Salbutamol in acute organophosphorus insecticide poisoning – a pilotdose-response phase II study

Background: Treatment of acute organophosphorus (OP) insecticide poisoning is difficult, with many patients dying despite best care. Pre-clinical studies have shown benefit from salbutamol, possibly due speeding alveolar fluid clearance or reducing bronchoconstriction. In this small pilot dose-response study, we aimed to explore whether addition of nebulized salbutamol to standard care might improve resuscitation.

Methods: We performed a single-blind phase II study comparing the effect of two different doses of nebulized salbutamol versus saline placebo, in addition to standard treatment. Primary outcome was oxygen saturations over the first 60?min of resuscitation; secondary outcomes included heart rate, incidence of dysrhythmias, time to ‘atropinization’, atropine dose required, and mortality.

Result: Seventy-five patients were randomized to receive 5?mg (Salb5, n?=?25) or 2.5mg (Salb2.5, n?=?25) of salbutamol, or saline placebo (NoSalb, n?=?25), by nebulizer. Oxygen saturations did not differ between groups over the first 60?min of resuscitation (median AUC NoSalb: 1376 [95% CI 1282 to 1470], Salb2.5: 1395 [1305 to 1486], Salb5: 1233 [1100 to 1367]; p?=?.9898). Heart rate was also similar across the three arms. Median time to full atropinization, and atropine dose required, were the same for all three arms (NoSalb 15.0 [10–16] min and 12.6 [8.0–13.4] mg, Salb2.5 15.0 [10–16] min and 12.6 [9.3–16.8] mg, and Salb5 15.0 [10–20] min and 12.6 [10.7–20.6] mg; p?=?.4805 and p?=?.1871, respectively). Three (12%) patients died in the Salb2.5 and Salb5 groups and two (8%) in the NoSalb group.

Conclusion: This pilot study, within the limitations of its small size and variation between patients, found no apparent evidence that administration of nebulized salbutamol improved resuscitation of patients with acute OP insecticide self-poisoning. The data obtained provides a basis to design further studies to ultimately test the role of salbutamol in OP insecticide poisoning.     

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

Background: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity.Objective: Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation.Methods: We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation.Results: In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni-corrected significance threshold of p < 1 × 10^–7. Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 × 10^–11) and blood arsenic concentrations (p = 1.48 × 10^–11). Three additional novel methylation loci—SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)—were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci.Conclusions: We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions.Citation: Argos M, Chen L, Jasmine F, Tong L, Pierce BL, Roy S, Paul-Brutus R, Gamble MV, Harper KN, Parvez F, Rahman M, Rakibuz-Zaman M, Slavkovich V, Baron JA, Graziano JH, Kibriya MG, Ahsan H. 2015. Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh. Environ Health Perspect 123:64–71; http://dx.doi.org/10.1289/ehp.1307884     

Nutrition Therapy for the Critically Ill Surgical Patient With Aortic Aneurysmal Rupture

Background: Our goal is to define nutrition therapy in critically ill patients after surgical repair of acute ruptured or dissecting aortic aneurysm to identify opportunities for quality improvement. Methods: International, prospective studies in 2007–2009 and 2011 were combined. Sites provided institutional and patient characteristics including from intensive care units (ICUs) admission to ICU discharge for a maximum of 12 days. We selected patients with aortic aneurysmal rupture or acute dissection staying in the ICU for ≥ 3 days. Results: There were 104 eligible patients from 72 distinct ICUs analyzed. Overall, 86.5% received artificial nutrition. There were 50.0% patients who received enteral nutrition (EN) only, 29.8% patients received a combination of EN and parenteral nutrition (PN), 6.7% patients received PN only, and 13.5% did not receive any nutrition. The mean time from admission to initiation of EN was 3.0 days (SD ± 2.4 days). The adequacy of calories from nutrition support was 46.8% (range 0%‐111%) with a mean of 10.0 kcal/kg/day. Of the total of 83 patients who received EN, 53 patients (63.8%) had interruption of EN. The reasons included fasting, intolerance, patients deemed too sick for enteral feeding, and loss of enteral feeding route. For patients with gastrointestinal intolerance, 3/30 patients (10%) received small bowel feeding and 23/30 patients (76.7%) of patients received motility agents. Conclusion: Postoperative critically ill patients with aortic aneurysmal rupture or acute dissection are at high risk for inadequate nutrition therapy, and there may be inadequate utilization of strategies to improve nutrition uptake.     

Autoantibodies, lupus and the science of sabotage

Anti-double-stranded DNA antibodies (anti-dsDNA) and antiphospholipid antibodies (APL) are important in the pathogenesis of systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS) respectively. Not all anti-dsDNA or APL antibodies can cause clinical effects. Those that are particularly likely to cause tissue damage tend to be of IgG isotype and to possess particular binding properties. Rigorous statistical analysis of published sequences of human monoclonal anti-DNA and APL antibodies showed that IgG antibodies with binding properties characteristic of pathogenicity tend to have multiple somatic mutations in their variable regions. The distribution of these mutations suggests that they have been selected by antigen. This leads to accumulation of certain residues at the antigen-binding sites of these antibodies. Arginine residues are especially important. A computer-generated model of the pathogenic human monoclonal anti-DNA antibody B3 predicted that arginines in the heavy and light chain complementarity-determining regions (CDRs) would interact with dsDNA. We expressed cloned sequences encoding the B3 heavy and light chains in vitro to produce whole IgG. The cloned sequences of the heavy and light chains were manipulated to express a range of variant IgG antibodies. Binding assays on the expressed antibodies showed that altering specific arginine residues reduced binding to dsDNA in a way consistent with computer generated structural models. Changing the pattern of somatic mutations in the light chain altered binding to both dsDNA and histones, but in different ways. A single arginine-to-serine mutation in light-chain CDR1 of B3 reduced binding to both those antigens and may also have reduced the pathogenicity of the expressed antibodies in severe combined immunodeficiency (SCID) mice. Monoclonal human APL were expressed using the same system. Nineteen different heavy-light combinations were expressed. The ability to bind cardiolipin correlated well with the presence of exposed arginine residues in the heavy- and light-chain CDRs. The heavy chain of the pathogenic APL antibody IS4 contains four exposed arginines in CDR3. The results of mutagenesis studies suggested that two of these promote binding to cardiolipin whereas the other two have no such effect.     

Supplementation of dietary vitamins,protein and probiotics on semen traits and immunohistochemical study of pituitary hormones in zinc-induced molted broiler breeders

The purpose of this study was to investigate the effect of dietary vitamin E and vitamin C, probiotics mixture and protein level and their combination on semen quality and immunohistochemical study of some pituitary hormones in male broiler breeders. One hundred and eighty male broiler breeders 65 weeks old were divided into six groups by completely randomized design. The birds were subjected to zinc-induced molt by mixing zinc oxide at the rate of 3000 mg/kg in the feed. After molting, one group was fed control diet (CP16%). The other groups were fed vitamin E (100 IU/kg), vitamin C (500 IU/kg), probiotics (50 mg/L of drinking water), protein (CP14%) and combination of these components. These treatments were given for five weeks. After the feeding period, semen samples were taken and analyzed for semen volume, sperm concentration, motility and dead sperm percentage. Pituitary samples were collected from three birds per replicate and were processed for immunohistochemical study. The results of semen quality parameters revealed that semen volume and sperm motility were significantly high in the vitamin E fed group, while the dead sperm percentage decreased significantly in the vitamin C group. The morphometric analysis revealed that compared to other groups, vitamin E caused a significant increase in the size and area of FSH, LH gonadotropes and lactotropes. These results showed that vitamin E alone may play some role in the enhancement of semen quality and growth of gonadotropes and lactotropes.     

Situating language in a minimal social context: how seeing a picture of the speaker’s face affects language comprehension

Natural use of language involves at least two individuals. Some studies have focused on the interaction between senders in communicative situations and how the knowledge about the speaker can bias language comprehension. However, the mere effect of a face as a social context on language processing remains unknown. In the present study, we used event-related potentials to investigate the semantic and morphosyntactic processing of speech in the presence of a photographic portrait of the speaker. In Experiment 1, we show that the N400, a component related to semantic comprehension, increased its amplitude when processed within this minimal social context compared to a scrambled face control condition. Hence, the semantic neural processing of speech is sensitive to the concomitant perception of a picture of the speaker’s face, even if irrelevant to the content of the sentences. Moreover, a late posterior negativity effect was found to the presentation of the speaker’s face compared to control stimuli. In contrast, in Experiment 2, we found that morphosyntactic processing, as reflected in left anterior negativity and P600 effects, is not notably affected by the presence of the speaker’s portrait. Overall, the present findings suggest that the mere presence of the speaker’s image seems to trigger a minimal communicative context, increasing processing resources for language comprehension at the semantic level.     

Dissections of regional lymph nodes for treatment of skin cancer: predicting annual caseloads that will optimise outcomes

IntroductionDissection of regional lymph nodes (RLNs) can lead to significant morbidity and a high prevalence of complications. Published guidance states that these procedures should be carried out by surgeons who are members of a specialist skin multidisciplinary team who carry out a combined minimum of 15 axillary/groin dissections per year. However, there is little evidence to guide this minimum figure of procedures. We report on the burden of service provision and prevalence of complications across the South West of England and Wales.MethodsA 12-month review of dissections of RLNs for skin cancer was undertaken covering five Plastic Surgery Units with a collective catchment of 8.4 million people. Detailed data were collected on patient demographics, pathology, timing of surgery, and prevalence of complications.ResultsA total of 163 dissections were carried out. Forty-three per cent of patients experienced one or more complication. In that 12-month period, an average of 8 axillary/groin dissections was carried out per surgeon. A funnel plot demonstrated that the prevalence of complications for individual surgeons was within the limit of the plot but, in many cases, this was based only on a relatively small number of procedures per consultant. If surgeons carried out 10 procedures per year, the upper and lower limits on the plot were 73% and 11%, respectively.ConclusionsFunnel plots can provide a useful guide as to whether the prevalence of complications for procedures for individual surgeons lies within acceptable limits. Based on these results, 10 procedures per consultant per year should be sufficient to enable meaningful assessment of the prevalence of complications.