tbuckley/cabot-search huggingface dataset:
α1-Antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy
Authors: David A. Lomas, Ravi Mahadeva
Journal: Journal of Clinical Investigation (2002)

The serine proteinase inhibitors, or serpins, are a superfamily of proteins that are found in a wide range of species, including plants, viruses, and humans.The family includes proteins as diverse as α 1 -antichymotrypsin, C1 inhibitor, antithrombin, and plasminogen activator inhibitor-1, which have key regulatory functions in the inflammatory, complement, coagulation, and fibrinolytic cascades.Members of the serpin superfamily are characterized by more than 30% sequence homology with α 1 -antitrypsin and conservation of tertiary structure.The structure is based on three β-sheets (A-C) and an exposed mobile reactive loop that presents a peptide sequence as a pseudosubstrate for the target proteinase.In the case of α 1 -antitrypsin, the loop presents the P1-P1′ residues methionine-serine as a "bait" for neutrophil elastase.After docking, the proteinase is inactivated by a mousetrap action that swings it from the upper to the lower pole of the protein in association with the insertion of the reactive loop as an extra strand in β-sheet A. This six-stranded protein bound to its target enzyme is then recognized by hepatic receptors and cleared from the circulation.The reactive loop/β-sheet A interaction of serpins is crucial for their role as effective antiproteinases but also renders them liable to undergo conformational transitions that cause disease.Point mutations can destabilize β-sheet A to allow incorporation of the loop of another serpin molecule (see ref. 1 for review).Sequential reactive loop insertion results in chains of polymers that are retained within the cell of synthesis.This process is best characterized in mutants of α 1antitrypsin that result in liver damage, a consequence of protein retention within hepatocytes (see Perlmutter, this Perspective series, ref. 2; and ref. 3).It is also recognized to underlie plasma deficiency of anti-thrombin, C1 inhibitor, and α 1 -antichymotrypsin in association with thrombosis, angio-edema, and emphysema, respectively.Moreover, in the neuron-specific proteinase inhibitor neuroserpin, the same process underlies a novel early-onset inclusion body dementia termed familial encephalopathy with neuroserpin inclusion bodies (FENIB).We review here the role of serpin dysfunction and polymerization in a range of diseases that can be grouped together as the serpinopathies.Our understanding of the structural basis of polymerization provides novel strategies to block polymer formation in vitro.The long-term aim must be to turn these into therapies that are effective in preventing polymerization in vivo.
Changing Face of Medical Practice
Authors: S. C. Dyke
Journal: BMJ (1970)

regarding the subconsultant grade (31 Jan- uary, p. 304).Although I am happy to ac- cept that Mr. Bennett appears to have been misreported, nevertheless his suggestion is not one that would commend itself in any future staffing structure.Dr. Thompson stresses that his remarks were factual.However, by admitting that there are "medical assistants who already carry out
Abstract 278: Post-transciptional activation of anti-oxidant enzymes by imatinib
Authors: Emily N. Terry, Alan M. Diamond
Journal: Cancer Research (2012)

Abstract Patients with Chronic Myelogenous Leukemia (CML) can be treated with targeted bcr-abl kinase inhibitors, such as imatinib. Recently, we reported that mononuclear cells obtained from individuals treated with imatinib often exhibit an increase in the enzyme activity of the antioxidant selenoprotein, glutathione peroxidase (GPx). Treatment of the bcr-abl positive cell line KU812 resulted in increased GPx enzyme and GPx1 protein levels in a dose (100-150 nM) and time (0-7 days) dependent manner, with a maximal increase of 3-fold. Imatinib-induced changes in other anti-oxidant enzymes were also assessed. Of these, no change in the levels of either catalase or GPx-4 were detected, although the levels of manganese superoxide dismutase (MnSOD) increased by a maximal level of 4-fold in imatinib-treated cells. Similar results were obtained in another bcr-abl positive, CML cell line, MEG-01. The elevation in the levels of these proteins occurred via a post-transcriptional mechanism as no increase in the steady state levels of the corresponding mRNA was detected by RT-PCR. The effect of imatinib was likely to be dependent on the presence of the bcr-abl fusion product as no changes in either GPx-1 or MnSOD were detected in either the immortalized lymphocyte cell line GM10832 or the prostate cancer-derived LNCaP human cell lines, neither of which contain bcr-abl. Since the mammalian Target of Rapamycin (mTOR) is a known protein substrate for the abl kinase, and mTOR activity can regulate protein translation, it was investigated whether inhibiting mTOR with rapamycin (1ng/ml) affected GPx-1 and MnSOD levels. Exposure of the KU812 and MEG-01 cells, as well as LNCaP and GM10832 with rapamycin resulted in increased GPx-1 protein and enzyme levels (2- to 4-fold), but had no measurable effects on MnSOD. These results indicate that imatinib, likely by the inhibition of bcr-abl, can post-transcriptionally enhance both GPx-1 and MnSOD levels, although by different mechanisms. These data may have therapeutic significance as both of these anti-oxidant enzymes may influence several different clinically relevant biological processes, including DNA damage susceptability, cell signaling and apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 278. doi:1538-7445.AM2012-278
Hopes raised for HIV vaccine
Authors: Z. Kmietowicz
Journal: BMJ (1997)

American scientists have blocked the transmission of HIV-1 in chimpanzees with a new vaccine based on DNA. It is the first time anyone has managed to protect against HIV infection in the chimpanzee, the closest relative to humans in terms of immunological responses.

The research team concludes that at the very least their study shows that their DNA vaccine is capable of “interrupting the establishment of persistent infection,” describing it as an “unprecedented” effect ( Nature Medicine 1997;3:526-32).



The HIV vaccine uses the genes of a weakened …
Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again
Authors: Alan R. Shuldiner, John C. McLenithan
Journal: Journal of Clinical Investigation (2004)

The Randle cycle, which has been invoked to explain the reciprocal relationship between fatty acid oxidation and glucose oxidation, has long been implicated as a potential mechanism for hyperglycemia and type 2 diabetes mellitus (T2DM). Now genetic, functional genomic, and transgenic approaches have identified PPARgamma coactivators (PGC-1alpha and PGC-1beta) as key regulators of mitochondrial number and function. They regulate adaptive thermogenesis as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis in liver, and even glucose-regulated insulin secretion in beta cells. PGC-1alpha and PGC-1beta mRNA levels and the mitochondrial genes they regulate are decreased in muscle of people with prediabetes and T2DM. A new report indicates that PGC-1alpha and PGC-1beta mRNA levels decrease with age in individuals with a genetic variant in PGC-1alpha, and these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These findings provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and T2DM.
Antagonism of Anticoagulants Dicoumarol, Tromexan, and Phenylindandione by Vitamin K1
Authors: M. Toohey
Journal: BMJ (1952)

<h3>Abstract</h3> Computational Psychiatry is a rapidly emerging field that uses model-based quantities to infer the behavioural and neuronal abnormalities that underlie psychopathology. If successful, this approach promises key insights into (pathological) brain function as well as a more mechanistic and quantitative approach to psychiatric nosology – structuring therapeutic interventions and predicting response and relapse. The basic procedure in computational psychiatry is to build a computational model that formalises a behavioural or neuronal process. Measured behavioural (or neuronal) responses are then used to infer the model parameters of a single subject or a group of subjects. Here, we provide an illustrative overview over this process, starting from the modelling of choice behaviour in a specific task, simulating data and then inverting that model to estimate group effects. Finally, we illustrate cross-validation to assess whether between-subject variables (e.g., diagnosis) can be recovered successfully. Our worked example uses a simple two-step maze task and a model of choice behaviour based on (active) inference and Markov decision processes. The procedural steps and routines we illustrate are not restricted to a specific field of research or particular computational model but can, in principle, be applied in many domains of computational psychiatry. <b>Significance Statement:</b> We provide an overview over the process of using formal models to understand psychiatric conditions, which is central in the emerging research field of ‘Computational Psychiatry’. This approach promises key insights into both healthy and pathological brain function as well as a more mechanistic understanding of psychiatric nosology, which may have important consequences for therapeutic interventions or predicting response and relapse. In a worked example, we discuss the generic aspects of using a computational model to formalise a task, simulating data and estimating parameters as well as inferring group effects between patients and healthy controls. We also provide routines that can be used for these steps and are freely available in the academic software SPM.
The Darkening in Colour of Certain Urines on Exposure to the Air
Authors: R. Maguire
Journal: BMJ (1884)

MANY urines in perfectly normal conditions show a slight deepening of tint when exposed to the air, but so slight as to be hardly perceptible.The presence of certain bodies in the urine may, however, develop this phenomenon to an extraordinary degree.One instance is a matter of common observation.All urines contain a quantity of indican, and if the urine be allowed to standl until putrefied, a blue film is formed on the surface, from the oxidation of the indican to indigo-blue; if the indican be present in excess, a greater development of the colour may take place, and the blue tint may be diffused throughout the
Use of Calcium and Secretin in the Diagnosis of Gastrinoma (Zollinger-Ellison Syndrome)
Authors: Clifford W. Deveney, Karen S. Deveney, Bernard M. Jaffe, Rayford S. Jones, Lawrence W. Way
Journal: Annals of Internal Medicine (1977)

Sixty-five patients with peptic ulcer disease were evaluated for gastrinoma (Zollinger-Ellison syndrome) by measuring changes in serum gastrin concentration after intravenous (i.v.) administration of calcium or secretin, or both. The presence of gastrinoma was established in all 20 patients whose serum gastrin increased by 395 pg/ml or more after i.v. calcium and in all 18 patients whose serum gastrin concentration increased by 110 pg/ml or more after i.v. secretin. The experience with these 65 patients shows that stimulation by calcium or secretin may confirm the presence of gastrinoma in cases where the diagnosis would otherwise remain obscure. Although a positive response to calcium or secretin is diagnostic for gastrinoma a negative response does not exclude this diagnosis. Stimulation with secretin is preferred for screening for gastrinoma because it is quicker and more reliable than calcium.
Extracorporeal Hemolysis of Blood in a Microwave Blood Warmer
Authors: Parker J. Staples, Paul F. Griner
Journal: New England Journal of Medicine (1971)

Marked hemoglobinemia and hemoglobinuria developed in a 13-year-old girl during an operative repair for scoliosis. Residual blood from 1 of 5 U of whole blood, preheated in a microwave blood warmer and administered during the procedure, was found to be hemolyzed. The blood warmer was studied in an effort to reproduce extracorporeal hemolysis. Faulty placement of the blood container in the heating unit was found to produce improper heating through nonrotation of the container. No change in plasma hemoglobin or red-cell filterability was found when normally heated samples were compared with unheated control samples. Improperly heated blood revealed a marked increase in plasma hemoglobin (maximum, 949 mg per 100 ml) and a reduction in filterability of residual cells (maximum, 19 per cent). Morphologic changes (e.g., budding) were identified in improperly but not properly heated red cells. These studies indicate the production of extracorporeal hemolysis and reduced viability of a population of nonhemolyzed cells through improper heating of blood in a microwave blood warmer.
Persistent Pain and Well-being
Authors: Oye Gureje, Michael Von Korff, Gregory E. Simon, Richard Gater
Journal: JAMA (1998)

Context.—There is little information on the extent of persistent pain across cultures. Even though pain is a common reason for seeking health care, information on the frequency and impacts of persistent pain among primary care patients is inadequate.Objective.—To assess the prevalence and impact of persistent pain among primary care patients.Design and Setting.—Survey data were collected from representative samples of primary care patients as part of the World Health Organization Collaborative Study of Psychological Problems in General Health Care, conducted in 15 centers in Asia, Africa, Europe, and the Americas.Participants.—Consecutive primary care attendees between the age of majority (typically 18 years) and 65 years were screened (n=25916) and stratified random samples interviewed (n=5438).Main Outcome Measures.—Persistent pain, defined as pain present most of the time for a period of 6 months or more during the prior year, and psychological illness were assessed by the Composite International Diagnostic Interview. Disability was assessed by the Groningen Social Disability Schedule and by activity-limitation days in the prior month.Results.—Across all 15 centers, 22% of primary care patients reported persistent pain, but there was wide variation in prevalence rates across centers (range, 5.5%-33.0%). Relative to patients without persistent pain, pain sufferers were more likely to have an anxiety or depressive disorder (adjusted odds ratio [OR], 4.14; 95% confidence interval [CI], 3.52-4.86), to experience significant activity limitations (adjusted OR, 1.63; 95% CI, 1.41-1.89), and to have unfavorable health perceptions (adjusted OR, 1.26; 95% CI, 1.07-1.49). The relationship between psychological disorder and persistent pain was observed in every center, while the relationship between disability and persistent pain was inconsistent across centers.Conclusions.—Persistent pain was a commonly reported health problem among primary care patients and was consistently associated with psychological illness across centers. Large variation in frequency and the inconsistent relationship between persistent pain and disability across centers suggests caution in drawing conclusions about the role of culture in shaping responses to persistent pain when comparisons are based on patient samples drawn from a limited number of health care settings in each culture.
Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991
Authors: R. J. Kuczmarski
Journal: JAMA (1994)

To examine trends in overweight prevalence and body mass index of the US adult population.Nationally representative cross-sectional surveys with an in-person interview and a medical examination, including measurement of height and weight.Between 6000 and 13,000 adults aged 20 through 74 years examined in each of four separate national surveys during 1960 to 1962 (the first National Health Examination Survey [NHES I]), 1971 to 1974 (the first National Health and Nutrition Examination Survey [NHANES I]), 1976 to 1980 (NHANES II), and 1988 to 1991 (NHANES III phase 1).In the period 1988 to 1991, 33.4% of US adults 20 years of age or older were estimated to be overweight. Comparisons of the 1988 to 1991 overweight prevalence estimates with data from earlier surveys indicate dramatic increases in all race/sex groups. Overweight prevalence increased 8% between the 1976 to 1980 and 1988 to 1991 surveys. During this period, for adult men and women aged 20 through 74 years, mean body mass index increased from 25.3 to 26.3; mean body weight increased 3.6 kg.These nationally representative data document a substantial increase in overweight among US adults and support the findings of other investigations that show notable increases in overweight during the past decade. These observations suggest that the Healthy People 2000 objective of reducing the prevalence of overweight US adults to no more than 20% may not be met by the year 2000. Understanding the reasons underlying the increase in the prevalence of overweight in the United States and elucidating the potential consequences in terms of morbidity and mortality present a challenge to our understanding of the etiology, treatment, and prevention of overweight.
Statistics in Oncology
Authors: Stephanie R. Land, Judith Abrams, Marc Buyse, Richard J. Chappell
Journal: Journal of Clinical Oncology (2008)

Stephanie R. Land, Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA Judith Abrams, Karmanos Cancer Institute, Wayne State University, Detroit, MI Marc Buyse, International Drug Development Institute, Louvain-la-Neuve, Belgium Richard J. Chappell, Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, WI
District general hospital or teaching hospital?
Authors: P W. Sellar
Journal: BMJ (1999)

After at least four, and probably more, job changes since passing out through the doors of medical school, you may be ready for some stability in your nomadic medical career. This will be especially so if you have a family that has, willingly or otherwise, been displaced from hospital accommodation or a rented home on a number of occasions, each time meaning lost friends and adjustment to new schools and circumstances. The prospect of a final move into a permanent job and the chance to settle down is usually quite a relief; it is an opportunity not to be wasted, but also not to be rushed. The only problem is that jobs come up suddenly, and, once taken, there may be no new vacancies in a specific area or subspecialty for many more years, so decisions need to be made quickly.

As with buying a house, which may also be required in the process of taking up a consultant post, knowing what you want is helpful. As every despised estate agent knows, three important points should be borne in mind: location, location, and location. However, having an open mind about places that you might not have immediately considered is also wise, especially if your specialty is oversubscribed. The following points may help you assess what you want or can expect from a job location and highlight the advantages of the humbler district general hospital compared with the often overrated advantages of a teaching hospital.

Easy access to elderly parents or other dependent relatives may be important, but such dependants may be happy to relocate near you. A spouseos job may also seem to be fixed, but many employers can offer relocation possibilities. If your partner also works in the health service, it may be well worth inquiring informally, before an …
The jaundiced heart
Authors: Lawrence Deckelbaum
Journal: Hepatology (1987)

Patients with obstructive jaundice are susceptible to postoperative shock and kidney failure. The cause of these potentially fatal complications has not been fully clarified. The present study was designed to assess the role of myocardial dysfunction in the hemodynamic disturbance of obstructive jaundice. We studied the effect of isolated cholemia on left ventricular performance in five conscious dogs before and 2 weeks after choledochocaval anastomosis by using measurements of systolic time intervals (STIs) and maximal dp/dt. Mean left ventricular ejection time (LVET) decreased after cholemia from 159 ± 2.8 msec to 139 ± 2.6 msec (p &lt; 0.005), while mean preejection period (PEP) and mean PEP/LVET were increased from 41 ± 8.5 msec to 87 ± 14 msec (p &lt; 0.05) and from 0.39 ± 0.06 to 0.62 ± 0.1 (p &lt; 0.01), respectively. During cholemia, STIs were unchanged after intravenous administration of ouabain, whereas in the control period, there was shortening of mean PEP from 71 ± 8.8 msec to 58 ± 7.6 msec (p &lt; 0.05) and of Q-S 2 from 257 ± 12 msec to 235 ± 14 msec (p &lt; 0.005) in response to ouabain. Maximal dp/dt decreased after choledochocaval anastomosis from 4543 ± 593 mm Hg/sec to 3666 ± 648 Hg/sec (p &lt; 0.025). We conclude that cholemia in the dog is clearly associated with impaired left ventricular performance. The present data also support a previously published in vitro study from our laboratory showing that cholemia blunts the myocardial contractile response to sympathomimetic agents. The cardiodepressor effect of cholemia may explain the increased tendency of patients with obstructive jaundice to postoperative shock and renal failure.
Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the childhood asthma prevention study (CAPS)
Authors: Seema Mihrshahi, Jennifer K. Peat, Guy B. Marks, Craig M. Mellis, Euan R. Tovey, Karen Webb, Warwick J. Britton, Stephen R. Leeder
Journal: Journal of Allergy and Clinical Immunology (2003)
Prevention of Tetanus
Authors: J. D. Whittall
Journal: BMJ (1970)

<b>Aims and Methods:</b> Thyroid function tests were initially carried out on 122 children with Down’s syndrome aged 6–14 years and then repeated four to six years later in 103 adolescents (85% of the group of 122) when they were aged 10–20 years (median 14.4 years). At the second test two were hypothyroid and two with isolated raised thyroid stimulating hormone (IR-TSH) were receiving thyroxine. <b>Results:</b> At the first test there were 98 (80%) euthyroid children: 83 were retested and four (5%) had IR-TSH. At the first test 24 had IR-TSH: 20 were retested and 14 (70%) had become normal. Seventeen with IR-TSH on initial testing had a thyrotrophin releasing hormone test within three months; TSH had become normal in eight (47%) of these children. There was no association between reported clinical symptoms and IR-TSH, but there were clear symptoms in one of the two with definite hypothyroidism. <b>Conclusions:</b> The likelihood ratio for a positive result on second testing when raised TSH and positive antibody status on first testing are combined is 20. This suggests initial testing results could be used as a basis to select a subgroup for further testing at say five yearly intervals unless new symptoms emerge in the interim. It also suggests that yearly screening (as recommended by the American Academy of Pediatrics, 2001) is probably not justified in the first 20 years of life.