tbuckley/cabot-search huggingface dataset:
Biological Variation in HbA1c Predicts Risk of Retinopathy and Nephropathy in Type 1 Diabetes
Authors: Patrick J. Twomey, Adie Viljoen, Timothy M. Reynolds, Anthony S. Wierzbicki
Journal: Diabetes Care (2004)

Rathmann and Giani (1) point out that there is a greater diversity of diabetes prevalence in Europe than suggested by our recent article (2) on the global prevalence of diabetes. We agree with this point. Unfortunately, the data from their study (3) in Augsburg, Germany, had not been published when the data for our article were assembled in 2002. As described in the article, we plan to update the estimates of diabetes prevalence and will include the …
The role of nitric oxide and cell adhesion molecules on the microcirculation in ischaemia-reperfusion
Authors: A. M. Lefer, D. J. Lefer
Journal: Cardiovascular Research (1996)

The microcirculation undergoes a profound degree of endothelial dysfunction within minutes (i.e., 2.5 to 5 min) following reperfusion of ischaemic vasculature. This has been documented in the coronary and mesenteric microcirculation. The endothelial dysfunction is characterized by a loss in basal and agonist-mediated nitric oxide (NO) produced by the vascular endothelium. The loss of NO results in upregulation of cell adhesion molecules (CAMs) particularly P-selectin 10-20 min following reperfusion. Thus, CAM upregulation renders the endothelium sticky, and a marked degree of leukocyte adherence (particularly neutrophils) occurs 20 min following reperfusion. This enhanced involvement of neutrophils leads to neutrophil infiltration into the underlying tissue (e.g., myocardium) within 2-3 h of reperfusion. The infiltration of neutrophils leads to reperfusion injury (i.e., necrosis) which is significant at 3 h but becomes profound at 4.5 h following reperfusion. Cardiac necrosis can be significantly attenuated by treatment with NO, an organic NO donor, L-arginine, or specific blockers of CAMs given just prior to reperfusion. This approach is a promising one for a variety of types of reperfusion injury.
Prostaglandin E<sub>2</sub>and nitric oxide mediate the acute inflammatory (erythemal) response to topical 5-aminolaevulinic acid photodynamic therapy in human skin
Authors: R.C.C. Brooke, M. Sidhu, A. Sinha, R.E.B. Watson, P.S. Friedmann, G.F. Clough, L.E. Rhodes
Journal: British Journal of Dermatology (2013)

Topical 5-aminolaevulinic acid photodynamic therapy (5-ALA-PDT) causes a clinical inflammatory response in human skin. While histamine mediates the immediate reaction, the mediators of the prolonged erythema are unknown.To look for involvement of the proinflammatory mediators prostaglandin (PG)E2 and nitric oxide (NO) in topical PDT-induced erythema in human skin.A series of studies was performed in healthy volunteers (n = 35). Following definition of the erythemal time course and dose response to 5-ALA-PDT, duplicate 5-ALA dose series were iontophoresed into the skin of each ventral forearm and exposed to 100 J cm(-2) broadband red light. Within subject, arms were randomized to control, or treatment with the cyclooxygenase and NO synthase inhibitors indometacin and Nω -nitro-l-arginine methyl ester (l-NAME), respectively, and the impact on 5-ALA-PDT-induced erythema was quantified. Additionally, release of PGE2 and NO was directly assessed by sampling dermal microdialysate at intervals following 5-ALA-PDT administration.A 5-ALA dose-related delayed erythema occurred by 3 h (r = 0·97, P < 0·01), with erythema persisting to 48 h post-PDT. Topical indometacin applied immediately post-PDT reduced the slope of erythemal response at 3 h and 24 h (P < 0·05). Intradermal injection of l-NAME into 5-ALA-PDT-treated sites reduced the slope of response at 24 h post-PDT (P < 0·001), while significantly inhibiting erythema from 3 h to 48 h post-PDT (P < 0·01). Analysis of dermal microdialysate showed release of NO and PGE2 following treatment.Topical 5-ALA-PDT upregulates PGE2 and NO in human skin, where they play a significant role in the clinical inflammatory response. The potential relevance of these mediators to PDT in human cutaneous pathology warrants study.
Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum
Authors: J. R. Jass, H. Iino, A. Ruszkiewicz, D. Painter, M. J. Solomon, D. J. Koorey, D. Cohn, K. L. Furlong, M. D. Walsh, J. Palazzo, T. B. Edmonston, R. Fishel, J. P. Young, B. A. Leggett
Journal: Gut (2000)

<h3>AIM</h3> Colorectal cancer has been described in association with hyperplastic polyposis but the mechanism underlying this observation is unknown. The aim of this study was to characterise foci of dysplasia developing in the polyps of subjects with hyperplastic polyposis on the basis of DNA microsatellite status and expression of the DNA mismatch repair proteins hMLH1, hMSH2, and hMSH6. <h3>MATERIALS AND METHODS</h3> The material was derived from four patients with hyperplastic polyposis and between one and six synchronous colorectal cancers. Normal (four), hyperplastic (13), dysplastic (13), and malignant (11) samples were microdissected and a PCR based approach was used to identify mutations at 10 microsatellite loci, TGFβIIR, IGF2R, BAX, MSH3, and MSH6. Microsatellite instability-high (MSI-H) was diagnosed when 40% or more of the microsatellite loci showed mutational bandshifts. Serial sections were stained for hMLH1, hMSH2, and hMSH6. <h3>RESULTS</h3> DNA microsatellite instability was found in 1/13 (8%) hyperplastic samples, in 7/13 (54%) dysplastic foci, and in 8/11 (73%) cancers. None of the MSI-low (MSI-L) samples (one hyperplastic, three dysplastic, two cancers) showed loss of hMLH1 expression. All four MSI-H dysplastic foci and six MSI-H cancers showed loss of hMLH1 expression. Loss of hMLH1 in MSI-H but not in MSI-L lesions showing dysplasia or cancer was significant (p&lt; 0.001, Fisher<i>9</i>s exact test). Loss of hMSH6 occurred in one MSI-H cancer and one MSS focus of dysplasia which also showed loss of hMLH1 staining. <h3>CONCLUSION</h3> Neoplastic changes in hyperplastic polyposis may occur within a hyperplastic polyp. Neoplasia may be driven by DNA instability that is present to a low (MSI-L) or high (MSI-H) degree. MSI-H but not MSI-L dysplastic foci are associated with loss of hMLH1 expression. At least two mutator pathways drive neoplasia in hyperplastic polyposis. The role of the hyperplastic polyp in the histogenesis of sporadic DNA microsatellite unstable colorectal cancer should be examined.
Control of Apoptosis in the Immune System: Bcl-2, BH3-Only Proteins and More
Authors: Vanessa S. Marsden, Andreas Strasser
Journal: Annual Review of Immunology (2003)

Apoptotic cell death plays a critical role in the development and functioning of the immune system. During differentiation, apoptosis weeds out lymphocytes lacking useful antigen receptors and those expressing dangerous ones. Lymphocyte death is also involved in limiting the magnitude and duration of immune responses to infection. In this review, we describe the role of the Bcl-2 protein family, and to a lesser extent that of death receptors (members of the tumor necrosis factor receptor family with a death domain), in the control of lymphoid and myeloid cell survival. We also consider the pathogenic consequences of failure of apoptosis in the immune system.
Occipito-Posterior Presentations
Authors: A. D. L. Napier
Journal: BMJ (1883)

May 12, 1,M.and this is, as a rule, so complete that the whole body feels unsup- ported, as if floating in air.Pain, even at this stage, frequently persists, showing how little influence this drug evidently has on the sensory nerves.In some cases, spasmodic contractions of the voluntary muscles result, and this is more especially to be noted in the muscles of the jaw.Dimness of vision in mnany cases quickly follows, the pupils in some remaining unaltered, in others being appaxently contracted.The pupil responds to light, but accom- modation is interfered with, objects at a distance being very indis- tinct.The pulse is invariably rapid, but quite regular.Sensibility to touch is unaltered.Numbness and tingling have been constant symptoms in all the cases.
Altered Renal Distal Tubule Structure and Renal Na+ and Ca2+ Handling in a Mouse Model for Gitelman’s Syndrome
Authors: Johannes Loffing, Volker Vallon, Dominique Loffing-Cueni, Fintan Aregger, Kerstin Richter, Laurence Pietri, May Bloch-Faure, Joost G.J. Hoenderop, Gary E. Shull, Pierre Meneton, Brigitte Kaissling
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Gitelman’s syndrome, an autosomal recessive renal tubulopathy caused by loss-of-function mutations in the thiazide-sensitive NaCl co-transporter (NCC) of the distal convoluted tubule (DCT), is characterized by mild renal Na<sup>+</sup> wasting, hypocalciuria, hypomagnesemia, and hypokalemic alkalosis. For gaining further insights into the pathophysiology of Gitelman’s syndrome, the impact of NCC ablation on the morphology of the distal tubule, on the distribution and abundance of ion transport proteins along its length, and on renal tubular Na<sup>+</sup> and Ca<sup>2+</sup> handling in a gene-targeted mouse model was studied. NCC-deficient mice had significantly elevated plasma aldosterone levels and exhibited hypocalciuria, hypomagnesemia, and compensated alkalosis. Immunofluorescent detection of distal tubule marker proteins and ultrastructural analysis revealed that the early DCT, which physiologically lacks epithelial Na<sup>+</sup> (ENaC) and Ca<sup>2+</sup> (TRPV5) channels, was virtually absent in NCC-deficient mice. In contrast, the late DCT seemed intact and retained expression of the apical ENaC and TRPV5 as well as basolateral Na<sup>+</sup>-Ca<sup>2+</sup> exchanger. The connecting tubule exhibited a marked epithelial hypertrophy accompanied by an increased apical abundance of ENaC. Ca<sup>2+</sup> reabsorption seemed unaltered in the distal convolution (<i>i.e.</i>, the DCT and connecting tubule) as indicated by real-time reverse transcription-PCR, Western blotting, and immunohistochemistry for TRPV5 and Na<sup>+</sup>-Ca<sup>2+</sup> exchanger and micropuncture experiments. The last experiments further indicated that reduced glomerular filtration and enhanced fractional reabsorption of Na<sup>+</sup> and Ca<sup>2+</sup> upstream and of Na<sup>+</sup> downstream of the DCT provide some compensation for the Na<sup>+</sup> transport defect in the DCT and contribute to the hypocalciuria. Thus, loss of NCC leads to major structural remodeling of the renal distal tubule that goes along with marked changes in glomerular and tubular function, which may explain some of the clinical features of Gitelman’s syndrome.
Phase I Study of Concomitant Chemoradiotherapy with Paclitaxel, Fluorouracil, Gemcitabine, and Twice-Daily Radiation in Patients with Poor-Prognosis Cancer of the Head and Neck
Authors: Michael T. Milano, Daniel J. Haraf, Kerstin M. Stenson, Mary Ellyn Witt, Cathy Eng, Bharat B. Mittal, Athanassios Argiris, Harold Pelzer, Mark F. Kozloff, Everett E. Vokes
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We previously demonstrated high locoregional control, in patients with poor-prognosis head and neck cancer (HNC), using paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant hyperfractionated radiotherapy. In the present phase I trial, gemcitabine, a novel antimetabolite with strong radiation-enhancing activity, replaces hydroxyurea. We sought to determine the recommended phase II dose and clinical efficacy in poor-prognosis HNC patients. Experimental Design: Seventy-two patients enrolled. Eligibility criteria included recurrent or second primary HNC, metastases or expected 2-year survival &amp;lt;20%. Chemoradiotherapy consisted of 5-fluorouracil, 600 mg/m2/d, for 5 days; paclitaxel, 100 mg/m2 on Day 1; and concurrent 1.5 Gy twice-daily radiation for 5 days. Gemcitabine was dose escalated, 50–300 mg/m2 on day 1. Cycles repeated every 14 days until the completion of chemoradiation. Dose-limiting toxicities (DLTs) included: neutropenic fever; grade ≥4 neutropenia or thrombocytopenia for &amp;gt;4 days; grade ≥4 mucositis or dermatitis for &amp;gt;7 days; or grade 3 toxicity necessitating chemotherapy dose reductions. Non-DLT dose reductions in 5-fluorouracil and/or paclitaxel were allowed. Results: Seventy-nine percent of assessable patients experienced a clinical response. Five-year actuarial survival is 33.0%, and locoregional control is 61.4%. The recommended phase II dose of gemcitabine in this regimen is 100 mg/m2 during cycles 1–5 (1 of 7 patients with DLT) or 200 mg/m2 delivered only during cycles 3–5 (3 of 19 with DLT). Grades 3 and 4 mucositis (56 and 21%, respectively) and dermatitis (25 and 21%, respectively) were common. Conclusions: Gemcitabine, 5-fluorouracil, paclitaxel, and twice-daily radiation, delivered on alternating weeks, is active in patients with poor-prognosis HNC, although severe mucositis limits the clinical applicability of this regimen. Refinements in radiotherapy, including intensity-modulated radiation therapy, may improve the tolerance for this regimen.
Analysis of p53 protein expression levels on ovarian cancer tissue microarray using automated quantitative analysis elucidates prognostic patient subsets
Authors: A. Psyrri, P. Kountourakis, Z. Yu, C. Papadimitriou, S. Markakis, R.L. Camp, T. Economopoulos, M.A. Dimopoulos
Journal: Annals of Oncology (2007)
Left ventricular aneurysm
Authors: C. H. Beckerling, B. H. Gibb, H. G. H. Houghton, B. T. Le Roux
Journal: Thorax (1969)

Left ventricular aneurysm in African patients is most often luetic; the only other common left ventricular aneurysm in African patients is agnogenic and not a complication of coronary artery disease. The management of a left ventricular aneurysm by surgical excision with cardiorespiratory bypass in an African patient is described. The literature which relates to left ventricular aneurysm in African patients is briefly reviewed.
Polyspecificity of antistreptococcal murine monoclonal antibodies and their implications in autoimmunity.
Authors: M W Cunningham, R A Swerlick
Journal: The Journal of Experimental Medicine (1986)

mAbs produced by immunization of BALB/c mice with Streptococcus pyogenes M type 5 membranes were further characterized for their reaction with S. pyogenes pep M5 protein and with autoantigens associated with human cell lines. mAbs 36.2.2 and 54.2.8 simultaneously reacted with M protein and a membrane protein(s) of S. pyogenes. When cell lines were mixed with 54.2.8, we saw nuclear fluorescence along with staining of the cytoskeleton. Subsequent experiments revealed that 54.2.8 was an anti-DNA antibody that reacted with DNA, poly(I), poly(dT), and weakly with cardiolipin. Its reactivity with the cytoskeleton could be blocked with anti-vimentin. On the other hand, 36.2.2 reacted with the cytoskeleton, sparing the nucleus, and was inhibited by the alpha helical proteins myosin, actin, and keratin. mAb 54.2.8 was inhibited with myosin, but not with actin and keratin. None of the antibodies studied were inhibited by collagen, and none of them were rheumatoid factors. The results imply that Group A streptococci can activate B cell clones against myosin, alpha helical proteins, or DNA, thereby contributing to the enhancement of autoantibody production.
The ETA Receptor Blocker LU 135252 Prevents Chronic Transplant Nephropathy in the “Fisher to Lewis” Model
Authors: STEPHAN R. ORTH, GIULIO ODONI, KERSTIN AMANN, PIOTR STRZELCZYK, MANFRED RASCHACK, EBERHARD RITZ
Journal: Journal of the American Society of Nephrology (1999)

The effect of the orally highly bioavailable and specific endothelin A (ET(A)) receptor antagonist LU 135252 was assessed in a model of chronic renal allograft nephropathy. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Fisher autografts and kidneys after uninephrectomy served as controls. All animals received low-dose cyclosporin A (CsA; 1.5 mg/kg body wt) for 10 d after surgery. Allotransplanted animals were then randomized to receive standard diet or a diet designed to deliver 30 mg of LU 135252/kg body wt per d for 35 wk. BP was monitored telemetrically. Treatment with LU 135252 did not affect systolic or diastolic pressure. Indices of glomerulosclerosis (GSI), and tubulointerstitial and vascular damage were measured. Chronic transplant nephropathy was almost completely prevented by LU 135252 compared with untreated allografts or kidneys of uninephrectomized controls, i.e., GSI 0.7 +/- 0.12 versus 1.6 +/- 0.25 (P < 0.001) versus 0.7 +/- 0.06 (P < 0.001). Allograft weight and serum creatinine were significantly lower in treated versus untreated animals. The results are consistent with the notion that ET(A) receptor-mediated events play a role in the genesis of chronic transplant nephropathy.
Determinants of HIV-1 Mutational Escape From Cytotoxic T Lymphocytes
Authors: Otto O. Yang, Phuong Thi Nguyen Sarkis, Ayub Ali, Jason D. Harlow, Christian Brander, Spyros A. Kalams, Bruce D. Walker
Journal: The Journal of Experimental Medicine (2003)

CD8+ class I–restricted cytotoxic T lymphocytes (CTLs) usually incompletely suppress HIV-1 in vivo, and while analogous partial suppression induces antiretroviral drug-resistance mutations, epitope escape mutations are inconsistently observed. However, escape mutation depends on the net balance of selective pressure and mutational fitness costs, which are poorly understood and difficult to study in vivo. Here we used a controlled in vitro system to evaluate the ability of HIV-1 to escape from CTL clones, finding that virus replicating under selective pressure rapidly can develop phenotypic resistance associated with genotypic changes. Escape varied between clones recognizing the same Gag epitope or different Gag and RT epitopes, indicating the influence of the T cell receptor on pressure and fitness costs. Gag and RT escape mutations were monoclonal intra-epitope substitutions, indicating limitation by fitness constraints in structural proteins. In contrast, escape from Nef-specific CTL was more rapid and consistent, marked by a polyclonal mixture of epitope point mutations and upstream frameshifts. We conclude that incomplete viral suppression by CTL can result in rapid emergence of immune escape, but the likelihood is strongly determined by factors influencing the fitness costs of the particular epitope targeted and the ability of responding CTL to recognize specific epitope variants.
Regulation of <i>Helicobacter pylori cagA</i> Expression in Response to Salt
Authors: John T. Loh, Victor J. Torres, Timothy L. Cover
Journal: Cancer Research (2007)

Abstract Helicobacter pylori infection and a high dietary salt intake are risk factors for the development of gastric adenocarcinoma. In this study, we tested the hypothesis that high salt concentrations might alter gene expression in H. pylori. Transcriptional profiling experiments indicated that the expression of multiple H. pylori genes, including cagA, was regulated in response to the concentrations of sodium chloride present in the bacterial culture medium. Increased expression of cagA in response to high salt conditions was confirmed by the use of transcriptional reporter strains and by immunoblotting. H. pylori CagA is translocated into gastric epithelial cells via a type IV secretion pathway, and on entry into target cells, CagA undergoes tyrosine phosphorylation and causes multiple cellular alterations. Coculture of gastric epithelial cells with H. pylori grown under high salt conditions resulted in increased tyrosine-phosphorylated CagA and increased secretion of interleukin-8 by the epithelial cells compared with coculture of the cells with H. pylori grown under low salt conditions. Up-regulation of H. pylori cagA expression in response to high salt concentrations may be a factor that contributes to the development of gastric adenocarcinoma. [Cancer Res 2007;67(10):4709–15]
Pilot Study of Idarubicin-Based Intensive-Timing Induction Therapy for Children With Previously Untreated Acute Myeloid Leukemia: Children's Cancer Group Study 2941
Authors: Beverly J. Lange, Patricia Dinndorf, Franklin O. Smith, Carola Arndt, Dorothy Barnard, Stephen Feig, James Feusner, Nita Seibel, Margie Weiman, Richard Aplenc, Robert Gerbing, Todd A. Alonzo
Journal: Journal of Clinical Oncology (2003)

Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891.On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891.Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P <.001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P =.007), mean duration of course 1 by a week (P =.002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P =.02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P =.004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891.In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.
Effect of ageing on peak expiratory flow variability and nocturnal exacerbations in bronchial asthma
Authors: V Bellia, G Cuttitta, F Cibella, AM Vignola, G Crescimanno, P D'Accardi, F Catalano, G Bonsignore
Journal: European Respiratory Journal (1997)

The aim of this study was to evaluate the role of ageing on variability of airflow obstruction and on the specific pattern of nocturnal exacerbations ("morning dipping" of peak expiratory flow (PEF)) in asthma. Two groups of stable asthmatics (Group A: 23 patients, aged 14-47 yrs; Group B: 20 patients, aged 53-74 yrs), that were similar for duration of disease, degree of obstruction and response to bronchodilators, were studied. PEF was monitored four times daily for 2 weeks, and amplitude of variation and "morning dip" were calculated. Both PEF amplitude and "morning dip" were greater in the older patients (p<0.005). Amplitude was negatively correlated with baseline forced expiratory volume in one second (FEV1) in both groups (p<0.01); multiple correlation with age, duration of disease, baseline FEV1 and degree of reversibility was significant in the older group only. Morning dip was inversely correlated to baseline FEV1 (p<0.01) and reversibility (p<0.05). Nocturnal symptoms were reported by all of the five Group A "dippers", but by only 6 of the 13 Group B "dippers" (p<0.04). Ageing contributes to increased variability of airway calibre in asthma. Aged patients are potentially at risk because functional evidence of nocturnal asthma may frequently be accompanied by a poor subjective awareness. Therefore, a more extensive practice of PEF monitoring is recommended in aged asthmatics.