tbuckley/cabot-search huggingface dataset:
The class III antiarrhythmic drugs dofetilide and sotalol prevent AF induction by atrial premature complexes at doses that fail to terminate AF
Authors: K Derakhchan
Journal: Cardiovascular Research (2001)

Background: Clinical trials suggest that sotalol and dofetilide are much more effective in preventing atrial fibrillation (AF) than in terminating it. This study evaluated potential mechanisms of discordant sotalol and dofetilide effects on AF termination vs. prevention. Methods: We applied 240-electrode epicardial mapping and programmed stimulation in a vagotonic dog model of AF before and after dofetilide or sotalol. Results: Under control conditions, sustained AF could be induced by single S2 extrastimuli that caused unidirectional block and macroreentry. Sotalol (2 mg/kg) and dofetilide (0.04 mg/kg) failed to terminate AF in any dog, but prevented AF induction by S2 stimuli in 19/22 (86%) and 4/5 (80%) of animals, respectively. With sotalol and dofetilide, unidirectional block still occurred, but wavefront reentry failed. The prevention of S2-induced reentry was related to large increases in the effective refractory period (ERP) at a BCL of 1000 ms, leading to ERPs that exceeded the conduction delay following S2. Reverse use-dependent effects resulted in smaller ERP increases at BCLs closer to the AF cycle length. Although the number of zones of reactivation per cycle during sustained AF were decreased by sotalol and dofetilide, the changes were small and insufficient to terminate AF. Conclusions: Sotalol and dofetilide prevent AF initiation by premature depolarizations at doses that fail to terminate vagotonic AF, by increasing ERP at the basic cycle length beyond the associated conduction delay that leads to reentry.
Polychlorinated biphenyls as hormonally active structural analogues.
Authors: J D McKinney, C L Waller
Journal: Environmental Health Perspectives (1994)

Among the environmental chemicals that may be able to disrupt the endocrine systems of animals and humans, the polychlorinated biphenyls (PCBs) are a chemical class of considerable concern. One possible mechanism by which PCBs may interfere with endocrine function is their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB molecular structure and the responses they evoke in biological systems. These physicochemical properties determine the molecular reactivities of PCBs and are responsible for their recognition at biological acceptors and receptors, as well as for triggering molecular mechanisms that lead to tissue response. "Coplanarity" of PCB phenyl rings and "laterality" of chlorine atoms are important structural features determining specific binding behavior with proteins and certain toxic responses in biological systems. We compare qualitative structure-activity relationships for PCBs with the limited information on the related non-coplanar chlorinated diphenyl ethers, providing further insights into the nature of the molecular recognition processes and support for the structural relationship of PCBs to thyroid hormones. Steroidlike activity requires conformational restriction and possibly hydroxylation. We offer some simple molecular recognition models to account for the importance of these different structural features in the structure-activity relationships that permit one to express PCB reactivities in terms of dioxin, thyroxine, and estradiol equivalents. The available data support the involvement of PCBs as mimics of thyroid and other steroidal hormones. The potential for reproductive and developmental toxicity associated with human exposure to PCBs is of particular concern.(ABSTRACT TRUNCATED AT 250 WORDS)
EU drug monitoring agency voices concerns over “legal highs”
Authors: Rory Watson
Journal: BMJ (2010)

Wolfgang Gotz, the director of the European Monitoring Centre for Drugs and Drug Addiction, urged governments not to cut funding of drug treatment programmes when he presented the agency’s annual report in Lisbon on 10 November.

As public expenditure is being drastically cut back to reduce massive national debts, Mr Gotz made a special plea for treatment schemes to reduce drug use—on which more than one million people in the European Union now depend—to be spared the budgetary axe.

“At a time when effective responses need to be sustained, austerity measures could lead to reductions in treatment services,” he warned. “Current pressures …
Fibrinolytic pattern in recurrent spontaneous abortions: No relationship between hypofibrinolysis and anti‐phospholipid antibodies
Authors: G. M. Patrassi, M. T. Sartori, A. Ruffatti, M. Viero, L. Di Lenardo, D. Cazzanello, A. Ghirardello, G. Boeri, G. Saggiorato, A. Girolami
Journal: American Journal of Hematology (1994)

Abstract Patients with antiphospholipid antibodies may suffer from thrombotic events and recurrent spontaneous abortions. A defective fibrinolytic potential has been described in women with recurrent fetal losses. We investigated the prevalence of anticardiolipin antibodies and of various fibrinolytic abnormalities in 64 females with a history of at least two abortions of unknown origin. Anticardiolipin antibodies were present in the serum of 31 patients (48.4%). The overall prevalence of fibrinolytic disorders was 67.2% (43 cases) and resulted significantly higher than that of aCL positivity ( P = 0.03). In most of cases the impaired fibrinolytic potential after venous occlusion test was due to increased PAI‐1 levels; only in a few instances a defective fibrinolytic response was due to reduced t‐PA release, a combined defect or an intrinsic fibrinolytic deficiency. After division of patients in two groups on the basis of the aCL presence, the distribution of different fibrinolytic defects was similar in aCL positive and negative women, suggesting the lack of correlation between hypofibrinolysis and aCL antibodies. Plasminogen abnormalities resulted compatible with congenital hypoplasminogenemia in two aCL negative women, whereas in four aCL positive patients they were suggestive for acquired dysplasminogenemia. Our results indicate that patents with recurrent spontaneous abortions may present fibrinolytic disorders, which occur independently and more often than aCL positivity. An accurate investigation of the fibrinolytic potential, and, namely, of PAI‐1 levels, should be included in the study of females suffering from repeated fetal losses. © 1994 Wiley‐Liss, Inc.
The Correlation Between the Expression of Differentiation Markers in Rat Small Intestinal Mucosa and the Transcript Levels of Schlafen 3
Authors: Pavlo L. Kovalenko, Marc D. Basson
Journal: JAMA Surgery (2013)

<h3>Importance</h3> The normal absorptive function and structural maintenance of the intestinal mucosa depend on a constant process of proliferation of enterocytic stem cells followed by progressive differentiation toward a mature phenotype. The mechanisms that govern enterocytic differentiation in the mucosa of the small intestine are poorly understood. <h3>Objective</h3> To determine whether schlafen 3 (but not other schlafen proteins) act in vivo and whether its effects are limited to the small intestine. We have previously demonstrated in nonmalignant rat intestinal IEC-6 cells that schlafen 3 levels correlate with the expression of various differentiation markers in vitro in response to differentiation stimuli. <h3>Design</h3> Randomized controlled experiment. <h3>Setting</h3> Animal science laboratory. <h3>Participants</h3> Male Sprague-Dawley rats 8 to 13 weeks old. <h3>Main Outcomes and Measures</h3> Messenger RNA (mRNA) from jejunal and colonic mucosa was isolated, and transcript levels of schlafen proteins 1, 2, 3, 4, 5, 13, and 14; sucrase isomaltase (SI); dipeptidyl peptidase 4 (Dpp4); glucose transporter type 2 (Glut2); and villin were measured by quantitative reverse transcriptase–polymerase chain reaction. We tested parallel variations in protein levels by Western blotting and Dpp4 enzyme activity. <h3>Results</h3> The transcript level of schlafen 3 (Slfn3) correlated with the levels of the differentiation markers SI, Dpp4, Glut2, and villin. However, the expression of schlafen proteins 1, 2, 4, 5, 13, and 14 did not correlate with the expression of the differentiation markers. The mucosal mRNA levels of Slfn3, SI, Glut2, and Dpp4 were all substantially higher in the rat jejunum than in colonic mucosa by a mean (SE) factor of 51.0 (13.2) for 6 rats (<i>P</i> &lt; .05), 599 (99) for 8 rats (<i>P</i> &lt; .01), 12.5 (5.5) for 8 rats (<i>P</i> &lt; .01), and 14.0 (3.9) for 8 rats (<i>P</i> &lt; .01), respectively. In IEC-6 cells, infection with adenovirus-expressing GFP-tagged Slfn3 significantly increased Slfn3 expression and Dpp4-specific activity compared with GFP-expressing virus (in 6 rats;<i>P</i> &lt; .05). <h3>Conclusions and Relevance</h3> Taken together with our previous in vitro observations, the results suggest that small intestinal enterocytic epithelial differentiation in rats may be regulated by Slfn3 in vivo, as in vitro, and that these effects may be specific to the small intestinal enterocytic phenotype as opposed to that of the mature colonocyte. Slfn3 human orthologs may be targeted to stimulate intestinal differentiation in patients with short bowel syndrome.
Minnesota Studies on Community-based Approaches to Weight Loss and Control
Authors: Robert W. Jeffery
Journal: Annals of Internal Medicine (1993)

Community-based approaches to weight control including worksite interventions, intervention by home correspondence, and multimodal community strategies are reviewed. Community-based programs have shown the ability to treat large numbers of obese persons, many of whom probably would not spontaneously seek professional care. Community-based approaches produce modest weight losses at lower costs than do clinical interventions. Although no community program has yet to reduce the prevalence of obesity in the general population, this area is relatively new and deserves further study. Recommended areas for future research include strategies for recruitment to community programs and primary prevention of weight gain.
Is secondary lymphoid‐organ chemokine (SLC/CCL21) much more than a constitutive chemokine?
Authors: H. M. Serra, C. E. Baena‐Cagnani, Y. Eberhard
Journal: Allergy (2004)

Chemokines are a superfamily of small cytokines with activities ranging from leukocyte traffick to hematopoiesis, angiogenesis, and tissue organogenesis. Secondary lymphoid‐organ chemokine (SLC/CCL21) was originally reported as a chemokine constitutively expressed by stromal cells and high endothelial venules in secondary lymphoid tissues and endothelium of afferent lymphatics, directing CCR7 + cells. More recently, others and we have demonstrated that SLC/CCL21 is up‐regulated in different skin inflammatory conditions. Thereafter, this molecule is much more than a constitutive chemokine, which could play a role in effector and regulatory immune functions.
Emergence and outbreak of carbapenemase-producing KPC-3 Klebsiella pneumoniae in Spain, September 2009 to February 2010: control measures
Authors: A Robustillo Rodela, C Díaz-Agero Pérez, T Sanchez Sagrado, P Ruiz-Garbajosa, M J Pita López, V Monge
Journal: Eurosurveillance (2012)

This report describes the epidemiological features of the first outbreak caused by KPC3 carbapenemase-producing Klebsiella pneumoniae (KPC-3-KP) in Spain and how it was effectively controlled. From 16 September 2009 to the end of February 2010, seven patients infected or colonised with KPC-3-KP were detected. Stool surveillance cultures were recovered from patients, doctors, nurses, nursing assistants, cleaners and hospital porters working in the affected units. Hand swabs were taken from workers and patients’ relatives for culturing. Environmental samples were also taken. Patients infected or colonised with KPC-3-KP were placed in single rooms under contact precautions and 4% chlorhexidine soap was used for their daily hygiene. Staff attended educational seminars and workshops on hand hygiene and isolation of patients. An alcohol-based disinfectant was used for surface cleaning and disinfecting. The floor was cleaned with a disinfectant containing benzalkonium chloride and didecyldimethylammonium. All samples collected were negative for KPC-3-KP. After implementing the control measures, no further cases were reported in the affected units. All cases had comorbidities, long hospital stay and aggressive/intensive antimicrobial treatment. This study emphasises the importance of early intensification of infection control to interrupt the transmission of KPC-producing organisms.
Mediators of Immediate Hypersensitivity Reactions
Authors: William E. Serafin, K. Frank Austen
Journal: New England Journal of Medicine (1987)

PATIENTS with immediate hypersensitivity reactions are commonly encountered by physicians in both primary care and various specialty practices. Such patients present a broad spectrum of illnesses, ranging in severity from mild urticaria or seasonal rhinitis to fatal anaphylactic shock. For many years the pathophysiology of these illnesses has been known to involve the release of inflammatory mediators by mast cells and basophils. Over the past 10 years, considerable progress has been made in elucidating the structure and function of these mediators. Thus, many of the signs and symptoms of allergic responses in humans can now be attributed to specific mast-cell . . .
Decreased urinary oestriol concentrations in pregnant women during hexamine hippurate treatment.
Authors: S Kivinen, R Tuimala
Journal: BMJ (1977)

<h3>Background and Objectives</h3> Application of local anesthetics may lead to nerve damage. Increasing evidence suggests that risk of neurotoxicity is higher in patients with diabetic peripheral neuropathy. In addition, block duration may be prolonged in neuropathy. We sought to investigate neurotoxicity in vitro and block duration in vivo in a genetic animal model of diabetes mellitus type 2. <h3>Methods</h3> In the first experiments, neurons harvested from control Zucker diabetic fatty (ZDF) rats were exposed to acute (24 hours) or chronic (72 hours) hyperglycemia, followed by incubation with lidocaine 40 mM (approximately 1%). In a second experiment, neurons harvested from control ZDF rats, or diabetic ZDF rats, were incubated with lidocaine, with or without SB203580, an inhibitor of the p38 mitogen-activated protein kinase. Finally, we performed sciatic nerve block (lidocaine 2%, 0.2 mL) in control or diabetic ZDF rats and measured motor and nociceptive block duration. <h3>Results</h3> In vitro, neither acute nor chronic hyperglycemia altered neurotoxic properties of lidocaine. In vitro, incubation of neurons with lidocaine resulted in a slightly decreased survival ratio when neurons were harvested from diabetic (57% ± 19%) as compared with control (64% ± 9%) rats. The addition of SB203580 partly reversed this enhanced neurotoxic effect and raised survival to 71% ± 12% in diabetic neurons and 66% ± 9% in control rats, respectively. In vivo, even though no difference was detected at baseline testing, motor block was significantly prolonged in diabetic as compared with control rats (137 ± 16 vs 86 ± 17 min). <h3>Conclusions</h3> In vitro, local anesthetic neurotoxicity was more pronounced on neurons from diabetic animals, but the survival difference was small. In vivo, subclinical neuropathy leads to substantial prolongation of block duration. We conclude that early diabetic neuropathy increases block duration, whereas the observed increase in toxicity was small.
Diagnosis and Treatment of Bone Tumors in Children
Authors: Spencer A. Rowland
Journal: JAMA (1960)

Of 338 pathologically verified bone tumors in children, 145 were benign and 193 malignant. The following procedures for diagnosis and treatment were recommended: every child with persistent pain (often referred), swelling, or limitation of motion of a skeletal part should be roentgenologically studied immediately; if the location of a radioresistant bone tumor permits, the type is best determined by biopsy distal to two tourniquets; fresh frozen specimens are examined by an experienced pathologist; and if osteogenic sarcoma or fibrosarcoma is present, amputation should be undertaken promptly. The over-all survival rate of 18.1 per cent in the treatment of 106 osteogenic sarcomas supports the plan as outlined.
Endothelial Nitric Oxide Production and Insulin Sensitivity
Authors: John R. Petrie, Shinichiro Ueda, David J. Webb, Henry L. Elliott, John M.C. Connell
Journal: Circulation (1996)

Background Insulin sensitivity varies up to threefold in apparently healthy individuals, but the mechanism for this is unknown. We have examined the hypothesis that vascular endothelial nitric oxide production and insulin sensitivity are directly related in humans. Methods and Results Nineteen healthy male subjects were studied on 3 separate days 1 week apart during which time they underwent measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (soluble insulin 1.5 mU·kg −1 ·min −1 ) and measurement of in vivo basal and stimulated endothelial nitric oxide production by forearm venous occlusion plethysmography. There was a correlation between insulin sensitivity and forearm vasoconstrictor responses to N G -monomethyl- l -arginine, the substrate inhibitor of nitric oxide synthase ( r =.52, P &lt;.05). No correlations were observed between insulin sensitivity and noradrenaline, acetylcholine, or sodium nitroprusside responses. Conclusions Endothelial nitric oxide synthesis and insulin sensitivity are positively related in healthy humans, which suggests a direct physiological link.
Germany is poised to change law on organ donation to allow automatic "opting in"
Authors: A. Tuffs
Journal: BMJ (2010)

The German government has announced plans to change the transplantation law to increase the number of organ donors, after the former Social Democrat foreign minister Frank-Walter Steinmeier donated a kidney to his wife, prompting renewed public focus on the shortage of donated organs.

Only 4050 transplantations were carried out in 2009 in Germany, and around 12 000 patients are awaiting an organ.

Various measures have been proposed to boost the number of organ donors, from improving recruitment of donors in hospitals to radical changes to the current legislation to an …
742 Expression of CD40 ligand (CD154) is specifically upregulated in the liver of patients with primary biliary cirrhosis
Authors: M MAYO, B COMBES, S KHILNANI, M ALHALIMI, R JEYARAJAH, P LIPSKY
Journal: Hepatology (2003)

Five different target mitochondrial autoantigens recognized by sera from patients with primary biliary cirrhosis (PBC) have been identified as subunits of the following 2-oxo acid dehydrogenase complexes: the pyruvate dehydrogenase complex (PDC), the branched chain 2-oxo acid dehydrogenase complex (BCOADC), and the 2-oxoglutarate dehydrogenase complex (OGDC). Unlike the E2 subunits of PDC (PDC-E2) and BCOADC (BCOADC-E2), the E2 subunits of OGDC (OGDC-E2) reactivity of PBC sera and the reactive epitope of OGDC-D2 have not hitherto been studied in detail. In this report, we took advantage of a recombinant fusion protein for OGDC-E2 to address these issues. Eighty of 268 (29.9%) PBC patient sera but none of the 45 controls reacted with recombinant OGDC-E2. The recombinant OGDC-E2 was judged to express the immunodominant epitope, because when sera from patients with PBC were preabsorbed with the recombinant fusion protein, such sera were depleted of reactivity against 48 kD OGDC-E2 when probed on beef heart mitochondria (BHM) but retained reactivity toward PDC-E2 and/or BCOADC-E2. Furthermore, affinity-purified PBC sera against recombinant OGDC-E2 reacted only with native OGDC-E2 and not with any other enzyme components of the 2-oxo acid dehydrogenase complex. Antimitochondrial autoantibodies (AMA) against OGDC-E2 included immunoglobulin (Ig)G2, IgG3 and IgM and the relative titers were as follows: IgG2 > IgG3 > IgM. Finally, using overlapping recombinant polypeptides, it was determined that a minimum of 81 amino acids (residues 67-147) corresponding to the lipoyl domain of OGDC-E2 are necessary for reactivity, suggesting that a conformational autoepitope is recognized by AMA. These data suggest that each of the 2-oxo acid dehydrogenase enzymes has distinct antigenicity despite their similarities in structure and function. The availability of recombinant OGDC-E2 autoantigen will allow the design of additional studies to further our understanding of the role of mitochondrial autoantigens in the pathogenesis of PBC. (Hepatology 1996 Mar;23(3):436-44)
Patients and Practitioners: Lay Perceptions of Medicine in Pre-Industrial Society
Authors: Morris J. Vogel
Journal: JAMA (1987)

This is a series of 11 studies, all but two of which focus on England in the 17th and 18th centuries. (One contribution is concerned with classical antiquity and another with traditional Arabic medicine.) The studies are based on diverse sources, examine different individuals and communities, and analyze separate fragments of a larger question—the interplay of health, culture, and society. Although diverse, the studies share a common goal: the understanding of health, sickness, and therapy from the perspective of the patient and the layman. This is not a book in which physicians command center stage. Even Galen is reduced to the status of a minor sycophant. Indeed, it is a central theme of this volume that physicians in preindustrial societies—and healers in general—appeared and served only at the beck and call of patients and their families. In these studies, the laity take an active and, at times, dominant role in