tbuckley/cabot-search huggingface dataset:
Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice
Authors: Junko Kato, Tomohiro Okamoto, Hiroyuki Motoyama, Ryosuke Uchiyama, Daniel Kirchhofer, Nico Van Rooijen, Hirayuki Enomoto, Shuhei Nishiguchi, Norifumi Kawada, Jiro Fujimoto, Hiroko Tsutsui
Journal: Hepatology (2012)

Concanavalin A (Con A) treatment induces severe hepatitis in mice in a manner dependent on T cells, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Treatment with the anticoagulant heparin protects against hepatitis, despite healthy production of IFN-γ and TNF. Here, we investigated molecular and cellular mechanisms for hypercoagulation-mediated hepatitis. After Con A challenge, liver of wild-type (WT) mice showed prompt induction of Ifnγ and Tnf, followed by messenger RNA expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), which initiate blood coagulation and inhibit clot lysis, respectively. Mice developed dense intrahepatic fibrin deposition and massive liver necrosis. In contrast, Ifnγ(-/-) mice and Ifnγ(-/-) Tnf(-/-) mice neither induced Pai1 or Tf nor developed hepatitis. In WT mice TF blockade with an anti-TF monoclonal antibody protected against Con A-induced hepatitis, whereas Pai1(-/-) mice were not protected. Both hepatic macrophages and sinusoidal endothelial cells (ECs) expressed Tf after Con A challenge. Macrophage-depleted WT mice reconstituted with hematopoietic cells, including macrophages deficient in signal transducer and activator of transcription-1 (STAT1) essential for IFN-γ signaling, exhibited substantial reduction of hepatic Tf and of liver injuries. This was also true for macrophage-depleted Stat1(-/-) mice reconstituted with WT macrophages. Exogenous IFN-γ and TNF rendered T-cell-null, Con A-resistant mice deficient in recombination-activating gene 2, highly susceptible to Con A-induced liver injury involving TF.Collectively, these results strongly suggest that proinflammatory signals elicited by IFN-γ, TNF, and Con A in both hepatic macrophages and sinusoidal ECs are necessary and sufficient for the development of hypercoagulation-mediated hepatitis.
When big may not be beautiful
Authors: N. Markham
Journal: BMJ (1998)

“Why grandmother, what a big hospital you've got,” said Little Red Riding Hood. “All the better to serve the people,” replied the wolf.

The virtue of the “big is beautiful” model of providing secondary health care is being extolled by many people. In particular the royal colleges seem to be swayed by the arguments that it makes sense to centralise scarce yet highly costly resources in large units and concentrate medical skills within them. And so it probably does for crowded towns and cities, but what of the sparsely populated rural areas?

Communities in such areas thrive on a proud tradition of parochial spirit, well established traditions, and an impressive sense of pride. They cherish their independence and are content that they remain relatively free from some of the social problems prevalent in big cities. The local hospital is highly regarded. It may serve only a population of 150 000 to 200 000, yet it can boast some of the most modern equipment available, …
The Early Bactericidal Activities of Rifampin and Rifapentine in Pulmonary Tuberculosis
Authors: Frik A. Sirgel, P. Bernard Fourie, Peter R. Donald, Nesri Padayatchi, Roxana Rustomjee, Jonathan Levin, Giorgio Roscigno, Jennifer Norman, Helen McIlleron, Denis A. Mitchison
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Comparison of the early bactericidal activity (EBA) of rifapentine and its pharmacokinetics with those of rifampin to determine the cause of poor clinical response and regrowth between doses, leading to rifamycin monoresistance at relapse. Objectives: Determination of the dose size of rifapentine that gives sufficient drug exposure to prevent regrowth. Methods: EBA study over initial 5 days of treatment of 123 patients, half at Durban and half at Cape Town, who received single rifapentine doses of 300, 600, 900, or 1,200 mg rifapentine or five daily doses of 150, 300, or 600 mg rifampin, with a pharmacokinetic study on 58 patients measuring standard parameters for each dose size of rifamycin and their desacetyl metabolites. Results: The EBAs for both rifamycins were similar, with a linear relationship to log dose at lower doses and a curvilinear response at higher doses giving a plateau at 1,136 mg rifapentine. The area under the concentration–time curve (AUC) divided by the minimal inhibitory concentration (MIC) agreed well for both rifamycins on the assumption that the only free 2% of free rifapentine and the 14% of free rifampin after plasma binding were active in the lesions. Conclusions: Only the free proportions of the rifamycins were active in lesions. From consideration of the pulse size and the duration of the postantibiotic lag, a 1,200-mg dose of rifapentine seemed necessary to improve response and to prevent regrowth between doses, and hence rifamycin monoresistance.
Health select committee criticises directors of public health
Authors: R. MacDonald
Journal: BMJ (2001)

Directors of public health were criticised by the Commons health select committee last week for not providing the necessary leadership in public health.

The report, which primarily covers England, set out to establish to what extent the Department of Health's actions are taking “public health out of the ghetto.” The report stated that public health is not a term understood by most of the public and that “it can be variously defined so as to cover trends of disease in a population, the provision …
An 11 year old boy with chest pain and fever
Authors: C A Christie-Johnston, T Connell, T Mildenhall, M Danchin
Journal: BMJ (2009)

A previously well 11 year old boy was transferred to a regional hospital by his local doctor after being given an empirical dose of intramuscular ceftriaxone (25 mg/kg) because of a 24 hour history of fever (40°C), vomiting, headache, neck pain, and rash.

On arrival the patient was alert, afebrile, and seemed to be haemodynamically stable, with a heart rate of 60 beats/min, blood pressure 120/70 mm Hg, respiratory rate 18 breaths/min, and a Glasgow coma score of 14. He had pronounced neck stiffness and a widespread non-blanching petechial rash but no focal neurological signs, and examination of his precordium and lung fields was normal. A blood culture was taken, and he was given a bolus of intravenous normal saline (20 ml/kg) plus cefotaxime (50 mg/kg), dexamethasone (0.15 mg/kg), and ondansetron (0.05 mg/kg).

Initial investigations showed a haemoglobin of 132 g/l (normal range 110-150), platelet count 288×109/l (150-400), and peripheral white blood cell count 34.7×109/l (6.0-17.0) (absolute neutrophil count 24.3×109/l; bands 6.9×109/l). Sodium was 141 mmol/l (135-145) and glucose was 5.3 mmol/l (3.0-5.4). C reactive protein was 143 mg/l (normal <8 mg/l) and international normalised ratio was 2.0 (0.8-1.2).

Within 90 minutes of arrival at the regional hospital, the patint’s clinical condition deteriorated greatly, with a decreasing level of consciousness (Glasgow coma score 10), and he was subsequently intubated and ventilated. Transfer to the intensive care unit was arranged, and intravenous aciclovir (16 mg/kg eight hourly) was added. A computed tomography brain scan and electroencephalogram were normal. A lumbar puncture was deferred because of the abnormal coagulation profile, but dexamethasone (0.15 mg/kg intravenously every six hours) was continued for four days on the presumptive diagnosis of meningitis. Inotrope support was not needed, and he was extubated within 24 hours of arrival.

On …
What would you do, doctor?
Authors: Daniel K Sokol
Journal: BMJ (2007)

Some ethicists believe that doctors should be like hairdressers. If you ask a hairdresser to shave your head, he or she will most probably do so. Similarly, such ethicists would argue, if a patient asks to have whiskers surgically implanted or his penis enlarged by injecting fat into the shaft (penoplasty), the surgeon should perform the operation once satisfied that this is what the (competent) patient truly wants. Increasingly, medical professionals are involved in procedures that, to most people, are distinctly odd. The principle of respect for autonomy—still gathering moral weight since its modern birth in the 1960s—seems to be constraining doctors' decision making to such an extent that they are no longer sure if they know what is best for patients. When they do know, they wonder whether communicating this is respecting patients' autonomy or violating it.

What does patient centred care—that current buzz term—require? Are doctors wise gatekeepers of medical …
Abstract B5: Epigenetic modification of AR in PC3 cells negatively regulates mTORC1/2 activity
Authors: Leigh Ellis, Remi Adelaiye, Shengyu Ku, Alejandro Godoy, Roberto Pili
Journal: Cancer Research (2012)

Abstract Wild type androgen receptor (AR) acts as a tumor suppressor and mediates the differentiation of non-malignant prostate epithelial cells. However, in the development of prostate cancer AR activity becomes critical for the development and progression of disease. Previous studies demonstrate that re-expressing wild type AR within an AR negative cell line (PC3) possesses tumor suppressor quality by reducing cell proliferation and tumorgenicity in mice. Further, it is documented that acetylation of AR in non-malignant cells is a post-translational modification associated with increased transcriptional activity of AR, whereas acetylation of AR in tumor cells results in negative regulation of AR transcriptional activity. We therefor are seeking to investigate the regulation of re-expressed AR within PC3 cells by induced acetylation post HDAC inhibition. Our preliminary data reveals that sensitivity to HDAC inhibition is increased with the re-expression of AR in PC3 cells. Further, epigenetic modification of AR in this model negatively regulates mTORC1 and mTORC2 expression and activity, independent of AR transcriptional activity. Ongoing experiments are being conducted to investigate further the role of epigenetic post-translational modification of AR and its negative regulation of mTORC1/2 signaling. Citation Format: Leigh Ellis, Remi Adelaiye, Shengyu Ku, Alejandro Godoy, Roberto Pili. Epigenetic modification of AR in PC3 cells negatively regulates mTORC1/2 activity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B5.
Live-Birth Rates and Multiple-Birth Risk Using In Vitro Fertilization
Authors: Laura A. Schieve
Journal: JAMA (1999)

Context To maximize birth rates, physicians who perform in vitro fertilization (IVF) often transfer multiple embryos, but this increases the multiple-birth risk.Live-birth and multiple-birth rates may vary by patient age and embryo quality.One marker for embryo quality is cryopreservation of extra embryos (if embryos are set aside for cryopreservation, higher quality embryos may have been available for transfer).Objective To examine associations between the number of embryos transferred during IVF and live-birth and multiple-birth rates stratified by maternal age and whether extra embryos were available (ie, extra embryos cryopreserved). Design and SettingRetrospective cohort of 300 US clinics reporting IVF transfer procedures to the Centers for Disease Control and Prevention in 1996.Subjects A total of 35 554 IVF transfer procedures. Main Outcome MeasuresLive-birth and multiple-birth rates (percentage of live births that were multiple).Results A total number of 9873 live births were reported (multiple births from 1 pregnancy were counted as 1 live birth).The number of embryos needed to achieve maximum live-birth rates varied by age and whether extra embryos were cryopreserved.Among women 20 to 29 years and 30 to 34 years of age, maximum live-birth rates (43% and 36%, respectively) were achieved when 2 embryos were transferred and extra embryos were cryopreserved.Among women 35 years of age and older, live-birth rates were lower overall and regardless of whether embryos were cryopreserved, live-birth rates increased if more than 2 embryos were transferred.Multiple-birth rates varied by age and the number of embryos transferred, but not by whether embryos were cryopreserved.With 2 embryos transferred, multiple-birth rates were 22.7%, 19.7%, 11.6%, and 10.8% for women aged 20 to 29, 30 to 34, 35 to 39, and 40 to 44 years, respectively.Multiple-birth rates increased as high as 45.7% for women aged 20 to 29 years and 39.8% for women aged 30 to 34 years if 3 embryos were transferred.Among women aged 35 to 39 years, the multiplebirth rate was 29.4% if 3 embryos were transferred.Among women 40 to 44 years of age, the multiple-birth rate was less than 25% even if 5 embryos were transferred. ConclusionsBased on these data, the risk of multiple births from IVF varies by maternal age and number of embryos transferred.Embryo quality was not related to multiple birth risk but was associated with increased live-birth rates when fewer embryos were transferred.
A biodegradable injectable implant for delivering micro and macromolecules using poly (lactic-co-glycolic) acid (PLGA) copolymers
Authors: N.H. Shah, A.S. Railkar, F.C. Chen, R. Tarantino, S. Kumar, M. Murjani, D. Palmer, M.H. Infeld, A.W. Malick
Journal: Journal of Controlled Release (1993)
Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis
Authors: G R Chandak
Journal: Gut (2004)

<b>Background and aims:</b> Mutations in the cationic trypsinogen (protease, serine, 1 (trypsin 1); PRSS1) gene are causally associated with recurrent acute and chronic pancreatitis. We investigated whether mutations in the PRSS1 gene are associated with hereditary and non-hereditary pancreatitis. As a modifier role has been proposed for trypsin inhibitor (serine protease inhibitor, Kazal type I; SPINK1) mutations, the role of SPINK1 mutations in these patients was also analysed. <b>Subjects and methods:</b> The coding regions of PRSS1 and SPINK1 genes were sequenced in 290 controls and 198 patients, of whom 120 were diagnosed as idiopathic (ICP), 41 as alcoholic (ACP), and 37 as hereditary pancreatitis (HP). Twenty four unaffected relatives of HP probands were also analysed and genotype-phenotype correlations and statistical analyses were performed. <b>Results:</b> No mutations in the PRSS1 gene were detected in any of the patients, including HP patients, while the N34S mutation was observed in the SPINK1 gene in the majority of HP patients (73%). Similarly, 26.8% of ACP (11 of 41) and 32.5% (39 of 120) of ICP patients also had SPINK1 mutations. The N34S mutation was observed in both homozygous and heterozygous conditions. In comparison, only 2.76% of the control population had the N34S allele (p&lt;0.001). The P55S mutation was observed in one ICP and one ACP patient, and in three normal individuals. Genotype-phenotype correlations did not suggest any significant difference in the age of onset, severity of disease, or pancreatic endocrine insufficiency in patients with or without mutated SPINK1 and irrespective of the allelic status of N34S SPINK1. <b>Conclusions:</b> Irrespective of the aetiology, mutations in the PRSS1 gene are not associated with chronic pancreatitis, including HP. In contrast, the N34S mutation in the SPINK1 gene shows a significant correlation in these patients. A comparable phenotype in terms of age of onset, diabetes mellitus, and other phenotypic features in patients with or without SPINK1 mutations and N34S homozygotes and heterozygotes suggests that there may still be involvement of other genetic or environmental factors.
"SPIROCHETAL PULMONARY GANGRENE TREATED WITH ARSPHENAMINS"
Authors: Benjamin S. Kline
Journal: JAMA (1925)

To the Editor:  —Through an error, the report of my discussion (The Journal, November 7, p. 1459) on the article on spirochetal pulmonary gangrene by myself and Dr. Berger was not corrected for publication. Because of the mistakes in that report, I will appreciate it if you publish the following:  In these cases, there is usually a pyorrhea, dental caries or some active lesion in the mouth associated with Vincent organisms. In one case at necropsy a molar tooth was found carious, the cavities filled with foul smelling, greenish material containing many spirochetes. These organisms are best stained by the Fontana silver impregnation method. The predominating organisms in early pulmonary gangrene are of the Vincent type.  Before ulceration occurs, there is usually a peribronchial and peribronchiolar consolidation. Then the lung has a moth-eaten appearance. It is mottled with gray-green, foul smelling areas containing Vincent organisms. Later there are small and
Final Report of a Case of a Very Large Innominate Aneurysm: Completely Cured by the Employment of Electrolysis through Ten Feet of Snarled, Coiled, Fine Gold Wire, Introduced into the Sac; Death at the Expiration of Three and a Half Years from Cerebral Thrombosis
Authors: D. D. Stewart
Journal: BMJ (1897)

LARGE INNOMINATE ANEURYSM.y BJO^L 3TS7 areola; there was rather an unpleasant itching, but I felt in no way ill, and the temperature was normal.After forty-
Psychological problems in intensive care.
Authors: P J Tomlin
Journal: BMJ (1977)

Intensive care units are now well established in modem hospital practice and there can be few clinicians in any specialty who have not had some of their patients treated in such units. Intensive care units form a collection of the most ill in hospital. In our own unit the average mortality based on the last 1700 patients admitted was 13-5%, although there was a wide variation depending on the type and number of diseases that individual patients had. Without the special care, technical skill, and resources that the unit provides, the mortality of these patients would have probably been about 80%O. Serious illness, of any sort, creates psychological problems for the patients-for example, the anxiety of the patient with ischaemic heart disease or the despair of the patient with obstructive lung disease are well known. Certain psychological problems, however, develop in patients in intensive care, which would appear to be particularly related to being in such a unit. Since patients may be referred into the unit from any medical or surgical discipline it is perhaps worth drawing attention to some of these psychological problems, particularly as occasionally they may be unexpectedly severe or bizarre.
Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis
Authors: Pablo Bellot, Juan Carlos García-Pagán, Rubén Francés, Juan G. Abraldes, Miguel Navasa, Miguel Pérez-Mateo, José Such, Jaime Bosch
Journal: Hepatology (2010)

Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial-DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial-DNA(−) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(+) as compared with bacterial-DNA(−) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. Conclusion: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction. (HEPATOLOGY 2010;.)
Cytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium
Authors: Daniel Y.C. Heng, J. Connor Wells, Brian I. Rini, Benoit Beuselinck, Jae-Lyun Lee, Jennifer J. Knox, Georg A. Bjarnason, Sumanta Kumar Pal, Christian K. Kollmannsberger, Takeshi Yuasa, Sandy Srinivas, Frede Donskov, Aristotelis Bamias, Lori A. Wood, D. Scott Ernst, Neeraj Agarwal, Ulka N. Vaishampayan, Sun Young Rha, Jenny J. Kim, Toni K. Choueiri
Journal: European Urology (2014)
Immunodeficiency Diseases Caused by Defects in Phagocytes
Authors: Julie A. Lekstrom-Himes, John I. Gallin
Journal: New England Journal of Medicine (2000)

Primary phagocytic defects must be included in the differential diagnosis of recurrent infection and fever in a child and occasionally in an adult. Early diagnosis is essential, because manifestations of infection are usually blunted and rapid intervention can be lifesaving. In general, patients are identified at a young age on the basis of their susceptibility to normally nonpathogenic bacteria or fungi. In some cases, the infectious agents point to the disorder (Table 1): catalase-positive microorganisms and aspergillosis species are characteristic of chronic granulomatous disease,1 and atypical mycobacteria suggest a defect in the interferon-γ–interleukin-12 axis.2 These bacterial infections contrast with the . . .
Mortality and the risk of malignancy in autoimmune liver diseases: A population-based study in Canterbury, New Zealand
Authors: Jing Hieng Ngu, Richard Blair Gearry, Chris Miles Frampton, Catherine Ann Malcolm Stedman
Journal: Hepatology (2011)

Abstract Population-based quantitative data on the mortality and cancer incidence of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are scarce. Our aim was to systematically investigate the survival and risk of malignancy on population-based cohorts of AIH, PBC, and PSC in Canterbury, New Zealand. Multiple case-finding methods were employed, including searches of all public and private, adult and pediatric outpatient clinics, hospital notes, laboratory, radiology, and pathology reports. Cases that fulfilled standardized diagnostic criteria were included. Kaplan-Meier survival estimates, standardized mortality ratios (SMR), and standard incidence ratios (SIR) for malignancy were calculated. A total of 130 AIH, 70 PBC, and 81 PSC patients were included contributing to 1,156, 625, and 613 person-years at risk, respectively. For AIH, PBC, and PSC cohorts, SMRs for all-cause mortality were 2.1 (95% confidence interval [CI] 1.4-3.1), 2.7 (95% CI 1.7-4.0), and 4.1 (95% CI 2.6-6.3), SMRs for hepatobiliary mortality were 42.3 (95% CI 20.3-77.9), 71.2 (95% CI 30.7-140.3), and 116.9 (95% CI 66.8-189.8), SIRs for all cancers were 3.0 (95% CI 2.0-4.3), 1.6 (95% CI 0.8-2.9), and 5.2 (95% CI 3.3-7.8), and SIRs for extrahepatic malignancy were 2.7 (95% CI 1.8-3.9), 1.6 (95% CI 0.8-2.9), and 3.0 (95% CI 1.6-5.1), respectively. Conclusion : This is the first population-based study to examine and compare the survival and cancer incidence in AIH, PBC, and PSC in the same population. The mortality for all three cohorts was significantly increased due to liver-related death, demonstrating the inadequacy of current management strategies. The risk of hepatic and extrahepatic malignancy was significantly increased in AIH and PSC patients. (Hepatology 2012)