tbuckley/cabot-search huggingface dataset:
Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype
Authors: J Yarden
Journal: Thorax (2005)

The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor alpha (TNFalpha), a member of the immune system.Three polymorphic loci in the promoter (-851c/t, -308g/a, -238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFalpha gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients' medical records.An association was found between the TNFalpha +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV1) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the -851c/t polymorphic locus. In the group of patients with more severe FEV1% predicted, a higher proportion of patients were homozygous for the -851c allele than in the other group of patients (p = 0.04, likelihood ratio chi2, odds ratio = 2.4).TNFalpha polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.
Younger teenagers are also at risk of mumps outbreaks
Authors: D Graham Mackenzie, Nick Hallam, Janet Stevenson
Journal: BMJ (2005)

Health inequalities under New Labour Relative rather than absolute gaps are important over time and placeEditor-We agree with Shaw et al that the method of measuring inequality in health outcomes used in setting the government targets is problematic (A Low, UKPHA (UK Public Health Association), 13th annual public health forum, Gateshead, April 2005). 1 However, the government's targets are based on reducing relative gaps in life expectancy and infant mortality. 2 The slope index of inequality (SII) used by Shaw et al measures absolute gaps.
Immunochemical localization and amino acid sequences of crossreactive epitopes within the group A streptococcal M6 protein.
Authors: K F Jones, S A Khan, B W Erickson, S K Hollingshead, J R Scott, V A Fischetti
Journal: The Journal of Experimental Medicine (1986)

mAbs 10A11, 10B6, and 10F5, raised against the native group A streptococcal M6 protein, were examined for their crossreactivity with non-laboratory passaged clinical isolates, representing 58 M serotypes, by bacterial dot blot immunoassay. mAb 10A11 crossreacted with 9, mAb 10B6 with 30, and mAb 10F5 with 30 different non-M6 serotypes. To identify the epitopes for these antibodies, the native M6 protein was cleaved with pepsin or staphylococcal V8 protease. Resultant peptides were purified by HPLC, examined for binding to crossreactive mAbs in ELISA, and reactive peptides were subjected to amino acid sequence analysis. Peptides were aligned with the amino acid sequence of the entire M6 protein predicted by the DNA sequence of the M6 gene. Competitive inhibition studies using peptides synthesized on the basis of peptide and DNA sequences, in concert with selective blocking of amino acid residues, allowed for the further identification and placement of these crossreactive epitopes within the M6 molecule. The 10A11 epitope was located within the six amino acid residues at position 134-139, which repeat at positions 159-164 and 184-189 within the variable amino terminal half of the native molecule. The conserved 10B6 and 10F5 epitopes were positioned within a 15-amino-acid span at position 275-289, with the possibility that either epitope could have been repeated at residues 239-247. Chemical modification of amino acids within this sequence aided in the differentiation of these two epitopes. Such studies should aid in the recognition of a sequence(s) common to a greater number of M serotypes, which may be useful for future vaccine development or group A streptococcal identification.
Diagnostic criteria for the sleep apnoea syndrome: time for consensus
Authors: WT McNicholas
Journal: European Respiratory Journal (1996)

The traditional diagnosis of sleep apnoea syndrome has been based on a particular apnoea frequency during sleep, and was originally set at ≥5 apnoeas·h-1 of sleep during the 1970s [1]. However, as experience developed with the clinical spectrum of patients with sleep apnoea, it was realized that hypopnoeas during sleep could have a similar clinical significance as complete apnoeas [2], and this realization led to the present clinical diagnostic criteria, which are based on the combined frequency of apnoeas and hypopnoeas during sleep. Unfortunately, there is not complete agreement as to what apnoea and hypopnoea frequency represents a clinically significant sleep apnoea syndrome, with some centres using a level of 10 episodes·h -1 [3‐5], and others 15 episodes·h -1 [6, 7]. A number of obvious deficiencies can be identified in the present approach to the diagnosis of obstructive sleep apnoea (OSA). Firstly, not all patients with an apnoea/hypopnoea index (AHI) of greater than 10 or 15 episodes·h-1 of sleep appear to have a clinically significant OSA syndrome. It has long been recognized that apnoeas during sleep become more frequent with advancing age, and many apparently normal elderly people have an AHI greater than the above thresholds [8, 9]. It is now accepted that a diagnosis of clinically significant OSA should be accompanied by compatible symptoms, and not be based simply on an arbitrary AHI threshold, particularly in borderline cases. Clinically significant OSA can occur, particularly among younger patients, at AHI frequencies below 10 episodes·h-1, and the recent description of the upper airway resistance syndrome [10] indicates that episodic partial upper airway obstruction without significant hypopnoea can mimic OSA in most
Racism in the National Health Service: lessons from the past
Authors: K. Walsh
Journal: Journal of the Royal Society of Medicine (2005)

Dr McNaught is right to point out examples of racism in the NHS (December 2004 JRSM 1 ).But what to do about it?Maybe we can learn some lessons from the past.Today there is an over-representation of black people in the mental health system but in the 1960s Irish people were over-represented. 2 Psychiatrists thought that the prevalence of schizophrenia was high in people from the west of Ireland and invented a new syndrome 'western seaboard psychosis'. 3 Anthropologists descended on the unsuspecting immigrants to ask them if their Catholic faith caused their minds to unbalance and psychiatrists followed to dole out antipsychotics.But then some proper research was done and it showed no excess of schizophrenia in Irish immigrants. 4 The methods of case collection in the early studies were poor and cross-cultural comparisons were not properly thought through. 3 Today Irish people are no more likely to be diagnosed with schizophrenia than anyone else.How did this happen?I would love to say that it was because of the new research or because of government initiatives.The research helped a bit but the main cures for anti-Irish discrimination were that the new immigrants were richer, better educated, better informed and more questioning.They would not be fobbed off with a misdiagnosis.An increasing understanding and appreciation of Irish culture also helped reduce anti-Irish discrimination generally.The most effective cure of all was time.A cynic would add that, nowadays, people have a new batch of immigrants (such as asylum seekers) to discriminate against.So we need fewer new policy drives and more changes of heart.These will only come from changes in society.Blaming individuals or even the NHS will not help.
Job security and a good episode of Scrubs
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2009)

Is the health service immune to an economic recession? I hold my hand up and admit that if it is a myth I have perpetrated it in these pages. I guess Nigel Edwards, director of policy for the NHS Confederation, would disagree (JRSM 2009;102:86–7 ). Mr Edwards has the advantage of being much closer to the NHS and its finances than most of us would wish to be. Moreover, he has the unenviable day job of bringing the hyperbole of politicians down to earth.

Primary care trusts and healthcare providers will feel the chill of disinvestment, suggests Edwards in his matter‐of‐fact editorial. He is concerned that quality of care will suffer. These are uncomfortable conclusions that call for our health service to implement greater efficiencies, something that many health professionals will find impossible to imagine. Nonetheless, is it difficult to believe that the financial crisis will affect healthcare in the way that it is devastating other industries and sectors?

A hybrid operating theatre might be an efficiency that is worth exploring (JRSM 2009;102:92–7 ). Mark Field and colleagues describe their experience of a purpose‐built hybrid theatre constructed at Liverpool Heart and Chest Hospital as part of the development of a regional thoracic aortic aneurysm service. Their conclusion after a single year’s experience is that improved collaboration between healthcare professionals is an important benefit for patients, and represents a new standard of care.

A drive for efficiency is a spur to innovation. All organizations are seeking to innovate, with the magic formula introducing cost savings while exceeding performance targets. For many, this is an impossible calculus. Cutting costs may well reduce quality and performance, as Edwards warns. Yet the introduction of any new technology, like the hybrid theatre, requires a more formal economic analysis so that the technology is introduced for better patient care rather than for the sake of its application.

Our revolutionary new technologies might be considered to be failed old ones by future doctors. Richard Smith was asked to give evidence to the Royal College of Physicians working party on the future doctor (JRSM 2009;102:89–91 ). Among an exhaustive list of thoughts about our future colleagues, he includes an important requirement that doctors have an understanding of systems: ‘Future doctors need to understand those complex systems and know most importantly how to improve them.’

Nigel Edwards would welcome those skills among current doctors. Future doctors, however, will probably find it hard to understand why those skills are required at all? In the era of the credit crunch, the appeal of medicine is probably job security and a good episode of Scrubs.
METASTASIS AND TUMOR RECURRENCE FROM RARE SOX9-POSITIVE CELLS IN MYCN-DRIVEN MEDULLOBLASTOMA
Authors: F. J. Swartling, V. Savov, M.  an er, S. Bolin, G. Fotaki, A. Dubuc, M. Remke, V. Ramaswamy, H. Weishaupt, M. D. Taylor
Journal: Neuro-Oncology (2014)

BACKGROUND: Tumor recurrence is the main cause of death for children with medulloblastoma, the most common malignant childhood brain tumor. The MYCN oncogene is a poor prognosis marker and is amplified in the molecularly defined SHH and Group 4 subgroups but rarely in WNT and Group 3 subgroups of human medulloblastoma. Recent findings on childhood brain tumor relapse mechanisms suggest spatiotemporal differences within these four subgroups. SOX9 is a transcription factor that is important for glial fate determination in the brain but has also been found to promote tumor metastasization. We previously showed how expression of SOX9 correlates well with human SHH tumors but only few scattered SOX9-positive cells are found in SHH-independent Group 3 and Group 4 human medulloblastoma. METHODS: In order to study recurrence processes experimentally, we used a previously described transgenic Tet-OFF (Glt1-tTA) inducible model of MYCN-driven SHH-independent medulloblastoma (GTML mouse). To recreate metastatic recurrence we further used a Tet-ON (SOX9-rtTA) model that drives MYCN expression from the SOX9 promoter upon doxycycline treatment. RESULTS: By crossing the GTML Tet-OFF model with a Tet-ON transgene we managed to study rare SOX9-positive tumor cells after SOX9-negative tumor cells were first depleted using doxycycline. SOX9-positive GTML cells were tumorigenic and reinitiated distant recurrences over time. The SOX9-positive cells further showed an increased resistance to MYCN-targeted therapies. Relapses showed similar histopathology but presented generally higher levels SOX9 as compared to primary GTML tumors. A similar correlation was found in Group 3 and Group 4 medulloblastoma patients where isolated metastases had consistently higher SOX9 levels as compared to corresponding primary tumors. Finally, we overexpressed SOX9 in normal cerebellar stem cells transduced with mutationally stabilized MYCN-T58A and injected them back into the cerebellum of adult mice. Surprisingly, SOX9-positive MYCN-T58A brain tumors migrated and developed in the forebrain in contrast to the cerebellar stem cells transduced with MYCN-T58A only. CONCLUSIONS: Our findings suggest that increased levels of SOX9 drives migration in MYCN-driven medulloblastoma. Rare SOX9-positive tumor cells show an increased therapy resistance and are alone capable of reinitiating childhood brain tumors. Further characterization of SOX9-positive cells in Group 3 and Group 4 tumors could help us understand what drives metastatic medulloblastoma relapse and could lead to new therapies directed against these particularly serious cell types. SECONDARY CATEGORY: Tumor Biology.
Sodium cromoglycate in the treatment of dermatitis herpetiformis
Authors: E. L. Rhodes
Journal: British Journal of Dermatology (1978)

Journal Article Sodium cromoglycate in the treatment of dermatitis herpetiformis Get access E. L. Rhodes E. L. Rhodes Department of Dermatology, St Helier Hospital, Carshalton, Surrey Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 99, Issue 5, 1 November 1978, Pages 581–582, https://doi.org/10.1111/j.1365-2133.1978.tb02029.x Published: 01 November 1978
Fat feeding in humans induces lipoproteins of density less than 1.006 that are enriched in apolipoprotein [a] and that cause lipid accumulation in macrophages.
Authors: T P Bersot, T L Innerarity, R E Pitas, S C Rall, K H Weisgraber, R W Mahley
Journal: Journal of Clinical Investigation (1986)

Formula diets containing lard or lard and egg yolks were fed to six normolipidemic volunteers to investigate subsequent changes in the composition of lipoproteins of d less than 1.006 g/ml and in their ability to bind and be taken up by receptors on mouse macrophages. Both formulas induced the formation of d less than 1.006 lipoproteins that were approximately 3.5-fold more active than fasting very low density lipoproteins (VLDL) in binding to the receptor for beta-VLDL on macrophages. Subfractionation of postprandial d less than 1.006 lipoproteins by agarose chromatography yielded two subfractions, fraction I (chylomicron remnants) and fraction II (hepatic VLDL remnants), which bound to receptors on macrophages. However, fraction I lipoproteins induced a 4.6-fold greater increase in macrophage triglyceride content than fraction II lipoproteins or fasting VLDL. Fraction I lipoproteins were enriched in apolipoproteins (apo) B48, E, and [a]. Fraction II lipoproteins lacked apo[a] but possessed apo B100 and apo E. The apo[a] was absent in normal fasting VLDL, but was present in the d less than 1.006 lipoproteins (beta-VLDL) of fasting individuals with type III hyperlipoproteinemia. The apo[a] from postprandial d less than 1.006 lipoproteins was larger than either of two apo[a] subspecies obtained from lipoprotein (a) [Lp(a)] isolated at d = 1.05-1.09. However, all three apo[a] subspecies were immunochemically identical and had similar amino acid compositions: all were enriched in proline and contained relatively little lysine, phenylalanine, isoleucine, or leucine. The association of apo[a] with dietary fat-induced fraction I lipoproteins suggests that the previously observed correlation between plasma Lp(a) concentrations and premature atherosclerosis may be mediated, in part, by the effect of apo[a] on chylomicron remnant metabolism.
Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes
Authors: Joel S. Parker, Michael Mullins, Maggie C.U. Cheang, Samuel Leung, David Voduc, Tammi Vickery, Sherri Davies, Christiane Fauron, Xiaping He, Zhiyuan Hu, John F. Quackenbush, Inge J. Stijleman, Juan Palazzo, J.S. Marron, Andrew B. Nobel, Elaine Mardis, Torsten O. Nielsen, Matthew J. Ellis, Charles M. Perou, Philip S. Bernard
Journal: Journal of Clinical Oncology (2009)

Purpose To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression–based “intrinsic” subtypes luminal A, luminal B, HER2-enriched, and basal-like. Methods A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen. Results The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for the combined model (subtype and tumor size) was a significant improvement on either the clinicopathologic model or subtype model alone. The intrinsic subtype model predicted neoadjuvant chemotherapy efficacy with a negative predictive value for pCR of 97%. Conclusion Diagnosis by intrinsic subtype adds significant prognostic and predictive information to standard parameters for patients with breast cancer. The prognostic properties of the continuous risk score will be of value for the management of node-negative breast cancers. The subtypes and risk score can also be used to assess the likelihood of efficacy from neoadjuvant chemotherapy.
Man with locked-in syndrome challenges GMC ruling on doctors' involvement in ending his life
Authors: C. Dyer
Journal: BMJ (2015)

A man with locked-in syndrome has launched a legal challenge to the General Medical Council’s (GMC) guidance limiting the extent to which doctors may help him in ending his life.

The man, referred to as Martin, asked the High Court in London to rule that GMC guidance on assisted suicide unreasonably prevents doctors from helping patients who want to die.

Martin, 50, who is almost totally paralysed after a stroke, tried to kill himself by refusing food and water, but the attempt failed “in distressing circumstances,” the …
Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization
Authors: Rakesh Verma, Iulia Kovari, Abdul Soofi, Deepak Nihalani, Kevin Patrie, Lawrence B. Holzman
Journal: Journal of Clinical Investigation (2006)

A properly established and maintained podocyte intercellular junction, or slit diaphragm, is a necessary component of the selective permeability barrier of the kidney glomerulus. The observation that mutation or deletion of the slit diaphragm transmembrane protein nephrin results in failure of podocyte foot process morphogenesis and concomitant proteinuria first suggested the hypothesis that nephrin serves as a component of a signaling complex that directly integrates podocyte junctional integrity with cytoskeletal dynamics. The observations made herein provide the first direct evidence to our knowledge for a phosphorylation-mediated signaling mechanism by which this integrative function is derived. Our data support the model that during podocyte intercellular junction formation, engagement of the nephrin ectodomain induces transient Fyn catalytic activity that results in nephrin phosphorylation on specific nephrin cytoplasmic domain tyrosine residues. We found that this nephrin phosphorylation event resulted in recruitment of the SH2-SH3 domain-containing adapter protein Nck and assembly of actin filaments in an Nck-dependent fashion. Considered in the context of the role of nephrin family proteins in other organisms and the integral relationship of actin dynamics and junction formation, these observations establish a function for nephrin in regulating actin cytoskeletal dynamics.
Trajectory Analysis of the Campus Serial Rapist Assumption
Authors: Kevin M. Swartout, Mary P. Koss, Jacquelyn W. White, Martie P. Thompson, Antonia Abbey, Alexandra L. Bellis
Journal: JAMA Pediatrics (2015)

<h3>Importance</h3> Rape on college campuses has been addressed recently by a presidential proclamation, federal legislation, advocacy groups, and popular media. Many initiatives assume that most college men who perpetrate rape are serial rapists. The scientific foundation for this perspective is surprisingly limited. <h3>Objective</h3> To determine whether a group of serial rapists exists by identifying cohesive groups of young men, indicated by their trajectories of rape likelihood across high school and college. <h3>Design, Setting, and Participants</h3> Latent class growth analysis of the 2 largest longitudinal data sets of adolescent sexual violence on college campuses using 2 distinct groups of male college students. The first group was used for derivation modeling (n = 847; data collected from August 1990 through April 1995) and the second for validation modeling (n = 795; data collected from March 2008 through May 2011). Final data analyses were conducted from February 16, 2015, through February 20, 2015. <h3>Main Outcomes and Measures</h3> Rape perpetration assessed using the Sexual Experiences Survey. <h3>Results</h3> Across samples, 178 of 1642 participants (10.8%) reported having perpetrated at least 1 rape from 14 years of age through the end of college. A 3-trajectory model best fit both the derivation and validation data sets. Trajectories reflected low or time-limited (92.6% of participants), decreasing (5.3%), and increasing (2.1%) rape patterns. No consistently high trajectory was found. Most men who perpetrated a rape before college were classified in the decreasing trajectory. During college, the increasing trajectory included 14 men (15.2%) who reported having perpetrated a rape, the decreasing trajectory included 30 men (32.6%), and the low or time-limited included 48 men (52.2%). No participant in the low or time-limited trajectory reported perpetrating a rape during more than 1 period. Most men (67 [72.8%]) who committed college rape only perpetrated rape during 1 academic year. <h3>Conclusions and Relevance</h3> Although a small group of men perpetrated rape across multiple college years, they constituted a significant minority of those who committed college rape and did not compose the group at highest risk of perpetrating rape when entering college. Exclusive emphasis on serial predation to guide risk identification, judicial response, and rape-prevention programs is misguided. To deter college rape, prevention should be initiated before, and continue during, college. Child and adolescent health care professionals are well positioned to intervene during the early teenage years by informing parents about the early onset of nonconsensual sexual behavior.