tbuckley/cabot-search huggingface dataset:
The antioxidant effects of a novel iron chelator salicylaldehyde isonicotinoyl hydrazone in the prevention of H2O2 injury in adult cardiomyocytes
Authors: M Horackova
Journal: Cardiovascular Research (2000)

Objective: This study was designed to investigate the cardioprotective effect of the novel lipophilic iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) against the oxidative stress exerted by H2O2 through the production of ⋅OH radical via the Fenton reaction and to compare them with those of the hydrophilic iron chelator deferoxamine (DFO) and the Na+/H+ exchange inhibitor methylisobutyl amiloride (MIA). Methods: We used long-term cultures of spontaneously beating adult guinea-pig ventricular cardiomyocytes developed and characterized previously in our laboratory. We assessed their contractile activity by video-recording as well as the underlying Cai2+ transients by Fura 2 fluorescence. In some experiments we also recorded these functional parameters, plus the electrical activity (action potentials) in response to electrical stimulation via suction pipettes, in individual freshly isolated myocytes. Results: Exposure of the regularly and synchronously beating cultured cardiomyocytes to 100 μM H2O2 initially caused a substantial prolongation of Cai2+ transients accompanied by an irregular contractile activity, then in contractile arrest and a severalfold increase in cytosolic [Ca2+] that occurred, within 30 min of H2O2 application. Similar effects were also observed using freshly isolated cardiomyocytes. The latter effects were first accompanied by significant prolongation of the action potential duration (APD) with superimposed early afterdepolarizations followed by a second phase with a very fast decrease in APD, contractions, as well as Cai2+ transients and a third phase of inexcitability, contractile arrest, increased cytoplasmic [Ca2+] and a final contracture. All these effects were irreversible in both types of preparations but they could be fully prevented by a 15-min preincubation with 200 μM SIH. Similar protective effects were observed with DFO, but in this case a much higher concentration had to be used (1 mM) and much longer (2 h) preincubation was needed. By contrast, 5 μM MIA failed to fully protect the cardiomyocytes, although a significant delay (10 min) of the effects of H2O2 was observed. Conclusions: The data indicate that SIH provides a very powerful and very fast protection against the oxidative stress exerted by H2O2 presumably via the iron-mediated Fenton reaction producing hydroxyl radical (⋅OH), whereas the protective effect of DFO is hindred by its very slow and rather limited intracellular entry, and the protection that MIA exerts via the inhibition of Na+/H+ exchange against H2O2 much less effective.
Phase 1 Trial of Gefitinib Plus Sirolimus in Adults with Recurrent Malignant Glioma
Authors: David A. Reardon, Jennifer A. Quinn, James J. Vredenburgh, Sridharan Gururangan, Allan H. Friedman, Annick Desjardins, Sith Sathornsumetee, James E. Herndon, Jeannette M. Dowell, Roger E. McLendon, James M. Provenzale, John H. Sampson, Robert P. Smith, Alan J. Swaisland, Judith S. Ochs, Peggy Lyons, Sandy Tourt-Uhlig, Darell D. Bigner, Henry S. Friedman, Jeremy N. Rich
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. Patients and Methods: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. Results: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. Conclusion: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.
Linezolid: safety and efficacy monitoring
Authors: Rupak Singla, Jose A. Caminero, Ashish Jaiswal, Neeta Singla, Sanjay Gupta, Roseleen Kaur Bali, Digambar Behera
Journal: European Respiratory Journal (2012)

From the authors:

We read with interest the comments by M.S. Bolhuis and co-workers on our article discussing the role of linezolid in treating multidrug-resistant (MDR) tuberculosis (TB) failures in India [1]. First, we would like to underline that our study was carried out in field conditions in a country with a high burden of MDR-TB cases and limited resources. We thank M.S. Bolhuis and co-workers for the opportunity to discuss the different perspectives of the Indian setting and those of a high-level tertiary hospital in a high-income country (India has one of the best existing TB control programmes).

M.S. Bolhuis and co-workers correctly conclude that only a randomised trial comparing linezolid versus a placebo, in addition to an adequate background regimen using drug susceptibility testing (DST) and therapeutic drug monitoring (TDM), would provide comprehensive results on …
Agricultural accidents: A study of 132 patients seen at addenbrooke's hospital, Cambridge, in 12 months
Authors: D. K. C. Cooper
Journal: BMJ (1969)

In a 12-month study 132 patients injured in agricultural accidents were treated at the Accident Service of Addenbrooke9s Hospital, Cambridge. Agricultural machinery and implements were concerned in 50% of the accidents and animals in 10%. The state of immunity against tetanus of these patients was found to be extremely low, only 9% being fully immunized, and 56% having never received a course of prophylactic adsorbed tetanus toxoid. While prevention is obviously the only real solution to accidents of any nature, legislation is not enough to achieve this, and the final responsibility lies with the farmworker to ensure that all safety precautions are followed.
Function and Health Status Outcomes in a Randomized Trial Comparing Preoperative and Postoperative Radiotherapy in Extremity Soft Tissue Sarcoma
Authors: A.M. Davis, B. O’Sullivan, R.S. Bell, R. Turcotte, C.N. Catton, J.S. Wunder, P. Chabot, A. Hammond, V. Benk, M. Isler, C. Freeman, K. Goddard, A. Bezjak, R.A. Kandel, A. Sadura, A. Day, K. James, D. Tu, J. Pater, B. Zee
Journal: Journal of Clinical Oncology (2002)

Morbidity associated with wound complications may translate into disability and quality-of-life disadvantages for patients treated with radiotherapy (RT) for soft tissue sarcoma (STS) of the extremities. Functional outcome and health status of extremity STS patients randomized in a phase III trial comparing preoperative versus postoperative RT is described.One hundred ninety patients with extremity STS were randomized after stratification by tumor size dichotomized at 10 cm. Function and quality of life were measured by the Musculoskeletal Tumor Society Rating Scale (MSTS), the Toronto Extremity Salvage Score (TESS), and the Short Form-36 (SF-36) at randomization, 6 weeks, and 3, 6, 12, and 24 months after surgery.One hundred eighty-five patients had function data. Patients treated with postoperative RT had better function with higher MSTS (25.8 v 21.3, P <.01), TESS (69.8 v 60.6, P =.01), and SF-36 bodily pain (67.7 v 58.5, P =.03) scores at 6 weeks after surgery. There were no differences at later time points. Scores on the physical function, role-physical, and general health subscales of the SF-36 were significantly lower than Canadian normative data at all time points. After treatment arm was controlled for, MSTS change scores were predicted by a lower-extremity tumor, a large resection specimen, and motor nerve sacrifice; TESS change scores were predicted by lower-extremity tumor and prior incomplete excision. When wound complication was included in the model, patients with complications had lower MSTS and TESS scores in the first 2 years after treatment.The timing of RT has minimal impact on the function of STS patients in the first year after surgery. Tumor characteristics and wound complications have a detrimental effect on patient function.
Should rituximab be used to treat antineutrophil cytoplasmic antibody associated vasculitis?
Authors: O Flossmann
Journal: Annals of the Rheumatic Diseases (2005)

It remains to be seen whether rituximab can live up to the high expectations and offer a more effective treatment for patients with AASV

The antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitides (AASV) are a group of multisystem diseases characterised by a predominantly small vessel vasculitis and the occurrence of ANCA in most, but not all, cases. The two main forms of AASV are distinguished by the presence of granulomata and destructive lesions of the upper respiratory tract in Wegener’s granulomatosis (WG), which are absent in microscopic polyangiitis (MPA).

Despite significant progress in the management of these diseases, there are still no fully satisfactory treatments for patients with either refractory or frequently relapsing disease. Current standard immunosuppressive treatment reduces mortality substantially, but a large proportion of patients, particularly those with WG, follow a frequently relapsing course.1 These patients are at high risk of cumulative toxicity from current treatments and also of increasing damage due to active disease.2 Cytotoxic drugs, especially cyclophosphamide, carry a substantial risk of severe side effects such as infertility and in the long term, malignancy (particularly bladder carcinoma), which makes them unappealing for the treatment of younger patients; additionally, there are problems of leucopenia and sepsis, which are of great concern, especially for the elderly.3,4 The advent of an effective and safe treatment for AASV would be a major advance in the management of these diseases.

Rituximab, a chimeric, monoclonal IgG1 antibody directed against CD20, leads to destruction of B cells via complement mediated lysis and antibody dependent cellular cytotoxicity. It was originally developed as an agent for the treatment of non-Hodgkin’s lymphoma.5 CD20, which is a trans-membrane surface antigen of B cells of unknown biological role, is not expressed on pre-B cells and plasma cells so these cells are not affected …
Gastric bypass and banding equally improve insulin sensitivity and β cell function
Authors: David Bradley, Caterina Conte, Bettina Mittendorfer, J. Christopher Eagon, J. Esteban Varela, Elisa Fabbrini, Amalia Gastaldelli, Kari T. Chambers, Xiong Su, Adewole Okunade, Bruce W. Patterson, Samuel Klein
Journal: Journal of Clinical Investigation (2012)

Bariatric surgery in obese patients is a highly effective method of preventing or resolving type 2 diabetes mellitus (T2DM); however, the remission rate is not the same among different surgical procedures. We compared the effects of 20% weight loss induced by laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery on the metabolic response to a mixed meal, insulin sensitivity, and β cell function in nondiabetic obese adults. The metabolic response to meal ingestion was markedly different after RYGB than after LAGB surgery, manifested by rapid delivery of ingested glucose into the systemic circulation, by an increase in the dynamic insulin secretion rate, and by large, early postprandial increases in plasma glucose, insulin, and glucagon-like peptide–1 concentrations in the RYGB group. However, the improvement in oral glucose tolerance, insulin sensitivity, and overall β cell function after weight loss were not different between surgical groups. Additionally, both surgical procedures resulted in a similar decrease in adipose tissue markers of inflammation. We conclude that marked weight loss itself is primarily responsible for the therapeutic effects of RYGB and LAGB on insulin sensitivity, β cell function, and oral glucose tolerance in nondiabetic obese adults.
Psychosis and autism as diametrical disorders of the social brain
Authors: Bernard Crespi, Christopher Badcock
Journal: Behavioral and Brain Sciences (2008)

Abstract Autistic-spectrum conditions and psychotic-spectrum conditions (mainly schizophrenia, bipolar disorder, and major depression) represent two major suites of disorders of human cognition, affect, and behavior that involve altered development and function of the social brain. We describe evidence that a large set of phenotypic traits exhibit diametrically opposite phenotypes in autistic-spectrum versus psychotic-spectrum conditions, with a focus on schizophrenia. This suite of traits is inter-correlated, in that autism involves a general pattern of constrained overgrowth, whereas schizophrenia involves undergrowth. These disorders also exhibit diametric patterns for traits related to social brain development, including aspects of gaze, agency, social cognition, local versus global processing, language, and behavior. Social cognition is thus underdeveloped in autistic-spectrum conditions and hyper-developed on the psychotic spectrum.;&gt;We propose and evaluate a novel hypothesis that may help to explain these diametric phenotypes: that the development of these two sets of conditions is mediated in part by alterations of genomic imprinting. Evidence regarding the genetic, physiological, neurological, and psychological underpinnings of psychotic-spectrum conditions supports the hypothesis that the etiologies of these conditions involve biases towards increased relative effects from imprinted genes with maternal expression, which engender a general pattern of undergrowth. By contrast, autistic-spectrum conditions appear to involve increased relative bias towards effects of paternally expressed genes, which mediate overgrowth. This hypothesis provides a simple yet comprehensive theory, grounded in evolutionary biology and genetics, for understanding the causes and phenotypes of autistic-spectrum and psychotic-spectrum conditions.
Mild cognitive impairment
Authors: Serge Gauthier, Barry Reisberg, Michael Zaudig, Ronald C Petersen, Karen Ritchie, Karl Broich, Sylvie Belleville, Henry Brodaty, David Bennett, Howard Chertkow, Jeffrey L Cummings, Mony de Leon, Howard Feldman, Mary Ganguli, Harald Hampel, Philip Scheltens, Mary C Tierney, Peter Whitehouse, Bengt Winblad
Journal: The Lancet (2006)
Kinetic studies of plasma free fatty acid and triglyceride metabolism in man
Authors: R. Philip Eaton, Mones Berman, Daniel Steinberg
Journal: Journal of Clinical Investigation (1969)

Plasma transport of free fatty acids (FFA) and triglyceride fatty acids (TGFA) was studied in seven subjects with normal lipid metabolism, one case of total lipodystrophy, and one case of familial hyperlipemia (Type V). Studies were carried out after intravenous injection of radioactive FFA, of lipoproteins previously labeled in vitro in the triglyceride moiety, or both. Computer techniques were used to evaluate a series of multicompartmental models, and a general model is proposed that yields optimum fitting of experimental data for both FFA and TGFA. The results show that as much as 20-30% of FFA leaving the plasma compartment in normal subjects is transported to an exchanging extravascular pool and quickly reenters the plasma pool as FFA. The rate of irreversible delivery of FFA from plasma to tissues averaged 358 muEq/min in normals. The lipodystrophy patient, despite the virtual absence of adipose tissue (confirmed at autopsy), had a plasma FFA concentration and a total FFA transport, both more than twice normal. Total TGFA transport ranged from 25 to 81 muEq/min in four normal controls. The rate constant for TGFA turnover in the patient with Type V hyperlipemia was so small that total transport could not be quantified from the data available; the TGFA half-life was over 500 min. In two normal subjects given injections of autologous lipoproteins labeled in vitro with triolein-(14)C and simultaneously given oleic acid-(3)H, it was shown that the time course for the disappearance of the TGFA in the in vitro labeled samples conformed almost exactly to that of the physiologically labeled lipoprotein TGFA synthesized from injected FFA (as evidenced by the simultaneous fitting of both sets of data using the same multicompartmental model and the same rate constants). Radioactivity appeared in the plasma FFA fraction at a significant rate after injection of plasma labeled in vitro with TGFA. It was estimated that as much as 50% of the total TGFA transported underwent rapid and rather direct conversion to FFA in the two normal subjects studied this way. The kinetic data suggest that such conversion of TGFA to FFA was not preceded by any extensive dilution, such as would result from complete mixing with tissue triglyceride stores.
Local eradication of rat colon cancer with photodynamic therapy: correlation of distribution of photosensitiser with biological effects in normal and tumour tissue.
Authors: H Barr, P Chatlani, C J Tralau, A J MacRobert, P B Boulos, S G Bown
Journal: Gut (1991)

Photodynamic therapy is a photochemical technique for the local destruction of tumours, entailing the interaction of light with an administered photosensitiser to produce a cytotoxic effect. We investigated the tissue distribution of the photosensitiser aluminium sulphonated phthalocyanine (AlSPc) in dimethylhydrazine induced colonic tumours and adjacent normal colon in rats. Forty eight hours after intravenous injection, most tumours contained twice as much AlSPc as normal colon. Tumour size and position in the colon did not affect AlSPc concentration. Microscopic fluorescence localisation of AlSPc showed significant photosensitiser accumulation in tumour stroma, whereas tumour and normal mucosa contained similar amounts. Thus, some normal tissue damage, where malignant cells invade normal areas, would inevitably accompany eradication of tumours. Tumour destruction and healing of colon after tumour eradication were examined histologically. There was sharp demarcation between necrotic areas (tumour or normal) and adjacent tissue and, whether the treated area was tumour or normal, healing occurred by regeneration of normal tissue. Some incompletely eradicated large tumours showed evidence of delayed bleeding. The possibility of selective uptake or preferential retention of the photosensitiser in tumours formed the initial basis for investigation of photodynamic therapy, but it is now clear that this is seldom the most important factor for tumour eradication. Of far greater importance is the nature of the biological effect of photodynamic therapy as necrosis of small tumours involving the full thickness of the bowel wall can be achieved with safe healing by regeneration of normal colon. The maximum depth of necrosis produced was only a few millimetres, so this technique is unlikely to be of value as the primary treatment for large colonic tumours but may prove of value for eradicating small lesions or as adjunctive therapy for eradication of small nests of tumour remaining or recurring in the tumour bed after conventional surgery.
A British Medical Association Lecture ON THE EARLY DIAGNOSIS OF ACUTE ABDOMINAL AFFECTIONS
Authors: W. M. Eccles
Journal: BMJ (1921)

To tlle plhysician belong acute thoracic affections, to the surgeon belong acute abdominal affections, to the general practitioner, in their early stages, belong both, and witlh hiim lies the responsibility of diagnosis, and decision as to the line of prompt troatment.Acute abdominal affections are generally surgical emergencies, but not always and necessanrily conditions requiring operative me asures, t1iough to be viewed from tlle first witlh tlhe possibility of surgical treatment always in mind.Hence it is that an early, rapid and decisive diagnosis is of the utmost importance for the saving of lhuman life.An old teaclher of mine, the late Dr. Samuel Gee, was insistent that in order to diagnose arialgt it was needful for the physician-and the surgeon, and still more the general practitioner-to be acquainted with the several conditions vliiclh could be present in any given case, for without such knowledge accurate diagnosis was impossible.Acute abdomninal conditions vary much, and it is essential for diaunosis to hiave a clear mental picture of each one which may be present.It is convenient, therefore,.to tabulate thje most frequent, with their percentage freltuency, as follows:1. Acute appendicitis.
Measurement of Cardiac Output in Man by Dye Dilution Curves Using Simultaneous Ear Oximeter and Whole Blood Cuvette Techniques
Authors: MAURICE MCGREGOR, PAUL SEKELJ, WILLIAM ADAM, Naomi M. Anderson, Andre Teri
Journal: Circulation Research (1961)

In 10 subjects, dye dilution curves were performed on 31 occasions by intravenous in jection of Coomassie blue dye. The curves were recorded by a conventional whole blood cuvette technique using arterial blood with drawn from the brachial artery, and by an ear oximetric technique. Comparison was made of the time contponents of the two curves and of the cardiac output values derived from them. The differences in time components were frequently considerable. It was con cluded that the ear curves were thus unsuit able for estimation of indices such as the "central blood volume." By contrast there was no systematic difference between the car diac output values computed by the two methods. The standard deviation of the differ ences between the two methods was 11.7 per cent of the average cardiac index observed. It was concluded that the ear oximetric tech nique employed offered a satisfactory method of studying the cardiac output in man.