tbuckley/cabot-search huggingface dataset:
Novel Paracellin-1 Mutations in 25 Families with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis
Authors: STEFANIE WEBER, LINDA SCHNEIDER, MELANIE PETERS, JOACHIM MISSELWITZ, GABRIELE RÖNNEFARTH, MICHAEL BÖSWALD, KLAUS E. BONZEL, TOMAS SEEMAN, TEREZA SULÁKOVÁ, EBERHARD KUWERTZ-BRÖKING, ALOJZ GREGORIC, JEAN-BERNARD PALCOUX, VELIBOR TASIC, FRIEDRICH MANZ, KARL SCHÄRER, HANNSJÖRG W. SEYBERTH, MARTIN KONRAD
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m2 for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.
The Treatment of Tetanus by the Intracerebral Injection of Antitoxin: With Notes of a Fatal Case Treated by this Method
Authors: C. F. Cuthbert
Journal: BMJ (1899)

of infection could be traced, nor between this case and the next, which occurred four weeks later.This.however, is the history of the disease everywhere.The general health of the gaol is very good; with i,8oo prisoners the death-rate per mille is only i i, a figure almost as good as any English prison and less than half the provincial (Bengal) death-rate for men from 15 to 45 years.The case is interesting on account of three features not hitherto reported in any case in India (i) lumbar puncture;(2) the finding and culture of the diplococcus intracellularis of Weischelbaum and the demonstration of Kernig's symptoms; the latter a valuable aid in diagnosis which has not yeb found its way into the textbooks.
GPs' enthusiasm for commissioning is "evaporating," claim peers
Authors: A. O'Dowd
Journal: BMJ (2011)

The enthusiasm of family doctors for taking a leading role in commissioning health services under the proposed NHS reforms is evaporating, claim peers.

In addition, the government’s listening exercise earlier this year to reconsider its proposed reforms has only helped to confuse the public over who is really in charge of and accountable for commissioning NHS services in the future, the peers heard during a debate in the House of Lords on 15 September.

The debate concerned the recommendations of the NHS Future Forum, the panel of experts appointed by the government to lead the listening exercise, which reported back in June on how the Health and Social Care Bill should be revised ( BMJ 2011;342:d3777, doi:10.1136/bmj.d3777). …
Predominant variable region gene usage by gamma/delta T cell receptor-bearing cells in the adult thymus.
Authors: A J Korman, S Marusic-Galesic, D Spencer, A M Kruisbeek, D H Raulet
Journal: The Journal of Experimental Medicine (1988)

Previous studies have indicated that the diversity of gamma genes expressed by gamma/delta-bearing murine T cells is limited, but comparable information concerning the expressed diversity of delta genes is lacking. In this study, we have investigated the rearrangement and expression of delta and gamma genes in T cell hybridomas that express gamma/delta T cell receptors. Three productive delta chain cDNA clones were isolated (delta 7.3, delta 7.1, and delta 2.3) that encode new variable region sequences. Two of the delta cDNAs differ significantly from those observed in the V alpha repertoire. In addition, one cDNA expressed a new J delta region (J delta 2), which was localized between J delta 1 and C delta genes. Using these and other delta gene probes and gamma gene probes, we found that five independent hybridomas expressed four different V delta s and three different V gamma s. However, analysis of an enriched population of gamma/delta-expressing cells from the adult thymus suggests that only a few V delta genes and one V gamma gene are used by the majority of the cells. These results suggest that important components of receptor chain that contribute to specificity (i.e., the germline V gene sequences) are relatively nondiverse in the thymic gamma/delta population.
Developmentally regulated, phospholipase C-mediated release of the major surface glycoprotein of amastigotes of Trypanosoma cruzi.
Authors: N W Andrews, E S Robbins, V Ley, K S Hong, V Nussenzweig
Journal: The Journal of Experimental Medicine (1988)

The surface of amastigotes of Trypanosoma cruzi is covered by Ssp-4, a major stage-specific glycoprotein. Ssp-4 is anchored to the cell membrane by GPI. It can be metabolically labeled with [3H]myristic acid, and is converted into a hydrophilic form by treatment with the glycan-specific phospholipase C of T. brucei, or after lysis of the parasites in non-ionic detergents. The hydrophilic form of Ssp-4 is recognized by antibodies to the cross-reactive determinant of the variant surface glycoprotein of African trypanosomes. Ssp-4 is progressively shed during the intra- or extracellular development of amastigotes preceding their transformation into epi- and trypomastigotes. We show here that T. cruzi contains a phospholipase C and that most shed Ssp-4 is hydrophilic, does not contain myristic acid, and reacts with anti-CRD. These observations provide strong evidence that phospholipase C mediates the release of this glycosyl-phosphatidylinositol-anchored protein under physiological conditions, as the parasite undergoes differentiation.
A Phase 1 Study of Mapatumumab (Fully Human Monoclonal Antibody to TRAIL-R1) in Patients with Advanced Solid Malignancies
Authors: Sébastien J. Hotte, Hal W. Hirte, Eric X. Chen, Lillian L. Siu, Lyly H. Le, Alfred Corey, Anne Iacobucci, Martha MacLean, Larry Lo, Norma Lynn Fox, Amit M. Oza
Journal: Clinical Cancer Research (2008)

Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that targets and activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4). Mapatumumab functions like the natural receptor ligand, TRAIL, a tumor necrosis factor superfamily member that is an important mediator of apoptosis in cancer cell lines. Promising preclinical activity with mapatumumab has been observed.This phase I, open-label, dose-escalation study assessed the tolerability and toxicity profile of > or =2 doses of mapatumumab administered i.v. in patients with advanced solid tumors. Patients received mapatumumab every 28 days until progression or dose-limiting toxicity.There were escalation levels from 0.01 to 20.0 mg/kg. Forty-one patients, 27 female, with a median age of 55 years (range, 23-81) were entered into the study and received 143 courses. The most common diagnoses were colorectal (10 patients) and ovarian cancer (9 patients). Patients received a median of two cycles (range, 1-33). Mapatumumab was well tolerated. Adverse events considered at least possibly related to mapatumumab that occurred most frequently included fatigue (36.2%), hypotension (34.1%), nausea (29.3%), and pyrexia (12.2%). The majority of adverse events were grade 1 or 2. The maximum tolerated dose was not reached. Linear pharmacokinetics was observed for doses up to 0.3 mg/kg and for the 20 mg/kg level, whereas exposure at 3 and 10 mg/kg increased less than proportionally. No objective responses were observed, but 12 patients had stable disease for 1.9 to 29.4 months.Mapatumumab is well tolerated and further evaluation of this TRAIL-R1 targeting agent is warranted.
Effects of oral steroids on immunoglobulins in bronchoalveolar lavage fluid in active sarcoidosis
Authors: M Spatafora, A Mirabella, GA Rossi, A Bonanno, L Riccobono, A Merendino, V Bellia, G Bonsignore
Journal: European Respiratory Journal (1988)

Immunoglobulin (Ig) levels increase in the lower respiratory tract of patients with pulmonary sarcoidosis. We evaluated the effects of prednisone therapy upon Ig concentrations in bronchoalveolar lavage (BAL) fluid of ten patients with active disease (greater than 30% T-lymphocytes in BAL and positive 67Gallium (67Ga) lung scan). Therapy significantly lowered T-lymphocyte percentages in BAL and 67Ga lung scan indices and was followed by a slight improvement of the studied functional parameters. Biochemical analysis of BAL showed a significant decrease of both IgG/albumin (baseline 1.24 +/- 0.21; after therapy 0.40 +/- 0.12) and IgA/albumin (baseline 0.55 +/- 0.07; after therapy 0.14 +/- 0.03) ratios in all patients. Conversely, comparisons of IgM/albumin ratios did not show any change over the study period (baseline 0.05 +/- 0.01; after therapy 0.06 +/- 0.03). Thus oral steroid treatment suppresses the alveolitis of pulmonary sarcoidosis, as shown not only by the reduction of lung T-cells and 67Ga lung uptake, but also by the decreased Ig levels in the alveolar spaces.
Changing Demographics, Epidemiology, and Survival of Incident Pulmonary Arterial Hypertension
Authors: Yi Ling, Martin K. Johnson, David G. Kiely, Robin Condliffe, Charlie A. Elliot, J. Simon R. Gibbs, Luke S. Howard, Joanna Pepke-Zaba, Karen K. K. Sheares, Paul A. Corris, Andrew J. Fisher, James L. Lordan, Sean Gaine, J. Gerry Coghlan, S. John Wort, Michael A. Gatzoulis, Andrew J. Peacock
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease.To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland.All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively.A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007-2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,(,) and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year.This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities.
Randomized Phase II Study of Two Irinotecan Schedules for Patients With Metastatic Breast Cancer Refractory to an Anthracycline, a Taxane, or Both
Authors: Edith A. Perez, David W. Hillman, James A. Mailliard, James N. Ingle, J. Michael Ryan, Tom R. Fitch, Kendrith M. Rowland, Carl G. Kardinal, James E. Krook, John W. Kugler, Shaker R. Dakhil
Journal: Journal of Clinical Oncology (2004)

A pressing need exists for agents active against anthracycline- or taxane-refractory metastatic breast cancer (MBC), or both. Previous clinical trials suggested that irinotecan might have such activity. We conducted this multicenter phase II study to assess efficacy and tolerability of two irinotecan schedules.MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m(2) weekly for 4 weeks, then a 2-week rest (weekly) or 240 mg/m(2) every 3 weeks.The weekly arm had 52 assessable patients; the every-3-weeks arm had 51 assessable patients. In the weekly arm, the objective response (complete regression [CR] + partial regression [PR]) rate was 23% (one CR, 11 PR; 95% CI, 13% to 37%). Median response duration was 4.9 months (range, 1.9 to 15.9 months), and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months). In the every-3-weeks arm, the objective response rate was 14% (nine PR; 95% CI, 6% to 26%), median response duration was 4.2 months (range, 3.1 to 13.9 months), and median overall survival was 8.6 months (95% CI, 7.0 to 12.3 months). Treatment generally was well tolerated, especially in the weekly arm. Grade 3 to 4 adverse events with > or = 10% incidence included neutropenia (29%) and diarrhea (17%) in the weekly arm and neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) in the every-3-weeks arm.Irinotecan is active with good tolerability in refractory MBC. Irinotecan (especially weekly) warrants additional study as monotherapy and in combination regimens in this setting.
The role of Na-Ca exchange current in the cardiac action potential
Authors: N.C. Janvier, M.R. Boyett
Journal: Cardiovascular Research (1996)

Since 1981, when Mullins published his provocative book proposing that the Na-Ca exchanger is electrogenic, it has been shown, first by computer simulation by Noble and later by experiment by various investigators, that inward iNaCa triggered by the Ca2+ transient is responsible for the low plateau of the atrial action potential and contributes to the high plateau of the ventricular action potential. Reduction or complete block of inward iNaCa by buffering intracellular Ca2+ with EGTA or BAPTA, by blocking SR Ca2+ release or by substituting extracellular Na+ with Li+ can result in a shortening of the action potential. The effect of block of outward iNaCa or complete block of both inward and outward iNaCa on the action potential has not been investigated experimentally, because of the lack of a suitable blocker, and remains a goal for the future. An increase in the intracellular Na+ concentration (after the application of cardiac glycoside or an increase in heart rate) or an increase in extracellular Ca2+ are believed to lead to an outward shift in iNaCa at plateau potentials and a shortening of the action potential. Changes in the Ca2+ transient are expected to result in changes in inward iNaCa and thus the action potential. This may explain the shortening of the premature action potential as well as the prolongation of the action potential when a muscle is allowed to shorten during the action potential. Inward iNaCa may play an important role in both normal and abnormal pacemaker activity in the heart.
Entire NHS commissioning system may need to be scrapped, MPs say
Authors: A. O'Dowd
Journal: BMJ (2010)

Commissioning in the NHS in England has been a 20 year long “costly failure” and may need to be scrapped, MPs have concluded.

After its recent inquiry the parliamentary health select committee published a highly critical report on commissioning on 30 March. The report gives its verdict of almost two decades of NHS commissioning in England since purchasers and providers were split in 1991.

The MPs said that primary care trusts were not commissioning effectively, were too passive, and lacked the clinical knowledge and other skills to challenge hospitals over the provision of services.

Frequent reorganisations in the NHS and a high turnover of staff had worsened the situation, they said.

The committee questioned whether the government’s “world class commissioning” initiative, designed to improve the quality of …
Avian Influenza Virus Exhibits Rapid Evolutionary Dynamics
Authors: Rubing Chen, Edward C. Holmes
Journal: Molecular Biology and Evolution (2006)

Influenza A viruses from wild aquatic birds, their natural reservoir species, are thought to have reached a form of stasis, characterized by low rates of evolutionary change. We tested this hypothesis by estimating rates of nucleotide substitution in a diverse array of avian influenza viruses (AIV) and allowing for rate variation among lineages. The rates observed were extremely high, at >10(-3) substitutions per site, per year, with little difference among wild and domestic host species or viral subtypes and were similar to those seen in mammalian influenza A viruses. Influenza A virus therefore exhibits rapid evolutionary dynamics across its host range, consistent with a high background mutation rate and rapid replication. Using the same approach, we also estimated that the common ancestors of the hemagglutinin and neuraminidase sequences of AIV arose within the last 3,000 years, with most intrasubtype diversity emerging within the last 100 years and suggestive of a continual selective turnover.
Molecular systematics of the parasitic protozoan Giardia intestinalis
Authors: P. T. Monis, R. H. Andrews, G. Mayrhofer, P. L. Ey
Journal: Molecular Biology and Evolution (1999)

The long-standing controversy regarding whether Giardia intestinalis is a single species prevalent in both human and animal hosts or a species complex consisting of morphologically similar organisms that differ in host range and other biotypic characteristics is an issue with important medical, veterinary, and environmental management implications. In the past decade, highly distinct genotypes (some apparently confined to particular host groups) have been identified by genetic analysis of samples isolated from different host species. The aim of this study was to undertake a phylogenetic analysis of G. intestinalis that were representative of all known major genetic groups and compare them with other Giardia species, viz. G. ardeae, G. muris, and G. microti. Segments from four "housekeeping" genes (specifying glutamate dehydrogenase, triose phosphate isomerase, elongation factor 1 alpha, and 18S ribosomal RNA) were examined by analysis of 0.48-0.69-kb nucleotide sequences determined from DNA amplified in polymerase chain reactions from each locus. In addition, isolates were compared by allozymic analysis of electrophoretic data obtained for 21 enzymes representing 23 gene loci. The results obtained from these independent techniques and different loci were essentially congruous. Analyses using G. ardeae and/or G. muris as outgroups supported the monophyly of G. intestinalis and also showed that this species includes genotypes that represent at least seven deeply rooted lineages, herein designated assemblages A-G. Inclusion of G. microti in the analysis of 18S rRNA sequence data demonstrated the monophyly of Giardia with the same median body morphology but did not support the monophyly of G. intestinalis, instead placing G. microti within G. intestinalis. The findings support the hypothesis that G. intestinalis is a species complex and suggest that G. microti is a member of this complex.
Hirsutism and Virilizing Syndromes
Authors: E J Segre, E L Klaiber, J Lobotsky, C W Lloyd
Journal: Annual Review of Medicine (1964)

Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is ...Read More
A Lecture ON COMBINED AORTIC AND MITRAL DISEASE IN RHEUMATIC CHILDREN: Delivered at the Hospital for Sick Children, Great Ormond Street
Authors: F. J. Poynton
Journal: BMJ (1905)

LADIES AND GENTLEMEN.-Ihave already in three of sormer lectures treated of some aspects of rheumatic cardiac disease in early life.In the first I dwelt upon the important part that micro-organisms take in producing endocarditis; the second, upon damage to the heart wall in rheumatism;and, in the third, I endeavoured to show the pardlelism the course of the rheumatic lesions in various organs, differentiated three types of rheumatic inrjury-namely:i.The simple, as in simple endocarditis.2. The malignant, as in rheumatic malignant endocarditis.3 The fibroid, as in mitral stenosis.In this lecture I shall direct your attention to an exceedingly serious group of rheumatic heart lesions, and illustrate thesi by a series of clinical cases, giving also the results of study of twenty-one examples which have been under my cire at one time or another during their illness.In all these cases there were evidences of mitral and aortic endocarditis, is to this combination of lesions in childhood that ask your attention.Rheumatism, as is well known, damages all parts of the heart-the pericardium, myocardium, and endocardium-
Serum eosinophilic cationic protein and lactoferrin related to smoking history and lung function
Authors: EJ Jensen, B Pedersen, E Schmidt, P Venge, R Dahl
Journal: European Respiratory Journal (1994)

Some smokers have an accelerated loss of lung function, possibly due to a chronic bronchial inflammation in which granulocytes are involved. Eosinophil cationic protein (ECP) and lactoferrin (LF) are granule proteins in the eosinophil and neutrophil granulocyte, respectively. We wanted to investigate the relationship of serum (s) ECP and LF concentrations to smoking history and lung function alteration. This partly cross-sectional and partly prospective study included 98 nonatopic smokers and 31 lifetime nonsmokers. As participants in a smoking cessation programme, 50 of the 98 smokers ceased smoking for > or = 1 year. Smoking history, lung function and blood samples were obtained at the start of the study, and smokers and ex-smokers also gave blood samples 3, 6 and 12 months later. s-ECP and s-LF were elevated in smokers compared to people who had never smoked. s-ECP was linearly associated with daily cigarette consumption and forced expiratory volume in one second (FEV1) residuals. In a multiple linear regression analysis, low s-ECP and high s-LF were associated with decreased FEV1 residuals. s-ECP and s-LF together accounted for 10.2% of the variation in FEV1 residuals. After smoking cessation, s-ECP and s-LF decreased within 6 months. s-ECP and s-LF are raised in smokers, and may serve as indicators of granulocyte activation. We speculate that they might contribute to prediction of accelerated lung function loss in smokers, but this question needs further investigation in a prospective study.