tbuckley/cabot-search huggingface dataset:
In vitro lymphocyte proliferation response to therapeutic insulin components. Evidence for genetic control by the human major histocompatibility complex.
Authors: D L Mann, N Mendell, C R Kahn, A H Johnson, A Rosenthal
Journal: Journal of Clinical Investigation (1983)

Genes in the major histocompatibility complex of mice and guinea pigs control immunologic responsiveness to insulins from other animal species. In order to determine if similar genetic control exists in man, we have examined lymphocyte proliferation responses to components of therapeutic insulins by employing lymphocytes from diabetic patients that receive insulin. Distinct groups of individuals demonstrated positive lymphocyte proliferative responses to beef insulin, beef and pork insulin, beef proinsulin, pork proinsulin, and protamine. Lymphocytes from the patient population were typed for the HLA-A, B, C, and DR antigens. An increased frequency of certain HLA antigens was found in those individuals that responded to the following therapeutic insulin components: beef, HLA-DR4; beef and pork, HLA-DR3; beef proinsulin, HLA-BW4, CW2, CW5, DR2, and DR5; protamine, HLA-CW3, CW5, and DR7. The results demonstrate that the human immune system recognized the structural differences between human and beef and/or pork insulin. These differences are two amino acids in the A chain, alpha loop, of beef insulin and the single terminal amino acid, alanine, which is common to pork and beef insulins. Positive responses to both beef proinsulin and pork proinsulin demonstrated the capability of restricted recognition of more complex proteins represented by the C-peptide in these insulin preparations. Lymphocyte proliferative responses to protamine were also restricted, which suggests a genetic control to this antigen. The association of these responses with HLA alloantigens strongly suggests that genes within the human major histocompatibility complex control recognition and lymphocyte response to therapeutic insulin components.
STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression
Authors: Ferenc A Scheeren, Marianne Naspetti, Sean Diehl, Remko Schotte, Maho Nagasawa, Erwin Wijnands, Ramon Gimeno, Florry A Vyth-Dreese, Bianca Blom, Hergen Spits
Journal: Nature Immunology (2005)
Genetic Risk Reclassification for Type 2 Diabetes by Age Below or Above 50 Years Using 40 Type 2 Diabetes Risk Single Nucleotide Polymorphisms
Authors: Jose M. de Miguel-Yanes, Peter Shrader, Michael J. Pencina, Caroline S. Fox, Alisa K. Manning, Richard W. Grant, Josèe Dupuis, Jose C. Florez, Ralph B. D'Agostino, L. Adrienne Cupples, James B. Meigs
Journal: Diabetes Care (2010)

To test if knowledge of type 2 diabetes genetic variants improves disease prediction.We tested 40 single nucleotide polymorphisms (SNPs) associated with diabetes in 3,471 Framingham Offspring Study subjects followed over 34 years using pooled logistic regression models stratified by age (<50 years, diabetes cases = 144; or ≥50 years, diabetes cases = 302). Models included clinical risk factors and a 40-SNP weighted genetic risk score.In people <50 years of age, the clinical risk factors model C-statistic was 0.908; the 40-SNP score increased it to 0.911 (P = 0.3; net reclassification improvement (NRI): 10.2%, P = 0.001). In people ≥50 years of age, the C-statistics without and with the score were 0.883 and 0.884 (P = 0.2; NRI: 0.4%). The risk per risk allele was higher in people <50 than ≥50 years of age (24 vs. 11%; P value for age interaction = 0.02).Knowledge of common genetic variation appropriately reclassifies younger people for type 2 diabetes risk beyond clinical risk factors but not older people.
Photoadaptation to ultraviolet (UV) radiation<i>in vivo</i>: photoproducts in epidermal cells following UVB therapy for psoriasis
Authors: V. Bataille, V.J. Bykov, P. Sasieni, S. Harulow, J. Cuzick, K. Hemminki
Journal: British Journal of Dermatology (2000)

Ultraviolet (UV) radiation is mutagenic and induces specific DNA lesions in human skin that are often found at dipyrimidine sites. These photoproducts are likely to be biologically relevant regarding skin carcinogenesis, as p53 mutations in skin tumours are most often found at these UV radiation-specific sites within DNA. Psoriasis patients receiving long-term phototherapy are at an increased risk of non-melanoma skin cancers.The aim of this study was to quantify DNA photoproducts in human epidermis in vivo following consecutive doses of UVB and to investigate variations in DNA damage according to skin type, UVB dose and age.Eleven psoriasis patients receiving UVB phototherapy three times a week were recruited and underwent skin biopsies on a non-sun-exposed site before starting phototherapy and after three, nine and 18 UVB exposures. A biopsy was also taken at least 4 weeks after stopping phototherapy. DNA was extracted from separated epidermis and three types of photoproducts were quantified using a novel 32P high-performance liquid chromatographic technique.The mean level of cyclobutane dipyrimidine dimers (CPDs) after three doses of UVB (dose range 0.03-0.15 J cm-2) was 3.2 (range 0.8-8.9) photoproducts per 106 normal nucleotides for TT=T dimers and 4.5 (range 0-14) per 106 normal nucleotides for TT=C dimers. The mean levels of TT-C 6-4 photoproducts after three doses of UVB were very low (0.2, range 0-1.8). Overall, the levels of TT=T and TT=C reached a plateau at three exposures and were found to decrease for subsequent exposures despite increasing UVB doses. Skin type was negatively associated with mean levels of CPDs. However, significant differences in levels of photoproducts were seen between individuals, even after adjusting for skin type. No association was found between challenge dose of UVB and photoproduct yield in this study.This study showed a great individual variation in the accumulation of DNA photoproducts following exposure to repetitive doses of UVB. Photoadaptive responses of human skin involving DNA repair, tanning and epidermal thickening are likely to explain the overall lack of increase in DNA lesions throughout phototherapy. This in vivo study confirms that psoriasis patients produce a significant amount of DNA photolesions at suberythemal doses of UVB. Further work is needed to investigate which host factors are most likely to predict susceptibility to UV radiation-induced DNA damage.
Report of the independent panel considering the retraction of two articles in The BMJ
Authors: I. Heath, S. Evans, C. Furberg, J. Hippisley-Cox, H. Krumholz, C. Mulrow, P. Wicks
Journal: BMJ (2014)

In May <i>The BMJ </i>corrected an error relating to adverse effects of statins in two articles but was asked to retract the articles. The editor referred the decision to an expert panel. Here, we publish its findings
Management of bloody diarrhoea in children in primary care
Authors: M Stephen Murphy
Journal: BMJ (2008)

Bloody diarrhoea is an uncommon symptom in children, and it may indicate the presence of serious disease. This review focuses on children presenting in a primary care setting. The non-specialist should be aware of the likely causes, initial management, and indications for specialist referral. The emphasis is on children in the developed world, although traveller’s diarrhoea is also considered. The epidemiology and management of this condition are different in the developing world, where infectious causes predominate. In recent years the reported incidence of inflammatory bowel disease increased greatly in the developed world and important advances have been made in its management. This diagnosis should always be considered carefully.

#### Sources and selection criteria 

I used the Medline database to search for evidence from the literature. Randomised controlled trials, meta-analyses, and Cochrane reviews were used when relevant and available. Other sources of evidence included large case series and cohort studies. I obtained information on the incidence of specific pathogens from the UK Health Protection Agency’s Centre for Infections

The likely diagnoses vary depending on age (box). At every age intestinal bacterial infections are an important cause. Inflammatory bowel disease may occur at any age but is more likely in older children (>1 year). In young infants non-specific (perhaps allergic) colitis is most likely. Other conditions are rarer but should be considered as they can be serious and even life threatening.

#### Causes of bloody diarrhoea (real or apparent) in infants and children

##### Infants aged <1 year

###### Common causes

###### Less common or rare causes

##### Infants aged >1 year

###### Common causes

###### Less common or rare causes

This is an important question because if it is assumed that bloody diarrhoea …
Low socioeconomic class is a risk factor for upper and lower gastrointestinal symptoms: a population based study in 15 000 Australian adults
Authors: Peter Bytzer, Stuart Howell, Melanie Leemon, Lisa J. Young, Michael P. Jones, Nicholas J. Talley
Journal: Gut (2001)

The association of social class with health has been extensively studied, yet relationships between social class and gastrointestinal symptoms remain almost unexplored.To examine relationships between social class and gastrointestinal symptoms in a population sample.The prevalence of 16 troublesome gastrointestinal symptoms was determined by a postal questionnaire sent to 15 000 subjects (response rate 60%) and compared with a validated composite measure of socioeconomic status (index of relative socioeconomic disadvantage). Comparisons across social class were explored for five symptom categories (oesophageal symptoms; upper dysmotility symptoms; bowel symptoms; diarrhoea; and constipation). Results are reported as age standardised rate ratios with the most advantaged social class as the reference category.There were clear trends for the prevalence rates of all gastrointestinal symptoms to increase with decreasing social class. These trends were particularly strong for the five symptom categories. Lower social class was associated with a significantly (p<0.0001) higher number of symptoms reported overall and with a higher proportion of individuals reporting 1-2 symptoms and more than five symptoms. In both sexes, the most pronounced effects for subjects in the lowest social class were found for constipation (males: rate ratio 1.83 (95% confidence intervals (CI) 1.16-2.51); females: rate ratio 1.68 (95% CI 1.31-2.04)) and upper dysmotility symptoms (males: rate ratio 1.45 (95% CI 1.02-1.88); females: rate ratio 1.35 (95% CI 1.07-1.63)). Oesophageal symptoms and diarrhoea were not associated with social class.Troublesome gastrointestinal symptoms are linked to socioeconomic status with more symptoms reported by subjects in low socioeconomic classes. Low socioeconomic class should be considered a risk factor for both upper and lower gastrointestinal symptoms.
Global health goals: lessons from the worldwide effort to eradicate poliomyelitis
Authors: R Bruce Aylward, Arnab Acharya, Sarah England, Mary Agocs, Jennifer Linkins
Journal: The Lancet (2003)

The Global Polio Eradication Initiative was launched in 1988. Assessment of the politics, production, financing, and economics of this international effort has suggested six lessons that might be pertinent to the pursuit of other global health goals. First, such goals should be based on technically sound strategies with proven operational feasibility in a large geographical area. Second, before launching an initiative, an informed collective decision must be negotiated and agreed in an appropriate international forum to keep to a minimum long-term risks in financing and implementation. Third, if substantial community engagement is envisaged, efficient deployment of sufficient resources at that level necessitates a defined, time-limited input by the community within a properly managed partnership. Fourth, although the so-called fair-share concept is arguably the best way to finance such goals, its limitations must be recognised early and alternative strategies developed for settings where it does not work. Fifth, international health goals must be designed and pursued within existing health systems if they are to secure and sustain broad support. Finally, countries, regions, or populations most likely to delay the achievement of a global health goal should be identified at the outset to ensure provision of sufficient resources and attention. The greatest threats to poliomyelitis eradication are a financing gap of US 210 million dollars and difficulties in strategy implementation in at most five countries.
Autoregulation of Glomerular Filtration Rate in Patients With Type 2 Diabetes During Isradipine Therapy
Authors: Per K. Christensen, Kamran Akram, Karen B. Kønig, Hans-Henrik Parving
Journal: Diabetes Care (2003)

OBJECTIVE—Calcium-channel blockade impairs renal autoregulation in animals. Impaired renal autoregulation leads to transmission of the systemic blood pressure (BP) into the glomerulus, resulting in capillary hypertension. Information on the impact of calcium antagonist treatment on renal autoregulation in humans is lacking. This study examines the effect of isradipine treatment on the autoregulation of the glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS—We performed a randomized double-blind crossover study with 5 mg o.d. isradipine retard and matching placebo in 16 hypertensive patients with type 2 diabetes. Each treatment arm lasted 4 weeks. On the last day of each treatment period, GFR (single-shot 51Cr-EDTA plasma clearance technique for 4 h) was measured twice between 8:00 a.m. and 5:00 p.m., first without clonidine and then after intravenous injection of 75 μg clonidine. BP was measured every 10 min (Takeda TM2420; A&amp;D, Tokyo). RESULTS—Clonidine reduced mean arterial BP (MABP) by 15 ± 1 vs. 11 ± 1 mmHg (means ± SE) during placebo and isradipine treatment, respectively (P &amp;lt; 0.05). GFR was reduced from 102 ± 4 to 99 ± 4 ml · min−1 · 1.73 m−2 with placebo (P &amp;lt; 0.01) and from 106 ± 5 to 98 ± 5 ml · min−1 · 1.73 m−2 during treatment with isradipine (P &amp;lt; 0.01). Mean difference (95% CI) between changes in GFR with placebo and isradipine was −4.6 ml · min−1 · 1.73 m−2 (−10.0 to 0.6) (P = 0.08). Six patients had a reduction in GFR &amp;gt;13% (exceeding the normal limit of autoregulation) combined with a complete pressure-passive vasculature (defined as ΔMABP% ≤ ΔGFR%) during isradipine treatment versus none during the placebo treatment (P &amp;lt; 0.05). CONCLUSIONS—Isradipine impairs GFR autoregulation in a sizeable proportion of hypertensive type 2 diabetic patients.
Physical Activity and NIDDM in African-Americans: The Pitt County Study
Authors: Sherman A James, Lama Jamjoum, T E Raghunathan, David S Strogatz, Eugene D Furth, Prabhaker G Khazanie
Journal: Diabetes Care (1998)

OBJECTIVE Studies directly examining the association between physical activity and NIDDM in African-Americans are rare. Consequently, the strength of this association in this ethnic minority group remains unclear. The current study broadly characterizes the types of physical activity engaged in by a community sample of working-class African-Americans and then quantifies the association between physical activity and NIDDM risk in this population. RESEARCH DESIGN AND METHODS During the 1993 reexamination of participants in the Pitt County Study in North Carolina, data on NIDDM history, current use of insulin or oral hypoglycemic drugs, and ∼12-h overnight fasting blood glucose (FBG) were obtained from 598 women and 318 men, ages 30-55 years. The presence of NIDDM was determined by current insulin or medication use and FBG ≥ 140 mg/dl. Study participants were assigned to one of four categories of physical activity: strenuous, moderate, low, or inactive. RESULTS The weighted prevalence of NIDDM in the sample was 7.1%. After adjustment was made for age, sex, education, BMI, and waist-to-hip ratio, NIDDM risk for moderately active subjects was one-third that for the physically inactive subjects (odds ratio [OR], 0.35; 95% CI, 0.12-0.98). The ORs for low (OR, 0.51; 95% CI, 0.20-1.29) and strenuous (OR, 0.65; 95% CI, 0.26-1.63) activity also tended to be lower. A summary OR that contrasted any activity versus no activity was 0.51 (95% CI, 0.23-1.13). CONCLUSIONS Moderate physical activity was strongly associated with reduced risk for NIDDM in this sample. While replication of these findings is needed, public health interventions designed to increase moderate (leisure-time) physical activity in black adults should be strongly encouraged.
A portable device based on the interrupter technique to measure bronchodilator response in schoolchildren
Authors: P.D. Bridge, H. Lee, M. Silverman
Journal: European Respiratory Journal (1996)

A new device for measuring airway resistance following brief airflow interruption (Microlab 4000; Micromedical Ltd, UK) was evaluated in 25 asthmatic school children in comparison with well-established methods. Airway resistance was measured during brief airflow interruption (Rint), before and after administration of salbutamol 200 micrograms by metered-dose inhaler, and in the spirometric parameters, forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF), and total respiratory system resistance at 6 Hz (Rrs,6) measured by the forced oscillation technique (FOT). The sensitivity index (SI) (mean change/baseline standard deviation) was calculated for each subject. At baseline, interrupter conductance, the reciprocal of Rint, correlated well with FEV1 (r = 0.837; p &lt; 0.001) and PEF (r = 0.773; p &lt; 0.001), and Rint correlated highly with Rrs,6 (r = 0.942; p &lt; 0.001). The median intrasubject coefficient of variation of the interrupter method was higher than the FOT or either spirometric parameter; Rint 11%, Rrs,6 9%, FEV1 5% and PEF 5%. However, the sensitivity to detect change after bronchodilator, expressed as the median SI, did not differ significantly between measurements: Rint 3.5, Rrs,6 3.6, FEV1 2.4 and PEF 3.0. A significant response (SI &gt; 2) was shown by the interrupter in 22 of the subjects compared with 16 by FEV1. The interrupter technique is useful for assessing changes in airway calibre in asthmatic school children, with a sensitivity at least as good as standard methods. Such a device could be of particular value in those too young to perform spirometry.
Neoadjuvant Chemotherapy in Small Cell Urothelial Cancer Improves Pathologic Downstaging and Long-term Outcomes: Results from a Retrospective Study at the MD Anderson Cancer Center
Authors: Siobhan P. Lynch, Yu Shen, Ashish Kamat, H. Barton Grossman, Jay B. Shah, Randall E. Millikan, Colin P. Dinney, Arlene Siefker-Radtke
Journal: European Urology (2012)
A norovirus outbreak triggered by copper intoxication on a coach trip from the Netherlands to Germany, April 2010
Authors: J Hoefnagel, D H van de Weerdt, O Schaefer, R Koene
Journal: Eurosurveillance (2012)

We report an unusual outbreak of norovirus infection on a coach trip. Overall, 30 of 40 people (including drivers and crew) developed nausea, vomiting and/or diarrhoea, 11 of them on the first day of the trip. The incidence epidemic curve showed a first peak on Day 1 and a second on Day 4. Nine passengers were hospitalised with gastrointestinal symptoms. Norovirus was found in stool samples from two patients, but the infection could not explain the first peak in the epidemic curve only a few hours after departure. Interviews with the passengers and an inspection of the coach and its water supply implicated the water used for coffee and tea as the potential source. Microbiological investigations of the water were negative, but chemical analysis showed a toxic concentration of copper. Blood copper levels as well as renal and liver function were determined in 28 of the 32 passengers who had been exposed to the water. One passenger who did not have gastrointestinal symptoms had an elevated copper level of 25.9 µmol/L, without loss of liver or renal function. It is likely that the spread of norovirus was enhanced because of vomiting of one of the passengers due to copper intoxication.
A host gene regulates the structure of the transmembrane envelope protein of murine leukemia viruses.
Authors: M A Coppola, C Y Thomas
Journal: The Journal of Experimental Medicine (1990)

Heterogeneity in the structure of the envelope proteins has been observed in many human and animal retroviruses and may influence pathogenicity. However, the biological significance of this heterogeneity and the mechanisms by which it is generated are poorly understood. We have studied a mouse model in which the envelope gene structure of lymphoma-associated viruses appears to be controlled by a single host gene. The inoculation of HRS and CWD mice with a leukemogenic murine leukemia virus (MuLV) results in recombination between the injected virus and envelope gene sequences of endogenous retroviruses. The genomes of HRS (class I) env recombinants and CWD (class II) env recombinants differ in the sequences encoding the NH2-terminal portion of the transmembrane envelope protein (TM). We have shown that an HRS gene linked to the MHC on chromosome 17 mediates a dominant selection for recombinant retroviruses with the class I envelope gene structure. CBA mice, which share the H-2k haplotype with HRS, also carry the dominant allele at this locus. This system provides a useful model for studies of host factors involved in the selection of specific variants of pathogenic retroviruses.
Cardioprotection by GSK-3 inhibition: role of enhanced glycogen synthesis and attenuation of calcium overload
Authors: Mohamed A. Omar, Lianguo Wang, Alexander S. Clanachan
Journal: Cardiovascular Research (2010)

Glycogen synthase kinase-3 (GSK-3) is a multi-functional kinase that regulates signalling pathways affecting glycogen metabolism, protein synthesis, mitosis, and apoptosis. GSK-3 inhibition limits cardiac ischaemia-reperfusion (IR) injury, but mechanisms are not clearly defined. This study tested the hypothesis that acute GSK-3 inhibition stimulates glycogen synthesis, repartitions glucose away from glycolysis, reduces proton (H+) production from glucose metabolism, and attenuates intracellular Ca2+ (Ca2+(i)) overload.In isolated perfused working rat hearts subjected to global ischaemia and reperfusion, the selective GSK-3 inhibitor, SB-216763 (SB, 3 micromol/L), when added either prior to ischaemia or at the onset of reperfusion, improved recovery of left-ventricular (LV) work. SB increased glycogen synthesis during reperfusion while glycolysis and H+ production were reduced. Rates of glucose and palmitate oxidation were improved by SB. Measurement of Ca2+(i) concentration by rapid acquisition indo-1 fluorescence imaging showed that SB, when added either prior to ischaemia or at the onset of reperfusion, reduced diastolic Ca2+(i) overload during reperfusion. In aerobic hearts depleted of glycogen by substrate-free perfusion to a level similar to that measured at the onset of reperfusion, SB accelerated glycogen synthesis and reduced glycolysis and H+ production independent of changes in LV work.Our study indicates that reduction in H+ production by GSK-3 inhibition is an early and upstream event that lessens Ca2+(i) overload during ischaemia and early reperfusion independent of LV work which enhances the recovery of post-ischaemic LV function and that may ultimately contribute to previously observed reductions in cell death and infarction.