tbuckley/cabot-search huggingface dataset:
33. Systemic Delivery of AAV8/DC190-GAA to Pompe Mice Normalizes Muscle Pathology and Corrects Motor Function Deficits
Authors: R.J. Ziegler, M.A. Zhao, S.D. Bercury, J.A. Fidler, J.W. Foley, D. Armentano, S. Ryan, T. Taksir, D. Griffiths, L.S. Shihabuddin, R.K. Scheule, S.H. Cheng
Journal: Molecular Therapy (2006)

Pompe disease, a lysosomal storage disorder, is generally known for it's characteristic degenerative myopathy. Massive accumulation of glycogen in lysosomes of striated and smooth muscle due to a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) results in muscle weakness and cardiorespiratory failure. In severely affected patients glycogen also accumulates in the central and peripheral nervous systems. Previously we demonstrated that systemic administration of AAV8/DC190-GAA to Pompe mice generated high circulating levels of GAA and reduced glycogen storage in cardiac and skeletal muscle to near normal levels. The current study was designed to determine if these effects on the viscera would be sufficient to prevent the loss of muscle strength and coordination shown to develop over time in the Pompe mouse. Since the GAA secreted into the blood should not cross the bloodbrain bloodbrain barrier, this study should also clarify the functional significance of peripheral and CNS glycogen storage in the Pompe mouse model. Two different concentrations of AAV8/DC190-GAA were injected into the tail vein of 10-week-old male Pompe mice. Treated Pompe mice, as well as vehicle-treated Pompe and B6129SF2/J normal control mice, were tested for their ability to perform in a battery of behavioral tests. Tests designed to measure muscle strength and coordination included accelerating and rocking Rota-rod, wire hang, and foot fault. As expected, the performance of the vehicle-treated Pompe mice declined over time when compared to wild type mice. In contrast the performance of AAV-treated Pompe mice was significantly improved over that of vehicle-treated Pompe mice, and was similar to normal mice. There was no significant difference between the two AAV8 dosing groups in any test except the wire hang. In this test the performance of the lower dose treatment group declined at the later time points. Severely affected patients rapidly accumulate glycogen, and infants are often not diagnosed until they show obvious myotonia. To model the treatment of this patient population, we administered AAV8/DC190-GAA to 10-month-old Pompe mice, an age at which they display significant muscle pathology and motor function decline. Mice treated at this advanced stage of the disease showed a partial recovery of muscle function, but performance was not normalized despite high circulating levels of GAA. We are currently measuring glycogen levels and studying the histopathology of muscle and CNS tissues from the mice in these studies. In summary, we have shown that systemic gene therapy treatment is capable of preventing degenerative myopathy and preserving motor function in Pompe mice, but is less effective in animals with pre-existing pathology.
Effect of Obesity and of Starvation on Insulin Activity
Authors: N. Samaan, J. Brown, R. Fraser, I. Trayner
Journal: BMJ (1965)

BRITISH 1153thromboembolic occlusive vascular disease, for which in any event side-effects render it unsafe.On the other hand, as the present studies demonstrate, Complamin clearly does not exploit the full fibrinolytic potential of the body, and a search for further modifications of nicotinic acid or other pharmacological substances which would produce a sustained fibrinolytic response would seem worth while.In particular, a non-toxic substance administered by mouth might, by long-term admini- stration to increase physiological fibrinolytic activity, have an important role in the prophylaxis of vascular thrombosis.Summary Complamin, a nicotinic-acid/theophylline ester, produces brisk but transient fibrinolytic activity when injected or infused intra- venously.A refractory state soon appears, in which patients do not respond to further therapy.However, prior fibrinolytic response to exercise dose not reduce the response to Complamin, nor is the fibrinolytic response to exercise reduced when exercise follows Complamin.It would therefore appear that resistance to repeated injections of Complamin is not due to exhaustion of the body's fibrinolytic potential.Side-effects of Complamin include flushing of the skin, abdominal pain, and hypotension, which may be severe.Because of the transient nature of the fibrinolytic response and the danger of hypotension, Complamin does not appear to have a place as a therapeutic agent in the treatment of thromboembolic occlusive vascular disease.We are grateful to Professor E. M. McGirr for his interest in this work, and to the colleagues who volunteered to participate in the studies.
Comprehensive health data across Asia-Pacific region available for first time
Authors: J. Parry
Journal: BMJ (2008)

A publication from the World Health Organization provides, for the first time, a comprehensive insight into health matters in the Asia-Pacific region.

The 600 page book, Health in Asia and the Pacific , published on 11 December and jointly produced by WHO’s South East Asia and Western Pacific regional offices, covers 48 countries and areas that between them account for 53% of the world’s population, 3.45 billion people.

Divided into three sections on health determinants, the regional health situation, and the development of health systems, the book gives governments and health specialists unprecedented access to the data they need to tackle the healthcare gap between rich and poor, which continues to afflict almost every country in …
Case Records: 3-1987
Authors: David J. Dickoff
Journal: New England Journal of Medicine (1987)

To the Editor: In Case 3–1987 (diagnosis: syringomyelia) (Jan. 15 issue),1 the otherwise erudite discussion by Dr. Michael Bresnan was marred by two errors that may have contributed to improper neurologic localization. He attributed decreased pinprick sensation in the right trigeminal distribution to involvement of the spinal nucleus of the fifth cranial nerve on the left, and right deviation of the tongue to involvement of the left hypoglossal nerve. The anatomy of the trigeminal and hypoglossal systems is a tricky business. Unipolar neurons subserving facial pinprick sensation are in the trigeminal ganglia. These descend in the spinal tract to synapse . . .
Enalapril versus digoxin in patients with congestive heart failure: A multicenter study
Authors: Richard F. Davies, Donald S. Beanlands, Claude Nadeau, Denis Phaneuf, Andrew Morris, J.Malcolm Arnold, John O. Parker, Ronald Baigrie, Paul Latour, W.Peter Klinke, Victoria Bernstein, Marie-Helene Leblanc, Henry Mizgala, Andrew Stevens, Guy Boisvert
Journal: Journal of the American College of Cardiology (1991)
Nobels: The Embarrassment of Repeated Wins
Authors: Daniel S. Greenberg
Journal: New England Journal of Medicine (1979)

Under a headline, "U.S. Domination of Nobel Prizes Seen Ending," a recent article in The Washington Post quoted several of the government's senior research officials to the effect that we're on the way down scientifically while other nations are on the way up."I think we will continue to win Nobel prizes, but not at the rate we have," Richard C. Atkinson, director of the National Science Foundation, was quoted as saying. "I think," he continued, "the Russians are going to start taking off, because they're pouring immense amounts of money into research. I just don't think we can go . . .
Medicine in the Framework of the University
Authors: F. Walshe
Journal: BMJ (1956)

It is not for me, a stranger in this city and university, to tell you, who all know it, the full story of Arthur Hall's part in the development of your medical school and its embodiment in the university as a faculty of medicine.I believe it is a story without parallel in our time in the creating of a university school of medicine, and we surely may not let this occasion pass without giving at least the bare bones of what this remarkable man undertook and accomplished in connexion with it.Hall's Versatility Shortly after his appointment to the staff of the Sheffield Royal Hospital, and in addition to his clinical responsibilities, he became in succession demonstrator, lecturer, and then professor of physiology.He took the initiative in securing for the school the whole-
New definition of myocardial infarction
Authors: D. Atar
Journal: BMJ (2008)

Features new subtypes of infarction and puts high demands on diagnostic assays 

The evolution of the definition of acute myocardial infarction tells a fascinating story of medical progress. Between the publication of the initial World Health Organization’s classification in 1979,1 and that published by the redefinition committee of the American College of Cardiology, American Heart Association, and European Society of Cardiology in 2000, much of our diagnostic reasoning changed.2 Biochemistry now takes centre stage, and the measurement of cardiac troponins has substantially increased diagnostic sensitivity.

Cardiologists predicted that these changes in diagnostic criteria and sensitivity would increase the incidence of acute myocardial infarction.3 They also predicted that the redefinition would have implications for individual patients and healthcare expenditure. Their predictions turned out to be correct, at least in part. A national registry in Norway found a 33% increase in acute myocardial infarction after the implementation of the 2000 criteria, …
236 TWELVE-WEEK COURSE OF PIFN-α-2A/RIBAVIRIN IS AN OPTIMIZED REGIMEN FOR TREATMENT OF HCV GENOTYPE 2 BUT NOT GENOTYPE 3 NON-CIRRHOTIC PATIENTS WITH RVR
Authors: L.E. Adinolfi, R. Zampino, B. Guerrera, L. Restivo, L. Rinaldi, A. Ciervo, V.R. Scialdone, M. Ferrara, G. Ruggiero
Journal: Journal of Hepatology (2010)
Glucose-induced microvascular functional changes in nondiabetic rats are stereospecific and are prevented by an aldose reductase inhibitor.
Authors: J R Williamson, E Ostrow, D Eades, K Chang, W Allison, C Kilo, W R Sherman
Journal: Journal of Clinical Investigation (1990)

Exposure of skin chamber granulation tissue vessels in nondiabetic rats to 11 or 15 mM D-glucose (but not L-glucose or 3-O-methylglucose) twice daily for 10 d induces vascular functional changes (increased albumin permeation and blood flow) identical to those in animals with mild or severe streptozotocin diabetes, respectively. These vascular changes are strongly linked to increased metabolism of glucose via the sorbitol pathway and are independent of nonenzymatic glycosylation as well as systemic metabolic and hormonal imbalances associated with the diabetic milieu. (J. Clin. Invest. 1990. 85:1167-1172.)
Cell-based Delivery of Oncolytic Viruses: A New Strategic Alliance for a Biological Strike Against Cancer
Authors: Anthony T Power, John C Bell
Journal: Molecular Therapy (2007)

Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique approach has been hindered by vulnerability to host defenses and inefficient systemic delivery. However, it now appears that delivery of oncolytic viruses within carrier cells may offer one solution to this critical problem. In this review, we compare the advantages and limitations of the numerous cell lineages that have been investigated as delivery platforms for viral therapeutics, and discuss examples showing how combined cell–virus biotherapeutics can be used to achieve synergistic gains in antitumor activity. Finally, we highlight avenues for future preclinical research that might be taken in order to refine cell–virus biotherapeutics in preparation for human trials. Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique approach has been hindered by vulnerability to host defenses and inefficient systemic delivery. However, it now appears that delivery of oncolytic viruses within carrier cells may offer one solution to this critical problem. In this review, we compare the advantages and limitations of the numerous cell lineages that have been investigated as delivery platforms for viral therapeutics, and discuss examples showing how combined cell–virus biotherapeutics can be used to achieve synergistic gains in antitumor activity. Finally, we highlight avenues for future preclinical research that might be taken in order to refine cell–virus biotherapeutics in preparation for human trials.
Postmarketing surveillance of adverse drug reactions in general practice. I: search for new methods.
Authors: W H Inman
Journal: BMJ (1981)

Spontaneous reporting of suspected adverse drug reactions through the yellow card system provides an effective means of early warning of potentially serious drug effects but occasionally fails because of under-reporting. Since more than 80% of medicines are prescribed by general practitioners we look to them to support new methods of postmarketing surveillance. No single method will be appropriate for all drugs, and yellow cards will always be required to detect rare events. It is proposed that adverse events experienced by the first 10 000 patients who receive certain new medicines should be recorded and transmitted to a monitoring centre and that a realistic target, which should be reached early in the market life of a new medicine, is the detection of any adverse event that occurs in more than in 1000 patients.
Antidepressant Medication as a Risk Factor for Type 2 Diabetes and Impaired Glucose Regulation
Authors: Katharine Barnard, Robert C. Peveler, Richard I.G. Holt
Journal: Diabetes Care (2013)

Antidepressant use has risen sharply over recent years. Recent concerns that antidepressants may adversely affect glucose metabolism require investigation. Our aim was to assess the risk of type 2 diabetes associated with antidepressants through a systematic review.Data sources were MEDLINE, Embase, PsycINFO, The Cochrane Library, Web of Science, meeting abstracts of the European Association for the Study of Diabetes, American Diabetes Association, and Diabetes UK, Current Controlled Trials, ClinicalTrials.gov, U.K. Clinical Research Network, scrutiny of bibliographies of retrieved articles, and contact with relevant experts. Relevant studies of antidepressant effects were included. Key outcomes were diabetes incidence and change in blood glucose (fasting and random).Three systemic reviews and 22 studies met the inclusion criteria. Research designs included 1 case series and 21 observational studies comprising 4 cross-sectional, 5 case-control, and 12 cohort studies. There was evidence that antidepressant use is associated with type 2 diabetes. Causality is not established, but rather, the picture is confused, with some antidepressants linked to worsening glucose control, particularly with higher doses and longer duration, others linked with improved control, and yet more with mixed results. The more recent, larger studies, however, suggest a modest effect. Study quality was variable.Although evidence exists that antidepressant use may be an independent risk factor for type 2 diabetes, long-term prospective studies of the effects of individual antidepressants rather than class effects are required. Heightened alertness to potential risks is necessary until these are complete.
Should chloride-rich crystalloids remain the mainstay of fluid resuscitation to prevent ‘pre-renal’ acute kidney injury?: con
Authors: Dileep N. Lobo, Sherif Awad
Journal: Kidney International (2014)

The high chloride content of 0.9% saline leads to adverse pathophysiological effects in both animals and healthy human volunteers, changes not seen after balanced crystalloids. Small randomized trials confirm that the hyperchloremic acidosis induced by saline also occurs in patients, but no clinical outcome benefit was demonstrable when compared with balanced crystalloids, perhaps due to a type II error. A strong signal is emerging from recent large propensity-matched and cohort studies for the adverse effects that 0.9% saline has on the clinical outcome in surgical and critically ill patients when compared with balanced crystalloids. Major complications are the increased incidence of acute kidney injury and the need for renal replacement therapy, and that pathological hyperchloremia may increase postoperative mortality. However, there are no large-scale randomized trials comparing 0.9% saline with balanced crystalloids. Some balanced crystalloids are hypo-osmolar and may not be suitable for neurosurgical patients because of their propensity to cause brain edema. Saline may be the solution of choice used for the resuscitation of patients with alkalosis and hypochloremia. Nevertheless, there is evidence to suggest that balanced crystalloids cause less detriment to renal function than 0.9% saline, with perhaps better clinical outcome. Hence, we argue that chloride-rich crystalloids such as 0.9% saline should be replaced with balanced crystalloids as the mainstay of fluid resuscitation to prevent 'pre-renal' acute kidney injury.
Cardiac Sympathetic Nerve Function in Congestive Heart Failure
Authors: Graeme Eisenhofer, Peter Friberg, Bengt Rundqvist, Arshed A. Quyyumi, Gavin Lambert, David M. Kaye, Irwin J. Kopin, David S. Goldstein, Murray D. Esler
Journal: Circulation (1996)

Background Increased availability of norepinephrine (NE) for activation of cardiac adrenoceptors (increased cardiac adrenergic drive) and depletion of myocardial NE stores may contribute to the pathophysiology and progression of congestive heart failure. This study used a comprehensive neurochemical approach to examine the mechanisms responsible for these abnormalities. Methods and Results Subjects with and without congestive heart failure received intravenous infusions of [ 3 H]NE. Cardiac spillover, reuptake, vesicular-axoplasmic exchange, and tissue stores of NE were assessed from arterial and coronary venous plasma concentrations of endogenous and [ 3 H]-labeled NE and dihydroxyphenylglycol. Tyrosine hydroxylase activity was assessed from plasma dopa, and NE turnover was assessed from measurements of NE metabolites. NE release and reuptake were both increased in the failing heart; however, the efficiency of NE reuptake was reduced such that cardiac spillover of NE was increased disproportionately more than neuronal release of NE. Cardiac NE stores were 47% lower and the rate of vesicular leakage of NE was 42% lower in the failing than in the normal heart. Cardiac spillover of dopa and NE turnover were increased similarly in congestive heart failure. Conclusions Increased neuronal release of NE and decreased efficiency of NE reuptake both contribute to increased cardiac adrenergic drive in congestive heart failure. Decreased vesicular leakage of NE, secondary to decreased myocardial stores of NE, limits the increase in cardiac NE turnover in CHF. Decreased NE store size in the failing heart appears to result not from insufficient tyrosine hydroxylation but from chronically increased NE turnover and reduced efficiency of NE reuptake and storage.
Nickel ENMs Activate HIF-1α
Authors: Rebecca Kessler
Journal: Environmental Health Perspectives (2011)

Much of the oil spilled during the BP Deepwater Horizon disaster in the Gulf of Mexico was burned to keep it from reaching the shoreline or harming sea life.NOAA scientists have analyzed the gas and aerosol emissions resulting from the burning of the spilled oil and found that over a 9-week period more than 1 million pounds of black carbon were generated, roughly the amount emitted in the same period by ship traffic in the region. 1 Compared with ship emissions, the particles generated by the oil burning rose to higher altitudes but also were larger and attracted fewer other substances, which may shorten their lifetime and make them less of a health and climate threat.These findings could be used by decisionmakers to help assess the tradeoffs of various response strategies during future disasters.Oil from the BP Deepwater Horizon disaster during a controlled burn, 6 May 2010.Transmission electron micrograph of norovirus particles.
The effect of dietary factors and vitamin supplementation on polyp size, frequency, and dysplasia in a regional colorectal cancer screening cohort
Authors: N. E. Burch, J. Huber
Journal: Gut (2011)

<h3>Introduction</h3> This pilot study aimed to evaluate the feasibility of detailed dietary evaluation in patients who have undergone colonoscopy as part of the National Bowel Cancer Screening Program (BCSP). This dietary data was then correlated with colonoscopy outcomes to identify any potential dietary factors which may impact on risk of polyp development. <h3>Methods</h3> 150 patients were posted a recruitment pack containing a 3-day food diary and vitamin supplementation questionnaire. Colonoscopy results for each patient were summarised with respect to polyp incidence, polyp characteristics, and other diagnoses. Completed food diaries were analysed to establish average daily macro and micro-nutrient composition using ‘Dietplan 6.09 software. Additional dietary supplement use was summarised from questionnaire responses to evaluate nature, frequency, and duration of supplement use. All dietary data were then evaluated with respect to colonoscopy outcomes to establish any potential associations. The control group was defined as those without polyps at their screening colonoscopy. <h3>Results</h3> A total of 30% of the research cohort returned a completed postal food diary and vitamin questionnaire. Individuals with polyps were more likely to participate (OR 1.56). A significant proportion regularly ingested dietary supplements such as multivitamins (29%), fish oils (24%), and probiotics (27%). There was a non-significant trend towards increased polyp incidence in those taking vitamin supplementation (OR 1.41). In contrast there was an apparent decreased polyp incidence in those taking fish oil supplements (0.76), and probiotics (OR 0.69). Higher vitamin E intake appeared to be protective against polyp development, with the effect approaching significance following independent samples t test (p=0.09). Increased average calcium intake was also associated with a non-significant trend towards decreased polyp incidence (p=0.17). Both cholesterol and fat intake were associated with a non-significant increased risk of polyps (p=0.15, and 0.16 respectively). <h3>Conclusion</h3> The BCSP population provides a unique platform for evaluation of dietary factors associated with colonic polyp development. This pilot study demonstrates an effective method for evaluation of these dietary factors, and despite relatively small numbers has shown some important trends which approach significance. Higher dietary intakes of vitamin E and calcium may protect against polyp development. Similarly fish oil supplementation and probiotics may also decrease risk of polyp development. Daily supplementation with multivitamins may increase polyp risk, although this is complex and multi-factorial. Large scale extension of this study needs to be undertaken to consolidate the pilot study findings.
Richard Worthington Smithells
Authors: P. S Boulter
Journal: BMJ (2002)

after a series of strokes.After 10 years with a general practice in Coventry, he left to establish a singlehanded practice in his home.No boundary existed between his work and his after-work activities.Today he would have been considered a workaholic, but he was simply at his most relaxed when with or on call for his patients.His favourite holiday was walking, particularly in the Lake District.His daily exercise was to gather and to saw logs for his fire.There was little he did not know about logs, their expert dissection, and the qualities they would demonstrate when they burned.He leaves a wife, Hildegard; four children; and seven grandchildren.[