tbuckley/cabot-search huggingface dataset:
Resistance to Remnant Nephropathy in the Wistar-Furth Rat
Authors: WAYNE R. FITZGIBBON, EDDIE L. GREENE, JASJIT S. GREWAL, FLORENCE N. HUTCHISON, SALLY E. SELF, SAJATA Y. LATTEN, MICHAEL E. ULLIAN
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The Wistar-Furth rat, an inbred strain resistant to actions of mineralocorticoids, was used to study the concept that mineralocorticoids contribute to progressive renal injury. It was postulated that if chronic nephropathy depends on aldosterone and if Wistar-Furth rats are resistant to aldosterone, remnant nephropathy would be attenuated in Wistar-Furth rats. Wistar-Furth rats and control Wistar rats were subjected to 5/6 nephrectomy or a sham procedure and then followed for 4 wk. Renal ablation resulted in hypertension at 4 wk in both strains (164 ± 5 [Wistar-Furth] versus 184 ± 7 [Wistar] mmHg mean arterial pressure), with sham animals remaining normotensive (134 ± 6 mmHg). Renal damage in response to 5/6 nephrectomy was greatly decreased in Wistar-Furth rats compared with Wistar rats. Albuminuria was markedly less in Wistar-Furth rats (12.7 ± 4.2 [Wistar-Furth] versus 97.4 ± 22.6 [Wistar] mg/d per 100 g body wt, P &lt; 0.01). Glomerular damage, consisting of mesangial proliferation, mesangial lysis, and segmental necrosis, was observed in 42% of glomeruli from Wistar rats but in 0% of glomeruli from Wistar-Furth rats ( P &lt; 0.01). To address the possibility that higher BP in partially nephrectomized Wistar rats mediated the greater renal damage, the study was repeated, with Wistar rats (not Wistar-Furth rats) being treated with a hydralazine-reserpine-hydrochlorothiazide regimen. Although this antihypertensive regimen equalized BP (conscious systolic) (144 ± 8 mmHg [Wistar] versus 157 ± 7 mmHg [Wistar-Furth] at 4 wk), albuminuria remained more than 10-fold greater in Wistar rats. In summary, renal damage upon 5/6 nephrectomy was markedly reduced in Wistar-Furth rats, a finding not attributable to reduced systemic BP. Since Wistar-Furth rats have been shown previously to be resistant to the actions of mineralocorticoids, the data from the present study support the hypothesis that aldosterone mediates, at least in part, the renal injury attendant to renal mass reduction.
Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis
Authors: Lan Shao, Hiroshi Fujii, Inés Colmegna, Hisashi Oishi, Jörg J. Goronzy, Cornelia M. Weyand
Journal: The Journal of Experimental Medicine (2009)

In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA+ T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.
A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis
Authors: Kenneth J. Katschke, Karim Y. Helmy, Micah Steffek, Hongkang Xi, JianPing Yin, Wyne P. Lee, Peter Gribling, Kai H. Barck, Richard A.D. Carano, Robin E. Taylor, Linda Rangell, Lauri Diehl, Philip E. Hass, Christian Wiesmann, Menno van Lookeren Campagne
Journal: The Journal of Experimental Medicine (2007)

Complement is an important component of the innate and adaptive immune response, yet complement split products generated through activation of each of the three complement pathways (classical, alternative, and lectin) can cause inflammation and tissue destruction. Previous studies have shown that complement activation through the alternative, but not classical, pathway is required to initiate antibody-induced arthritis in mice, but it is unclear if the alternative pathway (AP) plays a role in established disease. Previously, we have shown that human complement receptor of the immunoglobulin superfamily (CRIg) is a selective inhibitor of the AP of complement. Here, we present the crystal structure of murine CRIg and, using mutants, provide evidence that the structural requirements for inhibition of the AP are conserved in human and mouse. A soluble form of CRIg reversed inflammation and bone loss in two experimental models of arthritis by inhibiting the AP of complement in the joint. Our data indicate that the AP of complement is not only required for disease induction, but also disease progression. The extracellular domain of CRIg thus provides a novel tool to study the effects of inhibiting the AP of complement in established disease and constitutes a promising therapeutic with selectivity for a single complement pathway.
Effects of varicocele on male fertility
Authors: J. P. Jarow
Journal: Human Reproduction Update (2001)

Varicoceles are vascular lesions of the pampiniform plexus and are the most common identifiable abnormality found in men being evaluated for infertility. Despite the long history associated with varicoceles, there remains much controversy regarding their diagnosis and management. The purpose of this manuscript is to address three of the most pressing controversies: (i) the association of varicoceles with male infertility, (ii) whether varicoceles exert a progressive deleterious effect and (iii) the relationship of varicocele size and outcome following varicocele repair. The current literature is reviewed in an effort to answer these questions. Based upon this analysis, conclusions can be drawn regarding the best management of varicoceles in subfertile men, adolescents, young fertile men and men with subclinical varicoceles. Although there remain many controversies due to a paucity of data, there appears to be a significant difference between adults and adolescents with respect to a progressive deterioration of semen parameters and it is clear that subclinical varicoceles do not play a major role in male infertility.
Maternal Exposure to Toxoplasmosis and Risk of Schizophrenia in Adult Offspring
Authors: Alan S. Brown, Catherine A. Schaefer, Charles P. Quesenberry, Liyan Liu, Vicki P. Babulas, Ezra S. Susser
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The authors examined the relationship between maternal antibody to toxoplasmosis and the risk of schizophrenia and other schizophrenia spectrum disorders in offspring. Toxoplasmosis is known to adversely affect fetal brain development. METHOD: In a nested case-control design of a large birth cohort born between 1959 and 1967, the authors conducted serological assays for Toxoplasma antibody on maternal serum specimens from pregnancies giving rise to 63 cases of schizophrenia and other schizophrenia spectrum disorders and 123 matched comparison subjects. Toxoplasma immunoglobulin (Ig)G antibody was quantified by using the Sabin-Feldman dye test. The Ig titers were classified into three groups: negative (<1:16) (reference), moderate (1:16–1:64), and high (≥1:128). RESULTS: The adjusted odds ratio of schizophrenia/schizophrenia spectrum disorders for subjects with high maternal Toxoplasma IgG antibody titers was 2.61 (95% confidence interval=1.00–6.82). There was no association between moderate Toxoplasma Ig antibody titers and the risk of schizophrenia/spectrum disorders. CONCLUSIONS: These findings suggest that maternal exposure to toxoplasmosis may be a risk factor for schizophrenia. The findings may be explained by reactivated infection or an effect of the antibody on the developing fetus. Given that toxoplasmosis is a preventable infection, the findings, if replicated, may have implications for reducing the incidence of schizophrenia.
Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1. Implications for regulation of matrix degradation in liver.
Authors: J P Iredale, G Murphy, R M Hembry, S L Friedman, M J Arthur
Journal: Journal of Clinical Investigation (1992)

Hepatic lipocytes play a central role in the pathogenesis of liver fibrosis, both via production of extracellular matrix proteins and through secretion of matrix metalloproteinases. In this study, we have characterized lipocyte expression and release of tissue inhibitor of metalloproteinases-1 (TIMP-1), an important inhibitor of metalloproteinase activity, whose role in liver has not previously been examined. TIMP-1 was immunolocalized to human lipocytes, and secretion of TIMP-1 was confirmed by ELISA of culture media; (mean +/- SD) 159 +/- 79 ng of TIMP-1/10(6) cells per 24 h. Evidence for functional inhibitory activity of released TIMP-1 was obtained by (a) reverse zymography that demonstrated a single inhibitor band, M(r) 28 kD, that co-migrated with a TIMP-1-positive control sample; and (b) unmasking of inhibited gelatinase activity in lipocyte medium by separating it from TIMP-1 using gelatin sepharose chromatography; gelatinase activity in chromatographed medium increased more than 20-fold, compared with unfractionated medium, and could be reinhibited by adding back fractions that contained inhibitor. By Northern analysis, freshly isolated human lipocytes exhibited low levels of mRNA expression for TIMP-1, but this increased markedly relative to beta-actin expression with lipocyte activation during cell culture. We conclude that human hepatic lipocytes synthesize TIMP-1, a potent metalloproteinase inhibitor, and that TIMP-1 expression increases with lipocyte activation. These data indicate that hepatic lipocytes can regulate matrix degradation in the liver, and suggest that expression of TIMP-1 by activated lipocytes may contribute to the progression of liver fibrosis.
Anti-C1q autoantibodies amplify pathogenic complement activation in systemic lupus erythematosus
Authors: V. Michael Holers
Journal: Journal of Clinical Investigation (2004)

Patients with systemic lupus erythematosus (SLE) often develop glomerulonephritis (i.e., inflammation in the glomeruli of the kidney), commonly referred to as lupus nephritis. Patients with lupus nephritis typically have autoantibodies to the complement classical pathway protein C1q. Whether these anti-C1q antibodies play any role in the development of lupus nephritis has been unclear. In this issue of the JCI, a new study demonstrates that anti-C1q antibodies can amplify glomerular injury but only when they are bound within the glomerulus to C1q that has been already brought to that site by other types of glomerular-reactive autoantibodies . These studies are the first, to our knowledge, to provide a causal link between anti-C1q antibodies and target organ damage in SLE.
Circulating natural killer cells in psoriasis
Authors: A.L. Cameron, B. Kirby, C.E.M. Griffiths
Journal: British Journal of Dermatology (2003)

Summary Background Psoriasis is an immunologically mediated, probably autoimmune, disease in which T‐helper type 1 cytokines play an important role. Established autoimmune diseases, with similar mechanistic characteristics to psoriasis, include multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus and systemic lupus erythematosus. Natural killer (NK) and natural killer‐T (NK‐T) cells are considered key to the pathogenesis of these conditions, which are characterized by reduced numbers of NK cells in peripheral blood. NK and NK‐T cells have been implicated in the pathogenesis of psoriasis and are present in plaques of psoriasis. Objectives To investigate whether levels of NK and NK‐T cells are reduced in the peripheral blood of patients with psoriasis. Methods Fourteen patients with untreated psoriasis, mean ± SD age 46 ± 13 years, and 13 healthy volunteers, mean ± SD age 34 ± 9 years, were venesected and peripheral blood mononuclear cells isolated, labelled with a panel of antibodies to T‐cells and NK cells including CD3, CD56, CD57, CD16, CD94, CD158a, CD69 and cutaneous lymphocyte‐associated antigen (CLA) and analysed using triple‐colour flow cytometry. Results There were significantly fewer cells expressing the NK‐cell markers CD16 (P < 0·001), CD56 (P < 0·003), CD94 (P < 0·001) and CD158a (P < 0·02) in patients with psoriasis compared with normal controls. However, circulating numbers of NK‐T cells (CD3+ CD56+ CD57+), T‐cells (CD3+), activated lymphocytes (CD69+) or CLA+ cells were not significantly different between patients with psoriasis and controls. Conclusions Circulating NK cells are reduced in psoriasis. This finding is similar to those in established autoimmune diseases such as rheumatoid arthritis. This observation provides some evidence that psoriasis may be an autoimmune disease in which NK cells play a role.
The April Plebiscite
Authors: J. M. Rattray
Journal: BMJ (1948)

<h3>ABSTRACT</h3> <h3>Objectives</h3> To explore the impact of COVID-19 on companionship for women using maternity services in England, as part of the Achieving Safe and Personalised maternity care In Response to Epidemics (ASPIRE COVID-19 UK) study. <h3>Setting</h3> Maternity care provision in England. <h3>Participants</h3> Interviews were held with 26 national governmental, professional, and service-user organisation leads including representatives from the Royal College of Midwives, NHS England, Birthrights and AIMS (July-Dec). Other data included public-facing outputs logged from 25 maternity Trusts (Sept/Oct) and data extracted from 78 documents from 8 key governmental, professional and service-user organisations that informed national maternity care guidance and policy (Feb-Dec). <h3>Results</h3> Six themes emerged: ‘<i>Postcode lottery of care</i>’ highlights variations in companionship practices, ‘<i>Confusion and stress around ‘rules’’</i> relates to a lack of and variable information concerning companionship, ‘<i>Unintended consequences’</i> concerns the negative impacts of restricted companionship on service-users and staff, ‘<i>Need for flexibility’</i> highlights concerns about applying companionship policies irrespective of need, ‘‘<i>Acceptable’ time for support’</i> highlights variations in when and if companionship was ‘allowed’ antenatally and intrapartum; and ‘<i>Loss of human rights for gain in infection control’</i> emphasizes how a predominant focus on infection control was at a cost to psychological safety and women’s human rights. <h3>Conclusions</h3> Policies concerning companionship have been inconsistently applied within English maternity services during the COVID-19 pandemic. In some cases, policies were not justified by the level of risk, and were applied indiscriminately regardless of need. This was associated with psychological harms for some women and staff. There is an urgent need to determine how to balance risks and benefits sensitively and flexibly and to optimise outcomes during the current and future crisis situations. <h3>Strengths and limitations of this study</h3> This is the first paper to consider links between policy and practice in companionship in maternity care during the COVID-19 pandemic; Data triangulation across stakeholders, policy and practice provides nuanced and context related perspectives on why and how companionship was impacted; Stakeholders included representatives from all key agencies involved in maternity care; Practice related issues were collected from the maternity Trust website and social media-based public facing information, which may or may not reflect actual care practices; The study does not include information directly reported by parents and healthcare professionals.
High-Intensity Training Improves Plasma Glucose and Acid-Base Regulation During Intermittent Maximal Exercise in Type 1 Diabetes
Authors: Alison R. Harmer, Donald J. Chisholm, Michael J. McKenna, Norman R. Morris, Jeanette M. Thom, Greg Bennett, Jeff R. Flack
Journal: Diabetes Care (2007)

In individuals without diabetes, high-intensity exercise (HIE) training may reduce (1) the characteristic postexercise rise in plasma glucose with HIE (2–4) and reduces (5,6) the marked acid-base balance perturbations (5–8). In type 1 diabetes, continuous HIE induces sustained hyperglycemia (9,10), while very brief intermittent HIE may reduce hyperglycemia (11). Acid-base disturbances during exercise may be heightened in type 1 diabetes (12–14). Effects of HIE training on glycemia and acid-base balance during intermittent HIE in type 1 diabetes are unknown; thus, despite the potential clinical importance of such exercise, there is no evidence on which to base patient guidelines. The aim of the present study was thus to investigate the effects of HIE training on glycemia and acid-base regulation during intermittent HIE in type 1 diabetes.

Eight subjects with type 1 diabetes (duration of diabetes 7.1 ± 4.0 years) and seven subjects without diabetes (control group), all of whom were healthy and took no medications (other than insulin in type 1 diabetic subjects), consented to participate. The study was approved by the human ethics committees of The University of Sydney and the South Sydney West Area Health Service. Control subjects closely matched those with diabetes for age (type 1 diabetes 25 ± 4 years and control 25 ± 4 years), BMI (25.4 ± 3.2 and 23.8 ± 5.0 kg/m2, respectively), and V o2peak (42.7 ± 12.2 and 43.7 ± 6.2 ml · kg−1 · min−1), as detailed in a related study that reported effects of sprint training on muscle sodium-potassium ATPase and on plasma potassium during maximal exercise (15).

Testing was conducted after overnight fasting. Type 1 diabetic subjects delayed their morning insulin. Subjects completed four 30-s maximal exercise bouts (EB1–4) (each separated by …
Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation
Authors: A J Piper, D Wang, B J Yee, D J Barnes, R R Grunstein
Journal: Thorax (2008)

<h3>Background:</h3> Untreated, obesity hypoventilation is associated with significant use of health care resources and high mortality. It remains unclear whether continuous positive airway pressure (CPAP) or bilevel ventilatory support (BVS) should be used as initial management. The aim of this study was to determine if one form of positive pressure is superior to the other in improving daytime respiratory failure. <h3>Methods:</h3> A prospective randomised study was performed in patients with obesity hypoventilation referred with respiratory failure. After exclusion of patients with persisting severe nocturnal hypoxaemia (Spo<sub>2</sub> &lt;80% for &gt;10 min) or carbon dioxide retention (&gt;10 mm Hg) despite optimal CPAP, the remaining patients were randomly assigned to receive either CPAP or BVS over a 3-month period. The primary outcome was change in daytime carbon dioxide level. Secondary outcome measures included daytime sleepiness, quality of life, compliance with treatment and psychomotor vigilance testing. <h3>Results:</h3> Thirty-six patients were randomised to either home CPAP (n = 18) or BVS (n = 18). The two groups did not differ significantly at baseline with regard to physiological or clinical characteristics. Following 3 months of treatment, daytime carbon dioxide levels decreased in both groups (CPAP 6 (8) mm Hg; BVS 7 (7) mm Hg) with no between-group differences. There was no difference in compliance between the two treatment groups (5.8 (2.4) h/night CPAP vs 6.1 (2.1) h/night BVS). Although both groups reported an improvement in daytime sleepiness, subjective sleep quality and psychomotor vigilance performance were better with BVS. <h3>Conclusions:</h3> Both CPAP and BVS appear to be equally effective in improving daytime hypercapnia in a subgroup of patients with obesity hypoventilation syndrome without severe nocturnal hypoxaemia. <h3>Trial registration number:</h3> Australian Clinical Trials Registry ACTRN01205000096651.
Geoffrey Charles Downing Dutton
Authors: A. Dutton
Journal: BMJ (2014)

Geoffrey Charles Downing Dutton was born to Frederick and “Daisy” in Northwich, Cheshire. He attended Shrewsbury School and went on to study medicine at Gonville and Caius College, Cambridge, and the London Hospital, where he qualified in 1944. Because of the blitz he was evacuated to Warley Woods Hospital in Brentwood, Essex, to complete his preregistration year. It was here that he met a young nurse, Marjorie, whom he was to marry in December 1945, the start of a lifelong mutual devotion. After full registration he …
Oral misoprostol for induction of labour at term: randomised controlled trial
Authors: Jodie M Dodd, Caroline A Crowther, Jeffrey S Robinson
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To compare oral misoprostol solution with vaginal prostaglandin gel (dinoprostone) for induction of labour at term to determine whether misoprostol is superior. <b>Design</b> Randomised double blind placebo controlled trial. <b>Setting</b> Maternity departments in three hospitals in Australia. <b>Population</b> Pregnant women with a singleton cephalic presentation at ≥ 36+6 weeks9 gestation, with an indication for prostaglandin induction of labour. <b>Interventions</b> 20 μg oral misoprostol solution at ourly intervals and placebo vaginal gel or vaginal dinoprostone gel at six hourly intervals and placebo oral solution. <b>Main outcome measures</b> Vaginal birth within 24 hours; uterine hyperstimulation with associated changes in fetal heart rate; caesarean section (all); and caesarean section for fetal distress. <b>Results</b> 741 women were randomised, 365 to the misoprostol group and 376 to the vaginal dinoprostone group. There were no significant differences between the two treatment groups in the primary outcomes: vaginal birth not achieved in 24 hours (misoprostol 168/365 (46.0%) <i>v</i> dinoprostone 155/376 (41.2%); relative risk 1.12, 95% confidence interval 0.95 to 1.32; P = 0.134), caesarean section (83/365 (22.7%) <i>v</i> 100/376 (26.6%); 0.82, 0.64 to 1.06; P = 0.127), caesarean section for fetal distress (32/365 (8.8%) <i>v</i> 35/376 (9.3%); 0.91, 0.57 to 1.44; P = 0.679), or uterine hyperstimulation with changes in fetal heart rate (3/365 (0.8%) <i>v</i> 6/376 (1.6%); 0.55, 0.14 to 2.21; P = 0.401). Although there were differences in the process of labour induction, there were no significant differences in adverse maternal or neonatal outcomes. <b>Conclusions</b> This trial shows no evidence that oral misoprostol is superior to vaginal dinoprostone for induction of labour. However, it does not lead to poorer health outcomes for women or their infants, and oral treatment is preferred by women. <b>Trial registration</b> National Health and Medical Research Council, Perinatal Trials, PT0361.