced (Stage III and IV) Hodgkin's disease treated at the University of Florida from 1964 through 1989 (n = 141) were studied retrospectively for factors predictive of good outcome with single-modality therapy. Treatment modalities varied and were distributed as follows: combined-modality therapy (CMT), 55 patients; chemotherapy alone (CX), 50 patients; and radiotherapy alone (RT), 36 patients. Ten-year rates of freedom from relapse and overall survival for all Stage III patients were 66% and 59% compared with 36% and 35% for Stage IV patients. The RT subset was highly selected with the majority of patients having nonbulky Stage IIIA disease. Within the RT group, multivariate analysis identified the degree of splenic involvement and age as the factors most associated with freedom from relapse. In patients treated with CX, multivariate analysis identified bulky tumor (maximum transverse tumor dimension>6 cm) as the most important prognostic factor for relapse. In patients without bulky disease (<or = 6 cm), the probabilities of freedom from relapse and overall survival at 10 years, respectively, according to treatment group were 53% and 58% for RT patients, 60% and 56% for CX patients, and 83% and 71% for CMT patients. For patients without bulky disease, the probability of freedom from relapse was significantly better for the CMT group than for CX patients (p = 0.03) or RT patients (p = 0.04), but there was no statistical difference in overall survival among the three groups. In patients with bulky disease (>6 cm), the probabilities of freedom from relapse and overall survival at 10 years were 44% and 45% for RT patients, 9% and 0% for CX patients, and 72% and 58% for CMT patients. Freedom from relapse and overall survival were significantly better (p = 0.0001) for CMT patients compared with CX patients. Fatal hematopoietic disorders developed in 10 patients: 2 of 36 RT patients, 2 of 50 CX patients, and 6 of 55 CMT patients. Nine patients had received chemotherapy, and eight had six or more cycles of alkylator-based chemotherapy.

This retrospective study suggests that combined-modality therapy is preferable to single-modality therapy in the majority of patients with advanced Hodgkin's disease.

Does glycemic control in youth with type 2 diabetes decline as early as two years after diagnosis?

To determine the course of glycemic decline in a pediatric cohort with type 2 diabetes mellitus (T2DM) by defining longitudinal changes in hemoglobin A1c (HbA1c) and insulin requirement. We also followed markers of insulin reserve (fasting C-peptide and IGFBP-1) over time. Participants included two groups: (1) T2DM Nonacidotic (NA) (n = 46); and (2) T2DM diabetic ketoacidosis (n = 13). HbA1c, insulin dose, and fasting C-peptide and IGFBP-1 were obtained at baseline and every 6 months for 4 years. At baseline, Mann Whitney tests demonstrated that the diabetic ketoacidosis group had higher HbA1c (P = .002), required more insulin (P = .036), and had lower C-peptide (P = .003) than the NA group. Baseline insulin dose (Spearman r = -0.424, P = .009) and baseline IGFBP-1 (Spearman r = -0.349, P = .046) correlated negatively with C-peptide. Over time, HbA1c, insulin dose, and C-peptide changed significantly in a complex manner, with group differences. HbA1c reached a nadir at 6 to 12 months and began to rise after 1.5 years. Insulin requirements reached a nadir at 1 year and began to rise after 2 years.

Unlike adults, children with T2DM require increasing insulin doses over a 4-year period, and diabetic ketoacidosis at diagnosis predicts greater β-cell decline over time.

Is 30 minutes the golden period to perform emergency room thoratomy (ERT) in penetrating chest injuries?

Emergency room thoracotomy (ERT), a controversial procedure, was introduced to improve resuscitation of trauma patients. No study has been conducted to evaluate the importance of the time in the field (down time) in the initial survival of penetrating chest trauma requiring ERT. In addition to this, many factors have been considered to predict the success of ERT, but they are multiple and are not easy to assess in the brief period of decision making to perform an ERT. We decided, therefore, to see if the pre hospital time could be used as the principal parameter to predict whether TERT in emergency Department (ED) with the arrival of penetrating chest trauma is useful. Records of the Howard University Hospital Emergency Department (ED) were reviewed for all trauma patients between June 1992 and January 1995. The pre-admission data were obtained from Emergency Medical Service (EMS) reports, including the "down time". All patients who underwent ERT had vital signs documented by EMS in the field. Forensic autopsies were performed within 48 hours after death following practice standards already described. Between January 1987 and June 1994, 58 adult patients presented with penetrating chest trauma at the Howard University Hospital Emergency Department. Pre-admission data were available for 49 of 58 chest trauma patients. Sixteen patients (33%), with no documented vital signs in the field, were pronounced dead on arrival in the ED, and no ERT was performed on them. The remaining thirty-three patients (57%) underwent ERT. In all patients with chest injury, the Revised Trauma Score (RTS) was below 4 on arrival to the ED. Considering only the patients (n=33) that underwent ERT 82% (n=27) of patients had vital sings upon arrival in ED, 19% (n=6) had no vital signs until arrival to the ED. Patients with multiple wound GS or SW (more than four) died on arrival (18%; n=6). The patients with single gun shot wounds or stab wounds (GSW/SW) survived initially and underwent ERT (82%; n=27). Of the patients who underwent ERT, (n=6; 18%) had GSW and (12%), (n=4) had SW. Among those patients that died in ED, 12% (n=4) had a drop of SBP of more than 50 mmHg and only 24% (n=8) presented with a SBP less than 70 mmHg. Average scene time was 11.2+/-8.1 min, the transit time was 7.9+/-5.6 min and the average ED resuscitation time was 10+/-3.2 min. Of the patients that arrived in ED within 30 minutes 63% (n=20) survived the first 24 hours, and of these only 9% (n=3) had no vital signs upon arrival. The remaining 28% (n=6), who arrived in ED after half hour, either died during the transportation or upon arrival to the ED; none of them had vital signs upon arrival. All the patients transferred to the ICU died within 24 to 78 hr, secondary to severe arrhythmia or cerebral hypoxia. Autopsy was performed in all the patients. Among the patients that died upon arrival in the ED, the most common injury responsible for death was ventricular injury with exanguination in the first 24 hours. Of the 9% of patients that died in the ED after ERT, the injury was caused by a 9 mm caliber gun, which created a major laceration to the ventricle which was not possible to repair during the ERT. In the patients that died after stab wound (12%; n=4), the patients were stabbed at least 3 times in the chest and they died of arrhythmia. Among the survivors of ERT that were transported in ICU, uncontrollable arrhythmia and acute lung injury was the cause of death within 24-72 hours in 45% (n=15) of patients while cerebral hypoxia complicated irreparably the life expectancy with death at 72 hours in 60% (n=20) of patients.

The only role of ERT in our opinion is in patients who arrive within 30 minutes of pre hospital time, with a witnessed vital signed in the field. Multiple wounds, low SBP and higher caliber bullet injuries are also negative prognostic factors.

Does down-regulation of phosphoglucose isomerase/autocrine motility factor enhance gensenoside Rh2 pharmacological action on leukemia KG1α cells?

Ginsenoside Rh2, which exerts the potent anticancer action both in vitro and in vivo, is one of the most well characterized ginsenosides extracted from ginseng. Although its effects on cancer are significant, the underlying mechanisms remain unknown. In this study, we sought to elucidate possible links between ginsenoside Rh2 and phosphoglucose isomerase/autocrine motility factor (PGI/AMF). KG1α, a leukemia cell line highly expressing PGI/AMF was assessed by western blot analysis and reverse transcription- PCR (RT-PCR) assay after transfection of a small interfering (si)-RNA to silence PGI/AMF. The effect of PGI/ AMF on proliferation was measured by typan blue assay and antibody array. A cell counting kit (CCK)-8 and flow cytometry (FCM) were adopted to investigate the effects of Rh2 on PGI/AMF. The relationships between PGI/AMF and Rh2 associated with Akt, mTOR, Raptor, Rag were detected by western blot analysis. KG1α cells expressed PGI/AMF and its down-regulation significantly inhibited proliferation. The antibody array indicated that the probable mechanism was reduced expression of PARP, State1, SAPK/JNK and Erk1/2, while those of PRAS40 and p38 were up-regulated. Silencing of PGI/AMF enhanced the sensibility of KG1α to Rh2 by suppressing the expression of mTOR, Raptor and Akt.

These results suggested that ginsenoside Rh2 suppressed the proliferation of KG1α, the same as down-regulation of PGI/AMF. Down-regulation of PGI/ AMF enhanced the pharmacological effects of ginsenoside Rh2 on KG1α by reducing Akt/mTOR signaling.

Are aPC and oncogenic KRAS synergistic in enhancing Wnt signaling in intestinal tumor formation and progression?

Synchronous activation of the Wnt signaling pathway, mostly because of loss of function of the APC tumor suppressor, and of the oncogenic KRAS-signaling pathway is very frequent in colorectal cancer and is associated with poor prognosis. We have generated a compound transgenic mouse model, KRAS(V12G)/Apc(+/1638N), to recapitulate the human disease and compared it with single transgenic littermates. Compound mutant mice are characterized by a 10-fold increase in tumor multiplicity and by accelerated tumor progression, resulting in strongly enhanced morbidity and mortality. Tumors from compound mutant mice proliferate faster and show decreased levels of apoptosis. Several lines of evidence indicate that the observed increase in tumor multiplicity and malignant transformation is caused by the synergistic activation of Wnt signaling in cells with oncogenic KRAS and loss-of-function Apc mutations. Activated KRAS is known to induce tyrosine phosphorylation of beta-catenin, leading to its release from E-cadherin at the adherens junction. This results in an increased beta-catenin pool in the cytoplasma, its subsequent translocation to the nucleus, and the transcriptional activation of Wnt downstream target genes. Accordingly, intestinal tumors from KRAS(V12G)/Apc(+/1638N) mice show a significant increase in cells with nuclear accumulation of beta-catenin when compared with Apc(+/1638N) animals. Moreover, Apc/KRAS-mutant embryonic stem cells show a significantly enhanced beta-catenin/T-cell factor-mediated transcriptional activation, accompanied by increased beta-catenin nuclear localization.

This KRAS-induced increase in Wnt/beta-catenin signaling may enhance the plasticity and self-renewal capacity of the tumor, thus resulting in the drastically augmented tumor multiplicity and malignant behavior in compound mutant animals.

Does impaired insulin secretion increase the risk of Alzheimer disease?

Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia. The population-based Uppsala Longitudinal Study of Adult Men started 1970 when the 2,322 participants were 50 years old. Investigation at baseline included determinations of acute insulin response and glucose tolerance using the IV glucose tolerance test and Homeostasis Model Assessment insulin resistance index. During a median follow up of 32 years, 102 participants were diagnosed with AD, 57 with vascular dementia, and 394 with any dementia or cognitive impairment. Associations were analyzed using Cox proportional hazard models. A low insulin response at baseline was associated with a higher cumulative risk of AD (hazard ratio for 1 SD decrease, 1.31; 95% CI, 1.10-1.56) also after adjustment for age, systolic blood pressure, body mass index, serum cholesterol, smoking, education level, and insulin resistance. This association was stronger in subjects without the APOE epsilon4 allele. Impaired glucose tolerance increased the risk of vascular dementia (hazard ratio for 1 SD decrease, 1.45; 95% CI, 1.05-2.00) but not AD. Impaired insulin secretion, glucose intolerance, and estimates of insulin resistance were all associated with higher risk of any dementia and cognitive impairment.

In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.

Does neural activity to a partner 's facial expression predict self-regulation after conflict?

Failure to self-regulate after an interpersonal conflict can result in persistent negative mood and maladaptive behaviors. Research indicates that lateral prefrontal cortex (LPFC) activity is related to emotion regulation in response to laboratory-based affective challenges, such as viewing emotional pictures. This suggests that compromised LPFC function may be a risk factor for mood and behavior problems after an interpersonal conflict. However, it remains unclear whether LPFC activity to a laboratory-based affective challenge predicts self-regulation in real life. We investigated whether LPFC activity to a laboratory-based affective challenge (negative facial expressions of a partner) predicts self-regulation after a real-life affective challenge (interpersonal conflict). During a functional magnetic resonance imaging scan, healthy, adult participants in committed relationships (n = 27) viewed positive, negative, and neutral facial expressions of their partners. In a three-week online daily diary, participants reported conflict occurrence, level of negative mood, rumination, and substance use. LPFC activity in response to the laboratory-based affective challenge predicted self-regulation after an interpersonal conflict in daily life. When there was no interpersonal conflict, LPFC activity was not related to mood or behavior the next day. However, when an interpersonal conflict did occur, ventral LPFC (VLPFC) activity predicted mood and behavior the next day, such that lower VLPFC activity was related to higher levels of negative mood, rumination, and substance use.

Low LPFC function may be a vulnerability and high LPFC function may be a protective factor for the development of mood and behavior problems after an interpersonal stressor.

Does ursodeoxycholic acid improve the clinical course of primary sclerosing cholangitis over a 2-year period?

Ursodeoxycholic acid has been shown to be a useful agent in the clinical management of patients with primary biliary cirrhosis and autoimmune chronic active hepatitis. Its efficacy is presumed to be based upon its ability to act as a detergent and to incite a choleresis. Recent additional data suggest it also reduces HLA antigen expression on liver and biliary epithelial cells and impairs T cell reactivity. A randomized controlled study of 59 patients with primary sclerosing cholangitis was performed over a 24 months period with 3 groups being studied. Group I consisted of 20 patients who were given ursodeoxycholic acid 300 mg orally twice a day; group II consisted of 19 patients who were given colchicine 0.6 mg orally BID; and group III was an untreated medical control group. All three groups were seen at regular 3-month intervals and had quarterly, annual and terminal studies performed to assess their disease status. No difference between groups was evident after two full years of therapy when parameters of liver injury, liver function, liver size and hepatic copper content were compared between groups. Similarly, no difference in ERCP findings was evident between groups either at entry or after two years of therapy.

These data suggest that ursodeoxycholic acid is no better than colchicine or simple medical follow-up. Thus, neither ursodeoxycholic acid or colchicine can be considered to be effective therapies for primary sclerosing cholangitis.

Do hippocampal malformations necessarily evolve into hippocampal sclerosis?

Hippocampal malformations have been proposed to underlie or evolve into hippocampal sclerosis, a common cause of refractory partial epilepsy. We report two patients with chronic epilepsy and developmental abnormalities of the hippocampus and cortex. We seek to address, in patients with recurrent convulsive seizures over many decades, whether hippocampal malformations necessarily progress to hippocampal sclerosis. The first patient died at age 76 years and had experienced convulsive seizures for 43 years. The second patient, aged 64 years at death, had experienced convulsive seizures for 49 years. The brains were processed routinely. Immunohistochemistry for dynorphin and neuropeptide Y was performed. The first case exhibited bilateral perisylvian polymicrogyria. Both hippocampi demonstrated abnormal convolution in the CA1 subfield and subiculum. In the second case, periventricular heterotopia was found in the wall of the right lateral ventricle. The right hippocampus was abnormally oriented with excessive convolutions of the pyramidal cell layer between CA1 and the subiculum. In neither patient did the hippocampi exhibit neuronal loss. Furthermore, dynorphin immunohistochemistry revealed no reactivity in the molecular layers, and staining with neuropeptide Y confirmed normal numbers of hilar interneurons.

These two cases demonstrate histologically that, even in long-standing epilepsy, malformations of the hippocampus do not necessarily develop into hippocampal sclerosis.

Does aquaporin-4 inhibition mediate piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents?

Aquaporin-4(AQP4) is an abundant water channel protein in brain that regulates water transport to maintain homeostasis. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia. Although, both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We have found that Piroxicam binds to AQP4 with optimal binding energy value. Thus, we hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation. Rats were treated with Piroxicam OR placebo at 30 min prior, 2 h post and 4 h post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for neurological deficits and motor function just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, RT-PCR and western blot experiments. Piroxicam pretreatment thirty minutes prior to ischemia and four hour post reperfusion afforded neuroprotection as evident through significant reduction in cerebral infarct volume, improvement in motor behavior, neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde were also found to be significantly reduced in ischemic brain regions in treated animals. This neuroprotection was found to be associated with inhibition of acid mediated rise in intracellular calcium levels and also downregulated AQP4 expression.

Findings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia. Piroxicam could be clinically exploited for the treatment of brain stroke along with other anti-stroke therapeutics in future.

High-resolution ultrasonography of the TMJ: helpful diagnostic approach for patients with TMJ disorders ?

The purpose of this study was to investigate patients with a clinical diagnosis of internal derangement to determine the diagnostic value of static high resolution ultrasonography (HR-US) when compared with magnetic resonance imaging (MRI). Sixty-six patients (132 temporomandibular joints [TMJs]) with a clinical diagnosis of internal derangement were investigated by HR-US and MRI. MRI and HR-US investigations were performed by experienced radiologists. The sonograms were done with a real-time 12-Mhz linear-array scanner. The HR-US interpretation errors were re-evaluated retrospectively by the same radiologist knowing the MRI results by comparing these with the 'prospective' and 'retrospective' diagnoses. The prospective and retrospective diagnoses were also compared with each other. Eighty-seven of the 132 TMJs had a disc displacement proved by MRI in the closed-mouth position. At maximum mouth opening, 54 TMJs had a disc displacement. The prospective interpretations showed a sensitivity and specificity of 78% each, accounting for an accuracy of 78%. At maximum mouth opening, HR-US resulted in a sensitivity of 61%, a specificity of 88% and an accuracy of 77%. The retrospective interpretations yielded a sensitivity of 90%, a specificity of 84% and an accuracy of 88% in the closed-mouth position. At maximum mouth opening, HR-US showed a sensitivity of 73%, a specificity of 95% and an accuracy of 86%.

HR-US is suitable for the detection of disc displacements in the TMJ. However, further studies may be warranted to reduce the proportion of false-positive interpretations, thereby avoiding the application of unnecessary treatment.

Does multimodality imaging reveal a gradual increase in matrix metalloproteinase activity at aneurysmal lesions in live fibulin-4 mice?

We imaged the protease activity of matrix metalloproteinases (MMPs) upregulated during aneurysm formation, using protease-activatable near-infrared fluorescence probes. We tested whether these protease-activatable sensors can directly report the in vivo activity of the key biomarkers in aneurysm, using our genetically modified fibulin-4 mouse models for aneurysm formation. Mice homozygous for the fibulin-4 reduced-expression allele (fibulin-4(R/R)) show dilatation of the ascending aorta and a tortuous, stiffened aorta resulting from disorganized elastic fiber networks. Strikingly, even a moderate reduction in expression of fibulin-4 in the heterozygous fibulin-4(+/R) mice occasionally results in modest aneurysm formation. Aorta transcriptome and protein expression analysis of fibulin-4(+/R) and fibulin-4(R/R) animals identified excessive transforming growth factor-β signaling as the critical event in the pathogenesis of aneurysm formation. To determine whether a perturbed elastin lamellar structure arose from induction of transforming growth factor-β-regulated MMPs, we performed gelatin zymography and used a protease-activatable near-infrared fluorescence probe to monitor and quantify MMP upregulation in animals, using various in vivo optical imaging modules and coregistration of the fluorescence signal with CT images of the same animals. Gelatin zymography demonstrated a significant increase in the presence of the active form of MMP-9 in the aortic arch of fibulin-4(R/R) mice. In vivo analysis of MMP upregulation using the near-infrared fluorescence probe and subsequent isosurface concentration mapping from reconstructed tomographic images from fibulin-4(+/R) and fibulin-4(R/R) mice revealed a graded increase in activation of MMPs within the aneurysmal lesions.

We aimed to develop molecular imaging procedures for faster, earlier, and easier recognition of aortic aneurysms. We show that in vivo coregistration of MMP activity by noninvasive tomographic imaging methods allows the detection of increased MMP activity, even before the aneurysm has actually formed.

Does high mobility group B1 impair hepatocyte regeneration in acetaminophen hepatotoxicity?

Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose. Male C57BL/6 mice were treated with a single dose of APAP (350 mg/kg). 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 hours for a total of 2 doses. 24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST), markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration.

HMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.

Is hPV16 associated with younger age in women with cervical intraepithelial neoplasia grade 2 and 3?

To evaluate if women with HPV16 positive CIN2 and CIN3 are diagnosed at a younger age. We conducted a population-based cohort study including more than 40,000 women having a liquid based cervical cytology sample taken as part of routine screening. HPV analysis was performed using Hybrid Capture 2 and LiPAv2. The study population was linked to the Danish Pathology Data Bank to retrieve information on subsequent cervical histology. We included HR HPV positive CIN2/3 samples, comprising 173 CIN2 and 467 CIN3 lesions. Due to a high number of multiple concurrent HPV infections, the causative HPV type was assigned to a hierarchically group. In CIN3, the estimated proportion of lesions positive for HPV16 was 68.1% among women aged 20 years and decreased to 38.9% among women aged 50 years. A decrease in HPV16 positivity with increasing age was also observed in CIN2. In a multinomial logistic regression analysis, young age was strongly associated with HPV16 positivity in CIN3 lesions (OR=0.46 per 10 year increase in age, 95% CI: 0.32-0.65). The proportion of HPV16 and/or 18 positive lesions among women diagnosed with CIN2 and CIN3 below 30 years of age was 44% and 75%, respectively.

HPV16 positivity was significantly associated with younger age at diagnosis of CIN3. In a population vaccinated against HPV16 and 18, we will experience a shift to older ages in cervical precancerous lesions. These findings may imply that cervical cancer screening programs could start at an older age in HPV vaccinated populations.

Is cpG island methylation profile in non-invasive oral rinse samples predictive of oral and pharyngeal carcinoma?

There are currently no screening tests in routine use for oral and pharyngeal cancer beyond visual inspection and palpation, which are provided on an opportunistic basis, indicating a need for development of novel methods for early detection, particularly in high-risk populations. We sought to address this need through comprehensive interrogation of CpG island methylation in oral rinse samples. We used the Infinium HumanMethylation450 BeadArray to interrogate DNA methylation in oral rinse samples collected from 154 patients with incident oral or pharyngeal carcinoma prior to treatment and 72 cancer-free control subjects. Subjects were randomly allocated to either a training or a testing set. For each subject, average methylation was calculated for each CpG island represented on the array. We applied a semi-supervised recursively partitioned mixture model to the CpG island methylation data to identify a classifier for prediction of case status in the training set. We then applied the resultant classifier to the testing set for validation and to assess the predictive accuracy. We identified a methylation classifier comprised of 22 CpG islands, which predicted oral and pharyngeal carcinoma with a high degree of accuracy (AUC = 0.92, 95 % CI 0.86, 0.98).

This novel methylation panel is a strong predictor of oral and pharyngeal carcinoma case status in oral rinse samples and may have utility in early detection and post-treatment follow-up.

Does chronic magnesium deficiency decrease tolerance to hypoxia/reoxygenation injury in mouse heart?

Magnesium (Mg) deficiency has been reported to be associated with the development of the metabolic syndrome, cardiovascular diseases, and sudden death. We examined the influence of chronic Mg deficiency on cardiac tolerance to hypoxia/reoxygenation injury. Mice were fed an Mg-deficient diet for 4 weeks, and then their hearts were excised for Langendorff perfusion experiments. The levels of total Mg in the blood and heart were quantified by atomic absorption spectrometry. In Mg-deficient mice, the Mg concentration in whole blood was markedly decreased; however, that in the heart remained unchanged. When the hearts of control mice were exposed to hypoxia/reoxygenation, removal of extracellular Mg from a normal Krebs solution containing 1.2 mM Mg resulted in a significant decrease in the recovery of the tension-rate product (TRP) upon reoxygenation. In Mg-deficient mice, the recovery of TRP in the heart was reduced significantly in the absence of extracellular Mg compared to that in controls. The addition of Mg to the perfusate did not improve TRP recovery. During hypoxia/reoxygenation, cardiac damage evaluated by myocardial aspartate amino transferase (AST) release was greater in hearts of Mg-deficient mice than in that of control mice.

These results indicate that chronic Mg deficiency causes severe hypomagnesemia and a decrease in cardiac tolerance to hypoxia, without changing the intracellular Mg content. The decreased tolerance to hypoxia was not affected by the presence or absence of extracellular Mg, suggesting that some intracellular metabolic abnormalities develop in the cardiac myocytes of Mg-deficient mice.

Does rutin attenuate intestinal toxicity induced by Methotrexate linked with anti-oxidative and anti-inflammatory effects?

Methotrexate (MTX) is recognized as an anti-metabolite in cancer chemotherapy and is associated with various toxicities assigned to inflammation and oxidative stress. Rutin has been reported to have significant anti-inflammatory, antioxidant along with antiulcer properties. The present study was undertaken to corroborate the effect of rutin against MTX induced intestinal toxicity in experimental animals. Six groups of rats (n = 6) were dosed with normal saline (3 ml/kg,i.p.); MTX (2.5 mg/kg,i.p.); rutin (50 and 100 mg/kg,i.p.); rutin + MTX (50 mg/kg + 2.5 mg/kg,i.p.); rutin + MTX (100 mg/kg + 2.5 mg/kg,i.p.) for seven consecutive days and sacrificed on eighth day. The intestinal contents were scrutinized physiologically (pH, total acidity, free acidity, CMDI), biochemically (TBARS, protein carbonyl, SOD, catalase and GSH) and for immunoregulatory cytokines (IL-2, IL-4 and IL-10).

The administration of rutin demonstrated significant protection against intestinal lesions damaged by MTX. The treatment with rutin elicited noticeable inhibition of free acidity (26.20%), total acidity (22.05%) and CMDI (1.16%) in the experimental animals similar to control. In MTX treated toxic group, the levels of oxidative markers and immunoregulatory cytokines significantly increased in comparison to control, which was subsequently restored after rutin treatment. Rutin also demonstrated 75.63, 81.00 and 80.43% inhibition of cyclooxygenase-1 and 2, and 15-lipoxygenase respectively.

Do mitochondrial genome sequences effectively reveal the phylogeny of Hylobates gibbons?

Uniquely among hominoids, gibbons exist as multiple geographically contiguous taxa exhibiting distinctive behavioral, morphological, and karyotypic characteristics. However, our understanding of the evolutionary relationships of the various gibbons, especially among Hylobates species, is still limited because previous studies used limited taxon sampling or short mitochondrial DNA (mtDNA) sequences. Here we use mtDNA genome sequences to reconstruct gibbon phylogenetic relationships and reveal the pattern and timing of divergence events in gibbon evolutionary history. We sequenced the mitochondrial genomes of 51 individuals representing 11 species belonging to three genera (Hylobates, Nomascus and Symphalangus) using the high-throughput 454 sequencing system with the parallel tagged sequencing approach. Three phylogenetic analyses (maximum likelihood, Bayesian analysis and neighbor-joining) depicted the gibbon phylogenetic relationships congruently and with strong support values. Most notably, we recover a well-supported phylogeny of the Hylobates gibbons. The estimation of divergence times using Bayesian analysis with relaxed clock model suggests a much more rapid speciation process in Hylobates than in Nomascus.

Use of more than 15 kb sequences of the mitochondrial genome provided more informative and robust data than previous studies of short mitochondrial segments (e.g., control region or cytochrome b) as shown by the reliable reconstruction of divergence patterns among Hylobates gibbons. Moreover, molecular dating of the mitogenomic divergence times implied that biogeographic change during the last five million years may be a factor promoting the speciation of Sundaland animals, including Hylobates species.

Does wnt5a increase cardiac gene expressions of cultured human circulating progenitor cells via a PKC delta activation?

Wnt signaling controls the balance between stem cell proliferation and differentiation and body patterning throughout development. Previous data demonstrated that non-canonical Wnts (Wnt5a, Wnt11) increased cardiac gene expression of circulating endothelial progenitor cells (EPC) and bone marrow-derived stem cells cultured in vitro. Since previous studies suggested a contribution of the protein kinase C (PKC) family to the Wnt5a-induced signalling, we investigated which PKC isoforms are activated by non-canonical Wnt5a in human EPC. Immunoblot experiments demonstrated that Wnt5a selectively activated the novel PKC isoform, PKC delta, as evidenced by phosphorylation and translocation. In contrast, the classical Ca(2+)-dependent PKC isoforms, PKC alpha and beta2, and one of the other novel PKC isoforms, PKC epsilon, were not activated by Wnt5a. The PKC delta inhibitor rottlerin significantly blocked co-culture-induced cardiac differentiation in vitro, whereas inhibitors directed against the classical Ca(2+)-dependent PKC isoforms or a PKC epsilon-inhibitory peptide did not block cardiac differentiation. In accordance, EPC derived from PKC delta heterozygous mice exhibited a significant reduction of Wnt5a-induced cardiac gene expression compared to wild type mice derived EPC.

These data indicate that Wnt5a enhances cardiac gene expressions of EPC via an activation of PKC delta.

Are positive attitudes and preserved high level of motor performance important factors for return to work in younger persons after stroke : a national survey?

Significant numbers of younger persons with stroke should be given the opportunity to return to work. The aim of this study was to investigate factors of importance for return to work among persons after first ever stroke, in the age range 18-55 years. A questionnaire was sent to all persons who had experienced a first ever stroke, 18-55 years of age, registered in the Swedish national quality register for stroke care, Riks-Stroke. Of the 1068 who answered the questionnaire, 855 (539 men and 316 women) were in paid employment before their stroke, and were included in this study. Sixty-five percent returned to work and, of these, an equal proportion were men and women. Significant factors associated with return to work were the perceived importance of work (odds ratio (OR) 5.10), not perceiving themselves as a burden on others (OR 3.33), support from others for return to work (OR 3.66), retaining the ability to run a short distance (OR 2.77), and higher socioeconomic codes (OR 2.12). A negative association was found between those rehabilitated in wards intended for younger persons and return to work (OR 0.37).

External support from others, and positive attitudes towards return to work, were factors associated with successful return to work after stroke. Contrary to what was expected, independence in personal activities of daily living and cognitive factors were not associated with return to work to the same extent as persistent higher level of physical functions, such as ability to run a short distance.

Is myocardial performance impaired in patients with branch retinal vein occlusion?

To investigate whether the Tei index, which is an indicator of global myocardial function and an independent predictor of cardiac death, is increased in patients with branch retinal vein occlusion (BRVO). The Tei index was used to evaluate myocardial performance, in addition to conventional echocardiographic evaluation of myocardial structural and functional changes, in patients with BRVO, patients with hypertension and healthy controls. Out of 36 patients with BRVO (18 female, 18 male; 17 hypertensive, 19 normotensive), 29 patients with hypertension (15 female, 14 male) and 28 healthy controls (15 female, 13 male), there were no significant between-group differences in age and sex. The mitral A wave was higher and mitral E/A ratio, mitral E wave and ejection time were lower, in patients with BRVO than in healthy controls. Mean Tei index was significantly higher in the BRVO group than in patients with hypertension or healthy controls. Compared with healthy controls, the Tei index was significantly higher in hypertensive and normotensive patients with BRVO.

Myocardial performance is decreased in patients with BRVO, independent of whether or not they have hypertension.

Does professional counseling improve infant home monitoring?

Home apnea/bradycardia monitoring was widely used in the 80s and 90s in the hope that Sudden Infant Death (SID) could be prevented. As no evidence could be found in favor of this hypothesis, HM today is restricted to symptomatic preterm infants, infants with cardiorespiratory problems and infants after an apparent life threatening event (ALTE). HM can impose substantial stress on families, especially mothers. We introduced an intensive counseling program (IC) for home monitoring and evaluated its effects, using a questionnaire. The control group consisted of families who were using a home monitor before the IC program was instituted, and were instructed according to the standard protocol given by the "Austrian SIDS-Consensus". The IC program consisted of standard monitor instruction as well as instruction in infant cardiopulmonary resuscitation, and was extended by providing intensive support at the beginning and throughout the monitoring period with special regard to the monitor weaning phase. Fifty-eight percent of the 90 questionnaires of the IC-families and 66% of the 70 questionnaires of the control families were returned. Home monitoring was considered to be reassuring by more than 60% of the families. We found the following differences between the two groups: parents taking part in the IC program liked the instruction better, were less stressed by the monitor and reacted less aggressively to monitor alarms. They used the monitor predominantly during sleeping periods and for a shorter period of time (6 vs. 7 1/2 months). IC could not reduce SID related anxiety or change the feelings associated with the use of the home monitor.

Intensive counseling leads to a better use of home monitoring and reduces parents' stress. Even if home monitoring is used less frequently today, families should still be instructed and counselled intensively.

Does the Early C-reactive Protein Trend Have a Role in Monitoring Acute Diverticulitis Progression?

To investigate the variation of the values of the serum inflammation markers during the hospital stay of patients with acute diverticulitis and to evaluate the role of their initial trend in the early determination of the disease resistance to conservative measures. The electronic records of patients presenting with acute diverticulitis at the Oulu University Hospital, Finland during a 2-year period starting from December 2006 were retrospectively reviewed. Acute diverticulitis that was successfully treated conservatively was graded as mild. Severe disease was considered when a percutaneous or surgical intervention was necessitated during the same hospitalization or within the first month. Comparisons of the means of continuous variables were performed using the paired samples T test. One hundred and thirty-nine patients with mild acute diverticulitis had available data concerning the initial trends of the inflammation markers. The C-reactive protein (CRP) mean value showed a paradoxical significant increase in uncomplicated cases whereas the WBC count declined within the first 24 hours of hospitalization. Thereafter the CRP levels showed a significant daily decrease below the initial levels for the remainder of the in-hospital duration. The inflammation markers' initial trends in patients with severe disease did not change significantly.

A rise in the CRP value during the first 24 hours of hospitalization should not be necessarily considered as a deterioration of the clinical status. This trend has no role in the early evaluation of the clinical progression of acute diverticulitis as it may mislead the clinician towards potential invasive overtreatment.

Does prostaglandin E2 induce IL-6 and IL-8 Production by the EP Receptors/Akt/NF-κB Pathways in Nasal Polyp-Derived Fibroblasts?

Interleukin 6 (IL-6) and IL-8 participate in the pathogenesis of chronic rhinosinusitis with nasal polyps, and their levels are increased by prostaglandin E2 (PGE2) in different cell types. The purposes of this study were to determine whether PGE2 has any effect on the increase in the levels of IL-6 and IL-8 in nasal polyp-derived fibroblasts (NPDFs) and subsequently investigate the possible mechanism of this effect. Different concentrations of PGE2 were used to stimulate NPDFs at different time intervals. NPDFs were treated with agonists and antagonists of E prostanoid (EP) receptors. To determine the signaling pathway for the expression of PGE2-induced IL-6 and IL-8, PGE2 was treated with Akt and NF-κB inhibitors in NPDFs. Reverse transcription-polymerase chain reaction for IL-6 and IL-8 mRNAs was performed. IL-6 and IL-8 levels were measured byenzyme-linked immunosorbent assay (ELISA). The activation of Akt and NF-κB was evaluated by western blot analysis. PGE2 significantly increased the mRNA and protein expression levels of IL-6 and IL-8 in NPDFs. The EP2 and EP4 agonists and antagonists induced and inhibited IL-6 expression. However, the EP4 agonist and antagonist were only observed to induce and inhibit IL-8 expression level. The Akt and NF-κB inhibitors significantly blocked PGE2-induced expression of IL-6 and IL-8.

PGE2 increases IL-6 expression via EP2 and EP4 receptors, and IL-8 expression via the EP4 receptor in NPDFs. It also activates the Akt and NF-κB signal pathways for the production of IL-6 and IL-8 in NPDFs. These results suggest that signaling pathway for IL-6 and IL-8 expression induced by PGE2 might be a useful therapeutic target for the treatment of nasal polyposis.

Do young adults at risk for stimulant dependence show reward dysfunction during reinforcement-based decision making?

While stimulant-dependent individuals continue to make risky decisions, in spite of poor outcomes, much less is known about decision-making characteristics of occasional stimulant users (OSU) at risk for developing stimulant dependence. This study examines whether OSU exhibit inefficient learning and execution of reinforced decision-outcome contingencies. Occasional stimulant users (n = 161) and stimulant-naïve comparison subjects (CTL) (n = 48) performed a Paper Scissors Rock task during functional magnetic resonance imaging. Selecting a particular option was associated with a predetermined probability of winning, which was altered repeatedly to examine neural and behavioral characteristics of reinforced contingencies. Occasional stimulant users displayed greater anterior insula, inferior frontal gyrus, and dorsal striatum activation than CTL during late trials when contingencies were familiar (as opposed to being learned) in the presence of comparable behavioral performance in both groups. Follow-up analyses demonstrated that during late trials: 1) OSU with high cannabis use displayed greater activation in these brain regions than CTL, whereas OSU with low cannabis use did not differ from the other two groups; and 2) OSU preferring cocaine exhibited greater anterior insula, inferior frontal gyrus, and dorsal striatum activation than CTL and also displayed higher activation in the former two regions than OSU who preferred prescription stimulants.

Occasional stimulant users exhibit inefficient resource allocation during the execution of reinforced contingencies that may be a result of additive effects of cocaine and cannabis use. A critical next step is to establish whether this inefficiency predicts transition to stimulant dependence.

Is asymmetrical dimethylarginine related to renal function , chronic inflammation and macroangiopathy in patients with Type 2 diabetes and albuminuria?

Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients. ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 +/- 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD). ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55-0.70) micromol/l and 0.62 (0.50-0.79) micromol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48-0.63) micromol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42-0.80) micromol/l and 0.64 (0.50-0.96) micromol/l] compared with normoalbuminuric subjects [0.44 (0.37-0.53) micromol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA(1c) or plasma lipids.

Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation.

Does pulse cyclophosphamide inadequately suppress reoccurrence of minimal change nephrotic syndrome in corticoid-dependent children?

In minimal change nephrotic syndrome (MNCS), the most common primary nephrotic syndrome in children, approximately 95% of cases show excellent responses to steroid therapy. However, responding patients may become steroid dependent and experience serious side effects. Although oral cyclophosphamide has been recommended in these patients, long-term side effects such as gonadal toxicity are an important concern. Therefore, cyclophosphamide pulses given intravenously may provide an option that maintains remission with less-frequent side effects. We treated 20 primary steroid-dependent MCNS patients (15 boys and five girls) with intravenous cyclophosphamide. The patients were children with ages ranging from 3 to 15 years of age. Remission was induced by steroids followed by cyclophosphamide at a dose of 500 mg/m2 body surface area per month for 6 months. During this period, we attempted to completely withdraw steroids and maintain patients on cyclophosphamide alone. We monitored the patients for the occurrence of relapse and side effects during this period and for an additional 6 months after withdrawal of cyclophosphamide. At the end of the 6-month cyclophosphamide treatment period (i.e. 4 months after steroid discontinuation), nine patients (45%) were in remission on cyclophosphamide alone. However, patients that maintained treatment-free remission (cyclophosphamide responders) decreased to five (25%), two (10%) and one (5%) at 6 months, 1 year and 2 years, respectively.

We found that a 6-month course of pulse cyclophosphamide produced unfavourable effects in the majority of paediatric patients with steroid-dependent nephrotic syndrome.

Diagnostic accuracy of the Barthel Index for measuring activities of daily living outcome after ischemic hemispheric stroke: does early poststroke timing of assessment matter?

This study investigated the diagnostic accuracy of the Barthel Index (BI) in 206 stroke patients, measured within 72 hours, for activities of daily living at 6 months and determined whether the timing of BI assessment during the first days affects the accuracy of predicting activities of daily living outcome at 6 months. Receiver operating characteristic curves were constructed to determine the area under the curve and optimal cutoff points for BI at Days 2, 5, and 9. OR, sensitivity, specificity, positive predictive value, and negative predictive value were calculated to predict BI ≥19. The area under the curve ranged from 0.785 on Day 2 to 0.837 and 0.848 on Days 5 and 9. Comparison of the receiver operating characteristic curves showed that the area under the curve was significantly different between Days 2 and 5 (P<0.001) and between Days 2 and 9 (P<0.001). No significant difference was found between Days 5 and 9 (P=0.08). Using a BI cutoff score of 7, the positive predictive value gradually increased from 0.696 on Day 2 to 0.817 on Day 2 to 0.864 on Day 9, whereas negative predictive value declined from 0.778 on Day 2 to 0.613 on Day 9.

Assessment of the BI early poststroke showed good discriminative properties for final outcome of BI at 6 months. However, Day 5 proved to be the earliest time for making an optimal prediction of final outcome of activities of daily living. The BI should be measured at the end of the first week in hospital-based stroke units for early rehabilitation management.

Do αA-crystallin gene CpG islands hypermethylation in nuclear cataract after pars plana vitrectomy?

To investigate the DNA methylation status of αA-crystallin gene in cataract secondary to pars plana vitrectomy. Anterior capsular membranes of 40 eyes of 40 patients with cataract secondary to vitrectomy were collected. Another 20 eyes of 20 patients who received pars plana vitrectomy and phacoemulsification in the primary procedure, were recruited as control. Methylation status of the CpG islands of αA-crystallin gene was analyzed by pyrosequencing. Expression of αA-crystallin was evaluated by real-time polymerase chain reaction and western blot. In the post vitrectomy group, five patients with posterior subcapsular opacity and four patients with cortical opacity were excluded from further analysis. The remaining 31 patients with nuclear cataract were assigned into two groups according to tamponade types: 19 of octafluoropropane (C3F8) and 12 of silicone oil (SiO). The average nuclear color grading was elevated both in C3F8 and SiO groups after vitrectomy. Compared to the control group, hypermethylation of the CpG islands in the αA-crystallin gene promoter was found in both post vitrectomy groups, accompanied by significantly reduced αA-crystallin expression. No statistically significant differences were found between the C3F8 and SiO groups either for DNA methylation status or αA-crystallin expression.

CpG islands hypermethylation of αA-crystallin gene may be involved in nuclear cataract formation after pars plana vitrectomy.

Does temporal structure of variability decrease in upper extremity movements post stroke?

The objective of this study was to determine movement variability in the more-affected upper-extremity in chronic stroke survivors. We investigated two hypotheses: (1) individuals with stroke will have increased amount of variability and altered structure of variability in upper-extremity joint movement patterns as compared to age-matched controls; and (2) the degree of motor impairment and joint kinematics will be correlated with the temporal structure of variability. Sixteen participants with chronic stroke and nine age-matched controls performed three trials of functional reach-to-grasp. The amount of variability was quantified by computing the standard deviation of shoulder, elbow, wrist and index finger flexion/extension joint angles. The temporal structure of variability was determined by calculating approximate entropy in shoulder, elbow, wrist and index finger flexion/extension joint angles. Individuals with stroke demonstrated greater standard deviations and significantly reduced approximate entropy values as compared to controls. Furthermore, motor impairments and kinematics demonstrated moderate to strong correlations with temporal structure of variability.

Changes in the temporal structure of variability in upper-extremity joint angles suggest that movement patterns used by stroke survivors are less adaptable. This knowledge may yield additional insights into the impaired motor system and suggest better interventions that can enhance upper-extremity movement adaptability.

Does removal of peri-gastric fat prevent acute obstruction after Lap-Band surgery?

Acute postoperative gastroesophageal obstruction is a potential complication after laparoscopic adjustable gastric banding (LAGB). Utilizing the pars flaccida technique may increase the incidence due to the incorporation of perigastric fat, particularly in patients with greater visceral obesity. Removal of peri-gastric fat pads may be necessary to avoid postoperative obstruction. We present our experience of 267 LAGB operations using the LapBand System and the incidence of postoperative obstruction, before and after incorporating routine removal of peri-gastric fat pads. A retrospective review of a prospective database of 267 consecutive Lap-Band placements between July 2001 and November 2002 was conducted. All operations were completed laparoscopically using the pars flaccida technique, and all patients underwent esophagogram the morning after surgery. From July 2001 to May 2002, 143 Lap-Band placements were performed, with 11 patients (8%) having abnormal postoperative esophagograms. There were 43 males/100 females with mean BMI 48.3 (range 35 to 78.9). Complete esophageal obstruction was seen in 5 of these patients, all of whom underwent laparoscopic revision. Significantly delayed emptying was seen in the 6 remaining patients, who were managed conservatively with intravenous fluids from 2-7 days. In these 11 patients, there were 6 males/5 females with mean BMI 47.1 (range 37.3-57.9). Subsequently, removal of peri-gastric fat pads was routinely performed during Lap-Band placement. From June 2002 to November 2002, there were 43 males/81 females with mean BMI 48 (range 35-79); these 124 Lap-Band placements were performed with no abnormal postoperative esophagograms.

Routine removal of peri-gastric fat pads when using the pars flaccida technique for Lap Band surgery appears to prevent postoperative esophageal obstruction.

Does anti-Müllerian hormone measurement on any day of the menstrual cycle strongly predict ovarian response in assisted reproductive technology?

Recently, a new marker, the anti-Müllerian hormone (AMH), has been evaluated as a marker of ovarian response. Serum AMH levels have been measured at frequent time-points during the menstrual cycle, suggesting the complete absence of fluctuation. The aim of this study was to evaluate whether serum AMH measurement on any day of the menstrual cycle could predict ovarian response in women undergoing assisted reproductive technology (ART). This study included 48 women attending the IVF/ICSI programme. Blood withdrawal for AMH measurement was performed in all the patients independently of the day of the menstrual cycle. Women in the lowest AMH quartile (<0.4 ng/ml) were older and required a higher dose of recombinant FSH than women in the highest quartile (>7 ng/ml). All the cancelled cycles due to absent response were in the group of the lowest AMH quartile, whereas the cancelled cycles due to risk of ovarian hyperstimulation syndrome (OHSS) were in the group of the highest AMH quartile. This study demonstrated a strong correlation between serum AMH levels and ovarian response to gonadotrophin stimulation.

For the first time, clinicians may have a reliable serum marker of ovarian response that can be measured independently of the day of the menstrual cycle.

Does tumor necrosis factor-α ( TNF-α ) -863C/A promoter polymorphism is associate with type 2 diabetes in Tunisian population?

Tumor necrosis factor α (TNFα) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF α has been implicated in a wide range of autoimmune and infectious diseases, but also in conditions such as obesity and insulin resistance. The aim of the present study was to investigate the association between the -863C/A polymorphism in the promoter of the TNFα gene and type 2 diabetes in the Tunisian population. The polymorphism -863C/A in the TNFα gene was determined in 211 type 2 diabetes patients and 345 healthy controls using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis. A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with type 2 diabetes had significantly higher frequency of the CA+AA genotypes compared to controls [35.5% vs. 22.3%; OR (95%CI), 1.91 (1.31-2.8); p=0.001]. The type 2 diabetes patient group showed a significant higher frequency of the A allele compared to the controls (0.19 vs. 0.11; p=0.001). After adjustment by a stepwise logistic regression method, hypertension, dyslipidemia, and CA+AA genotype were found to be significantly associated with T2D.

The present study showed a significant and independent association between the -863C/A polymorphism of the TNFα gene and type 2 diabetes in the Tunisian population.

Do distinct 5-HT receptors mediate the peristaltic reflex induced by mucosal stimuli in human and guinea pig intestine?

The role of 5-hydroxytryptamine (5-HT) in regulating the peristaltic reflex in humans is unknown. The neural pathways subserving peristalsis induced by mucosal stimulation were characterized in human jejunum and guinea pig colon. Compartmented flat-sheet preparations that enable measurement of 5-HT and sensory transmitter release into one compartment and mechanical responses in adjacent compartments were used. Mucosal stimuli (2-8 brush strokes) caused concomitant release of 5-HT and calcitonin gene-related peptide (CGRP) into the compartment where stimulation was applied in both species; in contrast, muscle stretch caused release of CGRP only. CGRP release as well as ascending contraction and descending relaxation of circular muscle induced by mucosal stimulation were inhibited by a selective 5-HT4 antagonist in human jejunum and by selective 5-HT4 and 5-HT3 antagonists in guinea pig colon. The effects of the 5-HT3 and 5-HT4 antagonists in guinea pig colon were additive. A selective 5-HT1P antagonist mimicked the effect of the 5-HT4 antagonist. The CGRP antagonist human CGRP8-37 inhibited ascending and descending responses in both species.

5-HT released by mucosal stimulation initiates a peristaltic reflex by activating 5-HT4/5-HT1P receptors on sensory CGRP neurons in human intestine and 5-HT4/5-HT1P and 5-HT3 receptors in guinea pig colon.

Classification of soft-tissue injuries in open femur fractures: Relevant for systemic complications?

A broad range of systemic complications has been described to occur in patients with open major fractures. Various causes have been claimed to play a role. We therefore surveyed a nationwide trauma registry to assess risk factors associated with closed and various types of open femur fractures. This was a cohort study in a nationwide population-based prospective database. Inclusion criteria for selection from database are as follows: individuals with femur fracture, age 16 years or older, and survival until primary admission. Main groups included closed and open femur fracture. Patient demographics, injury severity (New Injury Severity Score), surgical fracture management, length of stay, and systemic complications (e.g., multiple organ failure [MOF], sepsis, mortality) were collected and statistically analyzed using SPSS statistics. Multivariate regression analysis was performed to stratify subgroups for the degree of open soft-tissue injury according to Gustilo and Anderson. Among 32,582 documented trauma victims (January 1, 2002, to December 31, 2010), a total of 5,761 met the inclusion criteria. Main groups: 4,423 closed (76.8%) and 1,338 open femur fractures (23.2%). Open fractures subgroups were divided into I° (334, 28.1%), II° (526, 44.3%), and III° (328, 27.6%). Open fractures were associated with an increased risk of prehospital hemorrhagic shock (p = 0.01), higher resuscitation requirements (p<0.001), MOF (p = 0.001), and longer in-hospital (p<0.001) and intensive care stay (p = 0.001). While New Injury Severity Score values showed a minor increase per subgroup, the prevalence of MOF, sepsis, and mortality multiplied with the degree of open soft-tissue injury. Especially patients with Type III open femur fractures received mass transfusions (28.2%, p<0.001), and mass transfusions were identified as independent predictor for sepsis (odds ratio [OR], 2.393; 95% confidence interval [CI], 1.821-3.143; p<0.001) and MOF (OR, 2.966; 95% CI, 2.409-3.651; p<0.001). Our data also indicate an increased mortality in patients with open femur managed outside Level I trauma centers (OR, 1.358; 95% CI, 1.018-1.812; p = 0.037).

Open femur fractures are associated with higher in-hospital complications related to incidence of MOF, associated intensive care unit stay, and hospital days when compared with closed femur fractures. For prevention of in-hospital complications, prompt hemorrhage control, surgical fracture fixation, cautious blood management, and triage to a Level I trauma center must be considered.

Does amniotic membrane transplantation induce apoptosis in T lymphocytes in murine corneas with experimental herpetic stromal keratitis?

To investigate the effect of human amniotic membrane transplantation (AMT) on T-cell immune response in murine corneas with herpetic stromal keratitis (HSK). Herpes simplex virus (HSV)-1-infected BALB/c mice with necrotizing HSK were treated with AMT. CD3(+) cell apoptosis was determined in treated corneas and in vitro by flow cytometric analysis using the annexin V/7-AAD system. The effect of interleukin (IL)-2, cyclosporine, rapamycin, or Fas on T-cell survival was measured. Activation phenotype was measured by (3)H-thymidine uptake and flow cytometry (CD25, CD69, major histocompatibility complex class II). Cytokine/chemokine secretion from amniotic membrane (AM)-treated corneas or draining lymph node cells was measured. The immune-modulating capacity of long-term AMT treatment and adoptive transfer of AM-treated splenocytes was tested. After AMT, HSK and corneal inflammatory cell infiltration improved, and T-lymphocyte apoptosis occurred. T-cell apoptosis was also induced in vitro, independently of rIL-2, cyclosporine, rapamycin, or Fas. AMT-treated corneas and cultured lymphocytes had reduced IL-2, IL-10, IL-12, CRG-2, and CCL-2 content. Long-term AMT treatment decreased the proliferative response and type 1 helper T-cell cytokine level in draining lymph node cells. The improvement in HSK did not persist. Delayed-type hypersensitivity or HSV-1-specific cytotoxicity was not altered

The results suggest that murine HSK improves after AMT through reduced local T-helper cell immune responses by inducing apoptosis in T lymphocytes, independently of passive apoptosis or activation-induced cell death. AM also reduces local T-helper cytokine and chemokine levels but does not result in immune deviation. Immunologic memory against HSV-1 is not affected by AMT, and long-term protection or tolerance is not induced.

Is MR spectroscopy really the best MR-based method for the evaluation of fatty liver in diabetic patients in clinical practice?

To investigate if magnetic resonance spectroscopy (MRS) is the best Magnetic Resonance (MR)-based method when compared to gradient-echo magnetic resonance imaging (MRI) for the detection and quantification of liver steatosis in diabetic patients in the clinical practice using liver biopsy as the reference standard, and to assess the influence of steatohepatitis and fibrosis on liver fat quantification. Institutional approval and patient consent were obtained for this prospective study. Seventy-three patients with type 2 diabetes (60 women and 13 men; mean age, 54 ± 9 years) underwent MRI and MRS at 3.0 T. The liver fat fraction was calculated from triple- and multi-echo gradient-echo sequences, and MRS data. Liver specimens were obtained in all patients. The accuracy for liver fat detection was estimated by receiver operator characteristic (ROC) analysis, and the correlation between fat quantification by imaging and histolopathology was analyzed by Spearman's correlation coefficients. The prevalence of hepatic steatosis was 92%. All gradient-echo MRI and MRS findings strongly correlated with biopsy findings (triple-echo, rho = 0.819; multi-echo, rho = 0.773; MRS, rho = 0.767). Areas under the ROC curves to detect mild, moderate, and severe steatosis were: triple-echo sequences, 0.961, 0.975, and 0.962; multi-echo sequences, 0.878, 0.979, and 0.961; and MRS, 0.981, 0.980, and 0.954. The thresholds for mild, moderate, and severe steatosis were: triple-echo sequences, 4.09, 9.34, and 12.34, multi-echo sequences, 7.53, 11.75, and 15.08, and MRS, 1.71, 11.69, and 14.91. Quantification was not significantly influenced by steatohepatitis or fibrosis.

Liver fat quantification by MR methods strongly correlates with histopathology. Due to the wide availability and easier post-processing, gradient-echo sequences may represent the best imaging method for the detection and quantification of liver fat fraction in diabetic patients in the clinical practice.

Is infection with specific Helicobacter pylori-cag pathogenicity island strains associated with interleukin-1B gene polymorphisms in Venezuelan chronic gastritis patients?

The cag pathogenicity island (cag-PAI) is one of the major virulence factors of Helicobacter pylori, showing considerable geographic variation. We investigated the prevalence of cagA, cagE, and cagT genes of cag-PAI and their association with proinflammatory IL-1B-511/-31/+3954 polymorphisms in Venezuelan chronic gastritis patients from a high-risk gastric cancer region. Presence of cag-PAI genes and IL-1B polymorphisms in 121 biopsy specimens was evaluated by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP), respectively. cagA (+) and triple-positive (cagAET (+)) strains were detected in 79.3% and 70.2% of patients, respectively. We found that infection with cagA (+) and cagAET (+) strains was associated (P < 0.05) with hosts harboring both IL-1B +3954C allele and IL-1B-511T/-31C/+3954C haplotype (TCC (+)). The frequency of gastric atrophy was significantly higher (P < 0.020) among cagAET (+)/IL-1B-TCC (+) combined genotype carriers.

Carriage of IL-1B +3954C allele and IL-1B-TCC (+) haplotype could favor colonization of bacterial cagAET (+) strains, and the combination of these bacterial and host haplotypes could play a synergistic role in development of premalignant gastric lesions. This work contributes to understanding of the complex interaction between H. pylori virulence factors and cytokine genotypes involved in gastrointestinal diseases.

Are respiratory effects of indoor particles in young children size dependent?

Extensive epidemiological studies have provided evidence of an association between elevated outdoor particulate air pollution and adverse health effects. However, while people typically spend majority of time indoors, there is limited knowledge on airborne indoor particles and on the correlation between the concentrations of indoor particles and health effects. Even insights into the influence of differently sized indoor particles on human health are still rare. The association between differentially sized indoor air particles and the development of respiratory diseases was studied for three year aged children. Short-term measurements of particle mass and number concentrations were carried out in children's rooms. Information on possible particle sources (smoking habits, type of heating, and traffic) and respiratory outcomes were obtained from questionnaires. Measured indoor particle concentrations were correlated with possible sources of indoor particles and with respiratory health impacts. Daily smoking, smoking more than 5 cigarettes per day at home and traffic density in front of the window of children's room were found to be related to indoor exposure by particles of different diameters. High indoor particle exposures were associated with an increased risk for the development of obstructive bronchitis and in some extent of non-obstructive bronchitis. The strongest impact was observed for the mass concentration of particles <1 μm and the number concentration of particles >0.5 μm. The risk increases still remain significant if tested for stability changing the number of adjustment variables or omitting randomly selected cases, respectively.

Our results show significant associations between indoor particle concentrations and the risks for respiratory diseases in young children. The applied short-term measurements can help to assess the health risks of indoor particles with different sizes within epidemiological studies.

Is autosomal recessive retinitis pigmentosa with RP1 mutations associated with myopia?

To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25-Q75) was determined and multiple comparisons were performed. arRP patients with RP1 mutations had SE median at -4.0 dioptres (D) OD (Ocula Dextra); -3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (-0.50 D OD; -0.75 D OS) and Usher syndrome patients (-0.50 D OD; -0.38 D OS) were significantly less myopic (p<0.0001). Conversely, myopia of xlRP patients with either an RPGR mutation (-4.50 D OD; -5.25 D OS) or an RP2 mutation (-6.25 D OD; -6.88 D OS) was not significantly different from the arRP group with RP1 mutations. arRP without RP1 mutations, Usher syndrome and adRP with RP1 mutation had a narrow IQR (-9.06 to -1.13 D), whereas arRP with RP1 mutations and xlRP with RP2 or RPGR mutations had a larger range (-9.06; -1.13 D).

arRP patients with RP1 mutations have myopia not different from patients with xlRP with RP2 or RPGR mutations, while RP patients from other genetic subgroups were emmetropic or mildly myopic. We suggest that arRP patients with high myopic refractive error should be preferentially analysed for RP1 mutations.

Do hard-on-Hard Bearings Are Associated With Increased Noise Generation in Young Patients Undergoing Hip Arthroplasty?

Patient-perceived noise from prostheses after total hip arthroplasty (THA) does occur, yet questions remain including the overall frequency of this finding, demographic and prosthesis-related factors, and the association of noise generation with patient-reported outcomes. The purposes of this study were (1) to determine the frequency with which patients report noise coming from the hip after THA; (2) to identify patient and prosthesis-related factors associated with noise generation; and (3) to ascertain if noise generation is associated with pain or functional impairment after THA. A five-center study was designed to quantify the degree of residual symptoms and functional deficits in patients undergoing THA. Three centers were academic practices, whereas two centers were private practices that provided training programs for orthopaedic residents and fellows. Each contributing surgeon was fellowship-trained and specialized in joint replacement. Inclusion criteria for this study were (1) men between 18 and 60 years old and women between 18 and 55 years old; (2) patients requiring primary hip surgery as a result of noninflammatory arthritis such as osteoarthritis, traumatic arthritis, or avascular necrosis; (3) a UCLA activity score of 6 or more before they were limited by pain; and (4) patients who had undergone a primary THA within 1 to 4 years before the start of the study and had a minimum of 1 year of clinical followup. Attempts were made to contact all identified patients meeting these inclusion criteria. Data were collected by an independent, third-party survey center blinded to the implant design and bearing surface used who administered questionnaires about residual symptoms, function, and pre- and postoperative activity levels using previously published survey instruments. Patients were specifically queried regarding perceived noise from their THA. We retrospectively identified 1242 eligible patients. Of the 1242 patients, 105 were found to have exclusions during the screening section of the questionnaire: postoperative infection (six THAs), fracture (two), dislocation (seven), or revision (17); limited activity level because of an operation on the opposite hip (34); and premorbid UCLA score of less than 6 (39). In addition, 128 individuals refused to participate, 156 were never available, 108 were not found as a result of a bad address/phone number, 48 were contacted but did not complete the interview, nine had died, and six had a language barrier. This left 682 of the 1137 eligible patients with completed surveys (60% response rate). The mean age was 50 ± 8 years at the time of surgery with 63% being men, and they were contacted at a mean of 3 ± 1 years postoperatively. Bearing surfaces (femoral head-acetabular liner) included 210 (31%) metal-on-metal, 144 (21%) ceramic-on-ceramic, 142 (21%) ceramic-on-polyethylene, 141 (21%) cobalt-chromium-on-polyethylene, and 44 (6%) oxidized zirconium-on-polyethylene. Differences in baseline demographic variables were accounted for using multiple logistic regression statistical analyses. Pearson's correlation coefficients were used to determine the association of noise generation with residual symptoms. Overall, 9% (61 of 682; 95% confidence interval [CI], 7-11) of young patients undergoing primary THA reported noise generation. Females (12% [30 of 251 patients]) were noted to have an increased likelihood of reporting noise versus males (7% [30 of 431 patients]; odds ratio, 1.8; 95% CI, 1.1-3.1; p = 0.03). After controlling for potential confounding variables including female sex and length of followup, patients receiving a ceramic-on-ceramic or metal-on-metal bearing surface (14% [50 of 355]) reported an increased frequency of grinding, popping, and clicking in the 30 days before survey administration versus those receiving a polyethylene liner with a ceramic, oxidized zirconium, or cobalt-chromium femoral head (3% [10 of 327 patients]; odds ratio, 5.6; 95% CI, 2.7-11.5; p < 0.001). Noise generation was associated with increased pain (r = 0.23, p < 0.001) and stiffness (r = 0.22, p < 0.001) after THA.

When interviewed by an independent third party, patients receiving a metal-on-metal or ceramic-on-ceramic bearing reported a higher frequency of noise generation versus patients receiving a polyethylene liner after THA. Young patients undergoing THA should be counseled that noise generation could be associated with increased pain after THA.