Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP)

BACKGROUND: Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen. METHODS/DESIGN: We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course. DISCUSSION: This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk. TRIAL REGISTRATION: EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT0105027

Neural circuits controlling behavior and autonomic functions in medicinal leeches

In the study of the neural circuits underlying behavior and autonomic functions, the stereotyped and accessible nervous system of medicinal leeches, Hirudo sp., has been particularly informative. These leeches express well-defined behaviors and autonomic movements which are amenable to investigation at the circuit and neuronal levels. In this review, we discuss some of the best understood of these movements and the circuits which underlie them, focusing on swimming, crawling and heartbeat. We also discuss the rudiments of decision-making: the selection between generally mutually exclusive behaviors at the neuronal level

Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of aseptic meningitis

BACKGROUND: The seasonality, clinical and radiographic features and outcome of aseptic meningitis have been described for regional outbreaks but data from a wider geographic area is necessary to delineate the epidemiology of this condition. METHODS: A retrospective chart review was completed of children presenting with aseptic meningitis to eight Canadian pediatric hospitals over a two-year period. RESULTS: There were 233 cases of proven enteroviral (EV) meningitis, 495 cases of clinical aseptic meningitis and 74 cases of possible aseptic meningitis with most cases occurring July to October. Headache, vomiting, meningismus and photophobia were more common in children ≥ 5 years of age, while rash, diarrhea and cough were more common in children < 5 years of age. Pleocytosis was absent in 22.3% of children < 30 days of age with proven EV meningitis. Enterovirus was isolated in cerebrospinal fluid (CSF) from 154 of 389 patients (39.6%) who had viral culture performed, and a nucleic acid amplification test for enterovirus was positive in CSF from 81 of 149 patients (54.3%). Imaging of the head by computerized tomography or magnetic resonance imaging was completed in 96 cases (19.7%) and 24 had abnormal findings that were possibly related to meningitis while none had changes that were definitely related to meningitis. There was minimal morbidity and there were no deaths. CONCLUSION: The clinical presentation of aseptic meningitis varies with the age of the child. Absence of CSF pleocytosis is common in infants < 30 days of age. Enterovirus is the predominant isolate, but no etiologic agent is identified in the majority of cases of aseptic meningitis in Canadian children

The Nuclear Protein Sge1 of Fusarium oxysporum Is Required for Parasitic Growth

Dimorphism or morphogenic conversion is exploited by several pathogenic fungi and is required for tissue invasion and/or survival in the host. We have identified a homolog of a master regulator of this morphological switch in the plant pathogenic fungus Fusarium oxysporum f. sp. lycopersici. This non-dimorphic fungus causes vascular wilt disease in tomato by penetrating the plant roots and colonizing the vascular tissue. Gene knock-out and complementation studies established that the gene for this putative regulator, SGE1 (SIX Gene Expression 1), is essential for pathogenicity. In addition, microscopic analysis using fluorescent proteins revealed that Sge1 is localized in the nucleus, is not required for root colonization and penetration, but is required for parasitic growth. Furthermore, Sge1 is required for expression of genes encoding effectors that are secreted during infection. We propose that Sge1 is required in F. oxysporum and other non-dimorphic (plant) pathogenic fungi for parasitic growth

The effects of applied water at various fractions of measured evapotranspiration on reproductive growth and water productivity of Thompson Seedless grapevines

The reproductive growth and water productivity (WPb) of Thompson Seedless grapevines were measured as a function of applied water amounts at various fractions of measured grapevine ETc for a total of eight irrigation treatments. Shoots were harvested numerous times during the growing season to calculate water productivity. Berry weight was maximized at the 0.6–0.8 applied water treatments across years. As applied water amounts increased soluble solids decreased. Berry weight measured at veraison and harvest was a linear function of the mean midday leaf water potential measured between anthesis and veraison and anthesis and harvest, respectively. As applied water amounts increased up to the 0.6–0.8 irrigation treatments there was a significant linear increase in yield. Yields at greater applied water amounts either leveled off or decreased. The reduction in yield on either side of the yearly maximum was due to fewer numbers of clusters per vine. Maximum yield occurred at an ETc ranging from 550 to 700 mm. Yield per unit applied water and WPb increased as applied water decreased. The results from this study demonstrated that Thompson Seedless grapevines can be deficit irrigated, increasing water use efficiency while maximizing yields

Chronic instability of the anterior tibiofibular syndesmosis of the ankle. Arthroscopic findings and results of anatomical reconstruction

<p>Abstract</p> <p>Background</p> <p>The arthroscopic findings in patients with chronic anterior syndesmotic instability that need reconstructive surgery have never been described extensively.</p> <p>Methods</p> <p>In 12 patients the clinical suspicion of chronic instability of the syndesmosis was confirmed during arthroscopy of the ankle. All findings during the arthroscopy were scored. Anatomical reconstruction of the anterior tibiofibular syndesmosis was performed in all patients. The AOFAS score was assessed to evaluate the result of the reconstruction. At an average of 43 months after the reconstruction all patients were seen for follow-up.</p> <p>Results</p> <p>The syndesmosis being easily accessible for the 3 mm transverse end of probe which could be rotated around its longitudinal axis in all cases during arthroscopy of the ankle joint, confirmed the diagnosis. Cartilage damage was seen in 8 ankles, of which in 7 patients the damage was situated at the medial side of the ankle joint. The intraarticular part of anterior tibiofibular ligament was visibly damaged in 5 patients. Synovitis was seen in all but one ankle joint. After surgical reconstruction the AOFAS score improved from an average of 72 pre-operatively to 92 post-operatively.</p> <p>Conclusions</p> <p>To confirm the clinical suspicion, the final diagnosis of chronic instability of the anterior syndesmosis can be made during arthroscopy of the ankle. Cartilage damage to the medial side of the tibiotalar joint is often seen and might be the result of syndesmotic instability. Good results are achieved by anatomic reconstruction of the anterior syndesmosis, and all patients in this study would undergo the surgery again if necessary.</p

Choriocapillaris and Choroidal Microvasculature Imaging with Ultrahigh Speed OCT Angiography

We demonstrate in vivo choriocapillaris and choroidal microvasculature imaging in normal human subjects using optical coherence tomography (OCT). An ultrahigh speed swept source OCT prototype at 1060 nm wavelengths with a 400 kHz A-scan rate is developed for three-dimensional ultrahigh speed imaging of the posterior eye. OCT angiography is used to image three-dimensional vascular structure without the need for exogenous fluorophores by detecting erythrocyte motion contrast between OCT intensity cross-sectional images acquired rapidly and repeatedly from the same location on the retina. En face OCT angiograms of the choriocapillaris and choroidal vasculature are visualized by acquiring cross-sectional OCT angiograms volumetrically via raster scanning and segmenting the three-dimensional angiographic data at multiple depths below the retinal pigment epithelium (RPE). Fine microvasculature of the choriocapillaris, as well as tightly packed networks of feeding arterioles and draining venules, can be visualized at different en face depths. Panoramic ultra-wide field stitched OCT angiograms of the choriocapillaris spanning ~32 mm on the retina show distinct vascular structures at different fundus locations. Isolated smaller fields at the central fovea and ~6 mm nasal to the fovea at the depths of the choriocapillaris and Sattler's layer show vasculature structures consistent with established architectural morphology from histological and electron micrograph corrosion casting studies. Choriocapillaris imaging was performed in eight healthy volunteers with OCT angiograms successfully acquired from all subjects. These results demonstrate the feasibility of ultrahigh speed OCT for in vivo dye-free choriocapillaris and choroidal vasculature imaging, in addition to conventional structural imaging.National Institutes of Health (U.S.) (NIH R01-EY011289-27)National Institutes of Health (U.S.) (NIH R01-EY013178-12)National Institutes of Health (U.S.) (NIH R44-EY022864-01)National Institutes of Health (U.S.) (NIH R01-CA075289-16)United States. Air Force Office of Scientific Research (AFOSR FA9550-10-1-0551)United States. Air Force Office of Scientific Research (AFOSR FA9550-12-1-0499

Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461

The deoxycytidine analog KP1212, and its prodrug KP1461, are prototypes of a new class of antiretroviral drugs designed to increase viral mutation rates, with the goal of eventually causing the collapse of the viral population. Here we present an extensive analysis of viral sequences from HIV-1 infected volunteers from the first “mechanism validation” phase II clinical trial of a mutagenic base analog in which individuals previously treated with antiviral drugs received 1600 mg of KP1461 twice per day for 124 days. Plasma viral loads were not reduced, and overall levels of viral mutation were not increased during this short-term study, however, the mutation spectrum of HIV was altered. A large number (N = 105 per sample) of sequences were analyzed, each derived from individual HIV-1 RNA templates, after 0, 56 and 124 days of therapy from 10 treated and 10 untreated control individuals (>7.1 million base pairs of unique viral templates were sequenced). We found that private mutations, those not found in more than one viral sequence and likely to have occurred in the most recent rounds of replication, increased in treated individuals relative to controls after 56 (p = 0.038) and 124 (p = 0.002) days of drug treatment. The spectrum of mutations observed in the treated group showed an excess of A to G and G to A mutations (p = 0.01), and to a lesser extent T to C and C to T mutations (p = 0.09), as predicted by the mechanism of action of the drug. These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach.Koronis Pharmaceutical

A Late Role for bmp2b in the Morphogenesis of Semicircular Canal Ducts in the Zebrafish Inner Ear

BACKGROUND:The Bone Morphogenetic Protein (BMP) genes bmp2 and bmp4 are expressed in highly conserved patterns in the developing vertebrate inner ear. It has, however, proved difficult to elucidate the function of BMPs during ear development as mutations in these genes cause early embryonic lethality. Previous studies using conditional approaches in mouse and chicken have shown that Bmp4 has a role in semicircular canal and crista development, but there is currently no direct evidence for the role of Bmp2 in the developing inner ear. METHODOLOGY/PRINCIPAL FINDINGS:We have used an RNA rescue strategy to test the role of bmp2b in the zebrafish inner ear directly. Injection of bmp2b or smad5 mRNA into homozygous mutant swirl (bmp2b(-/-)) embryos rescues the early patterning defects in these mutants and the fish survive to adulthood. As injected RNA will only last, at most, for the first few days of embryogenesis, all later development occurs in the absence of bmp2b function. Although rescued swirl adult fish are viable, they have balance defects suggestive of vestibular dysfunction. Analysis of the inner ears of these fish reveals a total absence of semicircular canal ducts, structures involved in the detection of angular motion. All other regions of the ear, including the ampullae and cristae, are present and appear normal. Early stages of otic development in rescued swirl embryos are also normal. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate a critical late role for bmp2b in the morphogenesis of semicircular canals in the zebrafish inner ear. This is the first demonstration of a developmental role for any gene during post-embryonic stages of otic morphogenesis in the zebrafish. Despite differences in the early stages of semicircular canal formation between zebrafish and amniotes, the role of Bmp2 in semicircular canal duct outgrowth is likely to be conserved between different vertebrate species

The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires. Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping