tbuckley/cabot-search huggingface dataset:
A human class II MHC–derived peptide antagonizes phosphatidylinositol 3-kinase to block IL-2 signaling
Authors: Michelle L. Boytim, Pamela Lilly, Katerina Drouvalakis, Shu-Chen Lyu, Ron Jung, Alan M. Krensky, Carol Clayberger
Journal: Journal of Clinical Investigation (2000)

MHC molecules bind antigenic peptides and present them to T cells. There is a growing body of evidence that MHC molecules also serve other functions. We and others have described synthetic peptides derived from regions of MHC molecules that inhibit T-cell proliferation or cytotoxicity in an allele-nonspecific manner that is independent of interaction with the T-cell receptor. In this report, we describe the mechanism of action of a synthetic MHC class II–derived peptide that blocks T-cell activation induced by IL-2. Both this peptide, corresponding to residues 65–79 of DQA*03011 (DQ 65-79), and rapamycin inhibit p70 S6 kinase activity, but only DQ 65-79 blocks Akt kinase activity, placing the effects of DQ 65-79 upstream of mTOR, a PI kinase family member. DQ 65-79, but not rapamycin, inhibits phosphatidylinositol 3-kinase (PI 3-kinase) activity in vitro. The peptide is taken up by cells, as demonstrated by confocal microscopy. These findings indicate that DQ 65-79 acts as an antagonist with PI 3-kinase, repressing downstream signaling events and inhibiting proliferation. Understanding the mechanism of action of immunomodulatory peptides may provide new insights into T-cell activation and allow the development of novel immunosuppressive agents.
Neck Circumference and Insulin Resistance in Chinese Adults: The Cardiometabolic Risk in Chinese (CRC) Study
Authors: Jun Liang, Fei Teng, Yanping Li, Xuekui Liu, Caiyan Zou, Yu Wang, Hongyan Li, Lu Qi
Journal: Diabetes Care (2013)

Neck circumference (NC) is a proxy for upper-body fat and a reliable screening measure for the identification of individuals with abnormal fat distribution. Recently, compelling evidence indicates that NC is positively associated with insulin resistance (IR) and a variety of cardiometabolic abnormalities, independent of overall adiposity and central obesity in Caucasians (1) or Chinese diabetic patients (2). However, it remains unknown whether NC affects IR in the general Chinese population.

In the current study, we analyzed the associations of NC with IR and cardiometabolic risk factors in 2,588 apparently healthy Chinese adults (20–87 years of age) from the Cardiometabolic Risk in Chinese (CRC) study (3). We found a significant association between NC and an increasing trend of homeostasis model assessment of insulin resistance (HOMA-IR), adjusting for age and other cardiometabolic risk factors, in …
Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4–dependent mechanism
Authors: Marcus D. Säemann, Thomas Weichhart, Maximilian Zeyda, Günther Staffler, Michael Schunn, Karl M. Stuhlmeier, Yuri Sobanov, Thomas M. Stulnig, Shizuo Akira, Alexander von Gabain, Uwe von Ahsen, Walter H. Hörl, Gerhard J. Zlabinger
Journal: Journal of Clinical Investigation (2005)

Tamm-Horsfall glycoprotein (THP) is expressed exclusively in the kidney and constitutes the most abundant protein in mammalian urine. A critical role for THP in antibacterial host defense and inflammatory disorders of the urogenital tract has been suggested. We demonstrate that THP activates myeloid DCs via Toll-like receptor-4 (TLR4) to acquire a fully mature DC phenotype. THP triggers typical TLR signaling, culminating in activation of NF-kappaB. Bone marrow-derived macrophages from TLR4- and MyD88-deficient mice were nonresponsive to THP in contrast to those from TLR2- and TLR9-deficient mice. In vivo THP-driven TNF-alpha production was evident in WT but not in Tlr4-/- mice. Importantly, generation of THP-specific Abs consistently detectable in urinary tract inflammation was completely blunted in Tlr4-/- mice. These data show that THP is a regulatory factor of innate and adaptive immunity and therefore could have significant impact on host immunity in the urinary tract.
FLUID BALANCE IN ELITE SHORT TRACK SPEED SKATERS
Authors: K Currell, E Simpson, S Mears, L James
Journal: British Journal of Sports Medicine (2013)

The aim of this study was to investigate sweat loss in elite short track speed skaters across 6 different training sessions over a three day period, and sweat sodium loss in one on ice training session. Nine male and three female elite short track speed skaters participated in the study (age 22±3 years, Body Weight: 68.1±10.2 kg). Six training sessions, comprising of an on ice speed session (Sp), on ice endurance session (En), on ice speed endurance session (SpEn), off ice strength session (St), a 40 minute aerobic off ice session (Ae) and an off ice sport specific conditioning session (SpCo). Sweat loss was calculated for each session by weighing the participants before and after each training session, as well as weighing fluid/ food consumed and urine produced during training. Sweat sodium concentration [Na + ] was calculated from forehead sweat patch analysis during En. Whole body sodium loss was calculated from sweat loss and [Na + ] for En. A One Way ANOVA was used to compare sweat loss in different training sessions. There was a difference in sweat loss between training sessions (F 5,66 =4.24, P=0.02), with both En (700±248 ml) and SpEn (681±304 ml) being different from St (299±162 ml). However, sweat loss in SP (514±242 ml), Ae (572±267 ml) and SpCo (522±128 ml) was not different from other sessions. During all sessions, no participants lost more than 2% in body weight, suggesting participants adequately consumed fluid during training to prevent dehydration. During En sweat sodium loss was 1.9±0.6 g, with a mean [Na + ] of 51±16 mmol/L. In conclusion, short track speed skaters consume adequate fluid to maintain fluid balance during a range of training sessions.
Nrdp1-Mediated Regulation of ErbB3 Expression by the Androgen Receptor in Androgen-Dependent but not Castrate-Resistant Prostate Cancer Cells
Authors: Liqun Chen, Salma Siddiqui, Swagata Bose, Benjamin Mooso, Alfredo Asuncion, Roble G. Bedolla, Ruth Vinall, Clifford G. Tepper, Regina Gandour-Edwards, XuBao Shi, Xiao-Hua Lu, Javed Siddiqui, Arul M. Chinnaiyan, Rohit Mehra, Ralph W. deVere White, Kermit L. Carraway, Paramita M. Ghosh
Journal: Cancer Research (2010)

Patients with advanced prostate cancer (PCa) are initially susceptible to androgen withdrawal (AW), but ultimately develop resistance to this therapy (castration-resistant PCa, CRPC). Here, we show that AW can promote CRPC development by increasing the levels of the receptor tyrosine kinase ErbB3 in androgen-dependent PCa, resulting in AW-resistant cell cycle progression and increased androgen receptor (AR) transcriptional activity. CRPC cell lines and human PCa tissue overexpressed ErbB3, whereas downregulation of ErbB3 prevented CRPC cell growth. Investigation of the mechanism by which AW augments ErbB3, using normal prostate-derived pRNS-1-1 cells, and androgen-dependent PCa lines LNCaP, PC346C, and CWR22 mouse xenografts, revealed that the AR suppresses ErbB3 protein levels, whereas AW relieves this suppression, showing for the first time the negative regulation of ErbB3 by AR. We show that AR activation promotes ErbB3 degradation in androgen-dependent cells, and that this effect is mediated by AR-dependent transcriptional upregulation of neuregulin receptor degradation protein-1 (Nrdp1), an E3 ubiquitin ligase that targets ErbB3 for degradation but whose role in PCa has not been previously examined. Therefore, AW decreases Nrdp1 expression, promoting ErbB3 protein accumulation, and leading to AR-independent proliferation. However, in CRPC sublines of LNCaP and CWR22, which strongly overexpress the AR, ErbB3 levels remain elevated due to constitutive suppression of Nrdp1, which prevents AR regulation of Nrdp1. Our observations point to a model of CRPC development in which progression of PCa to castration resistance is associated with the inability of AR to transcriptionally regulate Nrdp1, and predict that inhibition of ErbB3 during AW may impair CRPC development.
S10 Lung Clearance Index (LCI) and Pseudomonous aeruginosa in adults and children with Cystic Fibrosis (CF)
Authors: K O'Neill, J M Bradley, I Bradbury, E Johnston, A Reid, J McCaughan, JE Moore, MM Tunney, JS Elborn
Journal: Thorax (2013)

<h3>Introduction</h3> LCI obtained from multiple breath washout (MBW) is a sensitive measure of ventilation inhomogeneity in CF. Persistent colonisation with <i>P. aeruginosa</i> is associated with a decline in LCI in children (Kraemer <i>et al</i>. 2006). Further research is required to investigate the relationship between airways infection and LCI in adults. <h3>Objective</h3> To investigate the sensitivity of LCI to <i>P. aeruginosa</i> in adults and children compared with FEV<sub>1</sub>%pred and FEF<sub>25–75</sub>%pred. <h3>Methods</h3> Stable CF patients from adult &amp; paediatric Northern Ireland CF centres were recruited. LCI was derived from MBW, using 0.2% SF<sub>6</sub> and a modified Innocor<sup>TM</sup>device. <i>P. aeruginosa</i> status was determined from routine diagnostic culture of a sputum sample or deep throat swab. Patients categorised as having <i>P. aeruginosa </i>infection met the criteria of chronic infection as defined by the Leeds criteria (Lee <i>et al</i>. 2003). <h3>Analysis</h3> Receiver-operator characteristic (ROC) curves and area under the receiver operating curves (AUC<sub>ROC</sub>) indicate the level of sensitivity and specificity where 1.0 = perfect discrimination considering sensitivity and specificity. <h3>Results</h3> Sixty-seven adults were recruited (39M), median (IQR) age 27 (16) years. Mean (SD) FEV<sub>1</sub>%pred 71.8 (20.3), median (IQR) FEF<sub>25–75</sub>%pred 40.0 (46.7) and mean (SD) LCI 10.3 (3.0) lung volume turnovers. 49% had <i>P. aeruginosa </i>infection. Forty-three children were recruited (24M), mean (SD) age 11.7 (3.4) years. Mean (SD) FEV<sub>1</sub>%pred 85.2 (16.6), mean (SD) FEF<sub>25–75</sub>%pred 66.0 (27.6) and mean (SD) LCI was 7.8 (1.8) lung volume turnovers. 16% had <i>P. aeruginosa </i>infection Compared to FEV<sub>1</sub>%pred and FEF<sub>25–75</sub>%pred, LCI had the greatest sensitivity and specificity to discriminate between CF patients with and without <i>P. aeruginosa</i> in both adults and children. Adult AUC<sub>ROC</sub> (SE) for LCI = 0.82 (0.05), p &lt; 0.0001, compared with FEV<sub>1</sub>%pred = 0.66 (0.07), p = 0.021 and FEF<sub>25–75</sub>%pred = 0.64 (0.07), p = 0.044 (Figure 1). Child AUC<sub>ROC</sub> (SE) for LCI = 0.85 (0.10), p = 0.004, compared with FEV<sub>1</sub>%pred = 0.80 (0.12), p = 0.014 and FEF<sub>25–75</sub>%pred = 0.67 (0.13), p = 0.152. <h3>Conclusion</h3> LCI is more sensitive and specific to the presence of <i>P. aeruginosa</i> airways infection across the age groups in CF compared with spirometry. This project was funded by a US-Ireland Project Partnership Grant. <h3>References</h3> Kraemer, R <i>et al</i> 2006, <i>Respiratory </i> <i>Research</i>. Lee, T W R <i>et al</i> 2003, <i>Journal of Cystic Fibrosis.</i>
TASTE PREFERENCES AND FOOD INTAKE
Authors: A. Drewnowski
Journal: Annual Review of Nutrition (1997)

▪ Abstract Sensory responses to the taste, smell, and texture of foods help determine food preferences and eating habits. However, sensory responses alone do not predict food consumption. The view that a “sweet tooth” leads to obesity through excess sugar consumption is overly narrow. In reality, there are multiple links between taste perceptions, taste preferences, food preferences, and food choices and the amount of food consumed. Taste responses are influenced by a range of genetic, physiological, and metabolic variables. The impact of taste factors on food intake further depends on sex and age and is modulated by obesity, eating disorders, and other pathologies of eating behavior. Food preferences and food choices of populations are further linked to attitudinal, social, and—probably most important—economic variables such as income. Nutrition education and intervention strategies aimed at improving population diets ought to consider sensory pleasure response to foods, in addition to a wide range of demographic and sociocultural variables.
Cognitive behaviour therapy for adolescents with chronic fatigue syndrome
Authors: Maja Stulemeijer, Lieke W A M de Jong, Theo J W Fiselier, Sigrid W B Hoogveld, Gijs Bleijenberg
Journal: BMJ (2005)

Editor—Chaudhuri's concerns relate to a possible placebo effect and the way we treat our patients. We consider it unlikely that the positive effects of our treatment are attributable mainly to non-specific treatment factors, since the results were maintained at eight month follow up even in the absence of contacts with the therapist (unpublished data). Moreover, others have shown that cognitive behaviour therapy was more effective than attention control conditions shortly after treatment and at long term follow-up.1-3

At the start of therapy all patients experienced severe limitations in performing activities appropriate to age. A characteristic belief of patients with chronic fatigue syndrome, especially in case of passive patients, is that fatigue is made worse by exercise. This cognition, although functional in the first phase of the condition, is dysfunctional in the longer term and maintains activity avoidance and symptoms. By challenging these and other activity related cognitions, activity regulation is possible. Thus, patients are taught to regulate and increase their physical and other activities in a systematic and safe way. Our results show that this is possible. The distinction between physically passive and relatively active patients, based on actometry, is helpful to select the correct approach to help the patient.

As in other chronic conditions, we do not have one treatment that leads to recovery in all patients. We believe that our study clearly shows that many of the participants benefited from cognitive behaviour therapy and were able to function as normal adolescents again.
Peritonitis influences mortality in peritoneal dialysis patients.
Authors: L F Fried, J Bernardini, J R Johnston, B Piraino
Journal: Journal of the American Society of Nephrology (1996)

Mortality remains high in peritoneal dialysis (PD) patients. Known risk factors for mortality include age, diabetes, race, initial albumin level, and cardiovascular disease. Peritonitis is reported to cause death in 1 to 6% of PD patients but has not been well studied as a risk factor for mortality. This study examined 516 adults with a total of 896 yr on PD at one center to determine if peritonitis influenced mortality. Time at risk began on Day 1 of training and ended at death, transplant, or 60 days after transfer to hemodialysis or intermittent peritoneal dialysis. The overall mortality rate was 17.4/100 patient yr. Survival was lower for whites, men, diabetic patients, and older patients. Independent risk factors for mortality (by Cox proportional hazards) were race, diabetes, increased age, and increased peritonitis rate. Use of the Y-set was not associated with decreased mortality. Peritonitis was a risk factor only in whites, nondiabetic patients, and those patients over the age of 60. For every 0.5/yr increase in the peritonitis rate, the risk of death increased 10% in whites, 11% in those patients who were over the age of 60, and 4% for nondiabetic patients. Mortality rates did not decrease over time (1979 to 1995), although peritonitis rates fell significantly (P < 0.001). Rates of Gram-negative and fungal peritonitis showed no trend over time. Peritonitis contributed to 25 of 158 (15.8%) of deaths. Gram-negative/fungal peritonitis accounted for 14 deaths (9.5% of all Gram-negative/fungal episodes) whereas Staphylococcus epidermidis accounted for only 1 death (0.5% of all S. epidermidis episodes) (P < 0.001). Cardiovascular disease was more common in those patients whose deaths were unrelated to peritonitis (P < 0.01), whereas an infectious cause was more common in those patients whose deaths were peritonitis-related (P < 0.001). In this study, peritonitis was a risk factor for death in whites, nondiabetic patients, and older patients. However, the Y-set did not improve survival, perhaps because it does not decrease Gram-negative/fungal peritonitis. To have an impact on survival, efforts are needed to reduce the peritonitis that results from these more serious pathogens.
Science minister promises to promote evidence based policy making
Authors: A. O'Dowd
Journal: BMJ (2010)

The independence of scientific advice given to the government will be respected under new guidance to try and re-establish trust in the scientific community.

The move, announced by minister for universities and science David Willetts, is designed to repair the damage caused last year when the former home secretary Alan Johnson sacked chief drugs adviser David Nutt after he criticised government policy ( BMJ 2009;339:b4563 doi:10.1136/bmj.b4563).

Mr Willetts, giving an interview to the Times newspaper (9 June), said it was crucial that all ministers respect independent scientific advice.

The previous science minister, Lord Drayson, issued principles on how scientific advisers should offer advice to government in March and these have been added to the code of practice for ministers since the new coalition government …
Redox regulation of T-cell turnover by the p13 protein of human T-cell leukemia virus type 1: distinct effects in primary versus transformed cells
Authors: Micol Silic-Benussi, Ilaria Cavallari, Nicola Vajente, Silvia Vidali, Luigi Chieco-Bianchi, Fabio Di Lisa, Daniela Saggioro, Donna M. D'Agostino, Vincenzo Ciminale
Journal: Blood (2010)
Pooled Analysis of Individual Patient-Level Data From All Randomized, Double-Blind, Placebo-Controlled Trials of Darbepoetin Alfa in the Treatment of Patients With Chemotherapy-Induced Anemia
Authors: Heinz Ludwig, Jeffrey Crawford, Anders Österborg, Johan Vansteenkiste, David H. Henry, Alex Fleishman, Ken Bridges, John A. Glaspy
Journal: Journal of Clinical Oncology (2009)

Although numerous clinical trials have demonstrated the efficacy and tolerability of erythropoiesis-stimulating agents (ESAs) in patients with chemotherapy-induced anemia (CIA), results of some recent trials and one meta-analysis have suggested that ESAs may negatively impact survival and/or disease control in patients with cancer.To assess the benefits and risks of ESAs in CIA, we conducted a pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials in 2,122 patients with CIA receiving darbepoetin alfa (DA; n = 1,200) or placebo (n = 912).DA did not increase mortality (hazard ratio = 0.97; 95% CI, 0.85 to 1.1) and had no effect on progression-free survival (hazard ratio = 0.93; 95% CI, 0.84 to 1.04) and disease progression (hazard ratio = 0.92; 95% CI, 0.82 to 1.03), but, as expected, increased the risk for thromboembolic events (hazard ratio = 1.57; 95% CI, 1.10 to 2.26). Overall and progression-free survival were not affected by baseline hemoglobin and seemed better in patients who achieved hemoglobin more than 12 or more than 13 g/dL. Transfusions and rates of hemoglobin increase (> 1 g/dL in 14 days; > 2 g/dL in 28 days) owing to transfusions were associated with an increased risk for death and disease progression in both treatment groups; in the absence of transfusions, rates of hemoglobin increase did not appear to increase the risk for adverse outcomes. Compared with placebo, DA significantly reduced the risk of receiving one or more transfusion.There seemed to be no association between DA and risk of death or disease progression in this meta-analysis of individual patient data from DA studies conducted in CIA, the approved indication for ESAs in oncology.
Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia
Authors: Claire Seedhouse, Rowena Faulkner, Nadia Ashraf, Emma Das-Gupta, Nigel Russell
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Double-strand break repair via homologous recombination is essential in maintaining genetic integrity. RAD51 and XRCC3 are involved in the repair of DNA by this pathway, and polymorphisms have been identified in both the RAD51 (RAD51-G135C) and XRCC3 (XRCC3-Thr241Met) genes. The object of this study was to examine whether these polymorphisms may modulate susceptibility to the development of acute myeloid leukemia (AML), a disease that is characterized by genetic instability. Experimental Design: We studied the distribution of polymorphisms in RAD51 and XRCC3 in 216 cases of de novo AML, 51 cases of therapy-related AML (t-AML), and 186 control subjects using PCR followed by restriction enzyme digestion. The polymorphic deletion of the detoxification gene glutathione S-transferase M1 (GSTM1) was also examined by PCR. Results: The risk of the development of AML was found to be significantly increased when both variant RAD51-135C and XRCC3-241Met alleles are present [odds ratio (OR), 3.77; 95% confidence interval (CI), 1.39–10.24], whereas the risk of t-AML development is even higher (OR, 8.11; 95% CI, 2.22–29.68), presumably because of the large genotoxic insult these patients receive after their exposure to radiotherapy or chemotherapy. If we further divide the AML group into patients in which the burden of DNA damage is increased, because of the deletion of the GSTM1 gene, the risk of development of AML is further increased (OR, 15.26; 95% CI, 1.83–127.27). Conclusions: These results strongly suggest that DNA double-strand breaks and their repair are important in the pathogenesis of both de novo and t-AML.
Turner's syndrome and fertility: current status and possible putative prospects
Authors: R. Abir
Journal: Human Reproduction Update (2001)

Women with Turner’s syndrome should be carefully followed throughout life. Growth hormone therapy should be started at age 2–5 years. Hormone replacement therapy for the development of normal female sexual characteristics should be started at age 12–15 years and continued for the long term to prevent coronary artery disease and osteoporosis. Most women with Turner’s syndrome have ovarian dysgenesis; therefore, they are usually infertile, and in very rare cases have spontaneous menses followed by early menopause. Only 2% of the women have natural pregnancies, with high rates of miscarriages, stillbirths and malformed babies. Their pregnancy rate in oocyte donation programmes is 24–47%, but even these pregnancies have a high rate of miscarriage, probably due to uterine factors. A possible future prospect is cryopreservation of ovarian tissue containing immature follicles before the onset of early menopause, but methods of replantation and in-vitro maturation still need to be developed. Should these autologous oocytes indeed be used in the future, affected women would need to undergo genetic counselling before conception, followed by prenatal assessment.
We won't forget you, Bill
Authors: L. Farrell
Journal: BMJ (1998)

A month ago my car became unwell and I had to bring it to the mechanic. My opinion of the mechanic rested solely on his ability to fix my car; his personal life, and specifically whether or not he had committed adultery in the recent past, was of no concern to me. Neither was it any of my business. We are not made of rock, we are not gods; we are flesh and blood, we are all human, …