tbuckley/cabot-search huggingface dataset:
Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care
Authors: Katharine Bushby, Richard Finkel, David J Birnkrant, Laura E Case, Paula R Clemens, Linda Cripe, Ajay Kaul, Kathi Kinnett, Craig McDonald, Shree Pandya, James Poysky, Frederic Shapiro, Jean Tomezsko, Carolyn Constantin
Journal: The Lancet Neurology (2009)
New Section in <i>Circulation</i> : Implications of Contemporary Clinical Trials
Authors: Elliott Antman, Marc Pfeffer, William Stevenson, Joseph Loscalzo
Journal: Circulation (2010)

We are pleased to announce to our readers the launch of a new section in Circulation.The purpose is to provide a perspective on contemporary clinical trials in cardiovascular medicine.These trials need not be published in Circulation but must fulfill a minimum set of criteria so as to allow a multidisciplinary discussion of the trial across at least three of the following domains: clinical practice (medical/interventional), trial design and interpretation, regulatory implications, cardiovascular physiology, epidemiology, and health services research.Authors representing the three domains are invited to write a brief and independent commentary from a focused point of view.Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) 1 is a suitable trial to inaugurate this effort.Its purpose was to evaluate two management strategies for ischemic heart disease and 2 treatment approaches for glycemia in patients with type 2 diabetes mellitus and coronary artery disease (Ն50% stenosis and positive stress test or Ն70% and classical angina).All patients had to be considered eligible for elective percutaneous coronary intervention or coronary-artery bypass grafting prior to randomization.However, it is important to note that BARI 2D was not a comparison of percutaneous coronary intervention versus coronary-artery bypass grafting; the prespecified intended form of revascularization was used to stratify the randomization.Using a factorial design, the investigators compared an initial medical management strategy versus immediate revascularization and either an insulin-sensitizing or insulin-providing therapy.At 5 years, all cause mortality did not differ between the groups assigned to an initial medical therapy approach or immediate revascularization or between those receiving an insulin-sensitizing or insulin-providing glycemic treatment.Freedom from major cardiovascular events was significantly lower in the coronary-artery bypass grafting stratum among those allocated to immediate revascularization compared with initial medical therapy; a significant interaction with glycemic strategy was observed favoring the use of an insulin-sensitizing approach in those patients undergoing coronary-artery bypass grafting.Drs. Allison Goldfine and Vivian Fonseca discuss the impact of BARI 2D on management of diabetes mellitus; Dr. Valentin Fuster discusses the general cardiologist's decision making regarding revascularization in patients with type 2 diabetes mellitus; and Dr. Scott Solomon discusses the lessons learned from BARI 2D with respect to design and interpretation of cardiovascular trials in patients with diabetes mellitus.
Wolff-Parkinson-White syndrome in children: electrophysiologic and pharmacologic characteristics.
Authors: P C Gillette, A Garson, J D Kugler
Journal: Circulation (1979)

Intracardiac electrophysiologic studies were performed on 28 infants and children, ages 1 month to 18 years, with the Wolff-Parkinson-White syndrome to try to determine 1) the electrophysiologic characteristics of the accessory connection and 2) the mechanisms of associated supraventricular dysrhythmias. Although the antegrade refractory periods of the normal conduction system were shorter than those found in adults, those of the accessory connection were slightly longer. Reciprocating supraventricular tachycardia (SVT), which had been a clinical problem in 26 of 28, could be induced in the laboratory in all 26 subjects. The mechanism involved reentry with antegrade conduction through the atrioventricular (AV) node and retrograde through the accessory connection in 22. Eleven of these 22 had a wide QRS during tachycardia due to a bundle branch block. Three other subjects had wide QRS tachycardia, but the mechanism involved antegrade conduction through the accessory connection and retrograde through the AV node. The other patient had AV node reentry tachycardia. Two patients did not have clinical SVT, and in these two, SVT could not be induced. Neither patient had retrograde conduction through the accessory connection. The site of the accessory connection could be identified in 26 subjects by the sequence of retrograde activation of the atrium during SVT or ventricular pacing. Digitalis shortened the refractory period of the accessory connection in five of the eight patients studied.
A Feed-Forward Loop Involving Protein Kinase Cα and MicroRNAs Regulates Tumor Cell Cycle
Authors: Ezra E.W. Cohen, Hongyan Zhu, Mark W. Lingen, Leslie E. Martin, Wen-Liang Kuo, Eugene A. Choi, Masha Kocherginsky, Joel S. Parker, Christine H. Chung, Marsha Rich Rosner
Journal: Cancer Research (2008)

Protein kinase Calpha (PKCalpha) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKCalpha promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKCalpha inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCalpha inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKCalpha down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKCalpha and cyclin E protein expression are increased in primary tumors, and PKCalpha inversely correlates with miR-15a expression in primary tumors. Finally, PKCalpha is associated with poor prognosis in SCCHN. These results identify PKCalpha as a key regulator of SCCHN tumor cell growth by a mechanism involving activation of mitogen-activated protein kinase, an initiator of the cell cycle, and suppression of miR-15a, an inhibitor of DNA synthesis. Although the specific components may be different, this type of feed-forward loop network, consisting of a stimulus that activates a positive signal and removes a negative brake, is likely to be a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli.
Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial
Authors: Gerhard Hindricks, Milos Taborsky, Michael Glikson, Ullus Heinrich, Burghard Schumacher, Amos Katz, Johannes Brachmann, Thorsten Lewalter, Andreas Goette, Michael Block, Josef Kautzner, Stefan Sack, Daniela Husser, Christopher Piorkowski, Peter Søgaard
Journal: The Lancet (2014)
Diagnosis and Management of Hereditary Hemochromatosis
Authors: L S Valberg, C N Ghent
Journal: Annual Review of Medicine (1985)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
Urinary N-telopeptide (uNTx) is an independent prognostic factor for overall survival in patients with bone metastases from castration-resistant prostate cancer
Authors: S. Rajpar, C. Massard, A. Laplanche, E. Tournay, M. Gross-Goupil, Y. Loriot, M. Di Palma, A. Bossi, B. Escudier, A. Chauchereau, K. Fizazi
Journal: Annals of Oncology (2010)
Allergy testing in supermarkets: Misleads susceptible people
Authors: A B Kay, J C Ashley, M J Nelson
Journal: BMJ (1994)

working in primary care in the early stages of illness and to coordinate the many agencies that may help patients with late stage HIV infection.It is essential that we work in partnership with general practitioners and their facilitators to encourage more general practitioners to achieve the high standards of care of patients with HIV infection provided by many of their colleagues.
The occupational contribution to severe exacerbation of asthma
Authors: P. K. Henneberger, M. C. Mirabelli, M. Kogevinas, J. M. Anto, E. Plana, A. Dahlman-Hoglund, D. L. Jarvis, H. Kromhout, L. Lillienberg, D. Norback, M. Olivieri, K. Radon, K. Toren, I. Urrutia, S. Villani, J. P. Zock
Journal: European Respiratory Journal (2010)

The goal of this study was to identify occupational risk factors for severe exacerbation of asthma and estimate the extent to which occupation contributes to these events. The 966 participants were working adults with current asthma who participated in the follow-up phase of the European Community Respiratory Health Survey. Severe exacerbation of asthma was defined as self-reported unplanned care for asthma in the past 12 months. Occupations held in the same period were combined with a general population job-exposure matrix to assess occupational exposures. 74 participants reported having had at least one severe exacerbation event, for a 1-yr cumulative incidence of 7.7%. From regression models that controlled for confounders, the relative risk (RR) was statistically significant for low (RR 1.7, 95% CI 1.1–2.6) and high (RR 3.6, 95% CI 2.2–5.8) biological dust exposure, high mineral dust exposure (RR 1.8, 95% CI 1.02–3.2), and high gas and fumes exposure (RR 2.5, 95% CI 1.2–5.5). The summary category of high dust, gas, or fumes exposure had RR 3.1 (95% CI 1.9–5.1). Based on this RR, the population attributable risk was 14.7% among workers with current asthma. These results suggest occupation contributes to approximately one in seven cases of severe exacerbation of asthma in a working population, and various agents play a role.
Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease
Authors: Dick de Zeeuw, Tadao Akizawa, Paul Audhya, George L. Bakris, Melanie Chin, Heidi Christ-Schmidt, Angie Goldsberry, Mark Houser, Melissa Krauth, Hiddo J. Lambers Heerspink, John J. McMurray, Colin J. Meyer, Hans-Henrik Parving, Giuseppe Remuzzi, Robert D. Toto, Nosratola D. Vaziri, Christoph Wanner, Janet Wittes, Danielle Wrolstad, Glenn M. Chertow
Journal: New England Journal of Medicine (2013)

Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown.We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes.The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group.Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).
Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma
Authors: Emily Z. Keung, Kadir C. Akdemir, Ghadah A. Al Sannaa, Jeannine Garnett, Dina Lev, Keila E. Torres, Alexander J. Lazar, Kunal Rai, Lynda Chin
Journal: Journal of Clinical Investigation (2015)

Liposarcoma (LPS) can be divided into 4 different subtypes, of which well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) are the most common. WDLPS is typically low grade, whereas DDLPS is high grade, aggressive, and carries a worse prognosis. WDLPS and DDLPS frequently co-occur in patients. However, it is not clear whether DDLPS arises independently from WDLPS, or whether epigenomic alterations underly the histopathological differences of these subtypes. Here, we profiled 9 epigenetic marks in tumor samples from 151 patients with LPS and showed elevated trimethylation of histone H3 at Lys9 (H3K9me3) levels in DDLPS tumors. Integrated ChIP-seq and gene expression analyses of patient-derived cell lines revealed that H3K9me3 mediates differential regulation of genes involved in cellular differentiation and migration. Among these, Kruppel-like factor 6 (KLF6) was reduced in DDLPS, with increased H3K9me3 at associated regulatory regions. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and increased expression of the adipogenesis-associated factors PPARγ, CEBPα, and CEBPβ, suggesting that increased H3K9me3 may mediate DDLPS-associated aggressiveness and dedifferentiation properties. KLF6 overexpression partially phenocopied chaetocin treatment in DDLPS cells and induced phenotypic changes that were consistent with adipocytic differentiation, suggesting that the effects of increased H3K9me3 may be mediated through KLF6. In conclusion, we provide evidence of an epigenetic basis for the transition between WDLPS and DDLPS.
Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis.
Authors: M A Johnson, S Kwan, N J Snell, A J Nunn, J H Darbyshire, M Turner-Warwick
Journal: Thorax (1989)

In a randomised, controlled study alternate day prednisolone with an initial high dose phase ("prednisolone only series") has been compared with cyclophosphamide plus alternate day low dose prednisolone ("cyclophosphamide-prednisolone series") in 43 patients with previously untreated fibrosing alveolitis (five patients had received prednisolone in minimal dosage). In the prednisolone only series prednisolone 60 mg daily was given for one month and then reduced by 5 mg a week to 20 mg on alternate days or the minimum dose to maintain early improvement. Patients in the cyclophosphamide-prednisolone series received 100, 110, or 120 mg cyclophosphamide daily (depending on body weight) plus 20 mg prednisolone on alternate days. Treatment was continued indefinitely, or changed to the alternative regimen if the patient deteriorated, failed to improve, or developed drug toxicity. For response to treatment (as judged by change in breathlessness score, radiographic appearance, and lung function) patients were classified as improved, stable, or deteriorating. Deaths from cryptogenic fibrosing alveolitis were also analysed. Improvement had occurred at one or more assessments in seven of the 22 patients in the prednisolone only series and in five of the 21 patients in the cyclophosphamide-prednisolone series. At three years, however, only two of the 22 patients in the prednisolone only series were still improved and three stable, compared with one and seven of the 21 patients in the cyclophosphamide-prednisolone series (three of the seven had stopped treatment because of toxicity). Life table analysis suggested better survival in patients in the cyclophosphamide-prednisolone series but this was not significant. At three years 10 of 22 patients in the prednisolone only series had died compared with three of 21 patients in the cyclophosphamide-prednisolone series. With death or failure of first treatment regimen as outcome there was a significant advantage to the patients having cyclophosphamide-prednisolone. This advantage was explained in part by the better lung volumes in this group on admission. After allowance had been made for total lung capacity (TLC), no other factor was predictive of outcome. Analyses of subgroups according to TLC on admission showed that patients with a TLC below 60% predicted did badly and those with a TLC of 80% or more predicted did well with both regimens. Patients with an initial TLC of 60-79% predicted did better with the cyclophosphamide-prednisolone regimen. Side effects were uncommon in both series and those due to cyclophosphamide resolved when treatment was stopped. The combination of cyclophosphamide with prednisolone may be an alternative to prednisolone alone with an initial high dose phase. Many patients, however, failed to respond to either treatment.
Protein Kinase Cε Overexpression Alters Myofilament Properties and Composition During the Progression of Heart Failure
Authors: Paul H. Goldspink, David E. Montgomery, Lori A. Walker, Dalia Urboniene, Ronald D. McKinney, David L. Geenen, R. John Solaro, Peter M. Buttrick
Journal: Circulation Research (2004)

We report characterization of a transgenic mouse that overexpresses constitutively active protein kinase Cepsilon in the heart and slowly develops a dilated cardiomyopathy with failure. The hemodynamic, mechanical, and biochemical properties of these hearts demonstrate a series of temporal events that mark the progression of the disease. In the 3-month transgenic (TG) animals, contractile properties and gene expression measurements are normal, but an increase in myofibrillar Ca2+ sensitivity and thin filament protein phosphorylation is noted. At 6 months, there is a decrease in the myofibrillar Ca2+ sensitivity, a significant increase in beta-myosin heavy chain mRNA and protein, normal cardiac function, but a blunted response to an inotropic challenge. The transition at 9 months is especially interesting because age-related changes appear to contribute to the decline in function seen in the TG heart. At this point, there is a decline in baseline function and maximum tension produced by the myofibrils, which is coincident with the onset of atrial myosin light chain isoform re-expression in the ventricles. In the 12-month TG mice, there is clear hemodynamic and geometric evidence of failure. Alterations in the composition of the myofibrils persist but the phosphorylation of myosin light chain 2v is dramatically different at this age compared with all others. We interpret these data to implicate the disruption of the myofibrillar proteins and their interactions in the propagation of dilated cardiac disease.
Genomic and Proteomic Analyses Reveal Non-Neofunctionalized Vitellogenins in a Basal Clupeocephalan, the Atlantic Herring, and Point to the Origin of Maturational Yolk Proteolysis in Marine Teleosts
Authors: B. A. Kristoffersen, A. Nerland, F. Nilsen, J. Kolarevic, R. N. Finn
Journal: Molecular Biology and Evolution (2009)

Oocyte hydration is a unique event in oviparous marine teleosts that provides the single-celled egg with an essential pool of water for survival during early development in the saline oceanic environment. A conserved mechanism of maturational yolk proteolysis of a neofunctionalized vitellogenin (VtgAa) has been shown to underlie the hydration event in all teleosts that spawn pelagic eggs (pelagophils), and is argued to be a key adaptation for teleost radiation in the oceanic environment 55 Ma. We have recently shown that a small pool of free amino acids (FAAs) significantly contributes to the osmolarity of the ovulated egg in an ancestral marine teleost, the Atlantic herring that spawns benthic eggs (benthophil). To determine whether multiple forms of vtg exist and whether neofunctionalization of the gene products are related to the egg FAA pool in this species, genomic sequences conserved between the exons of Atlantic herring and zebrafish were amplified. This approach identified a small polymorphic intron between exons 9 and 10 in Atlantic herring and demonstrated that two closely related major vtg transcripts (chvtgAc1 and chvtgAc2) are expressed during oogenesis. A separate polymerase chain reaction–based approach identified a more ancestral phosvitinless transcript (chvtgC). Proteomic analyses of the translated products of the major vtg forms demonstrated that the yolk proteins are similarly processed during deposition, and oocyte maturation and reveal that vtgs have duplicated but not neofunctionalized in this species. Phylogenetic analyses consistently clustered the transcripts and proteins as the basal sister group to the Ostariophysi in full congruence with the Clupeocephalan rank, and suggest that expansion of ostariophysan vtgAo1 and vtgAo2 genes occurred in a lineage-specific manner after separation from the Clupeiformes. Three-dimensional modeling of the ChvtgAc1 sequence against the resolved lamprey lipovitellin module revealed that the tertiary structure is highly conserved, with most substitutions occurring on the outside of the molecule. The data indicate that the phosvitin domain, the smallest yet reported for teleosts, and an N-terminal fragment of the lipovitellin light chain contribute to the FAA pool. The present findings thus show that yolk proteolysis and the generation of an organic osmolyte pool of FAAs was an adaptive response to spawning in seawater also for the Clupeiformes, but that this process was not evolutionarily successful in terms of biodiversity until vtg gene neofunctionalization occurred in the Acanthomorpha.
Ocular manifestations of AIDS
Authors: M. D. de Smet
Journal: JAMA (1991)

<h3>SELECTED CASES</h3><h3>Case 1</h3> A 58-YEAR-OLD bisexual man presented to the eye clinic of the National Institutes of Health, Clinical Center, Bethesda, Md, with a 2-day history of shadows in his left eye that had progressed to a more confluent clouding of his peripheral field. Visual acuity was 6/6 (20/20) in his right eye and 6/12 (20/40) in his left. Retinal examination revealed an area of hemorrhagic retinitis extending to within 2 disc diameters of his optic nerve. A white perivascular sheath was noted along major vessels beyond the area of involvement. A diagnosis of cytomegalovirus (CMV) retinitis was made and the patient was started on ganciclovir sodium (5 mg/kg intravenously, twice a day) with resolution of the retinitis. However, after 6 weeks on maintenance ganciclovir therapy (5 mg/kg, once a day), he noted further change in his vision and had funduscopic evidence of CMV reactivation. He was given another
Murder in the Family: A Study of Some Homicidal Adolescents
Authors: JANE WATSON DUNCAN, GLEN M. DUNCAN
Journal: American Journal of Psychiatry (1971)

Five cases are presented in which a homicidal adolescent`s abrupt loss of control was associated with a change in his interpersonal relationship with the victim, together with a sequence of events progressively more unbearable and less amenable to his control. The authors suggest criteria for assessing the adolescent's potential for homicidal behavior within the family. A history of parental brutality is a significant consideration.