Miracle-dz/UniFAR-FTUs huggingface dataset:
Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk.

BACKGROUND Chronic inflammation plays an important role in several human cancers and may be involved in the etiology of prostate cancer. Toll-like receptors (TLRs) are important in the innate immune response to pathogens and in cross-talk between innate immunity and adaptive immunity. Our previous finding of an association of TLR4 gene sequence variants and prostate cancer risk provides evidence for a role of TLRs in prostate cancer. In this study, we investigated whether sequence variants in the TLR6-TLR1-TLR10 gene cluster, residing within a 54-kb region on 4p14, were associated with prostate cancer risk. METHODS We selected 32 single-nucleotide polymorphisms (SNPs) covering these three genes and genotyped these SNPs in 96 control subjects from the Cancer Prostate in Sweden (CAPS) population-based prostate cancer case-control study. Five distinct haplotype blocks were inferred at this region, and we identified 17 haplotype-tagging SNPs (htSNPs) that could uniquely describe >95% of the haplotypes. These 17 htSNPs were then genotyped in the entire CAPS study population (1383 case subjects and 780 control subjects). Odds ratios of prostate cancer for the carriers of a variant allele versus those with the wild-type allele were estimated using unconditional logistic regression. RESULTS The allele frequencies of 11 of the 17 SNPs were statistically significantly different between case and control subjects (P = .04-.001), with odds ratios for variant allele carriers (homozygous or heterozygous) compared with wild-type allele carriers ranging from 1.20 (95% confidence interval [CI] = 1.00 to 1.43) to 1.38 (95% CI = 1.12 to 1.70). Phylogenetic tree analyses of common haplotypes identified a clade of two evolutionarily related haplotypes that are statistically significantly associated with prostate cancer risk. These two haplotypes contain all the risk alleles of these 11 associated SNPs. CONCLUSION The observed multiple associated SNPs at the TLR6-TLR1-TLR10 gene cluster were dependent and suggest the presence of a founder prostate cancer risk variant on this haplotype background. The TLR6-TLR1-TLR10 gene cluster may play a role in prostate cancer risk, although further functional studies are needed to pinpoint the disease-associated variants in this gene cluster.
Thirty-year patency of a coronary sequential venous bypass graft.

BACKGROUND The optimal conduit of second choice in surgical coronary revascularization remains a matter of debate. Radial artery grafts are believed to have a better patency rate than the saphenous vein grafts, although no conclusive results have been reported. This report describes the late result of a coronary revascularization with sequential venous bypass performed 30 years earlier. METHODS An 80-year-old woman was admitted for dyspnoea on exertion and recent-onset angina due to severe aortic valve stenosis. Thirty years earlier, the patient had undergone revascularization with coronary bypass grafting performed using a sequential saphenous vein graft anastomosed on first diagonal branch and on left anterior descending coronary artery. Coronary angiography showed the occlusion of the native left anterior descending artery and the good patency of the previous described sequential vein graft. RESULTS Surgical inspection confirmed the patency and the soft pliability of the venous graft and the surgeon decided to do not replace the previous graft with a pedicled LIMA (Left Internal Mammary Artery) graft. The patient underwent 21-mm biological Edwards Perimount Magna Ease prosthesis implantation. Postoperative course was uneventful and the patient was discharged on the seventh day after surgery. CONCLUSIONS This case report demonstrated the potential extreme long-term patency of a sequential saphenous vein graft in coronary bypass surgery, raising the question if vein grafts should be really considered the conduits of last resort for coronary artery bypass surgery. Long-term follow-up of randomized trials comparing radial artery versus saphenous vein grafts are warranted in order to give conclusive answers to this ongoing debate.
Etanercept Administration to Neonatal SH3BP2 Knock‐In Cherubism Mice Prevents TNF‐α‐Induced Inflammation and Bone Loss

Cherubism is a genetic disorder of the craniofacial skeleton caused by gain‐of‐function mutations in the signaling adaptor protein, SH3‐domain binding protein 2 (SH3BP2). In a knock‐in mouse model for cherubism, we previously demonstrated that homozygous mutant mice develop T/B cell–independent systemic macrophage inflammation leading to bone erosion and joint destruction. Homozygous mice develop multiostotic bone lesions whereas cherubism lesions in humans are limited to jawbones. We identified a critical role of tumor necrosis factor α (TNF‐α) in the development of autoinflammation by creating homozygous TNF‐α‐deficient cherubism mutants, in which systemic inflammation and bone destruction were rescued. In this study, we examined whether postnatal administration of an anti‐TNF‐α antagonist can prevent or ameliorate the disease progression in cherubism mice. Neonatal homozygous mutants, in which active inflammation has not yet developed, were treated with a high dose of etanercept (25 mg/kg, twice/week) for 7 weeks. Etanercept‐treated neonatal mice showed strong rescue of facial swelling and bone loss in jaws and calvariae. Destruction of joints was fully rescued in the high‐dose group. Moreover, the high‐dose treatment group showed a significant decrease in lung and liver inflammatory lesions. However, inflammation and bone loss, which were successfully treated by etanercept administration, recurred after etanercept discontinuation. No significant effect was observed in low‐dose–treated (0.5 mg/kg, twice/week) and vehicle‐treated groups. In contrast, when 10‐week‐old cherubism mice with fully active inflammation were treated with etanercept for 7 weeks, even the high‐dose administration did not decrease bone loss or lung or liver inflammation. Taken together, the results suggest that anti‐TNF‐α therapy may be effective in young cherubism patients, if treated before the inflammatory phase or bone resorption occurs. Therefore, early genetic diagnosis and early treatment with anti‐TNF‐α antagonists may be able to prevent or ameliorate cherubism, especially in patients with a mutation in SH3BP2. © 2014 American Society for Bone and Mineral Research.
Screening for cognitive impairment in older African-Caribbeans

Background. There are increasing numbers of older African-Caribbeans in the United Kingdom. Screening instruments are commonly used in the detection of cognitive impairment, but have not been assessed within this population. This study aimed to develop culturally modified versions of screening instruments for cognitive impairment (Mini-Mental State Examination (MMSE) and Abbreviated Mental Test (AMT)) and to determine their sensitivity and specificity in the diagnosis of dementia. Methods. The instruments were modified using a process involving a community group of African-Caribbeans and an academic group of health professionals. They were used in a two-stage study involving community resident African-Caribbeans aged 60 years or over in inner-city Manchester, comparing the screening instruments against a computerized diagnostic interview. Results. One hundred and thirty people completed the study. The results for the largest subgroup, the Jamaicans (N = 96) were analysed. Effects of gender, age and education on the MMSE and AMT scores were evaluated. The correlations between the screening instruments and diagnostic interview were highly significant (P < 0·001). At appropriate cut-offs both screening instruments demonstrated high sensitivity and acceptable specificity levels. Conclusions. A defined process with lay input has assisted in producing culturally modified versions of the MMSE and AMT that perform well compared with a diagnostic interview, if an appropriate cut-off is used. They are easy to administer and acceptable to older African-Caribbean people. The results need to be viewed within the limitations of the current study.
Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms

Background Symptom dimensions have not yet been comprehensively tested as predictors of the substantial heterogeneity in outcomes of antidepressant treatment in major depressive disorder. Method We tested nine symptom dimensions derived from a previously published factor analysis of depression rating scales as predictors of outcome in 811 adults with moderate to severe depression treated with flexibly dosed escitalopram or nortriptyline in Genome-based Therapeutic Drugs for Depression (GENDEP). The effects of symptom dimensions were tested in mixed-effect regression models that controlled for overall initial depression severity, age, sex and recruitment centre. Significant results were tested for replicability in 3637 adult out-patients with non-psychotic major depression treated with citalopram in level I of Sequenced Treatment Alternatives to Relieve Depression (STAR*D). Results The interest-activity symptom dimension (reflecting low interest, reduced activity, indecisiveness and lack of enjoyment) at baseline strongly predicted poor treatment outcome in GENDEP, irrespective of overall depression severity, antidepressant type and outcome measure used. The prediction of poor treatment outcome by the interest-activity dimension was robustly replicated in STAR*D, independent of a comprehensive list of baseline covariates. Conclusions Loss of interest, diminished activity and inability to make decisions predict poor outcome of antidepressant treatment even after adjustment for overall depression severity and other clinical covariates. The prominence of such symptoms may require additional treatment strategies and should be accounted for in future investigations of antidepressant response.
Functional cardiac MR imaging with steady‐state free precession (SSFP) significantly improves endocardial border delineation without contrast agents

Contrast between blood and myocardium in standard turbo gradient echo MR techniques (TFE) used routinely in clinical practice is mainly caused by unsaturated inflowing blood. Steady‐state free precession (SSFP) has excellent contrast even in the absence of inflow effects. In 45 subjects cardiac cine loops in two long axis projections were acquired using TFE and compared with SSFP. A visual score (range 0 worst – 3 best) was assigned for endocardial border delineation for six myocardial segments in two long axis views. Endocardial border delineation score for TFE was 1.3 ± 0.3 per segment and 2.4 ± 0.3 for SSFP (P < 0.0001). Signal intensity blood/signal intensity myocardium was 1.5 ± 0.4 at enddiastole and 1.4 ± 0.3 at systole for TFE and 3.5 ± 1.1 and 3.2 ± 1.3 for SSFP, respectively (P < 0.0001). SSFP increases contrast between blood and myocardium more than twofold, resulting in an improved endocardial border definition. This may reduce variability for the determination of cardiac volumes and ejection fraction. J. Magn. Reson. Imaging 2001;14:362–367. ©2001 Wiley‐Liss, Inc.
Cardiovascular fitness as a predictor of mortality in men.

OBJECTIVE To examine the relations of cardiorespiratory fitness, as measured by maximal oxygen uptake and exercise test duration at the initiation of the study, with overall, cardiovascular disease (CVD)-related, and non-CVD-related mortality. METHODS A population-based cohort study of 1294 men with no CVD, pulmonary disease, or cancer at baseline in Kuopio and surrounding communities in eastern Finland. During an average follow-up of 10.7 years, there were 124 overall, 42 CVD-related, and 82 non-CVD-related deaths. RESULTS The relative risk of overall death in unfit men (maximal oxygen uptake <27.6 mL/kg per minute) was 2.76 (95% confidence interval, 1.43-5.33) (P =.002), and the relative risk of CVD-related death was 3.09 (95% confidence interval, 1.10-9.56) (P =.05), compared with fit men (maximal oxygen uptake >37.1 mL/kg per minute) after adjusting for age, examination years, smoking, and alcohol consumption. The relative risk of non-CVD-related death in unfit men was almost the same magnitude as for overall death. Furthermore, adjustment for serum lipid levels, blood pressure, plasma fibrinogen level, diabetes, and fasting serum insulin level did not weaken these associations significantly. Exercise test duration also had a strong inverse relation to overall, CVD-related, and non-CVD-related mortality. Poor cardiorespiratory fitness was comparable with elevated systolic blood pressure, smoking, obesity, and diabetes in importance as a risk factor for mortality. CONCLUSIONS Cardiorespiratory fitness had a strong, graded, inverse association with overall, CVD-related, and non-CVD-related mortality. Maximal oxygen uptake and exercise test duration represent the strongest predictors of mortality.
Prevalence of antibodies to neurofilament polypeptides in patients with rheumatoid arthritis complicated by peripheral neuropathy.

OBJECTIVE Neurofilaments are essential components of the axon cytoskeleton. Neurofilament defects are suspected in several neurodegenerative conditions, and antibodies to neurofilaments have been found in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Our main objectives were: (i) to determine the prevalence of anti-neurofilaments antibodies in patients with rheumatoid arthritis (RA) complicated by peripheral neuropathy; and (ii) to relate the clinical features of RA and peripheral neuropathy to anti-neurofilament antibodies. METHODS In this study we used an ELISA technique to measure IgG antibody levels against three neurofilament polypeptides (NF-L, 70 kD; NF-M, 150 kD; and NF-H, 200 kD) in RA patients with peripheral neuropathy, and compared them with the antibody levels in uncomplicated RA controls and healthy volunteers. RESULTS Abnormal antibody levels to one or more of the neurofilament polypeptides were found in 9 (32%) of the peripheral neuropathy patients, but only in 3 (9%) of the RA and healthy controls. There were significant correlations between the levels of antibodies against the different neurofilaments; the cross-reactivity of some sera with different neurofilament proteins was also observed. There was no significant correlation between the levels of anti-neurofilament antibodies and measures of RA disease activity. CONCLUSIONS We conclude that a significant proportion of our RA patients with neuropathy had abnormal antibody levels to one or more neurofilaments and that the measurement of these antibodies may provide a useful diagnostic test.
The Impact of Physiological, Therapeutic and Psychosocial Variables on Glycemic Control in Youth with Type 1 Diabetes Mellitus

OBJECTIVE Intensive management of type 1 diabetes mellitus (DM1) in youth is challenging. We evaluated the relative impact of variables related to DM1 among groups of pre/early pubertal, midpubertal and postpubertal youths with DM1. METHODS In this cross-sectional study of 153 youth with DM1, we ascertained Tanner stage, insulin dose and delivery modality (CSII vs MDI), daily blood glucose monitoring (BGM) frequency, and most recent hemoglobin A1c (HbA1c). We collected questionnaires from patients and their parents on diabetes-specific family conflict and family involvement in diabetes management tasks. We assessed predictors of glycemic control according to pubertal status. RESULTS Insulin doses increased between pre/ early puberty and midpuberty (p <0.0001); daily BGM frequency (p = 0.02) and family involvement for DM management (p <0.001) were lowest in the postpubertal group. HbA1c was similar among all three puberty groups (8.4+/-1.4). Lower levels of child-reported DM-specific family conflict, more frequent BGM, and CSII use were significantly associated with lower HbA1c (R2 = 0.20, p <0.001). CONCLUSION Although glycemic control was not significantly worse in midpubertal and post-pubertal patients, family involvement for DM management and adherence to BGM were lower in late adolescence. Interventions to optimize glycemic control may include minimizing DM-specific conflict, increasing BGM frequency, and implementing CSII use.
Long-term Outcome of Children With Biliary Atresia Who Were Not Transplanted After the Kasai Operation: >20-year Experience at a Children's Hospital

Objective: Sequential strategies combining the Kasai operation as a first-line treatment and liver transplantation as a second-line option, if necessary, have been accepted for patients with biliary atresia (BA). To understand the role of the Kasai operation in the treatment of BA, it is necessary to analyze the long-term outcome of the operation alone and to evaluate the present status of survivors retaining their native livers. Materials and Methods: A retrospective chart review was carried out for a group of 80 patients who had undergone the Kasai operation between 1970 and 1986 at the Kanagawa Children's Medical Center. Results: The 5-, 10-, and 20-year survival rates of patients with their native livers were 63%, 54%, and 44%, respectively. The survival rates varied significantly depending on the type of BA, age at initial Kasai operation, era of surgery, and surgical method. By age 20, nearly half of the adult survivors had already developed liver cirrhosis and its sequelae. Episodes of cholangitis and gastrointestinal bleeding occurred after 20 years of age in 37% and 17% of the adult patients, respectively, and 20% of the adult patients died of liver failure or underwent living-related partial liver transplantation in their 20s. Five female patients gave birth to a total of 9 children, and 1 male patient fathered a child. Conclusions: Although increasing numbers of patients with BA survive 20 years or more after the Kasai operation, meticulous lifelong postoperative care should be continued for the survivors because of the possibility of hepatic deterioration.
CD28 Signaling in T Regulatory Precursors Requires p56lck and Rafts Integrity to Stabilize the Foxp3 Message1

Naturally occurring CD4+25highFoxp3+ T regulatory (T-reg) cells are critical for maintaining tolerance to self and non-self Ags. The Foxp3 master-regulatory gene and CD28 costimulation are both required for thymic development and suppressogenic function of CD4+25highFoxp3+ T-regs. Herein, we show that the sole CD28 stimulation of T-reg thymic precursors augments Foxp3 expression through the increase in Foxp3 mRNA span life by a mechanism involving p56lck and its binding motif on CD28 cytosolic tail, as well as the lipid rafts. We found that 1) the glycosphingolipids and cholesterol components of lipid rafts were highly expressed and unusually partitioned in T-reg thymic precursors as compared with the conventional T cell precursors, 2) the CD28 receptor density on cell membrane is proportional with the content of cholesterol in lipid rafts and with the level of Foxp3 mRNA expression in T-reg precursors, and 3) the CD28-mediated increase of Foxp3 mRNA span life was paralleled by an increased proliferative and suppressogenic capacity of terminally differentiated CD4+25highFoxp3+ T-reg precursors. Thus, the functional integrity of CD28 receptor p56lck and plasma membrane lipid rafts are all prerequisites for up-regulation and long-term expression of Foxp3 mRNA transcripts in CD4+25highFoxp3+ T-reg precursors.
Microstructured β-Tricalcium Phosphate Putty versus Autologous Bone for Repair of Alveolar Clefts in a Goat Model

For the first time it was demonstrated that an osteoinductive calcium phosphate-based putty is effective in the restoration of complex maxillofacial defects. In these defects, adequate mechanical confinement by multiple bony walls and osteoconduction from multiple surfaces are usually lacking. This study compares the efficacy of a microstructured beta-tricalcium phosphate (β-TCP) putty with autologous bone for the repair of alveolar cleft defects. A total of 10 Dutch milk goats were operated on in a split-mouth study design in which two-wall bony alveolar clefts were created and successively repaired with autologous bone (the gold standard) at one side and β-TCP putty at the other. After 24 weeks of implantation, histomorphometric and micro–computer tomography analyses proved that the β-TCP putty group showed equal bone quality and volume to clefts reconstructed with autologous bone. In addition, surgical handling of the putty is superior to the use of calcium phosphates in a granular form. Therefore, the results of this study open a clear trajectory for the clinical use of β-TCP putty in the reconstruction of the alveolar cleft and other challenging two-wall bony defects.
Characterization of Urinary Tract Infection-Associated Shiga Toxin-Producing Escherichia coli

ABSTRACT Enterohemorrhagic Escherichia coli (EHEC), a subgroup of Shiga toxin (Stx)-producing E. coli (STEC), is a leading cause of diarrhea and hemolytic-uremic syndrome (HUS) in humans. However, urinary tract infections (UTIs) caused by this microorganism but not associated with diarrhea have occasionally been reported. We geno- and phenotypically characterized three EHEC isolates obtained from the urine of hospitalized patients suffering from UTIs. These isolates carried typical EHEC virulence markers and belonged to HUS-associated E. coli (HUSEC) clones, but they lacked virulence markers typical of uropathogenic E. coli. One isolate exhibited a localized adherence (LA)-like pattern on T24 urinary bladder epithelial cells. Since the glycosphingolipids (GSLs) globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer) are well-known receptors for Stx but also for P fimbriae, a major virulence factor of extraintestinal pathogenic E. coli (ExPEC), the expression of Gb3Cer and Gb4Cer by T24 cells and in murine urinary bladder tissue was examined by thin-layer chromatography and mass spectrometry. We provide data indicating that Stxs released by the EHEC isolates bind to Gb3Cer and Gb4Cer isolated from T24 cells, which were susceptible to Stx. All three EHEC isolates expressed stx genes upon growth in urine. Two strains were able to cause UTI in a murine infection model and could not be outcompeted in urine in vitro by typical uropathogenic E. coli isolates. Our results indicate that despite the lack of ExPEC virulence markers, EHEC variants may exhibit in certain suitable hosts, e.g., in hospital patients, a uropathogenic potential. The contribution of EHEC virulence factors to uropathogenesis remains to be further investigated.