Selective expansion of viral variants following experimental transmission of a reconstituted feline immunodeficiency virus quasispecies

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development

Lithium and boron in calcified tissues of vicuna and its relation to the chronic exposure by water ingestion in the Andean lithium triangle

Vicuna is a wild, endangered species of Andean camelid living in the hyperarid Andean plateau. In the central part of the plateau, the Lithium Triangle defines a zone with lithium‐rich salt pans. Brine pools naturally form within the salt pans, and the adaptation strategy of vicuna consists of drinking from brine pools. Together with reporting the first chemical data on vicuna bones and teeth, we analyzed lithium, boron, and arsenic in water and brines, with the aim of assessing their relation to chronic exposure by water ingestion. We collected and analyzed bones of vicuna specimens lying in an Andean salt pan, together with brine and water samples. Brine and water samples are highly saline and contain large amounts of lithium, boron, and arsenic. Lithium (13.50–40 mg kg–1 ) and boron (40–46.80 mg kg–1 ), but not arsenic, were found in the vicuna bones and teeth. Based on our results and on previously reported data on human tissues in the Andes, we conducted statistical assessments of the relationships between lithium and boron in body tissues and water samples, and discuss their environmental significance in the context of the Lithium Triangle.Fil: López Steinmetz, Romina Lucrecia. Universidad Nacional de Jujuy. Instituto de Ecorregiones Andinas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Ecorregiones Andinas; Argentina. Universidad Nacional de Jujuy. Instituto de Geología Minera; ArgentinaFil: Fong, Shao Bing. University of Melbourne; AustraliaFil: Boyer, Emile. Universite de Rennes I; FranciaFil: López Steinmetz, Lorena Cecilia. Universidad Nacional de Córdoba. Instituto de Investigaciones Psicológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Psicológicas; ArgentinaFil: Tejerina, Norberto Elio. Universidad Nacional de Jujuy. Instituto de Geología Minera; ArgentinaFil: Meuric, Vincent. Universite de Rennes I; Franci

Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival

Thrombomodulin (TM) is an endothelial receptor that exhibits anticoagulant, antifibrinolytic and anti-inflammatory activity by inhibiting thrombin and cellular adhesion. In this study, the expression and significance of TM was examined in primary colorectal cancer and its prognostic implications explored. TM immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections, from primary lesions of 200 patients with colorectal carcinoma. Institutional Ethical approval was granted and clinical data retrieved from patients' records. All normal colonic tissue expressed TM on endothelial cells. TM tumour cell expression was demonstrated in 53 (26.5%) cases and 147 (73.5%) showed no neoplastic cell staining. On univariate and multivariate analysis TM expression on tumour cells correlated significantly with tumour stage, differentiation, Jass score and 5 year survival. TM expression decreases as overall stage and tumour size increase (P=0.03). In all, 91% TM positive tumours were well differentiated and 85% of TM negative tumours were poorly differentiated (P<0.01). Five year survival rates of patients with positive and negative TM expression were 71 and 41%, respectively. Survival rate was poorer in those patients who were TM negative compared with those who were positive (P<0.01). A total of 101 (50.5%) of the cases were node negative. In this group, 5 year survival rates of patients with positive and negative TM expression were 87.5 and 37.8%, respectively, demonstrating a poorer survival rate for those who are node negative and TM negative at the time of surgery (P<0.001). This study demonstrates that loss of TM is a key indicator in tumour biology and prognosis

Postpartum psychiatric disorders

Pregnancy is a complex and vulnerable period that presents a number of challenges to women, including the development of postpartum psychiatric disorders (PPDs). These disorders can include postpartum depression and anxiety, which are relatively common, and the rare but more severe postpartum psychosis. In addition, other PPDs can include obsessive–compulsive disorder, post-traumatic stress disorder and eating disorders. The aetiology of PPDs is a complex interaction of psychological, social and biological factors, in addition to genetic and environmental factors. The goals of treating postpartum mental illness are reducing maternal symptoms and supporting maternal–child and family functioning. Women and their families should receive psychoeducation about the illness, including evidence-based discussions about the risks and benefits of each treatment option. Developing effective strategies in global settings that allow the delivery of targeted therapies to women with different clinical phenotypes and severities of PPDs is essential

In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed-chest porcine model of reperfused acute myocardial infarction: importance of microvasculature

BACKGROUND: Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI. METHODS AND RESULTS: Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 x 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 x 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 x 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO. CONCLUSION: We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Factors Regulating Early Life History Dispersal of Atlantic Cod (Gadus morhua) from Coastal Newfoundland

To understand coastal dispersal dynamics of Atlantic cod (Gadus morhua), we examined spatiotemporal egg and larval abundance patterns in coastal Newfoundland. In recent decades, Smith Sound, Trinity Bay has supported the largest known overwintering spawning aggregation of Atlantic cod in the region. We estimated spawning and dispersal characteristics for the Smith Sound-Trinity Bay system by fitting ichthyoplankton abundance data to environmentally-driven, simplified box models. Results show protracted spawning, with sharply increased egg production in early July, and limited dispersal from the Sound. The model for the entire spawning season indicates egg export from Smith Sound is 13%•day−1 with a net mortality of 27%•day–1. Eggs and larvae are consistently found in western Trinity Bay with little advection from the system. These patterns mirror particle tracking models that suggest residence times of 10–20 days, and circulation models indicating local gyres in Trinity Bay that act in concert with upwelling dynamics to retain eggs and larvae. Our results are among the first quantitative dispersal estimates from Smith Sound, linking this spawning stock to the adjacent coastal waters. These results illustrate the biophysical interplay regulating dispersal and connectivity originating from inshore spawning of coastal northwest Atlantic