Anxiety: An Evolutionary Approach

Anxiety disorders are among the most common mental illnesses, with huge attendant suffering. Current treatments are not universally effective, suggesting that a deeper understanding of the causes of anxiety is needed. To understand anxiety disorders better, it is first necessary to understand the normal anxiety response. This entails considering its evolutionary function as well as the mechanisms underlying it. We argue that the function of the human anxiety response, and homologues in other species, is to prepare the individual to detect and deal with threats. We use a signal detection framework to show that the threshold for expressing the anxiety response ought to vary with the probability of threats occurring, and the individual's vulnerability to them if they do occur. These predictions are consistent with major patterns in the epidemiology of anxiety. Implications for research and treatment are discussed

HC4 The Potential Impact Of Recommendations Made Through The Common Drug Review Program At The Canadian Agency For Drugs And Technologies In Health

A full-length cDNA clone specifying the nuclear-encoded subunit VIb of human cytochrome c oxidase (COX) was isolated from a human skeletal muscle cDNA expression library. This was done with antiserum directed against the group of subunits VIa, b and c of bovine heart COX. A potential ribosome-binding site was located immediately upstream from the initiation codon. The predicted amino acid sequence revealed 85% similarity with the corresponding subunit of bovine heart COX. Subunit VIb lacks a cleavable presequence for mitochondrial addressing. We assume that there are no tissue-specific isoforms of subunit VIb, since (i) in a Northern blot experiment a single hybridizing band of approx. 500 nucleotides was demonstrated in RNA from liver, skeletal muscle, MOLT-4 cells and fibroblasts and (ii) a full-length cDNA clone with an identical sequence was isolated from a human liver cDNA library. Steady-state levels of the coxVIb transcript were different in the tissues examined

Overview of Attention Deficit Hyperactivity Disorder in Young Children

Attention deficit hyperactivity disorder (ADHD) is a complex disorder, which can be seen as a disorder of life time, developing in preschool years and manifesting symptoms (full and/or partial) throughout the adulthood; therefore, it is not surprising that there are no simple solutions. The aim of this paper is to provide a short and concise review which can be used to inform affected children and adults; family members of affected children and adults, and other medical, paramedical, non-medical, and educational professionals about the disorder. This paper has also tried to look into the process of how ADHD develops; what are the associated problems; and how many other children and adults are affected by such problems all over the world basically to understand ADHD more precisely in order to develop a better medical and or non-medical multimodal intervention plan. If preschool teachers and clinicians are aware of what the research tells us about ADHD, the varying theories of its cause, and which areas need further research, the knowledge will assist them in supporting the families of children with ADHD. By including information in this review about the connection between biological behavior, it is hoped that preschool teachers and clinicians at all levels will feel more confident about explaining to parents of ADHD children, and older ADHD children themselves about the probable causes of ADHD

Correcting pervasive errors in RNA crystallography through enumerative structure prediction

Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors and steric clashes. To address these problems, we present enumerative real-space refinement assisted by electron density under Rosetta (ERRASER), coupled to Python-based hierarchical environment for integrated 'xtallography' (PHENIX) diffraction-based refinement. On 24 data sets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves the average Rfree factor, resolves functionally important discrepancies in noncanonical structure and refines low-resolution models to better match higher-resolution models

Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity

Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions.

Background: Live attenuated SIV induces potent protection against superinfection with virulent virus; however the mechanism of this vaccine effect is poorly understood. Such knowledge is important for the development of clinically acceptable vaccine modalities against HIV. Results: Using a novel, doxycycline dependent, replication-competent live-attenuated SIVmac239Δnef (SIVrtTAΔnef), we show that under replication-permissive conditions SIV-rtTAΔnef is fully viable. Twelve rhesus macaques were infected with a peak plasma vRNA on average two log10 lower than in 6 macaques infected with unconditionally replication-competent SIVΔnef. Consistent with the attenuated phenotype of the viruses the majority of animals displayed low or undetectable levels of viraemia by 42-84 days after infection. Next, comparison of circulating T cells before and after chronic infection with parental SIVΔnef revealed a profound global polarisation toward CD28-CCR7- T-effector memory 2 (TEM2) cells within CD95+CD4+ and CD95+CD8+ populations. Critically, a similar effect was seen in the CD95+ CD4+ population and to somewhat lesser extent in the CD95+ CD8+ population of SIV-rtTAΔnef chronically infected macaques that were maintained on doxycycline, but was not seen in animals from which doxycycline had been withdrawn. The proportions of gut-homing T-central memory (TCM) and TEM defined by the expression of α4β7 and CD95 and differential expression of CD28 were increased in CD4 and CD8 cells under replication competent conditions and gut-homing CD4 TCM were also significantly increased under non-permissive conditions. TEM2 polarisation was seen in the small intestines of animals under replication permissive conditions but the effect was less pronounced than in the circulation. Intracellular cytokine staining of circulating SIV-specific T cells for IL-2, IFN-γ, TNF-α and IL-17 showed that the extent of polyfunctionality in CD4 and CD8 T cells was associated with replication permissivity; however, signature patterns of cytokine combinations were not distinguishable between groups of macaques. Conclusion: Taken together our results show that the global T memory cell compartment is profoundly skewed towards a mature effector phenotype by attenuated SIV. Results with the replication-conditional mutant suggest that maintenance of this effect, that may be important in vaccine design, might require persistence of replicating virus

HIV type 1 that select tRNA(His) or tRNA(Lys1,2) as primers for reverse transcription exhibit different infectivities in peripheral blood mononuclear cells.

The replication in human peripheral blood mononuclear cells (PBMC) of unique HIV-1 that select tRNA(His) or tRNA(Lys1,2) for reverse transcription was compared to the wild-type virus that uses tRNA(Lys,3). HIV-1 with only the primer-binding site (PBS) changed to be complementary to these alternative tRNAs initially replicated more slowly than the wild-type virus in PBMC, although all viruses eventually reached equivalent growth as measured by p24 antigen. Viruses with only a PBS complementary to the 3' terminal 18 nucleotides of tRNA(His) or tRNA(Lys1,2) reverted to use tRNA(Lys3). HIV-1 with mutations in the U5-PBS to allow selection of tRNA(His) and tRNA(Lys1,2) following long-term growth in SupT1 cells were also evaluated for growth and PBS stability following replication in PBMC. Although both viruses initially grew slower than wild type, they maintained a PBS complementary to the starting tRNA and did not revert to the wild-type PBS after long-term culture in PBMC. Analysis of the U5-PBS regions following long-term culture in PBMC also revealed few changes from the starting sequences. The virus that stably used tRNA(His) was less infectious than the wild type. In contrast, the virus that stably used tRNA(Lys1,2) evolved to be as infectious as wild-type virus following extended culture in PBMC. The results of these studies highlight the impact of the host cell on the tRNA primer selection process and subsequent infectivity of HIV-1

Household Transmission of Rotavirus in a Community with Rotavirus Vaccination in Quininde, Ecuador

Background: We studied the transmission of rotavirus infection in households in peri-urban Ecuador in the vaccination era. Methods: Stool samples were collected from household contacts of child rotavirus cases, diarrhea controls and healthy controls following presentation of the index child to health facilities. Rotavirus infection status of contacts was determined by RT-qPCR. We examined factors associated with transmissibility (index-case characteristics) and susceptibility (householdcontact characteristics). Results: Amongst cases, diarrhea controls and healthy control household contacts, infection attack rates (iAR) were 55%, 8% and 2%, (n = 137, 130, 137) respectively. iARs were higher from index cases with vomiting, and amongst siblings. Disease ARs were higher when the index child was ,18 months and had vomiting, with household contact ,10 years and those sharing a room with the index case being more susceptible. We found no evidence of asymptomatic infections leading to disease transmission. Conclusion: Transmission rates of rotavirus are high in households with an infected child, while background infections are rare. We have identified factors associated with transmission (vomiting/young age of index case) and susceptibility (young age/sharing a room/being a sibling of the index case). Vaccination may lead to indirect benefits by averting episodes or reducing symptoms in vaccinees

Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial

Background: Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care in a low-resource setting. Methods: The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoint done across 14 hospitals in India. Patients aged 18 years or older who had had a stroke within the past month, had residual disability and reasonable expectation of survival, and who had an informal family-nominated caregiver were randomly assigned to intervention or usual care by site coordinators using a secure web-based system with minimisation by site and stroke severity. The family members of participants in the intervention group received additional structured rehabilitation training—including information provision, joint goal setting, carer training, and task-specific training—that was started in hospital and continued at home for up to 2 months. The primary outcome was death or dependency at 6 months, defined by scores 3–6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by masked observers. Analyses were by intention to treat. This trial is registered with Clinical Trials Registry-India (CTRI/2013/04/003557), Australian New Zealand Clinical Trials Registry (ACTRN12613000078752), and Universal Trial Number (U1111-1138-6707). Findings: Between Jan 13, 2014, and Feb 12, 2016, 1250 patients were randomly assigned to intervention (n=623) or control (n=627) groups. 33 patients were lost to follow-up (14 intervention, 19 control) and five patients withdrew (two intervention, three control). At 6 months, 285 (47%) of 607 patients in the intervention group and 287 (47%) of 605 controls were dead or dependent (odds ratio 0·98, 95% CI 0·78–1·23, p=0·87). 72 (12%) patients in the intervention group and 86 (14%) in the control group died (p=0·27), and we observed no difference in rehospitalisation (89 [14%]patients in the intervention group vs 82 [13%] in the control group; p=0·56). We also found no difference in total non-fatal events (112 events in 82 [13%] intervention patients vs 110 events in 79 [13%] control patients; p=0·80). Interpretation: Although task shifting is an attractive solution for health-care sustainability, our results do not support investment in new stroke rehabilitation services that shift tasks to family caregivers, unless new evidence emerges. A future avenue of research should be to investigate the effects of task shifting to health-care assistants or team-based community care. Funding: The National Health and Medical Research Council of Australia

Envelope Determinants of Equine Lentiviral Vaccine Protection

Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection. © 2013 Craigo et al