tbuckley/cabot-search huggingface dataset:
Breast milk against coeliac disease
Authors: L M Sollid
Journal: Gut (2002)

Should we advise mothers to continue breast feeding while gluten is introduced into their babies’ diets?

Coeliac disease is a multifactorial disorder developing as a result of a complex interplay between genetic and environmental factors.1 HLA and non-HLA genes are involved, and gluten is obviously a critical environmental factor as the disease goes into remission when gluten is eliminated from the diet. The important case control study by Ivarsson et al concludes that feeding with breast milk when gluten is introduced in children under the age of two years protects against coeliac disease. Breast milk can therefore be considered an environmental factor for this disease as well.

Proving causality using epidemiology is demanding.2 There may be both recognised and unrecognised confounding factors associated with breast feeding, which are not properly adjusted for. The authors controlled for one obvious factor—gluten intake. Introducing large amounts of gluten increased the risk of coeliac disease compared with small or medium amounts. Notwithstanding, multivariate analysis demonstrated that breast feeding at the time of gluten introduction in itself reduced the risk of coeliac disease. A plausible mechanism would strengthen the evidence for a causal relationship. What could then be the mechanisms for this protective effect?

The lactating mammary gland and the infant intestine is an immunological dyad.3,4 Human milk contains defence factors such as secretory IgA antibodies, free secretory component, lysozyme, and lactoferrin which …
The pathophysiology of cardiac syndrome X — a tale of paradigm shifts
Authors: S Rosen
Journal: Cardiovascular Research (2001)

See article by Gulli et al. [18] (pages 208–216) in this issue. 

The aetiology of cardiac syndrome X — the problem of the patient with chest pain of anginal quality, ischaemic-like changes on the stress electrocardiogram (ECG) but a normal coronary arteriogram — continues to fascinate many engaged in cardiovascular research. It is a field of endeavour which has gone through a number of ‘paradigm shifts’ during the 28 years since the term was coined by Harvey Kemp [1], commenting on the ‘Group X’ subset of patients in Arbogast and Bourassa’s seminal paper on patients with angina and ‘normal or near normal’ coronary angiograms [2].

The first and most obvious mechanism of chest pain to be indicated was that of true myocardial ischaemia, but since the epicardial vessels were normal by definition, the microcirculation seemed the likely site of impairment of flow (or flow reserve) [3]. In recent years, newer methods of measurement of myocardial blood flow, especially non-invasive techniques that have permitted comparison with true normal controls, have done much to undermine this notion [4]. This is because in the vast majority of syndrome X patients, coronary vasodilator reserve is within the normal range and besides this, no relationships have been demonstrable amongst coronary vasodilator reserve, pain perception and ECG changes [5]. In addition, the preservation of left ventricular function and the absence of unequivocal evidence of lactate release during stress, call into question whether ischaemia as it is usually understood has very much pathophysiological relevance [6–9]. It is should be acknowledged with admiration that in Arbogast and Bourassa’s original paper [2], almost all of these points are made explicitly. (Furthermore, in this author’s opinion, the position has not been altered to any significant extent by more recent explorations of other mediators … 

* Correspondence address: Department of Cardiology, Ealing Hospital, Uxbridge Road, Middlesex UB1 3HW, UK. Tel.: +44-20-8967-5359; fax: +44-20-8967-5007 stuart.rosen{at}ic.ac.uk
DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN
Authors: Fatih Ozaltin, Binghua Li, Alysha Rauhauser, Sung-Wan An, Oguz Soylemezoglu, Ipek Isik Gonul, Ekim Z. Taskiran, Tulin Ibsirlioglu, Emine Korkmaz, Yelda Bilginer, Ali Duzova, Seza Ozen, Rezan Topaloglu, Nesrin Besbas, Shazia Ashraf, Yong Du, Chaoying Liang, Phylip Chen, Dongmei Lu, Komal Vadnagara, Susan Arbuckle, Deborah Lewis, Benjamin Wakeland, Richard J. Quigg, Richard F. Ransom, Edward K. Wakeland, Matthew K. Topham, Nicolas G. Bazan, Chandra Mohan, Friedhelm Hildebrandt, Aysin Bakkaloglu, Chou-Long Huang, Massimo Attanasio
Journal: Journal of the American Society of Nephrology (2012)

Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy. Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN. This gene encodes the diacylglycerol kinase DGKε, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgkε colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGKε variants affect the intracellular concentration of diacylglycerol. Taken together, these results not only identify a genetic cause of a glomerular microangiopathy but also suggest that the phosphatidylinositol cycle, which requires DGKE, is critical to the normal function of podocytes.
Differential Effects of Endothelin-1 Antagonists on Erythropoietin-Induced Hypertension in Renal Failure
Authors: EDITH BROCHU, SONIA LACASSE-M, RICHARD LARIVIÈRE, IRIS KINGMA, JOHN H. GROSE, MARCEL LEBEL
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Recently, it was reported that blood vessel immuno-reactive endothelin-1 (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1 receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ET A and nonselective ET A /ET B receptor antagonists are equally effective. Renal failure was induced by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and hypertension. After a 4-wk stabilization period, the animals received either rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4 wk. In protocol A, half of the rats in each group were simultaneously treated with the ET A /ET B receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ET A receptor antagonist LU135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk after the onset of treatment. Serum creatinine levels and hematocrit were measured before treatment and at the end of the study. Creatinine clearance rates and plasma irET-1 concentrations were determined at the end of the study. rhEPO corrected the anemia, but aggravated the hypertension. There was a slight and similar increase in serum creatinine throughout the treatment period in all groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle ( P &lt; 0.05). Treatment with LU135252 corrected the increase in BP in rhEPO-treated rats (160 ± 7 mmHg versus 187 ± 9 mmHg, P &lt; 0.05). In contrast, bosentan did not attenuate the progression of hypertension in rhEPO-treated rats (172 ± 10 mmHg versus 168 ± 9 mmHg, NS). In summary, selective ET A but not ET A /ET B receptor blockade can prevent the aggravation of hypertension in renal failure rats treated with rhEPO. These results suggest that the endothelin system may be involved in the pathogenesis of rhEPO-induced hypertension in uremic rats with a differential role for ET A and ET B receptors.
Antiphospholipid antibody syndrome: the problems and the promise
Authors: W.W. Piette
Journal: British Journal of Dermatology (2000)

In this month’s journal, Creamer et al. report two cases of widespread cutaneous necrosis associated with the antiphospholipid syndrome and provide a brief review of possible pathophysiologic mechanisms and of previously reported cases.1 Skin findings are frequent in patients with antiphospholipid syndrome, but catastrophic complications are not limited to the skin.2 Despite the recognition of antiphospholipid antibody syndrome, and glimpses into possible disease mechanisms, there are major, clinically relevant, problems in identification of patients at risk and of patient‐specific disease mechanisms, and in the often limited effect of therapy on treating and preventing thrombosis. As with any antibody associated disease, such as pemphigus or the ANCA‐positive vasculitides, antiphospholipid antibodies (aPL) are often present in varying titres over a period of months or years without active disease. What triggers episodes of thrombosis, such as those seen in widespread cutaneous necrosis? Inflammatory states, especially those associated with infection or with major surgery, are one such trigger, shifting the balance between haemorrhage and thrombosis toward thrombosis. Both patients reported in this issue did have infections preceding their disease, which may have contributed to their episodes, but how many viral or bacterial syndromes must have occurred previously without inducing thrombosis? There is as yet no good way to predict when patients at risk may begin clotting, nor to recognize any event as a likely trigger for such thrombosis.
Collagen I Promotes Metastasis in Pancreatic Cancer by Activating c-Jun NH2-Terminal Kinase 1 and Up-regulating N-Cadherin Expression
Authors: Yasushi Shintani, Michael A. Hollingsworth, Margaret J. Wheelock, Keith R. Johnson
Journal: Cancer Research (2006)

Abstract We have previously shown that N-cadherin expression is associated with tumor invasion, and that some cancer cells respond to specific extracellular matrix molecules by up-regulating N-cadherin. Pancreatic cancer is characterized by excessive deposition of type I collagen. Here, we show that human pancreatic cancer cells respond to collagen I, but not other matrices, by increasing motility and up-regulating mesenchymal markers, including N-cadherin. Both collagen I–mediated motility and metastasis in a mouse model for pancreatic cancer were inhibited by N-cadherin knockdown. Furthermore, inhibiting c-Jun NH2-terminal kinase (JNK) with chemical inhibitors or short hairpin RNA abrogated all collagen I–induced changes. We show that JNK1 is activated in response to collagen I, which increases tumorigenesis by up-regulating N-cadherin expression and by increasing motility. (Cancer Res 2006; 66(24): 11745-53)
Surgical resection rate in lung cancer
Authors: C K CONNOLLY, I JOHNSTON, R MILROY, R JONES, C M LAROCHE
Journal: Thorax (1999)

The case history is described of a young woman who presented with primary pulmonary hypertension and non-specific inflammatory signs.The patient received prolonged immunosuppressive treatment with low dose methotrexate and prednisone without any vasodilator agent.After one year the pulmonary artery pressure fell from a mean value of 47 mm Hg to 30 mm Hg and there was a corresponding clinical response.This case suggests that, in patients with pulmonary hypertension of unknown origin, immunopathogenetic factors should be sought in order to consider the utility of immunosuppressive therapy.
Glomerular Size and Charge Selectivity in the Mouse after Exposure to Glucosaminoglycan-Degrading Enzymes
Authors: Marie Jeansson, Bo[Combining Diaeresis]rje Haraldsson
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. This is the first functional study of glomerular size and charge selectivity in mice. The aim was to investigate the controversial issue of glomerular permselectivity in animals exposed to glucosaminoglycan-degrading enzymes, hyaluronidase, and heparinase. Fractional clearances (θ) for FITC-Ficoll and albumin were estimated in isoflurane anesthetized mice in vivo and in cooled isolated perfused kidneys (cIPK). In cIPK, a significant increase of θalbumin from 0.0023 (95% confidence interval, 0.0014 to 0.0033) in controls to 0.0130 (95% confidence interval, 0.0055 to 0.0206) was seen after hyaluronidase treatment. The θ for neutral Ficoll of similar size as albumin was 0.063 to 0.093 in all groups. According to a heterogeneous charged fiber model, the fiber volume fraction of negatively charged fibers decreased by 10% after enzyme treatments. It is concluded that glomerular size and charge selectivity in mice is similar to that previously shown for rats. Moreover, hyaluronic acid, chondroitin sulfate, and heparan sulfate are of importance for charge selectivity. E-mail: [email protected]
Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis
Authors: A C Ford, N J Talley, P S Schoenfeld, E M M Quigley, P Moayyedi
Journal: Gut (2008)

<h3>Objective:</h3> Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence for treatment of the condition with antidepressants and psychological therapies is conflicting. <h3>Design:</h3> Systematic review and meta-analysis of randomised controlled trials (RCTs). MEDLINE, EMBASE and the Cochrane Controlled Trials Register were searched (up to May 2008). <h3>Setting:</h3> RCTs based in primary, secondary and tertiary care. <h3>Patients:</h3> Adults with IBS. <h3>Interventions:</h3> Antidepressants versus placebo, and psychological therapies versus control therapy or "usual management". <h3>Main outcome measures:</h3> Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. <h3>Results:</h3> The search strategy identified 571 citations. Thirty-two RCTs were eligible for inclusion: 19 compared psychological therapies with control therapy or "usual management", 12 compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Study quality was generally good for antidepressant but poor for psychological therapy trials. The RR of IBS symptoms persisting with antidepressants versus placebo was 0.66 (95% CI, 0.57 to 0.78), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms persisting with psychological therapies was 0.67 (95% CI, 0.57 to 0.79). The NNT was 4 for both interventions. <h3>Conclusions:</h3> Antidepressants are effective in the treatment of IBS. There is less high-quality evidence for routine use of psychological therapies in IBS, but available data suggest these may be of comparable efficacy.
A molecular portrait of breast cancer metastasis to the brain
Authors: Patricia S. Steeg, Julie Bronder, Robert Weil, Sean Davis, Maria J. Merino, Andreas Stark, H. Maximilian Mehdorn, Paul S. Meltzer, Diane Palmieri
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

SY34-3 

Approximately 15% of breast cancer patients develop brain metastases; mean survival is less than one year. The incidence of brain metastases is expected to rise as systemic control improves and tumor cells colonize the brain as a sanctuary site. The brain microenvironment and the blood:brain barrier are hypothesized to provide distinct selection pressures for metastatic growth. To analyze the gene expression of breast cancer brain metastases, we have examined 16 surgically resected brain metastases of breast cancer and compared them to a cohort of unrelated primary breast carcinomas, matched for histology, hormone receptor status, and TNM stage. RNA isolated from laser captured microdissected tumor cells was amplified using a T7-based amplification protocol prior to cDNA microarray analysis on a 30K microarray. A panel of genes were identified which exhibit differential expression patterns between primary tumors and brain metastases, verified by RT-PCR. Therpeutic strategies based on gene expression profiles will be discussed.
Obstructive sleep apnoea in a puerperal patient with Hallermann‐Streiff syndrome
Authors: T. Shiomi, C. Guilleminault, H Izumi, S Yamada, K Murata, T Kobayashi
Journal: European Respiratory Journal (1999)

A 26 yr old puerperal female with Hallermann-Streiff syndrome developed serious obstructive sleep apnoea syndrome during pregnancy. She underwent an elective Caesarean section delivery, but ending the pregnancy did not improve her clinical symptoms. By treating her with nasal continuous positive airway pressure, a worsening of her headaches and glaucoma was prevented. The administration of acetazolamide controlled all of her symptoms. Treatment with nasal ventilation is the best initial approach. It is also important to assure normal oxygenation before pregnancy since the foetus may suffer from the severe deprivation that may occur in these patients.
Pulmonary hypertension and pulmonary arterial hypertension: a clarification is needed
Authors: N. Galiè, M. Palazzini, A. Manes
Journal: European Respiratory Journal (2010)

The growing interest in pulmonary hypertension (PH) in many medical specialties including cardiology, rheumatology and respiratory medicine, is possibly due to the recent availability of specific drugs approved for a group of rare conditions defined as pulmonary arterial hypertension (PAH). The terms “pulmonary hypertension” and “pulmonary arterial hypertension” appear to be quite similar, and this has led to confusion and ambiguity in both common clinical practice and the medical literature 1. It is, therefore, important to clarify the different definitions of PH, the relationship between the haemodynamic measurement and the echocardiographic estimate, and the additional diagnostic methods required for the final clinical diagnosis. In addition, it is relevant to highlight the significant role of right heart catheterisation in the diagnostic algorithm of a patient with PH.

PH cannot be considered to be a specific “disease”. PH has been defined as an increase in mean pulmonary arterial pressure ( P pa) ≥25 mmHg at rest, as assessed by right heart catheterisation 2–5. Recent re-evaluation of the available data has shown that the normal P pa±sd at rest is 14±3 mmHg with an upper limit of normal of ∼20 mmHg 6, 7. The significance of P pa 21–24 mmHg is unclear. Patients presenting with P pa in this range need further evaluation in epidemiological studies. The definition of PH on exercise as a P pa >30 mmHg, as assessed by right heart catheterisation, is not supported by published data and healthy individuals can reach much higher values 6, 8. Therefore, no definition for PH on exercise as assessed by right heart catheterisation can be provided at the present time. An additional, very important haemodynamic parameter that characterises the definitions of PH is pulmonary capillary wedge pressure ( P pcw). In fact, according to various …
Elevated Blood Pressure in Pregnancy and Subsequent Chronic Disease Risk
Authors: Tuija Männistö, Pauline Mendola, Marja Vääräsmäki, Marjo-Riitta Järvelin, Anna-Liisa Hartikainen, Anneli Pouta, Eila Suvanto
Journal: Circulation (2013)

Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension.The Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [95% CI, 1.24-1.68]), myocardial infarcts (HR, 1.75 [95% CI, 1.40-2.19]), myocardial infarct death (HR, 3.00 [95% CI, 1.98-4.55]), heart failure (HR, 1.78 [95% CI, 1.43-2.21]), ischemic stroke (HR, 1.59 [95% CI, 1.24-2.04]), kidney disease (HR, 1.91 [95% CI, 1.18-3.09]), and diabetes mellitus (HR, 1.52 [95% CI, 1.21-1.89]). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 [95% CI, 1.35-3.41]), heart failure (HR, 1.43 [95% CI, 1.13-1.82]), and diabetes mellitus (HR, 1.42 [95% CI, 1.13-1.78]), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 [95% CI, 1.05-1.50]). Results were similar in nonsmoking women aged <35 years with normal weight and no diabetes mellitus during pregnancy.Elevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy.
Genes of tolerance
Authors: C. A. Akdis, K. Blaser, M. Akdis
Journal: Allergy (2004)

Activation‐induced cell death, anergy and/or immune response modulation by T‐regulatory cells (T Reg ) are essential mechanisms of peripheral T‐cell tolerance. There is growing evidence that anergy, tolerance and active suppression are not entirely distinct, but rather, represent linked mechanisms possibly involving the same cells and multiple suppressor mechanisms. Skewing of allergen‐specific effector T cells to T Reg cells appears as a crucial event in the control of healthy immune response to allergens and successful allergen‐specific immunotherapy. The T Reg cell response is characterized by abolished allergen‐induced specific T‐cell proliferation and suppressed T helper 1 (Th1)‐ and Th2‐type cytokine secretion. In addition, mediators of allergic inflammation that trigger cAMP‐associated G‐protein coupled receptors, such as histamine receptor 2 may contribute to peripheral tolerance mechanisms. The increased levels of interleukin‐10 (IL‐10) and transforming growth factor‐ β (TGF‐ β ) that are produced by T Reg cells potently suppress immunoglobulin E (IgE) production, while simultaneously increasing production of noninflammatory isotypes IgG4 and IgA, respectively. In addition, T Reg cells directly or indirectly suppress effector cells of allergic inflammation such as mast cells, basophils and eosinophils. In conclusion, peripheral tolerance to allergens is controlled by multiple active suppression mechanisms. It is associated with regulation of antibody isotypes and effector cells to the direction of a healthy immune response and opens a window for novel therapies of allergic diseases.
Reduced Collagen Deposition in Infarcted Myocardium Facilitates Induced Pluripotent Stem Cell Engraftment and Angiomyogenesis for Improvement of Left Ventricular Function
Authors: Bo Dai, Wei Huang, Meifeng Xu, Ronald W. Millard, Mei Hua Gao, H. Kirk Hammond, Donald R. Menick, Muhammad Ashraf, Yigang Wang
Journal: Journal of the American College of Cardiology (2011)
Posterior compartment syndrome following ruptured Baker's cyst.
Authors: D P Petros, J F Hanley, P Gilbreath, R D Toon
Journal: Annals of the Rheumatic Diseases (1990)

A 35 year old man presented with the sudden onset of left leg pain and swelling. Empirical anticoagulation for presumed deep vein thrombophlebitis was followed by acute worsening of symptoms. On further evaluation the patient was found to have a ruptured Baker9s cyst and an acute posterior compartment syndrome.