tbuckley/cabot-search huggingface dataset:
Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel
Authors: Toshana L. Foster, Mark Verow, Ann L. Wozniak, Matthew J. Bentham, Joseph Thompson, Elizabeth Atkins, Steven A. Weinman, Colin Fishwick, Richard Foster, Mark Harris, Stephen Griffin
Journal: Hepatology (2011)

Abstract: The hepatitis C virus (HCV) p7 ion channel plays a critical role during infectious virus production and represents an important new therapeutic target. Its activity is blocked by structurally distinct classes of small molecules, with sensitivity varying between isolate p7 sequences. Although this is indicative of specific protein–drug interactions, a lack of high-resolution structural information has precluded the identification of inhibitor binding sites, and their modes of action remain undefined. Furthermore, a lack of clinical efficacy for existing p7 inhibitors has cast doubt over their specific antiviral effects. We identified specific resistance mutations that define the mode of action for two classes of p7 inhibitor: adamantanes and alkylated imino sugars (IS). Adamantane resistance was mediated by an L20F mutation, which has been documented in clinical trials. Molecular modeling revealed that L20 resided within a membrane-exposed binding pocket, where drug binding prevented low pH-mediated channel opening. The peripheral binding pocket was further validated by a panel of adamantane derivatives as well as a bespoke molecule designed to bind the region with high affinity. By contrast, an F25A polymorphism found in genotype 3a HCV conferred IS resistance and confirmed that these compounds intercalate between p7 protomers, preventing channel oligomerization. Neither resistance mutation significantly reduced viral fitness in culture, consistent with a low genetic barrier to resistance occurring in vivo . Furthermore, no cross-resistance was observed for the mutant phenotypes, and the two inhibitor classes showed additive effects against wild-type HCV. Conclusion: These observations support the notion that p7 inhibitor combinations could be a useful addition to future HCV-specific therapies. (HEPATOLOGY 2011;)
Ciguatera Fish Poisoning and Climate Change: Analysis of National Poison Center Data in the United States, 2001–2011
Authors: Daniel B. Gingold, Matthew J. Strickland, Jeremy J. Hess
Journal: Environmental Health Perspectives (2014)

Warm sea surface temperatures (SSTs) are positively related to incidence of ciguatera fish poisoning (CFP). Increased severe storm frequency may create more habitat for ciguatoxic organisms. Although climate change could expand the endemic range of CFP, the relationship between CFP incidence and specific environmental conditions is unknown.We estimated associations between monthly CFP incidence in the contiguous United States and SST and storm frequency in the Caribbean basin.We obtained information on 1,102 CFP-related calls to U.S. poison control centers during 2001-2011 from the National Poison Data System. We performed a time-series analysis using Poisson regression to relate monthly CFP call incidence to SST and tropical storms. We investigated associations across a range of plausible lag structures.Results showed associations between monthly CFP calls and both warmer SSTs and increased tropical storm frequency. The SST variable with the strongest association linked current monthly CFP calls to the peak August SST of the previous year. The lag period with the strongest association for storms was 18 months. If climate change increases SST in the Caribbean 2.5-3.5 °C over the coming century as projected, this model implies that CFP incidence in the United States is likely to increase 200-400%.Using CFP calls as a marker of CFP incidence, these results clarify associations between climate variability and CFP incidence and suggest that, all other things equal, climate change could increase the burden of CFP. These findings have implications for disease prediction, surveillance, and public health preparedness for climate change.
P516 Pro-C5: A NOVEL SEROLOGICAL MARKER OF TRUE TYPE V COLLAGEN FORMATION DETECTS PORTAL HYPERTENSION IN CIRRHOSIS
Authors: D.J. Leeming, M.J. Nielsen, M.A. Karsdal, S.S. Veidal, J. Trebicka, F. Bendtsen, A. Krag, S. Møller
Journal: Journal of Hepatology (2014)
An Important Toxic Effect of Digitalis Overdosage on the Vision
Authors: Paul D. White
Journal: New England Journal of Medicine (1965)

IN 1785 William Withering, in his famous book entitled "An Account of the Foxglove," writing concerning the effects of digitalis (page 184), said that "the foxglove when given in very large and quickly repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow...."In the early 1820's Purkinje, the great Czech physician, also described the toxic effect of digitalis on the vision, especially the rosettes of light seen by the patient, and Cushny, professor of pharmacology in the University of Edinburgh, writing his noted book on digitalis, which was published in 1925, had this to say . . .
An Investigation of Modifying Effects of Metallothionein Single-Nucleotide Polymorphisms on the Association between Mercury Exposure and Biomarker Levels
Authors: Yi Wang, Jaclyn M. Goodrich, Brenda Gillespie, Robert Werner, Niladri Basu, Alfred Franzblau
Journal: Environmental Health Perspectives (2012)

Background: Recent studies have suggested that several genes that mediate mercury metabolism are polymorphic in humans.Objective: We hypothesized that single-nucleotide polymorphisms (SNPs) in metallothionein (MT) genes may underlie interindividual differences in mercury biomarker levels. We studied the potential modifying effects of MT SNPs on mercury exposure–biomarker relationships.Methods: We measured total mercury in urine and hair samples of 515 dental professionals. We also surveyed occupational and personal exposures to dental amalgam and dietary fish consumption, from which daily methylmercury (MeHg) intake was estimated. Log-transformed urine and hair levels were modeled in multivariable linear regression separately against respective exposure surrogates, and the effect modification of 13 MT SNPs on exposure was investigated.Results: The mean mercury levels in urine (1.06 μg/L) and hair (0.51 μg/g) were not significantly different from the U.S. general population (0.95 μg/L and 0.47 μg/g, respectively). The mean estimated daily MeHg intake was 0.084 μg/kg/day (range, 0–0.98 μg/kg/day), with 25% of study population intakes exceeding the current U.S. Environmental Protection Agency reference dose of 0.1 μg/kg/day. Multivariate regression analysis showed that subjects with the MT1M (rs2270837) AA genotype (n = 10) or the MT2A (rs10636) CC genotype (n = 42) had lower urinary mercury levels than did those with the MT1M or MT2A GG genotype (n = 329 and 251, respectively) after controlling for exposure and potential confounders. After controlling for MeHg intake, subjects with MT1A (rs8052394) GA and GG genotypes (n = 24) or the MT1M (rs9936741) TT genotype (n = 459) had lower hair mercury levels than did subjects with MT1A AA (n = 113) or MT1M TC and CC genotypes (n = 15), respectively.Conclusion: Our findings suggest that some MT genetic polymorphisms may influence mercury biomarker concentrations at levels of exposure relevant to the general population.
Myocardial collagen turnover in hypertrophic cardiomyopathy: comparison to healthy subjects
Authors: Raffaella Lombardi, Sandro Betocchi, Maria Angela Losi, Quirino Ciampi, Carlo G. Tocchetti, Elpidio Pezzella, Filippo Finizio, Mariano Aversa, Marianna Miranda, Veronica De Crescenzo, Massimo Chiariello
Journal: Journal of the American College of Cardiology (2002)
A Good-Looking Cast
Authors: Vernon L. Nickel
Journal: JAMA (1966)

To the Editor:—  In reply, the first paragraph is typical of recollections of happenings which occurred many years ago, but which may have been actually somewhat different. However, I have no doubt that the cast looked gosh awful at that time, and agree that they still do.  The efficacy of medical treatment as judged by this patient's husband may reflect personal worry, grief at being separated from his wife, and the fear of what might happen to her. While close family ties are to be commended, a better way to judge medical treatment might be the actual patient's opinion of his care. For instance, it would be interesting to contrast the amount of pain endured during reduction of the fracture to that during the trip home. Other factors, such as period of healing, residual deformity, and permanent disability, might likewise show revealing differences.  Since Dr. Filinger appears to be more
Effect of Prone and Supine Positions on Functional Residual Capacity, Oxygenation, and Respiratory Mechanics in Ventilated Infants and Children
Authors: ANDREW H. NUMA, JÜRG HAMMER, CHRISTOPHER J. L. NEWTH
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Although numerous reports have described the improvement in Pa O2 in patients in the prone position, the underlying mechanism has yet to be determined. Some authors have suggested this phenomenon may be related to an increase in functional residual capacity (FRC); however, no previous studies have described positional changes in FRC in children with severe lung disease or in those under neuromuscular blockade. We measured arterial blood gases, FRC, Rrs, and Crs in supine and prone positions in 30 patients under neuromuscular blockade with lung disorders including moderately severe restrictive (n = 10) and obstructive (n = 10) disease and control subjects without significant lung disease (n = 10). Prone positioning was not associated with a significant increase in FRC in the cohort of 30 patients, nor in any of the subgroups. Although individual patients demonstrated large improvements in oxygenation, a statistically significant (but clinically insignificant) increase in aaPo 2 ratio was observed only in the subgroup of patients with obstructive disease (0.35 ± 0.03 to 0.38 ± 0.04, p = 0.027). There was no correlation between changes in FRC and changes in aaPo 2 (r = 0.225, p = 0.23). A significant improvement in Rrs occurred in the prone position compared to supine in patients with obstructive lung disease, decreasing from 0.264 ± 0.024 to 0.216 ± 0.021 cm H2O/ml/s, p = 0.009. No significant changes in Crs were seen in the prone position. We conclude that prone positioning has no effect on FRC and in this series of 30 patients significantly improved oxygenation only in patients with obstructive airway disease. A significant decrease in Rrs in patients with obstructive lung disease was also observed.
Microvascular Complications at Time of Diagnosis of Type 2 Diabetes Are Similar Among Diabetic Patients Detected by Targeted Screening and Patients Newly Diagnosed in General Practice
Authors: Annemieke M.W. Spijkerman, Jacqueline M. Dekker, Giel Nijpels, Marcel C. Adriaanse, Piet J. Kostense, Dirk Ruwaard, Coen D.A. Stehouwer, Lex M. Bouter, Robert J. Heine
Journal: Diabetes Care (2003)

OBJECTIVE—To investigate whether screening-detected diabetic patients differ from diabetic patients newly diagnosed in general practice with regard to the presence of microvascular complications. RESEARCH AND DESIGN METHODS—Diabetic patients, identified by a population-based targeted screening procedure consisting of a screening questionnaire and a fasting capillary whole-blood glucose measurement followed by diagnostic testing, were compared with patients newly diagnosed with diabetes in general practice. Retinopathy was assessed with fundus photography, impaired foot sensitivity was assessed with Semmes-Weinstein monofilaments, and the presence of microalbuminuria was measured by means of the albumin-to-creatinine ratio (ACR). RESULTS—A total of 195 screening-detected type 2 diabetic patients and 60 patients newly diagnosed in general practice participated in the medical examination. The prevalence of retinopathy was higher in screening-detected type 2 diabetic patients than in patients newly diagnosed in general practice, but not significantly higher. The prevalence of retinopathy was 7.6% (95% CI 4.6–12.4) in screening-detected type 2 diabetic patients and 1.9% (0.3–9.8) in patients newly diagnosed in general practice. The prevalence of impaired foot sensitivity was similar in both groups, 48.1% (40.9–55.3) and 48.3% (36.2–60.7), respectively. The ACR was 0.61 (interquartile range 0.41–1.50) in screening-detected type 2 diabetic patients and 0.99 (0.53–2.49) in patients newly diagnosed in general practice. The difference in prevalence of microalbuminuria was not statistically significant. The prevalence of microalbuminuria was 17.2% (95% CI 12.5–23.2) and 26.7% (17.1–39.0) in screening-detected type 2 diabetic patients and patients newly diagnosed in general practice, respectively. CONCLUSIONS—Targeted screening for type 2 diabetes (with a screening questionnaire as a first step) resulted in the identification of previously undiagnosed diabetic patients with a considerable prevalence of microvascular complications.
The Humanities, Humanistic Behavior, and the Humane Physician: A Cautionary Note
Authors: Robert M. Arnold, Gail J. Povar, Joel D. Howell
Journal: Annals of Internal Medicine (1987)

Efforts to teach and evaluate humanistic qualities in physicians in residency training are marred by ambiguous goals. The humane physician can be characterized by four distinct qualities: technical competence, humanistic attitude, knowledge of humanistic concepts, and humanistic behavior. Education in the humanities can foster humanistic attitudes, but it cannot promise to lead to changes in behavior. Likewise, although formal training in communication teaches the skills necessary for humanistic behavior, without an understanding of humanistic concepts these skills may not serve medical or moral ends. Evaluation of the humane physician must also include modalities that test attitude, knowledge, and behavior. Testing one characteristic does not ensure competence in other areas; knowledge of the requirements for informed consent, for example, does not guarantee one's ability to discuss this concept effectively with patients. In this article, we suggest ways to combine the humanities and communication skills in the clinical setting and we emphasize both the training and the evaluation of humane physicians.
Is it true that coeliacs do not digest gliadin? Degradation pattern of gliadin in coeliac disease small intestinal mucosa
Authors: D Bernardo, J A Garrote, I Nadal, A J Leon, C Calvo, L Fernandez-Salazar, A Blanco-Quiros, Y Sanz, E Arranz
Journal: Gut (2009)

Prolyl-endopeptidase supplementation has been proposed to favour gliadin degradation as an alternative treatment for coeliac disease (CD), although the real usefulness of this therapy in vivo is still under discussion.1 However, our data point to alternative treatments aiming to modify the intestinal microbiota in patients with CD by the use of probiotics and/or prebiotics. We propose that the induction of gliadin proteolysis in the human gut might not be the solution but the origin of CD.

We have carried out gliadin zymograms using a complete protein solution from duodenal mucosa of patients with CD, both untreated patients with positive serology, genetics and duodenal inflammation (n = 20), and treated patients on a gluten-free diet (GFD) with negative serology and recovering mucosa (n = 9). We have also analysed 18 non-CD controls, without mucosal inflammation and negative serology.

Figure 1 reveals for the first time to our knowledge, and in contrast to what would be expected, the existence of a specific gliadinase pattern in duodenal samples from patients with CD. This pattern was observed regardless of the phase …
Whistleblower who was excluded from work for five years wins apology
Authors: Clare Dyer
Journal: BMJ (2008)

A junior doctor who was excluded from work for five years after she objected to the inclusion of patients’ medical records, including her own, on research databases without consent has received an unreserved apology from her employers in the High Court.

Named only as Dr Z to preserve her anonymity, she is subject to a gagging order and cannot discuss her case. However, the BMJ understands that she will not return to her job but has accepted compensation for the false allegations made against her and for the blight on her career.

Acting without a lawyer, she brought a libel action against her employers, Cambridgeshire Primary Care Trust, and the East of England Strategic Health Authority, which hosted her training scheme.

Damian Brown, for the trust and the authority, said in a statement in open court that Dr Z, whom he described as “a talented young …
UK clinical trials must be registered to win ethics committee approval
Authors: C. Dyer
Journal: BMJ (2013)

Clinical trials in the United Kingdom will have to be registered on a publicly accessible database as a condition of winning approval from ethics committees, under a new rule from the UK Health Research Authority that takes effect on 30 September.

The move is a start on implementing the authority’s action plan to increase transparency in research, set out in a discussion paper last May, which included ensuring that the outcomes of clinical trials are published.1

The authority, which has signed up to the AllTrials campaign on disseminating clinical trial data (alltrials.net), confirmed in July that …
Analysis of Reptilian APOBEC1 Suggests that RNA Editing May Not Be Its Ancestral Function
Authors: Francesco Severi, Andrea Chicca, Silvestro G. Conticello
Journal: Molecular Biology and Evolution (2010)

The Activation Induced Deaminase (AID)/APOBEC family of deaminases targeting nucleic acids arose at the beginning of the vertebrate radiation and further expanded in mammals. Following an analysis of the available genomic data, we report the identification of the APOBEC5, a novel group of paralogues in tetrapods. Moreover, we find bona fide homologues of Apolipoprotein B Editing Complex 1 (APOBEC1) in the genomes of anole lizard and zebra finch, thus implying its appearance prior to the divergence of the amniotes. apolipoprotein B editing complex 1 (APOBEC1), in contrast with other AID/APOBECs acting on DNA, is an RNA-editing enzyme that targets the transcript of Apolipoprotein B (ApoB), thereby causing the translation of a truncated form of the protein. 3′RACE experiments reveal a lizard APOBEC1-like molecule lacking a C-terminal region important for mammalian ApoB RNA editing. This observation pairs with the finding that lizard ApoB is not deaminated at the region corresponding to the mammalian site of editing. Similar to mammalian APOBEC1, the lizard protein is able to deaminate DNA in bacteria and shows a conserved mutational context. Although not precluding the possibility that lizard APOBEC1 acts on unknown mRNA targets, these findings suggest that its ability to target DNA predates its role in RNA editing.
Effect of free radical scavengers on diaphragmatic fatigue.
Authors: G Supinski, D Nethery, D Stofan, A DiMarco
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Recent studies have suggested that free radical scavenger administration reduces the rate of development of diaphragm fatigue. Much of this work has been done, however, using in vitro muscle preparations; the purpose of the present study was to assess the effect of scavengers on in vivo diaphragm contractile function. To accomplish this, we compared the rate of development of fatigue of the electrically stimulated diaphragm in four groups of dogs: (1) animals given intravenous polyethylene glycol adsorbed superoxide dismutase (PEG-SOD, 2,000 units/kg) 1 h before a fatigue trial; (2) a group given intravenous dimethylsulfoxide (DMSO, 0.5 ml/kg of a 50% solution) before fatigue; (3) a group given saline before fatigue; and (4) a group treated with denatured PEG-SOD (2,000 units/kg) before fatigue. We measured diaphragmatic concentrations of thiobarbituric acid reactive substances (TBAR), a marker of free radical-mediated lipid peroxidation, on muscle samples taken at the conclusion of fatigue trials. As a control, we also measured TBAR concentrations for muscle samples taken from nonfatigued diaphragm. We found that the rate of development of diaphragm fatigue was much greater in saline and denatured PEG-SOD-treated groups than for animals pretreated with either PEG-SOD or DMSO, with force falling to 23 +/- 4, 21 +/- 4, 50 +/- 7, and 47 +/- 6% of its initial value, respectively, over a 2-h period of electrophrenic stimulation in these four groups of animals (p < 0.01). TBAR concentrations in fatigued diaphragm from saline and denatured PEG-SOD-treated animals were significantly higher than levels for either nonfatigued fresh diaphragm or fatigued diaphragm taken from PEG-SOD- or DMSO-treated animals (p < 0.01). These data suggest that diaphragm fatigue resulting from repetitive low-frequency stimulation is associated with lipid peroxidation within this muscle and that pretreatment with free radical scavengers prevents lipid peroxidation and reduces the rate of development of fatigue.
Arylamines suppress their own activation and that of nitroarenes in V79 Chinese hamster cells by competing for acetyltransferases.
Authors: F Kiefer, O Cumpelik, R Reen, J Doehmer, F J Wiebel
Journal: Environmental Health Perspectives (1994)

The effect of 2-aminofluorene (2-AF) on the toxicity of 2-aminoanthracene (2-AA) and 1,6-dinitropyrene (1,6-DNP) was studied in N-acetyltransferase-proficient V79-NHr1A2 cells genetically engineered for the expression of cytochrome P4501A2, and in wild-type V79-NH cells. 2-AA inhibited the growth of V79-NHr1A2 cells and induced the formation of micronuclei at concentrations of 0.1 to 1.0 microM, but was virtually without toxic effects at a concentration of 10 microM. Addition of 2-AF protected against the cytotoxic and genotoxic effects elicited by low concentrations of 2-AA. Half-maximum protection was observed at 0.2 to 0.5 microM 2-AF. The arylamine also prevented the cytotoxicity caused by 1,6-DNP in V79-NH cells and completely suppressed the formation of 1-acetylamino-6-nitropyrene from 1,6-DNP in these cells. The results indicate that arylamines and related N-hydroxyarylamines are substrates for the same acetyltransferase in V79-NH cells. In consequence, arylamines are capable of suppressing the activation of their proximate cytotoxic and genotoxic products in these cells and, presumably, in vivo.
Macrophage activation: increased ingestion of IgG-coated erythrocytes after administration of interferon inducers to mice.
Authors: S I Hamburg, R E Manejias, M Rabinovitch
Journal: The Journal of Experimental Medicine (1978)

In vitro phagocytosis of IgG-opsonized sheep erythrocytes (EA) was used to measure the in vivo activation of mouse peritoneal macrophages. Uptake of EA as enhanced by the extraperitoneal administration of Newcastle disease virus, vesicular stomatitis virus, tilorone or polyinosinic-polycytidylic acid. Ingestion of EA was similarly stimulated by lipopolysaccharide or killed Corynebacterium parvum. Dose-response curves relating concentrations of IgG to phagocytosis were parallel for both treated and control animals. This indicates that the heterogeneity of the macrophage populations did not change and that the overall populations were activated with respect to phagocytic ability. Numbers of macrophages were not increased (except in C. parvum-treated mice), suggesting that resident, rather than newly recruited macrophages, were activated by the different agents.