Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds

Subtype-specific neuraminidase (NA) mutations conferring resistance to NA inhibitors (NAIs) have been reported during in vitro passages and in clinic. In this study, we evaluated the impact of various NA mutations (E119A/G/V, H274Y, R292K and N294S) on the susceptibility profiles to different NAIs (oseltamivir, zanamivir and peramivir) using recombinant NA proteins of influenza A/WSN/33 (H1N1) and A/Sydney/5/97-like (H3N2) viruses. In the Nl subtype, the E119V mutation conferred cross-resistance to oseltamivir, zanamivir and peramivir [1,727-2,144 and 5,050-fold increase in IC50 values compared with wild-type (WT)] whereas only oseltamivir-resistance (1,028-fold increase in IC50) was conferred by the same mutation in the N2 subtype. The N294S mutation conferred resistance to oseltamivir in both the NI and N2 subtypes (197- and 1,879-fold increase in IC50 values, respectively) whereas the H274Y mutation conferred resistance to oseltamivir (754-fold increase) and peramivir (260-fold increase) in the N1 subtype only. The virulence of reverse genetics-rescued A/WSN/33 viruses harbouring H274Y and N294S NA mutations was investigated in Balb/c mice. The WT and H274Y recombinants had identical LD50 values (103 PFUs) and generated similar viral lung titres, whereas a higher LD50 (10 PFUs) and a 1-log decrease in viral lung titres were obtained with the N294S mutant. This study shows that some NA mutations at framework residues may confer resistance to one or three NAIs depending on the viral subtype. It suggests that certain drug-resistant NA mutants may still be virulent although additional studies using clinical isolates are needed to confirm our results.     

Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction

BACKGROUND: Transforming growth factor (TGF)-beta is a locally generated cytokine involved in healing processes and tissue fibrosis, all relevant for cardiac remodeling and the development of heart failure after myocardial infarction (MI). However, data regarding the function of TGF-beta after ischemic injury are inconclusive. METHODS AND RESULTS: We tested the effect of TGF-beta inhibition by application of a blocking antibody in mice with MI. Starting 1 week before or 5 days after coronary artery ligation mice were treated with intraperitoneal injections of an anti-TGF-beta (5 mg/kg bodyweight 1D11, Genzyme) or control antibody. Mortality over 8 weeks was significantly higher in the groups treated with the anti-TGF-beta antibody. Both, pre or post MI treatments were associated with increased left ventricular dilatation after MI as determined by serial echocardiography. In anti-TGF-beta treated mice collagen production decreased and matrix-metalloproteinase expression increased. However, the expression of TGF pro-inflammatory cytokine TNF-alpha was not altered by the treatment. Anti-TGF-beta treatment before or after coronary artery ligation increases mortality and worsens left ventricular remodeling in mice with non-reperfused MI. The detrimental effects of TGF-beta inhibition may be mediated by alterations in extracellular matrix remodeling.     

Stress signaling through Ca2+/calmodulin-dependent protein phosphatase calcineurin mediates salt adaptation in plants

Calcineurin (CaN) is a Ca²⁺- and calmodulin-dependent protein phosphatase (PP2B) that, in yeast, is an integral intermediate of a salt-stress signal transduction pathway that effects NaCl tolerance through the regulation of Na⁺ influx and efflux. A truncated form of the catalytic subunit and the regulatory subunit of yeast CaN were coexpressed in transgenic tobacco plants to reconstitute a constitutively activated phosphatase in vivo. Several different transgenic lines that expressed activated CaN also exhibited substantial NaCl tolerance, and this trait was linked to the genetic inheritance of the CaN transgenes. Enhanced capacity of plants expressing CaN to survive NaCl shock was similar when evaluation was conducted on seedlings in tissue culture raft vessels or plants in hydroponic culture that were transpiring actively. Root growth was less perturbed than shoot growth by NaCl in plants expressing CaN. Also, NaCl stress survival of control shoots was enhanced substantially when grafted onto roots of plants expressing CaN, further implicating a significant function of the phosphatase in the preservation of root integrity during salt shock. Together, these results indicate that in plants, like in yeast, a Ca²⁺- and calmodulin-dependent CaN signal pathway regulates determinants of salt tolerance required for stress adaptation. Furthermore, modulation of this pathway by expression of an activated regulatory intermediate substantially enhanced salt tolerance.     

Resection margin influences the outcome of patients with bilobar colorectal liver metastases

AIM To evaluate the outcome of patients with bilobar colorectal liver metastases(CRLM) and identify clinicopathological variables that influenced survival.METHODS Patients with bilobar CRLM were identified from a prospectively maintained hepatobiliary database during the study period(January 2010-June 2014). Collated data included demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome. Down-staging therapy included Oxaliplatinor Irinotecan- based regimens, and Cetuximab was also used in patients that were K-RAS wild-type. Response to neo-adjuvant therapy was assessed at the multidisciplinary team meeting and considered for surgery if all macroscopic CRLM were resectable with a clear margin while preserving sufficient liver parenchyma.RESULTS Of the 136 patients included, thirty-two(23.5%) patients were considered inoperable and referred for palliative chemotherapy, and thirty-four(25%) patients underwent liver resection. Seventy(51.4%) patients underwent down-staging therapy, of which 37(52.8%) patients responded sufficiently to undergo liver resection. Patients that failed to respond to down-staging therapy(n = 33, 47.1%) were referred for palliative therapy. There was a significant difference in overall survival between the three groups(surgery vs down-staging therapy vs inoperable disease, P 0.001). All patients that underwent hepatic resection, including patients that had down-staging therapy, had a significantly better overall survival compared to patients that were inoperable(P 0.001). On univariate analysis, only resection margin significantly influenced disease-free survival(P = 0.017). On multi-variate analysis, R0 resection(P = 0.030) and female(P = 0.036) gender significantly influenced overall survival. CONCLUSION Patients undergoing liver resection with bilobar CRLM have a significantly better survival outcome. R0 resection is associated with improved disease-free and overall survival in this patient group.     

Knowledge,attitude, and practice among farmworkers applying pesticides in cultivated area of the Jericho district: a cross-sectional study

Background

The excessive use of pesticides has chronic and acute toxic effects on human health. The aim of this study was to assess knowledge, attitudes, practices, and toxicity symptoms in farmworkers applying pesticides in a cultivated area of the Jericho district.

Risk factors for paediatric cancer in the Gaza Strip: a case-control study

Background

Cancer is a serious health problem and the third leading cause of death in the occupied Palestinian territory, both in adults and children. For most children younger than 18 years who have cancer, there is no obvious cause. The aim of this study was to identify the main risk factors for paediatric cancer in the Gaza Strip.

Management of acute meningococcal septicaemia in Al-Nasser Paediatric Hospital: a retrospective cohort study

Background

Acute meningococcal septicaemia is a fulminant disease, and mortality and long-term morbidity can be very high if not treated appropriately. We aimed to evaluate case fatality rate of all children admitted with acute meningococcal septicaemia.

Risk profile of myocardial infarction in young versus older adults

Background

In developing countries, the number of adults who develop myocardial infarction (MI) at a young age is high. The popularity of waterpipe smoking (WPS) has increased among the same age group. It is unknown if WPS contributes to the incidence of early-onset MI.

Neck circumference and blood pressure among children: a systematic review and meta-analysis

Emerging evidence suggested that large neck circumference (NC) in children and adolescents may be an indicator of increased blood pressure. We sought to conduct a systematic review and meta-analysis regarding the association between NC and blood pressure in children. Pertinent studies were identified by searching PubMed and Scopus databases, up to January 2018. Studies which reported the correlation coefficient between NC, systolic blood pressure and diastolic blood pressure in children (aged <18 years) were selected. Fifteen studies met eligibility criteria for the quantitative synthesis. Overall, NC was significantly correlated with systolic blood pressure (effect size (z) = 0.39; 95% confidence interval [CI] = 0.29–0.49; P < .001; meta r = 0.371; r² = 0.13) and diastolic blood pressure (effect size (z) = 0.25; 95% CI = 0.19–0.32; P < .001; meta r = 0.0.245; r² = 0.06). NC had a positive relationship with the risk of hypertension (odds ratio [OR] = 1.35; 95% CI: 1.05–1.75). Furthermore, studies conducted in Western regions (OR = 1.55; 95% CI: 1.12–2.14) reported higher risk of hypertension in association with NC than those conducted in the Eastern regions (OR = 1.14; 95% CI: 1.03–1.25).NC seems to be a novel anthropometric measurement in children and adolescents. It can be a good predictor of elevated blood pressure, especially in the Western population.