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Does closure of the zone of apposition at correction of complete atrioventricular septal defect improve outcome?

Outcome after correction of atrioventricular septal defect depends to a great deal on the postoperative function of the left atrioventricular valve. The related role of the zone of apposition ('cleft') has been debated: should it be closed (bileaflet repair) or should it be left untouched (trileaflet repair)? This study aims to answer the question by comparing the outcome of patients treated according to these two approaches. We reviewed all our patients who underwent repair of complete atrioventricular septal defect from 1984 to 1997 and selected those in whom the closure of the zone of apposition in principle would have been possible. Two groups with similar characteristics were constituted: group I (n=63), where the zone of apposition was deliberately not closed as part of a trileaflet repair (postoperative open zone of apposition) and group II (n=96), where it was electively closed as part of a bileaflet AV valve repair (closed zone of apposition). Since we changed from a trileaflet to a bileaflet repair in 1987, the two groups differ in terms of size and length of follow-up. Outcome was compared with regard to survival and freedom from reoperation for left atrioventricular valve incompetence. Late atrioventricular valve function was evaluated by Echo-Doppler. For statistical analysis, we used Chi-square or Fisher's exact test, the Mann-Whitney test and the log-rank test for comparison of Kaplan-Meier curves. The difference was considered statistically significant with a P-value of 0.05 or less. Early mortality was 9.5% (6/63) in group I and 3.1% (3/96) in group II (P=0.16). Actuarial survival after 1, 4 and 8 years was 80.4, 68.4 and 64.8%, respectively, for group I. Actuarial survival for group II was 94.7, 92.1 and 92.1% (P=0.0002). Freedom from reoperation for left atrioventricular valve regurgitation was 90.2, 85.6 and 77.8% for group I at the same time interval. It was a constant 97.9% for group II (P=0.0016). At reoperation, left atrioventricular valve regurgitation was present through the open zone of apposition in 63% of group I cases. The follow-up is 96% (126/131) complete. An increase in degree of left atrioventricular valve incompetence was noted in 28% (11/39) of group I cases and in 9% (8/87) of group II cases (P=0.0131).

This study demonstrates the advantage of closing the zone of apposition ('cleft') as part of repair of complete atrioventricular septal defect. Survival, freedom from reoperation for left atrioventricular valve incompetence and over-all outcome were more favourable in patients of group II. The zone of apposition should be surgically addressed whenever the morphology of the left atrioventricular valve allows for closure without producing stenosis.

The HercepTest and routine C-erbB2 immunohistochemistry in breast cancer: any difference?

The proto-oncogene c-erbB2, located on chromosome 17q21, encodes a 185-kD transmembrane glycoprotein. It is known to be overexpressed, amplified, or both in 20% to 30% of breast cancers. C-erbB2 belongs to the human epidermal growth factor receptor (tyrosine kinase receptor) family that plays an important role in cell cycle regulation and differentiation. Although there are various methods to assess c-erbB2 status in breast cancer, protein overexpression determined by immunohistochemistry and gene amplification using fluorescence in situ hybridisation are most commonly utilised. This study compares the results of the DAKO HercepTest with the immunohistochemical assay (A0485, DAKO), which is routinely used in our pathology laboratory. Paraffin-embedded breast cancer tissues from 41 patients operated in a tertiary hospital during the year 2000 were subjected to immunohistochemistry by the above methods. C-erbB2 positivity was defined by cytoplasmic membrane staining of 2+ or 3+ intensity. Overexpression of c-erbB2 protein was present in 36.6% and 41.5% of cases when detected by HercepTest and the DAKO A0485 antibody, respectively. There was almost perfect agreement between both methods (k = 0.898) when positive versus negative results were considered, and moderate agreement in terms of individual staining intensities (k = 0.554).

Routine immunohistochemistry using the DAKO A0485 antibody is a reliable, cost-effective alternative to the HercepTest in determining prognosis and suitability of patients for Herceptin therapy.

Do tuberculous peritonitis -- miss it?

Incidence of tuberculosis is sharply rising in the United States, and tuberculous peritonitis is often diagnosed late in the course of the disease, resulting in undue patient morbidity and mortality. Purpose of this study was to better identify which clinical, laboratory, radiologic, and invasive procedures were most useful in diagnosing tuberculous peritonitis. All cases of tuberculous peritonitis diagnosed between 1982 and 1994 were reviewed retrospectively to discern which laboratory, radiographic, and procedural tests were helpful in diagnosing the condition. Twenty-eight cases of tuberculous peritonitis were diagnosed during the studied period. Two patients were not diagnosed until autopsy. Patients from all socioeconomic classes and multiple races ranged in age from 3 to 69 (mean, 29.5) years. Most patients presented with a chronic wasting illness, mild abdominal pain, and fever. Purified protein derivative was only positive in 5 of 16 patients. Chest radiographs were suggestive of pulmonary tuberculosis (TB) in five patients. Ultrasound examination of the abdomen was helpful in five patients, and computed tomographic scan was suspicious in 16 of 17 patients. Sputum for acid fast bacillus (AFB) smear was positive in 3 of 14 patients, and paracentesis for AFB smear was positive in 1 of 8 patients. Routine blood work was not helpful. Laparoscopy was diagnostic in five of seven patients. Laparotomy and tissue biopsy of characteristic tissue for AFB smear and culture was diagnostic in 20 of 20 patients. Once diagnosed, all patients responded rapidly to empiric antituberculous medical therapy, except one patient with miliary TB who died shortly after diagnosis. A trend in earlier diagnosis was noted in recent years and is felt to be the result of an elevated index of suspicion.

TB peritonitis may be fatal but is medically cured if diagnosed in a timely fashion. It is essential that the clinician suspect the disease in appropriate patients. Tests frequently associated with TB such as chest radiograph and purified protein derivative are not sensitive in detection of TB peritonitis. Computed tomographic scan is the most useful radiographic study. Mini laparotomy with tissue biopsy for smear and culture is the most sensitive and specific diagnostic procedure.

Does speech and magnetic resonance imaging result following autologous fat transplantation to the velopharynx in patients with velopharyngeal insufficiency?

To measure velopharyngeal closure with magnetic resonance imaging (MRI) and to evaluate speech when treating velopharyngeal insufficiency (VPI) with autologous fat transplantation to the velopharynx. Nine patients were recruited. Six patients had undergone cleft palate repair and subsequently developed VPI. Three were noncleft patients of which one had developed VPI after nasopharyngeal cancer treatment; another patient had developed VPI after combined adenotonsillectomy, and a third patient had VPI of unknown etiology. Preoperative and 1-year postoperative MRIs were obtained during vocal rest and during phonation. Data measured were the velopharyngeal distance in the sagittal plane and the velopharyngeal gap area in the axial plane. Preoperative and 1-year postoperative audio recordings were blinded for scoring independently by three senior speech therapists. When comparing preoperative and 1-year postoperative MRI during phonation we found a significant reduction of the median velopharyngeal distance from 4 to 0 mm (p = .011), and a significant reduction of the median velopharyngeal gap area from 42 to 34 mm(2) (p = .038). Nasal turbulence improved significantly (p = .011). Hypernasality/hyponasality and audible nasal emission did not change significantly.

Autologous fat transplantation to the velopharynx resulted in a significant reduction of the velopharyngeal distance and the velopharyngeal gap area during phonation, as measured by MRI. This was in accordance with a significant improvement in nasal turbulence. However, hypernasality and audible nasal emission did not change significantly and could not be correlated to the MRI findings.

Is tRALI due to pulmonary venule damage from leucocytes with cholesterol crystal formation?

There are two presumed mechanisms for the pulmonary oedema in transfusion-related acute lung injury (TRALI). One is antibodies to leucocytes while the other is biologically active lipids. We evaluated the vascular injury due to the former. The pulmonary vasculature was studied by light microscopy (LM) and scanning electron microscopy (SEM) in three fatal cases of TRALI and compared with that of two autopsied control patients. Lung tissue from two of the TRALI cases and both controls was studied by gas chromatography-mass spectroscopy (GC-MS) to identify crystals present in the former. All three TRALI cases exhibited massive pulmonary oedema by weight and light microscopy and extensive defects by SEM in the endothelium of venules of the lungs. Such endothelial defects were absent in controls. Thrombi, composed of crystals, were present in venules and small veins diffusely throughout the lungs in Case 1. Similar crystals were identified in Case 2. The crystals in the lung vessels were identified morphologically as cholesterol and were proximate to the cytoplasmic defects of the endothelial surfaces. By GC-MS, there were markedly elevated levels of cholesterol and fatty acids in the two TRALI lungs tested compared with the lungs of the two controls.

Pulmonary damage in TRALI is related to formation of cholesterol crystals that appear to pierce endothelial membranes of venules. The endothelial defects lead to plasma extravasation into the alveoli causing TRALI.

Does the HOXB13 G84E Mutation be Associated with an Increased Risk for Prostate Cancer and Other Malignancies?

A rare nonconservative substitution (G84E) in the HOXB13 gene has been shown to be associated with risk of prostate cancer. DNA samples from male patients included in the Mayo Clinic Biobank (MCB) were genotyped to determine the frequency of the G84E mutation and its association with various cancers. Subjects were genotyped using a custom TaqMan (Applied Biosystems) assay for G84E (rs138213197). In addition to donating a blood specimen, all MCB participants completed a baseline questionnaire to collect information on medical history and family history of cancer. Forty-nine of 9,012 male patients were carriers of G84E (0.5%). Thirty-one percent (n = 2,595) of participants had been diagnosed with cancer, including 51.1% of G84E carriers compared with just 30.6% of noncarriers (P = 0.004). G84E was most frequently observed among men with prostate cancer compared with men without cancer (P < 0.0001). However, the mutation was also more commonly observed in men with bladder cancer (P = 0.06) and leukemia (P = 0.01). G84E carriers were more likely to have a positive family history of prostate cancer in a first-degree relative compared to noncarriers (36.2% vs. 16.0%, P = 0.0003).

Our study confirms the association between the HOXB13 G84E variant and prostate cancer and suggests a novel association between G84E and leukemia and a suggestive association with bladder cancer. Future investigation is warranted to confirm these associations in order to improve our understanding of the role of germline HOXB13 mutations in human cancer.

Alanine aminopeptidase activity in urine: a new marker of chronic alcohol abuse?

The purpose of this study was to evaluate the activity of urinary alanine aminopeptidase (AAP), the enzyme released from the brush border membranes of renal proximal tubules, as a new biological marker of chronic alcohol abuse. The AAP activity was assayed and compared between a group of 76 alcoholics undergoing detoxification and a group of 37 alcoholics abstaining from alcohol for at least 6 weeks. In all patients, the enzyme activity was measured both in untreated urine (uAAP) and after removal of endogenous AAP inhibitors by molecular filtration on Sephadex (eAAP). There was a correlation between the uAAP and eAAP activities in both groups of patients (r = 0.61 and r = 0.81 in abstinent alcoholics and in alcoholics undergoing detoxification, respectively), and both the uAAP activity and the eAAP activity were significantly and markedly higher in alcoholics being detoxified than in their abstinent counterparts. As revealed by receiver operating characteristic analysis, the discriminative power of the eAAP activity assay was higher than that of the uAAP activity assay. The area under the corresponding receiver operating characteristic curves was 0.84 +/- 0.04 and 0.78 +/- 0.05 (mean +/- SE), respectively.

The results of this study demonstrate that the assays of urinary AAP activity, which relate to the nephrotoxic effects of alcohol abuse, could be a valuable complement to the other presently used markers of chronic alcohol abuse that are generally based on ethanol hepatotoxicity. Compared with the uAAP activity test, the eAAP activity test is of clear diagnostic advantage.

Do iL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype?

"Alternatively-activated" macrophages are found in Th2-mediated inflammatory settings such as nematode infection and allergic pulmonary inflammation. Due in part to a lack of markers, these cells have not been well characterized in vivo and their function remains unknown. We have used murine macrophages elicited by nematode infection (NeM(phi)) as a source of in vivo derived alternatively activated macrophages. Using three distinct yet complementary molecular approaches we have established a gene expression profile of alternatively activated macrophages and identified macrophage genes that are regulated in vivo by IL-4. First, genes abundantly expressed were identified by an expressed sequence tag strategy. Second, an array of 1176 known mouse genes was screened for differential expression between NeM(phi) from wild type or IL-4 deficient mice. Third, a subtractive library was screened to identify novel IL-4 dependent macrophage genes. Differential expression was confirmed by real time RT-PCR analysis.

Our data demonstrate that alternatively activated macrophages generated in vivo have a gene expression profile distinct from any macrophage population described to date. Several of the genes we identified, including those most abundantly expressed, have not previously been associated with macrophages and thus this study provides unique new information regarding the phenotype of macrophages found in Th2-mediated, chronic inflammatory settings. Our data also provide additional in vivo evidence for parallels between the inflammatory processes involved in nematode infection and allergy.

Do contour analysis of an implant -- soft tissue interface?

Studies of peri-implant soft tissue on in vivo models are commonly based on histological sections prepared using undecalcified or 'fracture' techniques. These techniques require the cutting or removal of implant during the specimen preparation process. The aim of this study is to explore a new impression technique that does not require any cutting or removal of implant for contour analysis of soft tissue around four types of titanium (Ti) surface roughness using an in vitro three-dimensional oral mucosal model (3D OMM). The 3D OMM was constructed by co-culturing a keratinocyte cell line TR146 and human oral fibroblasts on to an acellular dermis scaffold. On the fourth day, a Ti disk was placed into the model. Four types of Ti surface topographies, i.e. polished, machined, sandblasted and anodized were tested. After 10 d of culture, the specimens were processed based on undecalcified (ground sectioning), electropolishing and impression techniques for contour analysis of the implant-soft tissue interface. Under light microscopic examination of the ground and electropolishing sections, it was found that the cell line-based oral mucosa formed a peri-implant-like epithelium attachment on to all four types of Ti surfaces. In contour analysis, the most common contour observed between the cell line-based oral mucosa and Ti surface was at an angle ranging between 45° and 90°.

The in vitro cell line-based 3D OMM formed a peri-implant-like epithelium at the implant-soft tissue interface. The contour of the implant-soft tissue interface for the four types of Ti surface was not significantly different.

Do anthropometry-based equations overestimate the urea distribution volume in hemodialysis patients?

Protein intake in hemodialysis patients can be estimated indirectly from the protein equivalent of total nitrogen appearance (PNA) during the interdialytic period. A reliable estimate of the patient's urea distribution volume (UDV) is required to assess protein intake from PNA values. UDV values are derived frequently from simple anthropometric equations. UDV values based on anthropometric methods were compared with UDV values determined by direct dialysate quantitation (DDQ) in 54 stable chronic hemodialysis patients. The anthropometric methods included the following: the Watson equations (WAT), a fixed proportion of postdialysis body weight, 58% for males and 55% for females (% body wt), and skinfold thickness measurements (SFT). Postdialysis blood samples were drawn at 15-minutes postdialysis. UDV(WAT) and UDV(SFT) overestimated UDV(DDQ) by about 8 L [limits of agreement (LOA): 2.6 to 14.2 L] in males and about 6 L (LOA: -0.8 to 12.4 L) in females. The overestimation by UDV(%BW) was even larger: 10.5 L (LOA: 2.0 to 19.0 L) in males and 11.1 L (LOA: 2.1 to 20.1 L) in females. The difference between UDV(%BW) and UDV(DDQ) correlated with the percentage of body fat (r = 0.57) and body mass index (r = 0.48). In a subgroup of seven patients, UDV was also determined by dilution (DIL) of the stable isotope [(13)C]urea. UDV(WAT) and UDV(%BW) overestimated UDV(DIL) significantly. In contrast, UDV(DDQ) was significantly smaller than UDV(DIL), even after correction for incomplete postdialysis equilibration. PNA values calculated using the various UDV estimates were compared with dietary protein intake (DPI) assessed from food records. PNA(DDQ) (61 +/- 10 g/day) did not differ significantly from DPI (63 +/- 13 g/day), but the agreement in individual patients varied considerably (LOA, -24 to 20 g/day). Anthropometric-based PNA values overestimated DPI by 8 to 16 g/day.

Anthropometry-based equations overestimate UDV values in hemodialysis patients, leading to an overestimation of PNA values. Although PNA measurements by DDQ appear to be more reliable for assessing protein intake, PNA(DDQ) values should be interpreted with caution in individual hemodialysis patients.

Do nPY controls fear conditioning and fear extinction by combined action on Y₁ and Y₂ receptors?

Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y₁ and inhibition of Y₂ receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown. Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice. NPY KO mice display a dramatically accelerated acquisition of conditioned fear. Deletion of Y₁ receptors revealed only a moderately accelerated acquisition of conditioned fear, while lack of Y₂ receptors was without any effect on fear learning. However, the strong phenotype seen in NPY KO mice was reproduced in mice lacking both Y₁ and Y₂ receptors. In addition, NPY KO mice showed excessive recall of conditioned fear and impaired fear extinction. This behaviour was replicated only after deletion of both Y₁ and Y₂ receptors. In Y₁ receptor single KO mice, fear extinction was delayed and was unchanged in Y₂ receptor KO mice. Deletion of NPY and particularly Y₂ receptors resulted in a generalization of conditioned fear.

Our data demonstrate that NPY delays the acquisition, reduces the expression of conditioned fear while promoting fear extinction. Although these effects appear to be primarily mediated by Y₁ receptors, the pronounced phenotype of Y₁Y₂ receptor double KO mice suggests a synergistic role of Y₂ receptors in fear acquisition and in fear extinction.

Is enhancement of muscle cell glucose uptake by medicinal plant species of Canada 's native populations mediated by a common , metformin-like mechanism?

The purpose of the present study was to elucidate the mechanisms of action mediating enhancement of basal glucose uptake in skeletal muscle cells by seven medicinal plant products recently identified from the pharmacopeia of native Canadian populations (Spoor et al., 2006). Activity of the major signaling pathways that regulate glucose uptake was assessed by western immunoblot in C2C12 muscle cells treated with extracts from these plant species. Effects of extracts on mitochondrial function were assessed by respirometry in isolated rat liver mitochondria. Metabolic stress induced by extracts was assessed by measuring ATP concentration and rate of cell medium acidification in C2C12 myotubes and H4IIE hepatocytes. Extracts were applied at a dose of 15-100 microg/ml. The effect of all seven products was achieved through a common mechanism mediated not by the insulin signaling pathway but rather by the AMP-activated protein kinase (AMPK) pathway in response to the disruption of mitochondrial function and ensuing metabolic stress. Disruption of mitochondrial function occurred in the form of uncoupling of oxidative phosphorylation and/or inhibition of ATPsynthase. Activity of the AMPK pathway, in some instances comparable to that stimulated by 4mM of the AMP-mimetic AICAR, was in several cases sustained for at least 18h post-treatment. Duration of metabolic stress, however, was in most cases in the order of 1h.

The mechanism common to the seven products studied here is analogous to that of the antidiabetic drug Metformin. Of interest is the observation that metabolic stress need not be sustained in order to induce important adaptive responses. The results support the use of these products as culturally adapted treatments for insulin resistance and hyperglycemia in susceptible aboriginal populations where adherence to modern diabetes pharmaceuticals is an issue. The mechanism reported here may be widespread and mediate the antidiabetic activity of traditional remedies from various other cultures.

Experience in the screening of Streptococcus group B infection during pregnancy: can severe neonatal infection be prevented?

GBS has been responsible for most cases of severe perinatal infection in the last few decades. 10-30% of women is colonised; the vertical transmission is approximately 50% with pregnant carriers. Since the bacterium is responsible for approximately 50% of perinatal sepsis's, and the same time patients may recover with severe residual symptoms, prevention is of great importance. The authors screened 1762 out of 2214 women before giving birth at the Obst. and Gyn. Ward of the St. Jones Hosp. and the Obst. and Gyn. Ward of Semmelweis University Kútvölgyi Clinic between May. 1998 and Dec. 1999 following the recommendations issued in 1992 and modified in 1997 by the Committee on Infectious Diseases and the Committee on Fetus and Newborn. The rate of positive cultures was approximately 10%, and the rate of colonised newborn was 1.36%. No severe diseases with residual symptoms were recorded during the period of examination.

On the bases of the international literature and their own experiences the authors recommend the GBS screening and prophylaxis by antibiotics based on positive cultures and risk factors.

Does octreotide ameliorate gastric lesions in chronically mild stressed rats?

To evaluate the effect of chronic mild stress (CMS) on the emergence of gastric ulcers and possible modulation by octreotide, a synthetic somatostatin analogue. Adult male Wistar rats were subjected to nine different unpredictable random stress procedures for 21 d, a multifactorial interactional animal model for CMS. Octreotide was administered daily for 21 d at two dose levels (50 and 90 μg/kg) before exposure to stress procedure. Macro- and microscopical assessments were made, in addition to quantification of plasma corticosterone and gastric mucosal inflammatory, oxidative stress, and apoptotic biomarkers. Exposure to CMS elevated plasma corticosterone (28.3 ± 0.6 μg/dL, P = 0.002), an event that was accompanied by gastric lesions (6.4 ± 0.16 mm, P = 0.01) and confirmed histopathologically. Moreover, the insult elevated gastric mucosal lipid peroxides (13 ± 0.5 nmol/g tissue, P = 0.001), tumor necrosis factor-α (3008.6 ± 78.18 pg/g tissue, P < 0.001), prostaglandin E2 (117.1 ± 4.31 pg/g tissue, P = 0.002), and caspase-3 activity (2.4 ± 0.14 OD/mg protein, P = 0.002). Conversely, CMS mitigated interleukin-10 (627.9 ± 12.82 pg/g tissue, P = 0.001). Furthermore, in animals exposed to CMS, octreotide restored plasma corticosterone (61% and 71% from CMS, P = 0.002) at both dose levels. These beneficial effects were associated with a remarkable suppression of gastric lesions (38% and 9% from CMS, P = 0.01) and reversal of derangements in gastric mucosa.

The current investigation provides evidence that exposure to CMS induces gastric ulceration, which was alleviated by administration of octreotide possibly possessing antioxidant, anti-inflammatory, and anti-apoptotic actions.

Do brain fMRI study of crave induced by cue pictures in online game addicts ( male adolescents )?

To study crave-related cerebral regions induced by game figure cues in online game addicts. fMRI brain imaging was done when the subjects were shown picture cues of the WoW (World of Warcraft, Version: 4.1.014250) game. 10 male addicts of WoW were selected as addicts' group, and 10 other healthy male non-addicts who were matched by age, were used as non-game addicts' group. All volunteers participated in fMRI paradigms. WoW associated cue pictures and neutral pictures were shown. We examined functional cerebral regions activated by the pictures with 3.0 T Philips MRI. The imaging signals' database was analyzed by SPM5. The correlation between game craving scores and different image results were assessed. When the game addicts watch the pictures, some brain areas show increased signal activity namely: dorsolateral prefrontal cortex, bilateral temporal cortex, cerebellum, right inferior parietal lobule, right cuneus, right hippocampus, parahippocampal gyrus, left caudate nucleus. But in these same brain regions we did not observe remarkable activities in the control group. Differential image signal densities of the addict group were subtracted from the health control group, results of which were expressed in the bilateral dorsolateral prefrontal cortex, anterior cingulate cortex, inferior parietal lobe and inferior temporal gyrus, cerebellum, right insular and the right angular gyrus. The increased imaging signal densities were significant and positively correlated with the craving scale scores in the bilateral prefrontal cortex, anterior cingulate cortex and right inferior parietal lobe.

Craving of online game addicts was successfully induced by game cue pictures. Crave related brain areas are: dorsolateral prefrontal cortex, anterior cingulate cortex, and right inferior parietal lobe. The brain regions are overlapped with cognitive and emotion related processing brain areas.

Is prostate stromal cell telomere shortening associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial?

Telomeres are repetitive nucleoproteins that help maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing chromosomal fusions by suppressing double-strand break signals. We recently observed that men treated for clinically localized prostate cancer with shorter telomeres in their cancer-associated stromal cells, in combination with greater variation in cancer cell telomere lengths, were significantly more likely to progress to distant metastases, and die from their disease. Here, we hypothesized that shorter stromal cell telomere length would be associated with prostate cancer risk at time of biopsy. Telomere-specific fluorescence in situ hybridization (FISH) analysis was performed in normal-appearing stromal, basal epithelial, and luminal epithelial cells in biopsies from men randomized to the placebo arm of the Prostate Cancer Prevention Trial. Prostate cancer cases (N = 32) were either detected on a biopsy performed for cause or at the end of the study per trial protocol, and controls (N = 50), defined as negative for cancer on an end-of-study biopsy performed per trial protocol (e.g., irrespective of indication), were sampled. Logistic regression was used to estimate the association between mean telomere length of the particular cell populations, cell-to-cell telomere length variability, and risk of prostate cancer. Men with short stromal cell telomere lengths (below median) had 2.66 (95% CI 1.04-3.06; P = 0.04) times the odds of prostate cancer compared with men who had longer lengths (at or above median). Conversely, we did not observe statistically significant associations for short telomere lengths in normal-appearing basal (OR = 2.15, 95% CI 0.86-5.39; P= 0 .10) or luminal (OR = 1.15, 95% CI 0.47-2.80; P = 0.77) cells.

These findings suggest that telomere shortening in normal stromal cells is associated with prostate cancer risk. It is essential to extend and validate these findings, while also identifying the cellular milieu that comprises the subset of cells with short telomeres within the prostate tumor microenvironment.

Do [ Rosiglitazone and all-trans retinoic acid inhibit human myeloma cell proliferation via apoptosis signaling pathway modulation ]?

To investigate the effects of artificial ligand of peroxisome proliferators activated receptors (PPARs), rosiglitazone (RGZ) and all trans-retinoic acid (ATRA) on human myeloma cell line growth in vitro and in vivo. U266 and RPMI 8226 cells were treated with different concentration of RGZ in the presence or absence of ATRA and the results were studied by 3H-TdR thymidine incorporation (for cells proliferation), Annexin V-PI staining and caspase-3 activity assay (for cells apoptosis), RT-PCR (for FLIP, XIAP and survivin mRNA expression), and tumor formation test in BALB/c nude mice. Exposure to RGZ induced proliferation inhibition in a dose-dependent manner in both U266 (r = 0.991, P < 0.01) and RPMI 8226 cells (r = 0.961, P < 0.01). A combination of RGZ with ATRA could enhance the inhibition effect (P < 0.001 in U266, P < 0.01 in RPMI8226). 10 micromol/L of RGZ induced apoptosis of (9.8 +/- 1.7)% in U266 cells and (10.7 +/- 3.3)% in RPMI8226 cells, in a time and dose dependent manner and combined with ATRA intensified the apoptosis induction effects (P < 0.01 in both cell lines). The FLIP, XIAP and survivin mRNAs were expressed in both cell lines and their levels decreased significantly after cultured with RGZ. The addition of RGZ + ATRA in the culture further decreased the levels. Caspase-3 activity increased substantially with the increase of RGZ concentration and the addition of RGZ + ATRA in the culture medium showed similar synergism effect on caspase-3 activation (P < 0.01). The xenograft of U266 cells in BALB/c nude mice were inhibited by RGZ and so did more by the combination of RGZ and ATRA (P < 0.01).

The down-regulation of FLIP, XIAP and Survivin induced by RGZ can activate caspase-3, whereby induced apoptosis and proliferation inhibition in myeloma cells. ATRA can enhance these effects of RGZ.

Does the posterior approach reduce the risk of thin cement mantles with a straight femoral stem design?

The properties of the cement mantle around a prosthesis are important. We investigated whether the surgical approach to the hip influences the quality and thickness of the cement mantle when using a straight femoral stem design. In a consecutive multi-surgeon series, we reviewed the radiographs of 270 patients after cemented Exeter total hip arthroplasty. 135 stems were introduced using an antero-lateral (transgluteal) approach and 135 stems were introduced using a posterior approach. Anterior-posterior and lateral radiographs were reviewed and cement mantle thickness was measured in Gruen zones 1-14. We graded cement mantle quality according to the Barrack classification. Barrack grading did not reveal any difference in cement mantle quality between the two groups. AP and lateral radiographs showed no difference in stem alignment between the groups. The risk of a thin cement mantle (< 2 mm) was lower with a posterior approach (OR = 1.8, 95% CI: 1-3; p = 0.03). The greatest risk of a cement mantle thickness of < 2 mm occurred in Gruen zones 8-9 regardless of the surgical approach used.

With a straight femoral stem design, the posterior approach to the hip joint appears to give a lower risk of a thin cement mantle. Irrespective of the approach, there was a risk of thin cement mantles in Gruen zones 8 and 9, which highlights the importance of lateral radiographs in the postoperative radiographic assessment of total hip replacements.

Do high progesterone concentrations induce acrosome reaction with a low cytotoxic effect?

To determine the optimal conditions to obtain live acrosome-reacted spermatozoa for micromanipulation. Experiments were performed to determine time and dose-dependent effects of calcium ionophore A23187 or steroids on acrosome reaction of fertile donor sperm. The percentages of total reacted and live reacted spermatozoa were assessed with the peanut agglutinin lectin procedure. Incubation with 1 mmol/L progesterone (P) induced 48% +/- 17% acrosome reaction after 6 hours. Motility and viability remained high (49% +/- 3% and 70% +/- 2%, respectively) and thus the percentage of live reacted spermatozoa was 27% +/- 5%. Incubation with A23187 (5 mumol/L for 30 minutes) gave similar results for the percentage of live reacted spermatozoa (26% +/- 4%) but with a lower motility and viability (25% +/- 7% and 53% +/- 2%, respectively; P less than 0.05).

These results show that high concentration of P is an effective way to induce acrosome reaction in preparation for micromanipulation.

Do positive alcohol expectancies have a critical developmental period in pre-adolescents?

Positive outcome expectancies have been shown to predict initiation of alcohol use in children and to mediate and moderate the relationship between dispositional variables and drinking behavior. Negative outcome expectancies for alcohol appear to weaken as children progress to middle adolescence, but positive expectancies tend to increase during this time. Positive alcohol expectancies have been found to increase in children in third and fourth grades, indicating what some investigators have termed a possible critical period for the development of positive expectancies. In the present study, we assessed alcohol expectancies at baseline, 6, 12, and 18 months in 277 second-through sixth-grade students. Children completed the Alcohol Expectancy Questionnaire-Adolescent. Univariate analyses of covariance were conducted. There were significant main effects for grade on positive alcohol-expectancy change for Global Positive Transformations at 12 and 18 months, Social Behavior Enhancement or Impediment at 6 and 12 months, and Relaxation/Tension Reduction at 6 and 18 months, whereby a consistent pattern emerged in that lower grades did not differ from each other, but they differed significantly from the higher grades.

Data support a critical developmental period for positive alcohol expectancies, with the greatest change observed between third and fourth grade and between fourth and fifth grade, and only in those expectancies clearly describing positive outcomes (e.g., Relaxation/Tension Reduction) via positive or negative reinforcement versus those with either combined or ambiguous outcomes (e.g., Social Behavior Enhancement or Impediment).

Does chronic clomipramine treatment restore hippocampal expression of glial cell line-derived neurotrophic factor in a rat model of depression?

Because there is evidence that certain neurotrophic factors are involved in depression and the mechanism of antidepressant treatment, it is hypothesized that neurotrophic factors may also play a functional role in the etiology of depression and treatment. Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor (TGF-β)-super-family. We performed a study to assess the impact of chronic unpredictable stress (CUS) and clomipramine treatment on GDNF expression in the rat hippocampus. Using a rat model of CUS-induced depression, we administered clomipramine, one of the typical antidepressants, every day for 3 weeks starting 2 weeks after the beginning of the experiment. GDNF level in the hippocampus was detected by immunohistochemsitry, Western blot analysis, and reverse transcription-polymerase chain reaction (RT-PCR). Behavioral changes were measured by forced swimming test (FST) and open field test (OFT). Animals exposed to CUS showed depression-like behavior and exhibited a significant decrease in GDNF expression in the hippocampus. Chronic clomipramine treatment reversed the behavioral deficits and the decrease in GDNF levels induced by CUS.

The relatively small number of the depression-model rats may cause some bias of behavioral tests.

Is longitudinal restriction spectrum imaging resistant to pseudoresponse in patients with high-grade gliomas treated with bevacizumab?

Antiangiogenic therapies, such as bevacizumab, decrease contrast enhancement and FLAIR hyperintensity in patients with high-grade gliomas in a manner that may not correlate with actual tumor response. This study evaluated the ability of an advanced DWI technique, restriction spectrum imaging, to improve conspicuity within regions of restricted diffusion compared with ADC in patients treated with bevacizumab and to demonstrate that unlike ADC, restriction spectrum imaging is less affected by bevacizumab-induced reductions in FLAIR hyperintensity. Restriction spectrum imaging cellularity maps and DWI were available for 12 patients with recurrent high-grade gliomas at baseline and following initiation of bevacizumab. VOIs were drawn for regions of restricted diffusion, surrounding FLAIR hyperintensity, and normal-appearing white matter; and intensity values within regions of restricted diffusion and FLAIR hyperintensity were normalized to normal-appearing white matter. Normalized values were compared between restriction spectrum imaging cellularity maps and ADC at baseline and on treatment by using repeated-measures ANOVA. All patients exhibited decreases in contrast enhancement and FLAIR hyperintensity following treatment. Normalized intensity values were higher on restriction spectrum imaging cellularity maps compared with ADC in regions of restricted diffusion, whereas intensity values were higher on ADC compared with restriction spectrum imaging cellularity maps in regions of FLAIR hyperintensity. Bevacizumab-induced decreases in FLAIR hyperintensity had a greater effect on ADC than on the restriction spectrum imaging cellularity maps, with the relative sensitivity of ADC to changes in FLAIR hyperintensity being >20 times higher than that on restriction spectrum imaging cellularity maps.

Restriction spectrum imaging is less influenced by reductions in FLAIR hyperintensity compared with ADC, which may confer an advantage of restriction spectrum imaging over ADC for interpreting tumor response on imaging following antiangiogenic therapy.

Does emergent Surgery Independently Predict 30-Day Mortality After Paraesophageal Hernia Repair : Results from the ACS NSQIP Database?

Patients undergoing emergency surgery for paraesophageal hernia (PEH) repair have a higher adjusted mortality risk based on Nationwide Inpatient Sample (NIS). We sought to examine this relationship in the National Surgical Quality Improvement Program (NSQIP), which adjusts for patient-level risk factors, including factors contributing to patient frailty. This is a retrospective analysis of the NSQIP from 2009 through 2011. A modified frailty index was created based on previously validated methodology. Of 3498 patients with PEH repair, 175 (5 %) underwent emergent surgery. Older age, lower BMI, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), current dialysis, SIRS, and sepsis were significantly more common among emergent patients. These patients also had a poorer functional status, higher American Society of Anesthesiologists (ASA), and higher frailty scores and more likely to undergo open surgery. Postoperative complications were proportionally more common, and LOS was longer (8.5 vs. 3.4 days) among emergent patients (all p < 0.05). In univariate analysis, emergent patients demonstrated ten times greater mortality than the elective surgery group (8 vs. 0.8 %). On adjusted analysis, emergent surgery was no longer independently associated with mortality. Frailty score 2 or above and preoperative sepsis significantly predicted increased mortality while laparoscopic repair and BMI 25-50 and BMI ≥30 (vs. BMI <18.5) were significantly protective in the entire group of patients.

Increased mortality among patients undergoing emergent PEH repair may be related to severity of disease and other preoperative comorbid illness. Without an emergent indication, some of these patients likely would have been excluded as candidates for elective surgical intervention.

Does hydrogen sulfide attenuate spatial memory impairment and hippocampal neuroinflammation in β-amyloid rat model of Alzheimer 's disease?

Endogenously produced hydrogen sulfide (H(2)S) may have multiple functions in brain. An increasing number of studies have demonstrated its anti-inflammatory effects. In the present study, we investigated the effect of sodium hydrosulfide (NaHS, a H(2)S donor) on cognitive impairment and neuroinflammatory changes induced by injections of Amyloid-β(1-40) (Aβ(1-40)), and explored possible mechanisms of action. We injected Aβ(1-40) into the hippocampus of rats to mimic rat model of Alzheimer's disease (AD). Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia. The expression of interleukin (IL)-1β and tumor necrosis factor (TNF)-α was measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The expression of Aβ(1-40), phospho-p38 mitogen-activated protein kinase (MAPK), phospho-p65 Nuclear factor (NF)-κB, and phospho-c-Jun N-terminal Kinase (JNK) was analyzed by western blot. We demonstrated that pretreatment with NaHS ameliorated learning and memory deficits in an Aβ(1-40) rat model of AD. NaHS treatment suppressed Aβ(1-40)-induced apoptosis in the CA1 subfield of the hippocampus. Moreover, the over-expression in IL-1β and TNF-α as well as the extensive astrogliosis and microgliosis in the hippocampus induced by Aβ(1-40) were significantly reduced following administration of NaHS. Concomitantly, treatment with NaHS alleviated the levels of p38 MAPK and p65 NF-κB phosphorylation but not JNK phosphorylation that occurred in the Aβ(1-40)-injected hippocampus.

These results indicate that NaHS could significantly ameliorate Aβ(1-40)-induced spatial learning and memory impairment, apoptosis, and neuroinflammation at least in part via the inhibition of p38 MAPK and p65 NF-κB activity, suggesting that administration of NaHS could provide a therapeutic approach for AD.

Secretory cells in adenomatoid odontogenic tumour: tissue induction or metaplastic mineralisation?

To undertake a detailed histological investigation of a large series of adenomatoid odontogenic tumours (AOT) to document the frequency and histomorphology of secretory cells which might indicate an inductive capacity. Haematoxylin and eosin stained sections of 51 cases of AOT were reviewed. Selected cases were stained with periodic acid-schiff (PAS) and Congo red. In five cases, secretory structures with a circular arrangement of tall columnar cells secreting enameloid-like matrix material were identified. Such structures have only very rarely been identified in AOT and their frequency, distribution and morphology have not been adequately documented.

We have documented the presence of tall secretory columnar cells, arranged in a circular configuration actively secreting enameloid-like material and believe that such an ordered arrangement of secretory cells is more likely a result of tissue induction rather than metaplasia. The origin of these secretory structures from the pseudo-ductular component is unlikely but cannot be ruled out.

Do neuroactive antiretroviral drugs influence neurocognitive performance in less advanced HIV-infected patients responding to highly active antiretroviral therapy?

To analyze the effect of antiretroviral therapy, including drugs that have good penetration in cerebrospinal fluid (CSF), on neuropsychologic performance. One hundred sixty-five HIV-1-infected patients exposed to a stable highly active antiretroviral therapy (HAART) regimen were studied. Neuropsychologic examinations were performed for all patients. A total of 50.3% of patients were impaired. In multivariate analysis, older age (for 10-year increase, odds ratio [OR] = 4.8, 95% confidence interval [CI]: 2.2 to 10.4; P< 0.0001) and higher plasma HIV-1 RNA levels (OR = 1.90, 95% CI: 1.1 to 3.2; P = 0.021) at testing were independently associated with an increased probability of impaired neurocognitive performance, whereas higher educational level was a protective factor (OR = 0.76, 95% CI: 0.65 to 0.90; P=0.001). A significant linear correlation was observed between the neuropsychologic z score for 8 tests (NPZ8) score, a quantitative parameter of neurocognitive impairment, and CD4 cell count at neuropsychologic testing (R = 0.273, P = 0.001) and between the NPZ8 score and the patient's age (R = 0.288, P = 0.001).

Our study indicates that the use of stable HAART, including multiple drugs that have good CSF penetration, was not associated with neuropsychologic performance. To prevent independent replication of HIV in CSF with better control of a relevant reservoir of HIV is one of the crucial aims of therapeutic strategy.

Do runs of homozygosity reveal signatures of positive selection for reproduction traits in breed and non-breed horses?

Modern horses represent heterogeneous populations specifically selected for appearance and performance. Genomic regions under high selective pressure show characteristic runs of homozygosity (ROH) which represent a low genetic diversity. This study aims at detecting the number and functional distribution of ROHs in different horse populations using next generation sequencing data. Next generation sequencing was performed for two Sorraia, one Dülmen Horse, one Arabian, one Saxon-Thuringian Heavy Warmblood, one Thoroughbred and four Hanoverian. After quality control reads were mapped to the reference genome EquCab2.70. ROH detection was performed using PLINK, version 1.07 for a trimmed dataset with 11,325,777 SNPs and a mean read depth of 12. Stretches with homozygous genotypes of >40 kb as well as >400 kb were defined as ROHs. SNPs within consensus ROHs were tested for neutrality. Functional classification was done for genes annotated within ROHs using PANTHER gene list analysis and functional variants were tested for their distribution among breed or non-breed groups. ROH detection was performed using whole genome sequences of ten horses of six populations representing various breed types and non-breed horses. In total, an average number of 3492 ROHs were detected in windows of a minimum of 50 consecutive homozygous SNPs and an average number of 292 ROHs in windows of 500 consecutive homozygous SNPs. Functional analyses of private ROHs in each horse revealed a high frequency of genes affecting cellular, metabolic, developmental, immune system and reproduction processes. In non-breed horses, 198 ROHs in 50-SNP windows and seven ROHs in 500-SNP windows showed an enrichment of genes involved in reproduction, embryonic development, energy metabolism, muscle and cardiac development whereas all seven breed horses revealed only three common ROHs in 50-SNP windows harboring the fertility-related gene YES1. In the Hanoverian, a total of 18 private ROHs could be shown to be located in the region of genes potentially involved in neurologic control, signaling, glycogen balance and reproduction. Comparative analysis of homozygous stretches common in all ten horses displayed three ROHs which were all located in the region of KITLG, the ligand of KIT known to be involved in melanogenesis, haematopoiesis and gametogenesis.

The results of this study give a comprehensive insight into the frequency and number of ROHs in various horses and their potential influence on population diversity and selection pressures. Comparisons of breed and non-breed horses suggest a significant artificial as well as natural selection pressure on reproduction performance in all types of horse populations.

Does low arginine/asymmetric dimethylarginine ratio deteriorate systemic hemodynamics and organ blood flow in a rat model?

Both arginine and asymmetric dimethylarginine (ADMA) play a crucial role in the arginine-nitric oxide pathway. Low arginine and high ADMA levels can be found in critically ill patients after major surgery. The aim of this study was to evaluate the effects of low arginine plasma concentrations in combination with high ADMA plasma concentrations on hemodynamics and organ blood flow. Randomized, placebo-controlled animal laboratory investigation. Male Wistar rats (n = 21), anesthetized. Rats were randomly assigned to three groups: a control group, an ADMA group, or an arginase (ASE)/ADMA group. In the control group, rats received (at t = 0) an intravenous (IV) infusion of 1.5 mL 0.9% NaCl during a 20-minute period. After 60 minutes (t = 60), rats received an IV bolus of 1.0 mL 0.9% NaCl. In the ADMA group, rats received an IV infusion of 1.5 mL 0.9% NaCl during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg). In the ASE/ADMA group, rats received an IV infusion of 1.5 mL ASE (3200 IU) solution during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg). Infusion of ADMA (20 mg/kg) and ASE (3200 IU) resulted in increased plasma ADMA levels and decreased arginine levels. During the whole experiment, systemic hemodynamics (heart rate, mean arterial pressure [MAP], and cardiac output) were measured. In addition, organ blood flow was measured at t = 90 and t = 180 minutes, using fluorescent microspheres. Compared with the control group, MAP and systemic vascular resistance were increased after infusion of ADMA. Infusion of ASE in combination with ADMA significantly deteriorated systemic hemodynamics (MAP, cardiac output, stroke volume, and systemic vascular resistance) and organ blood flow through the kidney and spleen. In addition, an initial decrease in arterial flow, followed by a later major increase, and panlobular apoptosis and necrosis of the liver was observed.

The current study shows that low arginine plasma levels in combination with high ADMA plasma levels deteriorates systemic hemodynamics and reduces blood flow through the kidney and spleen and liver. These data suggest that a diminished nitric oxide production may be involved in the onset of organ failure.

Data quality of surgery for carotid artery stenosis. Are the national vascular registries reliable?

To study completeness of reporting carotid endarterectomies, including peri-operative stroke and mortality rate, in a national vascular registry, NorKar, and a national administrative registry, The Norwegian Patient Register (NPR). Comparative registry-based national study. Member hospitals of NorKar, including 89% of carotid endarterectomies in Norway, were compared with relevant data in NPR for the years 2000-2002. We compared procedure-codes, diagnosis-codes, in-hospital death and the occurrence of peri-operative stroke after treatment for carotid artery stenosis in the two registries to evaluate completeness. Compared with the NPR numbers, 16% of carotid endarterectomies were missing in the reports from member hospitals of NorKar. Further, during this three-year period, there was an under-reporting of seven strokes and two deaths. The discrepancy was most pronounced in 2001.

There is an under-reporting of patients operated on for carotid artery stenosis in NorKar according to NPR numbers as well as an under-reporting of early deaths and strokes. There is a need for better quality data in the NorKar Registry. Registry quality would be likely to improve if patient identifiable data were available in both registries.

The quantified self: closing the gap between general knowledge and particular case?

This paper addresses the movements 'evidence-based' (EBM) and 'personalized' (PM) medicine. The former is being criticized for failing to do justice to clinical complexity and human individuality. The latter aims at tailoring medical knowledge for every patient in a personalized fashion. Instrumental to this effort is the technological development engendering unlimited amounts of data about bodily fragments. The aim of this article is to stimulate a debate about the notion of the body and knowledge in medicine. An authentic sickness history is used as a vantage point for a more comprehensive account of biomedicine. The analysis of the sickness history demonstrates how biomedical logic guided all approaches in the care for this particular patient. Each problem was identified and treated separately, whereby neglecting the interaction between body parts and systems, and between the woman's bodily condition and her experiences. The specialists involved seemed to look for phenomena that fit categories of disorders 'belonging' to their field. These approaches engendered unintended effects: chronification, poly-pharmacy and multi-morbidity, leading to an unsustainable increase in medical costs.

The article elucidates how the status that professionals ascribe to the body has vital implications for what they regard as relevant and how they interpret the information they have collected. On this ground, we challenge both the prevailing and tacitly accepted separation between the physical body and human experience and the view of knowledge underpinning EBM and PM. The growing molecularization of the body veils decisive sources of human illness.

Do concealed maternal blood glucose excursions correlate with birth weight centile?

The objective of this study was to test the hypothesis that maternal blood glucose excursions correlate with deviation from optimized birth weight. Patients were recruited for 3-day continuous glucose monitoring (CGM) plus self-blood glucose monitoring followed by routine diabetes screening at 26-28 weeks gestation. Patients and caregivers were blinded to CGM results. The magnitude and duration of blood glucose (BG) excursions were measured as a "glycemia index." A customized birth weight centile was calculated. Twenty-three patients consented, 21 completed the study: 5 diabetic and 16 nondiabetic individuals. The duration of CGM was 72 (+/-7.2) hours, and each patient performed self-BG monitoring >/=3 times per day. All diabetic and 10 nondiabetic patients had several measured BG excursions above 130 mg/dl. A positive correlation was observed between birth weight centile and glycemia index above 130 (p < 0.03); the trend persisted for nondiabetic patients alone (p < 0.05). No significant correlation was noted between birth weight centile and average 3-day CGM values, 3-day fasting BG, average 3-day self-BG monitoring values, or diabetes screening BG value.

The glycemia index has a better correlation with birth weight centile than BG measured by conventional methods in a mixed diabetic and nondiabetic population. Fetal exposure to maternal blood glucose excursions correlates positively with fetal growth, even in nondiabetic patients with apparently normal glucose tolerance.

Does zoledronic acid inhibit visceral metastases in the 4T1/luc mouse breast cancer model?

It is established that bisphosphonates (BPs), specific inhibitors of osteoclasts, have beneficial effects on bone metastases of breast cancer. In addition, recent studies have reported that BPs have anticancer effects and suppress visceral metastases, too. However, the results of clinical studies are still conflicting. In the present study, we examined the effects of the BP zoledronic acid (ZOL), one of the most potent BPs currently available, on visceral metastases of breast cancer using an animal model in which mouse breast cancer cells 4T1/luc implanted at the orthotopic mammary fat pad spontaneously metastasize to multiple organs including bone, lung, and liver in female BALB/c mice. The 4T1/luc-bearing mice received single or four i.v. injections of ZOL (0.5 or 5 microg/mouse) during the whole experimental period. Bone metastases were reduced by the ZOL treatment. More importantly, ZOL significantly suppressed lung and liver metastases. Furthermore, ZOL prolonged overall survival of the tumor-bearing mice. Of interest, apoptosis in 4T1/luc cells colonized in bone was increased by ZOL; however, those in lung were not changed. In vitro studies demonstrated that ZOL inhibited cell migration and invasion and promoted apoptosis of 4T1/luc cells.

These results are consistent with the notion that ZOL affects breast cancer metastasis to visceral organs as well as bone. These effects of ZOL may be attributable to inhibition of migration and invasion of breast cancer cells. Clinical relevance of our experimental results needs to be determined in breast cancer patients with visceral metastases.

Does supracervical hysterectomy provide more support to the vaginal apex than total abdominal hysterectomy?

The objective of the study was to assess whether cervical preservation at the time of hysterectomy may help prevent subsequent apical vaginal vault prolapse. Supracervical hysterectomies were performed in 12 unembalmed cadavers. Successive hanging weights of 1, 2, 3, and 4 kg were loaded against the cervical stump and distances moved were recorded. The same process was repeated after completion of a total hysterectomy. Average distances pulled with 1, 2, 3, and 4 kg of traction against the cervical stump were 17.8 +/- 1.9, 24.1 +/- 2.5, 29.0 +/- 2.8, and 34.3 +/- 3.5 mm, respectively. After total hysterectomy, these distances were 17.5 +/- 2.5, 23.5 +/- 2.6, 29.3 +/- 3.1, and 34.5 +/- 3.6 mm, respectively.

In unembalmed cadavers, it appears that total abdominal hysterectomy and supracervical hysterectomy provide equal resistance to forces applied to the vaginal apex.

Does endothelium-derived hyperpolarizing factor mediate bradykinin-stimulated tissue plasminogen activator release in humans?

Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. In 33 healthy subjects (age 40.3 ± 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 µmol/min), fluconazole (0.4 µmol·min(-1)·l(-1)), and N(G)-monomethyl-L-arginine (L-NMMA, 8 µmol/min) to block nitric oxide, and their combination in separate studies. BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 ± 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 ± 9.0 to 21.3 ± 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 ± 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 ± 5.7 to -0.8 ± 3.6 ng/min/100 ml, p = 0.0002). L-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant).

BK-stimulated t-PA release is partly due to cytochrome P450-derived epoxides and is inhibited by K(+)Ca channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.

Does ascl2 knockdown result in tumor growth arrest by miRNA-302b-related inhibition of colon cancer progenitor cells?

Achaete scute-like 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor, controls the fate of intestinal stem cells. However, the role of Ascl2 in colon cancer progenitor cells remains unknown. The cell line HT-29 (47.5-95% of CD133(+) population) and LS174T (0.45% of CD133(+) population) were chosen for functional evaluation of Ascl2 in colon cancer progenitor cells after gene knockdown by RNA interference. Immunohistochemistry demonstrated that Ascl2 was significantly increased in colorectal adenocarcinomas. Downregulation of Ascl2 using RNA interference in cultured colonic adenocarcinoma HT-29 and LS174T cells reduced cellular proliferation, colony-forming ability, invasion and migration in vitro, and resulted in the growth arrest of tumor xenografts in vivo. The Ascl2 protein level in CD133(+) HT-29 cells was significantly higher than in CD133(-) HT-29 cells. Ascl2 blockade via shRNA interference in HT-29 cells (shRNA-Ascl2/HT-29 cells) resulted in 26.2% of cells staining CD133(+) compared with 54.7% in control shRNA-Ctr/HT-29 cells. The levels of 'stemness' associated genes, such as CD133, Sox2, Oct4, Lgr5, Bmi1, and C-myc, were significantly decreased in shRNA-Ascl2/HT-29 and shRNA-Ascl2/LS174T cells in vitro as well as in the corresponding tumor xenograft (CD133 was not performed in shRNA-Ascl2/LS174T cells). The shRNA-Ascl2/HT-29 cells had inhibited abilities to form tumorspheres compared with control. The microRNA (miRNAs) microarrays, identified 26 up-regulated miRNAs and 58 down-regulated miRNAs in shRNA-Ascl2/HT-29 cells. Expression levels of let-7b, miRNA-124, miRNA-125b, miRNA-17, miRNA-20a and miRNA-302b, involved in the regulation of 'stemness', were quantified with qPCR, which confirmed their identities. Restoration of miRNA-302b, via its mimic, led to the restoration of shRNA-Ascl2/HT-29 'stemness' characteristics, including tumorsphere formation and 'stemness' associated genes levels, and the recovery of cellular behaviors, including colony-forming ability, invasion and migration in vitro.

Ascl2 may be a potential target for the inhibition of colon cancer progenitor cells, and functions through a miR-302b-related mechanism.

Is intestinal alkaline phosphatase protective to the preterm rat pup intestine?

Necrotizing enterocolitis (NEC) is the most common surgical emergency in neonates, with a mortality rate between 10 and 50%. The onset of necrotizing enterocolitis is highly variable and associated with numerous risk factors. Prior research has shown that enteral supplementation with intestinal alkaline phosphatase (IAP) decreases the severity of NEC. The aim of this study is to investigate whether IAP is protective to the preterm intestine in the presence of formula feeding and in the absence of NEC. Preterm rat pups were fed formula with or without supplementation with IAP, and intestine was obtained on day of life 3 for analysis of IAP activity, mRNA expression of TNFα, IL-6 and iNOS and permeability and cytokine expression after LPS exposure. There was no difference in the absolute and intestine specific alkaline phosphatase activity in both groups. Rat pups fed IAP had decreased mRNA expression of the inflammatory cytokines TNFα, IL-6 and iNOS. Pups supplemented with IAP had decreased permeability and inflammatory cytokine expression after exposure to LPS ex vivo when compared to formula fed controls.

Our results support that IAP is beneficial to preterm intestine and decreases intestinal injury and inflammation caused by LPS.

Does pulse transit time improve detection of sleep respiratory events and microarousals in children?

To evaluate the additional information provided by pulse transit time (PTT), a noninvasive tool, when using during polysomnography for the diagnosis of sleep breathing disorders in a pediatric population. Respiratory and microarousals events were scored twice. The first scoring was performed using nasal pressure, thermistors, thoracic and abdominal movements, and oxygen saturation. The second scoring, blinded to the first scoring, was performed using PTT in combination with all the other signals. Microarousals were scored once visually on the EEG trace (cortical arousals [CAs]) and once using the PTT signal (autonomic arousals [AAs]) blinded to EEG. For the whole group of 16 children studied (mean age, 9.5 years), there was no significant difference between the respiratory disturbance index (RDI) with or without PTT analysis (22.4 +/- 13.5/h vs 20.4 +/- 14.3/h; not significant [mean +/- SD]). Among the children exhibiting a "without PTT" RDI < 30/h, 5 of 12 children (41.66%) showed a clinically significant >/= 5/h increase in RDI when using PTT. AAs detected by PTT were significantly more frequent than CAs during rapid eye movement (REM) sleep (7.4 +/- 3.9/h vs 3.2 +/- 2.3/h; p < 0.001) and slow wave sleep (SWS) [6.0 +/- 4.3/h vs 0.6 +/- 0.5/h; p < 0.0001].

The quantification of respiratory effort using PTT improves the detection of respiratory events in children. The detection of microarousals is improved particularly in REM and SWS.

Disability and rehabilitation: do we ever think about needed dental care?

To foster an awareness of the need for oral health care as a component of a programme for rehabilitation of individuals with disabilities. A case study of the USA is used to illustrate the evolving community residential settings for individuals with disabilities and the resulting complexities in the delivery of health services. Examples of oral health conditions frequently present in individuals with disabilities are provided. National and local reports indicate that barriers exist in the delivery of oral health services for individuals with intellectual/developmental and later life disabilities.

Oral health care is a component of rehabilitation, as long as attendant pain erodes energy and aspirations of individuals with disabilities. Dental practitioners face many of the same complex difficulties encountered by other health practitioners in the provision of services for individuals with disabilities. The need is for the practitioners in the many health fields to play an important role in developing an awareness of, and referrals for, necessary oral health care.

Does chronic intermittent toluene inhalation in adolescent rats result in metabolic dysfunction with altered glucose homeostasis?

Abuse of toluene-containing inhalants is an increasing public health problem, especially among adolescents. Abuse during adolescence is associated with emaciation, while industrial exposure leads to altered glycaemic control suggesting metabolic instability. However, the relationship between adolescent inhalant abuse and metabolic dysfunction remains unknown. To model human abuse patterns, we exposed male adolescent Wistar rats [postnatal day (PND) 27] to chronic intermittent inhaled toluene (CIT, 10,000 ppm) or air (control) for 1 h·day(-1) , three times a week for 4 weeks. Feeding and body composition were monitored. After 4 weeks, circulating metabolic hormone concentrations and responses to a glucose tolerance test (GTT) were measured. Dietary preference was measured by giving animals access to either a 'western diet' plus standard chow (WC + SC) or standard chow alone during 4 weeks of abstinence. Metabolic hormones and GTT were subsequently measured. Adolescent CIT exposure significantly retarded weight gain, altered body composition, circulating metabolic hormones and responses to a GTT. While reduced body weight persisted, responses to a GTT and circulating hormones appeared to normalize for animals on standard chow following abstinence. In CIT-exposed WC + SC rats, we observed impaired glucose tolerance associated with altered metabolic hormones. Analysis of hypothalamic genes revealed differential expression profiles in CIT-exposed rats following both the exposure period and abstinence, suggesting a central contribution to inhalant-induced metabolic dysfunction.

CIT exposure during adolescence has long-term effects on metabolic function, which may increase the risk of disorders related to energy balance and glycaemic control.

Does asian sand dust enhance rhinovirus-induced cytokine secretion and viral replication in human nasal epithelial cells?

Asian sand dust (ASD) originating in the arid deserts of Mongolia and China causes annual severe air pollution events in the Asia-Pacific area, including Korea, Japan, and China. ASD is thought to impact public health by aggravating or inducing respiratory illness. Among the most common respiratory illnesses is the common cold caused by rhinovirus (RV) infection. To date, however, the impact of ASD on RV infection has not been studied. In this study, we investigated the effect of ASD on RV infection in human nasal epithelial cells. Primary human nasal epithelial cells grown at an air-liquid interface were treated with ASD and/or RV. After RV infections were confirmed using semi-nested reverse transcription-polymerase chain reaction (RT-PCR), mRNA expression and protein secretion of the inflammatory cytokines interferon-γ (IFN-γ), interleukin-1β (IL-1β),IL-6, and IL-8, indicators of the severity of RV-induced inflammation, were measured by real-time PCR and enzyme-linked immunosorbent assays. Viral titer was also assayed by culturing viruses to compare viral replication between RV-only and ASD-plus-RV groups. ASD significantly increased RV-induced IFN-γ, IL-1β, IL-6, and IL-8 mRNA levels and protein secretion in primary nasal epithelial cells. In addition, ASD caused a significant increase in RV replication.

Our results suggest that ASD may potentiate common cold symptoms associated with RV infection not only by enhancing IFN-γ, IL-1β, IL-6, and IL-8 secretion, but also by increasing viral replication.

Gastrointestinal symptoms after pelvic radiotherapy: role for the gastroenterologist?

To analyze the cause of GI symptoms after pelvic radiotherapy (RT) in a consecutive series of patients with symptoms beginning after RT. A striking lack of evidence is available concerning the optimal treatment for the 50% of patients who develop permanent changes in bowel habits affecting their quality of life after pelvic RT. As a result, in the UK, most such patients are never referred to a gastroenterologist. All diagnoses were prospectively recorded from a consecutive series of patients with symptoms that started after RT and who were referred during a 32-month period to a gastroenterology clinic. Patients either underwent direct access flexible sigmoidoscopy or were investigated in a standard manner by one gastroenterologist after first being seen in the clinic. A total of 265 patients referred from 15 institutions were investigated. They included 90 women (median age, 61.5 years; range, 22-84 years) and 175 men (median age, 70 years; range, 31-85 years). RT had been completed a median of 3 years (range, 0.1-34 years) before the study in the women and 2 years (range, 0-21 years) before in the men. Of the 265 patients, 171 had primary urologic, 78 gynecologic, and 16 GI tumors. The GI symptoms included rectal bleeding in 171, urgency in 82, frequency in 80, tenesmus, discomfort, or pain in 79, fecal incontinence in 79, change in bowel habit in 42, weight loss in 19, vomiting without other obstructive symptoms in 18, steatorrhea in 7, nocturnal defecation in 8, obstructive symptoms in 4, and other in 24. After investigation, significant neoplasia was found in 12%. One-third of all diagnoses were unrelated to the previous RT. More than one-half of the patients had at least two diagnoses. Many of the abnormalities diagnosed were readily treatable. The symptoms were generally unhelpful in predicting the diagnosis, with the exception of pain, which was associated with neoplasia (p<0.001).

The results of our study have shown that radiation enteritis is not a single disease entity. More than one-half of the patients had more than one GI diagnosis contributing to their symptoms. After pelvic RT, specific GI symptoms were not a reliable measure of the underlying diagnoses, and the evaluation of new GI symptoms is worthwhile. An algorithm for this purpose is proposed.

Does childhood trauma mediate the association between ethnic minority status and more severe hallucinations in psychotic disorder?

Ethnic minority status and childhood trauma are established risk factors for psychotic disorders. Both are found to be associated with increased level of positive symptoms, in particular auditory hallucinations. Our main aim was to investigate the experience and effect of childhood trauma in patients with psychosis from ethnic minorities, hypothesizing that they would report more childhood trauma than the majority and that this would be associated with more current and lifetime hallucinations. In this cross-sectional study we included 454 patients with a SCID-I DSM-IV diagnosis of non-affective or affective psychotic disorder. Current hallucinations were measured with the Positive and Negative Syndrome Scale (P3; Hallucinatory Behaviour). Lifetime hallucinations were assessed with the SCID-I items: auditory hallucinations, voices commenting and two or more voices conversing. Childhood trauma was assessed with the Childhood Trauma Questionnaire, self-report version. Patients from ethnic minority groups (n = 69) reported significantly more childhood trauma, specifically physical abuse/neglect, and sexual abuse. They had significantly more current hallucinatory behaviour and lifetime symptoms of hearing two or more voices conversing. Regression analyses revealed that the presence of childhood trauma mediated the association between ethnic minorities and hallucinations.

More childhood trauma in ethnic minorities with psychosis may partially explain findings of more positive symptoms, especially hallucinations, in this group. The association between childhood trauma and these first-rank symptoms may in part explain this group's higher risk of being diagnosed with a schizophrenia-spectrum diagnosis. The findings show the importance of childhood trauma in symptom development in psychosis.

Centralization of paediatric intensive care: are critically ill children appropriately referred to a regional centre?

To evaluate the appropriateness of emergency referrals for inter-hospital transfers by local physicians in hospitals without intensive care facilities to a regional tertiary paediatric intensive care unit (PICU). A prospective, descriptive study in a tertiary PICU and hospitals without paediatric intensive care facilities in and around the London area, UK. All patients (<18 years) referred for emergency admission to the PICU from district hospitals (n = 436) as well as those admitted through other modes of admission (n = 286) between 1 October 1998 and 30 June 1999 were prospectively studied. Admissions and transfers were deemed appropriate if the risk of mortality using the Paediatric Risk of Mortality (PRISM II) score was greater than 1%, and/or if the patient required a unique ICU-dependent therapy. Effectiveness was estimated using PRISM II derived observed-to-expected mortality ratio. Of the 436 emergency referrals 398 (91.3%) were retrieved and transported to the PICU. Of these, 38 referrals were thought to be inappropriate after telephone consultation and were not transferred. Of the emergency referrals 376 (94.4%) had a mortality risk greater than 1% or required an ICU-dependent therapy on admission day. Thus 86.2% (376/436) of the referrals and 94.4% (376/398) of transfers were considered appropriate. The PRISM II derived standardized mortality rate was 0.694 (95% CI 0.517-0.913) in the overall population and 0.613 (95% CI 0.434-0.843) amongst the emergency referrals.

Physicians at local hospitals within a centralized system of delivering paediatric intensive care were able to maintain adequate assessment skills in recognition and requesting for appropriate transfers of the most ill and efficiently utilized resources available at the regional centre.

Do chitosan nanoparticles amplify the ocular hypotensive effect of cateolol in rabbits?

To assess the potential of chitosan (CS) nanoparticles for ocular drug delivery by investigating their intraocular retention by γ-scintigraphy and intraocular pressure reduction. Carteolol (CRT) loaded CS-NPs were prepared by ionotropic gelation method. A four-factor three-level Box-Behnken design was employed to investigate the influence of independent variables on particle size, loading capacity and entrapment efficiency. Characterization was done for particle size, encapsulation efficiency, loading capacity and in vitro drug release and transcorneal permeation, histopathology and confocal microscopy, in vitro ocular tolerance. Intraocular retention was assessed by γ-scintigraphy, and intraocular pressure was measured by tonometer betamethasone induced glaucoma rabbits.

The optimized nanoparticles showed a particle size of 243 nm (PDI - 0.304±0.04) and drug loading 49.21±2.73% with entrapment efficiency of 69.57±3.54%. In vitro release studies showed a sustained release for 24h as compared to drug solution. Ex vivo studies showed good permeation with non-significant changes in cornea anatomy indicating its safe nature. γ-Scintigraphy study showed good spread and retention (<0.05) in precorneal area as compared to the aqueous CRT solution and prolonged reduction in intraocular pressure (P<0.001).

Is the fluoride level in drinking water a gold standard for the control of dental caries?

Clinical examination of children and analysis of samples of drinking water. The maximum reduction of caries in relation to fluoride levels in Pakistan was witnessed between the fluoride concentrations of 0.00-0.33ppm.

There are no gold standards for setting up a universal optimal level of fluoride in drinking water and each country needs to determine the concentration of fluoride in their drinking water in accordance with its socio-economic and climatic conditions, dietary and oral hygiene habits of its population, and local research to determine how much fluoride is beneficial in the control of caries.

Does hypermethylation of EDNRB promoter contribute to the risk of colorectal cancer?

Colorectal cancer (CRC) is one of the most common digestive malignancies in the world. EDNRB is a new candidate tumor suppressor gene which is often down-regulated or even silenced by promoter hypermethylation in various human cancers. However, the function of EDNRB gene in CRC remains unknown. In this study, we examined the expression and DNA methylation of EDNRB in CRC tissues. A total of 42 paired CRC and adjacent normal tissue samples were used to determine mRNA levels and DNA methylation status of EDNRB gene by qRT-PCR and methylation-specific PCR (MSP), respectively. Our study showed that EDNRB promoter hypermethylation was more frequently in CRC tissues than in the normal tissues (92.86 versus 59.52, p = 0.001). Consequently, significantly lower level of EDNRB mRNA was found in CRC tumor samples than in normal samples (0.31 ± 0.91 versus 0.70 ± 1.18, p = 0.032).

Our results suggested that EDNRB promoter hypermethylation might downregulate its gene expression in CRC, and thus played an important role in the development of CRC.

Does protein tyrosine phosphatase 1B deficiency potentiate PERK/eIF2α signaling in brown adipocytes?

Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and body mass, and has been implicated in endoplasmic reticulum (ER) stress. Herein, we assess the role of PTP1B in ER stress in brown adipocytes, which are key regulators of thermogenesis and metabolic response. To determine the role of PTP1B in ER stress, we utilized brown adipose tissue (BAT) from mice with adipose-specific PTP1B deletion, and brown adipocytes deficient in PTP1B and reconstituted with PTP1B wild type (WT) or the substrate-trapping PTP1B D181A (D/A) mutant. PTP1B deficiency led to upregulation of PERK-eIF2α phosphorylation and IRE1α-XBP1 sub-arms of the unfolded protein response. In addition, PTP1B deficiency sensitized differentiated brown adipocytes to chemical-induced ER stress. Moreover, PERK activation and tyrosine phosphorylation were increased in BAT and adipocytes lacking PTP1B. Increased PERK activity resulted in the induction of eIF2α phosphorylation at Ser51 and better translatability of ATF4 mRNA in response to ER stress. At the molecular level, we demonstrate direct interaction between PTP1B and PERK and identify PERK Tyr615 as a mediator of this association.

Collectively, the data demonstrate that PTP1B is a physiologically-relevant modulator of ER stress in brown adipocytes and that PTP1B deficiency modulates PERK-eIF2α phosphorylation and protein synthesis.

Do major stress hormones suppress the response of macrophages through down-regulation of TLR2 and TLR4?

Severe trauma often leads to diminished cytokines especially from macrophages to Toll-like receptor (TLR) agonists. However, the molecular mechanisms remain to be elucidated. As surgical trauma could also induce neuroendocrine hormones to modulate the immune system, we investigated the effects of major hormones, including endogenous glucocorticoid (corticosterone (CORT)), epinephrine (E), and norepinephrine (NE) on the expression and response of TLR2 and TLR4 in macrophages. Rat macrophages were pretreated by each hormone (1000 ng/mL of CORT, E, and NE) for 24 h, then restimulated with Pam3CSK4 or lipopolysaccharide (LPS) for further 24 h, and supernatant tumor necrosis factor-alpha (TNF-α) was measured. Additionally, macrophages were incubated with different concentrations of hormones (0-10,000 ng/mL) for 48 h or with 1000 ng/mL of hormones for 0-48 h, the expressions of TLR2 and TLR4 and intracellular molecules (MyD88, IRAK1, and TRAF6) in macrophages were analyzed by real-time quantitative polymerase chain reaction (PCR) and RT-PCR, respectively. Pam3CSK4-stimulated TNF-α production was significantly reduced from macrophages pretreated with CORT, and both Pam3CSK4- and LPS-stimulated TNF-α were suppressed with E. Moreover, CORT down-regulated only TLR2 expression in both time- and dose-dependent manner, but both TLR2 and TLR4 mRNA expressions were down-regulated in time- and dose-dependent manner after exposure to E. However, the transcript expression of MyD88, IRAK1, and TRAF6 remained unchanged after exposure to each hormone.

These results suggested that the down-regulation of TLR2 and TLR4 expressions by CORT and E is involved in the hyporesponsiveness of macrophages.

Does microRNA-21 inhibit platelet-derived growth factor-induced human aortic vascular smooth muscle cell proliferation and migration through targeting activator protein-1?

This study is to investigate whether microRNA (miR)-21 inhibits platelet-derived growth factor-induced human aortic vascular smooth muscle cell (VSMC) proliferation and migration through targeting activator protein-1 (AP-1). VSMCs were transfected with the miR-21 or miR-21 inhibitor. Cell proliferation was determined using methyl thiazolyl tetrazolium assay. Cell migration was detected by transwell assay. Luciferase reporter assay was used to study the interaction between miR-21 and AP-1. The levels of mRNA were determined using quantitative real-time polymerase chain reaction, while protein expression was measured using Western blotting assay. Low expression of miR-21 significantly inhibited VSMC proliferation, invasion and migration. The mRNA levels and protein expression of α-SMA and AP-1 were down-regulated by low expression of miR-21. In addition, luciferase reporter assay demonstrated that AP-1 might be a direct target gene of miR-21 in VSMC initiation and development. Moreover, up-regulation of AP-1 was critical for miR-21-mediated inhibitory effects on platelet-derived growth factor-induced cell proliferation and migration in human VSMCs.

In summary, miR-21 is a key molecule in regulating human VSMC proliferation and migration by targeting AP-1, suggesting that specific modulation of miR-21 in human VSMCs may become an attractive approach for the treatment of proliferative vascular diseases.

Does sopoongsan inhibit mast cell-mediated anaphylactic reactions and inflammatory cytokine secretion?

Mast cells are key effector cells in the early-phase allergic inflammation and in diverse immunological and pathological processes. Sopoongsan (SPS), a traditional Korean medicine, has been used as therapeutics for allergic diseases such as atopic dermatitis (AD). The precise effect in experimental models of SPS, however, remains unknown. In this report, we investigated the effect of SPS on mast cell-mediated anaphylactic reactions and cytokine production in in vivo and in vitro murine models. Compound 48/80-induced histamine and ear swelling were measured with the various concentrations of SPS. The amount of dye was determined colorimetrically after antidinitrophenyl IgE antibody-induced passive cutaneous anaphylaxis reaction. Secretion of tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and IL-6 in supernatants from HMC-1 cells was measured by a sandwich enzyme-linked immunosorbent assay. The expression level of nuclear factor (NF)-kappaB/Rel A in the nucleus and the activation of mitogen-activated protein kinases (MAPKs) were examined by Western blot analysis. SPS inhibited the degranulation and histamine release from the rat peritoneal mast cells activated by compound 48/80. Compound 48/80-induced ear swelling was significantly reduced. SPS also showed an inhibitory effect of passive cutaneous anaphylaxis reaction. Significantly reduced levels (p < 0.05) of TNF-alpha, IL-8 and IL-6 were observed in the human mast cell line with SPS and SPS components. In addition, SPS inhibited an increase of NF-kappaB and extracellular signal-regulated kinase 1/2 activity.

These findings suggest that SPS has an inhibitory effect on atopic allergic reaction and this might be useful for the clinical application to treat allergic diseases such as AD.

Are myocardial apoptosis and infarction after ischemia/reperfusion attenuated by kappa-opioid receptor agonist?

It remains unclear whether U50488H (a selective kappa-opioid receptor agonist) produces anti-apoptotic effect during ischemia and reperfusion (I/R). Therefore, the effect of U50488H on myocardial apoptosis was investigated in the present study. Rats were subjected to 45min coronary artery occlusion and 180min of reperfusion. U50488H (1.5mg/kg IV) was given prior to occlusion. Nor-Binaltorphimine (nor-BNI) (2mg/kg IV), a selective kappa-opioid receptor antagonist, was given 10min prior to U50488H. Cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) assay and in situ identification of nuclear DNA fragmentation. The ultrastructure injury of myocardium, myocardial infarct size, and plasma CK and LDH were reduced significantly with administration of U50488H before I/R, whereas the effects of U50488H were abolished by nor-BNI. DNA fragments were visualized by agarose electrophoresis, and clear DNA ladder formation was observed in myocardial tissue from hearts subjected to I/R. Administration of U50488H before ischemia exerted a significant anti-apoptotic effect as evidenced by markedly weaker DNA ladder formation. TUNEL staining showed U50488H treatment before I/R significantly reduced the percentage of apoptotic cells, which was blocked by 5-HD, a mitochondrial k(ATP) channel blocker. In accordance, U50488H treatment significantly inhibited I/R-induced elevated activities of caspase-3 and caspase-9. U50488H also produced an increase in Bcl-2 and a decrease in Bax protein expression in the I/R heart, and the anti-apoptotic effects of U50488H were all blocked by nor-BNI.

U50488H reduces myocardial necrosis and apoptosis after I/R and activation of kappa-opioid receptor may mediate a role in U50488H-induced myocardial protection.

Is plasma alpha 2 macroglobulin increased in nephrotic patients as a result of increased synthesis alone?

alpha 2 Macroglobulin (alpha 2M), a protease inhibitor, is often increased in plasma of patients with the nephrotic syndrome. Although it has been speculated that synthesis is increased, no direct measurements have been performed. alpha 2M synthesis in both normal subjects (N = 4) and nephrotic patients (N = 7) were measured using endogenous labeling with 13C valine in order to establish the mechanism of increased plasma level in the nephrotic syndrome and the relationship between alpha 2M synthesis rate and plasma concentration over a wide range of plasma concentration values. A primed (15 mumol/kg)/continuous (15 mumol/kg/hr) infusion was administered for six hours. Blood samples were collected at different intervals and at each time point alpha 2M was isolated from EDTA plasma using immunoprecipitation and SDS-polyacrylamide gel electrophoresis (PAGE). Care was taken to ensure that the alpha 2M used for combustion had not been subjected to proteolysis. The rate of appearance of 13C valine derived from the isolated alpha 2M was measured by gas chromatography combustion isotope ratio mass spectrometry. Plasma alpha 2M was significantly elevated in nephrotic subjects (3.13 +/- 0.33 g/liter) versus controls (1.64 +/- 0.15 g/liter; P = 0.012). The alpha 2M fractional synthesis rate [(FSR), which is equal to fractional catabolic rate (FCR) in steady state] was the same in the two groups: 2.70 +/- 0.18%/day for the nephrotic patients versus controls 2.74 +/- 0.21%/day. However, the alpha 2M absolute synthesis rate (ASR) was significantly (P = 0.012) increased in the patients (3.69 +/- 0.33 mg/kg/day) versus controls (2.06 +/- 0.35 mg/kg/day). Plasma alpha 2M concentration correlated directly to its ASR (r2 = 0.821; P = 0.0001; N = 11).

Increased plasma alpha 2M concentration in nephrotic patients is therefore a result of increased synthesis alone.

Are calcium channel blockers inadequate for malignant hyperthermia crisis?

Malignant hyperthermia (MH) results from disordered calcium (Ca(2+)) homeostasis in skeletal muscle during general anesthesia. Although Ca(2+) channel blockers may be given to treat the tachycardia and circulatory instability, coadministration of Ca(2+) channel blockers and dantrolene is contraindicated during MH crisis. We evaluated the effect of Ca(2+) channel blockers on Ca(2+) homeostasis and their interactions with dantrolene in human skeletal muscle. Human skeletal muscle samples were obtained by biopsy and divided into two groups according to the results of the Ca(2+)-induced Ca(2+) release rate test. Differentiated myotubes were labeled with Fura-2, and changes in the 340/380-nm ratio were used to calculate changes in Ca(2+) concentration following nifedipine treatment in the absence or presence of dantrolene. Nifedipine induced a transient increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) in a dose-dependent manner. The half-maximal concentration (EC(50)) for nifedipine was 0.718 ± 0.329 μM in the accelerated group and 1.389 ± 0.482 μM in the nonaccelerated group (P = 0.009). The addition of 50 μM dantrolene attenuated by 15.4% the increase in [Ca(2+)](i) caused by the 0.5 μM nifedipine.

Ca(2+) channel blockers led to increased [Ca(2+)](i) in human skeletal muscle cells. The increase is thus scarcely affected by dantrolene treatment. Data provide a greater physiologic basis for avoiding the use of Ca(2+) channel blockers during MH crisis.

Does integration of proteomic and transcriptomic profiles identify a novel PDGF-MYC network in human smooth muscle cells?

Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. However, neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated. Expression profiling and quantitative proteomics analysis of PDGF-treated primary human bladder smooth muscle cells identified 1,695 genes and 241 proteins as differentially expressed versus non-treated cells. Analysis of gene expression data revealed MYC, JUN, EGR1, MYB, RUNX1, as the transcription factors most significantly networked with up-regulated genes. Forty targets were significantly altered at both the mRNA and protein levels. Proliferation, migration and angiogenesis were the biological processes most significantly associated with this signature, and MYC was the most highly networked master regulator. Alterations in master regulators and gene targets were validated in PDGF-stimulated smooth muscle cells in vitro and in a model of bladder injury in vivo. Pharmacologic inhibition of MYC and JUN confirmed their role in SMC proliferation and migration. Network analysis identified the diaphanous-related formin 3 as a novel PDGF target regulated by MYC and JUN, which was necessary for PDGF-stimulated lamellipodium formation.

These findings provide the first systems-level analysis of the PDGF-regulated transcriptome and proteome in normal smooth muscle cells. The analyses revealed an extensive cohort of PDGF-dependent biological processes and connected key transcriptional effectors to their regulation, significantly expanding current knowledge of PDGF-stimulated signaling cascades. These observations also implicate MYC as a novel target for pharmacological intervention in fibroproliferative expansion of smooth muscle, and potentially in cancers in which PDGFR-dependent signaling or MYC activation promote tumor progression.

Does surgical volume influence short-term outcomes of laparoscopic hysterectomy?

To evaluate whether surgical volume has an impact on short-term outcomes of laparoscopic hysterectomy. This is a retrospective analysis of 1016 laparoscopic hysterectomies. The surgeons were divided into 2 groups based on a cutoff of 30 cases. Patient characteristics, the rates of laparotomy (4.5% vs 6.7%), and serious complications (3.6% vs 5.5%) were similar between 9 "high" and the remaining 39 "low volume" gynecologists, respectively (P<.05). Mean operating time was longer in the "low volume" group. Compared with their first 29 hysterectomies, the "high volume" surgeons decreased their operating time significantly in their subsequent cases. The "high volume" surgeons improved their conversion rate (9.2% vs 2.4%; P<.0001) over time but not their serious complications.

In laparoscopic hysterectomy, increasing the surgical volume can reduce the operating time and the risk for conversion to laparotomy but not the rate of serious complications.

Does a 5-year exercise program in children improve muscle strength without affecting fracture risk?

High level of physical activity (PA) is associated with great muscle strength and high fracture risk. This prospective controlled population-based study evaluated how a pediatric PA intervention program influenced muscle strength and fracture risk. We carried out a school-based exercise intervention program with 200 min of PA per week for 5 years in 335 girls and 408 boys aged 6-9 years at study start. An age-matched control cohort including 756 girls and 782 boys continued with 60 min of PA per week. We registered fractures during the study period and calculated rate ratio. In a sub-sample, including 74 girls and 107 boys in the intervention and 51 girls and 54 boys in the control group, we measured knee flexion and extension strength by a computerized dynamometer and leg composition by dual energy X-ray absorptiometry. Group comparisons were adjusted for differences in age, baseline value for the measured parameter and changes in height. Children in the intervention group had a rate ratio to sustain a fracture of 1.03 (0.78, 1.36) (mean and 95 % confidence interval) (p = 0.79). The annual gain in flexion peak torque muscle strength was greater in both girls (at 60°/s) [1.1 Nm (0.5, 1.8), p < 0.01] and boys (at 180°/s) [0.7 Nm (0.1, 1.2), p < 0.05] in the intervention than in the control group, while leg composition was similar.

Increased PA during a 5-year period, starting in the pre-pubertal period, improves the gain in muscle strength without affecting the fracture risk.

Do lignin biosynthesis perturbations affect secondary cell wall composition and saccharification yield in Arabidopsis thaliana?

Second-generation biofuels are generally produced from the polysaccharides in the lignocellulosic plant biomass, mainly cellulose. However, because cellulose is embedded in a matrix of other polysaccharides and lignin, its hydrolysis into the fermentable glucose is hampered. The senesced inflorescence stems of a set of 20 Arabidopsis thaliana mutants in 10 different genes of the lignin biosynthetic pathway were analyzed for cell wall composition and saccharification yield. Saccharification models were built to elucidate which cell wall parameters played a role in cell wall recalcitrance. Although lignin is a key polymer providing the strength necessary for the plant's ability to grow upward, a reduction in lignin content down to 64% of the wild-type level in Arabidopsis was tolerated without any obvious growth penalty. In contrast to common perception, we found that a reduction in lignin was not compensated for by an increase in cellulose, but rather by an increase in matrix polysaccharides. In most lignin mutants, the saccharification yield was improved by up to 88% cellulose conversion for the cinnamoyl-coenzyme A reductase1 mutants under pretreatment conditions, whereas the wild-type cellulose conversion only reached 18%. The saccharification models and Pearson correlation matrix revealed that the lignin content was the main factor determining the saccharification yield. However, also lignin composition, matrix polysaccharide content and composition, and, especially, the xylose, galactose, and arabinose contents influenced the saccharification yield. Strikingly, cellulose content did not significantly affect saccharification yield.

Although the lignin content had the main effect on saccharification, also other cell wall factors could be engineered to potentially increase the cell wall processability, such as the galactose content. Our results contribute to a better understanding of the effect of lignin perturbations on plant cell wall composition and its influence on saccharification yield, and provide new potential targets for genetic improvement.

Are common PTP4A1-PHF3-EYS variants specific for alcohol dependence?

We previously reported a risk genomic region (ie, PTP4A1-PHF3-EYS) for alcohol dependence in a genome-wide association study (GWAS). We also reported a rare variant constellation across this region that was significantly associated with alcohol dependence. In the present study, we significantly increased the marker density within this region and examined the specificity of the associations of common variants for alcohol dependence. One African-American discovery sample (681 cases with alcohol dependence and 508 controls), one European-American replication sample (1,409 alcohol dependent cases and 1,518 controls), and one European-Australian replication sample (a total of 6,438 family subjects with 1,645 alcohol dependent probands) underwent association analysis. A total of 38,714 subjects from 18 other cohorts with 10 different neuropsychiatric disorders served as contrast groups. We found 289 SNPs that were nominally associated with alcohol dependence in the discovery sample (p < .05). Fifty-six associations of them were significant after correction (1.9 × 10(-6) ≤ p ≤ 1.6 × 10(-5)). No markers were significantly associated with other neuropsychiatric disorders after experiment-wide correction.

We confirmed with our previous findings that PTP4A1-PHF3-EYS variants were significantly associated with alcohol dependence, which were replicable across multiple independent populations and were specific for alcohol dependence. These findings suggested that this region might harbor a causal variant(s) for alcohol dependence.

Does anti-VLA-4 antibody reduce intimal hyperplasia in the endarterectomized carotid artery in nonhuman primates?

Recently, very late antigen-4 (VLA-4) has been shown to mediate initial monocyte adhesion and migration to the injured artery. We hypothesized that blocking monocyte adhesion using a specific monoclonal antibody against VLA-4 may reduce intimal hyperplasia. Bilateral carotid endarterectomies were performed in eight adult baboons. Among them, five animals received an intravenous bolus injection of anti-VLA-4 antibody (3 mg/kg) during surgery and again after 2 weeks. Three animals underwent bilateral carotid endarterectomies and served as untreated control subjects. Specimens were harvested at 4 weeks and subjected to morphometric analysis, cell proliferation assay, and immunostaining for macrophages. All of the endarterectomized arteries were patent except for one in the treated group. The number of macrophages in the intimal tissues was significantly reduced in the treated arteries compared with that in the control vessels (15.78 +/- 3.05 cells/section versus 33.50 +/- 6.13 cells/section; p < 0.001). The cell proliferation rate was significantly lower (p < 0.001) in the treated vessels (2.88% +/- 1.07%) compared with the control vessels (4.89% +/- 0.77%). The intimal area at the endarterectomized sites of carotid arteries was significantly less (p < 0.05) in the group treated with the anti-VLA-4 antibody (1.10 +/- 0.68 mm2) than in the control group (2.00 +/- 0.52 mm2).

These data show that blocking monocyte adhesion by use of an anti-VLA-4 antibody significantly reduces the number of intimal macrophages, intimal cell proliferation, and intimal hyperplasia in injured carotid arteries in baboons. This study supports a central role for macrophages in the development of intimal hyperplasia and may suggest a new therapeutic strategy to prevent clinical restenosis.

Cytoplasmic beta-catenin is lacking in a subset of melanoma-associated naevi, but is detectable in naevus-associated melanomas: potential implications for melanoma tumorigenesis?

An excess of intracellular beta-catenin protein is triggered by various genetic alterations in melanoma cell lines, and has been suggested to play a role in melanoma tumorigenesis. To investigate the role played in vivo by beta-catenin in melanoma tumorigenesis, we compared the cytoplasmic detection of beta-catenin in benign melanocytic cells vs. malignant melanoma cells presumably generated from these benign melanocytic cells. For this purpose, melanocytic naevi occurring in association with melanoma, which were suggested to be melanoma precursors, were compared with their associated melanoma for beta-catenin cytoplasmic immunoreactivity. Fifty-seven consecutive cases of primary cutaneous melanoma were considered, and 15 of them were found to be associated with a melanocytic naevus portion. The naevus portion showed features of acquired melanocytic naevus (total 12 cases: five dysplastic, seven intradermal) or congenital growth pattern naevus (total three cases: one superficial, two deep). All specimens were immunohistochemically investigated for beta-catenin. Virtually all primary cutaneous melanomas, including those associated with a naevus portion, showed cytoplasmic beta-catenin positivity. However, the intradermal naevus portion was consistently cytoplasmic beta-catenin negative, while both the dysplastic and the congenital naevus portions were cytoplasmic beta-catenin positive.

Beta-catenin excess may play a role in melanoma tumorigenesis, because beta-catenin cytoplasmic reactivity was found in primary cutaneous melanoma but not in its associated intradermal naevus precursor. As, however, beta-catenin cytoplasmic reactivity was detected not only in primary cutaneous melanoma but also in its associated dysplastic/congenital naevus precursors, beta-catenin stabilization alone is not sufficient to play a decisive role for melanoma onset.

Is skeletal muscle blood flow a determinant of insulin resistance in essential hypertension?

To investigate the haemodynamic effects of insulin and their relationship to insulin resistance in essential hypertension. Group comparison between patients with essential hypertension and normal controls. Outpatient clinics serving the greater Belfast area. Eleven patients with essential hypertension and eight age-, sex- and weight-matched control subjects were recruited. Administration of all antihypertensive agents to the hypertensive patients was stopped 6 weeks prior to the study. Leg blood flow was measured using venous occlusion plethysmography. Insulin action was assessed using the hyperinsulinaemic euglycaemic clamp technique. The hypertensive subjects were insulin-resistant compared with the normal controls. Insulin infusion resulted in similar increases in calf blood flow in the two groups. There was no correlation between calf blood flow and measurements of insulin sensitivity in either group.

Differences in whole-body glucose uptake in hypertensive and control subjects are not likely to be related to differences in insulin-induced stimulation of muscle blood flow.

Is elevated mean platelet volume associated with presence of colon cancer?

Colon cancer is the second most common cancer in developed countries. Activated platelets play a key role in inflammation and atherothrombosis, with mean platelet volume (MPV) is an early marker of platelet activation. The aim of the study was to clarify the relevance of MPV in patients with colon cancer. We measured MPV levels in 128 patients with colon cancer before and after surgery, and 128 controls matched for age, gender, body mass index (BMI) and smoking status. The odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer were calculated using multivariate logistic regression analyses across MPV quartiles. Patients with colon cancer had higher MPV compared with controls. Surgical tumor resection resulted in a significant decrease in MPV levels (11.4 fL vs 10.7 fL; p<0.001). A positive correlation between MPV and tumor-nodule-metastases (TNM) stage was found. Furthermore, after adjusting for other risk factors, the ORs (95%CIs) for colon cancer according to MPV quartiles were 1.000, 2.238 (1.014-4.943), 3.410 (1.528-7.613), and 5.379 (2.372-12.198), respectively.

The findings show that patients with colon cancer have higher MPV levels compared with controls, and these are reduced after surgery. In addition, MPV was found to be independently associated with the presence of colon cancer. Further studies are warranted to assess the utility of MPV as a novel diagnostic screening tool for colon cancer.

Normotensive pseudoexfoliation glaucoma: a new phenotype?

We herein report the clinical profile of five eyes of three patients with normotensive pseudoexfoliation glaucoma. Three patients who presented with clinical evidence of pseudoexfoliation with evident glaucomatous damage and normal intraocular pressure underwent comprehensive ophthalmic evaluation, central corneal thickness, diurnal IOP recording (in two patients), and visual field examination. Five eyes of the three patients were found to have advanced glaucomatous damage, thin cornea, and an IOP recording of<23 mm Hg at all occasions. Case 1 had macular branch retinal vein occlusion while case 3 had disc collaterals.

Normotensive pseudoexfoliation glaucoma may represent a new phenotype highlighting the possible role of pressure-independent mechanisms of glaucoma in pseudoexfoliation.

Does respiratory health contribute to the effects of long-term air pollution exposure on cardiovascular mortality?

There is growing epidemiological evidence that short-term and long-term exposure to high levels of air pollution may increase cardiovascular morbidity and mortality. In addition, epidemiological studies have shown an association between air pollution exposure and respiratory health. To what extent the association between cardiovascular mortality and air pollution is driven by the impact of air pollution on respiratory health is unknown. The aim of this study was to investigate whether respiratory health at baseline contributes to the effects of long-term exposure to high levels of air pollution on cardiovascular mortality in a cohort of elderly women. We analyzed data from 4750 women, aged 55 at the baseline investigation in the years 1985-1994. 2593 of these women had their lung function tested by spirometry. Respiratory diseases and symptoms were asked by questionnaire. Ambient air pollution exposure was assessed by the concentrations of NO2 and total suspended particles at fixed monitoring sites and by the distance of residency to a major road. A mortality follow-up of these women was conducted between 2001 and 2003. For the statistical analysis, Cox' regression was used. Women with impaired lung function or pre-existing respiratory diseases had a higher risk of dying from cardiovascular causes. The impact of impaired lung function declined over time. The risk ratio (RR) of women with forced expiratory volume in one second (FEV1) of less than 80% predicted to die from cardiovascular causes was RR = 3.79 (95%CI: 1.64-8.74) at 5 years survival time and RR = 1.35 (95%CI: 0.66-2.77) at 12 years. The association between air pollution levels and cardiovascular death rate was strong and statistically significant. However, this association did only change marginally when including indicators of respiratory health into the regression analysis. Furthermore, no interaction between air pollution and respiratory health on cardiovascular mortality indicating a higher risk of those with impaired respiratory health could be detected.

Respiratory health is a predictor for cardiovascular mortality. In women followed about 15 years after the baseline investigation at age 55 years long-term air pollution exposure and impaired respiratory health were independently associated with increased cardiovascular mortality.

Pseudomigraine with lymphocytic pleocytosis: a calcium channelopathy?

To report the clinical findings of 10 patients diagnosed with pseudomigraine with lymphocytic pleocytosis and the results of mutational analysis of the CACNA1A gene in 8 of these patients. Pseudomigraine with lymphocytic pleocytosis, also referred to as headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL), is characterized by episodic transient neurologic dysfunction associated with moderate to severe headache and cerebrospinal fluid lymphocytic pleocytosis. Episodes are recurrent and the condition is self-limiting. The etiology of this sporadic condition remains unknown, but the episodic nature and its ability to be triggered by angiography is somewhat reminiscent of the phenotypic features of familial hemiplegic migraine, a condition caused by mutations in the CACNA1A gene.DESIGN/ Utilizing retrospective chart review, we describe the clinical features of pseudomigraine with lymphocytic pleocytosis in 10 patients. Whole blood was taken from 8 patients (2 were lost to follow-up) and used for DNA testing. The CACNA1A gene was screened for mutations using heteroduplex analysis and direct DNA sequencing. Clinical features of pseudomigraine with lymphocytic pleocytosis included transient episodes of weakness, sensory and visual symptoms, aphasia, and confusion lasting minutes up to 4 hours. Sensory symptoms, typically affecting the face and arm, were the most common presentation. Localization of symptoms did not conform to vascular territories. Headache was typically throbbing and most often bilateral. Genetic analysis did not identify any mutations in the CACNA1A gene.

Similarities between familial hemiplegic migraine and pseudomigraine with lymphocytic pleocytosis include recurrent headache with reversible neurologic deficit, cerebrospinal fluid lymphocytic pleocytosis, and triggers such as angiography. Even so, heteroduplex analysis and DNA sequencing failed to identify any sporadic mutations or shared polymorphisms in the exons or the intron/exon boundaries of the CACNA1A gene. These results do not support a role of the CACNA1A gene in the etiology of pseudomigraine with lymphocytic pleocytosis.

Do locking screws work in plates bent at holes?

To assess whether plate bending at a hole significantly changes the biomechanical properties of a locked screw. Coronal plane bends of 5-, 15-, or 45-degree angles were placed in 3.5-mm locking compression plates with the apex at a locking hole. An additional 45-degree angle test group was created in which a threaded screw head insert was placed before bending. Ten plates were tested in each group and compared with nonbent controls in a stepwise cyclic loading protocol. Statistically significant differences in protocol survival were shown between the control group and the 15-degree angle (P = 0.006) and 45-degree angle (P = 0.0007) groups. An apparent decrease in protocol survival in the 5-degree angle group did not reach statistical significance (P = 0.17). The average number of cycles survived was significantly different between the control group and the 15-degree angle (P = 0.027) and 45-degree angle (P = 0.0002) groups. The mean cycles to failure for the 5-degree angle group was 16% lower than for controls but did not reach statistical significance (P = 0.37). The test group bent to an angle of 45 degrees after placement of a threaded screw head insert showed no difference in protocol survival or in mean number of cycles survived compared with the regular 45-degree angle group.

Bending of a 3.5-mm locking compression plate by more than 5 degrees at a locking hole results in a statistically significant decrease in survival of the corresponding locked screw. This effect cannot be prevented by the placement of a threaded screw head insert before bending.

Is expression of CCR8 increased in asthma?

Chemokines and their receptors could play key roles in the recruitment of T cells to the asthmatic lung. CCR8 is preferentially expressed on T-helper type 2 cells, and is thought to play a role in the pathogenesis of human asthma. Determine the expression of CCR8 on T cells in blood, bronchoalveolar lavage (BAL) and bronchial mucosa from asthmatics and normal subjects. CCR8 expression in blood and BAL from asthma and normal subjects was studied using flow cytometry. CCR8 expression on IFN-gamma+ and IL-4+/IL-13+ blood and BAL T cells was studied following stimulation with Phorbol-Myristate-Acetate and Calcium Ionophore. Paraffin-embedded bronchial biopsies were used to study CCR8 in bronchial epithelium. The percentage of CD3+ cells expressing CCR8 in the blood was higher in asthmatics (4.7+/-0.4%) compared with normal subjects (3.0+/-0.4%; P<0.01). There was an approximately sixfold enrichment of CCR8 on IL-4+/IL-13+ cells compared with IFN-gamma+ T cells (P<0.001) in both asthmatic and normal subjects in both blood and BAL. Significantly more BAL T cells expressed CCR8 in asthmatic (8.6+/-0.8%) compared with normal subjects (3.9+/-0.7%) (P<0.01). In paired blood-BAL samples from asthmatics, significantly more CCR8+CD3+ T cells were present in BAL (9.0+/-0.9%) than in blood (5.6+/-0.9%; P<0.05). There were more CCR8-positive cells in bronchial biopsies from asthmatic (93+/-11 cells/mm2) compared with normal subjects (30+/-16 cells/mm2) (P<0.05). The ligand CCL1 was increased in the BAL of asthmatics compared with normal subjects (35+/-6 vs. 12.9+/-7 pg/mL; P<0.05).

There may be a role for CCR8 in the recruitment of T cells to the lung in asthmatics.

Use of external fixators for open tibial injuries in the rural third world: panacea of the poor?

A retrospective study of 41 patients with open tibial fractures and 1 with infected non-union, treated with tubular external fixators. The average cost to the patient of an external fixator was approximately Rs 600 (or US $12), which compares very favourably with costs of internal fixation of similar effectiveness.

In rural India, the use of locally made external fixators for primary and definitive treatment of open tibial fractures is cost effective.

Is matrix metalloproteinase-7 ( MMP-7 ) polymorphism a risk factor for endometrial cancer susceptibility?

The goal of our study was to evaluate the influence of genetic polymorphisms of matrix metalloproteinases (MMP)-2, MMP-3 and MMP-7 on susceptibility to endometrial cancer. In the present study, we enrolled a total of 118 patients with endometrial cancer confirmed by histopathology, and 229 unrelated healthy individuals. Polymorphism for the MMP-2 (rs2285053), MMP-3 (rs3025058) and MMP-7 (rs11568818) genes was genotyped by polymerase chain reaction-restriction enzyme length polymorphism. The frequencies of MMP-7 -181 G/G and A/G genotypes were found to be significantly higher in cancer patients compared with healthy controls (p = 0.017). Stratification showed that individuals with MMP-7 -181 G allele were at increased risk for endometrial cancer when >50 years of age [odds ratios (OR) = 2.03; 95% confidence interval (CI) 1.21-3.39], endometrioid (OR = 1.80; 95% CI 1.11-2.92), low (stage I-II) (OR = 1.73; 95% CI 1.05-2.83) or high stage (stage III-IV) (OR = 2.69; 95% CI 1.16-6.24). Compared with the A/A genotype, the A/G + G/G genotype modified the risk of developing endometrial carcinoma and significance was detected in patients over 50 years old, and those with endometrioid type and high stage endometrial cancer. However, no significant difference in MMP-2 (-735 C/T) and MMP-3 (6A/5A) genotypes was observed between endometrial carcinoma cases and controls.

This is the first report on the association of MMP-2, MMP-3 and MMP-7 gene polymorphisms in endometrial cancer. Our results suggest that individuals with the MMP-7 -181 G/G and A/G genotype may have an increased risk of developing endometrial cancer.

Does combined analysis reveal a core set of cycling genes?

Global transcript levels throughout the cell cycle have been characterized using microarrays in several species. Early analysis of these experiments focused on individual species. More recently, a number of studies have concluded that a surprisingly small number of genes conserved in two or more species are periodically transcribed in these species. Combining and comparing data from multiple species is challenging because of noise in expression data, the different synchronization and scoring methods used, and the need to determine an accurate set of homologs. To solve these problems, we developed and applied a new algorithm to analyze expression data from multiple species simultaneously. Unlike previous studies, we find that more than 20% of cycling genes in budding yeast have cycling homologs in fission yeast and 5% to 7% of cycling genes in each of four species have cycling homologs in all other species. These conserved cycling genes display much stronger cell cycle characteristics in several complementary high throughput datasets. Essentiality analysis for yeast and human genes confirms these findings. Motif analysis indicates conservation in the corresponding regulatory mechanisms. Gene Ontology analysis and analysis of the genes in the conserved sets sheds light on the evolution of specific subfunctions within the cell cycle.

Our results indicate that the conservation in cyclic expression patterns is much greater than was previously thought. These genes are highly enriched for most cell cycle categories, and a large percentage of them are essential, supporting our claim that cross-species analysis can identify the core set of cycling genes.

Does interruption of CD28-mediated costimulation during allergen challenge protect mice from allergic airway disease?

Allergic asthma is a T(H)2-promoted hyperreactivity with an immediate, IgE, and mast cell-dependent response followed by eosinophil-dominated inflammation and airway obstruction. Because costimulation by CD28 is essential for T(H)2 but not T(H)1 responses, we investigated the effect of selective interference with this pathway in mice using the models of ovalbumin and house dust mite-induced airway inflammation. To study the role of CD28 in the effector phase of allergic airway inflammation, we developed an inducibly CD28-deleting mouse strain or alternatively used a CD28 ligand-binding site-specific mouse anti-mouse mAb blocking CD28 engagement. We show that even after systemic sensitization to the allergen, interruption of CD28-mediated costimulation is highly effective in preventing airway inflammation during challenge. In addition to improving airway resistance and histopathologic presentation and reducing inflammatory infiltrates, antibody treatment during allergen challenge resulted in a marked relative increase in regulatory T-cell numbers among the CD4 T-cell subset of the challenged lung.

Selective interference with CD28-mediated costimulation during allergen exposure might be an attractive therapeutic concept for allergic asthma.

Screening for alcoholism in the primary care setting: are we talking to the right people?

This study assessed which demographic groups were most likely to consume alcohol excessively, and which groups had received inquiries and discussion about alcohol use from their physicians compared with discussions about other health risks. This was a cross-sectional study using data from the Centers for Disease Control Behavioral Risk Factors Surveillance System 1997 data set that represents a stratified random sample in the United States. We selected 23,349 adults who reported a routine physical examination within the last 3 years. The main variables involved responses to questions about alcohol intake and whether the respondent's physician had initiated discussions about drinking. Physicians spoke to patients about alcohol use much less frequently than about other health-related behaviors. Discussions were roughly targeted to groups with the largest intake. However, physicians were least likely to speak with white patients, women, and widows who drank significantly.

Regularly asking patients about alcohol use could substantially reduce the under-recognition of alcoholism. Since brief counseling is effective, negative consequences of excessive alcohol intake may be avoided.

Does phenome-Wide Association Study of Rheumatoid Arthritis Subgroups identify Association between Seronegative Disease and Fibromyalgia?

The differences between seronegative and seropositive rheumatoid arthritis (RA) have not been widely reported. We performed electronic health record (EHR)-based phenome-wide association studies (PheWAS) to identify disease associations in seropositive and seronegative RA. A validated algorithm identified RA subjects from the de-identified EHR. Serotypes were determined by values of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA). We tested EHR-derived phenotypes using PheWAS comparing seropositive RA against seronegative RA, yielding disease associations. PheWAS was also performed on RF-positive versus RF-negative subjects and ACPA-positive versus ACPA-negative subjects. Following PheWAS, select phenotypes were then manually reviewed and fibromyalgia was specifically evaluated using a validated algorithm. There were 2199 individuals identified with RA and either RF or ACPA testing. Of these, 1382 (63%) were seropositive. Seronegative RA was associated with "Myalgia and Myositis" (odds ratio [OR] 2.1, P=3.7x10

This PheWAS in RA patients identifies a strong association between seronegativity and fibromyalgia. It also affirms relationships between seropositivity with chronic airway obstruction and seropositivity with tobacco use. These findings demonstrate the utility of the PheWAS approach to discover novel phenotype associations within different subgroups of a disease. This article is protected by copyright. All rights reserved.

Does bimatoprost-induced calcium signaling in human T-cells involve prostanoid FP or TP receptors?

The prostamide bimatoprost and prostanoid FP receptor agonists are highly efficacious drugs for glaucoma treatment. The presence of both prostamide and prostanoid FP receptors in bimatoprost-sensitive preparations has made prostamide receptor classification difficult. This study investigated a novel bimatoprost-sensitive preparation. Human peripheral blood T lymphoblasts (Molt-3) and human osteoblasts (hFOB) were cultured for intracellular calcium signaling studies and quantitative real-time PCR analysis of RNA. Bimatoprost stimulated concentration-related increases in [Ca(2 +)](i) in a human T-cell line that does not express human FP receptor/variants, according to PCR analysis. The calcium signal induced by bimatoprost was not antagonized by prostanoid FP receptor antagonist/partial agonist AL-8810 or selective TP receptor antagonist SQ 29548. Conversely, bimatoprost did not elevate [Ca(2 +)](i) in human osteoblasts, which were confirmed to contain RNA of human FP receptor/variants.

Molt-3 cells have been identified as a bimatoprost-sensitive preparation in which the activity of bimatoprost is independent of prostanoid FP receptors.

Does dNA hypermethylation contribute to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer?

It has long been known that malignant transformation is associated with abnormal expression of carbohydrate determinants. The aim of this study was to clarify the cause of cancer-associated abnormal glycosylation in gastrointestinal (GI) cancers. We compared the expression levels of "glyco-genes," including glycosyltransferases and glycosidases, in normal GI mucosa and in gastric and colorectal cancer cells. To examine the possibility that DNA hypermethylation contributed to the down-regulation of these genes, we treated GI cancer cells with 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferase. The silencing of some of these glyco-genes, but not up-regulation of certain molecules, was observed. The Sd(a) carbohydrate was abundantly expressed in the normal GI mucosa, but its expression was significantly decreased in cancer tissues. When human colon and gastric cancer cells were treated with 5-aza-dC, cell surface expression of Sd(a) and the transcription of B4GALNT2, which catalyzes the synthesis of the Sd(a), were induced. The promoter region of the human B4GALNT2 gene was heavily hypermethylated in many of the GI cancer cell lines examined as well as in gastric cancer tissues (39 out of 78 cases). In addition, aberrant methylation of the B4GALNT2 gene was strongly correlated with Epstein-Barr virus-associated gastric carcinomas and occurred coincidentally with hypermethylation of the ST3GAL6 gene.

Epigenetic changes in a group of glycosyltransferases including B4GALNT2 and ST3GAL6 represent a malignant phenotype of gastric cancer caused by silencing of the activity of these enzymes, which action may eventually induce aberrant glycosylation and expression of cancer-associated carbohydrate antigens.

Does heparin-binding epidermal growth factor-like growth factor attenuate acute lung injury and multiorgan dysfunction after scald burn?

Impaired gut barrier function and acute lung injury (ALI) are significant components of the multiorgan dysfunction syndrome that accompanies severe burns. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to reduce inflammation, preserve gut barrier function, and protect the lungs from acute injury in several models of intestinal injury; however, comparable effects of HB-EGF after burn injury have never been investigated. The present studies were based on the hypothesis that HB-EGF would reduce the severity of ALI and multiorgan dysfunction after scald burns in mice. Mice were randomized to sham, burn (25% of total body surface area with full thickness dorsal scald), and burn + HB-EGF groups. The HB-EGF group was pretreated with two enteral doses of HB-EGF (1200 μg/kg/dose). Mice were resuscitated after injury and sacrificed at 8 h later. Their lungs were harvested for determination of pulmonary myeloperoxidase activity, wet:dry ratios, and terminal deoxynucleotidyl transferase dUTP nick end label and cleaved caspase 3 immunohistochemistry. Lung function was assessed using the SCIREQ Flexivent. Splenic apoptosis was quantified by Western blot for cleaved caspase 3, and intestinal permeability was measured using the everted gut sac method. Mice subjected to scald burn injury had increased lung myeloperoxidase levels, increased pulmonary and splenic apoptosis, elevated airway resistance and bronchial reactivity, and increased intestinal permeability compared with sham mice. These abnormalities were significantly attenuated in mice that were subjected to scald burn injury but treated with enteral HB-EGF.

These data suggest that HB-EGF protects mice from ALI after scald burn and attenuates the severity of postburn multiorgan dysfunction.

Does [ Overexpression of PPARγ induce adipogenic steatosis in mouse primary hepatocytes ]?

To investigate the effects of PPARγ overexpression on steatosis in mouse primary hepatocytes. Primary hepatocytes isolated from C57BL/6J mice were infected with either Ad/LacZ or Ad/PPARγ for 48 h. Steatosis of the primary hepatocytes was checked by Oil Red O staining. The mRNA and protein expression of adipocyte-specific genes PPARγ, aP2 and CideA were analyzed by using RT Real-time PCR and Western Blot. Primary hepatocytes were small and even. Hepatocyte nuclei were round with dispersed chromatin and prominent nucleoli. Accumulated lipid droplets were observed in Ad/PPARγ-infected hepatocytes, but in Ad/LacZ-infected hepatocytes. Moreover, compared with Ad/LacZ-infected hepatocytes, the mRNA expression of PPARγ, aP2, FGF21 and CideA in Ad/PPARγ-infected hepatocytes were significantly induced, the protein expression of PPARγ and its target aP2 strongly increased.

over expression of PPARγ induces adipogenic steatosis in mouse primary hepatocytes.

Does mitomycin C cause toxicity in the cornea after photorefractive keratectomy?

In this study, we investigated the wound-healing process after photorefractive keratectomy with mitomycin C (MMC) in hen corneas. In addition, we evaluated the synergistic effect of ethanol and MMC. Forty-eight adult hens were divided into 3 groups: A: ethanol-assisted debridement plus MMC; B: mechanical debridement plus MMC; and C: mechanical debridement (MMC-untreated control). Photorefractive keratectomy was performed, and the animals were followed up for up to 60 days. Epithelial healing was measured with fluorescein. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end-labeling assay and proliferation was measured by BrdU incorporation. Both myofibroblast differentiation and collagen deposition were evaluated by immunofluorescence and histology. Epithelial wound closure was similar in all 3 groups (P>0.05). Significant reduction in haze was observed in groups A and B compared with C (P<0.01), but there was no difference between groups A and B (P>0.05). Furthermore, there was no difference in the number of apoptotic cells between groups. Proliferation was delayed in both groups A and B compared with C (P<0.01), but groups A and B did not differ significantly (P>0.05). Myofibroblasts, cellular density, and collagen deposition were lower in both groups A and B compared with C (P<0.01), but they were not significantly different from each other (P>0.05).

Topical application of MMC in hen corneas reproduces the wound healing observed in humans by reducing haze, keratocyte proliferation, myofibroblast differentiation, and new collagen deposition. Synergistic cytotoxic effects of ethanol and MMC were not observed.

Solid-pseudopapillary tumor of the pancreas: a surgical enigma?

Solid-pseudopapillary tumors (SPTs) of the pancreas have been reported as rare lesions with "low malignant potential" occurring mainly in young women. This study was designed to define the clinicopathological characteristics and the effect of surgical intervention. A retrospective review from January 1985 to July 2000 was performed. Clinicopathological, operative, and survival data were obtained. The Kaplan-Meier method and chi2 analysis were performed. All cases were re-reviewed by a senior pathologist. During this time, 24 patients were diagnosed as having SPTs (0.9%). Twenty females and four males were identified, with a median age of 39 years (range, 12-79). The median size of the lesions was 8.0 cm (range, 1-20). Two patients' tumors were found to be unresectable at initial presentation because of vascular invasion; both patients have remained alive with disease, one for 13 years and the other 1 year. At a median follow-up of 8 years, one recurrence occurred in 17 patients who underwent complete resection. Microscopic margin positive (P = .26), invasion of surrounding structures (P = .51), and size>5 cm (P = .20) were not significant predictors of survival. Four patients presented with synchronous liver metastasis and underwent resection of the primary tumor and the liver metastasis, with one patient dying of progression of metastatic disease at 8 months, another alive with recurrence in the liver at 6 years, and the last two alive without evidence of disease at 1 month and 11 years.

SPT occurs predominantly in women (82%), although it can occur in men; all age groups are affected. Complete resection is associated with long-term survival even in the presence of metastatic disease.

Do high concentrations of isoflurane block the sympathetic nervous system activation from desflurane?

The volatile anesthetic desflurane has been associated with neurocirculatory responses that have been relatively refractory to adjuvant treatment. We have employed desflurane to evaluate the integrity of the sympathetic nerve recording after establishment of the anesthetized state with another anesthetic agent. This retrospective evaluation of data from volunteers determined if higher concentrations of isoflurane that were sufficient to block the neurocirculatory response to laryngeal and tracheal stimulation would abolish the neurocirculatory response to desflurane. Data from eight, healthy, young volunteers met our criteria for inclusion. They had been anesthetized with propofol or thiopental and intubated after neuromuscular blockade. Each subject was monitored with radial artery blood pressure (BP), heart rate (HR)(ECG), and sympathetic microneurography. Isoflurane had been administered to achieve a steady state concentration of 1.5 MAC (minimum alveolar concentration) while oxygenation and carbon dioxide were monitored with pulse oximetry and infrared spectrometry, respectively. A deep level of anesthesia was confirmed when laryngoscopy and endotracheal tube movement failed to elicit a neurocirculatory response. A brief exposure to 11% desflurane in the inspired gas was then provided. The responses to desflurane included significant increases in HR, range 32-84 b/min, and BP, range 15-72 mm Hg (P < 0.05). Sympathetic nerve activity increased substantially in the three volunteers with functional nerve recordings.

In healthy volunteers receiving 1.5 MAC isoflurane, which was sufficient to block the neurocirculatory response to laryngoscopy and tracheal stimulation, there were striking increases in sympathetic outflow, HR and BP when 11% desflurane was substituted for isoflurane.

Biobank bootstrapping: is biobank sustainability possible through cost recovery?

The pre-eminent goal of biobanks is to accelerate scientific discovery and support improvements in healthcare through the supply of high quality biospecimens to enable excellent science. Despite the need for retrospective future-proofed cancer repositories, they are presented with significant fiscal challenges. While it was once thought that biobanks could recover most, if not all, operational costs through distribution fees, biobanks have been consistently unable to fully realize this dream. Using data from three mature Canadian cancer biobanks, common attributes and assumptions related to cost recovery were evaluated. The values were entered into a simple financial model to determine the cost recovery potential for biobanks. Over a 5-year period analyzed, aliquots from almost 40% (8990) of 23055 cases collected have been distributed in whole or in part to researchers. The financial modeling demonstrates that, based on values derived from the real life experiences of three major Canadian biobanks, full cost recovery through distribution is not feasible. A more realistic, experience based, expectation of cost recovery from distribution fees is in the range of 5%-25%, and this range is lower if only academic research is supported as opposed to also supporting industry researchers.

Biobanks are expensive and, to mitigate costs, are frequently challenged to operate under "self-sustainable" financial models. However, the only possible route to self-sustainability through distribution fees in today's market would require an almost exclusive targeting of commercial researchers and, even then, evidence suggests this is an impossible goal to attain. Support for biobanks should recognize that they exist to further development of personalized treatments and diagnostics essential for precision medicine. For biobanks to continue to achieve this goal, pro bono publicum, funders need to be aware of the full funding requirements of biobanks and create appropriate funding streams.

Does cerebrospinal Fluid Biomarker for Alzheimer Disease predict Postoperative Cognitive Dysfunction?

Postoperative cognitive dysfunction (POCD) affects 16 to 21% of the elderly 3 months after anesthesia and surgery and is associated with adverse outcomes. The exact cause of POCD remains unknown. The authors hypothesized that elderly individuals with Alzheimer disease (AD) neuropathology, identified by cerebrospinal fluid (CSF) analysis, would have increased the risk for POCD. CSF samples were collected from 59 patients 60 yr or older who received combined spinal and general anesthesia for elective total hip replacement. Patients underwent neuropsychological testing preoperatively and at 7 days, 3 months, and 12 months postoperatively. POCD at 3 months and cognitive decline at 12 months were calculated by using the reliable change index. CSF amyloid β1-42 (Aβ1-42), total-tau, phosphorylated-tau, and neurofilament light were assayed with enzyme-linked immunosorbent assay methods. POCD was identified in 5 of 57 patients (8.8%) at 3 months. For Aβ1-42, 11 patients were below the cut-point for AD neuropathology of whom 3 were classified with POCD (27.3%; 95% CI, 6.0 to 61%), whereas of the 46 patients above the cut-point, 2 were classified with POCD (4.3%; 95% CI, 0.5 to 14.8%) (P = 0.01). There was no significant difference in the incidence of POCD in relation to the cut-points for any of the other analytes.

Low CSF Aβ1-42 may be a significant predictor of POCD at 3 months. This indicates that patients with AD neuropathology even in the absence of clinically detectable AD symptoms may be susceptible to POCD.

Is waiting time to lymph node biopsy dependent on referral method : do n't write , phone?

Patients with lymphadenopathy are commonly referred to general surgeons for diagnostic lymph node biopsy. We were concerned at potential long waits for this service in our hospital and thus wanted to compare the efficiency of written and telephone referral with a view to identifying the optimum care pathway for these patients. Sixty patients were included in a 2-year retrospective review (excluding referrals associated with breast lumps which were managed separately). Hospital Episode Statistics data were used to analyse notes for the source and method of referral, waiting time to biopsy, clinic attendance and diagnosis. Of referrals, 33% were from haematology and 28% from general practice. Overall, 47% of patients were referred by letter; of these, 64% were seen in clinic before biopsy. Personal referral between clinicians, by direct discussion, e-mail or fax led to a mean wait of 4 days, compared to 51 days when patients were referred by letter. Clinic attendance had no significant bearing on diagnostic accuracy or complication rate. Neoplasia accounted for 43% of diagnoses and infection (including four cases of tuberculosis) for 10%. Of biopsies, 33% showed benign changes, 8% were unrecorded and 5% were incorrect.

In this study, 43% of biopsies revealed malignancy and we advise that lymph node biopsy requests should be managed on a fast-track pathway, expedited by direct personal request. Following this study, we have implemented a fast-track pathway for such patients.

Does survival in human colorectal cancer correlate with expression of the T-cell costimulatory molecule OX-40 ( CD134 )?

The T-cell costimulatory molecule OX-40 (CD134) is expressed on activated CD4(+) ("helper") T cells. Such cells have been detected in human cancers, and engagement of OX-40 improves colon cancer immunity in an animal model. Sections of primary colon cancers, normal margins, mesenteric lymph nodes, and metastases were stained for OX-40 by immunohistochemistry. Cancer registry data were reviewed. High levels of OX-40 positive tumor-infiltrating lymphocytes were found in 15 of 72 primary tumors. Thirty-one cases had prominent lymphocytic infiltrates expressing OX-40 at the invasive margin of the tumor. Overall, 50% of primary tumors showed high expression of OX-40. Nearly all mesenteric lymph nodes expressed OX-40, whether tumor was present or not. Normal margins of colon did not show high levels of OX-40. High OX-40 expression in the primary tumor correlated with better survival (mean survival high OX-40, 47 months, low OX-40, 35 months, P <0.05), although this correlation was not stage-independent.

High levels of OX-40 positive lymphocytes are present in half of primary colon cancers, and this expression in primary tumors significantly correlates with better survival. This correlation with survival and our previous preclinical research suggest a basis for an OX-40 immunotherapy trial.

Will the use of low-molecular-weight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada?

One-year follow-up data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial show that use of low-molecular-weight heparin (enoxaparin) compared with unfractionated heparin in patients hospitalized with unstable angina or non-Q-wave myocardial infarction is associated with a 10% reduction in the cumulative 1-year risk of death, myocardial infarction, or recurrent angina. Given the higher acquisition cost of enoxaparin relative to unfractionated heparin, we assessed whether the reduced use of revascularization procedures and related care makes enoxaparin a cost-saving therapy in Canada. We analyzed cumulative 1-year resource use data on the 1259 ESSENCE patients enrolled in Canadian centers (40% of the total ESSENCE sample). Patient-specific data on use of drugs, diagnostic cardiac catheterization, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and hospital days were available from the initial hospital stay and cumulative to 1 year. Hospital resources were costed with the use of data from a teaching hospital in southern Ontario that is a participant in the Ontario Case Costing Project. During the initial hospital stay, use of enoxaparin was associated with reduced use of diagnostic catheterization and revascularization procedures, with the largest effect being reduced use of percutaneous transluminal coronary angioplasty (15.0% vs 10.6%; P =.03). At 1 year, the reduced risk and costs of revascularization more than offset increased drug costs for enoxaparin, producing a cost-saving per patient of $1485 (95% confidence interval $-93 to $3167; P =.06). Sensitivity analysis with lower hospital per diem costs from a community hospital in Ontario still predicts cost savings of $1075 per patient over a period of 1 year.

The acquisition and administration cost of enoxaparin is higher than for unfractionated heparin ($101 vs $39), but in patients with acute coronary syndrome, the reduced need for hospitalization and revascularization over a period of 1 year more than offsets this initial difference in cost. Evidence from this Canadian substudy of ESSENCE supports the view that enoxaparin is less costly and more effective than unfractionated heparin in this indication.

Is standards and guidelines for observational studies : quality in the eye of the beholder?

Patient care decisions demand high-quality research. To assist those decisions, numerous observational studies are being performed. Are the standards and guidelines to assess observational studies consistent and actionable? What policy considerations should be considered to ensure decision makers can determine if an observational study is of high-quality and valid to inform treatment decisions? Based on a literature review and input from six experts, we compared and contrasted nine standards/guidelines using 23 methodological elements involved in observational studies (e.g., study protocol, data analysis, and so forth). Fourteen elements (61%) were addressed by at least seven standards/guidelines; 12 of these elements disagreed in the approach. Nine elements (39%) were addressed by six or fewer standards/guidelines. Ten elements (43%) were not actionable in at least one standard/guideline that addressed the element.

The lack of observational study standard/guideline agreement may contribute to variation in study conduct; disparities in what is considered credible research; and ultimately, what evidence is adopted. A common set of agreed on standards/guidelines for conducting observational studies will benefit funders, researchers, journal editors, and decision makers.

Does brain perfusion correlate of medial temporal lobe atrophy and white matter hyperintensities in mild cognitive impairment?

To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI). 56 MCI patients (age = 69.3 +/- 7.0, 32 females) underwent brain MR scan and (99m)Tc ECD SPECT. We evaluated MTA according to Scheltens' fivepoint scale on T1 MR images, and assessed WMHs using the rating scale for age-related white matter changes on T2-weighted and FLAIR MR images. We divided MCI into age-matched subgroups with high and low MTA and high and low WMHs load. We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing high vs. low MTA and high vs. low WMHs, setting p-value at 0.001 uncorrected, thresholding cluster extent at 100 voxels, using proportional scaling and entering age and WMHs or MTA respectively as nuisance covariates. MCI with high compared with low MTA showed hypoperfusion in the left hippocampus and in the left parahippocampal gyrus. MCI with high compared with low WMHs showed a hypoperfusion area in the left insular region and superior temporal gyrus.

MTA in MCI is associated with hippocampal gray matter hypoperfusion while WMHs is associated with gray matter hypoperfusion in areas of the insula and temporal neocortex. These results confirm that MTA is associated with local functional changes and suggest that WMHs may be associated with remote brain cortical dysfunction.

Does financial strain explain the association between children's morbidity and parental non-employment?

To investigate whether family financial resources explain the association between parental labour market participation and children's health in families in Denmark and Sweden. Parent reported questionnaire data from the survey of health and welfare among children and adolescents in the Nordic countries, 1996. 4299 children aged 2-17 years. Three indicators measured children's health: recurrent psychosomatic symptoms, chronic illness, and prescribed medicine. Four variables and a composite index were used to measure family financial resources. The variable on family labour market participation consisted of five groups according to family type and parents' labour market participation. Children in families with one or both parents without paid work had an increased prevalence of recurrent psychosomatic symptoms (odds ratio from 1.52 to 3.20) and chronic illnesses (odds ratio from 1.43 to 2.25), whereas the use of prescribed medicine did not differ (odds ratio from 0.67 to 1.15). The five indicators on family financial resources only slightly reduced the odds ratios for recurrent psychosomatic symptoms (odds ratio from 1.12 to 2.75) and chronic illnesses (odds ratio from 1.34 to 2.22), and the odds ratios for children's use of prescribed medicine remained unchanged and non-significant (odds ratio from 0.62 to 1.18).

Financial strain associated with non-employment does not explain the increased prevalence of health problems among children in families affected by non-employment in Denmark and Sweden. However, the associations between family labour market participation and children's health differ according to family financial status.

Does continuous proton pump inhibitor treatment decrease upper gastrointestinal bleeding and related death in rural area in Japan?

Proton pump inhibitors (PPI) have been rarely used for prevention of upper gastrointestinal bleeding (UGIB) induced by non-steroidal anti-inflammatory drugs (NSAIDs) and/or aspirin in Japan. The increased incidence of UGIB in the aged society is becoming a serious problem. The aim of this study was to retrospectively evaluate whether PPI can prevent UGIB. We examined records of 2367 patients (aged 67.9 ± 15.1 years, male 1271) attending the only hospital serving the rural area, with little population movement. We investigated the correlation between the frequency of usage of medicine (PPI, histamine 2 receptor antagonists [H2RA], NSAIDs, aspirin) and incidence of UGIB over 12 years. UGIB was defined as cases with hematemesis and/or melena and definite bleeding at upper gastrointestinal endoscopy. The annual incidence of UGIB of inhabitants (16,065 ± 375.3 persons/year) was evaluated. The frequency of usage of medicine was compared with the total number of patients prescribed any medication (1080 ± 33.2 persons/year). The frequency of PPI usage has increased significantly 4.6%→30.8% (P < 0.05). NSAIDs and aspirin usage increased significantly in the latter half of the survey period (P < 0.05). The annual incidence of UGIB significantly decreased 160.8 →23.6/100,000 inhabitants per annum (P ≤ 0.05) due to widespread use of PPI. No patients died due to UGIB after 2006. The incidence of UGIB and the prevalence of PPI usage were found to have a negative correlation (r = -0.804, P = 0.0016).

By widespread use of PPI, UGIB and related death has declined significantly. This survey showed that continuous PPI treatment decreases UGIB and related death in community medicine.

Do endometriotic ovarian cysts negatively affect the rate of spontaneous ovulation?

Do endometriotic ovarian cysts influence the rate of spontaneous ovulation?

Endometriotic cysts, no matter what their volume, do not influence the rate of spontaneous ovulation in the affected ovary.

Does arsenic exposure in pregnancy increase the risk of lower respiratory tract infection and diarrhea during infancy in Bangladesh?

Previous studies have reported associations between prenatal arsenic exposure and increased risk of infant mortality. An increase in infectious diseases has been proposed as the underlying cause of these associations, but there is no epidemiologic research to support the hypothesis. We evaluated the association between arsenic exposure in pregnancy and morbidity during infancy. This prospective population-based cohort study included 1,552 live-born infants of women enrolled during 2002-2004 in Matlab, Bangladesh. Arsenic exposure was assessed by the concentrations of metabolites of inorganic arsenic in maternal urine samples collected at gestational weeks 8 and 30. Information on symptoms of lower respiratory tract infection (LRTI) and diarrhea in infants was collected by 7-day recalls at monthly home visits. In total, 115,850 person-days of observation were contributed by the infants during a 12-month follow-up period. The estimated risk of LRTI and severe LRTI increased by 69% [adjusted relative risk (RR) = 1.69; 95% confidence interval (CI), 1.36-2.09)] and 54% (RR = 1.54; 95% CI, 1.21-1.97), respectively, for infants of mothers with urinary arsenic concentrations in the highest quintile (average of arsenic concentrations measured in early and late gestation, 262-977 µg/L) relative to those with exposure in the lowest quintile (< 39 µg/L). The corresponding figure for diarrhea was 20% (RR = 1.20; 95% CI, 1.01-1.43).

Arsenic exposure during pregnancy was associated with increased morbidity in infectious diseases during infancy. Taken together with the previous evidence of adverse effects on health, the findings strongly emphasize the need to reduce arsenic exposure via drinking water.

Assessing Patient Reported Outcomes Measures via Phone Interviews Versus Patient Self-Survey in the Clinic: Are We Measuring the Same Thing?

Longitudinally following patients requires a full-time employee (FTE)-dependent data inflow infrastructure. There are efforts to capture patient-reported outcomes (PROs) by the use of non-FTE-dependent methodologies. In this study, we set out to assess the reliability of PRO data captured via FTE-dependent compared with non-FTE-dependent methodologies. A total of 119 adult patients (65 men) who underwent 1-and 2-level lumbar fusions at Duke University Medical Center were enrolled in this prospective study. Enrollment criteria included available demographic, clinical, and PRO data. All patients completed 2 sets of questionnaires--the first a phone interviews and the second a self-survey. There was at least a 2-week period between the phone interviews and self-survey. Questionnaires included the Oswestry Disability Index (ODI), the visual analog scale for back pain (VAS-BP), and the visual analog scale for leg pain (VAS-LP). Repeated-measures analysis of variance was used to compare the reliability of baseline PRO data captured. A total of 39.49% of patients were smokers, 21.00% had diabetes, and 11.76% had coronary artery disease; 26.89% reported history of anxiety disorder, and 28.57% reported history of depression. A total of 97.47% of patients had a high-school diploma or General Education Development, and 49.57% attained a 4-year college degree or postgraduate degree. We observed a high correlation between baseline PRO data captured between FTE-dependent versus non-FTE dependent methodologies (ODI: r = -0.89, VAS-BP: r = 0.74, VAS-LP: r = 0.70). There was no difference in PROs of baseline pain and functional disability between FTE-dependent and non-FTE-dependent methodologies: baseline ODI (FTE-dependent: 47.73 ± 16.77 [mean ± SD] vs. non-FTE-dependent: 45.81 ± 12.11, P = 0.39), VAS-LP (FTE-dependent: 6.13 ± 2.78 vs. non-FTE-dependent: 6.46 ± 2.79, P = 0.36) and VAS-BP (FTE-dependent: 6.33 ± 2.90 vs. non-FTE-dependent: 6.53 ± 2.48, P = 0.57).

Our study suggests that there is great reliability between PRO data captured between FTE-dependent and non-FTE-dependent methodologies.

Are infection-related hospitalizations associated with increased mortality in patients with inflammatory bowel diseases?

Serious infections are an important side effect of immunosuppressive therapy used to treat Crohn's disease (CD) and ulcerative colitis (UC). There have been no nationally representative studies examining the spectrum of infection related hospitalizations in patients with IBD. Our study consisted of all adult CD and UC related hospitalizations from the Nationwide Inpatient Sample 2007, a national hospitalization database in the United States. We then identified all infection-related hospitalizations through codes for either the specific infections or disease processes (sepsis, pneumonia, etc.). Predictors of infections as well as the excess morbidity associated with infections were determined using multivariate regression models. There were an estimated 67,221 hospitalizations related to infections in IBD patients, comprising 27.5% of all IBD hospitalizations. On multivariate analysis, infections were independently associated with age, co-morbidity, malnutrition, TPN, and bowel surgery. Infection-related hospitalizations had a four-fold greater mortality (OR 4.4, 95% CI 3.7-5.2). However, this varied by type of infection with the strongest effect seen for sepsis (OR 15.3, 95% CI 12.4-18.6), pneumonia (OR 3.6, 95% CI 2.9-4.5) and C. difficile (OR 3.2, 95% CI 2.6-4.0), and weaker effects for urinary infections (OR 1.4, 95%CI 1.1-1.7). Infections were also associated with an estimated 2.3 days excess hospital stay (95% CI 2.2-2.5) and $12,482 in hospitalization charges.

Infections account for significant morbidity and mortality in patients with IBD and disproportionately impact older IBD patients with greater co-morbidity. Pneumonia, sepsis and C difficile infection are associated with the greatest excess mortality risk.

Are 3 cycles of bleomycin, etoposide and cisplatin or 4 cycles of etoposide and cisplatin equivalent optimal regimens for patients with good risk metastatic germ cell tumors of the testis?

Standard chemotherapy for good prognosis metastatic nonseminomatous germ cell tumors of the testis currently includes etoposide and cisplatin. The optimal number of cycles and the need for bleomycin remain matters of debate. Three cycles of bleomycin, etoposide and cisplatin (BEP) or 4 cycles of etoposide and cisplatin are supposed to represent equivalent optimal regimens. We analyzed the therapeutic outcome of 75 patients with good risk metastatic nonseminomatous germ cell tumor of the testis who were routinely treated at our institute. The chemotherapy regimens consisted of 4 cycles of BEP in 17 patients, 3 cycles of BEP in 23 patients, and 4 cycles of etoposide and cisplatin in 35 patients. All 75 patients achieved a complete or partial response with normal serum tumor markers. After a median followup of 3.5 years (range 2 to 7.5) the overall no evidence of disease rate was 91% (100, 96 and 83% in patients treated with 4 cycles of BEP, 3 cycles of BEP, and 4 cycles of etoposide and cisplatin, respectively). When considering the number of adverse events in each treatment group, that is the number of surgical complete responses or relapses after complete remission, results appeared similar with 3 or 4 cycles of BEP (2 and 3, respectively) but lower in patients who received 4 cycles of etoposide and cisplatin (11 adverse events). Of the 35 patients treated with etoposide and cisplatin 4 (11%) died of disease while only 1 of the 40 (3%) treated with BEP died of disease.

Four cycles of etoposide and cisplatin could yield inferior results compared to 3 cycles of BEP in patients with good risk nonseminomatous germ cell tumor of the testis. Our results highlight the need for a randomized trial addressing the question of therapeutic equivalence between these 2 chemotherapy regimens.

Basal forebrain amnesia: does the nucleus accumbens contribute to human memory?

To analyse amnesia caused by basal forebrain lesions. A single case study of a patient with amnesia after bleeding into the anterior portion of the left basal ganglia. Neuropsychological examination included tests of attention, executive function, working memory, recall, and recognition of verbal and non-verbal material, and recall from remote semantic and autobiographical memory. The patient's MRI and those of other published cases of basal forebrain amnesia were reviewed to specify which structures within the basal forebrain are crucial for amnesia. Attention and executive function were largely intact. There was anterograde amnesia for verbal material which affected free recall and recognition. With both modes of testing the patient produced many false positive responses and intrusions when lists of unrelated words had been memorised. However, he confabulated neither on story recall nor in day to day memory, nor in recall from remote memory. The lesion affected mainly the nucleus accumbens, but encroached on the inferior limb of the capsula interna and the most ventral portion of the nucleus caudatus and globus pallidus, and there was evidence of some atrophy of the head of the caudate nucleus. The lesion spared the nucleus basalis Meynert, the diagnonal band, and the septum, which are the sites of cholinergic cell concentrations.

It seems unlikely that false positive responses were caused by insufficient strategic control of memory retrieval. This speaks against a major role of the capsular lesion which might disconnect the prefrontal cortex from the thalamus. It is proposed that the lesion of the nucleus accumbens caused amnesia.

Does [ Klotho gene attenuate the progression of hypertension and heart damage in spontaneous hypertensive rats ]?

To assess the effect of Klotho gene transduction on the progression of hypertension and heart damage in spontaneous hypertensive rats (SHRs). An adeno-associated virus (AAV) carrying full-length mouse Klotho cDNA (rAAV.mKL) was constructed for in vivo expression of Klotho. Three different groups of male SHRs and a control group of sex and age-matched Sprague Dawley (SD) rats (5 rats per group) were used. The experimental groups of SHRs received an IV injection of phosphate buffered saline (PBS), rAAV.mKL and rAAV.EGFP, respectively. The control group only received equal-volume of PBS. The whole study has spanned 12 weeks. Plasma levels of insulin-like growth factor-1 (IGF-1) and insulin were measured with ELISA. The weight of whole heart was measured to calculate the heart weight index (HWI). EGFP expression of heart frozen sections was observed by fluorescence microscopy. Expression of mRNA and protein of Klotho, IGF-1, IGF-1 receptor (IGF-1R) and p-Akt were determined with RT-PCR, immunohistochemical analysis, and Western blotting. Hypertrophic myocardial cell and collagen fiber were observed by histological examination following Haematoxylin-Eosin and Masson staining. Transduction of rAAV.mKL can significantly prevent the increase of blood pressure in SHRs. Compared with the control group, the levels of Klotho mRNA and protein have both increased, and the plasma levels of IGF-1, insulin and glucose were elevated, whereas the expression of phosphor-Akt (also called Protein Kinase B, PKB) was decreased in the rAAV.mKL group. Furthermore, a decrease of hypertrophic myocardial cells and collagen fibers was noticed in the rAAV.mKL group compared with the control group.

The Klotho gene can attenuate the progression of hypertension and abolishes myocardial hypertrophy and myocardial fibrosis. The protective effect observed in the rAAV.mKL group of SHRs may be attributed to increased Klotho protein and suppression of insulin and IGF-1 signaling pathways through inhibition of Akt phosphorylation.

Does clevudine demonstrate potent antiviral activity in naïve chronic hepatitis B patients?

Clevudine has demonstrated antiviral potency in the treatment of naïve chronic hepatitis B patients in pivotal studies. The objectives of this study were to evaluate the safety and efficacy of a 1-year treatment with clevudine in chronic hepatitis B patients. This is a post-marketing surveillance using case report forms which were submitted to the health authorities. Analysis of individual data showed that hepatitis B virus (HBV) DNA after a 1-year treatment was <141,500 copies/ml in 96% of hepatitis B e antigen (HBeAg)-positive and 100% of HBeAg-negative patients. The proportion of patients with HBV DNA <2,000 copies/ml after a 1-year treatment was 74%: 71% of HBeAg-positive and 93% of HBeAg-negative patients. Most of the patients with HBV DNA below the detection limit with each assay at week 24 showed sustained viral suppression up to week 48. The proportion of patients who showed normal alanine aminotransferase at week 48 was 86% in HBeAg-positive patients and 87% in HBeAg-negative patients. The rates of HBeAg-loss were 21%. Two patients showed viral breakthrough during treatment.

Clevudine monotherapy demonstrates potent antiviral activity as well as biochemical and serological response with a 0.7% rate of viral breakthrough in naïve chronic hepatitis B patients.

Do molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value?

Altered microRNAs (miRNA) expression, a typical feature of many cancers, is reportedly associated with prognosis according to several studies. Although numerous studies on miRNAs in pancreatic ductal adenocarcinoma have also attempted to identify prognostic biomarkers, more large-scale clinical studies are needed to establish the clinical significance of the results. Present study aimed to identify prognosis-related molecular subtypes of primary pancreas tumors using miRNA expression profiling. Expression profiles of 1733 miRNAs were obtained by using microarray analysis of 104 pancreatic tumors of Korean patients. To detect subgroups informative in predicting the patient's prognosis, we applied unsupervised clustering methods and then analyzed the association of the molecular subgroups with survival time. Then, we constructed a classifier to predict the subgroup using penalized regression models. We have determined three pancreatic ductal adenocarcinoma tumor subtypes associated with prognosis based on miRNA expression profiles. These subtypes showed significantly different survival time for patients with the same clinical conditions. This demonstrates that our prognostic molecular subgroup has independent prognostic utility. The molecular subtypes can be predicted with a classifier of 19 miRNAs. Of the 19 signature miRNAs, miR-106b-star, miR-324-3p, and miR-615 were related to a p53 canonical pathway, and miR-324, miR-145-5p, miR-26b-5p, and miR-574-3p were related to a Cox-2 centered pathway.

Our prognostic molecular subtypes demonstrated that miRNA profiles could be used as prognostic markers. Additionally, we have constructed a classifier that may be used to determine the molecular subgroup of new patient sample data. Further studies are needed for validation.

Is decreased plasma nesfatin-1 level related to the thyroid dysfunction in patients with type 2 diabetes mellitus?

Thyroid dysfunction is frequently observed in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is still poorly understood. The present study aimed to investigate whether nesfatin-1 played a role in the thyroid dysfunction in patients with T2DM. 55 euthyroid patients were enrolled in this study including 30 patients with T2DM and 25 patients with impaired glucose regulation (IGR). 30 age-matched healthy people were also included as the control. The plasma levels of nesfatin-1, thyrotropin (TSH), and glycosylated hemoglobin (HbA1c) as well as the body mass index (BMI) were comparatively analyzed among the three groups. The nesfatin-1 was significantly lower in patients with T2DM than in patients with IGR and in the control. On the contrary, the TSH level was significantly higher in patients with T2DM than in patients with IGR and in the control. Simple regression analysis showed that the plasma nesfatin-1 was negatively correlated with the TSH and HbA1c levels and positively correlated with the BMI. With multiple stepwise regression analysis, the nesfatin-1 remained to be independently correlated with the TSH, BMI, and HbA1c.

The study was suggesting a role of nesfatin-1 in thyroid dysfunction in patients with T2DM.

Practice style traits: do they help explain practice behaviours of stroke rehabilitation professionals?

The gap in knowledge translation from research to clinical practice is under scrutiny in stroke rehabilitation. One possible reason for this gap may be a poor understanding of clinicians' practice style traits and how they influence practice behaviours. To identify the prevalence of practice style traits in physical therapists and occupational therapists working in stroke rehabilitation and, to explore associations between these traits and practice behaviours, where practice behaviours are defined as the clinicians' reasons for choosing assessments and interventions used in practice. The influence of more traditional personal and organizational factors on practice behaviours was also explored. Cross-sectional survey of a representative random sample of 243 clinicians (117 occupational therapists and 126 physical therapists) working across the continuum of stroke care in Ontario, Canada. A telephone-administered validated clinical practice survey elicited information in 4 areas: practice style traits using the validated Practice Style Questionnaire, therapists' reasons for choosing assessments and interventions (practice behaviours), personal factors and organizational factors. For both disciplines, the most prevalent trait was pragmatist and the least prevalent was seeker. Seekers were the most likely to use evidence-based reasons for choosing assessments, but this finding did not reach significance (chi2 = 5.430, df = 3; p = 0.14). The most typical reason for choosing an intervention was that the clinician had learned it during professional training, an interesting finding given that approximately half of clinicians had more than 10 years of experience. Of the 21 potential explanatory variables examined, few explained clinicians' reasons for choosing assessments or interventions.

While understanding practice traits is not going to be the single solution to closing the knowledge translation gap, it may help to guide best practice implementation strategies.