tbuckley/cabot-search huggingface dataset:
Missense Mutations in Plakophilin-2 Cause Sodium Current Deficit and Associate With a Brugada Syndrome Phenotype
Authors: Marina Cerrone, Xianming Lin, Mingliang Zhang, Esperanza Agullo-Pascual, Anna Pfenniger, Halina Chkourko Gusky, Valeria Novelli, Changsung Kim, Tiara Tirasawadichai, Daniel P. Judge, Eli Rothenberg, Huei-Sheng Vincent Chen, Carlo Napolitano, Silvia G. Priori, Mario Delmar
Journal: Circulation (2013)

Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy.We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end.This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.
Large Gastric Folds, Local or Widespread
Authors: Maurice M. Reeder
Journal: JAMA (1974)

<h3>COMMON</h3> Carcinoma "Hypertrophic gastritis" Lymphoma Normal variant ("hyperrugosity") Ménétrier disease Peptic ulcer; hyperacidity Postoperative stomach Varices <h3>UNCOMMON</h3> Amyloidosis Crohn disease Corrosive gastritis, acute Eosinophilic gastritis Lymphoid hyperplasia (pseudolymphoma) Metastatic neoplasm; extension from carcinoma of pancreas Multiple polyps Pancreatitis, acute Phlegmonous gastritis Postfreezing gastritis Postirradiation gastritis Zollinger-Ellison syndrome <h3>Diagnosis</h3> Ménétrier disease. <h3>COMMENT</h3> A 35-year-old man complained of intractable epigastric distress with intermittent nausea and vomiting over a period of three years. The roentgenogram from the upper gastrointestinal series shown in Fig 1 demonstrates the chronicity of the disease process. Of interest is a low serum protein value in the patient's laboratory profile. Shortly after the upper gastrointestinal series in 1965, gastroscopy and gastric biopsy were performed. The biopsy specimen showed findings typical of Ménétrier disease. Because of the patient's intractable
LEFT ATRIAL VOLUME AS A PREDICTOR OF REVERSIBLE MYOCARDIAL DYSFUNCTION IN PATIENTS WITH DILATED CARDIOMYOPATHY WHO HAVE NO DELAYED ENHANCEMENT ON MAGNETIC RESONANCE IMAGING
Authors: Jeonggeun Moon, In Jeong Cho, Chi Young Shim, Seok-Min Kang, Yangsoo Jang, Namsik Chung, Jong-Won Ha
Journal: Journal of the American College of Cardiology (2010)
Scintigraphic Detection of Focal Biliary Obstruction
Authors: GORDON D. DRAKE, RENE P. DU CRET, DEBORAH L. DAY, ROBERT J. BOUDREAU
Journal: Clinical Nuclear Medicine (1989)

Both CT and ultrasound have been described to be more sensitive than nuclear scintigraphy in the evaluation of biliary obstruction. In this case, only the scintigraphic study adequately demonstrated the pathophysiologic abnormality associated with partially obstructed dilated debris-filled intrahepatic ducts.
Pronethalol and Cardiac Arrhythmias
Authors: R. M. Sykes
Journal: BMJ (1964)

injected to pregnant rats.No cardiovascular abnormalities were produced, but anoph- thalmia occurred in some of the test foetuses.In addition abnormalities of the central nervous system were produced.The net incidence of malformations in this series was similar to that occurring in my own.In view of the work of Robson and his co-workers,' who have demonstrated abnor- malities in the rodent placenta following the administration of 5H.T., it is tempting to suggest the possibility that microphthalmia and other abnormalities in the derivatives of the neural ectoderm in these animals could be related to anoxia.This possibility is supported by the findings of Brent and Franklin,4 who clamped the uterine vessels for up to three hours on the ninth day of gestation of the rat.On the twenty-first day the abnormalities observed were microphthalmia, renal aplasia and agenesis, anen- cephaly, and hydrocephalus.
Fluphenazine Enanthate and Fluphenazine Decanoate: A Comparison of Their Duration of Action and Motor Side Effects
Authors: H. M. VAN PRAAG, L. C. W. DOLS
Journal: American Journal of Psychiatry (1973)

Fluphenazine enanthate and fluphenazine decanoate—two long-acting neuroleptics—were administered in a controlled comparative study to 30 patients with acute psychoses of different character and origin. The study compared the duration of action and affinity for the extrapyramidal system of the two drugs. The decanoate ester acted longer than the enanthate ester and provoked fewer motor side effects. Since these side effects greatly reduce the patient's motivation to cooperate in taking depot medication, the decanoate ester is to be preferred.
Application and Evaluation of Portable Field Instruments for Measuring Forced Expiratory Volume of Children and Adults in Environmental Health Surveys
Authors: Robert M. Burton, Walter M. Kozel, Robert L. Penley, George H. Ward, Robert S. Chapman
Journal: Environmental Health Perspectives (1974)

In support of Health Effects Research Studies, pulmonary function tests are periodically administered to a large number of children. The ventilatory performance of these children is being evaluated by measuring the 0.75-sec forced expiratory volume (FEV(0.75)) with a waterless mechanical volume spirometer used in conjunction with an electronic timing unit. During a 1-yr testing period, operation with the volume spirometer and the EPA designed electronic timing unit proved to be highly successful. The volume spirometer was found to be more advantageous in conducting tests at remote field stations than the water spirometer and other electronic instruments which measure flow rate with a transducer element. The volume spirometer is lightweight, easy to operate, and has the capability of easy and accurate field calibration when used in conjunction with the electronic timing unit. Presently the volume spirometer and EPA designed electronic timing package are employed in all Community Health and Surveillance System (CHESS) pulmonary function testing studies.
Breathlessness during exercise in COPD: how do the drugs work?
Authors: P M A Calverley
Journal: Thorax (2004)

Salmeterol reduces breathlessness during exercise without necessarily changing exercise duration

The inability to exercise because of distressing breathlessness is one of the most frequent problems experienced by patients with chronic obstructive pulmonary disease (COPD)1 and is a major determinant of impaired quality of life.2 Our understanding of why this occurs and how best to treat it has improved significantly in the last decade. At one level the problem appears relatively straightforward. Exercise invariably involves an increase in whole body oxygen consumption and carbon dioxide production, which requires an appropriate rise in alveolar ventilation if arterial carbon dioxide tension is to remain constant. In patients with COPD the ability to increase minute ventilation is restricted as is the capacity to empty their lungs quickly, hence exercise limitation occurs at a lower workload than in age matched healthy subjects. Although there is much truth in this simple scheme, it does not do justice to the many complex adaptive responses that patients use to cope with their chronic airflow obstruction, nor does it explain the variability seen in both the duration of exercise and the intensity of breathlessness in patients with apparently similar levels of airflow obstruction.

Unsurprisingly, the general relationship of ventilatory capacity, commonly established indirectly from the forced expiratory volume in 1 second (FEV1),3 is not simple. While the 12 minute walking distance is broadly related to the severity of airflow obstruction,4 spirometric measurements are not very precise indicators of exercise capacity in the individual patient. Differences in ventilation-perfusion matching during exercise mean that individuals with more “wasted ventilation” achieve their maximum sustainable ventilation sooner for the same degree of alveolar ventilation.5 Differences in pre-morbid fitness are also relevant. Patients who are less fit progress to anaerobic metabolism (and hence increased carbon dioxide production) …
CXCL10 Impairs β Cell Function and Viability in Diabetes through TLR4 Signaling
Authors: Fabienne T. Schulthess, Federico Paroni, Nadine S. Sauter, Luan Shu, Pascale Ribaux, Leena Haataja, Robert M. Strieter, Jose Oberholzer, Charles C. King, Kathrin Maedler
Journal: Cell Metabolism (2009)
PROGRESSION FROM NEW ONSET TO ESTABLISHED PERSISTENT ATRIAL FIBRILLATION: CORRELATING CLINICAL CLASSIFICATIONS WITH IMPLANTABLE DEVICE DATALOG INSIGHTS
Authors: Rangadham Nagarakanti, Sanjeev Saksena, Douglas Hettrick, Jodi Koehler, Andrea Grammatico, Luigi Padeletti
Journal: Journal of the American College of Cardiology (2010)
Recent Advances: Psychiatry
Authors: R. Ramsay, T. Fahy
Journal: BMJ (1995)

Psychiatric illness stands out as having a rich multifactorial aetiology. This makes it unreasonable to expect massive advances because of the complexity of studies needed to understand it. Acknowledging the multifactorial nature of psychiatric illness, over the past year researchers have tried to consolidate information about different disorders—for example, by studying environmental aspects of the more biological conditions and biological aspects of the traditionally more environmental disorders—and in drawing up treatment protocols. Schizophrenia There have been some promising developments in the treatment of schizophrenia, with both pharmacological and psychological interventions. It is now recognised that the atypical neuroleptic drug clozapine is effective in 30-60% of patients with schizophrenia who do not respond to conventional neuroleptics.1 2 As up to 2% of patients treated with clozapine develop agranulocytosis, obligatory blood monitoring has been introduced, which can be a considerable obstacle to compliance for many chronically psychotic patients. The introduction of clozapine in Britain in 1990 was followed by the release of another atypical neuroleptic, risperidone, in 1993. The clinical effects of these drugs have stimulated investigations into the neurochemistry of schizophrenia and are leading to the formulation and testing of different hypotheses to explain the disorder's complex phenomenology. Conventional neuroleptics are presumed to exert their effect through blockade of dopamine D2 receptors. Clozapine has a more complex pharmacology, with a lower occupancy of D2 receptors and higher occupancy of D1 receptors than conventional neuroleptics,3 4 in addition to potent blockade of 5HT2 receptors. The finding that clozapine also selectively binds to the D4 receptor led to speculation about the role of this receptor in the aetiology of schizophrenia. There is, however, no difference between patients who respond to clozapine and those who do not respond in the distribution of alleles for the D4 gene,5 which suggests that clozapine's …
NICE rejects drug for metastatic breast cancer because of cost and poor efficacy
Authors: M. Pownall
Journal: BMJ (2010)

The National Institute for Health and Clinical Excellence (NICE) has rejected use of the cancer drug lapatinib in advanced or metastatic breast cancer that is ErbB2/HER 2 positive because of the treatment’s high cost and “small extra benefit” compared with existing treatments.

Final draft guidance from NICE, which is not yet a formal recommendation to the NHS, says treatment with the drug costs about £25 000 (€30 100; $36 500) per year, and extends survival by about 10 weeks.

NICE concluded that “the drug did not represent good value for money when compared with the alternative, currently available …
Effect of oral contraceptives on sebum excretion rate.
Authors: R J Pye, G Meyrick, M J Pye, J L Burton
Journal: BMJ (1977)

Oral contraceptives containing a high dose of oestrogen reduce the sebum excretion rate (SER) and improve acne vulgaris, but more progestogenic preparations may exacerbate acne. The effect on the SER of several oral contraceptives with varying progestogenic potencies was studied in 81 women. The predominantly progestogenic pills (Eugynon 30, Gynovlar) produced no significant change in SER, whereas the rate in women taking a more oestrogenic pill (Minovlar) was significantly reduced compared with the rate in controls. Progestogens therefore do not exacerbate acne by inducing seborrhoea, but in the doses we studied they nullified the inhibitory effect of oestrogens on the sebaceous glands. Acne-prone women who require an oral contraceptive should be given a predominantly oestrogenic preparation.
Leptin Directly Activates SF1 Neurons in the VMH, and This Action by Leptin Is Required for Normal Body-Weight Homeostasis
Authors: Harveen Dhillon, Jeffrey M. Zigman, Chianping Ye, Charlotte E. Lee, Robert A. McGovern, Vinsee Tang, Christopher D. Kenny, Lauryn M. Christiansen, Ryan D. White, Elisabeth A. Edelstein, Roberto Coppari, Nina Balthasar, Michael A. Cowley, Streamson Chua, Joel K. Elmquist, Bradford B. Lowell
Journal: Neuron (2006)
Calorie Content of Sugar-Coated Tablets
Authors: Arnold E. Nicholson
Journal: JAMA (1961)

<h3>To the Editor:—</h3> Quite frequently the question is posed by members of the medical profession as to the caloric content of a sugar-coated tablet. This question is understandable, since certain types of tablet coatings have been advertised to be noncaloric, with the inference that a sugar coating might be harmful. For this reason, some concern is created in the minds of physicians as to the caloric content of standard sugar coatings. We should like to point out that the amount of sugar in the coating of a tablet is negligible. For example, the amount of sugar present in an enteric-coated 5-grain (0.325-gm.) aspirin tablet (usually much larger than most coated tablets) is 175 mg., which would represent a caloric content of 0.7 calories. Even with multiple daily dosage, it is difficult to imagine any pathological condition in which this amount of sucrose would be contraindicated.
Vasodilator Effects of Endothelin-Converting Enzyme Inhibition and Endothelin ET <sub>A</sub> Receptor Blockade in Chronic Heart Failure Patients Treated With ACE Inhibitors
Authors: Michael P. Love, William G. Haynes, Gillian A. Gray, David J. Webb, John J.V. McMurray
Journal: Circulation (1996)

The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ETA receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ETA and ETB receptors in healthy subjects and patients with CHF.Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF was measured by venous occlusion plethysmography. In CHF patients (n = 10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ETA receptor antagonist) increased FBF by 52 +/- 10% (P = .0006) and 31 +/- 6% (P = .002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15 +/- 5% (P = .0007). Forearm vasoconstriction to endothelin-1 (an ETA and ETB receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n = 10; CHF versus control subjects, P < .001), whereas vasoconstriction to sarafotoxin S6c (an ETB receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n = 10; CHF versus control subjects. P < .05).ECE inhibitors and ETA receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ETA and ETB receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.
Points: Invisible printing: a problem for the partially sighted
Authors: F H Stevenson
Journal: BMJ (1981)

Obstructive sleep apnoea syndrome (OSAS) might be a cause of heart failure. The present study aimed to assess left ventricular mass and myocardial performance index (MPI) in OSAS patients. A total of 67 subjects without any cardiac or pulmonary disease, referred for evaluation of OSAS, had overnight polysomnography and echocardiography. According to apnoea-hypopnoea index (AHI), subjects were classified into three groups: mild OSAS (AHI: 5–14; n = 16), moderate OSAS (AHI: 15-29; n = 18), and severe OSAS (AHI: ≥30; n = 33). Thickness of interventricular septum (IVS) and posterior wall (LVPW) were measured by M-mode, along with left ventricular mass (LVM) and LVM index (LVMI). Left ventricular MPI was calculated as (isovolumic contraction time+isovolumic relaxation time)/aortic ejection time by Döppler echocardiography. There were no differences in age or body mass index among the groups, but blood pressures were higher in severe OSAS compared with moderate and mild OSAS. In severe OSAS, thickness of IVS (11.2±1.1 mm), LVPW (11.4±0.9 mm), LVM (298.8±83.1 g) and LVMI (144.7±39.8 g·m<sup>−2</sup>) were higher than in moderate OSAS (10.9±1.3 mm; 10.8±0.9 mm; 287.3±74.6 g; 126.5±41.2 g·m<sup>−2</sup>, respectively) and mild OSAS (9.9±0.9 mm; 9.8±0.8 mm; 225.6±84.3 g; 100.5±42.3 g·m<sup>−2</sup>, respectively). In severe OSAS, MPI (0.64±0.14) was significantly higher than in mild OSAS (0.50±0.09), but not significantly higher than moderate OSAS (0.60±0.10). In conclusion, severe and moderate obstructive sleep apnoea syndrome patients had higher left ventricular mass and left ventricular mass index, and also left ventricular global dysfunction.
High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models
Authors: Rute B Marques, Ashraf Aghai, Corrina M A de Ridder, Debra Stuurman, Sander Hoeben, Agnes Boer, Rebecca P Ellston, Simon T Barry, Barry R Davies, Jan Trapman, Wytske M van Weerden
Journal: European Urology (2014)
Focus: Brussels: Combating drug trafficking across the single market
Authors: R Watson
Journal: BMJ (1994)

Suggestions for tackling the growing drugs epidemic are as varied as the professional backgrounds and political beliefs of those who confront the problem. Doctors, social workers, customs officers, police and politicians all have different, and sometimes conflicting, remedies.

But drug trafficking and drug misuse are international; despite the many standpoints, the fight against drugs will probably be more effective with international cooperation. So the European Union seems to think, as it is taking advantage of the new powers granted in the Maastricht Treaty to act against drug misuse. More opportunities for coordinated action among the 12 European Union members, and possibly among 15 or 16 countries from next year, exist now than six months ago.

That cooperation runs right through the three main pillars of the European Union constructed by the new …
Comparison of mosquito nets, proguanil hydrochloride, and placebo to prevent malaria.
Authors: C. G. Nevill, W. M. Watkins, J. Y. Carter, C. G. Munafu
Journal: BMJ (1988)

One hundred and ninety students aged 6 to 18 at a boarding school 120 km west of Nairobi in the Rift Valley participated in a comparative trial of malaria prophylaxis. Treatment with a combination of amodiaquine 25 mg/kg over three days plus doxycycline 100 mg twice daily for five days cleared their blood of Plasmodium falciparum. They were then randomly divided into the following three groups matched for age and sex: one group slept under mosquito nets; one group received one or two tablets (100 mg each) of proguanil hydrochloride daily according to weight; one group received one or two placebo tablets daily which were the same size and colour as the proguanil tablets. Malaria was diagnosed when asexual P falciparum were seen on blood films and was treated with pyrimethamine-sulphadoxine. At the end of one school term 188 of the 190 students had completed the study. One new infection was found during 3893 days of follow up in the mosquito net group, eight new infections over 3667 days in the proguanil group, and 35 new infections over 3677 days in the placebo group, representing a reduction of 97.3% and 77.1% in attack rates for the mosquito net method and for treatment with proguanil respectively. Both provide effective protection from malaria.
Augmentation of mouse natural killer activity and induction of interferon by tumor cells in vivo.
Authors: J Y Djeu, K Y Huang, R B Herberman
Journal: The Journal of Experimental Medicine (1980)

Conventional and nude mice inoculated with syngeneic or allogenic tumor cells developed a rapid rise in serum interferon (IF) levels, peaking within 24 h. Within the same period, natural killer (NK) activity was readily boosted in the spleen. Both activities usually declined at 3 d. Cells that lacked the ability to augment NK activity also failed to induce detectable levels of IF. The boosting of IF and NK functions did not appear to be a result of contamination of the tumor lines by viruses because inoculation of several type C viruses into normal mice had no effect, and other viruses, like lymphocytic choriomeningitis virus and influenza, elevated IF and NK levels with a significantly later kinetics, peaking 3-4 d. The IF induced by tumor cells was heat and acid labile, species specific, and appeared to be in the type II class, although it was susceptible to antisera against Newcastle disease virus-induced IF. These data suggest that an early, nonthymus-dependent consequence of tumor-cell recognition is the production of IF, which, in turn, activates NK cells to lyse the tumor cells.
New Revelations about the Role of STATs in Stature
Authors: Erica A. Eugster, Ora Hirsch Pescovitz
Journal: New England Journal of Medicine (2003)

In this issue of the Journal, Kofoed et al. (pages 1139–1147) describe a novel mechanism for impaired growth in the form of a mutation in the gene for the intracytoplasmic protein signal transducer and activator of transcription 5b (STAT5b). The mutation disrupts the intracellular signaling that promulgates the physiologic effects of growth hormone. This finding illuminates an important arena of molecular genetic abnormalities involving the growth hormone–insulin-like growth factor I (IGF-I) axis.The most striking feature of the patient described by Kofoed et al. is profound growth failure, manifested by a height at a chronologic age of 16.5 years that . . .