tbuckley/cabot-search huggingface dataset:
The Blood-Testis Barrier and Its Implications for Male Contraception
Authors: C. Yan Cheng, Dolores D. Mruk
Journal: Pharmacological Reviews (2011)

The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body. It divides the seminiferous epithelium into the basal and the apical (adluminal) compartments. Meiosis I and II, spermiogenesis, and spermiation all take place in a specialized microenvironment behind the BTB in the apical compartment, but spermatogonial renewal and differentiation and cell cycle progression up to the preleptotene spermatocyte stage take place outside of the BTB in the basal compartment of the epithelium. However, the BTB is not a static ultrastructure. Instead, it undergoes extensive restructuring during the seminiferous epithelial cycle of spermatogenesis at stage VIII to allow the transit of preleptotene spermatocytes at the BTB. Yet the immunological barrier conferred by the BTB cannot be compromised, even transiently, during the epithelial cycle to avoid the production of antibodies against meiotic and postmeiotic germ cells. Studies have demonstrated that some unlikely partners, namely adhesion protein complexes (e.g., occludin-ZO-1, N-cadherin-β-catenin, claudin-5-ZO-1), steroids (e.g., testosterone, estradiol-17β), nonreceptor protein kinases (e.g., focal adhesion kinase, c-Src, c-Yes), polarity proteins (e.g., PAR6, Cdc42, 14-3-3), endocytic vesicle proteins (e.g., clathrin, caveolin, dynamin 2), and actin regulatory proteins (e.g., Eps8, Arp2/3 complex), are working together, apparently under the overall influence of cytokines (e.g., transforming growth factor-β3, tumor necrosis factor-α, interleukin-1α). In short, a "new" BTB is created behind spermatocytes in transit while the "old" BTB above transiting cells undergoes timely degeneration, so that the immunological barrier can be maintained while spermatocytes are traversing the BTB. We also discuss recent findings regarding the molecular mechanisms by which environmental toxicants (e.g., cadmium, bisphenol A) induce testicular injury via their initial actions at the BTB to elicit subsequent damage to germ-cell adhesion, thereby leading to germ-cell loss, reduced sperm count, and male infertility or subfertility. Moreover, we also critically evaluate findings in the field regarding studies on drug transporters in the testis and discuss how these influx and efflux pumps regulate the entry of potential nonhormonal male contraceptives to the apical compartment to exert their effects. Collectively, these findings illustrate multiple potential targets are present at the BTB for innovative contraceptive development and for better delivery of drugs to alleviate toxicant-induced reproductive dysfunction in men.
ABC of colorectal cancer: Adjuvant therapy
Authors: R. S J Midgley
Journal: BMJ (2000)

Rachel S J Midgley is clinical research fellow at the CRC Institute for Cancer Studies, University of Birmingham.



The ABC of colorectal cancer is edited by D J Kerr, professor at the Institute for Cancer Studies, University of Birmingham; Annie Young, research fellow at the School of Health Sciences, University of Birmingham; and F D Richard Hobbs, professor in the department of primary care and general practice, University of Birmingham. The series will be published as a book by the end of 2000.
Words are not costly displays: Shortcomings of a testosterone-fuelled model of language evolution
Authors: Chris Knight, Camilla Power
Journal: Behavioral and Brain Sciences (2006)

Only by misconstruing the term performative are the authors able to argue that males surpass females in “performative applications” of language. Linguistic performatives are not costly displays of quality, and syntax cannot be explained as an outcome of behavioural competition between pubertal males. However, there is room for a model in which language co-evolves with the unique human life-history stage of adolescence.
Pain: The Gift Nobody Wants
Authors: Bashir Qureshi
Journal: JAMA (1994)

Pain has the mysterious power to overrule everything else in life. It can be a friend when it is a symptom of a disease and prompts a patient to see the doctor. It can be an enemy when it gets you down and makes life hell. There are two sides to every picture. Paul Brand tells his life history and experiences with pain-afflicted patients in three countries—21 years in India, 25 years in England, and 27 years in the United States—and reveals both sides of pain. The first part of the book recounts Dr Brand's path into medicine, particularly his experiences in India in the colonial times. Part two is devoted to his career in pain, especially dealing with patients with leprosy. In part three, he becomes very philosophical and teaches how to manage pain. Coauthor Philip Yancey, appears to be a writer whose experiences or messages do not appear
Risk of a Recurrent Cardiovascular Event in Individuals With Type 2 Diabetes or Intermediate Hyperglycemia
Authors: Amber A.W.A. van der Heijden, Esther van’t Riet, Sandra D.M. Bot, Suzanne C. Cannegieter, Coen D.A. Stehouwer, Caroline A. Baan, Jacqueline M. Dekker, Giel Nijpels
Journal: Diabetes Care (2013)

OBJECTIVE To investigate risk of a recurrent cardiovascular event and its predictors in a population-based cohort. RESEARCH DESIGN AND METHODS Participants of the Hoorn Study who had experienced a first cardiovascular event after baseline (n = 336) were followed with respect to a recurrent event. Absolute risk of a recurrent event was calculated for individuals with normal glucose metabolism, intermediate hyperglycemia, and type 2 diabetes. Cox regression models were used to investigate which variables, measured before the first vascular event, predicted a recurrent event using the stepwise backward procedure. RESULTS During a median follow-up of 4.1 years, 44% (n = 148) of the population developed a recurrent vascular event. The rate of recurrent events per 100 person-years was 7.2 (95% CI 5.8–8.7) in individuals with normal glucose metabolism, compared with 9.8 (6.6–14.0) in individuals with intermediate hyperglycemia and 12.5 (8.5–17.6) in individuals with type 2 diabetes. Higher age (hazard ratio 1.02 [95% CI 1.00–1.04]), male sex (1.56 [1.08–2.25]), waist circumference (1.02 [1.02–1.03]), higher systolic blood pressure (1.01 [1.01–1.02]), higher HbA1c (%, 1.13 [0.97–1.31]/ mmol/mol, 1.01 [1.00–1.03]), and family history of myocardial infarction (1.38 [0.96–2.00]) predicted a recurrent cardiovascular event. CONCLUSIONS Individuals with type 2 diabetes, but not individuals with intermediate hyperglycemia, are at increased risk for a recurrent vascular event compared with individuals with normal glucose metabolism. In people with a history of cardiovascular disease, people at increased risk of a recurrent event can be identified based on the patient’s risk profile before the first event.
In vivo effects of antibodies to immune response gene products. I. Haplotype-specific suppression of humoral immune responses with a monoclonal anti-I-A.
Authors: J T Rosenbaum, N E Adelman, H O McDevitt
Journal: The Journal of Experimental Medicine (1981)

Immune response (Ir) gene products control immunologic function at several critical sites. We administered in vivo a monoclonal antibody reactive with I-Ak to F1 mice with the genotype H-2k/b. These treated mnice made a markedly reduced antibody response to antigen (H,G)-A--L, under the control of I-Ak, but not to antigen (T,G)-A--L, under the control of I-Ab. This relative specificity was lost if the antigen was given in complete Freund's adjuvant rather than aqueous solution. The monoclonal antibody reduced the antibody titer in an ongoing, secondary response as well. Several potential mechanisms can be postulated for this effect. This haplotypic specificity might ultimately be relevant to human disease.
The Prevalence of Retinopathy Is Similar in Diabetes Mellitus Secondary to Chronic Pancreatitis With or Without Pancreatectomy and in Idiopathic Diabetes Mellitus
Authors: Charles Couet, Pierre Genton, Jean Paul Pointel, Jacques Louis, Patrice Gross, Etienne Saudax, Gerard Debry, Pierre Drouin
Journal: Diabetes Care (1985)

In a retrospective study, we compared the prevalence of retinopathy in two groups of 88 diabetic patients (84 men, 4 women) with either diabetes mellitus secondary to chronic pancreatitis (CP-DM group) or idiopathic diabetes mellitus (I-DM group). The patients of these two groups were pair-matched according to age (48.7 ± 1.1 versus 48.8 ± 1.0 yr in CP-DM and I-DM groups, respectively; mean ± SEM), sex, duration of diabetes (7.96 ± 0.56 versus 8.08 ± 0.8 yr) and therapy (80 on insulin and 8 on oral hypoglycemic agents in each group). Retinopathy was assessed by bilateral ophthalmoscopic examination of the fundus after pupillary dilation in all 176 patients and by fluorescein angiography in 47 patients with CP-DM and 35 patients with I-DM. Forty-one percent of patients in the CP-DM group and 45.5% of patients in the I-DM group had diabetic retinopathy (P &amp;gt; 0.5). In each group, patients with retinopathy were older than patients without retinopathy (51.6 ± 1.3 versus 46.7 ± 1.8 yr in the CP-DM group, P &amp;lt; 0.01, and 52.1 ± 1.5 versus 46.0 ± 1.2 yr in the ID-M group, P &amp;lt; 0.01). They had diabetes of longer duration (10.9 ± 1.0 versus 5.9 ± 0.6 yr in the CP-DM group, P &amp;lt; 0.001, and 10.5 ± 1.0 versus 6.0 ± 0.6 yr in the ID-M group, P &amp;lt; 0.001). The prevalence of retinopathy increased parallel to the duration of diabetes in a similar way in both groups. The part played in the pathogenesis of retinopathy by the following factors is also discussed: blood glucose control, arterial blood pressure, plasma total cholesterol and triglyceride levels, and family history of diabetes mellitus. Our data suggest that patients with diabetes secondary to chronic pancreatitis are at similar risks of retinopathy.
Analysis of Risk Factors for Outcomes After Unrelated Cord Blood Transplantation in Adults With Lymphoid Malignancies: A Study by the Eurocord-Netcord and Lymphoma Working Party of the European Group for Blood and Marrow Transplantation
Authors: Celso A. Rodrigues, Guillermo Sanz, Claudio G. Brunstein, Jaime Sanz, John E. Wagner, Marc Renaud, Marcos de Lima, Mitchell S. Cairo, Sabine Fürst, Bernard Rio, Christopher Dalley, Enric Carreras, Jean-Luc Harousseau, Mohamad Mohty, Denis Taveira, Peter Dreger, Anna Sureda, Eliane Gluckman, Vanderson Rocha
Journal: Journal of Clinical Oncology (2008)

To determine risk factors of umbilical cord blood transplantation (UCBT) for patients with lymphoid malignancies.We evaluated 104 adult patients (median age, 41 years) who underwent unrelated donor UCBT for lymphoid malignancies. UCB grafts were two-antigen human leukocyte antigen-mismatched in 68%, and were composed of one (n = 78) or two (n = 26) units. Diagnoses were non-Hodgkin's lymphoma (NHL, n = 61), Hodgkin's lymphoma (HL, n = 29), and chronic lymphocytic leukemia (CLL, n = 14), with 87% having advanced disease and 60% having experienced failure with a prior autologous transplant. Sixty-four percent of patients received a reduced-intensity conditioning regimen and 46% low-dose total-body irradiation (TBI). Median follow-up was 18 months.Cumulative incidence of neutrophil engraftment was 84% by day 60, with greater engraftment in recipients of higher CD34(+) kg/cell dose (P = .0004). CI of non-relapse-related mortality (NRM) was 28% at 1 year, with a lower risk in patients treated with low-dose total-body irradiation (TBI; P = .03). Cumulative incidence of relapse or progression was 31% at 1 year, with a lower risk in recipients of double-unit UCBT (P = .03). The probability of progression-free survival (PFS) was 40% at 1 year, with improved survival in those with chemosensitive disease (49% v 34%; P = .03), who received conditioning regimens containing low-dose TBI (60% v 23%; P = .001), and higher nucleated cell dose (49% v 21%; P = .009).UCBT is a viable treatment for adults with advanced lymphoid malignancies. Chemosensitive disease, use of low-dose TBI, and higher cell dose were factors associated with significantly better outcome.
Multiple Myeloma—Intermittent, Combination Chemotherapy Compared with Low-Dose Continuous Alkylator Therapy.
Authors: Ralph P. George
Journal: Annals of Internal Medicine (1971)

Meeting Abstracts1 May 1971Multiple Myeloma—Intermittent, Combination Chemotherapy Compared with Low-Dose Continuous Alkylator Therapy.Ralph P. George Jr., M.D., James L. Poth, M.D., David Gordon, M.D., Stanley L. Schrier, M.D.Ralph P. George Jr., M.D.Search for more papers by this author, James L. Poth, M.D.Search for more papers by this author, David Gordon, M.D.Search for more papers by this author, Stanley L. Schrier, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-74-5-836_5 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptControversy exists regarding the efficacy of various treatment schedules and drug combinations for patients with multiple myeloma. This study compared results of long-term, continuous alkylator therapy with those of intermittent, high-dose pulse therapy using melphalan and prednisone in combination. During the past 2 years 31 patients with multiple myeloma were treated with high-dose, combination pulse therapy using melphalan, 0.25 mg/kg body weight/day, and prednisone, 2.0 mg/kg body weight/day. Both drugs were given orally for 4 days at 6-week intervals. The results were compared with previous experience at the Stanford University Hospital using continuous, low-dose alkylator therapy in 22 patients with... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Stanford, Calif. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1971Volume 74, Issue 5Page: 836-837KeywordsCombination chemotherapyDrugsHeart rateMultiple myeloma Issue Published: 1 May 1971 PDF DownloadLoading ...
Use of carbon monoxide to measure luminal stirring in the rat gut.
Authors: M D Levitt, T Aufderheide, C A Fetzer, J H Bond, D G Levitt
Journal: Journal of Clinical Investigation (1984)

We used carbon monoxide (CO) as a probe to quantitatively measure intestinal unstirred water layers in vivo. CO has several features that make it uniquely well suited to measure the unstirred layer in that its tight binding to hemoglobin makes uptake diffusion limited, and its relatively high lipid solubility renders membrane resistance negligible relative to the water barriers of the unstirred layer and epithelial cell. The unique application of CO was the measurement of the absorption rate of CO both from the gas phase as well as a solute dissolved in saline. Several lines of evidence showed that a gut stripped free of saline and then filled with gas contained a negligible unstirred layer. Thus, absorption of CO from the gas phase measured resistance of just the epithelial cell. Subtraction of this value from the resistance of CO absorption from saline provided a direct measure of unstirred layer resistance. Studies in the rat showed for a 3-min absorption period that the conventionally calculated apparent unstirred layer for the jejunum was 411 micron and for the colon was 240 micron. However, this conventionally calculated unstirred layer resistance did not truly depict the situation in the rat gut, since there was a continuing depletion of CO from outer surfaces of luminal contents throughout the experiment period. This produced a continually increasing diffusion barrier with time. Calculation of expected absorption rate from unstirred cylinders with the dimensions of the rat gut indicated that there was virtually no stirring in the small intestine and minimal stirring in the colon. The technique described in this paper appears to be simpler and to require fewer assumptions for validity than other techniques previously used to measure unstirred layers in vivo.
The Electro-encephalogram in Clinical Neurology
Authors: R. A. Krynauw
Journal: BMJ (1939)

relations, if they exist, can be more readily established.One action which is retained by compouLnds based on phenylethylamine, in spite of considerable changes in the molecule, is an action on smooth muLscle.In some cases this can be described as a sympathomimetic action, in others as a direct action on muscle, in others as a mixture of these actions.In virtue of these actions they affect all organs containing smooth mnuscle--- heart, blood vessels, bronchi, intestinal canal, uterus, spleen, etc.They have thus a wide range of activity with potential therapeutic uses.Some of them also stimulate the central nervous system, especially the motor cortex and the respiratory centre.Some examples have been given of how the molecule can be altered to diminish or intensify the various effects of the resulting compounds.The assessment of their therapeutic values, usually a slow process, probably lags behind the pharmacological know- ledge we already possess, but some consideration of such therapeutic progress as has been made will be given in the second lecture.
Lipopolysaccharide-neutralizing antibody reduces hepatocyte injury from acute hepatotoxin administration
Authors: Mark J. Czaja, Jun Xu, Yue Ju, Elaine Alt, Phyllis Schmiedeberg
Journal: Hepatology (1994)

Endogenous lipopolysaccharide has been implicated as a cofactor in the hepatocellular injury and death resulting from toxic liver injury. To prevent this lipopolysaccharide-induced injury and to further understand the mechanism of this effect, an anti-lipopolysaccharide antibody was administered to rats in which toxic hepatocellular injury was induced. Rats were given the hepatotoxin galactosamine together with an isotypic control antibody B55 or the anti-lipopolysaccharide antibody E5. E5 treatment resulted in reductions of serum AST levels of 43% at 36 hr (p&lt;0.02) and 60% at 48 hr (NS) after galactosamine administration. These decreases in AST values were accompanied by diminished histological evidence of injury and inflammation. In carbon tetrachloride-induced liver injury, E5 similarly reduced serum AST levels at 36 and 48 hr by 47% (p&lt;0.04) and 54% (p&lt;0.03), respectively. E5 treatment was equally effective in reducing AST levels 48 hr after administration of carbon tetrachloride, whether the initial dose of antibody was given 1 hr before or 3 or 6 hr after the administration of this toxin. To understand the mechanism of this E5 effect, the activation of the toxic cytokine tumor necrosis factor-α and the chemotactic cytokine monocyte chemoattractant protein 1 was examined by Northern-blot analysis of RNA from rat livers after galactosamine-induced injury and treatment with B55 or E5. Despite E5’s efficacy in reducing hepatocellular damage, E5 treatment did not affect the timing or magnitude of tumor necrosis factor-α or monocyte chemoattractant protein 1 activation during galactosamine-induced injury. These data suggest that antibody neutralization of lipopolysaccharide may be an effective therapy for toxic liver injury and that the mechanism of this effect is not through the prevention of cytokine expression. (Hepatology 1994;19:1282-1289.)
Exploring the Etiology of Alzheimer Disease Using Molecular Genetics
Authors: Corinne L. Lendon
Journal: JAMA (1997)

Alzheimer disease (AD), the most common cause of dementia in the elderly, exists in both familial and sporadic forms. Genetic studies have led to the identification of 3 genes, β-amyloid precursor protein (<i>APP</i>), presenilin-1 (<i>PS1</i>), and presenilin-2 (<i>PS2</i>), which, when mutated, can cause familial forms of AD. Mutations in each of these genes result in elevated levels of Aβ42/43, a proteolytic processing fragment of<i>APP</i>that is deposited in brains of AD patients. Transgenic mice carrying AD-causing mutations in<i>APP</i>develop spontaneous agerelated β-amyloid (Aβ) deposition and memory impairment. Genetic linkage and association studies have also shown that the ϵ4 allele of the apolipoprotein E (<i>APOE</i>) gene increases risk for AD in a dose-dependent manner in both familial and sporadic forms of AD and may account for as much as 50% of the attributable risk.<i>APOE</i>genotyping may be useful both as an adjunct to diagnosis and in identifying patient groups for therapeutic intervention. While the biological basis for the association of<i>APOE</i>ϵ4 with AD is not known, age of onset and Aβ deposition are positively correlated with ϵ4 allele dosage in some cases, suggesting that this risk may also be mediated directly or indirectly through Aβ. Because 50% of AD cases have no<i>APOE</i>ϵ4 alleles and families showing mendelian inheritance of AD exist in whom there are no mutations in any of the<i>APP, PS1</i>, or<i>PS2</i>genes, it is likely that there are additional AD risk factors, both genetic and environmental, still to be identified.
Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia
Authors: Tilmann Bochtler, Friedrich Stölzel, Christoph E. Heilig, Christina Kunz, Brigitte Mohr, Anna Jauch, Johannes W.G. Janssen, Michael Kramer, Axel Benner, Martin Bornhäuser, Anthony D. Ho, Gerhard Ehninger, Markus Schaich, Alwin Krämer
Journal: Journal of Clinical Oncology (2013)

In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics.This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia. Patients were newly diagnosed with non-M3 AML and were fit for intensive chemotherapy.Cytogenetic subclones were detected in 418 (15.8%) of 2,639 patients from the whole study population and in 418 (32.8%) of 1,274 patients with aberrant karyotypes. Among those, 252 karyotypes (60.3%) displayed a defined number of distinct subclones, and 166 (39.7%) were classified as composite karyotypes. Subclone formation was particularly frequent in the cytogenetically adverse group, with subclone formation in 69.0%, 67.1%, and 64.8% of patients with complex aberrant, monosomal, and abnl(17p) karyotypes (P < .001 each). Two-subclone patterns typically followed a mother-daughter evolution, whereas for ≥ three subclones, a branched pattern prevailed. In non-core binding factor AML, subclone formation was associated with inferior event-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariate analysis. Subgroup analysis showed that subclone formation adds prognostic information particularly in the cytogenetic adverse-risk group. Allogeneic stem-cell transplantation improved the prognosis of patients with subclone karyotypes as shown in landmark analyses.Cytogenetic subclones are frequent in AML and permit tracing of clonal evolution and architecture. They bear prognostic significance with clonal heterogeneity as an independent adverse prognostic marker in cytogenetically adverse-risk AML.
TCT-318 Cardioprotection with Glucagon-like Peptide-1 (GLP-1) may occur independent of coronary collaterals and metabolic substrate utilisation
Authors: Liam M. McCormick, Stephen P. Hoole, Paul A. White, Philip A. Read, Richard G. Axell, Sophie J. Clarke, Michael O'Sullivan, Nick E. West, David P. Dutka
Journal: Journal of the American College of Cardiology (2013)