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Should laparoscopic paraesophageal hernia repair be abandoned in favor of the open approach?

The most appropriate approach to the repair of large paraesophageal hernias remains controversial. Despite early results of excellent outcomes after laparoscopic repair, recent reports of high recurrence require that this approach be reevaluated. For this study, 60 primary paraesophageal hernias consecutively repaired at one institution from 1990 to 2002 were reviewed. These 25 open transabdominal and 35 laparoscopic repairs were compared for operative, short-, and long-term outcomes on the basis of quality-of -life questionnaires and radiographs. No difference in patient characteristics was detected. Laparoscopic repair resulted in lower blood loss, fewer intraoperative complications, and a shorter length of hospital stay. No difference in general or disease-specific quality-of-life was documented. Radiographic follow-up was available for 78% open and 91% laparoscopic repairs, showing anatomic recurrence rates of 44% and 23%, respectively (p = 0.11).

Laparoscopic repair should remain in the forefront for the management of paraesophageal hernias. However, there is considerable room for improvement in reducing the incidence of recurrence.

Does the F309S mutation increase factor VIII secretion in human cell line?

The capacity of a human cell line to secrete recombinant factor VIII with a F309S point mutation was investigated, as was the effect of the addition of chemical chaperones (betaine and sodium-4-phenylbutyrate) on the secretion of factor VIII. This work used a vector with a F309S mutation in the A1 domain to investigate FVIII production in the HEK 293 human cell line. Factor VIII activity was measured by chromogenic assay. Furthermore, the effects of chemical drugs on the culture were evaluated. The addition of the F309S mutation to a previously described FVIII variant increased FVIII secretion by 4.5 fold. Moreover, the addition of betaine or sodium-4-phenylbutyrate increased the secretion rate of FVIIIΔB proteins in HEK 293 cells, but the same effect was not seen for FVIIIΔB-F309S indicating that all the recombinant protein produced had been efficiently secreted.

Bioengineering factor VIII expressed in human cells may lead to an efficient production of recombinant factor VIII and contribute toward low-cost coagulation factor replacement therapy for hemophilia A. FVIII-F309S produced in human cells can be effective in vivo.

Does [ BRCA1 regulate progesterone receptors A and B protein expressions in breast cancer cells in vitro ]?

To study the regulatory role of BRCA1 in the expression of progesterone receptors A and B (PRA and PRB) in breast cancer cells. Breast cancer MCF-7 cells were transfected with pFlag-CMV2-BRCA1 wt plasmid containing a full-length BRCA1 cDNA or with BRCA1-specific siRNA via lipofectamine 2000 to induce overexpression or suppressed expression of BRCA1, respectively. Twenty-four hours after the transfection, the cells were incubated in fresh culture medium containing 100 nmol/L progesterone for 24 h. The total RNA extract or whole cell lysate was prepared for detecting BRCA1, PRA and PRB expressions using RT-PCR and Western blotting. The protein expressions of PRA and PRB were significantly decreased whereas their mRNA expressions remained unchanged in MCF-7 cells overexpressing BRCA1. In MCF-7 cells with BRCA1 knock-down, in contrast, the PRA and PRB protein expressions were markedly increased.

In breast cancer cells, exogenous and endogenous BRCA1 can both down-regulate the expressions of PRA and PRB at the protein level.

Are th1 and Th17 lymphocytes expressing CD161 implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis?

Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR). A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased. Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161+CD4+ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1.

This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161+CD4+ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR.

Does gadd45γ regulate cardiomyocyte death and post-myocardial infarction left ventricular remodelling?

Post-infarction remodelling is accompanied and influenced by perturbations in mitogen-activated protein kinase (MAPK) signalling. The growth arrest and DNA-damage-inducible 45 (Gadd45) proteins are small acidic proteins involved in DNA repair and modulation of MAPK activity. Little is known about the role of Gadd45 in the heart. Here, we explored the potential contribution of Gadd45 gamma (γ) isoform to the acute and late phase of heart failure (HF) after myocardial infarction (MI) and determined the mechanisms underlying Gadd45γ actions. The Gadd45γ isoform is up-regulated in murine cardiomyocytes subjected to simulated ischaemia and in the mouse heart during MI. To mimic the situation observed during MI, we enhanced Gadd45γ content in cardiomyocytes with a single injection of an adeno-associated viral (AAV9) vector encoding Gadd45γ under the cTNT promoter. Gadd45γ overexpression induces cardiomyocyte apoptosis, fibrosis, left ventricular dysfunction, and HF. On the other hand, genetic deletion of Gadd45γ in knockout mice confers resistance to ischaemic injury, at least in part by limiting cardiomyocyte apoptosis. Mechanistically, Gadd45γ activates receptor-interacting protein 1 (RIP1) and caspase-8 in a p38 MAPK-dependent manner to promote cardiomyocyte death.

This work is the first to demonstrate that Gadd45γ accumulation during MI promotes the development and persistence of HF by inducing cardiomyocyte apoptosis in a p38 MAPK-dependent manner. We clearly identify Gadd45γ as a therapeutic target in the development of HF.

Do selective type IV phosphodiesterase inhibitors prevent IL-4-induced IgE production by human peripheral blood mononuclear cells?

Selective type IV phosphodiesterase (PDE) inhibitors elicit anti-inflammatory and bronchodilatory activities in vitro and in vivo which suggest that these drugs could provide a new therapeutic approach for asthma treatment. Regarding the role of IgE production in allergic and inflammatory reactions of the airways, we investigated the effect of selective PDE inhibitors on IL-4-driven IgE production by peripheral blood mononuclear cells (PBMC) or by purified B lymphocytes. PBMC or purified B lymphocytes from non-allergic donors were stimulated for 13 days with IL-4 (100 U/mL) in the presence or in the absence of selective PDE inhibitors. IgE production is evaluated by an ELISA technique. The selective PDE IV inhibitors, rolipram and Ro 20-1724 (10 microM), inhibit IL-4-induced IgE production by PBMC, but not by purified B lymphocytes. No modification of the IgE production was noted with the selective PDE III inhibitors, milrinone and SK&F 94-836, or the selective PDE V inhibitor, SK&F 96-231 (10 microM). Flow cytometry experiments showed that the effect of Rolipram could not be explained by the inhibition of the cell surface expression of the IL-4 receptor. Similarly, no significant effect of PDE IV inhibitors was observed on PHA-induced cell proliferation. The incubation of monocytes only with rolipram was sufficient to achieve a significant reduction of IgE production induced by IL-4.

Taken together, these results indicate that PDE IV inhibitors reduce IL-4-induced IgE production by PBMC and suggest that the inhibition of IgE production could be explained by a failure of monocytes to provide the necessary costimulatory signals.

Sinus Computed Tomography Imaging in Pediatric Cystic Fibrosis: Added Value?

To evaluate the prevalence of computed tomography (CT) sinus imaging in a pediatric cystic fibrosis (CF) population, determine changes in Lund Mackay (LM) scores over time, and estimate radiation exposure. Case series with chart review. Tertiary care children's hospital. In total, 202 pediatric patients with CF who underwent endoscopic sinus surgery (ESS) were included. The total number of CT scans was calculated for each patient, with specific focus on the indications for and subsequent outcomes of the sinus CT scan subgroup. Patients underwent a total of 1718 CT scans, 832 of which were sinus CT scans (mean of 4.2 sinus scans per patient). Disease evaluation (54%) and preoperative planning (35%) were the most common indications. Otolaryngologists were more likely to order imaging for preoperative evaluation, and those scans were more likely to result in surgery compared with those requested by other physicians (P<.001). Ninety CT scans (10.8%) led to no change in management. There was no significant difference in LM scores between patients admitted to the hospital or prescribed antibiotics and those who were not. There was also no significant change in LM score following ESS after adjusting for age and sex (P = .23).

Based on LM scores, all sinus CT scans in patients with CF reveal moderate to severe sinus disease. Effort should be made to minimize radiation exposure in patients with CF by limiting sinus CT scans to the preoperative context or for evaluation of potential sinusitis complications.

Does expression of a transgene encoding mutant p193/CUL7 preserve cardiac function and limits infarct expansion after myocardial infarction?

Transgenic mice expressing the dominant interfering p193 protein in cardiomyocytes (MHC-1152stop mice) exhibit an induction of cell cycle activity and altered remodelling after experimental myocardial infarction (MI). To determine whether the altered remodelling results in improved cardiac function in the MHC-1152stop mice after MI, as compared with non-transgenic mice. MHC-1152stop mice and non-transgenic littermates were subjected to experimental MI via permanent occlusion of the coronary artery. Infarct size was determined at 24 h and at 4 weeks after MI, and left ventricular pressure-volume measurements were performed at 4 weeks after MI in infarcted and sham-operated animals. Infarct size in MHC-1152stop mice and non-transgenic littermates was not statistically different at 24 h after MI, as measured by tetrazolium staining. Morphometric analysis showed that infarct scar expansion at 4 weeks after MI was reduced by 10% in the MHC-1152stop mice (p<0.05). No differences in cardiac function were detected between sham-operated MHC-1152stop mice and their non-transgenic littermates. However, at 4 weeks after MI, the ventricular isovolumic relaxation time constant (tau) was decreased by 19% (p<0.05), and the slope of the dP/dt(max)-EDV relationship was increased 99% (p<0.05), in infarcted MHC-1152stop mice as compared with infarcted non-transgenic littermates.

Expression of the dominant interfering p193 transgene results in a decrease in infarct scar expansion and preservation of myocardial function at 4 weeks after MI. Antagonism of p193 activity may represent an important strategy for the treatment of MI.

Should children with suspected obstructive sleep apnea syndrome and normal nap sleep studies have overnight sleep studies?

Overnight polysomnography (ONP) is the "gold standard" for the diagnosis of sleep-disordered breathing, but it is expensive and time-consuming. Thus, daytime nap studies have been used as screening tests. If the findings of a nap study are normal or mildly abnormal, should ONP be performed? Do specific abnormalities in nap studies predict abnormal findings in ONP? To answer these questions, we conducted this study. Retrospective chart review. Children's hospital. One hundred forty-three children with suspected obstructive sleep apnea syndrome secondary to isolated adenotonsillar hypertrophy, who had normal or mildly abnormal nap studies, and underwent ONP. We compared daytime nap and overnight polysomnograms in 143 children (52 girls; mean [+/- SD] age, 5.6 +/- 3.1 years). Total sleep time was 1 h in daytime nap, and 5.1 +/- 1.3 h in ONP. The interval between the two studies was 5.9 +/- 4.8 months. The findings of 59% of the nap studies were mildly abnormal, while 66% of overnight studies were abnormal. No individual nap study parameter (including short obstructive apneas, hypopneas, hypoxemia, hypoventilation, snoring, paradoxical breathing, gasping, retractions) had good sensitivity at predicting abnormal overnight polysomnograms, but most had good specificity and positive predictive value.

We conclude that individual nap study parameters are not very sensitive in predicting abnormal ONP findings. However, when nap study parameters are abnormal, the chance of obstructive sleep apnea syndrome is high.

Are age and Breslow depth associated with a positive sentinel lymph node in patients with cutaneous melanocytic tumors of uncertain malignant potential?

Atypical melanocytic neoplasms present a therapeutic dilemma. Current consensus is to perform a sentinel lymph node (SLN) biopsy as part of management. However, it is unclear whether this is required in all patients. We present our experience with sentinel lymphadenectomy in these patients and examine the clinical and pathologic variables associated with a positive SLN. A prospectively maintained melanoma database was queried for patients with controversial melanocytic lesions. All patients between January 1997 and January 2009 were included. Demographic and pathologic information was collected and correlated with results of SLN biopsy. Thirty-one patients underwent SLN biopsy. Median patient age was 19 years (range 5 to 59 years) and median tumor Breslow depth was 1.35 mm. Five patients (16%) had a positive SLN. Those with a positive SLN were younger (median 11 vs 23.5 years, p = 0.02) and had a greater Breslow depth (median 1.90 vs 1.09; p = 0.03) than those who were SLN negative. Median follow-up was 16 months for patients with at least 6 months of follow-up time and there have been no recurrences identified.

We report an SLN positive rate of 16% in patients with atypical melanocytic tumors. Younger age and greater Breslow depth are associated with having a positive SLN. These results confirm earlier work demonstrating the importance of SLN biopsy in this disease and highlight the need to measure Breslow depth in these lesions so that they can be appropriately stratified as to the need for SLN biopsy.

Does cigarette smoking influence the phenotype of Crohn's disease?

The clinical subclassification of Crohn's disease by phenotype has recently been reevaluated. We have investigated the relationships between smoking habit, age at diagnosis, disease location, and progression to stricturing or penetrating complications using the Montreal classification. 408 patients (157 male, median age 29.4 yr) were assessed. Data were collected on smoking habit, age at diagnosis, anatomical distribution, and disease behavior. Follow-up data were available on all patients (median 10 yr). At diagnosis, ex-smokers (N = 53) were older than nonsmokers (N = 177) or current smokers (N = 178, medians 43.2 vs 28.3 or 28.9 yr, respectively, P<0.001). Disease location differed according to smoking habit at diagnosis (chi(2)= 24.1, P= 0.02) as current smokers had less colonic (L2) disease than nonsmokers or ex-smokers (30%vs 45%, 50%, respectively). In univariate Kaplan-Meier survival analysis, smoking habit at diagnosis was not associated with time to development of stricturing disease, internal penetrating disease, perianal penetrating disease, or time to first surgery. Patients with isolated colonic (L2) disease were slower to develop strictures (P<0.001) or internal penetrating disease (P= 0.001) and to require surgery (P<0.001). Cox models with smoking habit as time-dependent covariates showed that, relative to ileal (L1) location of disease, progression to stricturing disease was less rapid for patients with colonic (L2) disease (HR 0.140, P<0.001), but not independently affected by smoking habit. Progression to surgery was also slower for colonic (L2) than ileal (L1) disease location (HR 0.273, P<0.001), but was independent of smoking habit.

Smoking habit was associated with age at diagnosis and disease location in Crohn's disease, while disease location was associated with the rate of development of stricturing complications and requirement for surgery. The pathogenic basis of these observations needs to be explained.

Does hirano body expression impair spatial working memory in a novel mouse model?

Hirano bodies are actin-rich intracellular inclusions found in the brains of patients with neurodegenerative conditions such as Alzheimer's disease or frontotemporal lobar degeneration-tau. While Hirano body ultrastructure and protein composition have been well studied, little is known about the physiological function of Hirano bodies in an animal model system. Utilizing a Cre/Lox system, we have generated a new mouse model which develops an age-dependent increase in the number of model Hirano bodies present in both the CA1 region of the hippocampus and frontal cortex. These mice develop normally and experience no overt neuron loss. Mice presenting model Hirano bodies have no abnormal anxiety or locomotor activity as measured by the open field test. However, mice with model Hirano bodies develop age-dependent impairments in spatial working memory performance assessed using a delayed win-shift task in an 8-arm radial maze. Synaptic transmission, short-term plasticity, and long-term plasticity was measured in the CA1 region from slices obtained from both the ventral and dorsal hippocampus in the same mice whose spatial working memory was assessed. Baseline synaptic responses, paired pulse stimulation and long-term potentiation measurements in the ventral hippocampus were indistinguishable from control mice. In contrast, in the dorsal hippocampus, synaptic transmission at higher stimulus intensities were suppressed in 3 month old mice with Hirano bodies as compared with control mice. In addition, long-term potentiation was enhanced in the dorsal hippocampus of 8 month old mice with Hirano bodies, concurrent with observed impairment of spatial working memory. Finally, an inflammatory response was observed at 8 months of age in mice with Hirano bodies as assessed by the presence of reactive astrocytes.

This study shows that the presence of model Hirano bodies initiates an inflammatory response, alters hippocampal synaptic responses, and impairs spatial working memory in an age-dependent manner. This suggests that Hirano bodies may promote disease progression. This new model mouse provides a tool to investigate how Hirano bodies interact with other pathologies associated with Alzheimer's disease. Hirano bodies likely play a complex and region specific role in the brain during neurodegenerative disease progression.

Are adolescents accurate in self-report of frequencies of sexually transmitted diseases and pregnancies?

Many surveys of adolescent behavior are dependent on self-reported data. We sought to assess the accuracy of adolescent self-report of sexually transmitted diseases (STDs) and pregnancies. We randomly selected 149 (118 females, 31 males) adolescents to participate in this accuracy study. Follow-up questionnaires were administered to the 126 patients (99 females, 27 males) who returned after enrollment. Patients were asked about STDs and pregnancies during the follow-up period which ranged from 6 months to 1 year. All patient charts were reviewed to validate post-testing history. Return visits were made by 126 patients (84%). Fifty-one (40%) denied having had an STD at all during the follow-up period but were found to have had at least one STD. Another 11 (9%) admitted having had an STD but had multiple STDs in excess of what they reported. Only 46% of the patients provided accurate information on the follow-up questionnaire. Of the 99 girls who returned for follow-up, the inaccurate patients (10%) consisted of 9 who reported no visits for a pregnancy but had a pregnancy documented in their charts and 1 who underreported her number of pregnancies. Reliability analysis of the accuracy of STD and pregnancy self-report for our patients showed kappas ranging from 0.185 to 0.413 (slight and fair to moderate, respectively). Pearson correlation coefficients were 0.3107 and 0.4364 for STD and pregnancy, respectively.

Our patients' histories of visits for STDs and pregnancies are often not substantiated by review of their medical records. The reason for the inaccuracies in self-report of sexual behaviors is unclear. Further research in this area should be done. Physicians must confirm patient history concerning sexual practices through appropriate record review and medical evaluation.

Are enhancing the continuum for substance abusers?

In 2001, Pikes Peak Mental Health Center (Colorado Springs, Colorado) spearheaded a community collaboration to increase service capacity for substance abusers and reduce recidivism. In 2003, a Substance Abuse Advisory Council generated community support through substance abuse education activities and fund raising. It developed a program that entailed a recovery home and shelter for clients, intensive case management, and outpatient programs. A task force was initiated to develop community solutions. Each stakeholder evaluated the issue of substance abuse as it related to his or her agency's perspective and collaborated to develop solutions within a broader community context. The project's goals were to (1) establish community awareness regarding the discrepancies between quality in care and the complex interactions of substance abuse variables, (2) eliminate the fragmentation between care providers, and (3) produce an enhanced continuum of care. Improvements were evident in all six performance measures (p < .05)--detoxification access, services, and continuum of care. For example, overall reduction in the recidivism rate has shown a 23% decrease since the project's inception. Capacity increased by 42% from 2004 to 2005. Since 2003, self-referrals to the detoxification unit have increased by 44%.

On the basis of the outcomes, Pikes Peak Mental Health Center's Detoxification/Acute Unit has obtained funding to continue and expand existing services to target the indigent behavioral health community.

Is diabetes mellitus a poor prognostic factor for hepatocellular carcinoma?

There are scarce data regarding the impact of diabetes mellitus on the prognosis of hepatocellular carcinoma managed conservatively. The objective of this study was to compare the overall survival among diabetic and non-diabetic patients suffering from hepatocellular carcinoma and treated mainly by non-surgical means. We identified patients who underwent treatment for hepatocellular carcinoma over a period of 6.5 years at a single center in Lahore, Pakistan. Data regarding age, gender, morphology of tumor, size of tumor, Child-Pugh class, the Barcelona-Clínic Liver Cancer (BCLC) stage, treatment given, and outcome was retrieved from the medical records. Patients were classified as diabetic if there were at least two documented readings of fasting blood glucose level of more than 126 mg/dl or random blood glucose of more than 200 mg/dl or the patient was already diagnosed and on oral hypoglycemic agents or insulin. Statistical tests were applied to test for differences between diabetic and non-diabetic patients in terms of clinical features at presentation, treatments received, and disease outcomes. A total of 282 patients were diagnosed as having hepatocellular carcinoma during the study period. Diabetic and non-diabetic patients were comparable in terms of the mean age at diagnosis of hepatocellular carcinoma, sex, whether the tumor was unifocal or multifocal, Child-Pugh class, BCLC stage, and infection with hepatitis B and/or C virus. Diabetic patients were significantly more likely to have initial alpha-feto protein levels lower than 200 IU/ml compared to non-diabetic patients. There was no difference among diabetic and non-diabetic patients in terms of the treatments they received or the outcomes. Non-diabetic and diabetic patients had a mean disease-free survival of 8.29 and 6.95 months, respectively, and overall survival of 15.48 and 15.36 months, respectively. Multivariate linear regression analyses, after adjusting for age and gender of the patient and the BCLC stage of the tumor among the subset of patients documented to have died during the follow-up period, showed that there was no significant difference between diabetic and non-diabetic patients in terms of overall survival. BCLC stage, however, was significantly associated with overall survival.

Diabetes mellitus has no prognostic significance in patients with hepatocellular carcinoma.

Does quadricep and hamstring activation during drop jump with changes in drop height?

Compare the muscle activation patterns of the quadricep-hamstring during drop jumps with increasing demands of drop heights. Observational. University biomechanics laboratory. Fifteen male and eight female college physical education students. Electromyographic activity of the rectus femoris (RF) and biceps femoris (BF) during the landing and takeoff phase of drop jumps from 20 to 60-cm heights. The ground contact time, vertical ground reaction force (vGRF), knee flexion angle during ground contact, and jump height after takeoff were also analyzed. The activation of RF was higher in the drop jump from 60-cm than that from 20- and 30-cm (comparing 107.0 ± 45.9 to 82.3 ± 30.8 and 88.9 ± 38.9 %MVIC, P<.05) during the landing phase. Activation of BF remained similar across all drop heights. Drop jump from 60-cm resulted in greater contact time during takeoff phase and peak vGRF, and resulted in greater maximum knee flexion but straighter knee at ground contact than from lower drop heights.

At drop height of 60-cm, the altered knee muscular activation and movement patterns may diminish the effectiveness of plyometric training and increase the potential injury risk of knee.

Does adiponectin elevation by telmisartan ameliorate ischaemic myocardium in Zucker diabetic fatty rats with metabolic syndrome?

This study investigated whether telmisartan, a selective angiotensin type 1 (AT1) receptor antagonist and gamma peroxisome proliferator-activated receptor (PPAR-γ) partial agonist, reduces myocardial ischaemia/reperfusion (I/R) injury in an experimental model of metabolic syndrome. Zucker Diabetic Fatty (ZDF) rats were treated for 3 weeks with telmisartan at doses of 2, 7 and 12 mg/kg/day. After treatment, rats were subjected to a 25-min occlusion of the left descending coronary artery followed by 2-h reperfusion (I/R). Telmisartan reduced the extension of the infarct size in a dose-dependent fashion and decreased the levels of plasma troponin I, a specific marker of myocardial damage. Telmisartan also caused a dose-dependent increase in adiponectin both in plasma and cardiac tissue of infarcted ZDF rats. These levels were minimally increased (p < 0.05 vs. vehicle) by telmisartan 7 mg/kg/day and reached the maximum values with the highest dose of 12 mg/kg/day (p < 0.01 vs. vehicle). In contrast, within the infarcted tissue telmisartan decreased the expression of markers of inflammation such as the transcription factor NF-κB, the toll-like receptors TLR2 and TLR4 as well as TNF-α cytokine. Nitrosative stress was maximal in vehicle-treated infarcted hearts as evidenced by increased expression of iNOS, which was almost abolished after treatement with telmisartan.

Treatment of ZDF rats for 3 weeks with telmisartan, a dual angiotensin II receptor antagonist and partial PPAR-γ receptor agonist, resulted in a significant reduction of myocardial damage induced by I/R and was associated with increased adiponectin and a decrease in inflammatory markers.

Does lipopolysaccharide-induced Notch signaling activation through JNK-dependent pathway regulate inflammatory response?

Notch and TLR pathways were found to act cooperatively to activate Notch target genes and to increase the production of TLR-induced cytokines in macrophages. However, the mechanism of LPS-induced Notch activation and its role in sepsis still remains unclear. We analyzed the expression patterns of Notch components in a LPS-stimulated murine macrophage cell line using real-time PCR and western blotting. The role of DAPT, a gamma-secretase inhibitor that is known to be a potent Notch inhibitor, in LPS-induced cytokine release and experimental sepsis in mice was also explored. Student's t-test was used to analyze the difference between the two groups. We found that Notch signaling was activated after LPS stimulation. The expression of Jagged 1, a Notch ligand, induced by LPS occurred in a JNK-dependent manner. In addition, Notch target genes were upregulated by early Notch-independent activation followed by delayed Notch-dependent activation after LPS stimulation. Disruption of Notch signaling by DAPT attenuated the LPS-induced inflammatory responses, including vascular endothelial growth factor (VEGF) and high-mobility group box chromosomal protein 1 (HMGB1), both in vitro and in vivo and partially improved experimental sepsis survival.

These findings support the existence of a synergistic effect of Notch signaling and the LPS pathway both in vitro and in vivo. Therefore, in the future Notch inhibitors may be utilized as adjunctive agents for the treatment of sepsis syndrome.

Retinal detachments in southern New Zealand: do poorer patients have poorer outcomes?

To investigate associations between socioeconomic status, retinal detachment type and post-operative visual outcomes in southern New Zealand. A retrospective review of all cases of rhegmatogenous retinal detachments in Dunedin Hospital over two years was performed. Patient demographics and macula involvement at presentation were the primary outcome measures. The New Zealand Deprivation Index was used to group patients into low (30% least deprived), medium (middle 40%) and high (30% most deprived). Patients were excluded if they were not from New Zealand, or had traumatic detachments. During the study period, 95 retinal detachments in 94 patients were managed in Dunedin Hospital. Only 15% of retinal detachments occurred in the most deprived. More deprived patients had longer delays before assessment in hospital (mean of 29.8 days versus 10.1 days for the least deprived and 12.8 days for the medium category, overall p=0.025). There was no evidence of an association between deprivation and macula-off status (overall p=0.650) or visual acuity at one or three months (p=0.063 and p=0.328 respectively). Nor was there an association between referral pathway and macula-off status (p=0.242).

Retinal detachment in southern New Zealand may be less common amongst those with the most deprived socioeconomic status who also experience longer delays till first treatment; but there was no association between socioeconomic status and patients being macula-off at presentation, or having poorer visual outcomes. More targeted patient education towards our most deprived citizens may reduce delays in treatment, and result in better visual outcomes.

Do tGF-beta signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells?

A signaling interaction between transforming growth factor-beta (TGF-beta) and androgens promotes apoptosis in human prostate cancer cells LNCaP-TbetaRII (androgen-sensitive and TGF-beta responsive). This study investigated the contribution of androgen receptor (AR) in the combined effect of TGF-beta and dihydrotestosterone (DHT), on regulation of apoptosis and AR- and TGF-beta mediated transcriptional activity in human prostate cancer cells. Transcriptional activation in response to TGF-beta (5 ng/ml) and DHT (1 nM) was evaluated using transient transfections and luciferase assays in human prostate cancer cells, LNCaP-TbetaRII and PC-3, overexpressing the wild type AR. The apoptotic response to DHT/TGFbeta treatment was correlated with AR cellular distribution and the AR interaction with TGF-beta intracellular effector Smad4. The results revealed that TGF-beta signaling induced AR-mediated transcriptional activation in two androgen-responsive promoters [probasin and prostate specific antigen (PSA)]. TGF-beta1 induced transcriptional activity enhanced by DHT in both cell lines (LNCaP-TbetaRII and PC-3-AR) via AR-Smad4 interaction. This interaction however does not exclusively drive TGF-beta mediated apoptosis as DHT failed to enhance such an effect in PC-3 AR (wt) cells.

These results demonstrate that the AR status determines the sensitivity of prostate cancer cells to the apoptotic effects of TGF-beta1, thus providing a new insight into the mechanism via which TGF-beta cross-sections the AR axis toward the functional convergence of the two pathways in the development of androgen-independent prostate cancer. This study is potentially significant in defining the contribution of AR status to the emergence of androgen-independent prostate tumors.

Is prenatal diagnosis by minimally invasive first-trimester transcervical sampling unreliable?

We investigated whether reliable prenatal diagnosis is possible from fetal cells harvested transcervically in first-trimester pregnancies. Fetal cells were obtained transcervically from 87 women undergoing pregnancy termination. Fetal gender was determined in 51 pregnancies with three different polymerase chain reaction techniques and in 36 pregnancies with fluorescent in situ hybridization. In known male pregnancies the number of male fetal cells present was also determined. Polymerase chain reaction detected male deoxyribonucleic acid in up to 79% of cases in male pregnancies and up to 45% of cases in female pregnancies. Fetal gender was correctly predicted in up to 72% of cases with fluorescent in situ hybridization. However, fetal cells were identified in < 40% of informative male pregnancies and were present in low numbers-0.7% to 3.4% in swabs and 4.4% to 24.8% in flushes.

The use of fetal cells obtained by minimally invasive first-trimester transcervical sampling is unreliable for prenatal diagnosis.

Does attention modulate step initiation postural adjustments in Parkinson freezers?

In view of freezing of gait's circumstances of occurrence in Parkinson's disease, attentional resources appear to be involved in step initiation failure. Anticipatory postural adjustments (APAs) are essential because they allow unloading of the stepping leg and so create the conditions required for progression. Our main objective was to establish whether or not a change in attentional load during step initiation modulates APAs differently in patients with vs. without freezing of gait. Three groups of 15 subjects were recruited: elderly people and parkinsonian patients with or without freezing of gait. Attention was modulated before step execution by means of an auditory oddball discrimination task with event-related potential recording. The primary endpoint was the occurrence of inappropriate APAs following the attentional task, i.e. APAs not followed by a step after an intercurrent auditory stimulus. In parkinsonian patients with freezing of gait, inappropriate APAs were recorded in 63% of the trials and were observed more frequently than in patients without freezing of gait (51%) and elderly controls (48%). Furthermore, inappropriate APAs in freezers were longer and more ample than in parkinsonian non-freezers and controls. Lastly, postural preparation was impaired in the parkinsonian patients.

Our results indicate that allocation of attentional resources during step preparation influences the release of APAs differently in freezers and non-freezers. Modulating attentional load is partly responsible for triggering an inappropriate motor program. This difficulty in focusing attention or resisting interference may contribute (at least in part) to the gait initiation failure observed in parkinsonian freezers.

Does tissue ischemia actually contribute to leak after sleeve gastrectomy?

Staple line leak, although rare, is among the most common postoperative complications after sleeve gastrectomy (SG) and usually occurs in the gastroesophageal (GE) junction. Increased intragastric pressure, regional ischemia, and technical failure of stapling devices have been reported as the main risk factors of postoperative leak. The aim of this study was to evaluate the impact of ischemia and intraluminal pressure in leak appearance. Landrace swine (n = 12) were subjected to SG and total gastrectomy subsequently. Lactic acid, glycerol, and pyruvate were measured by microdialysis in GE junction and pylorus before and nine times after operation, and lactate/pyruvate (L/P) ratio was calculated as well. Moreover, ex vivo air was insufflated inside the tubularized stomach till a rupture of the staple line occurs. Maximum air pressure reached and location of rupture were recorded. Increase of lactic acid and L/P ratio were demonstrated in GE junction measurements; however, when the measurements between GE junction and pylorus were compared, no statistically significant differences were found, with the exception of a slightly increased lactate concentration in pylorus in the midst of measurements. The maximum air pressure recorded varied from 3 to 75 mmHg (mean 24.5 mmHg) and the majority of ruptures (n = 8) occurred in GE junction. In one of them, clip displacement was noticed.

No evidence of increased ischemia in GE junction compared to pylorus was recorded. Increased intraluminal pressure and stapling malfunction may play the most important role in leak appearance.

Does expression pattern of GATA-3 in embryonic and fetal human skin suggest a role in epidermal and follicular morphogenesis?

The transcription factor GATA-3 was recently identified as a master regulator in the specification of the inner root sheath. Additionally, it seems to play a role in skin barrier physiology. p63 binds and transactivates the GATA-3 promoter. While the expression profile of GATA-3 is delineated for the mouse, little is known about its expression in the adult human hair follicle and no studies are published about its distribution during human cutaneous embryogenesis. We examined samples from embryonic, fetal and adult human skin for the expression of GATA-3 using immunohistochemistry. GATA-3 is expressed late during human skin development. Its expression pattern is comparable to the mouse and confined to the Huxley layer and inner root sheath cuticle but sparing the Henle layer. In addition, GATA-3 localizes to the spinous cell layer of the interfollicular epidermis.

From the described expression pattern, it is highly probable that GATA-3 plays a role in follicular and epidermal morphogenesis. What the anatomically confined expression of GATA-3 to the spinous layer means biologically for the physiology of the skin is still unclear. Likewise, it still needs to be shown if GATA-3 could be exploited in the diagnosis of adnexal neoplasms.

Can dual energy X-ray absorptiometry provide a valid assessment of changes in thigh muscle mass with strength training in older adults?

To determine how dual-energy X-ray absorptiometry (DXA) compares to computed tomography (CT) for measuring changes in total thigh skeletal muscle (SM) mass with strength training (ST) in older adults. Fifty previously sedentary, relatively healthy older men (n=23, 60 (s.d.=7.5) years) and women (n=27, 60 (s.d.=9.3) years). Results indicate that there was a significant increase in thigh SM mass with ST measured by both CT (3.9+/-0.4%) and DXA (2.9+/-0.6%) methods (both P<0.001), and there was not a significant difference in percent change between the two methods, although there was a substantial absolute difference ( approximately 2 kg) at baseline between the two methods. Although Bland-Altman plots indicate overall agreement between the percent thigh SM mass changes of DXA vs CT methods, the 3.4% error associated with DXA was greater than the thigh SM mass change from DXA. However, the CT measured change in thigh SM mass was greater than its error (0.6%).

DXA overestimates baseline and after ST thigh SM mass, and may not be able to detect small changes in thigh SM mass with ST due to its higher error. Although DXA has certain advantages that warrant is used in epidemiologic and intervention studies, improvements to DXA are needed for the accurate assessment of small changes in thigh SM mass.

Does prophylactic ibuprofen improve pain with IUD insertion : a randomized trial?

To evaluate if ibuprofen 800mg reduces pain with intrauterine device (IUD) insertion among U.S. women. We conducted a randomized, double-blind, placebo-controlled trial of women undergoing IUD insertion approximately 2-6weeks following first-trimester uterine aspiration. Subjects were randomized to receive ibuprofen 800mg or placebo 30-45min prior to IUD insertion. A 100-mm visual analog scale (VAS) was administered to measure pain after speculum insertion (baseline) and immediately following IUD insertion. A total of 202 women were enrolled, with 101 randomized to each group (ibuprofen or placebo). Sociodemographic characteristics and baseline VAS scores were similar between groups. The median pain score with IUD insertion was 41.5mm in the placebo group and 38.0mm in the ibuprofen group (p=.50). Mean and median pain scores did not differ between placebo and ibuprofen when nulliparous and parous women were analyzed independently. Overall, median pain scores were 17.5mm higher in nulliparous women than parous women (p=.004). Median pain scores did not differ by age, IUD-type, history of dysmenorrhea or time since aspiration.

Administration of ibuprofen 800mg prior to IUD insertion does not reduce pain associated with the procedure for U.S. women. Overall, nulliparous women report more pain with IUD insertion than multiparous women.

Does ursodeoxycholic acid improve cholestasis in infants with cystic fibrosis?

To describe two infants with cholestatic jaundice treated with ursodeoxycholic acid (UDCA). Two infants with cystic fibrosis (CF)-associated hepatobiliary disease, manifesting as cholestatic jaundice and elevated liver enzymes within the first 6 weeks of life, had improved biochemical indices of liver function following treatment with UDCA 20-40 mg/kg/d.

To our knowledge, this is the first report of UDCA treatment in infants with CF-associated cholestatic jaundice. Infants and children require treatment with increased doses of UDCA to compensate for reduced intestinal absorption of bile acid and immaturity of the enterohepatic circulation.

Does protein kinase C regulate prairie dog gallbladder ion transport?

Gallstone formation is characterized by increased biliary calcium (Ca2+) level and altered gallbladder absorption. Recent studies suggest that luminal Ca2+ regulates gallbladder ion transport via intracellular calcium ([Ca2+]ic). Ca2+-calmodulin and protein kinase C (PKC) are two major systems through which [Ca2+]ic carries out second-messenger functions in many cell types. We have previously shown that Ca2+-calmodulin regulates basal gallbladder ion transport in prairie dog. The present study tests the hypothesis that PKC is also essential in regulation of gallbladder ion transport in this model. The role of PKC in regulation of gallbladder ion transport was determined by studying the effects of phorbol esters, synthetic analogues of diacylglycerol, which directly activates PKC. Gallbladders were mounted in Ussing chambers, and standard electrophysiologic parameters were recorded after exposing tissues to either 10(-5) mol/L of 4-alpha-phorbol 12,13-didecanoate (PDD), 4-beta-phorbol 12-myristate 13-acetate, 4-beta-phorbol 12,13-dibutyrate (PDB), or 10(-4) mol/L serotonin. Unidirectional Na+, Cl-, and H2O fluxes were measured before and after treatment with only inactive PDD and most active PDB. Mucosal and serosal exposure of tissues to either 4-beta-phorbol 12-myristate 13-acetate or PDB resulted in a decrease in short-circuit current and transepithelial potential difference without any change in tissue resistance. Serotonin induced similar changes in gallbladder electrical properties. PDB caused an inhibition of mucosal to serosal fluxes of Na+, Cl-, and H2O, with a decrease in net Na+ absorption, an increase in net Cl- secretion, and a conversion of net H2O absorption to net H2O secretion. Serosal-to-mucosal fluxes of Na+, Cl-, and H2O did not change. Inactive PDD had no effect on either electrophysiologic parameters or ion and water fluxes. Pretreatment of tissues with PKC antagonist 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine blocked the phorbol ester-induced inhibition of ion transport.

PKC regulates gallbladder ion transport in the prairie dog by inhibiting Na+ absorption and stimulating Cl- secretion.

Do financial incentives of introducing case mix reimbursement increase feeding tube use in nursing home residents?

To determine whether adoption of Medicaid case mix reimbursement is associated with greater prevalence of feeding tube use in nursing home (NH) residents. Secondary analysis of longitudinal administrative data about the prevalence of feeding tube insertion and surveys of states' adoption of case mix reimbursement. NHs in the United States. NH residents at the time of NH inspection between 1993 and 2004. Facility prevalence of feeding tubes reported at the state inspection of NHs reported in the Online Survey, Certification and Reporting database and interviews with state policy makers regarding the adoption of case mix reimbursement. Between 1993 and 2004, 16 states adopted Resource Utilization Group case mix reimbursement. States varied in the prevalence of feeding tubes in their NHs. Although the use of feeding tube increased substantially over the years of the study, once temporal trends and facility fixed effects were accounted for, case mix reimbursement was not associated with greater prevalence of feeding tube use.

The adoption of Medicaid case mix reimbursement was not associated with an increase in the prevalence of feeding tube use.

Do fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer?

Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively.

Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.

Is Kidney Injury Molecule 1 a Valuable Tool for the Early Diagnosis of Contrast-Induced Nephropathy?

Three thousand two hundred patients who had undergone coronary angiography were included in the study. Thirty-two patients were diagnosed with CIN. Twenty patients who had undergone coronary angiography but did not have CIN were evaluated as a control group (n = 20). The diagnosis of CIN was performed according to the KDIGO 2012 Acute Kidney Injury Guideline criteria. Urinary KIM-1 levels were measured by enzyme-linked immunosorbent assay before as well as on the 6th and 48th hours of contrast exposure. Serum creatinine levels were measured before as well as on the 24th and 48th hours after angiographic procedure. We demonstrated that KIM-1 levels increased in the patients with CIN significantly on the sixth hour when compared with the baseline (P<0.01; median levels, 0.27 and 0.70 mg/dL) but not in the controls (P = 0.107). The precontrast and 48th-hour KIM-1 levels were median ones and were also significantly different (P = 0.001, the median levels were 0.27 and 0.60 mg/dL, respectively).

Because creatinine is a sensitive but a late marker of CIN, KIM-1 may be used for early diagnosis and early initiation of treatment and may reduce risk for morbidity.

Does patient safety concerns arising from test result that return after hospital discharge?

Failure to relay information about test results pending when patients are discharged from the hospital may pose an important patient-safety problem. Few data are available on the epidemiology of test results pending at discharge or on physician awareness of these results. To determine the prevalence, characteristics, and physician awareness of potentially actionable laboratory and radiologic test results returning after hospital discharge. Cross-sectional study. Two tertiary care academic hospitals. 2644 consecutive patients discharged from hospitalist services from February to June 2004. The main outcomes were the prevalence and characteristics of potentially actionable test results returning after hospital discharge, awareness of these results by inpatient and primary care physicians, and satisfaction of inpatient physicians with current systems for follow-up on test results. The authors prospectively collected data on test results pending at the time of discharge and, as results returned after discharge, surveyed hospitalists, junior residents, and primary care physicians about those results that were potentially actionable according to a physician-reviewer. A total of 1095 patients (41%) had 2033 test results return after discharge. Of these results, 191 (9.4% [95% CI, 8.0% to 11.0%]) were potentially actionable. Surveys were sent regarding 155 results, and 105 responses were returned. Of the 105 results in the surveys with responses, physicians had been unaware of 65 (61.6% [CI, 51.3% to 70.9%]); of these 65, they agreed with physician-reviewers that 24 (37.1% [CI, 25.7% to 50.2%]) were actionable and 8 (12.6% [CI, 6.4% to 23.3%]) required urgent action. Inpatient physicians were dissatisfied with their systems for following up on test results returning after discharge.

The authors were unable to determine whether physicians' lack of awareness of test results returning after discharge was associated with adverse outcomes.

Does unbiased analysis of pancreatic cancer radiation resistance reveal cholesterol biosynthesis as a novel target for radiosensitisation?

Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques. Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model. Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model.

Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

Is tRPV1 receptor blockade ineffective in different in vivo models of migraine?

It has been proposed that TRPV1 receptors may play a role modulating trigeminal sensory processing. We used models of trigeminovascular nociceptive activation to study the involvement of TRPV1 receptors in the rat. Due to a possible role of TRPV1 receptors in cortical spreading depression (CSD), an experimental phenomenon sharing many features with migraine aura, we also utilized a model of mechanically induced CSD. Male Sprague Dawley rats (N = 39) were anesthetized and cannulated for monitoring and drug administration to study the effects of the TRPV1 receptor antagonist A-993610 (8 mg kg(-1) IV). Wide-dynamic-range neurons, responding to electrical stimulation of the middle meningeal artery (MMA)/dura mater were identified and recorded using electrophysiological techniques. Intravital microscopy was used to study neurogenic dural vasodilation (NDV) of the MMA comparing capsaicin and electrical stimulation, and the effect of A-993610 on mechanically induced CSD was examined. Administration of A-993610 had no significant effect on trigeminal firing of A- or C-fibers elicited by electrical stimulation of the MMA. It also showed no effect on NDV whilst blocking vasodilation due to intravenous capsaicin injection. The mechanically induced CSD response could not be altered by A-993610 administration.

Although there is evidence that TRPV1 receptors play an important role in sensory processing in general, the new data do not support a role in the treatment of acute migraine.

Is the Lymphocyte-to-Monocyte Ratio a Superior Predictor of Overall Survival in Comparison to Established Biomarkers of Resectable Colorectal Cancer?

The study aims to investigate the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients with colorectal cancer (CRC) undergoing curative resection and to compare it to established biomarkers including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), modified Glasgow prognostic score (mGPS), and combined BRAF-mismatch repair (MMR) status. The prognostic significance of systemic inflammatory markers in CRC such as the NLR, PLR, and mGPS has been well defined. Commonly used genetic markers such as combined BRAF-MMR status have also been found to be prognostic. Recent evidence, although limited, suggests that the preoperative LMR may be prognostic in CRC. Data from the Northern Sydney Local Health District from January 1998 to December 2012 were retrospectively collected. Of 3281 consecutive patients identified, 1623 patients who underwent curative resection were deemed eligible for inclusion. The relation between the LMR, clinicopathologic variables, and other biomarkers were analyzed in Kaplan-Meier log-rank survival analysis and then multivariate Cox regression models looking for association with overall survival (OS). In multivariate analysis of all patients, elevated LMR was associated with better OS (hazard ratio 0.569, 95% confidence interval: 0.478-0.677, P < 0.001) independent of age (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and grade (P = 0.049). The NLR, PLR, and combined BRAF-MMR status were not independently significant. In multivariate subgroup analysis of 389 patients with mGPS, LMR remained the only independently significant biomarker (hazard ratio 0.620, 95% confidence interval: 0.437-0.880, P = 0.007).

The LMR is an independent predictor of OS in patients with CRC undergoing curative resection and appears to be superior to pre-existing biomarkers.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.

Are the effects of noradrenaline, adrenaline and dopamine infusions on VO2 and metabolism transient?

To determine whether noradrenaline, adrenaline and dopamine have persistent actions on VO2 and metabolism. Descriptive laboratory investigation. Laboratory of the Department of Anaesthesiology at a University Hospital. 9 volunteers. VO2 and the plasma concentration of glucose and free fatty acids were measured prior to and during a 4 h infusion of saline (control), noradrenaline (0.14 microgram/kg min) adrenaline (0.08 microgram/kg min) or dopamine (7 micrograms/kg min), n = 9 each. VO2 was measured using an open circuit gas exchange system. VO2 increased from 250 +/- 22 ml/min to 280 +/- 38 ml/min during noradrenaline, to 298 +/- 30 ml/min during adrenaline and to 292 +/- 39 ml/min during dopamine infusion. The plasma glucose concentration increased from 6.2 +/- 0.6 mmol/l to 8.8 +/- 0.8 mmol/l, 13.2 +/- 1.4 and 7.3 +/- 0.4 mmol/l during infusion of noradrenaline, adrenaline or dopamine, respectively. The plasma free fatty acid concentration increased from 0.28 +/- 0.10 mmol/l to 0.79 +/- 0.21 mmol/l during noradrenaline and to 0.52 +/- 0.09 mmol/l during dopamine. In contrast, free fatty acid values averaged baseline values at the end of the adrenaline infusion after an initial increase to 0.72 +/- 0.31 mmol/l.

Administration of noradrenaline, adrenaline or dopamine resulted in persistent increases in VO2 in volunteers. With the exception of the transient adrenaline effect on fatty acids the metabolic actions were steady during 4 h of adrenergic stimulation. Since the adrenergic effect on VO2 is persistent over time a similar action in patients (e.g. septic shock) during treatment with adrenoceptor agonists may be important. Thus, an increase in VO2 during therapy may not only reflect an oxygen debt but also a pharmacodynamic action of adrenoceptor mediated calorigenic and metabolic induction.

Quality of phonological representations: a window into the lexicon?

There is a great deal of evidence to support the robust relationship between phonological awareness and literacy development. Researchers are beginning to understand the relationship between the accuracy and distinctiveness of stored phonological representations and performance on phonological awareness tasks. However, many of the tasks currently used to assess the integrity of underlying representations are confounded by requiring spoken output. This paper describes the development of the Quality of Phonological Representations (QPR) task, a task that does not require speech output, and its evaluation in the context of a larger study examining predictors of literacy outcomes in Western Australia.METHODS & The QPR task was given as part of a larger task battery to a cohort of 235 mainstream children in the last term of their Preprimary year (average age = 5;5) and to 179 children at follow-up at the end of Year 2 (average age = 7;9).OUTCOMES & Normative data for both accuracy and reaction time are presented in percentile tables (appendix B). In their Preprimary year, children were able to identify correct productions of multi-syllabic words (hits) on average 87.5% of the time, rising to an average of 93.8% in Year 2. As expected, children became quicker at making these judgements, reaction time shifting from an average of 1.1 s in Preprimary to 0.83 s in Year 2. A similar pattern was observed with the data for correct rejections. To make these judgements, the children had to identify a pseudo-word as an incorrect pronunciation by 'Katie the computer'. In the Preprimary year, children were able to reject correctly the pseudo-words on average 68.5% of the time, rising to an average of 81.7% in Year 2. As expected, children became quicker at making these judgements, reaction time shortening from an average of 1.4 s in Preprimary to 0.81 s in Year 2. The QPR task was shown to have moderate reliability and concurrent validity.

The QPR task appears to be a useful and cost-effective addition to task batteries aiming to identify at-risk children in the early stages of schooling. The ability to profile children's phonological awareness skills and gain insight into their underlying phonological representation skills allows more informed goal setting and intervention planning.

Does the selective phosphodiesterase-5 inhibitor tadalafil induce microvascular and metabolic effects in type 2 diabetic postmenopausal females?

The objective of the study was to explore the acute in vivo effects of the selective phosphodiesterase-5 inhibitor tadalafil on local microcirculation and regional metabolism in skeletal muscle and adipose tissue (AT). We studied eight postmenopausal female patients with type 2 diabetes (T2D) and eight nondiabetic controls (Ctrl) in the postabsorptive state and 180 min after the administration of tadalafil 10 mg. Intramuscular and sc microdialysis were combined with measurements of forearm (FBF) and AT blood flow as well as with arterial and deep venous blood sampling. Muscle capillary recruitment, as ascertained by the permeability surface area product for glucose (PS(glu)), forearm glucose uptake (FGU), interstitial lactate, and glycerol concentrations, was measured. When compared with Ctrl, T2D patients exhibited lower (P = 0.01) PS(glu) but similar FGU and FBF. After tadalafil, PS(glu) (P = 0.01) and muscle interstitial-arterial (I-A) lactate concentration gradient (P < 0.01) increased significantly in both groups, whereas FBF, FGU, and I-A glycerol remained unchanged. In AT, tadalafil did not significantly affect local blood flow, whereas the sc interstitial (I) lactate and I-A lactate concentrations increased (P < 0.01), and the I-A glycerol decreased in both groups. Finally, in multivariate analysis the PS(glu) was a strong and independent predictor of muscle glucose disposal (β: 0.737 and 0.963, P < 0.05, in Ctrl and T2D, respectively).

Tadalafil emerges as an acutely acting modulator of microvascular recruitment and glucose metabolism in skeletal muscle and adipose tissue. We suggest that selective phosphodiesterase-5 blockade may provide a path forward to new therapeutics in the setting of insulin resistance.

Is nephronectin expression in glomeruli of renal biopsy specimens from various kidney diseases : nephronectin expressed in the mesangial matrix expansion of diabetic nephropathy?

In a previous proteomic study, we detected increased expression of nephronectin in the glomeruli from patients with diabetic nephropathy (DN). The aim of the present study was to clarify the usefulness of determining glomerular expression of nephronectin in kidney disease. We performed immunohistochemical staining for nephronectin in renal biopsy specimens from patients with a variety of kidney diseases (n = 190). The percentage of nephronectin-positive areas in the glomeruli was analyzed using an image analyzer. Nephronectin immunoreactivity was clearly, strongly positive in the mesangial expansion and nodular lesions of DN (n = 18), whereas nephronectin immunoreactivity was negative in IgA glomerulonephritis, membranoproliferative glomerulonephritis, lupus nephritis, membranous glomerulonephritis, minor glomerular abnormalities, crescentic glomerulonephritis, and other kidney diseases, such as amyloidosis and light chain deposition disease. Nephronectin was stained weakly in sclerotic lesions, such as focal segmental glomerulosclerosis and hypertensive nephropathy. The percentage of nephronectin-positive areas in the glomeruli from DN patients [15.1 ± 4.7% (n = 18)] was significantly higher than that for other kidney diseases [5.5 ± 3.6% (n = 172)] (p < 0.001). In multiple regression analyses, fasting plasma glucose and hemoglobin A1c were significantly associated with the increase in the percentage of nephronectin-positive areas in the glomeruli (β = 0.23, p < 0.001 and β = 0.16, p = 0.045, respectively).

The expression of nephronectin was sufficient to discriminate DN from other kidney diseases with mesangial matrix expansion and nodular lesions. We consider that nephronectin staining could be helpful in the diagnosis of DN.

Do thromboembolic events predispose the brain to widespread cerebral infarction after delayed transient global ischemia in rats?

Transient distal platelet accumulation after common carotid artery thrombosis (CCAT) leads to hemodynamic, metabolic, and molecular events that may influence the response of the postthrombotic brain to secondary insults. We investigated how a thromboembolic insult would affect histopathological outcome when combined with an ischemic insult induced 24 hours later. Three groups of rats underwent either (1) CCAT+10 minutes of normothermic 2-vessel occlusion (n=6), (2) CCAT+sham ischemia procedures (n=6), or (3) sham CCAT procedures+10 minutes of 2-vessel occlusion (n=6). At 7 days, rats were perfused for quantitative histopathological and immunocytochemical analysis. Rats undergoing combined insults (group 1) had significantly larger areas of ischemic injury (P<0.05) within the cerebral cortex, striatum, and thalamus compared with the other, single-injury groups. Increased ischemic damage included selective neuronal necrosis, infarction, and focal hemorrhage. By means of glial fibrillary acidic protein immunocytochemistry and lectin histochemistry, reactive astrocytes and microglia were found to be associated with widespread tissue necrosis. In contrast, infrequent infarction or CA1 hippocampal neuronal necrosis was observed in groups 2 and 3, respectively.

A prior thromboembolic event is a risk factor for widespread cerebral infarction and hemorrhage when combined with a delayed ischemic insult. The understanding of what factors enhance the susceptibility of the postthrombotic brain to secondary insults may aid in the development of neuroprotective strategies to be applied after transient ischemic attacks to prevent the initiation of stroke.

Are tablets a practical source of protein substitute in phenylketonuria?

A phenylalanine-free amino acid based protein substitute is necessary to provide the major source of protein in phenylketonuria (PKU). Protein substitutes in PKU are usually given as drinks. These are unpalatable and compliance is often poor. Tablets containing a suitable mixture of phenylalanine-free amino acids (Aminogran Food Supplement, UCB) are now available. To compare the effectiveness and acceptability of these tablets with conventional protein substitute drinks. Twenty one subjects with PKU, aged 8-25 years, participated in a randomised crossover study. During one phase, subjects received at least 40% of their protein substitute requirements from the amino acid tablets and the rest from their usual protein substitute tablets. During the other phase, they received their usual protein substitute. Each period lasted 12 weeks. Blood phenylalanine concentrations were measured at least once every two weeks and other plasma amino acids were measured at the beginning, at crossover, and at the end of the study. The subjects kept a diary of all protein substitute taken. Compliance appeared to be better with the new tablets than with patients' usual protein substitutes. Ninety per cent (18/20) recorded that they took the tablets as prescribed, compared with 65% (13/20) fully compliant with their usual protein substitute. Moreover, plasma phenyalanine was lower on the amino acid tablets, and the median difference in blood concentrations between the two groups was 46 micro mol/l (95% CI 14.8 to 89.0, p = 0.02). Tyrosine increased by a median of 16 micro mol/l daily on the amino acid tablets (95% CI 7.1 to 40.5, p = 0.01). Most subjects (70%) preferred incorporating the new tablets into their usual protein substitute regimen.

Amino acid tablets are an effective and relatively popular protein substitute in older children, teenagers, and adults with PKU.

Is Middle Ear Pressure Effected by Nasal Packings after Septoplasty?

To investigate the effects of different types of nasal packings on middle ear pressure in patients undergoing septoplasty. Sixty patients who were suffering from nasal obstruction and who had to undergo septoplasty because of nasal septal deviation were included in the study. After the septoplasty, Merocel packings and internal nasal splints were intraoperatively applied in thirty patients each. Middle ear pressure was evaluated by tympanometry. Tympanometric peak pressures were used for this aim. Acoustic impedance measurements were performed in both ears, and the average values of the two ears were calculated. Tympanometric measurements were performed for patients during the preoperative period and on the 2(nd) and 5(th) postoperative days. There were 30 (5 females, 25 males; average age 23 years) patients in the internal nasal splint group and 30 (8 females, 22 males; average age 26 years) patients in the anterior Merocel packing group. When the values obtained by acoustic impedancemetry before the operation and on the postoperative 5(th) day were compared, there was no statistically significant difference between the groups. The middle ear pressure significantly decreased in the anterior Merocel packing group compared with that in the internal nasal splint group. The intragroup comparison of the acoustic impedance measurements of the internal nasal splint group revealed no significant difference between the preoperative acoustic impedance values and the values obtained on the postoperative 2(nd) day.

Cannulated silicone intranasal splints are better in terms of patient comfort after an intranasal surgery without effecting eustachian tube function.

Is ovarian cancer cell invasiveness associated with discordant exosomal sequestration of Let-7 miRNA and miR-200?

The role of exosomes in the pathogenesis and metastatic spread of cancer remains to be fully elucidated. Recent studies support the hypothesis that the release of exosomes from cells modifies local extracellular conditions to promote cell growth and neovascularisation. In addition, exosomes may modify the phenotype of parent and/or target cell. For example, sequestration of signaling mediators into exosomes may reduce their intracellular bioavailability to the parent cell thereby altering cell phenotype and metastatic potential. The fusion of released exosomes with target cell and delivery may also modify cell function and activity. In this study, to further elucidate the role of exosomes in ovarian cancer, the release of exosomes from two ovarian cancer cell lines of different invasive capacity and their miRNA content of exosomes were compared. The hypothesis to be tested was that ovarian cancer cell invasiveness is associated with altered release of exosomes and discordant exosomal sequestration of miRNA. High (SKOV-3) and low (OVCAR-3) invasive ovarian cancer cell lines were used to characterize their exosome release. SKOV-3 and OVCAR-3 cells were cultured (DMEM, 20% exosome-free FBS) under an atmosphere of 8% O2 for 24 hours. Cell-conditioned media were collected and exosomes were isolated by differential and buoyant density centrifugation and characterised by Western blot (CD63 and CD9). Exosomal microRNA (let-7a-f and miR-200a-c) content was established by real-time PCR. Exosomes were identified with by the presence of typical cup-shaped spherical vesicle and the expression of exosome markers: CD63, CD9. SKOV-3 cells released 2.7-fold more exosomes (1.22 ± 0.11 μg/106 cells) compared to OVCAR-3 (0.44 ± 0.05 μg/106 cells). The let-7 family miRNA transcripts were identified in both ovarian cancer cell lines and their exosomes. The let-7 family transcripts were more abundant in OVCAR-3 cell than SKOV-3 cells. In contrast, let-7 family transcripts were more abundant in exosomes from SKOV-3 than OVCAR-3. miR-200 family transcripts were only identified in OVCAR-3 cells and their exosomes.

The data obtained in this study are consistent with the hypothesis that the releases of exosomes varies significantly between ovarian cancer cell lines and correlates with their invasive potential.

Is a proapoptotic caspase recruitment domain protein gene , TMS1 , hypermethylated in human breast and gastric cancers?

Conway et al. demonstrated that methylation of the proapoptotic gene, TMS1, was observed in breast cancer cell lines and tissues, resulting in decreased TMS1 gene transcription. However, whether the TMS1 gene is hypermethylated in other cancers is uncertain. The expression of TMS1 mRNA was determined by quantitative RT-PCR. Methylation of the TMS1 gene was detected using methylation-specific PCR followed by bisulfite-modification of DNA. Methylation of the TMS1 gene was observed in breast, gastric and colorectal cancer cells. Down-regulation of TMS1 gene transcription in colorectal cancer cells was restored by treatment with a demethylating agent. Methylation of the TMS1 gene was observed in 2 out of 19 breast cancer specimens and 1 out of 9 gastric cancers, but in none of 13 colorectal cancers.

These results suggest a direct role for aberrant methylation of the TMS1 gene in the progression of breast and gastric cancer involving down-regulation of the proapoptotic TMS1 gene.

Is rat duodenal iron-binding protein mobilferrin a homologue of calreticulin?

Mobilferrin is a water soluble 56-kilodalton protein isolated from human and rat duodenal mucosa. It binds iron and other transitional metals in vivo and in vitro and is postulated to play a role in their absorption and intracellular metabolism. The purpose of this study was to characterize mobilferrin. Mobilferrin was characterized by identification of the N-terminal amino acid sequence, two-dimensional protein electrophoresis, and studies of mobilferrin and homologues using anti-mobilferrin antibody and competitive metal binding. The N-terminal amino acid sequence of mobilferrin was Asp-Pro-Ala-Ile-Tyr-Phe-Lys-Glu-Gln-Phe-Leu-Asp-Gly-Asp-Ala-Ser-Thr- and is a homologue of calreticulin (calregulin). The proteins had a similar molecular mass (56 kilodalton) and isoelectric point (4.7). Anti-mobilferrin antibodies react with calreticulin. Both proteins bind iron and calcium but have a greater affinity for iron.

Mobilferrin and calreticulin are homologues that bind iron with greater affinity than calcium and other transitional metals. Competitive binding of metals by mobilferrin provides insight into the absorptive pathway shared by both essential and toxic transitional metals.

Does the endotracheal tube move more often in obese patients undergoing laparoscopy compared with open abdominal surgery?

We compared the incidence of movements of the endotracheal tube (ETT) within the trachea in morbidly obese patients undergoing either laparoscopic or open gastroplasty. In a double-blinded, prospective, controlled study, 60 patients (body mass index, 35-60 kg/m(2)) were equally allocated to either laparoscopic LapBand gastroplasty (study group; Group 1) or open laparotomy gastroplasty (control; Group 2), both under standardized general anesthesia. Movements of the ETT were assessed with chest auscultation, peak inspiratory pressure, ETCO(2), SpO(2), and the Rapiscope at predetermined time points: after intubation (baseline values), 5 min before peritoneal inflation in Group 1 and 10 min postintubation in Group 2, at maximal abdominal inflation in Group 1 and 20 min into the procedure in Group 2, 5 min before and 5 min after changing the patient's position from neutral to 10 degrees head up and 10 degrees head down in Group 1 and 30 and 40 min into the procedure in Group 2, 2 min after abdominal deflation and table repositioning in Group 1 and at 50 min in Group 2, and just before extubation in both groups. Twenty-one events of ETT tip movement occurred in both groups. The tube moved in 15 (50%) study (laparoscopy) group patients compared with 6 (20%) controls (laparotomy; P < 0.05), 12 of the former having moved downward either after maximal abdominal insufflation or in association with head-down positioning. The tubes of five study group patients (17%) advanced into the right bronchus, compared with none in the controls (P < 0.05). All changes in position were rectified only by the Rapiscope.

Abdominal insufflation and changes in table position lead to more frequent movements of the endotracheal tube in obese patients undergoing laparoscopic versus open gastroplasty. The Rapiscope identifies all these changes, but not the clinically available variables.

Are prostatic luminal cell differentiation and prostatic steroid-binding protein ( PBP ) gene expression differentially affected by neonatal castration?

Although normal prostatic development is androgen-dependent, the prostate continues to grow in the neonate despite castration. However, the manner in which neonatal growth of the prostate occurs, in the absence of the testis, remains largely unknown. The purpose of this study was to examine the differentiation of prostatic epithelial cells after neonatal castration. Immunohistochemistry was utilized to detect the expression of differentiation products: basal-cell cytokeratin (CK 5), luminal-cell cytokeratin (CK 18), and prostatic steroid-binding protein (PBP), a ventral prostate-specific marker indicative of secretory function in luminal cells. The reverse transcription-polymerase chain reaction was used to detect transcription products of the three polypeptide subunits of PBP, designated C1, C2, and C3. Rats were castrated on day 5 after birth, and ventral prostates were collected on day 14. Dihydrotestosterone was injected (100 microg/animal every 2 days) in castrated animals to determine if PBP expression could be initiated by androgen. Although no major effects of castration were detected on the differentiation of stromal or basal cells (which differentiate prior to day 5), castration had a pronounced effect on luminal-cell differentiation. Castration inhibited PBP protein expression, but did not affect the expression of luminal-cell cytokeratin (CK 18) protein. Furthermore, castration reduced C1, C2, and C3 transcription. Androgen replacement to castrated animals allowed for the initiation of PBP expression, although its onset was delayed.

These observations indicate that the testis is not necessary for prostatic luminal-cell differentiation, but is necessary for full expression of luminal-cell secretory phenotype. Furthermore, our study suggests that factors of testicular origin, in addition to androgen, are needed for proper timing of PBP expression. This investigation establishes that the cytological and the physiological differentiation of the rat prostate are differentially regulated.

Does increased activation of the anterior cingulate cortex during processing of disgust face in individuals with social phobia?

Researchers have examined the role of differential activation of various brain regions involved in processing emotional information in subjects with social phobia. These studies have focused mostly on the activation of the amygdala. The anterior cingulate cortex (ACC) also has been implicated in processing emotional information, but its role in social phobia has not been examined. We recruited subjects with social phobia and matched them with non-anxious control subjects. Participants viewed facial expressions of disgust ("disgust faces") and neutral facial expressions ("neutral faces"). We measured brain activation, focusing on the ACC, using functional magnetic resonance imaging. We also recorded participants' ratings of emotional valence of faces, as well as response latencies to make these valence judgments. We repeated this procedure using three different sets of facial expressions. Individuals with social phobia exhibited a significant increase in ACC activity compared with non-anxious control subjects when processing disgust versus neutral faces. Additionally, compared with control subjects, subjects with social phobia were faster in their ratings of disgust faces and rated the neutral faces more negatively.

Our findings demonstrate that the ACC might be involved in affective processing of negative information in socially phobic subjects.

Ileocolic versus small-bowel intussusception in children: can US enable reliable differentiation?

To assess clinical and ultrasonographic (US) criteria that can be used to confidently differentiate ileocolic from small-bowel intussusception. Institutional review board approval was obtained for this retrospective study, and the need to obtain informed consent was waived. US and clinical data for children given a diagnosis of intussusception in the years 2007 through 2011 were evaluated. The diameters of the intussusception and the inner fat core, the outer bowel wall thickness, and the presence or absence of lymph nodes inside the intussusception and mesentery were noted. The Student t test, the Mann-Whitney test, and the Levene test were used for comparison of parametric variables, while the χ(2) and Fisher exact tests were used for comparison of categoric data. There were 200 cases of intussusception in 174 patients (126 boys, 48 girls; mean age, 17.2 months (range, 0 years to 7 years 1 month); 57 (28.5%) were small-bowel and 143 (71.5%) were ileocolic intussusceptions. Mean lesion diameter was 2.63 cm (range, 1.3-4.0 cm) for ileocolic versus 1.42 cm (range, 0.8-3.0 cm) for small-bowel intussusception (P<.0001). Mean fat core diameter was 1.32 cm (range, 0.6-2.2 cm) for ileocolic versus 0.1 cm (range, 0-0.75 cm) for small-bowel intussusception (P<.0001). The ratio of inner fat core diameter to outer wall thickness was greater than 1.0 in all ileocolic intussusceptions and was less than 1.0 in all small-bowel intussusceptions (P<.0001). Lymph nodes inside the lesion were seen in 128 (89.5%) of the 143 ileocolic intussusceptions versus in eight (14.0%) of the 57 small-bowel intussusceptions (P<.0001). Children with ileocolic intussusception had more severe clinical symptoms and signs, with more vomiting (P = .003), leukocytosis (P = .003), and blood in the stool (P = .00005).

The presence of an inner fatty core in the intussusception, lesion diameter, wall thickness, the ratio of fatty core thickness to outer wall thickness, and the presence of lymph nodes in the lesion may enable reliable differentiation between ileocolic and small-bowel intussusceptions.

Abundant immunoglobulin (Ig)G4-positive plasma cells in interstitial pneumonia without extrathoracic lesions of IgG4-related disease: is this finding specific to IgG4-related lung disease?

There have been few reports on immunoglobulin-G4 (IgG4)-related interstitial pneumonia (IP), and its clinical features remain unclear. The objective of this study was to assess whether IP with marked IgG4-positive plasma cell infiltration without extrathoracic lesions of IgG4-related disease (RD) should be diagnosed as a subtype of IgG4-RD or a separate entity. All consecutive patients with surgical lung biopsy-proven idiopathic IP with an IgG4/IgG-positive cell ratio of>40% and>50 IgG4+plasma cells in a high-power field without extrathoracic lesions of IgG4-RD were reviewed retrospectively. Five patients were enrolled into this study. All patients were male with a history of smoking. Four patients met the comprehensive diagnostic criteria for IgG4-RD. The remaining patient lacked data related to the serum IgG4 level. Histologically, a non-specific IP pattern was observed in all patients. The key morphological features of IgG4-RD, such as storiform fibrosis and obliterative phlebitis with lymphoplasmacytic infiltration in a loose background texture, were absent in every patient. In contrast, venule obstruction by densely packed lymphoplasmacytic infiltration was observed in two patients. Marked scarring and remodelling of the lung were also noted, which is not seen typically in IgG4-RD. A favourable response to corticosteroid monotherapy was observed in all patients; however, two patients developed lung cancer during the course of observation.

IP with marked IgG4-positive plasma cell infiltration without extrathoracic lesions of IgG4-RD had different pathological features from those of IgG4-RD, and it is appropriate to regard this as a separate entity.

Do physicians have a responsibility to provide futile or unreasonable care if a patient or family insists?

This article was written to argue that physicians are not ethically obligated to provide care which they consider futile, unreasonable, or both, either voluntarily or in response to patient or surrogate demands. Data used to prepare this article were drawn from published articles, including original investigations, position papers and editorials in the author's personal files. Articles were selected for their relevance to the subjects of medical ethics, the concepts of futility and medical reasonableness, case law, and healthcare reform. The author extracted all applicable data. Physicians may feel obligated to provide care in all clinical circumstances due to the single master view of medicine and the ethical principle of autonomy. However, care may be considered futile according to several definitions of that word, including that which describes futile treatment as something that does not benefit the patient as a whole. Furthermore, care may be considered unreasonable if it is excessive and not generally agreed upon. Physician refusal to provide futile or unreasonable care is supported by the ethical principles of nonmaleficence, beneficence, and distributive justice. The last principle is particularly relevant in the current climate of healthcare reform.

Although the issue of physician refusal of requested care has not been resolved by case law or legal statute, it is supported by compelling ethical principles. Physicians are not ethically required to provide futile or unreasonable care, especially to patients who are brain dead, vegetative, critically or terminally ill with little chance of recovery, and unlikely to benefit from cardiopulmonary resuscitation.

Do concussion History and Time Since Concussion Influence Static and Dynamic Balance in Collegiate Athletes?

Dynamic balance deficits exist following a concussion, sometimes years after injury. However, clinicians lack practical tools for assessing dynamic balance. To determine if there are significant differences in static and dynamic balance performance between individuals with and without a history of concussion. Cross sectional Setting: Clinical research laboratory. Forty-five collegiate student-athletes with a history of concussion (Hx) (23 males, 22 females; age=20.0±1.4 years; height=175.8±11.6 cm; mass=76.4±19.2 kg) and 45 matched controls with no history of concussion (23 males, 22 females; age=20.0±1.3 years; height=178.8±13.2 cm; mass=75.7±18.2 kg). Intrventions: Participants completed a static (Balance Error Scoring System) and dynamic (Y Balance Test-Lower Quarter) balance assessment. A composite score was calculated from the mean normalized Y Balance Test-Lower Quarter reach distances. Firm, foam, and overall errors were counted during the Balance Error Scoring System by a single reliable rater. One-way ANOVAs were used to compare balance performance between groups. Pearson's correlations were performed to determine the relationship between the time since the most recent concussion and balance performance. A Bonferonni adjusted a priori alpha α<0.025 was used for all analyses. Static and dynamic balance performance did not significantly differ between groups. No significant correlation was found between the time since the most recent concussion and balance performance.

Collegiate athletes with a history of concussion do not present with static or dynamic balance deficits when measured using clinical assessments. More research is needed to determine whether the Y Balance Test-Lower Quarter is sensitive to acute balance deficits following concussion.

Does vacuum-assisted wound closure achieve early fascial closure of open abdomens after severe trauma?

This study reviews the efficacy of vacuum-assisted wound closure (VAWC) to obtain primary fascial closure of open abdomens after severe trauma. The study population included shock resuscitation patients who had open abdomens treated with VAWC. The VAWC dressing was changed at 2- to 3-day intervals and downsized as fascial closure was completed with interrupted suture. The Trauma Research Database and the medical records were reviewed for pertinent data. Over 26 months, 35 patients with open abdomens were managed by VAWC. Six died early, leaving 29 patients who were discharged. Of these, 25 (86%) were successfully closed using VAWC at a mean of 7 +/- 1 days (range, 3-18 days). Of the four patients that failed VAWC, two developed fistulas. No patients developed evisceration, intra-abdominal abscess, or wound infection.

VAWC achieved early fascial closure in a high percentage of open abdomens, with an acceptable rate of complications.

Is impact of maternal diabetes on birthweight greater in non-Hispanic blacks than in non-Hispanic whites?

To determine the impact of maternal diabetes during pregnancy on racial disparities in fetal growth. Using linked birth certificate, inpatient hospital and prenatal claims data we examined live singleton births of mothers resident in South Carolina who self-reported their race as non-Hispanic white (NHW; n = 140,128) or non-Hispanic black (NHB; n = 82,492) and delivered at 28-42 weeks' gestation between 2004 and 2008. Prepregnancy diabetes prevalence was higher in NHB (3.0%) than in NHW (1.7%), while the prevalence of gestational diabetes mellitus (GDM) was similar in NHB (6.1%) and NHW (6.3%). At a delivery BMI of 35 kg/m(2), GDM exposure was associated with an average birthweight only 17 g (95% CI 4, 30) higher in NHW, but 78 g (95% CI 61, 95) higher in NHB (controlling for gestational age, maternal age, infant sex and availability of information on prenatal care). Figures for prepregnancy diabetes were 58 g (95% CI 34, 81) in NHW and 60 g (95% CI 37, 84) in NHB. GDM had a greater impact on birthweight in NHB than in NHW (60 g racial difference [95% CI 39, 82]), while prepregnancy diabetes had a large but similar impact. Similarly, the RR for GDM of having a large- relative to a normal-weight-for-gestational-age infant was lower in NHW (RR 1.41 [95% CI 1.34, 1.49]) than in NHB (RR 2.24 [95% CI 2.05, 2.46]).

These data suggest that the negative effects of GDM combined with obesity during pregnancy may be greater in NHB than in NHW individuals.

Is the glabellar reflex a poor measure of Parkinson motor severity?

The glabellar reflex (GR) is often interpreted as a clinical measure of parkinsonism, although data to support this are weak. It is one of ten items used in the Simpson Angus Scale, a popular measure of parkinsonism in psychiatric studies of neuroleptic drugs. We hypothesized that the GR might be a measure of hypomimia. This was a chart review of 99 consecutive patients with idiopathic Parkinson's disease (PD) seen in a movement disorders center. All patients had standard Unified Parkinson's Disease Rating Scale (UPDRS) motor scale assessments in addition to a standardized assessment of the glabellar reflex (GR). We compared the number of blinks to the hypomimia score (item 2 on UPDRS motor scale) and other measures of PD severity. We found that there was a statistically significant but weak correlation between the GR blink number and hypomimia as well as the total score on the UPDRS motor section. We also found that the blink number was widely discrepant for an individual hypomimia score.

The GR is not a useful measure of hypomimia or motor severity in PD.

Is role of C6ORF120 , an N-glycosylated protein , implicated in apoptosis of CD4⁺ T lymphocytes?

Although CD4(+) T cell apoptosis and CD8(+) T cell responses have been extensively studied during HIV infection, how apoptosis signals being initiated in CD4(+) T cells still need to be elucidated. The present study was designed to characterize the function-unknown gene, C6orf120, and elucidates its primary role in tunicamycin-induced CD4(+) T apoptosis. The C6orf120 coding sequence was amplified from peripheral blood mononuclear cells (PBMCs) total RNA of AIDS patients. The DNA fragment was inserted into the pET-32a expression system, transformed into Escherichia coli, and preparation of C6ORF120 recombinant protein. The magnetic cell separation technology was used to prepare primary CD4(+) T cells and CD8(+) T cells. The primary T cells were cultured at 1 × 10(6) cells/ml, treated with 0, 0.1, 1, 10, 100, and 200 ng/ml of C6orf120 recombinant protein for 48 hours, then harvested for cell cycle and apoptosis analysis. Tunicamycin (0.5 µmol/L) was used to induce endoplasmic reticulum stress in Jurkat cells. The biomarker 78 KDa glucose-regulated protein (GRp78) and growth arrest and DNA damage (GADD) were used to evaluate endoplasmic reticulum stress of Jurkat cells. We prepared C6ORF120 recombinant protein and its polyclonal antibody. Immunohistochemical analysis showed that C6orf120 mainly expressed in hepatocytes and cells in germinal center of lymph node. At concentration of 0.1, 1, 10, 100, and 200 ng/ml, C6orf120 recombinant protein could induce apoptosis of Jurkat cells and primary CD4(+) T cells, and promoting G2 phase of its cell cycle. Western blotting analysis showed that C6ORF120 recombinant protein increased the expression of GRp78 and GADD in Jurkat cells in vitro.

Our results suggested that C6ORF120 could induce apoptosis of CD4(+) T cells, at least in part, mediated with endoplasmic reticulum stress.

Does acute ketamine challenge increase resting state prefrontal-hippocampal connectivity in both humans and rats?

Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders. We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe. Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity. In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia.

This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.

Does assessment of pretest probability of disease improve the utility of echocardiography in suspected endocarditis in children?

To compare the yield rate (YR) of echocardiography when evaluating children with suspected infectious endocarditis (IE) in both the actual clinical setting and in the hypothetic setting where strict clinical criteria are applied. Study design Medical records of 101 children undergoing echocardiography for suspected IE were reviewed. Echocardiograms with positive findings were identified and the actual diagnostic YR was calculated. With the use of clinical criteria proposed by von Reyn (VR), the probability of IE was retrospectively classified as (1) rejected, (2) possible, or (3) probable. Theoretic YR of echocardiography was calculated for each classification. The actual YR of echocardiography was 12% (12/101). The YR of echocardiography by VR class was 0% in rejected, 20% in possible, and 80% in probable cases (chi(2) = 55.1, P<.0001). Echocardiography did not change the probability of IE in any patient classified as rejected, but allowed reassignment of disease probability in a significant proportion of patients with possible or probable IE.

The YR of echocardiography was significant when clinical probability of IE was intermediate-to-high, and low, with marginal clinical utility, when clinical probability was low. Strict pretest assessment of disease probability may lead to more effective utilization of echocardiography in this population.

Can rescaling dose of dialysis to body surface area in the HEMO study explain the different responses to dose in women versus men?

In the Hemodialysis (HEMO) Study, the lower death rate in women but not in men assigned to the higher dose (Kt/V) could have resulted from use of "V" as the normalizing factor, since women have a lower anthropometric V per unit of surface area (V/SA) than men.DESIGN, SETTING, PARTICIPANTS, & The effect of Kt/V on mortality was re-examined after normalizing for surface area and expressing dose as surface area normalized standard Kt/V (SAn-stdKt/V). Both men and women in the high-dose group received approximately 16% more dialysis (when expressed as SAn-stdKt/V) than the controls. SAn-stdKt/V clustered into three levels: 2.14/wk for conventional dose women, 2.44/wk for conventional dose men or 2.46/wk for high-dose women, and 2.80/wk for high-dose men. V/SA was associated with the effect of dose assignment on the risk of death; above 20 L/m(2), the mortality hazard ratio = 1.23 (0.99 to 1.53); below 20 L/m(2), hazard ratio = 0.78 (0.65 to 0.95), P = 0.002. Within gender, V/SA did not modify the effect of dose on mortality.

When normalized to body surface area rather than V, the dose of dialysis in women in the HEMO Study was substantially lower than in men. The lowest surface-area-normalized dose was received by women randomized to the conventional dose arm, possibly explaining the sex-specific response to dialysis dose. Results are consistent with the hypothesis that when dialysis dose is expressed as Kt/V, women, due to their lower V/SA ratio, require a higher amount than men.

Does nerve growth factor enhance cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms?

Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia but its role in cough is unknown. In this study the effects of NGF on the cough reflex and airway calibre were investigated in guinea pigs. The involvement of the tropomyosin-related kinase A (TrkA) receptor and transient receptor potential vanilloid-1 (TRPV1), and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway in any NGF-induced effects on cough and airway obstruction was also assessed. Guinea pigs were placed in a transparent whole-body plethysmograph box. Cough was assessed visually, acoustically and by analysis of the airflow signal. Airway obstruction was measured using enhanced pause (Penh) as an index. Exposure of guinea pigs to NGF did not induce a cough response nor a significant airway obstruction. However, exposure of guinea pigs to NGF immediately before citric acid inhalation resulted in a significant increase in the citric acid-induced cough and airway obstruction compared with vehicle-treated animals. Pretreatment with the TrkA receptor antagonist, K252a, or the TRPV1 antagonist, iodoresiniferatoxin, significantly inhibited the NGF-enhanced cough and airway obstruction. Exposure to NGF also increased p38 MAPK phosphorylation, but pretreatment with the p38 MAPK inhibitor, SB203580, did not affect either the NGF-enhanced cough or airway obstruction despite preventing the NGF-induced elevation in p38 MAPK phosphorylation.

The data show that NGF can enhance both cough and airway obstruction via a mechanism that involves the activation of the TrkA receptor and TRPV1 but not the p38 MAPK-dependent pathway.

Does novel KCNA5 mutation implicate tyrosine kinase signaling in human atrial fibrillation?

Emerging evidence has strongly implicated hereditary determinants for atrial fibrillation (AF). Loss-of-function mutations in KCNA5 encoding the ultrarapid delayed rectifier potassium current I(Kur) have been identified in AF families. The purpose of this study was to determine the clinical and biophysical phenotypes in a KCNA5 mutation with deletion of 11 amino acids in the N-terminus of the protein, which was identified in patients with lone AF. Patients with AF confirmed by ECG were prospectively enrolled in the Vanderbilt AF Registry, which comprises clinical and genetic databases. A KCNA5 mutation was generated by mutagenesis for electrophysiologic characterization. We identified a novel 33-bp coding region deletion in two Caucasian probands. One proband was part of a kindred that included four other members with AF, and all were mutation carriers. The mutation results in deletion of 11 amino acids in the N-terminus of the protein, a proline-rich region as a binding site for Src homology 3 (SH3) domains associated with Src-family protein tyrosine kinase (TK) pathway. In transfected cells, the mutant caused approximately 60% decreased I(Kur) versus wild-type (WT) (75 +/- 8 pA/pF vs 180 +/- 15 pA/pF, P <.01) and dominant-negative effect on WT current (105 +/- 10 pA/pF, P <.01). Pretreatment with the Src inhibitor PP2 prevented v-Src TK from 90% suppressed WT current. In contrast, the mutant channel displayed no response to v-Src TK.

Our data implicate abnormal atrial repolarization control due to variable TK signaling as a mechanism in familial AF and thereby suggest a role for modulation of this pathway in AF and its treatment.

Is acute electrical isolation a necessary but insufficient endpoint for achieving durable PV isolation : the importance of closing the visual gap?

Temporary, ablation-mediated effects such as oedema may cause reversible pulmonary vein (PV) isolation. To investigate this, point-by-point circumferential ablation was performed to achieve acute electrical PV isolation with an incomplete circumferential ablation line. Then, the impact of this intentional 'visual gap' (ViG) on the conduction properties of the ablation lesion set was assessed with adenosine and pacing manoeuvres. Twenty-eight patients undergoing ablation for paroxysmal (n= 20) or persistent atrial fibrillation (n= 8) were included. Pulmonary vein (PV) ablation was performed around ipsilateral vein pairs. Once acute isolation was achieved, ablation was halted and the presence and size of the ViG were calculated. The ViG electrophysiological properties were tested with pace capture along the ViG at 10 mA/2 ms, and assessment for dormant PV conduction with adenosine. Despite electrical isolation, a ViG was present in 75% (n= 42/56) of vein pairs (21 of 28 left PVs and 21 of 28 right PVs). There was no difference in the ViG size between the left and right PVs (22.1 ± 14.2 and 17.3 ± 11.3 mm, P > 0.05). Dormant PV connections were revealed by adenosine in more than a quarter (n= 12/42) of acutely isolated PV pairs, of which the majority were dependent on conduction through the ViG.

Electrical PV isolation can usually be achieved without complete circumferential ablation. However, more than a quarter of these 'isolated' PVs exhibit dormant conduction-predominantly via the un-ablated 'ViGs' in the ablation lesion set. These findings support the hypothesis that reversible tissue injury contributes to PV isolation that may be acute but not necessarily durable.

Does intracavernosal injection of vascular endothelial growth factor induce nitric oxide synthase isoforms?

To identify genes that are affected by vascular endothelial growth factor (VEGF), as an intracavernosal injection with VEGF improved the recovery of erectile function in a rat model of arteriogenic impotence, specifically examining the three nitric oxide synthase (NOS) genes, nNOS, eNOS, and iNOS. Male rats had their pudendal arteries ligated or underwent a sham operation. They were then treated by an intracavernosal injection with 4 microg of VEGF in phosphate-buffered saline (PBS) or PBS alone. At 6 and 24 h after treatment electrostimulation was applied to the cavernosal nerve and the intracorporal pressure measured. The erectile tissue was then harvested for RNA isolation and cryo-sectioning. The isolated RNA was used for microarray and reverse transcription-polymerase chain reaction (RT-PCR) analyses, and the tissue sections for immunohistochemical analysis. Microarray analysis detected nNOS, eNOS and iNOS at very low expression levels in PBS-treated rats; expression levels were higher for eNOS and iNOS in all VEGF-treated rats. These results were further confirmed by RT-PCR analysis. Immunohistochemical analysis identified the cavernosal endothelium and smooth muscle as the tissue types where eNOS and iNOS were up-regulated, respectively.

This is the first report of the induction of both eNOS and iNOS in the penis after intracavernosal VEGF. These events may help support a significant recovery of erectile function after interrupting the blood supply to the penis.

Channeling consumers to preferred providers and the impact of status quo bias: does type of provider matter?

To effectively bargain about the price and quality of health services, health insurers need to successfully channel their enrollees. Little is known about consumer sensitivity to different channeling incentives. In particular, the impact of status quo bias, which is expected to differ between different provider types, can play a large role in insurers' channeling ability. To examine consumer sensitivity to channeling strategies and to analyze the impact of status quo bias for different provider types.DATA SOURCES/ With a large-scale discrete choice experiment, we investigate the impact of channeling incentives on choices for pharmacies and general practitioners (GPs). Survey data were obtained among a representative Dutch household panel (n = 2,500). Negative financial incentives have a two to three times larger impact on provider choice than positive ones. Positive financial incentives have a relatively small impact on GP choice, while the impact of qualitative incentives is relatively large. Status quo bias has a large impact on provider choice, which is more prominent in the case of GPs than in the case of pharmacies.

The large impact of the status quo bias makes channeling consumers away from their current providers a daunting task, particularly in the case of GPs.

Does luffa operculata affect mucociliary function of the isolated frog palate?

Luffa operculata is a medicinal plant used in homeopathic and alternative medicine. In the United States, it is sold in a purified spray form, whereas a homemade L. operculata dry fruit infusion (DFI) is commonly used in Latin America. The L. operculata DFI is applied intranasally, inducing profuse mucous secretion and relieving nasal symptoms. Nevertheless, this medication may cause irritation of the nasal mucosa, as well as epistaxis or anosmia. Given the growing popularity of alternative medicine, a decision was made to evaluate the effects of this substance on mucous membranes. The effects of L. operculata DFI on mucociliary transport velocity, ciliary beat frequency, and transepithelial potential difference (PD) were evaluated in an isolated frog palate preparation. We tested 46 palates immediately before immersion and again at 5 and 20 minutes after immersion. Four groups (n = 10) were tested in frog Ringer: control; L. operculata DFI, 60 mg/L; 600 mg/L; and 1200 mg/L. An additional group was tested using L. operculata DFI prepared with water (600 mg/L of H2O, n = 6). Epithelial samples were harvested for ultrastructural study. In treated palates, mucociliary transport velocity and ciliary beat frequency decreased significantly (p < 0.001 and p < 0.008, respectively). There was a dose-dependent decrease in PD modulus (p < .007). Our PD findings indicated ion-fluid transport abnormalities, which were confirmed by transmission electron microscopy that showed enlargement of interepithelial spaces.

In this ex vivo model, the L. operculata DFI infusion promoted significant changes in the mucociliary function of the epithelium, suggesting that it is potentially noxious to human nasal mucosa.

Does 7-Chloroarctinone-b as a new selective PPARgamma antagonist potently block adipocyte differentiation?

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a therapeutic target for obesity, cancer and diabetes mellitus. In order to develop potent lead compounds for obesity treatment, we screened a natural product library for novel PPARgamma antagonists with inhibitory effects on adipocyte differentiation. Surface plasmon resonance (SPR) technology and cell-based transactivation assay were used to screen for PPARgamma antagonists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARgamma/RXRalpha heterodimerization and PPARgamma co-activator recruitment using yeast two-hybrid assay, Gal4/UAS cell-based assay and SPR based assay. The 3T3-L1 cell differentiation assay was used to evaluate the effect of the active compound on adipocyte differentiation. A new thiophene-acetylene type of natural product, 7-chloroarctinone-b (CAB), isolated from the roots of Rhaponticum uniflorum, was discovered as a novel PPARgamma antagonist capable of inhibiting rosiglitazone-induced PPARgamma transcriptional activity. SPR analysis suggested that CAB bound tightly to PPARgamma and considerably antagonized the potent PPARgamma agonist rosiglitazone-stimulated PPARgamma-LBD/RXRalpha-LBD binding. Gal4/UAS and yeast two-hybrid assays were used to evaluate the antagonistic activity of CAB on rosiglitazone-induced recruitment of the coactivator for PPARgamma. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture.

CAB shows antagonistic activity to PPARgamma and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.

Does lack of expression of HLA antigens on immature germ cells from ejaculate with antisperm antibodies?

The lack of expression of HLA antigen on immature germ cells from ejaculates with antisperm antibodies has been reported. The expression of human leukocyte antigens on immature germ cells from ejaculates with antisperm antibodies (ASA) was investigated by indirect immunofluorescence using a panel of monoclonal antibodies (MAb) and automated flow cytometry. Patients were divided into two groups: fertile (prevasectomic; N = 10), and ejaculates with ASA (10 samples with IgG and IgA ASA, and five semen samples with only IgG ASA). ASA were detected on sperm using the direct immunobead test. After centrifuging semen samples on a Ficoll-Hypaque gradient, round cells obtained at the gradient interface were gated by a flow cytometer. The "immature germ cell window" was defined in terms of cellular volume and granularity. The percentage of gated round cells from semen samples that reacted with anti-CD45 was always less than 5%, and with anti-CD44 less than 3%. This lack of reactivity of gated round cells with MAb specific for leukocytes and epithelial cells suggests that they were immature germ cells. Immature germ cells were unreactive with W6/32 and anti-beta-2-microglobulin MAb, which suggests that these cells do not express HLA class I molecules. Similarly, no reactivity of the immature germ cells with the MAb that recognize HLA class II molecules was found. No significant differences were observed in the expression of HLA molecules on immature germ cells between the different semen samples studied: fertile, and ejaculates with ASA.

The presence of ASA in ejaculate is not associated with abnormal HLA antigen expression on immature germ cells.

Are women with sickle cell trait at increased risk for preeclampsia?

Our purpose was to determine the rate of preeclampsia in women who are positive for sickle cell trait. All African-American women were tested for sickle cell trait with the "sickledex" screen at the fist prenatal visit and prospectively enrolled in this study from March 1994 to June 1995. "Sickledex" screens were confirmed with hemoglobin electrophoresis. Demographic data were collected at the time of enrollment. Outcome data, including preeclampsia (as defined by The American College of Obstetricians and Gynecologists criteria), gestational age at delivery, birth weight, and postpartum endometritis were collected immediately post partum. Assuming a 10% rate of positive sickle cell trait, 1100 patients were required to demonstrate a doubling in the rate of preeclampsia with 80% power and p < 0.05. The Student t test, the Mann-Whitney U test, chi 2 analysis, and Fisher's exact tests were used for statistical analysis. Of 1584 women enrolled in the study, 162 were positive for sickle cell trait. Sickle cell trait-positive women were older than the sickle cell trait-negative women (24.4 +/- 4.6 vs 23.0 +/- 4.4 years, p < 0.001), but there was no significant difference in parity. The rate of preeclampsia was significantly increased in sickle cell-positive women (24.7% vs 10.3%, p < 0.0001). There was no significant difference in the rate of chronic hypertension, diabetes, or smoking. Parous sickle cell-positive women more frequently gave a history of preeclampsia in a previous pregnancy (21.4% vs 9.3%, p < 0.0001). There was a statistically significant decrease in gestational age at delivery and birth weight in sickle cell trait-positive women (36.7 +/- 2.7 vs 37.7 +/- 3.0 weeks, p < 0.0001; and 3082 +/- 591 vs 3369 +/- 573 gm, p < 0.0001). The rate of postpartum endometritis was significantly increased in the women positive for sickle cell trait (12.3% vs 5.1%, p < 0.001), although both groups had a similar cesarean section rate (14.8% vs 12.6%, not significant).

This is the first prospective study to demonstrate that sickle cell trait-positive women are at significantly higher risk for development of perinatal complications that have traditionally been associated with sickle disease.

Do vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease?

Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion. At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion.

VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

Is the Montreal Cognitive Assessment ( MoCA ) superior to the Mini-Mental State Examination ( MMSE ) for the detection of vascular cognitive impairment after acute stroke?

The majority of patient with post-stroke Vascular Cognitive Impairment (VCI) have Vascular Cognitive Impairment No Dementia (VCIND). The Mini-Mental State Examination (MMSE) has been criticized as a poor screening test for VCIND due to insensitivity to visuospatial and executive function impairments. The Montreal Cognitive Assessment (MoCA) was designed to be more sensitive to such deficits and may therefore be a superior screening instrument for VCIND. Stable patients within 14days of their index stroke without significant physical disability, aphasia, dysarthria, active psychiatric illness or pre-existing dementia were eligible. Cognitive and neurological measures were administered after informed consent. 100 patients were recruited. Of the 57 patients with unimpaired MMSE scores, 18 (32%) patients had an impaired MoCA score. By comparison, only 2 out of the 41 (4.9%) patients with unimpaired MoCA scores had impaired MMSE scores. Moreover, MMSE domain subtest scores could not differentiate between groups of differing screening test results, whilst MoCA domain subtest scores (Visuospatial/Executive Function, Attention and Recall) could.

The MoCA is more sensitive than the MMSE in screening for cognitive impairment after acute stroke. Longitudinal studies are required to establish the prognostic value of MoCA and MMSE evaluation in the acute post-stroke period for cognitive impairment as defined by the standard method of formal neuropsychological evaluation 3-6 months after stroke.

Does polaprezinc attenuate the Helicobacter pylori-induced gastric mucosal leucocyte activation in Mongolian gerbils -- a study using intravital videomicroscopy?

We previously demonstrated that Helicobacter pylori colonization evokes gastric mucosal inflammation and an extensive increase in lipid peroxides and glutathione in Mongolian gerbils. Zinc and its derivative, polaprezinc, have been reported to be potent antioxidants in gastric mucosa. To examine the effect of polaprezinc on gastric mucosal oxidative inflammation in H. pylori-colonized Mongolian gerbils. Sixty-eight male Mongolian gerbils were orally inoculated with H. pylori (ATCC43504, 5 x 10(8) CFUs/gerbil; H. pylori group) and 35 gerbils were inoculated with the culture media (control group). Twenty-two gerbils in the H. pylori and 13 gerbils in the control group were fed with diets containing polaprezinc (0.06%, 100 mg/kg, 10 times the usual clinical dose) (H. pylori + polaprezinc group, polaprezinc group). The remaining gerbils were fed a standard laboratory chow diet. Neutrophil infiltration, assessed histologically and by the activity of myeloperoxidase, the contents of CXC-chemokine (GRO/CINC-1-like protein) and the contents of thiobarbituric acid-reactive substances, was evaluated in each group 12 weeks after the inoculation. Separately, gastric mucosal leucocyte activation and capillary perfusion were also assessed using intravital microscopy 2, 4, 8 and 12 weeks after the inoculation. In all H. pylori-inoculated animals, the bacterial infection persisted throughout the experimental period. Gastric mucosal lesion formation in the H. pylori group was significantly inhibited in the H. pylori + polaprezinc group. Elevated levels of myeloperoxidase activity, GRO/CINC-1 and thiobarbituric acid-reactive substances in the H. pylori group at 12 weeks were attenuated significantly by polaprezinc treatment. Enhanced levels of venular leucocyte activation observed in the H. pylori group were attenuated significantly in the H. pylori + polaprezinc group during both the early phase (2 weeks) and late phase (12 weeks).

Polaprezinc inhibited H. pylori-associated gastric mucosal oxidative inflammation, including initial micro-vascular leucocyte activation, in Mongolian gerbils.

Does prolactin locally produced by synovium infiltrating T lymphocytes induce excessive synovial cell functions in patients with rheumatoid arthritis?

To elucidate the role of prolactin (PRL) produced in joints as part of the pathological response of rheumatoid arthritis (RA), we studied PRL production and prolactin receptor (PRLR) expression in RA synovium and its effects on RA synovial cell functions. Proinflammatory cytokine and matrix metalloproteinase (MMP) production by RA synovial cells was estimated by ELISA, Western blotting analysis, and zymography. Expression of PRLR by RA synovial cells and local production of PRL were estimated by reverse transcription polymerase chain reaction and immunohistochemical staining. PRL enhanced RA synovial cell proliferation. Production of proinflammatory cytokine and MMP was augmented and production of tissue inhibitor of metalloproteinases (TIMP)-1 was inhibited by PRL treatment of RA synovial cells, suggesting that PRL enhances total collagenase activity in the joints. PRLR was exclusively expressed on fibroblast-like synovial cells and lymphocytes infiltrating into the synovium in patients with RA. Both synovium infiltrating T lymphocytes and, to a lesser extent, fibroblast-like synovial cells synthesized PRL, suggesting that PRL acts as a paracrine as well as autocrine activator of RA synovial cell functions. Stimulation of synovial cells by PRL induced rapid translocation of STAT-5 from cytoplasm into nuclei of RA synovial cells, suggesting that transcriptional regulation of RA synovial cell functions by PRL affects STAT-5. Inhibitors of PRL release, such as bromocriptine, inhibited proliferation of proinflammatory cytokines and collagenases by RA synovial cells.

Our findings emphasize the importance of PRL, locally produced by infiltrating T lymphocytes, for aberrant synovial cell functions in RA, and suggest possible clinical application of PRL inhibitors.

Is urine interleukin-6 an early biomarker of acute kidney injury in children undergoing cardiac surgery?

Interleukin-6 (IL-6) is a proinflammatory cytokine that increases early in the serum of patients with acute kidney injury (AKI). The aim of this study was to determine whether urine IL-6 is an early biomarker of AKI and determine the source of urine IL-6. Numerous proteins, including cytokines, are filtered by the glomerulus and then endocytosed and metabolized by the proximal tubule. Since proximal tubule injury is a hallmark of AKI, we hypothesized that urine IL-6 would increase in AKI due to impaired proximal tubule metabolism of filtered IL-6. Urine was collected in 25 consecutive pediatric patients undergoing cardiac bypass surgery (CPB). AKI was defined as a 50% increase in serum creatinine at 24 hours (RIFLE (Risk, Injury, Failure, Loss, End stage), R). Mouse models of AKI and freshly isolated proximal tubules were also studied. Urine IL-6 increased at six hours in patients with AKI versus no AKI (X2 = 8.1750; P < 0.0042). Urine IL-6 > 75 pg/mg identified AKI with a sensitivity of 88%. To assess whether increased urine IL-6 occurs in functional versus structural renal failure, mouse models of pre-renal azotemia after furosemide injection (no tubular injury), ischemic AKI (tubular injury) and cisplatin AKI (tubular injury) were studied. Urine IL-6 did not significantly increase in pre-renal azotemia but did increase in ischemic and cisplatin AKI. To determine if circulating IL-6 appears in the urine in AKI, recombinant human (h)IL-6 was injected intravenously and urine collected for one hour; urine hIL-6 increased in ischemic AKI, but not pre-renal azotemia. To determine the effect of AKI on circulating IL-6, serum hIL-6 was determined one hour post-intravenous injection and was increased in ischemic AKI, but not pre-renal azotemia. To directly examine IL-6 metabolism, hIL-6 was added to the media of normal and hypoxic isolated proximal tubules; hIL-6 was reduced in the media of normal versus injured hypoxic proximal tubules.

Urine IL-6 increases early in patients with AKI. Animal studies demonstrate that failure of proximal tubule metabolism of IL-6 results in increased serum and urine IL-6. Impaired IL-6 metabolism leading to increased serum IL-6 may contribute to the deleterious systemic effects and increased mortality associated with AKI.

Is increase in collagen turnover but not in collagen fiber content associated with flow-induced arterial remodeling?

Degradation and synthesis of collagen are common features in arterial geometrical remodeling. Previous studies described an association between arterial remodeling and an increase in collagen fiber content after balloon injury. However, this does not exclude that the association between collagen content and remodeling depends on arterial injury since the association of collagen fiber content and arterial remodeling, without arterial injury, has not been investigated. The aim of the present study was to study the relation between flow-induced arterial geometrical remodeling, without arterial injury, and collagen synthesis and degradation, collagen fiber content and cell-migration-associated moesin levels. In 23 New Zealand White rabbits an arteriovenous shunt (AV shunt) was created in the carotid and femoral artery to induce a structural diameter increase or a partial ligation (n = 27 rabbits) to induce a diameter decrease. In both models, arterial remodeling was accompanied by increased procollagen synthesis, reflected by increased procollagen mRNA or Hsp47 protein levels. In both models, however, no changes were detected in collagen fiber content. Active MMP-2 and moesin levels were increased after AV shunting.

Collagen synthesis and MMP-2 activation were associated with arterial remodeling. However, a change in collagen fiber content was not observed. These results suggest that, during flow-induced geometrical arterial remodeling, increases in collagen synthesis are used for matrix collagen turnover and cell migration but not to augment collagen fiber content.

Is social capital associated with coping, self-esteem, health and quality of life in long-term social assistance recipients?

Being a long-term social assistant recipient may in the long run have an impact on the individual's perception of health and quality of life, which in turn may become barriers to the return to work.AIM: The purpose of this article is to explore the relationships between social capital, coping, self-esteem, health and quality of life in a sample of people receiving social assistance, living in various municipalities in Norway. The present study has a cross-sectional, questionnaire and survey design, including a sample of 451 long-term social assistance recipients from 14 municipalities in Norway (response rate 53%). Different self-reported measures assessing social capital, coping, self-esteem, health and quality of life were used. To evaluate multivariate relationships, multiple linear hierarchical regression analyses were performed. The majority of the sample was men (58%), had education up to secondary school level (43%), and were married or registered partner (23%), with a mean age of 34 (SD 10.9; range 18-60). Demographic and social factors explain 7% of the variance in social capital. In the bivariate analysis, higher levels of social capital are significantly related to higher levels of coping (r = 0.30), self-esteem (r = 0.20), mental health (r = 0.30) and quality of life (r = -0.21). In the final regression model, with quality of life as the dependent variable, only coping, self-esteem and mental health are significantly related to quality of life. This model explains 40% of the variance in quality of life.

This study indicates that social capital is associated with health and quality of life through coping and self-esteem in a sample of long-term social assistance recipients.

Is non-muscle myosin IIA involved in focal adhesion and actin remodelling controlling glucose-stimulated insulin secretion?

Actin and focal adhesion (FA) remodelling are essential for glucose-stimulated insulin secretion (GSIS). Non-muscle myosin II (NM II) isoforms have been implicated in such remodelling in other cell types, and myosin light chain kinase (MLCK) and Rho-associated coiled-coil-containing kinase (ROCK) are upstream regulators of NM II, which is known to be involved in GSIS. The aim of this work was to elucidate the implication and regulation of NM IIA and IIB in beta cell actin and FA remodelling, granule trafficking and GSIS. Inhibitors of MLCK, ROCK and NM II were used to study NM II activity, and knockdown of NM IIA and IIB to determine isoform specificity, using sorted primary rat beta cells. Insulin was measured by radioimmunoassay. Protein phosphorylation and subcellular distribution were determined by western blot and confocal immunofluorescence. Dynamic changes were monitored by live cell imaging and total internal reflection fluorescence microscopy using MIN6B1 cells. NM II and MLCK inhibition decreased GSIS, associated with shortening of peripheral actin stress fibres, and reduced numbers of FAs and insulin granules in close proximity to the basal membrane. By contrast, ROCK inhibition increased GSIS and caused disassembly of glucose-induced central actin stress fibres, resulting in large FAs without any effect on FA number. Only glucose-induced NM IIA reorganisation was blunted by MLCK inhibition. NM IIA knockdown decreased GSIS, levels of FA proteins and glucose-induced extracellular signal-regulated kinase 1/2 phosphorylation.

Our data indicate that MLCK-NM IIA may modulate translocation of secretory granules, resulting in enhanced insulin secretion through actin and FA remodelling, and regulation of FA protein levels.

Is memory Enhancing Effect of Black Pepper in the AlCl3 Induced Neurotoxicity Mouse Model Mediated Through Its Active Component Chavicine?

Black pepper (Piper nigrum Linn.) has vital pharmacological properties with profound effects on central nervous system. Neurotoxic agents like Aluminum Chloride (AlCl3) cause the oxidative stress and result in improper processing of amyloid proteins leading to accumulation of amyloid β plaques. The study aimed to explore the neuroprotective potential of black pepper (BP) extract (12.5mg/kg/day) on memory enhancement and its effect on expression of amyloid precursor protein (APP) isoforms (APP770 and APP695) in AlCl3 induced neurotoxicity (250mg/kg) mouse model. The study included the isolation and identification of pure compound from BP (chavicine) which was found pharmacologically active. Morris water maze test, elevated plus maze, fear conditioning, context and cue dependent test and social preference tests were performed to investigate the learning and memory. Gene expression (APP isoforms) and in-vitro and ex-vivo DPPH free radical scavenging activity were performed to evaluate the role of BP. BP significantly improved memory in AlCl3 induced neurotoxicity mouse model along with effectively decreasing the expression of APP770 (amyloidogenic) isoform and improved level of APP695 (non-amyloidogenic) in hippocampus, amygdala and cortex. Fear extinction learning was considerably improved in BP treated group (7.83±2.03) than AlCl3 induced neurotoxicity group (39.75±4.25). In the hippocampus, BP significantly reduced the expression of APP770 (0.37±0.05) as compared to AlCl3 induced neurotoxicity group (0.72±0.06), and effectively increased (34.80±1.39) the percentage inhibition of DPPH free radicals as compared to AlCl3 induced neurotoxicity group (14±2.68).

The study revealed that BP improves memory and chavicine is a lead compound producing pharmacological effects of BP.

Does simvastatin reduce VCAM-1 expression in human umbilical vein endothelial cells exposed to lipopolysaccharide?

Reducing the expression of endothelial cell adhesion molecules (ECAMs) is known to decrease inflammation-induced vascular complications. In this paper we looked at whether statins can reduce inflammation-induced ECAM expression after lipopolysaccharide (LPS) treatment in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pretreated with different concentrations of simvastatin, atorvastatin, and rosuvastatin and subsequently exposed to 5 μg/ml LPS. Semi-quantitative RT-PCR analysis was used to measure the mRNA expression of ECAMs, including VCAM-1, ICAM-1, and E-selectin. VCAM-1 mRNA appeared to be the only target that was affected by the statins, with its expression being partially and almost completely reduced by simvastatin at 50 and 125 μM concentrations, respectively, and only partially reduced by atorvastatin, but not reduced by rosuvastatin. VCAM-1 protein production was inhibited by simvastatin at concentrations from 5 to 125 μM. Leukocyte-endothelial cell adhesion assay revealed that simvastatin could inhibit the adhesion of labelled U937 cells to the HUVEC monolayer.

This study showed that simvastatin reduces VCAM-1 expression in HUVECs exposed to LPS and decreases leukocyte-endothelial cell adhesion.

Does hospital procedure-specific volume affect treatment costs?

The long-run cost savings potential of private sector reform efforts, such as selective contracts with providers, depends in part on the relationship between procedure-specific volume and average hospital resources that are consumed in treating patients associated with that specific procedure. Study examines a model that estimates the relationship between hospital procedure-specific volume and average hospital treatment costs, using an elective surgical procedure as an example. Medicare Provider Analysis and Review (MedPAR) files for 1989 for hospitalizations in which a Medicare beneficiary received a knee replacement (KR) surgery during 1989. Hospital information was obtained from the American Hospital Association's 1989 Annual Survey. All patient-level data were aggregated to the hospital level to create a data file, with the hospital as the unit of observation. This study used administrative claims data and regression analysis to estimate the effect of hospital procedure-specific volume on average hospital treatment costs of patients receiving KR surgery. We also examined the stability of the volume-cost relationship across hospitals of different sizes. The average treatment costs associated with KR surgery are inversely related to a hospital's KR volume in the regression equation estimated using all hospitals performing KR surgery. The inverse relationship between cost and volume is found to be robust for different-size hospitals.

The potential cost savings associated with performing KR surgery at incrementally higher hospital volume level can amount to as much as 10 percent of the hospital's average treatment cost. However, the incremental cost savings associated with increased patient volume depends on the hospital's current volume level and its size.

Does economic incentive matter for rational use of medicine?

Before the new round of healthcare reform in China, primary healthcare providers could obtain a fixed 15 % or greater mark-up of profits by prescribing and selling medicines. There were concerns that this perverse incentive was a key cause of irrational medicine use. China's new Essential Medicines Program (EMP) was launched in 2009 as part of the national health sector reform initiatives. One of its core policies was to eliminate primary care providers' economic incentives to overprescribe or prescribe unnecessarily expensive drugs, which were regarded as consequences of China's traditional financing system for health institutions. The objective of the study was to measure changes in prescribing patterns in primary healthcare facilities after the removal of the economic incentives for physicians to overprescribe as a result of the implementation of the EMP. A comparison design was applied to 8,258 prescriptions in 2007 and 8,278 prescriptions in 2010, from 83 primary healthcare facilities nationwide. Indicators were adopted to evaluate medicine utilization, which included overall number of medicines, average number of Western and traditional Chinese medicines, pharmaceutical expenditure per outpatient prescription, and proportion of prescriptions that contained two or more antibiotics. We further assessed the use of medicines (antibiotics, infusion, hormones, and intravenous injection) per disease-specific prescription for hypertension, diabetes, coronary artery heart disease, bronchitis, upper respiratory tract infection, and gastritis. A difference-in-difference analysis was employed to evaluate the net policy effect. Overall changes in indicators were not found to be statistically significant between the 2 years. The results varied for different diseases. The number of Western drugs per outpatient prescription decreased while that of traditional Chinese medicines increased. Overuse of antibiotics remained an extensive problem in the treatment of many diseases, though there was some significant improvement in certain diseases, like diabetes in rural areas. Medicine expenditure per prescription also decreased.

It seems that the removal of a perverse economic incentive alone would not lead to improvement of healthcare providers' prescribing patterns. The rationality of the Essential Medicines List and the lack of payers' and providers' meaningful involvement in the development of the policy possibly contribute to the lack of significant changes in prescribing behaviors. It is suggested that China should adopt more comprehensive policies for healthcare facilities, physicians, patients, and payers, rather than just relying on economic incentives to improve rational use of medicines.

Does myocardial T2 mapping reveal age- and sex-related differences in volunteers?

T2 mapping indicates to be a sensitive method for detection of tissue oedema hidden beyond the detection limits of T2-weighted Cardiovascular Magnetic Resonance (CMR). However, due to variability of baseline T2 values in volunteers, reference values need to be defined. Therefore, the aim of the study was to investigate the effects of age and sex on quantitative T2 mapping with a turbo gradient-spin-echo (GRASE) sequence at 1.5 T. For that reason, we studied sensitivity issues as well as technical and biological effects on GRASE-derived myocardial T2 maps. Furthermore, intra- and interobserver variability were calculated using data from a large volunteer group. GRASE-derived multiecho images were analysed using dedicated software. After sequence optimization, validation and sensitivity measurements were performed in muscle phantoms ex vivo and in vivo. The optimized parameters were used to analyse CMR images of 74 volunteers of mixed sex and a wide range of age with typical prevalence of hypertension and diabetes. Myocardial T2 values were analysed globally and according to the 17 segment model. Strain-encoded (SENC) imaging was additionally performed to investigate possible effects of myocardial strain on global or segmental T2 values. Ex vivo studies in muscle phantoms showed, that GRASE-derived T2 values were comparable to those acquired by a standard multiecho spinecho sequence but faster by a factor of 6. Besides that, T2 values reflected tissue water content. The in vivo measurements in volunteers revealed intra- and interobserver correlations with R2=0.91 and R2=0.94 as well as a coefficients of variation of 2.4% and 2.2%, respectively. While global T2 time significantly decreased towards the heart basis, female volunteers had significant higher T2 time irrespective of myocardial region. We found no correlation of segmental T2 values with maximal systolic, diastolic strain or heart rate. Interestingly, volunteers´ age was significantly correlated to T2 time while that was not the case for other coincident cardiovascular risk factors.

GRASE-derived T2 maps are highly reproducible. However, female sex and aging with typical prevalence of hypertension and diabetes were accompanied by increased myocardial T2 values. Thus, sex and age must be considered as influence factors when using GRASE in a diagnostic manner.

Do puromycin-based vectors promote a ROS-dependent recruitment of PML to nuclear inclusions enriched with HSP70 and Proteasomes?

Promyelocytic Leukemia (PML) protein can interact with a multitude of cellular factors and has been implicated in the regulation of various processes, including protein sequestration, cell cycle regulation and DNA damage responses. Previous studies reported that misfolded proteins or proteins containing polyglutamine tracts form aggregates with PML, chaperones, and components of the proteasome, supporting a role for PML in misfolded protein degradation. In the current study, we have identified a reactive oxygen species (ROS) dependent aggregation of PML, small ubiquitin-like modifier 1 (SUMO-1), heat shock protein 70 (HSP70) and 20S proteasomes in human cell lines that have been transiently transfected with vectors expressing the puromycin resistance gene, puromycin n-acetyl transferase (pac). Immunofluorescent studies demonstrated that PML, SUMO-1, HSP70 and 20S proteasomes aggregated to form nuclear inclusions in multiple cell lines transfected with vectors expressing puromycin (puro) resistance in regions distinct from nucleoli. This effect does not occur in cells transfected with identical vectors expressing other antibiotic resistance genes or with vectors from which the pac sequence has been deleted. Furthermore, ROS scavengers were shown to ablate the effect of puro vectors on protein aggregation in transfected cells demonstrating a dependency of this effect on the redox state of transfected cells.

Taken together we propose that puromycin vectors may elicit an unexpected misfolded protein response, associated with the formation of nuclear aggresome like structures in human cell lines. This effect has broad implications for cellular behavior and experimental design.

Is high Single-dose Vancomycin Loading Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients?

Vancomycin loading doses are recommended; however, the risk of nephrotoxicity with these doses is unknown. The primary objective of this study was to compare nephrotoxicity in emergency department (ED) sepsis patients who received vancomycin at high doses (>20 mg/kg) versus lower doses (≤20 mg/kg). A retrospective cohort study was performed in three academic EDs. Inclusion criteria were age ≥ 18 years, intravenous vancomycin order, and hospital admission. Exclusion criteria were no documented weight, hemodialysis-dependent, and inadequate serum creatinine (SCr) values for the measured outcome. Analyses compared the incidence of nephrotoxicity for patients who received vancomycin at high dose (>20 mg/kg) versus low dose (≤20 mg/kg). A total of 2,131 consecutive patients prescribed vancomycin over 6 months were identified. Of these, 1,330 patients had three SCr values assessed for the primary outcome. High-dose initial vancomycin was associated with a significantly lower rate of nephrotoxicity (5.8% vs. 11.1%). After age, sex, and initial SCr were adjusted for, the risk of high-dose vancomycin compared to low-dose was decreased for the development of nephrotoxicity (relative risk = 0.60; 95% confidence interval = 0.44 to 0.82).

Initial dosing of vancomycin > 20 mg/kg was not associated with an increased rate of nephrotoxicity compared with lower doses. Findings from this study support compliance with initial weight-based vancomycin loading doses.

Does childhood obesity elevate blood pressure and total cholesterol independent of physical activity?

To compare the habitual physical activity, blood pressure, total cholesterol levels of obese and non-obese matched children. 546 obese children (BMI and sum of skinfolds > or = 90% tile) were matched for gender, race, age, and height (within 2 cm) with non-obese controls for a total sample of 1092 children. Systolic (BPsys) and diastolic (BPdia) blood pressure by mercury sphygmomanometer, total cholesterol by reflectance photometry, and physical activity by questionnaire. Mean comparisons indicated the obese children, regardless of gender, had higher BPsys (108 +/- 11 vs 104 +/- 10 mm Hg, P = 0.0001), BPdia (70 +/- 9 vs 68 +/- 8 mm Hg, P = 0.002), and greater total cholesterol levels (4.47 +/- 0.80 vs 4.11 +/- 0.75 mmol/L, P = 0.0001) than the non-obese subjects. Self-reported physical activity scores were not significantly different when comparing the obese and non-obese children. Correlations between self-reported activity and cholesterol or blood pressure were all very low and not significant (r < or = 0.06).

These results suggest that childhood obesity is associated with higher blood pressures and greater circulating cholesterol levels independent of physical activity levels.

Male breast cancer in Indian patients: is it the same?

Cancer of the male breast accounts for about 1% of all malignancies in men and 1% of all breast cancers. Poor level of awareness often results in late presentation and delayed diagnosis in our environment. This study was done to analyse the demographic data, management and survival of male breast cancers in Indian subset of patients and compare it with that of western literature. A 10 year (2001-2010) retrospective study of all male breast cancers was done. Data regarding the incidence, presentation, histopathology, stage and grade of tumor, management and outcome of patients were analysed. 26 cases of male breast cancer were encountered. This comprised 0.4% of all breast cancers seen in our department during the 10 year period. The ages of patients ranged from 45-75 years with a mean age of 57 years. Family history was present in 4 patients. Clinically, symptoms included self-detected lump in 23 (88.5%) patients, nipple retraction in 12 (46.1%) and pain in 12 (46.1%). All cases were unilateral (16 on right, 10 on left). Disease most commonly involved central quadrant (9 patients). Grade 3 disease was found in 13 patients and Stage 3 disease was most commonly encountered (13 patients). None of our patients received neo adjuvant chemotherapy. 20 (76.9%) patients had modified radical mastectomy and 6 (23.1%) had radical mastectomy. Most of our patients were hormone receptor positive (21 patients). Bilateral orchidectomy, Adjuvant chemotherapy, Adjuvant radiotherapy and Tamoxifen were offered in 3 (11.5%), 16 (61.5%), 17 (65.4%) and 15 (57.7%) patients respectively. Follow up ranged from 1-59 months.

Male breast cancer is rare in our centre. Late presentation with advanced disease is a common feature in our environment. Further multiinstitutional, prospective studies are needed for better understanding of management of male breast cancers in Indian subset of patients.

Is fatty acid metabolism altered in non-alcoholic steatohepatitis independent of obesity?

Non-alcoholic steatohepatitis (NASH) is associated with changes in fatty acid (FA) metabolism. However, specific changes in metabolism and hepatic mRNA expression related to NASH independent of simple steatosis, obesity and diet are unknown. Liver histology, serum and liver FA composition and estimated enzyme activities based on the FA ratios in cholesteryl esters and triglycerides were assessed in 92 obese participants of the Kuopio Obesity Surgery Study (KOBS) divided to those with normal liver, steatosis or NASH (30 men and 62 women, age 46.8±9.5years (mean±SD), BMI 44.2±6.2kg/m(2)). Plasma FA composition was also investigated in the Metabolic Syndrome in Men (METSIM) Study (n=769), in which serum alanine aminotransferase (ALT) was used as a marker of liver disease. Obese individuals with NASH had higher activity of estimated activities of delta-6 desaturase (D6D, p<0.002) and stearoyl-CoA desaturase 1 (SCD1, p<0.002) and lower activity of delta-5 desaturase (D5D, p<0.002) when compared to individuals with normal liver. Estimated activities of D5D, D6D and SCD1 correlated positively between liver and serum indicating that serum estimates reflected liver metabolism. Accordingly, NASH was associated with higher hepatic mRNA expression of corresponding genes FADS1, FADS2 and SCD. Finally, differences in FA metabolism that associated with NASH in obese individuals were also associated with high ALT in the METSIM Study.

We demonstrated alterations in FA metabolism and endogenous desaturase activities that associate with NASH, independent of obesity and diet. This suggests that changes in endogenous FA metabolism are related to NASH and that they may contribute to the progression of the disease.

Does mitomycin C eliminate the short-term intraocular pressure rise found following Molteno tube implantation?

Molteno implants remain popular for treating recalcitrant glaucomas. This study aimed to assess the effect of mitomycin C (MMC) use with Molteno tube implantation upon intraocular pressure (IOP) control and complication rates. In particular, the study aimed to assess any change that MMC might have upon the postoperative hypertensive phase. A retrospective case record study was conducted of all patients undergoing double plate Molteno implant surgery by one surgeon over 5 years. Eyes with recalcitrant glaucoma unresponsive to previous surgery, or deemed unlikely to succeed with trabeculectomy, underwent double plate Molteno tube implantation. Eyes that had MMC (0.3 mg/mL, 3 min) applied to Tenon's capsule over the secondary plate were compared with eyes that underwent surgery without adjunctive MMC application. Twenty-seven eyes received MMC and were similar to 26 eyes not receiving MMC in terms of glaucoma subtype, age, sex, previous surgery, preoperative IOP and postoperative IOP lowering agents. Those not receiving MMC had raised IOP 31-90 days post implantation compared with MMC treated eyes (P < 0.01) and more often received oral antifibrosis medication (P < 0.05). Complications were no more common with MMC except for initial overdrainage. Significant systemic complications from the use of oral antifibrosis medication were common.

The findings suggest a useful role for MMC. Caution is advised in case selection for MMC use. Mitomycin C treatment over the secondary plate alone permits removal of this plate if MMC-related complications occur without requiring removal of the whole implant.

Sphincter of oddi manometry: is it necessary to measure both biliary and pancreatic sphincter pressures?

Data are scant on the miss rate of sphincter of Oddi dysfunction if basal pressure in both biliary and pancreatic sphincter segments is not measured during manometry. Motility tracings with basal pressure measurements of both sphincter segments were retrospectively analyzed. Basal sphincter pressure greater than 40 mm Hg was considered abnormal in either sphincter segment. The study population consisted of 73 subjects (64 women, 9 men; age 45.3 +/- 1.6 yr). The basal pressures in the 2 sphincter segments were highly discordant (correlation coefficient = 0.2, p = 0.04). Basal pressures were normal in both segments in 19%, abnormal in both segments in 40%, and abnormal in 1 segment but normal in the other in 41%. The negative predictive value of normal biliary sphincter pressure in excluding sphincter dysfunction was 0. 42; when the pancreatic sphincter pressure was normal, the negative predictive value was 0.58. The incidence of pancreatitis with dual duct manometry was comparable to the institutional experience with all sphincter studies.

Although the clinical relevance of individually elevated sphincter pressures remains uncertain, there is significant discordance of basal pressures between the biliary and pancreatic sphincter segments. If only the biliary sphincter pressure were to be measured, one fourth of abnormal sphincter pressures would be missed. Therefore, if the first sphincter segment has a normal basal pressure, the other segment should also be evaluated.

Does deficiency in regulatory T cells result in development of antimitochondrial antibodies and autoimmune cholangitis?

There have been several descriptions of mouse models that manifest select immunological and clinical features of autoimmune cholangitis with similarities to primary biliary cirrhosis in humans. Some of these models require immunization with complete Freund's adjuvant, whereas others suggest that a decreased frequency of T regulatory cells (Tregs) facilitates spontaneous disease. We hypothesized that antimitochondrial antibodies (AMAs) and development of autoimmune cholangitis would be found in mice genetically deficient in components essential for the development and homeostasis of forkhead box 3 (Foxp3)(+) Tregs. Therefore, we examined Scurfy (Sf) mice, animals that have a mutation in the gene encoding the Foxp3 transcription factor that results in a complete abolition of Foxp3(+) Tregs. At 3 to 4 weeks of age, 100% of animals exhibit high-titer serum AMA of all isotypes. Furthermore, mice have moderate to severe lymphocytic infiltrates surrounding portal areas with evidence of biliary duct damage, and dramatic elevation of cytokines in serum and messenger RNAs encoding cytokines in liver tissue, including tumor necrosis factor alpha, interferon-gamma, interleukin (IL)-6, IL-12, and IL-23.

The lack of functional Foxp3 is a major predisposing feature for loss of tolerance that leads to autoimmune cholangitis. These findings reflect on the importance of regulatory T cells in other murine models as well as in patients with primary biliary cirrhosis.

Do cpG oligonucleotides activate the immune response in burned mice?

Immunosuppression after burn injury increases the risk of sepsis and multiple organ failure. We examined changes of immune function in mice after burn injury and investigated the immunostimulatory effect of oligodeoxynucleotides containing CpG motifs. Male BALB/c mice (8-10 wk old) received a full-thickness burn to 20% of their body surface area, after which the immunological parameters of splenic macrophages were evaluated. To assess the immunostimulatory effect of oligodeoxynucleotide treatment, splenic macrophages harvested from burned mice were incubated with oligodeoxynucleotides. Then cytokine production and major histocompatibility complex class II antigen expression were measured. To assess the in vivo effect of oligodeoxynucleotides, intraperitoneal administration was done on day 4 after burn injury, and class II antigen expression by splenic macrophages was measured 10 d later. Class II antigen expression and the synthesis of cytokines (interleukin-12, tumor necrosis factor-alpha, interleukin-6, and interleukin-1) by splenic macrophages were significantly reduced after burn injury, while incubation of splenic macrophages from burned mice with oligodeoxynucleotides partially enhanced the production of interleukin-12, tumor necrosis factor-alpha, interleukin-6, and interleukin-1. In addition, intraperitoneal administration of oligodeoxynucleotides enhanced class II antigen expression by splenic macrophages.

The reduction of class II antigen expression and synthesis of cytokines (interleukin-12, tumor necrosis factor-alpha, interleukin-6, and interleukin-1) by splenic macrophages after burn injury was partially reversed by oligodeoxynucleotide treatment. Therefore, immunostimulatory oligodeoxynucleotides may be a potential treatment for post-burn immunosuppression.

Does folic acid inhibit tau phosphorylation through regulation of PP2A methylation in SH-SY5Y cells?

Neurofibrillary tangles (NFTs), which are composed of intracellular filamentous aggregates of hyperphosphorylated tau protein, are one of the pathological hallmarks of Alzheimer's disease (AD). Because tau phosphorylation is regulated by phosphatases, abnormal metabolism of protein phosphatase 2A (PP2A) has been proposed to be a contributing factor to the disease process. To determine the function of folic acid on tau phosphorylation, an in vitro model of human neuroblastoma cells (SH-SY5Y) were exposed to folic acid (0-40 μmol/L) for 96 h, in the presence or absence of the phosphoesterase inhibitor okadaic acid (OA) (10 nmol/L) for 9 h. The data of western blot showed tau phosphorylation at the Ser396 site in OA-incubated SH-SY5Y cells was inhibited by folic acid in a concentration-dependent manner, with the folic acid concentration of 40 μmol/L providing maximal inhibition. Folic acid can downregulate tau protein phosphorylation by inhibiting the demethylation reactions of PP2A. High folic acid concentrations (20 and 40 μmol/L) increased SAM:SAH ratios and cell viability.

Therefore, we can speculate that folate deficiency may be a cause of PP2A deregulation, which can in turn lead to expression of the abnormal hyperphosphorylated form of tau.

Does in-hospital delay increase the risk of perforation in adults with appendicitis?

The influence of in-hospital delay (time between admission and operation) on outcome after appendectomy is controversial. A total of 1,827 adult patients underwent open or laparoscopic appendectomy for suspected appendicitis in eleven Swiss hospitals between 2003 and 2006. Of these, 1,675 patients with confirmed appendicitis were included in the study. Groups were defined according in-hospital delay (≤12 vs. >12 h). Delay>12 h was associated with a significantly higher frequency of perforated appendicitis (29.7 vs. 22.7%; P=0.010) whereas a delay of 6 or 9 h was not. Size of institution, time of admission, and surgical technique (laparoscopic vs. open) were independent factors influencing in-hospital delay. Admission during regular hours was associated with higher age, higher frequency of co-morbidity, and higher perforation rate compared to admission after hours. The logistic regression identified four independent factors associated with an increased perforation rate: age (≤65 years vs. >65 years, odds ratio (OR) 4.5, P<0.001); co-morbidity (Charlson index>0 vs. Charlson index=0, OR 2.3, P<0.001); time of admission (after hours vs. regular hours, OR 0.8, P=0.040), in-hospital delay (>12 vs. ≤12 h, OR 1.5, P=0.005). Perforation was associated with an increased reintervention rate (13.4 vs. 1.6%; P<0.001) and longer length of hospital stay (9.5 vs. 4.4 days; P<0.001).

In-hospital delay negatively influences outcome after appendectomy. In-hospital delay of more than 12 h, age over 65 years, time of admission during regular hours, and the presence of co-morbidity are all independent risk factors for perforation. Perforation was associated with a higher reintervention rate and increased length of hospital stay.

Gastro-oesophageal reflux and worse asthma control in obese children: a case of symptom misattribution?

Obese children for unknown reasons report greater asthma symptoms. Asthma and obesity both independently associate with gastro-oesophageal reflux symptoms (GORS). Determining if obesity affects the link between GORS and asthma will help elucidate the obese-asthma phenotype. Extend our previous work to determine the degree of associations between the GORS and asthma phenotype. We conducted a cross-sectional study of lean (20%-65% body mass index, BMI) and obese (≥95% BMI) children aged 10-17 years old with persistent, early-onset asthma. Participants contributed demographics, GORS and asthma questionnaires and lung function data. We determined associations between weight status, GORS and asthma outcomes using multivariable linear and logistic regression. Findings were replicated in a second well-characterised cohort of asthmatic children. Obese children had seven times higher odds of reporting multiple GORS (OR=7.7, 95% CI 1.9 to 31.0, interaction p value=.004). Asthma symptoms were closely associated with GORS scores in obese patients (r=0.815, p<0.0001) but not in leans (r=0.291, p=0.200; interaction p value=0.003). Higher GORS scores associated with higher FEV1-per cent predicted (p=0.003), lower airway resistance (R10, p=0.025), improved airway reactance (X10, p=0.005) but significantly worse asthma control (Asthma Control Questionnaire, p=0.007). A significant but weaker association between GORS and asthma symptoms was seen in leans compared with obese in the replicate cohort.

GORS are more likely to associate with asthma symptoms in obese children. Better lung function among children reporting gastro-oesophageal reflux and asthma symptoms suggests that misattribution of GORS to asthma may be a contributing mechanism to excess asthma symptoms in obese children.

Does polyphenon E inhibit the growth of human Barrett 's and aerodigestive adenocarcinoma cells by suppressing cyclin D1 expression?

Green tea consumption has been shown to exhibit cancer-preventive activities in preclinical studies. Polyphenon E (Poly E) is a well-defined green tea-derived catechin mixture. This study was designed to determine the effects of Poly E on the growth of human Barrett's and aerodigestive adenocarcinoma cells and the mechanisms involved in growth regulation by this agent. Human adenocarcinoma cells and immortalized Barrett's epithelial cells were used as model systems. Poly E inhibited the proliferation of immortalized Barrett's cells as well as various adenocarcinoma cells, and this was associated with the down-regulation of cyclin D1 protein expression. Inhibition of cyclin D1 led to dephosphorylation of the retinoblastoma protein in a dose-dependent manner; these changes were associated with G(1) cell cycle arrest. Poly E down-regulated cyclin D1 promoter activity and mRNA expression, suggesting transcriptional repression, and this correlated with decreased nuclear beta-catenin and beta-catenin/TCF4 transcriptional activity. MG132, an inhibitor of 26S proteosome, blocked the Poly E-induced down-regulation of cyclin D1, and Poly E promoted cyclin D1 polyubiquitination, suggesting that Poly E also inhibits cyclin D1 expression by promoting its degradation.

Poly E inhibits growth of transformed aerodigestive epithelial cells by suppressing cyclin D1 expression through both transcriptional and posttranslational mechanisms. These results provide insight into the mechanisms by which Poly E inhibits growth of Barrett's and adenocarcinoma cells, and provides a rationale for using this agent as a potential chemopreventive and therapeutic strategy for esophageal adenocarcinoma and its precursor, Barrett's esophagus.

Is attention deficit/hyperactivity disorders with co-existing substance use disorder characterized by early antisocial behaviour and poor cognitive skills?

Attention Deficit/Hyperactivity Disorder (ADHD) is associated with an increased risk of co-existing substance abuse. The Swedish legislation on compulsory healthcare can be applied to persons with severe substance abuse who can be treated involuntarily during a period of six months. This context enables a reliable clinical assessment of ADHD in individuals with severe substance use disorder (SUD). In the context of compulsory care for individuals with severe SUD, male patients were assessed for ADHD, co-morbid psychiatric symptoms, psychosocial background, treatment history, and cognition. The data from the ADHD/SUD group (n = 60) was compared with data from (1) a group of individuals with severe substance abuse without known ADHD (SUD group, n = 120), as well as (2) a group with ADHD from an outpatient psychiatric clinic (ADHD/Psych group, n = 107). Compared to the general SUD group in compulsory care, the ADHD/SUD group had already been significantly more often in compulsory care during childhood or adolescence, as well as imprisoned more often as adults. The most common preferred abused substance in the ADHD/SUD group was stimulant drugs, while alcohol and benzodiazepine abuse was more usual in the general SUD group. Compared to the ADHD/Psych group, the ADHD/SUD group reported more ADHD symptoms during childhood and performed poorer on all tests of general intellectual ability and executive functions.

The clinical characteristics of the ADHD/SUD group differed from those of both the SUD group and the ADHD/Psych group in several respects, indicating that ADHD in combination with SUD is a particularly disabling condition. The combination of severe substance abuse, poor general cognitive ability, severe psychosocial problems, including indications of antisocial behaviour, and other co-existing psychiatric conditions should be considered in treatment planning for adults with ADHD and SUD.

Does arterioplasty for Right Ventricular Outflow Tract Obstruction After Arterial Switch be a Durable Procedure?

Right ventricular outflow tract obstruction (RVOT) is the most common late complication requiring intervention after arterial switch operation (ASO). The durability of surgical management of this complication has not been well established. We retrospectively reviewed the charts of 38 consecutive patients who underwent RVOT reconstruction after ASO at our institution between 2004 and 2013. During the same time period, 223 consecutive patients underwent ASO for transposition of the great arteries at our institution. Thirty-five (16%) of the 223 patients developed RVOT obstruction, and 3 additional patients who had ASO done elsewhere presented to us with RVOT obstruction. Patient characteristics, site of stenosis, type of intervention, and outcomes were analyzed. Data are presented as median with interquartile ranges. The time interval between ASO and echocardiographic diagnosis of significant RVOT obstruction was 12.5 (3 to 23.7) months. After echocardiographic diagnosis, 33 (87%) children underwent cardiac catheterization. Obstruction involved the supravalvar main pulmonary artery (PA) in 21 (64%), branch PA in 14 (42%), pulmonary valve in 4 (12%), and sub-valvar area in 1 (3%). Ten of 33 patients who underwent catheterization had attempted percutaneous intervention, with 4 (40%) demonstrating significant response. Surgical intervention was performed at a median of 4 months in responders compared with 2.3 months in non-responders. Surgical repair included main PA plasty (36), extended to 1 or both branch PAs (26), or crossed the RVOT annulus (7). Surgical morbidity was 13% and there was no hospital or late mortality. At last follow-up, 41.2 months (21.4 to 81) after RVOT reconstruction, all patients had New York Heart Association grade 0 or 1 symptoms, and RV pressure was a median 36% of systemic pressure. Five (13%) patients underwent catheterization 26 months after surgery, with 2 requiring dilation at site of arterioplasty and 3 requiring distal branch PA intervention. One patient required reoperation for main PA stenosis. Freedom from re-intervention after surgery is 89%, 86%, and 86% at 2, 3, and 5 years, respectively.

Surgical management of RVOT obstruction after ASO is an effective and durable intervention in the intermediate term. Our results serve as a benchmark for expected outcomes in this disease process.

Screening for bacteriuria in diabetic patients. Is it possible to stop systematic urine cytobacteriological testing?

The discordance between test by urine dipstick (nitrites and leucocyte-esterase) and analysis in laboratory, with urinary culture on the same sample was studied in diabetic patients, from October 2000 to May 2002, to eventually stop systematic laboratory test. The dipstick result (Clinitek 20 Bayer) was classified as "possibility of bacteriuria" if one of the two tests was positive. Bacteriuria was considered significant if the laboratory test result gave, at least 10(5) bacteria per mL, (one strain), and at least 10(4) leucocytes. The out point was the dipstick negative predictive value (NPV). The study included 683 patients. The dipstick result was "possibility of bacteriuria" in 153 cases (22.4%). Thirty-nine bacteriuria (5.7%) were reported, including 2 dipstick false negatives. The NPV was 99.6% [IC 95% : 99.1-100].

The systematic laboratory tests were stopped.

Does the septic shock interfere experimental acute pancreatitis in rats?

Acute pancreatitis is a disease involving pro-inflammatory mediators. Two complex and multifactorial pathogenetic ways lead to edematous or necrotizing pancreatitis. The course of the disease is thought to be the consequence of an acute inflammatory response.AIM: The authors examined the impact of Escherichia coli LPS on the acute cerulein pancreatitis in rats. The study was performed on rats using the ceruleine pancreatitis model. The activation status of polymorphonuclear cells, blood IL-6 concentration, oxidative stress parameters, pancreatic enzymes concentration and microscopic alterations were determined at 5th and 9th h observations. In acute pancreatitis and acute pancreatitis with LPS groups, the peripheral polymorphonuclear cells activity was lower than in control one. Authors noticed the same neutrophil activation in acute pancreatitis after lipopolysaccharide administration although the peripheral blood polymorphonuclear cells count was significantly higher at the 9th h observation. LPS neither changed the oxidative stress within pancreatic gland, nor amylase or serum lipase activity. LPS given to acute pancreatitis animals resulted in significant increase of serum IL-6 concentration at 5th observation turning normal after 9th h.

Collected data supports thesis of early polymorphonuclear cells involvement in acute pancreatitis and oxidative stress evidence in pancreatic parenchyma. However, results did not reveal that administration of LPS amplified inflammatory response during the course of acute pancreatitis.

Subspecialty training: is it financially worthwhile?

To determine the financial return of additional training in a cognitive-oriented medical subspecialty (rheumatology) and in a procedure-oriented medical subspecialty (gastroenterology) relative to general internal medicine. Analysis of existing data to compare lifetime discounted earnings of physicians in different medical specialties. General internists, gastroenterologists, and rheumatologists were surveyed. Using data from surveys conducted by Medical Economics and the American College of Rheumatology, we constructed lifetime earnings streams that allowed the calculation of the net present values of discounted lifetime earnings in general internal medicine, gastroenterology, and rheumatology. Net present values of lifetime earnings were calculated for each group at two discount rates. Sensitivity analyses were done to estimate how changes in relative income would affect calculations of the net present values. The average net incomes before taxes for general internists, gastroenterologists, and rheumatologists in 1988 were $115,825, $201,875, and $118,056, respectively. At 5% and 10% discount rates, the net present values of the estimated career earnings stream for additional training in gastroenterology relative to general internal medicine were + $1,101,863 and + $512,952, respectively; for additional training in rheumatology relative to general internal medicine, the respective values were - $84,748 and - $92,467. If the incomes of general internists were decreased by 3% and the incomes of gastroenterologists were decreased by 25% to reflect the effect of potential changes due to the resource-based relative value scale (RBRVS), or if gastroenterology training were increased to 3 years and rheumatology fellowship stipends were increased by 30%, large differences would still exist between the groups.

Gastroenterologists have an extremely large return on their additional investment in training, but rheumatologists have a negative return. When considered exclusively as a financial decision, fellowship training in a cognitive-oriented medical subspecialty such as rheumatology is a poor investment. Even major changes in reimbursement policies will not affect the relative pecuniary attractiveness of procedure-oriented medical subspecialties.

Is demonstration of CDX2 highly antibody dependant?

CDX2 is a widely used immunohistochemical marker for intestinal differentiation in neoplasms. In the Nordic Immunohistochemical Quality Control external quality assessment scheme, only 45% of the laboratories participating in the CDX2 challenge in 2009 produced sufficient staining. A major cause of insufficient staining results appeared to be less successful primary antibody (Ab) clones. To evaluate the Ab performance in a standardized way, a comparative study was carried out. Tissue microarrays containing 309 non-neoplastic tissues and tumor samples with expected high, low, and no CDX2 expression were used. Five Abs were selected for comparison: EPR2764Y concentrated (Conc), EPR2764Y in a ready-to-use format, and DAK-CDX2, AMT28, and CDX2-88, all Conc. The CDX2 stains were scored blindly using the H-score method. Tissue/tumor samples with a maximum H-score of 150 to 300 (on the basis of the staining giving the highest score) were classified as CDX2 high expressors, samples with a maximum H-score of 10 to 149 as low expressors, and samples with a maximum H-score <10 as negative.

A total of 106 tumors were CDX2 positive with at least one of the Abs. For 56 high-expressor tumors, the mean H-scores with EPR2764Y Conc, EPR2764Y ready-to-use, DAK-CDX2, AMT28, and CDX2-88 were 262, 236, 234, 167, and 149, respectively, and the percentage of positive tumors 100, 100, 100, 98, and 93, respectively. For 50 low-expressor tumors, the mean H-scores with the same Abs were 59, 26, 28, 7, and 5, respectively, and the percentage of positive tumors 98, 58, 64, 18, and 14, respectively. With EPR2764Y Conc, CDX2 was demonstrated in 5/19 (26%) urothelial carcinomas, 7/64 (11%) lung adenocarcinomas, 5/30 (17%) large cell/sarcomatoid lung carcinomas, and 4/19 (21%) esophagus squamous cell carcinomas. In-house optimized protocols gave for all 4 Conc Abs better staining results than the vendors' recommended protocols. The sensitivity of CDX2 Abs and protocols must be taken into consideration when classifying neoplasms of unknown origin.