Chronic hepatitis B - New goals, new treatment

published_or_final_versio

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

The 2014 ALMA Long Baseline Campaign: An Overview

A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to ~15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from September to late November 2014, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at ~350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy

Short and long term treatment of asthma with intravenous nutrients

BACKGROUND: Asthma is an increasing problem in this country and others. Although medications for the treatment of asthma abound and are improving, there are inherent risks and side effects with all of them. Intravenous magnesium has been employed in the treatment of acute asthma, but its use has not become universal, nor has it been studied for the treatment of chronic asthma. It is known to be a safe drug with minimal side effects. In this study, the author investigates the use of magnesium and other nutrients in the treatment of both acute and chronic asthma. METHODS: In this non-blinded outcome study, following informed consent, forty-three (43) randomly selected volunteer patients with both acute and chronic asthma were treated with IV infusions described herein. All patients were observed with spirometry 10 minutes post-infusion; two sub-groups of patients were also observed after multiple infusions over a short period of time (less than one month) and a longer period of time (average 5.8 months). Pulmonary function was analyzed by spirometric testing with pre- and post-infusion spirometric measurements with the pre/post group. For longer term (Trend) patients, baseline spirometry measurements were compared to spirometry measurements after patients had received multiple infusions over a period of time. Eight (8) patients were measured for both pre/post and Trend data. RESULTS: The 38 pre-infusion/post-infusion patients with acute and chronic asthma demonstrated an overall average improvement (percentage improvement in percent predicted) of 45%. The 13 patients measured for improvement over time (Trend data, average duration 5.82 months), demonstrated an overall average improvement (percentage improvement in percent predicted) of 57%. Of the 13 patients in the multiple infusion group, 9 patients who received longer-term therapy (average duration of 12.58 months) for chronic asthma demonstrated an overall average improvement of 95% (percentage improvement in percent predicted). CONCLUSION: The use of intravenous treatment with multiple nutrients, including magnesium, for acute and chronic asthma may be of considerable benefit. Pulmonary function improved progressively the longer patients received treatment

New insights into perinatal testicular torsion

Perinatal testicular torsion is a relatively rare event that remains unrecognized in many patients or is suspected and treated accordingly only after an avoidable loss of time. The authors report their own experience with several patients, some of them quite atypical but instructive. Missed bilateral torsion is an issue, as are partial torsion, possible antenatal signs, and late presentation. These data are discussed together with the existing literature and may help shed new light on the natural course of testicular torsion and its treatment. The most important conclusion is that a much higher index of suspicion based on clinical findings is needed for timely detection of perinatal torsion. It is the authors’ opinion that immediate surgery is mandatory not only in suspected bilateral torsions but also in cases of possible unilateral torsions. There is no place for a more fatalistic “wait-and-see” approach. Whenever possible, even necrotic testes should not be removed during surgery because some endocrine function may be retained

Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice

Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were indentified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21+/− animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21+/− animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues

To see or not to see: investigating detectability of Ganges River dolphins using a combined visual-acoustic survey

Detection of animals during visual surveys is rarely perfect or constant, and failure to account for imperfect detectability affects the accuracy of abundance estimates. Freshwater cetaceans are among the most threatened group of mammals, and visual surveys are a commonly employed method for estimating population size despite concerns over imperfect and unquantified detectability. We used a combined visual-acoustic survey to estimate detectability of Ganges River dolphins (Platanista gangetica gangetica) in four waterways of southern Bangladesh. The combined visual-acoustic survey resulted in consistently higher detectability than a single observer-team visual survey, thereby improving power to detect trends. Visual detectability was particularly low for dolphins close to meanders where these habitat features temporarily block the view of the preceding river surface. This systematic bias in detectability during visual-only surveys may lead researchers to underestimate the importance of heavily meandering river reaches. Although the benefits of acoustic surveys are increasingly recognised for marine cetaceans, they have not been widely used for monitoring abundance of freshwater cetaceans due to perceived costs and technical skill requirements. We show that acoustic surveys are in fact a relatively cost-effective approach for surveying freshwater cetaceans, once it is acknowledged that methods that do not account for imperfect detectability are of limited value for monitoring

A DNA Vaccine against Chikungunya Virus Is Protective in Mice and Induces Neutralizing Antibodies in Mice and Nonhuman Primates

Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgias, conjunctivitis, rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity, and no licensed vaccines or therapeutics are currently available for the pathogen. While the Aedes aegypti mosquito is its primary vector, recent evidence suggests that other carriers can transmit CHIKV thus raising concerns about its spread outside of natural endemic areas to new countries including the U.S. and Europe. Considering the potential for pandemic spread, understanding the development of immunity is paramount to the development of effective counter measures against CHIKV. In this study, we isolated a new CHIKV virus from an acutely infected human patient and developed a defined viral challenge stock in mice that allowed us to study viral pathogenesis and develop a viral neutralization assay. We then constructed a synthetic DNA vaccine delivered by in vivo electroporation (EP) that expresses a component of the CHIKV envelope glycoprotein and used this model to evaluate its efficacy. Vaccination induced robust antigen-specific cellular and humoral immune responses, which individually were capable of providing protection against CHIKV challenge in mice. Furthermore, vaccine studies in rhesus macaques demonstrated induction of nAb responses, which mimicked those induced in convalescent human patient sera. These data suggest a protective role for nAb against CHIKV disease and support further study of envelope-based CHIKV DNA vaccines

Diet and asthma: looking back, moving forward

Asthma is an increasing global health burden, especially in the western world. Public health interventions are sought to lessen its prevalence or severity, and diet and nutrition have been identified as potential factors. With rapid changes in diet being one of the hallmarks of westernization, nutrition may play a key role in affecting the complex genetics and developmental pathophysiology of asthma. The present review investigates hypotheses about hygiene, antioxidants, lipids and other nutrients, food types and dietary patterns, breastfeeding, probiotics and intestinal microbiota, vitamin D, maternal diet, and genetics. Early hypotheses analyzed population level trends and focused on major dietary factors such as antioxidants and lipids. More recently, larger dietary patterns beyond individual nutrients have been investigated such as obesity, fast foods, and the Mediterranean diet. Despite some promising hypotheses and findings, there has been no conclusive evidence about the role of specific nutrients, food types, or dietary patterns past early childhood on asthma prevalence. However, diet has been linked to the development of the fetus and child. Breastfeeding provides immunological protection when the infant's immune system is immature and a modest protective effect against wheeze in early childhood. Moreover, maternal diet may be a significant factor in the development of the fetal airway and immune system. As asthma is a complex disease of gene-environment interactions, maternal diet may play an epigenetic role in sensitizing fetal airways to respond abnormally to environmental insults. Recent hypotheses show promise in a biological approach in which the effects of dietary factors on individual physiology and immunology are analyzed before expansion into larger population studies. Thus, collaboration is required by various groups in studying this enigma from epidemiologists to geneticists to immunologists. It is now apparent that this multidisciplinary approach is required to move forward and understand the complexity of the interaction of dietary factors and asthma

Cyanobacterial lipopolysaccharides and human health – a review

Cyanobacterial lipopolysaccharide/s (LPS) are frequently cited in the cyanobacteria literature as toxins responsible for a variety of heath effects in humans, from skin rashes to gastrointestinal, respiratory and allergic reactions. The attribution of toxic properties to cyanobacterial LPS dates from the 1970s, when it was thought that lipid A, the toxic moiety of LPS, was structurally and functionally conserved across all Gram-negative bacteria. However, more recent research has shown that this is not the case, and lipid A structures are now known to be very different, expressing properties ranging from LPS agonists, through weak endotoxicity to LPS antagonists. Although cyanobacterial LPS is widely cited as a putative toxin, most of the small number of formal research reports describe cyanobacterial LPS as weakly toxic compared to LPS from the Enterobacteriaceae. We systematically reviewed the literature on cyanobacterial LPS, and also examined the much lager body of literature relating to heterotrophic bacterial LPS and the atypical lipid A structures of some photosynthetic bacteria. While the literature on the biological activity of heterotrophic bacterial LPS is overwhelmingly large and therefore difficult to review for the purposes of exclusion, we were unable to find a convincing body of evidence to suggest that heterotrophic bacterial LPS, in the absence of other virulence factors, is responsible for acute gastrointestinal, dermatological or allergic reactions via natural exposure routes in humans. There is a danger that initial speculation about cyanobacterial LPS may evolve into orthodoxy without basis in research findings. No cyanobacterial lipid A structures have been described and published to date, so a recommendation is made that cyanobacteriologists should not continue to attribute such a diverse range of clinical symptoms to cyanobacterial LPS without research confirmation