tbuckley/cabot-search huggingface dataset:
Malaria: Submerged Awareness-Reply
Authors: Piero Olliaro
Journal: JAMA (1996)

<h3>In Reply.</h3> —Dr Hartwig's letter emphasizes some important points raised by our article. Indeed, we agree with Hartwig that malaria continues to be a major health threat throughout much of the tropical world. The title referred to the limited and diminishing awareness of this health threat in the United States and elsewhere in the industrialized world. The goal of the article was to alert readers to this problem. The looming crisis of parasite drug resistance presents an immediate threat to everyone who experiences acute episodes of malaria, including immune adults. It is especially threatening to all nonimmune persons, including children less than 5 years of age, pregnant women, both from endemic and nonendemic areas, refugees, migrant workers, and travelers. Antimalaria drug therapy remains the primary intervention for malaria infection worldwide, and drug resistance will compromise this intervention. Malaria is not the only infectious disease for which drug resistance is emerging
Abstract IA7: Novel mechanisms of resistance in BRAF-mutant melanoma
Authors: Poulikos I. Poulikakos
Journal: Clinical Cancer Research (2012)

Abstract Tumors with mutant BRAF(V600E) are dependent on ERK signaling for their growth. Unlike MEK inhibitors that suppress ERK signaling in all cells, RAF inhibitors suppress ERK signaling in cells with mutant BRAF, but paradoxically enhance ERK signaling in tumor and normal cells with wild-type BRAF. The mechanistic basis of this phenomenon lies in the interaction of these drugs with RAF dimers. Active RAS promotes homo- and heterodimerization of RAF. Binding of drug to one protomer in the RAF dimer transactivates the other. In BRAF(V600E) tumors, RAS is not activated, RAF is a monomer and thus transactivation is minimal. In these tumors, RAF inhibitors bind to and inhibit the RAF monomer and effectively suppress ERK signaling. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumor activity than MEK inhibitors. Indeed, RAF inhibitors have shown remarkable clinical activity in patients with melanomas that harbor mutant BRAF(V600E), however, resistance invariably develops. The mechanism of action of these drugs suggests that drug resistance could result from any lesion that increases RAF dimerization. These could include mechanisms that increase RAS activation in the tumor cells or lesions that cause RAF to dimerize in a RAF-independent manner. Indeed, mutations in NRAS and activation of receptor tyrosine kinases have now been associated with innate or acquired resistance to RAF inhibitors. We have found that aberrantly spliced forms of BRAF(V600E) are associated with resistance to RAF inhibitors in preclinical models and in patients that relapsed on the RAF inhibitor vemurafenib (PLX4032). These variants lack the RAS-binding domain, constitutively homodimerize in cells with low levels of RAS activity and confer resistance to the drug. Thus, RAF dimerization emerges as a common theme in RAF-inhibitor resistance mechanisms. Since a large part of resistance to RAF inhibitors is attributable to attenuation of the ability of the drug to inhibit RAF, one would predict that such tumors would retain at least partial sensitivity to inhibitors of downstream effectors of RAF such as MEK or ERK. Therefore, combinatorial approaches targeting upstream or downstream of RAF in addition to RAF inhibitors may delay or prevent the onset of these mechanisms of resistance.
Food as a Masticatory
Authors: Melvin Schlemenson
Journal: JAMA (1972)

<h3>To the Editor.—</h3> The need for weight reduction and weight control among overweight individuals has been well established. Frequently, it is necessary to reduce the weight of these individuals prior to elective surgery. Many methods of weight reduction including the use of drugs and surgical therapy (intestinal bypass) are now used. Each of these has wellknown disadvantages. Simple caloric restriction is extremely difficult for the obese compulsive eater. I have employed a simple method which has been effective. The patient follows a low caloric diet, but in order to satisfy the need for snacks and high caloric foods, the following program is recommended. The patient takes these foods into the mouth, chews them slowly, but does not swallow. Once mastication is completed, there are only two choices; swallowing, or ejecting into a bag or the garbage disposal. The food has served as a masticatory. The patient has had the satisfactions
Oral rapamycin for the prevention of in-stent restenosis
Authors: Roxana Mehran, Steven Marx, Srinivas Kesanakurthy, Yulia Adamian, Ali Aboufares, Issam Moussa, Spyros Kokolis, Michael Collins, Gishel New, Sotir Polena, Joseph Cosico, Alexandra J. Lansky, Jeffrey W. Moses, Gregg W. Stone, Martin B. Leon, George Dangas
Journal: Journal of the American College of Cardiology (2003)
Oxford Textbook of Clinical Hepatology
Authors: Frank Iber
Journal: JAMA (1992)

This new monograph was written largely by outstanding European investigators to contain all that is needed by the clinician treating liver disease. It is organized by 31 broad topics covering anatomy, pathology, pathogenesis, testing, clinical syndromes, and specific categories of disease and treatment. Special problems of systemic disease affecting the liver, effects of the liver on other organs, liver disease in the young or very old, and surgery are additional important topics. Each section is divided into one to 28 complete monographs on the particular topic at hand. The chapters feature boldface headings, line drawings, tables, and, occasionally, photomicrographs to present all information relevant to that topic. Several chapters are superbly illustrated with line drawings correlated with ultrasound and computed tomographic images, photomicrographs, or electron micrographs. Liver and portal vein anatomy, histology, function of sinusoidal cells, and structure of hepatic viruses are model chapters communicating clearly their message through combination
Screening Adults Aged 50 Years or Older for Hearing Loss: A Review of the Evidence for the U.S. Preventive Services Task Force
Authors: Roger Chou, Tracy Dana, Christina Bougatsos, Craig Fleming, Tracy Beil
Journal: Annals of Internal Medicine (2011)

Background: Hearing loss is common in older adults. Screening could identify untreated hearing loss and lead to interventions to improve hearing-related function and quality of life. Purpose: To update the 1996 U.S. Preventive Services Task Force evidence review on screening for hearing loss in primary care settings in adults aged 50 years or older. Data Sources: MEDLINE (1950 and July 2010) and the Cochrane Library (through the second quarter of 2010). Study Selection: Randomized trials, controlled observational studies, and studies on diagnostic accuracy were selected. Data Extraction: Investigators abstracted details about the patient population, study design, data analysis, follow-up, and results and assessed quality by using predefined criteria. Data Synthesis: Evidence on benefits and harms of screening for and treatments of hearing loss was synthesized qualitatively. One large (2305 participants) randomized trial found that screening for hearing loss was associated with increased hearing aid use at 1 year, but screening was not associated with improvements in hearing-related function. Good-quality evidence suggests that common screening tests can help identify patients at higher risk for hearing loss. One good-quality randomized trial found that immediate hearing aids were effective compared with wait-list control in improving hearing-related quality of life in patients with mild or moderate hearing loss and severe hearing-related handicap. We did not find direct evidence on harms of screening or treatments with hearing aids. Limitation: Non–English-language studies were excluded, and studies of diagnostic accuracy in high-prevalence specialty settings were included. Conclusion: Additional research is needed to understand the effects of screening for hearing loss compared with no screening on health outcomes and to confirm benefits of treatment under conditions likely to be encountered in most primary care settings. Primary Funding Source: Agency for Healthcare Research and Quality.
Detection of Anti-Glomercular Basement Membrane Antibodies by a Radioimmunological Technique CLINICAL APPLICATION IN HUMAN NEPHROPATHIES
Authors: P. Mahieu, P. H. Lambert, P. A. Miescher
Journal: Journal of Clinical Investigation (1974)

A radioimmunoassay for detection of anti-glomerular basement membrane (GBM) antibody was set up with a 70,000 mol wt GBM antigen, labeled with Iodine-(125)I and containing both types of oligosaccharidic chains present in the whole membrane. Separation of free radioactive antigens from antigens bound to immunoglobulins was obtained by precipitation with polyethylene glycol (mol wt, 6,000), at a final concentration of 20%. In the presence of normal human or rabbit sera, less than 20% of labeled antigens were precipitated. In the presence of rabbit anti-human GBM antibodies, up to 82% of GBM antigens were precipitated, while in the presence of sera or of kidney eluate from a patient with Goodpasture's syndrome, the precipitation of GBM antigens reached 43%. The avidity of rabbit anti-GBM antibodies for human GBM antigens is higher than that of human anti-GBM antibodies. In the case of Goodpasture's syndrome, the binding of anti-GBM antibodies to labeled antigens was inhibited more efficiently by the disaccharide-containing glycopeptide than by the heteropolysaccharide-containing glycopeptide purified from whole GBM.Anti-GBM antibodies were searched for in the serum of 300 normal blood donors, of 120 patients with glomerulonephritis (GN) and granular deposits, and of 14 patients with GN and linear deposits of immunoglobulins. After correction for the "nonspecific" precipitation, the average percentage (+/-1 SD) of labeled antigens precipitated in the serum of normal blood donors was 0.3+/-3.2%; 12 patients with GN and linear deposits exhibited high circulating anti-GBM antibody titers, while 8% of the patients with GN and granular deposits presented significant, albeit lower, anti-GBM activity in their sera.
Abstract 3067: Improved detection of BRAF mutation in clinical samples using PNA-mediated real-time PCR clamping techniques
Authors: Miae Oh, Minhye Cho, Jae-Jin Choi, Heekyung Park
Journal: Cancer Research (2011)

Abstract The BRAF mutation is a somatic mutation with the highest pathogenic cancer-associated prevalence and a biomarker used for detecting cancer and monitoring prognosis of cancer patients. Usually, mutation in the Exon15 codons V600E mutation (1799 T&amp;gt;A) represent more than 90% of BRAF mutations. However, techniques using PCR and direct sequencing have limitations and are unable to detect low-level mutations in cancers to give false negative diagnoses. We have developed a highly sensitive and simple method for detecting BRAF mutations using PNA-mediated real-time PCR clamping, PNAClampTM. PNAClampTM method is a simple, reliable and sensitive method with a detection limit of approximately 0.1% mutant alleles. The turnaround time for this method was only 2 hours. The method was utilized to detect BRAF mutations in fine needle aspiration biopsy (FNAB) specimens from papillary thyroid cancer (PTC) patients. V600E mutation was detected in 62% (52/84) of the FNAB specimens in the PTC samples, 10% higher rate compare with PCR and direct sequencing methods. In this report, we will discuss the results of clinical studies in detail including the comparison data. In summary, PNAClampTM method can serve a rapid, reliable, and economical alternative for BRAF mutation detection in clinical settings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3067. doi:10.1158/1538-7445.AM2011-3067
Negative dromotropic effects of Class I antiarrhythmic drugs in anisotropic ventricular muscle
Authors: M. Iida, I. Kodama, J. Toyama
Journal: Cardiovascular Research (1996)

In a computer simulation study to mimic cardiac action potential, the total open time of the sodium channel at each excitation has been shown by other authors to be longer during propagation parallel (longitudinal, L) to fiber orientation than perpendicular (transverse, T) to that. If this is the case in actual cardiac tissue, the Class I antiarrhythmic drug action on conduction would be affected by their mode of sodium channel block. The present study was designed to test this hypothesis.Effects of flecainide (F), quinidine (Q), aprindine (A) and SD3212 (S) on conduction velocity (theta), amplitude of extracellular potentials (phi e), and maximum upstroke velocity (Vmax) of action potentials were examined in isolated rabbit ventricular muscles with microscopic anisotropy.F (0.1-1 microM) or Q (2-10 microM), which blocks the sodium channel mainly during the activated state, caused a concentration- and frequency-dependent decrease in theta and phi e. The reduction was more prominent during L than T propagation, giving rise to a decrease in their anisotropic ratio (theta L/theta T). A (1-5 microM) or S (3-10 microM), which blocks the channel during the inactivated state, also decreased theta and phi e. However, the reduction was similar during L and T propagation, and the anisotropic ratio of theta and phi e remained unaffected. The decrease of maximum upstroke velocity (Vmax) of action potential by F or Q was greater during L than T propagation; VmaxL/VmaxT was decreased significantly. In contrast, the Vmax reduction by A(3 microM) or S (10 microM) was similar during L and T propagation.Different state-dependence of sodium channel block may underlie different negative dromotropic effects of Class I drugs in anisotropic cardiac muscle.
Cytokine-dependent long-term culture of highly enriched precursors of hematopoietic progenitor cells from human bone marrow.
Authors: J Brandt, E F Srour, K van Besien, R A Briddell, R Hoffman
Journal: Journal of Clinical Investigation (1990)

Human marrow cells positive for the CD34 antigen but not expressing HLA-DR, CD15, or CD71 antigens were isolated. In a liquid culture system supplemented with 48-hourly additions of recombinant interleukins IL-1 alpha, IL-3, IL-6, or granulocyte/macrophage colony-stimulating factor (GM-CSF), these cells were capable of sustaining in vitro hematopoiesis for up to eight weeks. The establishment of an adherent cell layer was never observed. Cultures containing no exogenous cytokine produced clonogenic cells for only 1 wk. IL-1 alpha and IL-6 were alone able to support hematopoiesis for 2 or 3 wk. Cells maintained with GM-CSF proliferated and contained assayable colony-forming cells for 3 or 4 wk, while maximal cellular expansion and generation of assayable progenitor cells occurred in the presence of IL-3 for 4-5 wk. When IL-3 was combined with IL-1 alpha or IL-6, hematopoiesis was sustained for 8 wks. Basophil numbers were markedly increased in the presence of IL-3. These studies indicate that marrow subpopulations can sustain hematopoiesis in vitro in the presence of repeated additions of cytokines. We conclude that a major function of marrow adherent cells in long-term cultures is that of providing cytokines which promote the proliferation and differentiation of primitive hematopoietic cells.
Stromelysin Promoter 5A/6A Polymorphism Is Associated With Acute Myocardial Infarction
Authors: Masahiro Terashima, Hozuka Akita, Kenji Kanazawa, Nobutaka Inoue, Shinichiro Yamada, Keiichi Ito, Yasuaki Matsuda, Eiji Takai, Chikao Iwai, Hiroyuki Kurogane, Yutaka Yoshida, Mitsuhiro Yokoyama
Journal: Circulation (1999)

Background —Rupture of the fibrous cap of an atherosclerotic plaque is a key event that predisposes to acute myocardial infarction (AMI). Matrix metalloproteinases (MMPs) may contribute to weakening of the cap, which favors rupture. Stromelysin, a member of MMP family, is identified extensively in human coronary atherosclerotic lesions. It can degrade most of the constituents of extracellular matrix as well as activating other MMPs, which suggests that it may play an important role in plaque rupture. Recently, a common variant (5A/6A) in the promoter of the stromelysin gene has been identified. The 5A/6A polymorphism could regulate the transcription of the stromelysin gene in an allele-specific manner. Methods and Results —To investigate the relation between the 5A/6A polymorphism in the promoter of the stromelysin gene and AMI, we conducted a case-control study of 330 AMI patients and 330 control subjects. The prevalence of the 5A/6A+5A/5A genotype was significantly more frequent in the patients with AMI than in control subjects (48.8% vs 32.7%, P &lt;0.0001). In logistic regression models, the odds ratio of the 5A/6A+5A/5A was 2.25 (95% CI, 1.51 to 3.35). The association of 5A/6A polymorphism with AMI was statistically significant and independent of other risk factors. Conclusions —The 5A/6A polymorphism in the promoter of the stromelysin gene is a novel pathogenetic risk factor for AMI.
Critical Points of Tumor Necrosis Factor Action in Central Nervous System Autoimmune Inflammation Defined by Gene Targeting
Authors: Heinrich Körner, D. Sean Riminton, Deborah H. Strickland, Frances A. Lemckert, John D. Pollard, Jonathon D. Sedgwick
Journal: The Journal of Experimental Medicine (1997)

Tumor necrosis factor (TNF)–dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35–55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF−/− mice. However, in the TNF−/− mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF−/− and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF−/− mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF−/− mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.
Recurrent Myoglobinuria Due to Muscle Carnitine Palmityl Transferase Deficiency
Authors: MICHAEL J. REZA
Journal: Annals of Internal Medicine (1978)

Three new cases of carnitine palmityl transferase deficiency are described. The syndrome consists of recurrent attacks of muscle cramps, weakness, malaise, and myoglobinuria. These attacks are especially likely to occur during prolonged exercise after fasting, eating a high-fat diet, or during cold weather. Occasionally after fasting alone, spontaneous muscle breakdown may occur. One patient studied in detail was excessively slow in producing ketones when he fasted. His myalgias and weakness appeared to be alleviated by β-hydroxybutyrate. Of eight other patients thought to have idiopathic recurrent myoglobinuria, three were found to have myophosphorylase deficiency, whereas five did not have deficiency of either enzyme. Carnitine palmityl transferase deficiency may be more common than previously supposed, may be in part amenable to dietary therapy, can be easily distinguished from myophosphorylase deficiency, and may provide insight into the metabolism of fatty acids and ketone bodies as well as energy requirements of skeletal muscle.
INVOLUNTARY EYE MOVEMENTS AS A CRITERION OF DEPTH OF INSULIN COMA
Authors: HENRY BRILL, RICHARD F. BINZLEY
Journal: American Journal of Psychiatry (1939)

Nystagmus and other involuntary eye movements are a constant feature of insulin shock. During the course of shock these reactions undergo a constant and progressive series of changes which have a distinct relation to the depth of induced coma, as judged by other criteria. One first sees a nystagmus characterized by a slow and a fast component. This is followed by a spontaneous pendular nystagmus or by conjugate deviation. Later, all spontaneous eye movements cease but nystagmus can be still elicited by stimulation. Finally, a depth is reached where no eye reaction can be elicited and this is shortly followed by signs of respiratory depression. The course, in general, seems to be one of stimulation of eye movements initially, followed by gradual depression. While the exact sequence of events is somewhat variable, successive observations afford a useful and delicate check on the progress of therapeutic coma if they are used in conjunction with other findings. One can judge with particular accuracy whether a given coma is becoming deeper or lighter.
Candida onychomycosis—an evaluation of the role of Candida species in nail disease
Authors: R.J. HAY, R. BARAN, M.K. MOORE, J.D. WILKINSON
Journal: British Journal of Dermatology (1988)

Nail infections caused by Candida species are normally associated with chronic paronychia or chronic mucocutaneous candidiasis (CMCC). However, the role of Candida in the pathogenesis of other primary nail dystrophies has been questioned in view of their response to antifungal therapy alone. In the present study of 86 patients with primary nail dystrophies from which Candida was isolated, three patterns of nail involvement were found. Nineteen patients, of whom 17 had CMCC, had total dystrophic onychomycosis of at least two nails. The second group consisted of 27 patients with paronychia and lateral onycholysis. In a further 40 patients, who did not have paronychia, Candida was isolated from nails showing primary distal and lateral onycholysis. These changes were mainly seen in patients with peripheral vascular disease, particularly Raynaud's disease, or Cushing's syndrome. Nail biopsies from patients in the latter two groups confirmed the presence of yeasts and mycelium in the nail plate and 17 (46%) of those receiving antifungal therapy with ketoconazole or itraconazole showed complete clearance of the nail dystrophy. Good responses to therapy were seen more frequently in patients with peripheral vascular disease or Cushing's syndrome of whom 15 (72%) recovered; distal erosion of the nail plate, mycelium in the nail plate on biopsy or direct microscopy together with the isolation of C. albicans were all associated with good responses to antifungals. In addition to patients with CMCC or paronychia, therefore, Candida appears to be a significant pathogen in some patients with primary onycholysis of the finger nails, particularly where there is underlying peripheral vascular disease or Cushing's syndrome.