tbuckley/cabot-search huggingface dataset:
Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6) Stimulates Extracellular Signal–regulated Kinase (ERK) Activity in CD40 Signaling Along a Ras-independent Pathway
Authors: Masaki Kashiwada, Yumiko Shirakata, Jun-Ichiro Inoue, Hiroyasu Nakano, Kenji Okazaki, Ko Okumura, Tadashi Yamamoto, Hitoshi Nagaoka, Toshitada Takemori
Journal: The Journal of Experimental Medicine (1998)

CD40 activates nuclear factor kappa B (NFκB) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal–regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor–associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NFκB activation. Here we report that transient expression of TRAF6 stimulated both ERK and NFκB activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH2-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40Δ246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40Δ246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40Δ246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.
Dok1 mediates high-fat diet–induced adipocyte hypertrophy and obesity through modulation of PPAR-γ phosphorylation
Authors: Tetsuya Hosooka, Tetsuya Noguchi, Ko Kotani, Takehiro Nakamura, Hiroshi Sakaue, Hiroshi Inoue, Wataru Ogawa, Kazutoshi Tobimatsu, Kazuo Takazawa, Mashito Sakai, Yasushi Matsuki, Ryuji Hiramatsu, Tomoharu Yasuda, Mitchell A Lazar, Yuji Yamanashi, Masato Kasuga
Journal: Nature Medicine (2008)
TWO PATIENTS WHO DETERMINED MY CAREER
Authors: J. Raison
Journal: BMJ (1996)

I was 17, home from school for Christmas with my surgeon father. He was aware of my unhappiness about his six year separation from my mother and of its persisting third party cause. In his affection he fostered my commitment to become a medical student.

When the telephone call came he asked if I would help him drive through the fog and wartime blackout to the children's hospital to deal with …
Prevention of Coronary and Stroke Events with Atorvastatin in Hypertensive Patients who have Average or Lower-than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial???Lipid Lowering Arm (ASCOT-LLA)
Authors: Peter S Sever, Bj??rn Dahl??f, Neil R Poulter, Hans Wedel, Gareth Beevers, Mark Caulfield, Rory Collins, Sverre E Kjeldsen, Arni Kristinsson, Gordon T McInnes, Jesper Mehlsen, Markku Nieminen, Eoin O'Brien, Jan ??stergren
Journal: Drugs (2004)
Recent Advances: Dermatology
Authors: M. H Lowitt, N. R. Lowitt
Journal: BMJ (1995)

Recent advances in dermatology and related fields have brought new answers to some old questions and new treatment options for some traditionally vexing diseases of the skin. This review focuses on several important reports of the past year, including progress in the understanding of pathogenesis, prevention, diagnosis, and treatment of some of the most difficult dermatologic maladies.

Since the discovery of its association with human immunodeficiency virus infection, Kaposi's sarcoma (1) has remained one of the most puzzling entities in the cutaneous repertoire of patients infected with HIV. An exhausting array of potential aetiological agents has been proposed.1 Until recently, even the basic categorisation of the condition (malignancy, reactive process, infection) has remained uncertain. Reports of Kaposi's sarcoma in homosexual men negative for HIV,2 coupled with the observation that among patients positive for HIV Kaposi's sarcoma was more common in homosexual men than in injecting drug users,3 led to the suspicion that the condition was sexually transmitted, presumably by a virus distinct from but often transmitted with HIV.



Fig 1 
HIV associated (epidemic) Kaposi's sarcoma



During the past year, several reports have emerged documenting the discovery of herpesvirus-like DNA sequences within Kaposi's sarcoma lesions.4 5 6 The DNA sequences (sometimes referred to as KS330(233) or KSHV) have been identified by polymerase chain reaction and by Southern blot hybridisation. These bits of DNA have been discovered in tissue from the lesions of patients with epidemic (HIV associated) Kaposi's sarcoma as well as classic Kaposi's sarcoma (on the legs of immunocompetent elderly men of Mediterranean descent) and African endemic Kaposi's sarcoma.5 The additional finding of similar sequences in tissue from some lymphomas in patients infected with HIV7 and in Kaposi's sarcoma from homosexual men negative for HIV6 lends support to the hypothesis that a novel group of …
P79 Bronchiectasis Severity In Primary Immunodeficiency - A Two Centre Study
Authors: A. Saleh, J. Hurst, J. Davison, C. Stroud, D. Lowe, A. De Soyza
Journal: Thorax (2014)

<h3>Introduction</h3> Up to 70% of patients with Primary Immunodeficiency syndromes such as Common Variable Immunodeficiency (CVID) have bronchiectasis. Within this population it is a major driver of morbidity.<sup>1</sup> The Bronchiectasis Severity Index (BSI) is capable of accurately categorising non-cystic fibrosis bronchiectasis patients into three severity groups that predict risk of hospitalisation and mortality at one and four years.<sup>2</sup> It consists of nine clinical parameters, and was derived and validated in a diverse international bronchiectasis population. Mild disease is defined as a BSI score of &lt;4, moderate 5–8 and severe &gt;9. This study aims to assess the relative severity of bronchiectasis associated with primary immunodeficiency. <h3>Methods</h3> 24 Patients from the Royal Free Hospital, London and 22 patients from the Freeman Hospital Newcastle were recruited. Age, body mass index,% predicted FEV1, number of hospitalisations in the last 2 years, number of exacerbations in the last year, medical research council dyspnoea (MRCD) score, Pseudomonas and other pathogen colonisation status and number or lobes involved on CT chest were obtained to calculate the BSI. Statistical analysis was carried out using SPSS V11. <h3>Results</h3> The 46 patients were 67.4% female with a mean age of 55.9. There were no significant differences in age, gender or disease severity between the two centres. The median BSI was 4 (i.e. mild disease). 56% of patients had mild disease, 21.7% were moderate and 21.7% severe bronchiectasis. These patients had markedly less severe disease than the mixed aetiology population of 603 patients used to derive the scoring tool. <h3>Conclusion</h3> Patients with primary Immunodeficiency associated bronchiectasis were younger with less severe disease compared to the BSI cohort population previously reported. This suggests good multidisciplinary care in Primary Immunodeficiency with earlier referral to respiratory specialists. It also correlates with our prior longitudinal data that FEV1 decline in immunodeficiency-related bronchiectasis is less rapid than other aetiologies.<sup>1</sup> <h3>Reference</h3> Hurst JR <i>et al</i>. Activity, severity and impact of respiratory disease in primary antibody deficiency syndromes. J C Immunol 2014;34:68–75 Chalmers JD <i>et al</i>. The bronchiectasis severity index. An international derivation and validation study. Am J RCCM 2014;189:576–585
The Treatment of Rheumatism by Blisters
Authors: A. B. R. Myers
Journal: BMJ (1882)

pain of to-morrow is all the greater from the anaethesia of to-day.Of two patients suffering from dental caries and who are intent upon con- tinuing the presence of the offending organ in the mouth, the one who submits to the pain without using anaesthetic remedies will get over the action which is causing the neuralgia much sooner, and will get better with a far less expenditure of patience in suffering than the man or woman who flies to stimulants for temporary relief from distress.The alcohol simply delays the action which is necessary for the removal of the exciting cause, and does not at all assist to its cure.In theoris- ing, however, upon the subject of alcoholic indulgence, we must bear in mind that, as a rule, children are total abstainers ; and I believe that, if we could separate those who have no hereditary taint in their dental appendages, and then follow the total abstainers through life, and compare them in their decline of years, it would be found that the total abstainers had suffered comparatively little from neuralgia
THE USES AND MISUSES OF VACCINES
Authors: J. A. B. Hicks
Journal: BMJ (1931)

recover aural health spontaneously.It is the recognition of those who do not thus recover aural health which is important, for a proportion of them wvill drift on to deaf- ness, which is as preventable in its early stages as it is irremediable in the stage in which we generally see it.The conditions which tend to cause the maintenance of the state of inflammation should be kept in mind.I will not deal with them, for, except for the occasional occurrcnce of a sinusitis, or a tonsillitis, they are the province of the physicians, who tell us that anaemias, liver deficiencies, constipation, acidosis, and the presence of a toxic focus are the common causes of the failure of estab- lishment of immunity from an infection.
Tuberculosis contact tracing.
Authors: C. Teale, D. B. Cundall, S. B. Pearson
Journal: BMJ (1992)

sampling error (probably the most important single cause of lack of correlation between histo- logical and cytological findings).Negative results ofsmear tests in women with cervical intraepithelial neoplasia grade III have also been attributed to sampling error.We believe that the argument of progression and sampling error also applies to many cases of mild dyskaryosis in which biopsy specimens taken after some follow up period or at the time of the smear test show cervical intra- epithelial neoplasia grade III.
Visualization and quantification of transmural concentration profiles of macromolecules across the arterial wall.
Authors: M S Penn, M R Koelle, S M Schwartz, G M Chisolm
Journal: Circulation Research (1990)

Transport parameters that describe a macromolecule entering the arterial wall from plasma can be obtained from concentration profiles of the labeled macromolecule entering the tissue. A new technique has been developed for measuring such concentration profiles, which offers spatial resolution superior to methods that measure profiles of radiolabeled macromolecules by serially sectioning tissue in planes parallel to the endothelium. In addition, this new method preserves cellular organization and tissue structure and permits measurement of concentration profiles underlying focal endothelial injuries or vascular lesions. The technique quantifies the concentration of a protein by measuring associated peroxidase activity. Although the present study was performed using horseradish peroxidase (HRP), the same principles can be applied to other macromolecules linked to HRP or microperoxidase. The colored reaction product of HRP was detected in transverse aortic sections using an image processing system. In the present study, profiles obtained by this new method were validated by comparison with HRP concentration profiles in rat aortas obtained by a serial slicing technique using radiolabeled HRP. We used the technique to measure high-resolution HRP concentration profiles in the intima and media of normal animals. These concentration profiles suggest that the internal elastic lamina acts as a major barrier to transport of macromolecules across the wall of the normal rat aorta. The new method should allow concentration profiles for macromolecules to be quantified in tissue surrounding vessels in the microcirculation, within the thickened intima of large vessels, and across coronary artery walls.
Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1
Authors: R Oostvogels, M C Minnema, M van Elk, R M Spaapen, G D te Raa, B Giovannone, A Buijs, D van Baarle, A P Kater, M Griffioen, E Spierings, H M Lokhorst, T Mutis
Journal: Leukemia (2012)

Donor T cells directed at hematopoietic system-specific minor histocompatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8+ cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA)-matched sibling. UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag+ hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus, with the capacity to induce relevant immunotherapeutic CTLs, it's HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based immunotherapy.
Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A
Authors: Hirokazu Kashiwagi, Masamichi Shiraga, Hisashi Kato, Tsuyoshi Kamae, Naoko Yamamoto, Seiji Tadokoro, Yoshiyuki Kurata, Yoshiaki Tomiyama, Yuzuru Kanakura
Journal: Blood (2005)
Older people are not getting discreet and appropriate continence care
Authors: J. Carlowe
Journal: BMJ (2009)

Older people are not always being treated with dignity when it comes to continence care, says research released this week.

Two studies, carried out by the University of Kent and the Royal College of Physicians’ Clinical Effectiveness and Evaluation Unit, found a huge variation in the quality of care given to patients with continence problems.

Key concerns raised by the findings related to dignity, privacy, and cleanliness.

In the first study researchers interviewed 33 people between the ages of 68 and 89 over a four month period about continence issues and how these affected their dignity. In the second study 10 patients were observed.

Both studies were conducted …
Quadriceps Weakness and Osteoarthritis of the Knee
Authors: Charles Slemenda
Journal: Annals of Internal Medicine (1997)

Background: The quadriceps weakness commonly associated with osteoarthritis of the knee is widely believed to result from disuse atrophy secondary to pain in the involved joint. However, quadriceps weakness may be an etiologic factor in the development of osteoarthritis. Objective: To explore the relation between lower-extremity weakness and osteoarthritis of the knee. Design: Cross-sectional prevalence study. Setting: Population-based, with recruitment by random-digit dialing. Participants: 462 volunteers 65 years of age or older. Measurements: Radiographs of the knee were graded for the presence of osteoarthritis. Knee pain and function were assessed with the Western Ontario and McMaster Universities Arthritis Index, the strength of leg flexors and extensors was assessed with isokinetic dynamometry, and lower-extremity lean tissue mass was assessed with dual-energy x-ray absorptiometry. Results: Among participants with osteoarthritis, quadriceps weakness, but not hamstring weakness, was common. The ratio of extensor strength to body weight was approximately 20% lower in those with than in those without radiographic osteoarthritis. Notably, among women with tibiofemoral osteoarthritis, extensor weakness was present in the absence of knee pain and was seen in participants with normal lower-extremity lean mass (extensor strength, 30.1 lb-ft for those with osteoarthritis and 34.8 lb-ft for those without osteoarthritis; P < 0.001). After adjustment for body weight, age, and sex, lesser quadriceps strength remained predictive of both radiographic and symptomatic osteoarthritis of the knee (odds ratio for prevalence of osteoarthritis per 10 lb-ft loss of strength, 0.8 [95% CI, 0.71 to 0.90] for radiographic osteoarthritis and 0.71 [CI, 0.51 to 0.87] for symptomatic osteoarthritis). Conclusion: Quadriceps weakness may be present in patients who have osteoarthritis but do not have knee pain or muscle atrophy; this suggests that the weakness may be due to muscle dysfunction. The data are consistent with the possibility that quadriceps weakness is a primary risk factor for knee pain, disability, and progression of joint damage in persons with osteoarthritis of the knee. For author affiliations and current author addresses, see end of text.
Modern Cardiac Surgery
Authors: Alan T. Marty
Journal: JAMA (1980)

This book alternates its attention between the growing edge of cardiac surgery and established cardiac surgical practice. More than half is devoted to congenital heart disease. Recoarctation after infant coarct repair is shown to be preventable with the subclavian angioplastic technique. Novel solutions for more difficult problems are also suggested. For instance, when a distinct pulmonary artery is angiographically absent in patients with pulmonary atresia, meticulous surgical exploration of the lung hilum can result in the discovery of a vessel suitable for aortopulmonary shunting. "Myocardial protection"—the current euphemism for minimizing operative myocardial injury—is well covered, as are complicated atrial septal defects, transposition, transplantation, and the merits of valvuloplasty vs valve replacement. Regarding the latter, one particularly deft chapter explains why the mere surgical imposition of a rigid mitral prothesis puts a considerable segment of ventricular muscle out of action. Nuances, such as what really causes the abnormal superior ECG axis
The gas we pass
Authors: George Dunea
Journal: BMJ (2004)

Benjamin Franklin once wrote that “it is universally known that in digesting our common food there is produced in the bowels of human creatures a great quantity of wind.” As escaping gas is offensive because of its smell, and retained gas causes pain and disease, he wished one would discover a drug that “shall render the natural discharges of wind from our bodies, not only inoffensive, but agreeable as perfumes.”

Alas, no such …
Free radicals and reperfusion-induced arrhythmias: protection by spin trap agent PBN in the rat heart.
Authors: D J Hearse, A Tosaki
Journal: Circulation Research (1987)

Using the isolated perfused rat heart with transient (10-minute) regional ischemia induced by coronary artery ligation, we have shown that PBN (N-tert-butyl-alpha-phenylnitrone), an organic spin trap agent designed specifically to form "stable" adducts with free radicals in electron spin resonance studies, can dramatically reduce the vulnerability of the myocardium to reperfusion-induced ventricular fibrillation. Studied in the concentration range of 5-1,000 microM/L, PBN added to the perfusate 5 minutes prior to ischemia exerted a dose-dependent protective effect. At the optimum concentration of 30 microM/L PBN reduced the incidence of ventricular fibrillation to 50% (6 of 12) from its control value of 100% (12 of 12). The antiarrhythmic effect was achieved without any substantial effect on coronary flow or heart rate. Investigating whether this was a direct antiarrhythmic effect, operating during reperfusion, or an indirect effect arising from the action of PBN on the heart during ischemia, PBN (30 microM/L) was added to the perfusion fluid 2 minutes before reperfusion. In the control group, 100% of the hearts fibrillated whereas only 50% fibrillated in the PBN group. Additional studies were designed to ascertain whether the drug caused an absolute reduction in vulnerability to reperfusion-induced arrhythmias (irrespective of the duration of ischemia) or whether it only shifted the ischemic time-reperfusion vulnerability curve to the right (i.e., delayed the onset of vulnerability). Thus, studies were undertaken to define the relation between the duration of ischemia and the incidence of reperfusion-induced arrhythmias in control hearts and hearts treated with PBN.(ABSTRACT TRUNCATED AT 250 WORDS)
Iron Overload, Public Health, and Genetics: Evaluating the Evidence for Hemochromatosis Screening
Authors: Mary E. Cogswell
Journal: Annals of Internal Medicine (1998)

Population screening for hemochromatosis done by using the transferrin saturation test has been advocated by experts to permit the initiation of therapeutic phlebotomy before the onset of clinical disease.The discovery of a gene associated with hemochromatosis has made DNA testing another option for screening and diagnosis. In this paper, U.S. Preventive Services Task Force criteria are used to evaluate the evidence for the usefulness of population screening done by using iron measures or genetic testing. Published clinical research offers little evidence to suggest that population screening for hemochromatosis done by using genetic testing improves clinical outcomes.Although one recently discovered mutation, C282Y, accounts for 60% to 92% of cases of the disease in series of patients with hemochromatosis, uncertainties remain about the clinical penetrance of various genotypes; the accuracy of genetic testing; and the ethical, legal, and social effects of genetic testing. Before population screening for hemochromatosis done by using transferrin saturation testing can be recommended, laboratory standardization needs to be addressed and questions about risk for clinical disease in asymptomatic persons with mutations or early biochemical expression of disease require resolution. Evidence from case series suggests that hemochromatosis may be associated with liver cancer, other liver disease, diabetes, bradyarrhythmias, and arthritis. In all studies but one, however, estimation of the magnitude and significance of this risk is limited by lack of adequate comparison groups. The need for population data to answer questions about penetrance among asymptomatic persons should not impede efforts to increase the detection and treatment of hemochromatosis in persons found to have elevated iron measures, a family history of hemochromatosis, or consistent early signs and symptoms of the disease.