tbuckley/cabot-search huggingface dataset:
Multimodal Assessment of Protein Functional Deficiency Supports Pathogenicity of BRCA1 p.V1688del
Authors: Arcangela De Nicolo, Emilio Parisini, Quan Zhong, Maurizia Dalla Palma, Kathryn A. Stoeckert, Susan M. Domchek, Katherine L. Nathanson, Maria A. Caligo, Marc Vidal, Michael E. Cusick, Judy E. Garber
Journal: Cancer Research (2009)

Unequivocal discrimination between neutral variants and deleterious mutations is crucial for appropriate counseling of individuals with a BRCA1 or BRCA2 sequence change. An increasing number of variants of uncertain significance (VUS) are being identified, the unclassified biological effect of which poses clinical concerns. A multifactorial likelihood-based approach recently suggested disease causality for BRCA1 p.V1688del, a VUS recurrent in Italian breast/ovarian cancer families. Whether and how this single amino acid deletion in the BRCA1 COOH terminus (BRCT) domain affects the function of the mutant protein (DeltaValBRCA1) has not been elucidated. We undertook comprehensive functional characterization of DeltaValBRCA1, comprising comparative structural modeling, analysis of protein stability and associations, and analysis of DNA repair function. Our model predicted BRCT domain destabilization and folding disruption caused by BRCA1 p.V1688del. Consistently, the recombinant DeltaValBRCA1 was less stable than wild-type BRCA1 and, unlike the latter, failed to associate with BRIP1, CtIP, and Rap80 and to relocalize to sites of DNA damage. Yeast two-hybrid analysis revealed a compromised interaction with FHL2 and KPNA2, which is likely responsible for improper subcellular localization of DeltaValBRCA1. In addition, we found four new breast/ovarian cancer families of Italian ancestry who carried this sequence alteration. These results provide the first evidence of the effect of BRCA1 p.V1688del on protein stability and function, supporting the view that it is a deleterious mutation. Multimodal analyses like ours could advance understanding of tumor suppression by BRCA1 and ultimately contribute to developing efficient strategies for screening and characterization of VUS.
A bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1 ganglioside-like structure.
Authors: N Yuki, T Taki, F Inagaki, T Kasama, M Takahashi, K Saito, S Handa, T Miyatake
Journal: The Journal of Experimental Medicine (1993)

There is a strong association between Guillain-Barré syndrome (GBS) and Penner's serotype 19 (PEN 19) of Campylobacter jejuni. Sera from patients with GBS after C. jejuni infection have autoantibodies to GM1 ganglioside in the acute phase of the illness. Our previous work has suggested that GBS results from an immune response to cross-reactive antigen between lipopolysaccharide (LPS) of the Gram-negative bacterium and membrane components of peripheral nerves. To clarify the pathogenesis of GBS, we have investigated whether GM1-oligosaccharide structure is present in the LPS of C. jejuni (PEN 19) that was isolated from a GBS patient. After extraction of the LPS, the LPS showing the binding activity of cholera toxin, that specifically recognizes the GM1-oligosaccharide was purified by a silica bead column chromatography. Gas-liquid chromatography-mass spectrometric analysis has shown that the purified LPS contained Gal, GalNAc, and NeuAc, which are sugar components of GM1 ganglioside. 1H NMR methods [Carr-Purcell-Meiboom-Gill (CPMG), total correlation spectroscopy (TOCSY), and nuclear Overhauser effect spectroscopy (NOESY)] have revealed that the oligosaccharide structure [Gal beta 1-3 GalNAc beta 1-4(NeuAc alpha 2-3)Gal beta] protrude from the LPS core. This terminal structure [Gal beta 1-3GalNAc beta 1-4(NeuAc alpha 2-3)Gal beta] is identical to the terminal tetrasaccharide of the GM1 ganglioside. This is the first study to demonstrate the existence of molecular mimicry between nerve tissue and the infectious agent that elicits GBS.
Urine Macrophage Migration Inhibitory Factor Reflects the Severity of Renal Injury in Human Glomerulonephritis
Authors: Fiona G. Brown, David J. Nikolic-Paterson, Prudence A. Hill, Nicole M. Isbel, John Dowling, Christine M. Metz, Robert C. Atkins
Journal: Journal of the American Society of Nephrology (2002)

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in experimental crescentic glomerulonephritis (GN). Renal expression of MIF is also upregulated in human GN and correlates with leukocytic infiltration, histologic damage, and renal dysfunction. The study presented here examined whether MIF can be measured in urine and if so, whether the urine MIF concentration reflects the degree of renal injury. Urine and serum MIF was measured by enzyme-linked immunosorbent assay in 10 normal healthy volunteers and in a cohort of 63 patients with GN (2 thin basement membrane disease [TBM], 15 membranous GN, 10 focal segmental glomerular sclerosis, 20 IgA glomerularnephritis, 11 crescentic GN, 10 systemic lupus erythematosis World Health Organization class IV). Renal MIF expression was assessed by immunostaining of biopsy tissue. MIF was detected in urine from normal volunteers (mean +/- SD; 191 +/- 132 pg MIF/micromol creatinine). The urine MIF concentration was unchanged in patients with nonproliferative nephropathies (343 +/- 397 pg MIF/micromol Cr) but was increased 3.4-fold in proliferative nephropathies (645 +/- 527 pg MIF/micromol Cr; P < 0.05 versus normal and nonproliferative). Stratified analysis showed the greatest increase in urine MIF in crescentic GN (4.5-fold). In contrast, serum MIF levels were not different between normal patients and any patient group. Immunostaining demonstrated a significant increase in renal MIF expression in proliferative glomerulonephritides that was associated with macrophage and T cell infiltration. There was a significant correlation between the urine MIF concentration and renal MIF expression, but not with serum MIF, indicating a renal origin for the excreted urine MIF. The urine MIF concentration also correlated with the degree of renal dysfunction, histologic damage, and leukocytic infiltration, but not with the amount of proteinuria. In conclusion, this study shows that the urine MIF concentration is significantly increased in proliferative forms of GN and correlates with the degree of renal injury. Urine MIF levels reflect MIF expression within the kidney and may be a useful noninvasive tool for monitoring patients with crescentic GN, particularly in disease exacerbation.
Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the thrombolysis in myocardial infarction trials
Authors: C.Michael Gibson, Juhana Karha, Sabina A Murphy, David James, David A Morrow, Christopher P Cannon, Robert P Giugliano, Elliott M Antman, Eugene Braunwald
Journal: Journal of the American College of Cardiology (2003)
Chancellor maps out three year public service spending plans
Authors: R. Coombes
Journal: BMJ (2002)

More than 40% of the UK government's public spending increase will go to the NHS and social services, Chancellor Gordon Brown announced this week.

But Mr Brown's spending review, which set out plans for 2003–6, gave no detail on how the extra money pledged for health will be spent. Details have yet to be finalised, but the review says that the current formula for distributing resources is under review and should be available …
Physiotherapy interventions in the BTS guidelines on the management of asthma (2011): a need for change?: Table 1
Authors: Roman Nowobilski, Maciej Plaszewski, Tomasz Wloch, Piotr Gajewski, Andrzej Szczeklik
Journal: Thorax (2011)

Updates to the British Thoracic Society (BTS) asthma guidelines have been recently highlighted by Turner and colleagues.1 2 To our concern, the content on physiotherapy interventions has not been revised or updated since the 2006 version.

We reviewed the contents of the new BTS guidelines relevant for physiotherapists. The timescale for literature search indicates that the relevant section was last updated in February 2006, with coverage in Medline …
Arterial Lesions in the Kenya Baboon
Authors: HENRY C. MCGILL, JACK P. STRONG, RUSSELL L. HOLMAN, NICHOLAS T. WERTHESSEN
Journal: Circulation Research (1960)

One hundred sixty-three baboons ( Papio doguera were sacrificed and autopsied immediately after being trapped in their natural habitat in Kenya, British East Africa. Approximately three-fourths of the 67 adults had some degree of aortic intimal lipid deposition, as indicated by gross Sudan IV staining, and a few animals had extensive fatty streaks. These fatty streaks were more frequent with advancing age, but there was no sex difference. Electron microscopy disclosed most of the intimal lipid droplets to be intracellular. Fibrous plaques were infrequent and had a variable but usually low lipid content. One elderly male had fibrous plaques with hemorrhage into their bases. Histologic sections of the coronary arteries showed many small musculo-elastic intimal plaques in which lipid could only rarely be demonstrated. The aortic intimal lipid deposits cannot be attributed to the consumption of excessive animal fat or to hypercholesterolemia. These results indicate that the baboon, like man, is highly susceptible to arterial intimal lipid deposition and that it promises to be an excellent animal for the experimental investigation of atherosclerosis. They further more caution that adequate controls be used in all experimental work involving arterial lesions in primates.
IVF and breast cancer: a systematic review and meta-analysis
Authors: Theodoros N. Sergentanis, Andreas-Antonios Diamantaras, Christina Perlepe, Prodromos Kanavidis, Alkistis Skalkidou, Eleni Th. Petridou
Journal: Human Reproduction Update (2013)

The effects of controlled ovarian hyperstimulation (COH) for IVF in terms of breast cancer risk remain controversial, despite the hormone-dependent nature of the latter. Eligible studies up to 15 February 2013 were identified and pooled effect estimates for relative risk (RR) were calculated separately for the investigations using the general population and those using infertile women, as a reference group. Fixed- or random-effects models were implemented and subgroup analyses were performed, as appropriate. Eight cohort studies were synthesized, yielding a total cohort size of 1 554 332 women among whom 14 961 incident breast cancer cases occurred, encompassing 576 incident breast cancer cases among women exposed to IVF. No significant association between IVF and breast cancer was observed either in the group of studies treating the general population (RR = 0.91, 95% confidence interval (CI): 0.74–1.11) or infertile women (RR = 1.02, 95% CI: 0.88–1.18), as a reference group. Of note were the marginal associations, protective for pregnant and/or parous women after IVF (pooled effect estimate = 0.86, 95% CI: 0.73–1.01) and adverse for women <30 years at first IVF treatment (pooled effect estimate = 1.64, 95% CI: 0.96–2.80). At present, COH for IVF does not seem to impart increased breast cancer risk. Longer follow-up periods, comparisons versus infertile women, subgroup analyses aiming to trace vulnerable subgroups, adjustment for various confounders and larger informative data sets are needed before conclusive statements for the safety of the procedure are reached.
Spontaneous and Induced Cardiac Arrhythmias in Subendocardial Purkinje Fibers Surviving Extensive Myocardial Infarction in Dogs
Authors: PETER L. FRIEDMAN, JAMES R. STEWART, ANDREW L. WIT
Journal: Circulation Research (1973)

The cellular electrophysiological mechanisms underlying the ventricular arrhythmias that accompany myocardial infarction were studied in isolated, superfused infarcted myocardium excised from dogs previously subjected to a two-stage ligation of the anterior descending coronary artery. Ventricular arrhythmias frequently occurred in the intact heart 24 hours after coronary occlusion. Surviving subendocardial Purkinje fibers in infarcts excised at this time were highly arrhythmic when they were studied with intracellular microelectrodes in vitro. These arrhythmias consisted of rapid, repetitive depolarizations and occurred spontaneously or could be induced by premature electrical stimulation. Premature stimulation also resulted in single unstimulated responses. In such instances, premature impulses conducted extremely slowly through the infarcted region where surviving Purkinje fiber action potential durations were extraordinarily prolonged. Conduction block at some sites in the infarct caused phenomena which were interpreted as reentrant beats. Some surviving subendocardial Purkinje fibers in the infarct demonstrated spontaneous diastolic depolarization and appeared to function as pacemakers in the absence of electrical stimulation. In some instances, these fibers constituted typical parasystolic foci, demonstrating both entrance and exit block. These results suggest that subendocardial Purkinje fibers which survive in an infarct may be the site of origin of some of the ventricular arrhythmias that accompany myocardial infarction.
The Epidemiology of At-Risk and Binge Drinking Among Middle-Aged and Elderly Community Adults: National Survey on Drug Use and Health
Authors: Dan G. Blazer, Li-Tzy Wu
Journal: American Journal of Psychiatry (2009)

Objective: The purpose of this article was to estimate the prevalence, distribution, and correlates of at-risk alcohol use (especially binge drinking) among middle-aged and elderly persons in the United States and to compare at-risk alcohol use between women and men. Method: Secondary analysis of the 2005 and 2006 National Survey on Drug Use and Health was conducted for 10,953 respondents aged 50 years and older. Among respondents, 6,717 were 50 to 64 years of age and 4,236 were ≥65 years. Social and demographic variables, alcohol use (including at-risk use), binge drinking, serious psychological distress, and self-rated health were assessed. Results: Overall, 66% of male respondents and 55% of female respondents reported alcohol use during the past year. At-risk alcohol use and binge drinking were more frequent among respondents 50 to 64 years of age relative to respondents aged 65 years or older. In the ≥65 years old age group, 13% of men and 8% of women reported at-risk alcohol use, and more than 14% of men and 3% of women reported binge drinking. Among male subjects, binge drinking compared with no alcohol use was associated with higher income and being separated, divorced, or widowed, while being employed and nonmedical use of prescription drugs were associated with binge drinking compared with no alcohol use among women. For all respondents, binge drinking relative to no alcohol use was associated with the use of tobacco and illicit drugs. Among women who reported using alcohol, being African American and less educated were associated with binge drinking, but race/ethnicity and educational level were not associated with binge drinking in men who reported using alcohol. Conclusions: At-risk and binge drinking are frequently reported by middle-aged and elderly adults nationwide and are therefore of public health concern. Clinicians working with middle-aged and older adults should screen for binge drinking and coexisting use of other substances.
Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells
Authors: Pietro Cirillo, Michael S. Gersch, Wei Mu, Philip M. Scherer, Kyung Mee Kim, Loreto Gesualdo, George N. Henderson, Richard J. Johnson, Yuri Y. Sautin
Journal: Journal of the American Society of Nephrology (2009)

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.
Increased expression of<i>Solute carrier family 12 member 5</i>via gene amplification contributes to tumour progression and metastasis and associates with poor survival in colorectal cancer
Authors: Lixia Xu, Xiaoxing Li, Muyan Cai, Jinna Chen, Xiangchun Li, William K K Wu, Wei Kang, Joanna Tong, Ka-Fai To, Xin-Yuan Guan, Joseph J Y Sung, Francis K L Chan, Jun Yu
Journal: Gut (2015)

Using whole genome sequencing, we identified gene amplification of solute carrier family 12 member 5 (SLC12A5) located at 20q13.12 in colorectal cancer (CRC). We analysed its amplification, overexpression, biological effects and prognostic significance in CRC.SLC12A5 amplification status was evaluated by fluorescence in situ hybridisation (FISH). The effects of SLC12A5 re-expression or knockdown were determined in proliferation, apoptosis, invasion and metastasis assays. SLC12A5 target genes and related pathways were identified by reporter activity and cDNA microarray analyses. Clinical impact of SLC12A5 overexpression was assessed in 195 patients with CRC.Amplification of SLC12A5 was verified in 78 out of 191 (40.8%) patients with primary CRC by FISH, which was positively correlated with its protein overexpression (p<0.001). Biofunctional investigation of SLC12A5 revealed that SLC12A5 significantly increased cell proliferation, G1-S cell cycle transition, invasion/migration abilities, but suppressed apoptosis in vitro and promoted xenograft tumour growth as well as lung metastasis in vivo. The antiapoptosis effect by SLC12A5 was mediated through inhibiting apoptosis-inducing factor and endonuclease G-dependent apoptotic signalling pathway; and the pro-metastasis role was by regulating key elements of the matrix architecture, including matrix metallopeptidase and fibronectin. After a median follow-up of 50.16 months, multivariate analysis revealed that patients with SLC12A5 protein overexpression had a significant decrease in overall survival. Kaplan-Meier survival curves showed that SLC12A5 overexpression was significantly associated with shortened survival in patients with CRC.SLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC.
Autism from Developmental and Neuropsychological Perspectives
Authors: Marian Sigman, Sarah J. Spence, A. Ting Wang
Journal: Annual Review of Clinical Psychology (2006)

In this review of the research literature on autism, we argue that the application of developmental and neuropsychological perspectives has contributed importantly to the understanding of the core deficits in autism and their underlying neural bases. The three classes of theories postulated to explain the developmental and neuropsychological deficits in autism are considered in terms of the specificity, uniqueness, and universality of these impairments in autism. Because we believe that a primary reason for our lack of understanding of the developmental trajectory in autism stems from our inability to diagnose the syndrome in the first three years of life, research approaches to early identification are discussed, as are longitudinal studies aimed at identifying later-life outcomes and their predictors. In contrast to the progress made in defining the core deficits and arriving at criteria for diagnosis, less progress has been made in identifying the causes of autism and in creating and testing interventions aimed at ameliorating the impairments of autism, possibly because these activities have been less tied to the developmental and neuropsychological models that have enlightened the investigation of core deficits.
PRENATAL DIAGNOSIS OF DYSMORPHIC NEONATAL-LETHAL TYPE II GLUTARICACIDURIA
Authors: J. Boué, R.A. Chalmers, B.M. Tracey, D. Watson, R.G.F. Gray, J.W. Keeling, G.S. King, B.R. Pettit, R.H. Lindenbaum, F. Rocchiccioli, J-M. Saudubray
Journal: The Lancet (1984)
British Society of Gastroenterology guidelines for the diagnosis of Barrett's oesophagus: are we casting the net too wide?
Authors: S J Murphy, B T Johnston, L J Murray
Journal: Gut (2006)

We read with interest the British Society of Gastroenterology guidelines for the diagnosis and management of Barrett’s columnar-lined oesophagus1 and the related commentary by Professor Playford ( Gut 2006; 55 :442–3). One of the new recommendations in these guidelines relates to the diagnosis of Barrett’s oesophagus. The guidelines state that “the presence of areas of intestinal metaplasia, although often present, is not a requirement for diagnosis”. This is out of step with guidelines from the US, where intestinal metaplasia is required to establish a diagnosis of Barrett’s oesophagus.2 The rationale for the British guidelines is that sampling errors at initial endoscopy may miss areas affected with …
Screening the athlete’s shoulder for impingement symptoms: a clinical reasoning algorithm for early detection of shoulder pathology
Authors: A M Cools, D Cambier, E E Witvrouw
Journal: British Journal of Sports Medicine (2008)

Chronic shoulder pain and dysfunction are common complaints among overhead athletes seeking care from physical medicine and rehabilitation. Impingement is a frequently described pathological condition in the overhead athlete. Impingement symptoms may be the result of rotator cuff pathology, shoulder instability, scapular dyskinesis or muscle dysfunction, biceps pathology, SLAP lesions and chronic stiffness of the posterior capsule. At present, numerous different shoulder tests have been described in literature and discussed with respect to their individual diagnostic accuracy. However, in view of the number of shoulder tests, it is often a challenge for the clinician to select the appropriate tests for diagnosing the underlying pathology. The purpose of this paper is to present and discuss a clinical algorithm which may be used in the early detection of the underlying causes of impingement symptoms. In this algorithm, a specific chronology and selection of diagnostic tests may offer the clinician a guideline in his physical examination of the athlete with shoulder pain.