Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential interaction of the tSXV motifs of the NR1 and NR2A NMDA receptor subunits with PSD‐95 and SAP97

The NR1 and NR2 subunits of the N‐methyl‐d‐aspartate (NMDA) receptor are encoded by distinct genes. In the rat brain, four C‐terminal variants of the NR1 subunit (NR1‐1 to NR1‐4) are encoded by a single gene, and are generated by alternative splicing of the C1 and C2 exon cassettes, while four different genes encode the NR2 subunits (NR2 A–D). Functional NMDA receptors result from the heteromultimeric assembly of NR1 variants with distinct NR2 subunits. The NR2B subunit interacts with post‐synaptic density protein 95 (PSD‐95), SAP97 and members of the membrane‐associated guanylate‐like kinase (MAGUK) family of proteins. This interaction occurs through the binding of the C‐terminal tSXV intracellular motif of the NR2B subunit to the N‐terminal PDZ (PSD‐95, discs‐large, ZO‐1) domains of the PSD‐95 and SAP97 proteins. Both NR1‐3 and NR1‐4 also display a consensus C‐terminal tSXV motif. Using the two‐hybrid genetic system in yeast and site‐directed mutagenesis, we compared the binding of the NR2A, NR1‐3 and NR1‐4 tSXV motifs with the PDZ domains of PSD‐95 and SAP97. The main conclusions of the present report are that: (i) while NR2A displays a strong interaction with PSD‐95 and SAP97, the NR1‐3 and NR1‐4 NMDA receptor subunits do not display any interaction despite the presence of tSXV motifs; (ii) the C‐terminal tSXV motif of the NR2A subunit is mandatory but not sufficient for efficient interaction with the PSD‐95 and SAP97 proteins; (iii) as yet unidentified upstream sequences of the receptor subunits determine whether the tSXV motifs will bind to the PSD‐95 and SAP97 PDZ domains; (iv) different tSXV motifs elicit interactions of variable strengths; and (v) residues in positions −3 and −4 modulate the binding affinity of the C‐terminal tSXV motifs. Using immunohistochemistry, we also compared the distribution of the PSD‐95, NR2A and SAP97 proteins in adult rat brain, and we show that in the cortex, hippocampus and cerebellum, there is evidence for colocalization of these proteins.
Clinical evaluation of the peritoneal equilibration test: a population-based study.

A total of 143 Peritoneal Equilibration Tests (PETs) were performed in 104 CAPD patients over a period of 18 months. A normal range (95% confidence limits) was constructed from 100 tests (68 consecutive new patients, 32 routine tests on problem-free patients) using a 2-dimensional plot of solute transfer (D/Pcreat) and ultrafiltration volume. These two parameters correlated inversely (r = -0.59, P < 0.0001) allowing calculation of a regression line. In the short term (< 3 months) D/Pcreat was stable across a wide range of values (0.45-0.98) with good correlation between tests indicating reproducibility (r = 0.94, P < 0.001). Repeated tests beyond 3 months were variable, explaining changes in the clinical picture, and in the majority of cases shifts in D/Pcreat and ultrafiltration parallelled the regression line for the whole population. Six of seven (85%) of patients with mechanical problems and 14 of 15 (93%) with poor ultrafiltration had at least one abnormal test, and these two problems could be distinguished in 90% of cases by 2-dimensional plotting. In five with ultrafiltration failure, dialysate volumes were less than predicted by solute clearance, and these patients failed continuous cycling peritoneal dialysis (CCPD). In contrast, a good response to CCPD was predicted correctly in five patients with high solute clearance. In nine patients with plasma creatinine > 1250 mumol/l the PET was normal. The PET is a useful adjunct to understanding and prescribing peritoneal dialysis, particularly when repeated tests are compared to a well-defined normal population.
Quantitative Detection of Promoter Hypermethylation in Multiple Genes in the Serum of Patients with Colorectal Cancer

OBJECTIVES:While promoter hypermethylation is a common molecular alteration of human colorectal cancer that could be detected in the bloodstream, we tested the feasibility of quantitative detection of aberrant DNA methylation in multiple genes in the serum samples of colorectal cancer patients.METHODS:The pre-therapeutic serum samples of 49 colorectal cancer patients and 41 age-matched controls with normal colonoscopy were examined. The presence of methylated DNA in APC (adenomatous polyposis coli), hMLH1 (human MutL homolog 1), and HLTF (helicase-like transcription factor) was detected by quantitative methylation-specific PCR (MethyLight). RESULTS:There was a significant difference in the concentration of methylated serum DNA between cancer patients and controls for HLTF (p = 0.015) and hMLH1 (p = 0.0001) genes, but not for APC gene (p = 0.21). In total, 28 patients with colorectal cancer and 4 controls had methylated DNA detected in at least one marker, which gave a sensitivity of 57% and specificity of 90%. All patients with methylation in two methylation markers had advanced (stage III/IV) cancer (p = 0.006) and patients with methylation in at least one marker tended to have a lower probability of survival (p = 0.08). CONCLUSION:The quantitative detection of aberrant DNA methylation in serum may be a promising high-throughput approach for the noninvasive screening and monitoring of colorectal cancer.
Survey on a Mammographic Screening Program in Istanbul, Turkey

Abstract: Breast cancers in Turkey tend to be diagnosed at advanced stages due to lack of organized comprehensive mammographic screening. In this study, factors associated with having a mammogram among healthy women of screening age in Bahcesehir county, a region in Istanbul, were investigated to assess the feasibility of organized breast cancer screening in Turkey. In this cross‐sectional study, 659 healthy women aged between 40 and 69 years were surveyed. A multiple‐choice questionnaire was used to obtain information regarding patient demographics, family history of cancer, and patient knowledge on mammographic screening. Factors associated with increased likelihood of having a mammogram included age older than 50 (OR = 1.75; 95% CI = 1.23–2.49), higher educational level (high school or university graduate; OR = 1.55; 95% CI = 1.07–2.25), and undergoing periodic gynecologic examinations (OR = 5.53; 95% CI = 3.88–7.89). Women aged between 40 and 49 years, who were most likely to have a mammogram within the last 2 years were characterized by a higher educational level (OR = 1.94; 95% CI = 1.14–3.31), periodic gynecologic examinations (OR = 4.06; 95% CI = 2.53–6.51), and a first or second degree family history of breast cancer (OR = 2.2; 95% CI = 1.06–4.50). In contrast, women aged between 50 and 69 years were more likely to have undergone mammography within the previous 2 years if they also had undergone periodic gynecologic examinations (OR = 8.63; 5.04–14.77). Our findings suggest that women of lower educational level and those who do not undergo routine wellness visits with their gynecologist will need to be specifically targeted for educational outreach to achieve broad screening compliance within the population.
Treosulfan and fludarabine low‐toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only treatment of proven long‐term efficacy in chronic myeloid leukaemia (CML), although high non‐relapse mortality (NRM) observed after conventional myeloablative conditioning limits its applicability. This phase II trial evaluated the efficacy and toxicity of a new preparative regimen consisting of treosulfan 3 × 14 g/m2 and fludarabine 5 × 30 mg/m2, in patients with CML in chronic phase. Among the 40 patients included, 18 received alloHSCT from a sibling and 22 from an unrelated donor. All patients engrafted with 92·5% of cases achieving complete donor chimaerism by day +100. All but one patient had achieved complete cytogenetic remission on day +100. Grade III or IV non‐haematological toxicities included: neutropenic fever (10%), nausea/vomiting (10%), elevated liver enzymes (5%) and infection (2·5%). The incidence of grade II–IV acute graft‐versus‐host disease (GVHD) was 22·5% and extensive chronic GVHD, 14%. The 2‐year probability of overall survival, leukaemia‐free survival and NRM was 85%, 82·5% and 15% respectively. At 1 year post‐transplant, 85% of survivors had a Karnofsky index of 100%. We concluded that treosulfan and fludarabine conditioning is a low‐toxicity regimen with high anti‐leukaemic potential that seems feasible in CML patients referred for alloHSCT.
Natural history of hearing loss in children with enlarged vestibular aqueduct syndrome.

OBJECTIVE To determine the natural history of hearing loss in children with enlarged vestibular aqueduct (EVA) syndrome. DESIGN (1) Retrospective cohort study and (2) systematic literature review. SETTING Tertiary pediatric centre. METHODS (1) Charts of children assessed by one physician between 1993 and 2000 were reviewed. (2) Source articles were identified by a search of Medline, Embase, and the Cochrane Library of the English-language literature through January 2006, with manual review of references. The search was limited to English, human, and age less than 18 years. MAIN OUTCOME MEASURES Pure-tone average. Hearing was classified as stable, progressive and fluctuating. RESULTS (1) Twenty-one children (39 ears) with EVA were identified. Eighty-two percent of ears had stable hearing, and 18% of ears demonstrated progressive hearing loss. (2) Seven source articles were identified and combined with the present data for a total of 310 ears with a mean follow-up of 4 years. Bilateral EVA was found to be six times more common than unilateral EVA, and there was an equal male to female ratio. Stable hearing was found in 67% of ears and progressive hearing loss in 33% of ears. Subgroup analysis demonstrated hearing fluctuations in 50% of progressive hearing loss ears and 34% of stable ears. CONCLUSIONS Stable hearing is observed in 67% of ears with EVA of which 34% will demonstrate fluctuations in hearing. Progression of hearing loss is seen in 33% of ears of which half will demonstrate fluctuations.
Sensory neuron growth cones comigrate with posterior lateral line primordial cells in zebrafish

The development of neuromasts and sensory neurons of the posterior lateral line was studied in zebrafish (Brachydanio rerio) in order to determine the relationship between growing axons of sensory neurons and the migratory cellular primordium of midbody line neuromasts. Scanning electron microscopy revealed that a primary system of six neuromasts develops during the second day after fertilization and evidence is presented that these arise from cells of a migratory primordium. The primordium is first detected in the postauditory region immediately adjacent to the developing sensory ganglion. Growth cones of posterior lateral line sensory neurons are found within the premigratory primordium when it is adjacent to the ganglion. At later times growth cones of these sensory neurons are found within the primordium as it migrates caudally along the midbody line.
No small surprise – small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour

Whole‐exome sequencing (WES) is revolutionizing medical diagnostics and taxonomy. In less than 5 years since its first use, WES has revealed unexpected molecular drivers of numerous cancers. Here, we describe our use of WES to uncover the true nature of an enigmatic pathological entity, small‐cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), which has resisted definitive characterisation since it was first described in 1979. We conducted WES using three families with SCCOHT and identified deleterious mutations in the chromatin‐remodelling gene SMARCA4 (encoding BRG1) in all cases. Follow‐up of these findings, using both Sanger sequencing and WES of formalin‐fixed paraffin‐embedded tumours, showed that virtually all SCCOHTs we studied lacked functional SMARCA4/BRG1. Notably, this gene, and the related SMARCB1 gene, is mutated in most, if not all, atypical teratoid/rhabdoid tumours and malignant rhabdoid tumours. Other groups have similar findings. We review the relationship between these three neoplasms, discuss how they were distinguished from morphologically similar neoplasms, consider their similarities and show how WES has revealed that SCCOHTs are in fact rhabdoid tumours. We propose that SCCOHT be renamed ‘malignant rhabdoid tumour of the ovary’ (MRTO) to reflect these observations. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Expression of p21Waf1, p27Kip1 and cyclin D1 proteins in breast ductal carcinoma in situ: Relation with clinicopathologic characteristics and with p53 expression and estrogen receptor status

p21Waf1 (p21), p27Kip1 (p27) and cyclin D1 have recently been reported as useful prognostic markers for patients with breast carcinoma. However, studies on these cell cycle regulators in ductal carcinoma in situ (DCIS) have been extremely limited. Therefore, we studied the immunohistochemical expression of p21, p27 and cyclin D1 proteins in 49 DCIS cases and compared the findings with the clinicopathologic parameters (age, tumor size, gross type, histologic type, histologic grade, necrosis and mitotic index), p53 and estrogen receptor (ER) status. A significant correlation was found between positive p21 immunoreactivity (67.3% of the cases) and well‐differentiated histologic grade, non‐comedo type, ER‐positive and p53‐negative (p53–) status. DCIS with p21+/p53– is likely to be the non‐comedo type. The overexpression of cyclin D1 (59.2% of the cases) correlated positively with the ER expression (P = 0.001). The p27 protein expression (46.9% of the cases) correlated with the cyclin D1 immunopositivity (P = 0.0003) and ER expression (P = 0.005). No significant associations were seen in the p27 or cyclin D1 expression and other clinicopathologic parameters. Our results suggest that p21 might be more related to the useful biologic markers in DCIS than p27 or cyclin D1. The significant positive association between p21, p27 or cyclin D1 and ER status, and close association of p27 and cyclin D1 expression might be implicated in the tumor biology of DCIS.
Exercise induces hepatosplanchnic release of heat shock protein 72 in humans

Physical exercise results in the appearance of heat shock protein (HSP) 72 in the circulation that precedes any increase in gene or protein expression in contracting skeletal muscle. In rodents, exercise increases liver HSP72 expression and the hepatosplanchnic viscera are known to release many acute phase proteins. In the present study, we tested the hypothesis that the splanchnic tissue beds release HSP72 during exercise. Seven male subjects performed 120 min of semi‐recumbent cycling at 62 ± 2 % of maximal oxygen uptake. Blood samples were obtained simultaneously from a brachial artery, a femoral vein and the hepatic vein prior to and at 30, 60 and 120 min of exercise. Leg blood flow (LBF) was measured by thermodilution in the femoral vein, and hepatosplanchnic blood flow (HBL) was measured using indocyanine green dye. Net leg and net hepatosplanchnic HSP72 balance were calculated as the product of LBF and femoral venous‐arterial HSP72 difference and the product of HBF and hepatic venous‐arterial HSP72 difference, respectively. Arterial plasma HSP72 was only detected in one subject at rest but progressively appeared in the arterial samples throughout exercise such that at 120 min it was detected in all subjects (0.88 ± 0.35 pg l−1; P < 0.05 compared with rest). The contracting muscle did not, however, contribute to this increase since there was no difference in the femoral venous‐arterial HSP72 concentration at any time. Rather, the increase in arterial HSP72 was accounted for, at least in part, by release from the hepatosplanchnic viscera with values increasing (P < 0.05) from undetectable levels at rest to 5.2 ± 0.2 pg min−1 after 120 min. These data demonstrate that the splanchnic tissues release HSP72 during exercise and this release is responsible, in part, for the elevated systemic concentration of this protein during exercise.
Childhood cancer incidence in Cuba, 2001 to 2003.

INTRODUCTION Estimating childhood cancer incidence globally is hampered by lack of reliable data and uniform age limits for classifying and analyzing data reported. In Cuba, cancer data has been systematically gathered and processed by the National Cancer Registry (NCR) since 1964. The International Classification of Childhood Cancer (ICCC) is currently recommended for registering neoplasms in the population aged < or =19 years. Cancer incidence data published by the Cuban Ministry of Public Health, however, uses ICCC diagnostic groups for the population aged <15 years, and topographic sites for the population aged > or =15 years. OBJECTIVE The objectives of this study are to describe cancer incidence in the Cuban population aged < or =19 years in 2001-2003 using the ICCC, as well as geographic distribution of incidence by sex and by principal diagnostic groups. METHODS A descriptive study of cancer incidence in the population aged < or =19 years was conducted using NCR data for 2001-2003. ICCC diagnostic groups and subgroups were used, and 5 age groups (<1, 1-4, 5-9, 10-14 and 15-19 years) were analyzed. Total incidence and percentages for each diagnostic group were calculated. Number of cases in each diagnostic group and subgroup was also recorded by age group, and age-specific rates per 100,000 population aged < or =19 years (ASR) and age-adjusted rates to the standard world population aged < or =19 years (AAR) were calculated. AARs for leukemias, lymphomas and central nervous system (CNS) tumors were used to analyze childhood cancer risk by sex and geographical distribution in the country's 14 provinces and Isle of Youth Special Municipality. RESULTS In 2001-2003, the NCR reported 1285 new cancer cases in the population aged < or =19 years for an overall incidence of 13.9 per 100,000 population aged < or =19 years (AAR). Highest risk was found in children aged <1 year with an ASR of 21.9 per 100,000 population aged < or =19 years. Leukemias, lymphomas and central nervous system tumors comprised 61.1% of new cases, and geographic distribution of these diagnostic groups varied by sex. Childhood cancer risk was highest for males in Ciego de Avila, Villa Clara and the Isle of Youth Special Municipality and highest for females in Sancti Spiritus, Villa Clara and Cienfuegos. CONCLUSIONS Incidence of childhood cancer in Cuba conforms to rates reported internationally and to the incidence pattern most common in Latin America. Further research is recommended to examine risk factors influencing geographical variations in incidence within Cuba.
Increased atherogenicity of low-density lipoprotein in heavy proteinuria.

BACKGROUND Heavy proteinuria is associated with marked abnormalities of lipoprotein metabolism and increased risk of atherogenesis. It is possible that qualitative as well as quantitative changes occur in lipoproteins to contribute to increased cardiovascular risk; for example, it is known that LDL exhibits heterogeneity, with small, dense LDL III particles being more atherogenic. METHODS We investigated LDL subfractions (measured by density gradient ultracentrifugation), VLDL subfractions, and post-heparin lipases in 12 patients with primary glomerular disease and 24-h albuminuria >2.5 g. These were compared to 23 age- and sex-matched controls. RESULTS Total LDL concentrations were similar in proteinuric patients and controls; however, there was a shift in subfraction distribution. The larger LDL I and LDL II particles were lower in the proteinuric group (29 +/- 24 vs 62 +/- 26 mg/dl P=0.011 and 121 +/- 80 vs 197 +/- 74 mg/dl P=0.028), whereas the concentration of atherogenic LDL III (small dense) was higher (135 +/- 64 vs 75 +/- 71 mg/dl P=0.0016). The concentration of total VLDL and both its subfractions were increased in the patients with proteinuria. Post-heparin hepatic and lipoprotein lipase levels were similar to normal. CONCLUSIONS These findings suggest that the atherogenicity of LDL is increased in patients with heavy proteinuria because of the redistribution towards smaller denser particles. Since small, dense LDL has a lower affinity for the LDL receptor, the altered nature of the lipoprotein in proteinuria may decrease its clearance by the receptor-mediated pathway and contribute to the reduced clearance of LDL observed in this population. This may contribute to progression of renal failure or the accelerated vascular disease found in patients with heavy proteinuria.
Current epidemiology and trends in invasive Haemophilus influenzae disease--United States, 1989-2008.

BACKGROUND With the introduction of Haemophilus influenzae serotype b (Hib) conjugate vaccines, there has been a dramatic reduction of Hib disease in young children and the epidemiological trends of invasive H. influenzae have shifted. METHODS Data were collected from active surveillance for invasive H. influenzae disease conducted through Active Bacterial Core surveillance sites during 1989-2008. RESULTS During 1999-2008, the estimated mean annual incidence of H. influenzae infection was 1.62 cases per 100 000 population; 15.3% of cases were fatal. Incidence was higher among adults aged ≥65 years, compared with other age groups. The largest burden of disease among children aged <5 years was in infants aged <1 year; many of these cases occurred during the first month of life in preterm or low-birth weight infants. An estimated 10% of the total burden of disease among children aged <5 years occurred in American Indian and Alaska Native children. During 1989-2008, 7559 cases of H. influenzae disease were reported from Active Bacterial Core surveillance sites. Small increases in the incidence of serotypes a, e, and f were observed during 1989-2008. The largest of these increases was in serotype f and was primarily among adults aged ≥18 years. CONCLUSIONS Since the introduction of Hib conjugate vaccines, the incidence of invasive disease caused by H. influenzae in the United States has decreased dramatically; however, a considerable burden of non-Hib disease is still present in the oldest and youngest age groups. There is no evidence of substantial replacement disease with non-b serotypes in young children in the United States.
Effectiveness of influenza vaccination in the elderly in South Africa

SUMMARY This study primarily aimed to estimate the association between influenza vaccination and the occurrence of hospitalization for acute respiratory or cardiovascular diseases, or all-cause death during the influenza season in an elderly population in South Africa. We conducted a nested case-control study using data from a cohort of 45 522 elderly members of a private medical funding organization during the moderate 2004 influenza season. In 1282 (2·8%) subjects the combined outcome occurred and the influenza vaccination rate in controls was 15·4%. After adjustments for measured confounders, vaccination was associated with a statistically significant reduction of 19% (95% confidence interval 3·1–32·9) in the combined outcome. Post-hoc sensitivity analysis of the potential impact of potential healthy user bias showed that confounding, if present, could have caused this finding. Our data were inconclusive regarding the benefits of influenza vaccination in elderly persons in South Africa and given the low vaccine uptake, long-term follow-up is warranted.