tbuckley/cabot-search huggingface dataset:
Evidence that the bulge region is a site of relative immune privilege in human hair follicles
Authors: K.C. Meyer, J.E. Klatte, H.V. Dinh, M.J. Harries, K. Reithmayer, W. Meyer, R. Sinclair, R. Paus
Journal: British Journal of Dermatology (2008)

Recent gene profiling data suggest that, besides the anagen hair bulb, the epithelial stem cell region in the outer root sheath of hair follicles (HFs), termed the bulge, may also represent an area of relative immune privilege (IP).To investigate whether the human HF bulge is a site of relative IP within anagen VI HFs.Anagen VI HFs from normal human scalp skin were analysed using immunohistological staining techniques, quantitative histomorphometry and statistical analysis. For functional evidence we performed full-thickness human scalp skin organ cultures to investigate whether interferon (IFN)-gamma, a key inducer of IP collapse in hair bulbs, has a similar effect on the putative bulge IP.Major histocompatibility complex (MHC) class Ia, beta(2)-microglobulin and MHC class II immunoreactivity are downregulated in the human bulge. The immunosuppressants alpha-melanocyte stimulating hormone, transforming growth factor-beta2, macrophage migration inhibitory factor and indoleamine-2,3-dioxygenase (IDO) are upregulated in the CD200+, stem cell-rich bulge region. These CD200+ cells also co-express HLA-E. Furthermore, IFN-gamma induces significant ectopic MHC class Ia expression in bulge cells of organ-cultured human scalp skin.These data suggest that the bulge of human anagen HFs represents a hitherto unrecognized site of relative IP in human skin. Simultaneously, we present the first evidence of IDO and HLA-E protein expression in normal human HFs. Bulge IP presumably protects the HF epithelial stem cell reservoir from autoaggressive immune attack whereas a loss of bulge IP may play a central role in the pathogenesis of cicatricial alopecias.
Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance.
Authors: L K Beitel, P Kazemi-Esfarjani, M Kaufman, R Lumbroso, A M DiGeorge, D W Killinger, M A Trifiro, L Pinsky
Journal: Journal of Clinical Investigation (1994)

We aim to correlate point mutations in the androgen receptor gene with receptor phenotypes and with clinical phenotypes of androgen resistance. In two families, the external genitalia were predominantly female at birth, and sex-of-rearing has been female. Their androgen receptor mutation changed arginine-839 to histidine. In a third family, the external genitalia were predominantly male at birth, and sex-of-rearing has been male: their codon 839 has mutated to cysteine. In genital skin fibroblasts, both mutant receptors have a normal androgen-binding capacity, but they differ in selected indices of decreased affinity for 5 alpha-dihydrotestosterone or two synthetic androgens. In transiently cotransfected androgen-treated COS-1 cells, both mutant receptors transactivate a reporter gene subnormally. The His-839 mutant is less active than its partner, primarily because its androgen-binding activity is more unstable during prolonged exposure to androgen. Adoption of a nonbinding state explains a part of this instability. In four other steroid receptors, another dibasic amino acid, lysine, occupies the position of arginine-839 in the androgen receptor. Androgen receptors with histidine or cysteine at position 839 are distinctively dysfunctional and appear to cause different clinical degrees of androgen resistance.
CHEILOTOMY FOR CRIPPLING TRAUMATIC ARTHRITIS OF THE HIP-JOINT
Authors: W. I. D. C. Wheeler
Journal: BMJ (1913)

MEDICAL JOURNAL of May 3rd. ; I have many times, in common with other surgeons,-*operated upon cases of chronic rheumatic arthritis to relieve pain and deformity, but as my last case is identical in all essential respects with the two cases described in the communication, and as the operation was performed on the patient's hip on October 22nd last, three months before Mr. Sampson Handley operated upon his first patient, it may be of interest to mention the outstanding features, and tllus put a third case on record.The question of priority is of no great importance, but Mr. Sampson Handleyand Dr. Preston Ball are in error in thinking that
Hypertension as a risk factor for glioma? Evidence from a population-based study of comorbidity in glioma patients
Authors: M.P.W.A. Houben, W.J. Louwman, C.C. Tijssen, J.L.J.M. Teepen, C.M. van Duijn, J.W.W. Coebergh
Journal: Annals of Oncology (2004)
Evolutionary Dynamics of Oncogenes and Tumor Suppressor Genes: Higher Intensities of Purifying Selection than Other Genes
Authors: M. A. Thomas
Journal: Molecular Biology and Evolution (2003)

Oncogenes and tumor suppressor genes (hereafter referred to as "cancer genes") result in cancer when they experience substitutions that prevent or distort their normal function. We examined evolutionary pressures acting on cancer genes and other classes of disease-related genes and compared our results to analyses of genes without known association to disease. We compared synonymous and nonsynonymous substitution rates in 3,035 human genes-approximately 10% of the genome-measuring the intensity of purifying selection on 311 human disease genes, including 122 cancer-related genes. Although the genes examined are similar to nondisease genes in product, expression, function, and pathway affiliation, we found intriguing differences in the selective pressures experienced by cancer genes relative to other (noncancer) disease-related and non-disease-related genes. We found a statistically significant increase in the intensity of purifying selection exerted on cancer genes (the average ratio of nonsynonymous to synonymous substitutions, omega, was 0.079) relative to all other disease-related genes groups (omega = 0.101) and non-disease-related genes (omega = 0.100). This difference indicates a striking increase in selection against nonsynonymous substitutions in oncogenes and tumor suppressor genes. This finding provides insight into the etiology of cancer and the differences between genes involved in cancer and those implicated in other human diseases. Specifically, we found a significant overlap between human oncogenes and tumor suppressor genes and "essential genes," human homologs of mouse lethal genes identified by knockout experiments. This insight may improve our ability to identify cancer-related genes and enhances our understanding of the nature of these genes.
Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases
Authors: Susan E. Swedo, Henrietta L. Leonard, Marjorie Garvey, Barbara Mittleman, Albert J. Allen, Susan Perlmutter, Sara Dow, Jason Zamkoff, Billinda K. Dubbert, Lorraine Lougee
Journal: American Journal of Psychiatry (1998)

The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS).The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities.The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure.The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies.
Endogenous Depression in General Practice
Authors: A. Shepherd
Journal: BMJ (1947)

approximately 150 cases, and I would say that it is safe if the following precautions are taken: (l) An attendant should be present during the administration; (2) it should be given only in small quantities if uterine inertia is present-; (3) prob- ably it should be avoided if there is evidence of liver damage- am, etc., Northallerton, Yorks.D. C. DEVrMr.
Role of p53-Dependent Activation of Caspases in Chronic Obstructive Uropathy: Evidence from p53 Null Mutant Mice
Authors: YEONG-JIN CHOI, LEONARDO MENDOZA, SUK-JOO RHA, DAVID SHEIKH-HAMAD, ELZBIETA BARANOWSKA-DACA, VINH NGUYEN, WAYNE C. SMITH, GEORGE NASSAR, WADI N. SUKI, LUAN D. TRUONG
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Chronic obstructive uropathy (COU) created by unilateral ureteric ligation is associated with increased renal cell apoptosis and p53 expression. Genetically engineered mice were used to examine the role of p53 in renal cell apoptosis in COU and the involved molecular pathways. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice were examined at days 4, 7, 15, 20, and 30 for apoptosis, and mRNA were examined for p53, members of the bcl-2 family, the death receptor family, and the common effectors of apoptosis. Obstructed kidneys in p53+/- and p53-/- mice exhibited equal attenuation of tubular and interstitial cell apoptosis (70 and 50%, respectively), compared with p53+/+ mice. However, p53 gene deficiency did not confer complete protection from apoptosis. Obstructed kidneys from p53-/- mice did not express p53 mRNA, whereas those from p53+/- and p53+/+ mice displayed mild and marked increase in their expression, respectively. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice displayed upregulation of mRNA for members of the bcl-2 family and most of the death receptor family, except for a lower level of tumor necrosis factor receptor-1, TRAIL, and FAP in p53+/+ mice. Obstructed kidneys in p53-/- and p53+/- mice showed virtual absence of caspase 11 and marked attenuation of caspases 1 and 12, contrasted with their strong expression in p53+/+ kidneys. These data suggest that apoptosis in obstructed kidneys involves p53-dependent as well as p53-independent pathways. The p53-dependent pathway may involve activation of caspases 1, 11, and 12, whereas the p53-independent pathway may involve activation of members of the bcl-2 and death receptor families.
Predictors of Loss of Lung Function in the Elderly
Authors: KENT A. GRIFFITH, DUANE L. SHERRILL, ERIN M. SIEGEL, TERI A. MANOLIO, HORACE W. BONEKAT, PAUL L. ENRIGHT
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Pulmonary function, as measured by spirometry (FEV1 or FVC), is an important independent predictor of morbidity and mortality in elderly persons. In this study we examined the predictors of longitudinal decline in lung function for participants of the Cardiovascular Health Study (CHS). The CHS was started in 1990 as a population-based observational study of cardiovascular disease in elderly persons. Spirometry testing was conducted at baseline, 4 and 7 yr later. The data were analyzed using a random effects model (REM) including an AR(1) error structure. There were 5,242 subjects (57.6% female, mean age 73 yr, 87.5% white and 12.5% African-American) with eligible FEV1 measures representing 89% of the baseline cohort. The REM results showed that African-Americans had significantly lower spirometry levels than whites but that their rate of decline with age was significantly less. Subjects reporting congestive heart failure (CHF), high systolic blood pressure ( > 160 mm Hg), or taking beta-blockers had significantly lower spirometry levels; however, the effects of high blood pressure and taking beta-blockers diminished with increasing age. Chronic bronchitis, pneumonia, emphysema, and asthma were associated with reduced spirometry levels. The most notable finding of these analyses was that current smoking (especially for men) was associated with more rapid rates of decline in FVC and FEV1. African-Americans (especially women) had slower rates of decline in FEV1 than did whites. Although participants with current asthma had a mean 0.5 L lower FEV1 at their baseline examination, they did not subsequently experience more rapid declines in FEV1.
Use of interferon-γ release assays in diagnosis of active TB infection - Experience of a rural UK hospital
Authors: Sam Roberts, Janet Anderson, Paul Godwin, Harold Stephen Ronald Hosker
Journal: European Respiratory Journal (2013)

Interferon gamma release assays (IGRA’s) can be used as supplementary tests for TB when culture results are unavailable. To assess the efficacy of this approach in our population, we identified all IGRA’s performed in our laboratory and retrospectively examined indication and clinical outcome.  Of 899 IGRA9s, all were T-SPOT.TB tests performed since September 2006. 377 were part of investigation for suspected active TB. 53 of these patients were subsequently diagnosed with TB based on microbiological evidence and/or clinical suspicion and response to treatment.  33 TB patients had a positive T-SPOT, 16 had a negative T-SPOT. Of patients with subsequent microbiological proof of TB, 10 had a positive T-SPOT and 4 had a negative result. T-SPOT sensitivity for pulmonary and nodal TB was 62.5% and 78.6% respectively. Overall sensitivity was 67.3%. Sensitivity in culture proven cases was 71.4%.  Of 287 negative T-SPOT’s, 16 patients were subsequently found to have TB giving a negative predictive value of 94.7%.  Our results show a lower sensitivity for T-SPOT in diagnosis of active TB than in other work (Dai et al. Eur J Clin Microbiol Infect Dis. 2012 Nov;31(11):3127-37. Goletti et al. PLoS ONE 2008 3(10): e3417). This is likely to reflect test performance in a clinical setting, where testing is performed in cases where cultures are difficult to obtain. In addition, the low prevalence of TB in our cohort compared to others may have reduced sensitivity.  We conclude that IGRA testing should be used with caution in diagnosis of active TB in low prevalence population and every effort should be made to obtain culture results. However, the test is of value as a negative predictor for TB.
Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins.
Authors: J P Lévesque, D I Leavesley, S Niutta, M Vadas, P J Simmons
Journal: The Journal of Experimental Medicine (1995)

Cytokines are known to be important regulators of normal hemopoiesis, acting in concert with components of the bone marrow microenvironment. Interactions with this microenvironment are known to regulate the proliferation, differentiation, and homing of hemopoietic progenitor (CD34+) cells. Adhesive interactions with the extracellular matrix retain CD34+ cells in close proximity to cytokines, but may also provide important costimulatory signals. Thus, the functional states of adhesion receptors are critical properties of CD34+ cells, but the physiological mechanisms responsible for regulating functional properties of cell adhesion receptors on primitive hemopoietic cells are still unknown. We confirm that the integrins very late antigen (VLA)-4 and VLA-5 are expressed on the CD34+ cell lines MO7e, TF1, and on normal bone marrow CD34+ progenitor cells, but in a low affinity state, conferring on them a weak adhesive phenotype on fibronectin (Fn). Herein, we show that the cytokines interleukin (IL)-3, granulocyte-macrophage CSF (GM-CSF), and KIT ligand (KL) are physiological activators of VLA-4 and VLA-5 expressed by MO7e, TF1, and normal bone marrow CD34+ progenitor cells. Cytokine-stimulated adhesion on Fn is dose dependent and transient, reaching a maximum between 15 and 30 min and returning to basal levels after 2 h. This cytokine-dependent activation is specific for VLA-4 and VLA-5, since activation of other beta 1 integrins was not observed. The addition of second messenger antagonists staurosporine and W7 abolished all cytokine-stimulated adhesion to Fn. In contrast, genistein inhibited KL-stimulated adhesion, but failed to inhibit GM-CSF- and IL-3-stimulated adhesion. Our data suggest that cytokines GM-CSF and IL-3 specifically stimulate beta 1 integrin function via an "inside-out" mechanism involving protein kinase activity, while KL stimulates integrin activity through a similar, but initially distinct, pathway via the KIT tyrosine-kinase. Thus, in addition to promoting the survival, proliferation, and development of hemopoietic progenitors, cytokines also regulate adhesive interactions between progenitor cells and the bone marrow microenvironment by modifying the functional states of specific integrins. These data are of importance in understanding the fundamental processes of beta 1 integrin activation and cellular response to mitogenic cytokines as well as on the clinical setting where cytokines induce therapeutic mobilization of hematopoietic progenitors.
Methods of semen collection not based on masturbation or surgical sperm retrieval
Authors: J Gerris
Journal: Human Reproduction Update (1999)

Although masturbation is the standard method for the collection of a sperm sample, both for diagnostic and therapeutic purposes, other approaches have been described and assessed. Production of semen using specially designed condoms has been shown to result in samples with better laboratory characteristics than samples obtained after masturbation or coitus interruptus. However, this has not resulted in a general acceptance and use of this approach, except in special circumstances where masturbation is impossible or unacceptable. Direct retrieval of spermatozoa from morning urine is another method which has been used to study spermache in boys, but not to treat fertility. Sperm production techniques such as vibro- and electrostimulation are dealt with elsewhere, as are surgical retrieval techniques used in azoospermia.
Dimerization of a Phage-Display Selected Peptide for Imaging of α<sub>v</sub>β<sub>6</sub>- Integrin: Two Approaches to the Multivalent Effect
Authors: Ajay N. Singh, Michael J. McGuire, Shunzi Li, Guiyang Hao, Amit Kumar, Xiankai Sun, Kathlynn C. Brown
Journal: Theranostics (2014)

The integrin αvβ6 is an emerging biomarker for non-small cell lung cancer (NSCLC). An αvβ6-binding peptide was previously selected from a phage-displayed peptide library. Here, we utilize a multivalent design to develop a peptidic probe for positron emission tomography (PET) imaging of αvβ6+ NSCLC tumors. Multimeric presentation of this peptide, RGDLATLRQL, on a bifunctional copper chelator was achieved using two approaches: dimerization of the peptide followed by conjugation to the chelator (H2-D10) and direct presentation of two copies of the peptide on the chelator scaffold (H2-(M10)2). Binding affinities of the divalent peptide conjugates are four-fold higher than their monovalent counterpart (H2-M10), suggestive of multivalent binding. PET imaging using the bivalent 64Cu-labeled conjugates showed rapid and persistent accumulation in αvβ6+ tumors. By contrast, no significant accumulation was observed in αvβ6- tumors. Irrespective of the dimerization approach, all divalent probes showed three-fold higher tumor uptake than the monovalent probe, indicating the role of valency in signal enhancement. However, the divalent probes have elevated uptake in non-target organs, especially the kidneys. To abrogate nonspecific uptake, the peptide's N-terminus was acetylated. The resultant bivalent probe, 64Cu- AcD10, showed drastic decrease of kidney accumulation while maintaining tumor uptake. In conclusion, we developed an αvβ6-integrin specific probe with optimized biodistribution for noninvasive PET imaging of NSCLC. Further, we have demonstrated that use of multivalent scaffolds is a plausible method to improve library selected peptides, which would be suboptimal or useless otherwise, for imaging probe development.
The Treatment of Piles by Injection
Authors: F. S. Edwards
Journal: BMJ (1888)

THE BRITSISH MEDICAL JOURNA-L.815 weeks afterwards, opened the abdomen in the linea alba below the umbilicus for the purpose of either removing the disease or draining the abscess; but it was found to be quite impossible either to bring the wall of the abscess forward or to remove the disease, for the intestines were matted over it firmly, and the abscess sac was quite fixed to all the surrounding parts, therefore aspiration was simiiply performed.The patient made a steady recovery, and from that time forth began to pass less and less pus with the uriiie, and to improve in her general health.She re- turned to her home in America, and six months afterwards wrote to say that she was strong and well, and was doing her house- hold work.REMAR1iS.-T1he last case presents many points of interest which in a paper oII kidiney surgery it would be irrelevant to touch upoil.It shows the fallacy of implicitly relying on cathe- terisation of the ureters, and also slhows that an antiseptic incision into a healthy kidiney, though an undesirable operation, is not necessarily productive of harm.Case v calls for few comments, the prognosis in advanced renal tuberculosis must always be serious.and nephrotomy was simply done to give relief.The interest lies in the fact that two years previously he was suspected of having renal calculus, of which lie had all the symptoms, and nephrotomy was then suggested.The method of performing nephrectomy, carried out in Case I, differs from those usually adopted, and seems to present certain advantages.1.The incision into the peritoneal cavity enables
Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation
Authors: Yongxing Wang, Young-Ah Suh, Maren Y. Fuller, James G. Jackson, Shunbin Xiong, Tamara Terzian, Alfonso Quintás-Cardama, James A. Bankson, Adel K. El-Naggar, Guillermina Lozano
Journal: Journal of Clinical Investigation (2011)

The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53R172H missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53R172H dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy.