tbuckley/cabot-search huggingface dataset:
Melanoma BRAF Fusions—Letter
Authors: Thomas Botton, Iwei Yeh, Boris C. Bastian
Journal: Clinical Cancer Research (2014)

We read with interest the article by Hutchinson and colleagues (1) describing melanomas harboring BRAF fusions and their sensitivity to MEK inhibition. We also have reported recurrent BRAF fusions in melanocytic neoplasms, including melanomas, and would like to comment on some of the conclusions reached by Hutchinson and colleagues, which we think are of clinical relevance.In our recently published study (2), we analyzed a clinical CGH database of 848 melanocytic tumors and found 10 cases with copy number transition within the BRAF locus. Massively parallel sequencing identified in-frame fusions of different 5′ partners to the intact kinase domain of BRAF, similarly as in Hutchinson and colleagues (1). Noticeably, all of the BRAF fusion tumors that we described presented spitzoid morphology, i.e., were primary tumors comprised of large epithelioid or spindled melanocytes.In an independent study analyzing 140 melanocytic tumors with a spitzoid morphology, we identified similar BRAF fusions in 5% cases. Remarkably, a total of 51% of the spitzoid lesions had fusions, mostly involving the receptor tyrosine kinases ALK, ROS1, RET, and NTRK1 (3). We noted that patients with kinase fusions were significantly younger than those without. Our findings suggest that melanocytic tumors presenting a spitzoid morphology might be enriched for fusion events, including those of BRAF, and thus likely overlap with the molecular subset of melanomas proposed by Hutchinson and colleagues (1). Detailed histologic characterization of the BRAF fusions tumors described in this report would be of interest.We also add a more nuanced perspective to the statement that the signaling of BRAF fusions would be “sensitive to MEK, but not BRAF, inhibition.” While we also found that the melanoma cell line C0902 harboring an AGK–BRAF fusion was comparatively resistant to vemurafenib, it was highly sensitive to sorafenib (2). The relevance of this observation was strongly supported by the dramatic and prolonged clinical response to sorafenib of the 17-year-old patient with widespread spitzoid melanoma (4). Similar response to a regimen containing sorafenib was recently described in a patient presented with an undifferentiated spindle-cell neoplasm harboring a KIAA1549–BRAF fusion (5).Thus, sensitivity of BRAF fusions may strongly depend on the type of RAF inhibitor.In conclusion, we think that clinicians should be particularly alerted of potential fusions in melanomas presenting in younger patients with a spitzoid morphology of the primary, and that sorafenib should be considered as an additional therapeutic option, for patients presenting melanomas with a BRAF fusion.See the Response, p. 6632No potential conflicts of interest were disclosed.This work was supported by NIH grant P01 CA025874.
The Hypocalcemia of Acute Pancreatitis
Authors: GORDON C. WEIR
Journal: Annals of Internal Medicine (1975)

Variables of calcium metabolism were measured in 11 patients with clearly documented acute pancreatitis. Total and ionized calcium levels were either low or in the low-normal range as were phosphorus and total magnesium levels. Parathyroid hormone levels were high, and there was a significant inverse correlation with ionized calcium. Gastrin levels were normal, calcitonin values were uniformly below the detection limit of the assay, and pancreatic glucagon levels were elevated. The hypocalcemia of acute pancreatitis was probably not caused by abnormalities of glucagon, calcitonin, or gastrin secretion. Furthermore, parathyroid hormone secretion was apparently not impaired. Hypomagnesemia possibly played a minor role. This study suggests that the hypocalcemia of acute pancreatitis is secondary to extraskeletal calcium sequestration or an as yet unidentified defect of bone metabolism, or both.
Methodological issues in therapeutic trials of COPD
Authors: P. Kardos
Journal: European Respiratory Journal (2009)

To the Editors: 

I read with great interest the paper by Suissa et al. 1, which has shed some light on the pitfalls when evaluating the effects of inhaled corticosteroids (ICS) on chronic obstructive pulmonary disease exacerbations. Indeed, they conclude, “various methodological shortcomings …the effectiveness of inhaled corticosteroids in treating chronic obstructive pulmonary disease remains doubtful” 1. The controversy about the role of ICS in COPD exacerbations is becoming even more complex, with the VIVACE 2 study reporting that pneumonia is associated with ICS use in COPD, a possible effect also reported in several more recent studies 3–5. Moreover, the considerable cost of ICS treatment should also be taken into account. Several other issues have been raised Aaron et al. 6 and some, but not all, of the aspects were already reflected 7.

The observed differences between former ICS users and ICS naive COPD patients in the …
Genetic counseling--still mostly genetics
Authors: W. A. Check
Journal: JAMA (1980)

After he has counseled parents who have been referred to him because their child was born with a birth defect, Henry Nadler, MD, director of medical genetics  professor of pediatrics at Northwestern University Medical School in Chicago, usually asks them leading nonmedical questions, such as How are the other children taking the news? or Have you had any trouble handling your friends' responses?  Sometimes people break down in response to these questions  confess that they have been hiding the news from their children or their friends, Nadler told JAMA MEDICAL NEWS. It is clear that they have had difficulty talking to other people about their child's birth defect but they were not sure whether they should bring up their concern in the counseling session. I believe it is perfectly reasonable for a genetic counselor to deal with these emotional problems, he said, and a good counselor can bring
Improvement of Defibrillation Efficacy and Quantification of Activation Patterns During Ventricular Fibrillation in a Canine Heart Failure Model
Authors: Jian Huang, Jack M. Rogers, Cheryl R. Killingsworth, Gregory P. Walcott, Bruce H. KenKnight, William M. Smith, Raymond E. Ideker
Journal: Circulation (2001)

Background —Little is known about the effects of heart failure (HF) on the defibrillation threshold (DFT) and the characteristics of activation during ventricular fibrillation (VF). Methods and Results —HF was induced by rapid right ventricular (RV) pacing for at least 3 weeks in 6 dogs. Another 6 dogs served as controls. Catheter defibrillation electrodes were placed in the RV apex, the superior vena cava, and the great cardiac vein (CV). An active can coupled to the superior vena cava electrode served as the return for the RV and CV electrodes. DFTs were determined before and during HF for a shock through the RV electrode with and without a smaller auxiliary shock through the CV electrode. VF activation patterns were recorded in HF and control animals from 21×24 unipolar electrodes spaced 2 mm apart on the ventricular epicardium. Using these recordings, we computed a number of quantitative VF descriptors. DFT was unchanged in the control dogs. DFT energy was increased 79% and 180% (with and without auxiliary shock, respectively) in HF compared with control dogs. During but not before HF, DFT energy was significantly lowered (21%) by addition of the auxiliary shock. The VF descriptors revealed marked VF differences between HF and control dogs. The differences suggest decreased excitability and an increased refractory period during HF. Most, but not all, descriptors indicate that VF was less complex during HF, suggesting that VF complexity is multifactorial and cannot be expressed by a scalar quantity. Conclusions —HF increases the DFT. This is partially reversed by an auxiliary shock. HF markedly changes VF activation patterns.
Origins and unconventional behavior of neutrophils in developing zebrafish
Authors: Dorothée Le Guyader, Michael J. Redd, Emma Colucci-Guyon, Emi Murayama, Karima Kissa, Valérie Briolat, Elodie Mordelet, Agustin Zapata, Hiroto Shinomiya, Philippe Herbomel
Journal: Blood (2007)
Time to Pardon the IUD?
Authors: Philip D. Darney
Journal: New England Journal of Medicine (2001)

The report in this issue of the Journal on the effect of copper intrauterine contraceptive devices on the risk of infertility in nulliparous women deserves the attention of American women and their clinicians.1 Despite the efficacy of the intrauterine device (IUD) in preventing pregnancy, concern that the use of an IUD may cause pelvic infection and infertility has made it a contraceptive option that is rarely used in the United States.Hubacher et al. report the results of a case–control study involving nearly 2000 women in Mexico City, Mexico.1 The study compared nulligravid infertile women who had tubal occlusion with . . .
ANASTOMOSIS OF DUODENUM.
Authors: C. P. THOMAS
Journal: JAMA (1896)

The patient, J. G. W., was brought to the Everett Hospital Feb. 13, 1896, shot in the abdomen, at close range, with a 38 caliber revolver, ball entering about three inches above and one inch to the left of the umbilicus, and lodged in the back. The abdomen was opened an hour after the injury was received, by a four-inch longitudinal incision at the bullet wound. The cavity was filled with blood; the patient in extreme shock and pulseless. A large hole in the mesentery, which was bleeding profusely, was closed with catgut. The duodenum had two small holes in it about six inches from the stomach, which were closed with fine silk by the Lembert suture. Another perforation was found about ten inches from the stomach which nearly severed the gut and tore the mesentery at the same place. This portion of the gut was resected and end-to-end anastomosis
Myocardial Extracellular Remodeling Is Associated With Ventricular Diastolic Dysfunction in Children and Young Adults With Congenital Aortic Stenosis
Authors: Susan M. Dusenbery, Michael Jerosch-Herold, Carsten Rickers, Steven D. Colan, Tal Geva, Jane W. Newburger, Andrew J. Powell
Journal: Journal of the American College of Cardiology (2014)
A FATAL CASE OF ACUTE VOLVULUS OF THE ILEUM
Authors: S. E. Denyer
Journal: BMJ (1909)

TuDILn 3 1293 bilious and the pain was intense, an attack usually lasting for rmore than a week.The most severe attack was in April, and -at that time she was confined to bed for a fortnight, and was ,extremely ill; but, owing to her condition-she was then in the seventh month of her pregnancy-operation was declined.The abdomen was noted to be unusually large.On the morning of June 18th she had what seemed to be the beginning of another attack, and an opiate was given to relieve the pain.This sub- -sided, but next morning her doctor was summoned early and found labour apparently progressing normally, though the patient was in rather a collapsed condition.After the birth of the child haemorrhage continued very freely, and I was sent -for.On my arrival the patient was moribund.On examina- tion by the vagina I discovered a second child lying high up in the uterus, which was quite lax.The child was turned and -delivered without any diffictulty; but the uterus did not con- tract, and was found to be firmly fixed to the liver.No manipulation could free it.There was no question of its rup- -ture, as the wall could be felt distinctly, and the hand passed up till the liver was reached.The patient died from loss of blood shortly after the delivery of the second child.No postmnortem examination was allowed.
Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey
Authors: Th. Hunziker, U.‐P. Künzi, S. Braunschweig, D. Zehnder, R. Hoigné
Journal: Allergy (1997)

Studies on the epidemiology of common adverse cutaneous drug reactions have rarely been reported, since they can only be successfully conducted in clinics of internal medicine employing consultant dermatologists and having a comprehensive or intensive system of monitoring. Between 1974 and 1993, the adverse skin reactions occurring in divisions of general internal medicine of three different hospitals were monitored by a computerized comprehensive system. The "drug-monitoring patient" was defined as the recipient of at least one drug during hospitalization. The relationship of the skin reactions to drug causality in these patients had to be either definite (proven by re-exposure) or probable (drug relation greater than that of nondrug causality). The skin reactions were classified into four diagnostic groups. Maculopapular exanthema, urticaria, and vasculitis were the three main groups. The fourth group comprised cases of nonhomogeneous but clinically well-defined special exanthema. For selected drugs and years of observation, special emphasis was placed on the study of time patterns (reaction time, exposure time). A total of 1317 definite or probable drug-induced skin reactions occurred during the hospitalization of 48,005 consecutively admitted "drug-monitoring patients": 1201 cases of maculopapular exanthema, 78 cases of urticaria, 18 cases of cutaneous vasculitis, and 20 cases of special exanthema (five of erythema multiforme minor, six of fixed eruption, one of photosensitivity reaction, and eight of acneiform eruption). The main drugs involved did not differ for the three main types of skin reactions, penicillins ranking in the first place, followed by sulfonamides--most often combined with trimethoprim--and in the third place nonsteroidal anti-inflammatory drugs. The reaction time (time from last drug exposure to first skin manifestation) for urticaria showed a relevant proportion of the acute type (within 1 h) and most of the subacute type (1-24 h). For maculopapular exanthema, the subacute or, rarely, the latent type (1-8 days, exceptionally more than 8 days) predominated. For aminopenicillins, the rate of occurrence of skin reactions increased with increasing exposure time up to 12 days, and then markedly diminished. Possibly due to the tendency to withdraw suspected drugs even in the case of minor (e.g., maculopapular) skin reactions, no severe events such as erythema multiforme major/Stevens-Johnson syndrome or toxic epidermal necrolysis occurred.
Silicone Pneumonitis after a Cosmetic Augmentation Procedure
Authors: Grigoriy E. Gurvits
Journal: New England Journal of Medicine (2006)

To the Editor: The injection of silicone for cosmetic procedures is common practice in the United States. We describe a case of severe silicone-induced pneumonitis leading to respiratory failure. A previously healthy 30-year-old woman presented with progressive cough and shortness of breath of 10 days' duration. For cosmetic augmentation, an unlicensed nurse had given the patient two silicone injections into her buttocks 12 days and 2 days before admission. At the initial evaluation, the patient's oxygen saturation was 63 percent while she was breathing ambient air; her pulse was 119 beats per minute, blood pressure 98/66 mm Hg, respiratory rate . . .
Purification and molecular weight studies on the components of a parietaria pollen extract
Authors: E. Bolzacchini, G. Di Gregorio, M. Nali, B. Rindone, S. Tollari, P. Falagiani, G. Riva, G. Crespi
Journal: Allergy (1988)

The pollen extract of the allergenic plant Parietaria judaica, growing throughout the Mediterranean region, has been purified by high performance liquid chromatography (HPLC) operating in size-exclusion followed by ion exchange. Molecular weight determination of the components and isoelectrofocusing studies on the enriched material have been performed.
Prospective Study of One Million Deaths in India: Rationale, Design, and Validation Results
Authors: Prabhat Jha, Vendhan Gajalakshmi, Prakash C Gupta, Rajesh Kumar, Prem Mony, Neeraj Dhingra, Richard Peto
Journal: PLoS Medicine (2005)

Background Over 75% of the annual estimated 9.5 million deaths in India occur in the home, and the large majority of these do not have a certified cause. India and other developing countries urgently need reliable quantification of the causes of death. They also need better epidemiological evidence about the relevance of physical (such as blood pressure and obesity), behavioral (such as smoking, alcohol, HIV-1 risk taking, and immunization history), and biological (such as blood lipids and gene polymorphisms) measurements to the development of disease in individuals or disease rates in populations. We report here on the rationale, design, and implementation of the world's largest prospective study of the causes and correlates of mortality. Methods and Findings We will monitor nearly 14 million people in 2.4 million nationally representative Indian households (6.3 million people in 1.1 million households in the 1998–2003 sample frame and 7.6 million people in 1.3 million households in the 2004–2014 sample frame) for vital status and, if dead, the causes of death through a well-validated verbal autopsy (VA) instrument. About 300,000 deaths from 1998–2003 and some 700,000 deaths from 2004–2014 are expected; of these about 850,000 will be coded by two physicians to provide causes of death by gender, age, socioeconomic status, and geographical region. Pilot studies will evaluate the addition of physical and biological measurements, specifically dried blood spots. Preliminary results from over 35,000 deaths suggest that VA can ascertain the leading causes of death, reduce the misclassification of causes, and derive the probable underlying cause of death when it has not been reported. VA yields broad classification of the underlying causes in about 90% of deaths before age 70. In old age, however, the proportion of classifiable deaths is lower. By tracking underlying demographic denominators, the study permits quantification of absolute mortality rates. Household case-control, proportional mortality, and nested case-control methods permit quantification of risk factors. Conclusions This study will reliably document not only the underlying cause of child and adult deaths but also key risk factors (behavioral, physical, environmental, and eventually, genetic). It offers a globally replicable model for reliably estimating cause-specific mortality using VA and strengthens India's flagship mortality monitoring system. Despite the misclassification that is still expected, the new cause-of-death data will be substantially better than that available previously.
Response to Fraser
Authors: Lois Jovanovic
Journal: Diabetes Care (2002)

The letter by Dr. Robert Fraser (1) adds to the article by Paretti et al. (2) and to my editorial entitled, “What is so bad about a big baby?” (3). Fraser underscores the fact that the peak postprandial glucose response in normal healthy pregnant women is at the 1-h postprandial time point. I appreciate that he combined his two studies into one table for reference. He showed that the highest blood glucose levels in normal pregnant women are <105 mg/dl, similar to the findings in the paper by Parretti et al., and in his table the peak appears 1 h after eating (lunch at 12 noon and peak response at …
gp91phox-Dependent Expression of Platelet CD40 Ligand
Authors: P. Pignatelli, V. Sanguigni, L. Lenti, D. Ferro, A. Finocchi, P. Rossi, F. Violi
Journal: Circulation (2004)

CD40 ligand (CD40L) expression on platelets is mediated by agonists, but the underlying mechanism is still unclear.CD40L expression was measured in platelets from healthy subjects both with and without the addition of antioxidants or a phospholipase A2 (PLA2) inhibitor and in platelets from 2 patients with an inherited deficiency of gp91phox. Immunoprecipitation analysis was also performed to determine whether normal platelets showed gp91phox expression. Unlike catalase and mannitol, superoxide dismutase inhibited agonist-induced platelet CD40L expression in healthy subjects. Immunoprecipitation analysis also showed that platelets from healthy subjects expressed gp91phox. In 2 male patients with inherited gp91phox deficiency, collagen-, thrombin-, and arachidonic acid-stimulated platelets showed an almost complete absence of superoxide anion (O(2)(-)) and CD40L expression. Incubation of platelets from healthy subjects with a PLA2 inhibitor almost completely prevented agonist-induced O(2)(-) and CD40L expression.These data provide the first evidence that platelet CD40L expression occurs via arachidonic acid-mediated gp91phox activation.
The cardiac pacemaker-specific channel Hcn4 is a direct transcriptional target of MEF2
Authors: Shinobu Kuratomi, Yoko Ohmori, Masayuki Ito, Kuniko Shimazaki, Shin-ichi Muramatsu, Hiroaki Mizukami, Hideki Uosaki, Jun K. Yamashita, Yuji Arai, Koichiro Kuwahara, Makoto Takano
Journal: Cardiovascular Research (2009)

AimsHcn4, which encodes the hyperpolarization-activated, cyclic nucleotide-sensitive channel (Ih), is a well-established marker of the cardiac sino-atrial node. We aimed to identify cis-elements in the genomic locus of the Hcn4 gene that regulate the transcription of Hcn4.
The allele 4 of neck region liver-lymph node-specific ICAM-3-grabbing integrin variant is associated with spontaneous clearance of hepatitis C virus and decrease of viral loads
Authors: S. Ezzikouri, K. Rebbani, F.-Z. Fakhir, R. Alaoui, S. Nadir, H. Diepolder, M. Thursz, S.I. Khakoo, S. Benjelloun
Journal: Clinical Microbiology and Infection (2013)
Investigating the steroids and long-acting 2-agonists combination: why do we need more?
Authors: A. Papi
Journal: European Respiratory Journal (2004)

Clinicians and scientists should work together, as the understanding of molecular mechanisms of diseases may help clinicians to improve their clinical practice. This is clearly exemplified by the studies on clinical and molecular interactions between long-acting inhaled β2‐agonists (LABA) and glucocorticoids in the treatment of asthma and chronic obstructive pulmonary disease. Indeed, the possibility of obtaining a drug synergism combining in a single inhaler, LABA and inhaled glucocorticoids, in the regular long-term treatment of moderate-to-severe persistent asthma in adults has intrigued many clinicians and scientists in the last few years.

Inhaled β2-agonists are the most effective bronchodilators, and inhaled glucocorticoids the most effective anti-inflammatory drugs currently available for the treatment of asthma in adults. Since 1994 1 many controlled clinical trials have conclusively demonstrated that the inhalation of a combination of low-dose glucocorticoids together with a LABA has at least the same efficacy as doubling the dose of the inhaled glucocorticoids in the long-term treatment of moderate-to-severe persistent asthma in adults 2.

Conventional wisdom had been that glucorticosteroids and LABAs act through separate and distinct pathways. Studies on the efficacy of inhaled glucocorticoids in the treatment of asthma have demonstrated that they have a relatively flat dose/response curve with most of the benefit obtained at the lowest doses 3, 4. The flatness of the dose/response means that the inflammation is suppressed by a relatively low dose of glucocorticoids. The addition of β2‐agonists may exert some additional actions on the airways that is complementary to the effect of glucocorticoids.

In vitro and in vivo data …
Does Race Interfere With the Doctor-Patient Relationship?
Authors: David Satcher
Journal: JAMA (1973)

Much has been written about the doctor-patient relationship and its many challenges and ramifications.<sup>1</sup>However, almost nothing is written about the effects of race on this relationship. This is unfortunate, since we live in an era of increasing concern for community medicine and for improving the delivery of medical care to all people. In discussing the effects of race on the doctor-patient relationship, our aim must not be merely to accuse or to place blame but to analyze critically the problem, with the goal of improving medical care delivery. Our silence on this issue tends to deny that we see racism as a major barrier to good medical care for many people in our society. We live in a racist society, and all around us the forces of racism help to determine the course of our lives and the nature of our relationship.<sup>2</sup>Unfortunately, racism knows no geographic