tbuckley/cabot-search huggingface dataset:
Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man.
Authors: M C Mitchell, S Schenker, K V Speeg
Journal: Journal of Clinical Investigation (1984)

Acetaminophen-induced hepatotoxicity results from hepatic enzymatic oxidation of acetaminophen to a toxic, electrophilic intermediate. Acetaminophen is ordinarily eliminated after conjugation with glucuronic acid and sulfate to nontoxic derivatives. Cimetidine has been shown to inhibit the hepatic oxidation of a number of drugs and to protect rats from acetaminophen-induced hepatic necrosis. The aim of this study was to define the mechanism by which cimetidine reduced acetaminophen-induced hepatic necrosis and to determine whether inhibition of formation of the reactive metabolite(s) of acetaminophen occurred also in man. In vivo cimetidine pretreatment decreased covalent binding of [3H]acetaminophen to the liver from 552 +/- 23.8 to 170 +/- 31.6 nmol/g protein 2 h after a toxic dose of acetaminophen in 3-methylcholanthrene pretreated rats (P less than 0.05). Cimetidine pretreatment also significantly reduced the rate of hepatic glutathione depletion. Both cimetidine and metiamide produced dose-dependent inhibition of acetaminophen oxidation in vitro, whereas inhibition by ranitidine and cimetidine sulfoxide was quantitatively less. Inhibition of acetaminophen oxidation by cimetidine and metiamide was primarily competitive with an inhibition constant (Ki) of 130 +/- 16 and 200 +/- 50 microM, respectively. By contrast, cimetidine inhibited acetaminophen glucuronidation minimally with a Ki of 1.39 +/- 0.23 mM. Similar results were obtained using human liver microsomes as a source of enzymes. In a dose-related fashion, cimetidine also reduced acetaminophen-induced toxicity to human lymphocytes when incubated with microsomes and NADPH. Pharmacokinetics of acetaminophen elimination were studied in normal volunteers with and without co-administration of cimetidine 300 mg every 6 h. In normal volunteers, cimetidine decreased the fractional clearance of the oxidized (potentially toxic) metabolites of acetaminophen more than the conjugated metabolites. This finding confirmed the hypothesis that cimetidine is a relatively selective inhibitor of the oxidation of acetaminophen to reactive metabolites in man as well as in animals. When considered together with the results of previous studies showing improved survival and decreased hepatoxicity in acetaminophen-poisoned animals, the present results provide a rational basis for assessing possible benefits of cimetidine treatment of acetaminophen overdoses in man.
1121-49 Homocysteine levels and methylenetetrahydrofolate reductase polymorphisms are not associated with restenosis after coronary artery stenting
Authors: Werner Koch, Marc Burghartz, Harald Lengnick, Petra Hoppmann, Siegmund Braun, Klaus Kölling, Albert Schömig, Adnan Kastrati
Journal: Journal of the American College of Cardiology (2004)
Abstract 1786: UV damage-induced histone H3 lysine 56 deacetylation regulates nucleotide excision repair and checkpoint signaling.
Authors: Aruna Battu, Altaf Ahmad Wani
Journal: Cancer Research (2013)

Abstract Nucleotide excision repair (NER) is the major pathway in cells for the removal of bulky photoproducts and ensuring integrity of the genome. NER constitutes lesion recognition, excision of damaged DNA, synthesis of a DNA fragment, and ligation of the repair patch. Nonetheless, DNA within the cells is compacted into chromatin and lesion recognition requires chromatin to be remodeled to permit access of repair and checkpoint machinery to the damage site. Consequent to repair of the lesions, chromatin structure is restored to its original state so that cells resume cell cycle progression. Although several reports have demonstrated the role of chromatin remodelers, histone modifications and histone chaperones in DNA damage response (DDR), knowledge of how these epigenetic mechanisms control the DDR is largely in its infancy. We and others have recently observed that histone H3 is deacetylated on lysine 56 immediately in response to UV-induced DNA damage. Acetylation is promptly restored upon completion of repair and is necessary for recovery from DNA damage induced cell cycle arrest. However, the function of H3K56 deacetylation in the DDR remains to be determined. We found that UV-induced deacetylation of H3K56 is abrogated in the presence of TSA and sodium butyrate, both of which inhibit class I histone deacetylases (HDACs). Knockdown of either HDAC1 or HDAC2 alone did not affect UV-induced deacetylation of H3K56. However, simultaneous knockdown of both HDAC1 and 2 resulted in retention of H3K56 acetylation after UV irradiation. Consistently, both HDAC1 and HDAC2 localized to sites of UV damage. These observations are consistent with that reported by Miller et. al., indicating that HDAC1 and HDAC2 are responsible for the deacetylation of H3K56 in response to DNA damage. Since the deacetylation of H3K56 is one of the most immediate responses to UV-irradiation, we assumed it to play a crucial role in NER. Accordingly, we observed that CPD removal was affected in H1299 cells with histone H3K56Q mutation that mimics constitutive acetylation. Furthermore, we found that localization of the checkpoint kinase ATM to UV damage sites was affected in these cells. Consequently, ATM-mediated H2AX phosphorylation was also found to be defective in the mutant cells. Based on our observations, we speculate that HDAC1 and 2 mediated H3K56 deacetylation regulates NER and checkpoint signaling cascade in response to UV damage. This work was supported by PHS grants ES2388, ES12991 and CA93413 and Pelotonia postdoctoral fellowship to AB. Citation Format: Aruna Battu, Altaf Ahmad Wani. UV damage-induced histone H3 lysine 56 deacetylation regulates nucleotide excision repair and checkpoint signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1786. doi:10.1158/1538-7445.AM2013-1786
EXPERIMENTAL RICKETS IN RATS
Authors: Alfred F. Hess, Lester J. Unger, Alwin M. Pappenheimer
Journal: The Journal of Experimental Medicine (1922)

Young rats on a diet low in phosphorus can be protected from rickets by irradiations with sunlight for about 15 minutes daily. In the winter months, however, this degree of light was found insufficient. The effective rays of the sun, in the intensities studied, did not penetrate window glass. They manifested some protective value after reflection from a smooth white surface. Irradiation of a few minutes with the rays of the mercury vapor lamp suffices to protect rats against rickets. This is true likewise of the rays from the carbon arc lamp. A standard protective dose of radiation can be formulated for rats on a standard diet. Light is able to prevent the occurrence of rickets in rats fed a rickets-producing diet characterized either by a low phosphorus and high calcium content, or a high phosphorus and low calcium content. Moderate variations in temperature do not alter the effective action of light rays. Pigmentation of the skin markedly lessens their effect, as demonstrated by the failure of a standard dose to protect black rats.
Prospects for hospital doctors
Authors: E. A. Harvey-Smith
Journal: BMJ (1967)

MEDIBAJOURNAL 359 cases in which the clinical and pathological features were typical of acute necrotizing encephalitis.From five of these brain biopsy material was examined by virus isolation studies and four yielded herpes simplex virus; three of these have been previously reported.2In all seven cases from which suitable tissue was available for electronmicroscopic study virus particles belonging to the herpes group have been identified.3This seems convincing evidence that most cases of acute necrotizing encephalitis are due to direct invasion of the brain by herpes simplex virus.The possibility of the successful treatment of acute necrotizing encephalitis with idoxuri- dine4 5 makes it vital to establish the diagnosis of herpes simplex encephalitis as early as possible in the disease before neuronal necrosis is advanced.As the results of virus isolation, the testing of paired sera for complement-fixing antibodies, and electron- microscopic examination are unlikely to be available for several days, histological exami- nation of brain biopsy material is likely to remain the most important means of making an early diagnosis.Fluorescent antibody studies for herpes simplex virus may also be of considerable value in making a rapid preliminary diagnosis, but their reliability in herpes encephalitis has not yet been adequately assessed.-Weare, etc.,
Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro
Authors: P Busk
Journal: Cardiovascular Research (2002)

Objective: Cardiac hypertrophy is induced by a number of stimuli and can lead to cardiomyopathy and heart failure. Present knowledge suggests that cell-cycle regulatory proteins take part in hypertrophy. We have investigated if the D-type cyclins are involved in cardiac hypertrophy. Methods: The expression and activity of the D-type cyclins and associated kinases in cardiomyocytes were studied during angiotensin II- and pressure overload-induced hypertrophy in rats (Rattus norvegicus) and in isolated, neonatal cardiomyocytes. Expression of the D-type cyclins was manipulated pharmacologically and genetically in neonatal myocytes. Results: In the left ventricle, there was a low, constitutive expression of the D-type cyclins, which may have a biological role in normal, adult myocytes. The protein level and the associated kinase activity of the D-type cyclins were up-regulated during hypertrophic growth. The increase in cyclin D expression could be mimicked in vitro in neonatal cardiac myocytes. Interestingly, the cyclin Ds were up-regulated by hypertrophic elicitors that stimulate different signalling pathways, suggesting that cyclin D expression is an inherent part of cardiac hypertrophy. Treatment of myocytes with the compound differentiation inducing factor 1 inhibited expression of the D-type cyclins and impaired hypertrophic growth induced by angiotensin II, phenylephrine and serum. The response to hypertrophic elicitors could be restored in differentiation inducing factor 1-treated myocytes by expressing cyclin D2 from a heterologous promoter. Conclusion: Our results point to the D-type cyclins as important regulators of cardiac hypertrophy. This supports the notion that cell-cycle regulatory proteins regulate hypertrophic growth.
Acute industrial poisoning.
Authors: D ApIvor
Journal: BMJ (1967)

MEDICATISOHRNAL paramedical, and nursing staff have been observed in the present outbreak, as in the past.Scrupulous attention to hygiene and sterile techniques is necessary to stop the spread of this infection, which can cause painful disability for many weeks with resi- dual corneal opacities.Since fingers seem particularly likely to transfer infection, it would be advisable to use disposable gloves for manipulating eyelids when rushed condi- tions prevent thorough cleansing of hands between patients.-Iam, etc.,
THE BRITISH ZONE OF THE ADVANCE
Authors: GEORGE de TARNOWSKY
Journal: JAMA (1918)

<h3>GENERAL CONSIDERATIONS</h3> It may be stated as a truism that any comparison between the French and English methods of treatment or evacuation of the wounded in their respective zones of advance is impossible, because of radical differences in the topography of the land and in the general conception of trench warfare. The English have maintained a comparatively short front, difficult to hold and correspondingly more difficult to advance in. They have pinned their faith in density of front, with continuous activity along the entire front, alternating with intense attacks in selected sectors. The enemy, constantly and diligently harassed, retaliates in kind; the pressure is constantly maintained, night and day. This unending "strafing" has naturally multiplied the problems of evacuation, increased the distance between the front lines and the regimental aid posts, and lengthened the elapsed time between the reception of a wound and its thorough surgical treatment. The evacuation hospitals
Viewpoint: Limiting Prostate Cancer Screening
Authors: Richard M. Hoffman
Journal: Annals of Internal Medicine (2006)

Prostate cancer screening is controversial, and major professional associations offer differing screening guidelines. The author addresses 3 key issues about prostate cancer screening: 1) the prostate-specific antigen (PSA) criteria to recommend a prostate biopsy, 2) the appropriate age to start screening, and 3) the appropriate age to stop screening. The author argues, on the basis of evidence published since 2000, that data supporting the efficacy of PSA screening remain unconvincing. The author recommends that screening should not be expanded to include average-risk men younger than age 50 years or older than age 75 years and that a PSA threshold below 4.0 ng/mL should not be used to trigger biopsy referral.
Choroidal neovascularization in transgenic mice expressing prokineticin 1: an animal model for age-related macular degeneration
Authors: Nobushige Tanaka, Masahito Ikawa, Nathan L. Mata, Inder M. Verma
Journal: Molecular Therapy (2005)

The prognosis of choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is poor and existing treatments are limited in retarding the progression of disease. The development of an animal model for AMD will be beneficial for finding potential treatments, including gene therapy. Recently prokineticin 1 (hPK1) was identified as a mitogen of fenestrated endothelium. We hypothesized that hPK1 could induce CNV, a hallmark of the exudative or wet form of AMD, since the endothelium of the choriocapillaris, but not retinal endothelium, has fenestration. We generated transgenic mice expressing hPK1 in the retina using the rhodopsin promoter. In these transgenic mice, an enlarged vascular bed of choroid resembling CNV was observed without any morphological changes in the retinal vasculature. In addition, the major fluorophore of lipofuscin, N-retinylidene-N-retinylethanolamine, which has several potential cytotoxic effects on the RPE, was accumulated approximately twice as much in the transgenic mouse eyes compared to controls. hPK1 could be one of the causative factors of AMD and the transgenic mouse exhibiting CNV may be useful to establish treatments for the wet form of AMD.
p37Ing1b Regulates B-Cell Proliferation and Cooperates with p53 to Suppress Diffuse Large B-Cell Lymphomagenesis
Authors: Andrew H. Coles, Concetta G.A. Marfella, Anthony N. Imbalzano, Heather A. Steinman, David S. Garlick, Rachel M. Gerstein, Stephen N. Jones
Journal: Cancer Research (2008)

Abstract The Inhibitor of Growth (ING) gene family encodes structurally related proteins that alter chromatin to regulate gene expression and cell growth. The initial member, ING1, has also been proposed to function as a tumor suppressor in human cancer based on its ability to suppress cell growth and transformation in vitro. Mouse Ing1 produces two proteins (p31 and p37) from differentially spliced transcripts. We have recently generated p37Ing1b-null mice and observed spontaneous follicular B-cell lymphomagenesis in this model to show that ING proteins can function in vivo as tumor suppressors. In this present report, we examine the role of p37Ing1b in the regulation of B-cell growth and explore the relationship between p37Ing1b and p53-mediated tumor suppression. Our results indicate that p37Ing1b inhibits the proliferation of B cells and follicular B cells regardless of p53 status, and loss of p53 greatly accelerates the rate of B-cell lymphomagenesis in p37Ing1b-null mice. However, in contrast to the highly penetrant follicular B-cell lymphomas observed in p37Ing1b-null mice, mice lacking both p37Ing1b and p53 typically present with aggressive diffuse large B-cell lymphomas (DLBL). Analysis of marker gene expression in p37Ing1b/p53 null tumors indicates that the double-null mice develop both nongerminal center and germinal center B-cell–like DLBL, and also documents up-regulation of nuclear factor-κB activity in p37Ing1b/p53-null B cells and B-cell tumors. These results confirm that p53 mutation is an important mechanistic step in the formation of diffuse large B-cell lymphomas and reveals a p53-independent role for Ing1b in suppressing B-cell tumorigenesis. [Cancer Res 2008;68(21):8705–14]
Diazepam in Incapacitated Cerebral-Palsied Children
Authors: Henry O. Marsh
Journal: JAMA (1965)

In a controlled study, 26 severely disabled cerebralpalsied children were given diazepam in oral doses or matching placebos, alternated every two or four weeks for a total period which varied from 5 weeks to 38 weeks, averaging five months. Results compiled from detailed semimonthly evaluations by therapists and nurses disclosed that ten children achieved excellent muscle relaxation during diazepam therapy (but no improvement with placebo) which accelerated progress in training in some, and facilitated management of all. In 16 children, improvement differences between drug and placebo trials were not significant. Athetoid patients responded better than spastics. Diazepam eliminated or suppressed the startle reflex in all children; it had no apparent effect on appetite, chewing, swallowing, drooling, or bed wetting. Side effects of lethargy were negligible, once optimal therapeutic doses, averaging 21/2 mg three times a day, were attained.
Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial
Authors: Kurt J Griffin, Paul A Thompson, Michael Gottschalk, Jennifer H Kyllo, Alex Rabinovitch
Journal: The Lancet Diabetes & Endocrinology (2014)
Delayed hyperbaric oxygen treatment for acute carbon monoxide poisoning.
Authors: A Ziser, A Shupak, P Halpern, D Gozal, Y Melamed
Journal: BMJ (1984)

Delayed hyperbaric oxygen treatment for acute carbon monoxide poisoningHyperbaric oxygen is the preferred treatment in acute carbon monoxide poisoning.Though it should be started as soon as possible, we wish to emphasise that anyone who has been exposed to carbon monoxide should be treated regardless of the delay between exposure and pre- sentation.'We present our experience with delayed hyperbaric oxygen treatment for acute carbon monoxide poisoning. Patients and resultsFrom January 1982 to February 1983 we treated 10 cases of acute carbon monoxide poisoning.In six cases there was a delay of seven to 16 hours from the time of rescue to the beginning of treatment with hyperbaric oxygen.The duration of exposure to the environment rich in carbon monoxide varied from a few minutes (three patients caught in fires) to 14 hours.Four of the six inhaled smoke.The table gives clinical details on the six patients.They were at different levels of consciousness when rescued.Electrocardiography showed ischaemic changes in two cases, and all had metabolic acidosis.Five made full mental and physical recoveries.One (case 2) did not improve: he developed hydrocephalus with increased intracranial pressure and finally died.
Value of bacterial antigen detection in the diagnostic yield of transthoracic needle aspiration in severe community acquired pneumonia.
Authors: F Bella, J Tort, M A Morera, J Espaulella, J Armengol
Journal: Thorax (1993)

BACKGROUND--Transthoracic needle aspiration (TNA) with an ultrathin needle is a safe and highly specific procedure for obtaining a diagnosis in bacterial pneumonias, but its sensitivity is at best 70%. A study was performed to assess whether Streptococcus pneumoniae and Haemophilus influenzae type b antigen detection by latex agglutination from the TNA sample enhanced the diagnostic yield. METHODS--Blood cultures, TNA with an ultrathin needle (culture, Gram stain, and latex agglutination), serological tests, and pneumococcal antigen detection in the urine by counterimmunoelectrophoresis were performed in samples from 18 of 23 consecutive patients with severe community acquired pneumonia. RESULTS--The causative organism was identified in 16 cases (88%): S pneumoniae (10 cases), S pneumoniae plus H influenzae (two cases), Legionella pneumophila (three cases), and Mycoplasma pneumoniae (one case). The investigation of antigens by latex agglutination in the pulmonary aspirate increased the diagnostic yield of TNA from 50% to 78% and provided a rapid diagnosis (in less than two hours) with therapeutic implications in seven cases. Its effectiveness was not modified by prior antibiotic therapy. CONCLUSIONS--A latex agglutination test on the pulmonary aspirate enhances the diagnostic yield of TNA in severe community acquired pneumonia.
How can we best prolong life? Benefits of coronary risk factor reduction in non-diabetic and diabetic subjects.
Authors: J S Yudkin
Journal: BMJ (1993)

OBJECTIVE--To compare the theoretical benefits of different approaches to reduce risk factors for coronary heart disease in subjects at risk. DESIGN--The results of findings from meta-analyses of intervention studies on cause specific mortality and of observational studies on smokers and ex-smokers were applied to observational data on 10 year cause specific mortality derived from the multiple risk factor intervention trial. Lifetable analyses were used to estimate gains in life expectancy. SUBJECTS--Diabetic and non-diabetic men initially 35-57 years of age. MAIN OUTCOME MEASURES--10 year mortality from coronary heart disease, 10 year total mortality, man years of intervention to prevent one death and one death from coronary heart disease, gain in life expectancy, and drug costs per year of additional life in diabetic and non-diabetic men of 45. RESULTS--In non-diabetic men a 10 year mortality from coronary heart disease of 14.4 per 1000 would be reduced by a mean of 0.58, 0.82, 2.64, and 2.74 per 1000 by antihypertensive treatment, lowering cholesterol concentration, taking aspirin, and stopping smoking respectively; a 10 year total mortality of 44.1 per 1000 would fall by a mean of 1.06, 5.16, and 8.65 per 1000 with antihypertensive and aspirin treatment and stopping smoking respectively and increased by a mean of 0.07 per 1000 with the lowering of cholesterol concentration. In diabetic men the reductions in mortality from coronary heart disease would be between three and five times greater, and total mortality would show mean reductions of 5.81, 0.56, 16.17, and 20.84 per 1000 respectively, with all interventions of significant benefit except the lowering of cholesterol concentration. Between 2400 and 3800 man years of pharmacological intervention were calculated as being necessary to prevent one death from coronary heart disease in a non-diabetic man, and between 800 and 1200 man years in a diabetic man. The loss of life expectancy associated with smoking and hypertension is greater than that accruing from hypercholesterolaemia, but stopping smoking would prolong life by a mean of around four years in a 45 year old non-diabetic man and three years in a diabetic man, whereas aspirin and antihypertensive treatment would provide approximately one year of additional life expectancy in both categories. CONCLUSIONS--Studies to date have shown little impact of drugs that lower cholesterol concentration and blood pressure on either coronary heart disease or total mortality. Although new treatments for hypercholesterolaemia and hypertension might help prevent coronary heart disease, other approaches to reduce the burden of premature death are required.