Understanding the evolution of the human immunodeficiency virus type 1 (HIV-1) envelope during disease progression can provide tremendous insights for vaccine development, and simian-human immunodeficiency virus (SHIV) infection of non-human primate provides an ideal platform for such studies. A newly developed clade C SHIV, SHIV-1157ipd3N4, which was able to infect rhesus macaques, closely resembled primary HIV-1 in transmission and pathogenesis, was used to infect several pig-tailed macaques. One of the infected animals subsequently progressed to AIDS, whereas one remained a non-progressor. The viral envelope evolution in the infected animals during disease progression was analyzed by a bioinformatics approach using ultra-deep pyrosequencing. Our results showed substantial envelope variations emerging in the progressor animal after the onset of AIDS. These envelope variations impacted the length of the variable loops and charges of different envelope regions. Additionally, multiple mutations were located at the CD4 and CCR5 binding sites, potentially affecting receptor binding affinity, viral fitness and they might be selected at late stages of disease. More importantly, these envelope mutations are not random since they had repeatedly been observed in a rhesus macaque and a human infant infected by either SHIV or HIV-1, respectively, carrying the parental envelope of the infectious molecular clone SHIV-1157ipd3N4. Moreover, similar mutations were also observed from other studies on different clades of envelopes regardless of the host species. These recurring mutations in different envelopes suggest that there may be a common evolutionary pattern and selection pathway for the HIV-1 envelope during disease progression.

To summarize the seroprevalence of human herpesvirus 8 (HHV-8) in mainland China, we conducted a systematic review and meta-analysis based on available literature. Data show that differences in HHV-8 prevalence vary considerably among different ethnic groups and geographic regions. Blood-borne transmission could be a potential route for HHV-8 infection in China.

We investigated the effect of age-related decline in executive ability on the application of emergent features to incongruent social category conjunctions (e.g., male midwife). When forming an impression of an incongruent conjunction, older adults used more emergent attributes (attributes associated exclusively with the category conjunction and not the constituents), relative to younger adults. Moreover, this relationship was mediated by a reduction in inhibitory ability (measured using a Stroop task) and processing speed (measured using a Digit Symbol Substitution Test, DSST). These findings are consistent with the notion that executive ability is pivotal in understanding social functioning in older adults. We discuss the implications of these findings for the continuing development of models outlining the processes and stages involved in perceiving social category conjunctions.

Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side effects. The discovery of new, effective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5 mg/kg/day, in 500 μl sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (~70%) and bone loss (~50%) compared with AA controls. SNS treatment also reduced spleen weight (without affecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered T-helper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our findings support the development of SNS as a therapeutic for RA.

BACKGROUND Opioid side effects are a great concern during the postoperative period in children. Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to effectively decrease postoperative pain, but their opioid-sparing effect is still controversial. In this present meta-analysis, we investigated the postoperative opioid-sparing effect of NSAIDs in children. METHODS A comprehensive literature search was conducted to identify clinical trials using NSAIDs and opioids as perioperative analgesic compounds in children and infants. Outcomes measured were opioid consumption, pain intensity, postoperative nausea and vomiting (PONV), and urinary retention. All outcomes were studied during postanesthesia care unit (PACU) stay and the first 24 postoperative hours. Data from each trial were combined to calculate the pooled odds ratios (ORs) or standardized mean difference (SMD) and their 95% confidence interval. RESULTS Twenty-seven randomized controlled studies were analyzed. Perioperative administration of NSAIDs decreased postoperative opioid requirement (both in the PACU and during the first 24 postoperative hours; SMD =-0.66 [-0.84,-0.48] and -0.83 [-1.11,-0.55], respectively), pain intensity in the PACU (SMD =-0.85 [-1.24,-0.47]), and PONV during the first 24 postoperative hours (OR = 0.75 [0.57-0.99]). NSAIDs did not decrease pain intensity during the first 24 postoperative hours (OR = 0.56 [0.26-1.2]) and PONV during PACU stay (OR = 1.02 [0.73-1.44]). Subgroup analysis according to the timing of NSAID administration (intraoperative versus postoperative), type of surgery, or coadministration of paracetamol did not show any influence of these factors on the studied outcomes except the reduction of pain intensity and the incidence of PONV during the first 24 postoperative hours, which were influenced by the coadministration of paracetamol and the type of surgery, respectively. CONCLUSION This meta-analysis shows that perioperative NSAID administration reduces opioid consumption and PONV during the postoperative period in children.

ABSTRACT: BACKGROUND: Assessment of pain in children is an important aspect of pain management and can be performed by observational methods or by self-assessment. The Faces Pain Scale-Revised (FPS-R) is a self-report tool which has strong positive correlations with other well established self-report pain intensity measures. It has been recommended for measuring pain intensity in school-aged children (4 years and older). The objective of this study is to compare the concordance and the preference for two versions, electronic and paper, of the FPS-R, and to determine whether an electronic version of the FPS-R can be used by children aged 4 and older. METHODS: The study is an observational, multicenter, randomized, cross-over, controlled, open trial. Medical and surgical patients in two pediatric hospitals (N = 202, age 4-12 years, mean age 8.3 years, 58% male) provided self-reports of their present pain using the FPS-R on a personal digital assistant (PDA) and on a paper version. Paper and electronic versions of the FPS-R were administered by a nurse in a randomized order: half the patients were given the PDA version first and the other half the paper version first. The time between the administrations was planned to be less than 30 minutes but not simultaneous. Two hundred and thirty-seven patients were enrolled; 35 were excluded from analysis because of misunderstanding of instructions or abnormal time between the two assessments. RESULTS: Final population for analysis comprised 202 children. The overall weighted Kappa was 0.846 (95%CI: 0.795; 0.896) and the Spearman correlation between scores on the two versions was rs = 0.911 (p<0.0001). The mean difference of pain scores was less than 0.1 out of 10, which was neither statistically nor clinically significant; 83.2% of children chose the same face on both versions of the FPS-R. Preference was not modified by order, sex, age, hospitalization unit (medical or surgical units), or previous analgesics. The PDA was preferred by 87.4% of the children who expressed a preference. CONCLUSION: The electronic version of the FPS-R can be recommended for use with children aged 4 to 12, either in clinical trials or in hospitals to monitor pain intensity.

Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62-102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05) and the histological presence of fatty liver (P<0.05) independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05), glucocorticoid receptor (GR; P<0.05), UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05) and IGF1 (P<0.01) expression were upregulated. The direct fetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (P<0.05) and this was opposed by fetal TP (P<0.05). Hepatic estrogen receptor (ERα; P<0.05) and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05) were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

Children with cystic fibrosis commonly experience abdominal pain; however this remains poorly characterised. This prospective cross-sectional study with a longitudinal design, examined the prevalence, causes and effect of pain management via daily diaries, validated questionnaires for pain characteristics, anxiety status and quality of life. One hundred and thirty CF patients aged 8 to 18years, regularly followed at our centre, were questioned on recurrent abdominal pain. Eight patients fulfilled the criteria; all wished to enter the study. Pain management included behavioural intervention with effective pain relief, and had a positive impact on anxiety and quality of life. This study is the first one to prospectively assess recurrent abdominal pain in CF. We documented a very low prevalence of 6%. We suggest that, ruling out abdominal discomfort, only a minority of CF children presented recurrent abdominal pain with a true negative impact on daily life. We emphasise the need for further studies including larger cohorts.

Chimeric viruses constructed between a highly pathogenic Feline Immunodeficiency Virus isolate (FIV-C36) and a less pathogenic but neurotropic strain (FIV-PPR) have been used to map viral genetic determinants of in vivo pathogenicity. Chimeric virus FIV-PCenv, which contains FIV-C36 genome from the 3' region of pol to upstream of the 3'LTR on an FIV-PPR backbone, was previously shown to be replication-competent in vivo, inducing altered CD4(+) T-cell and neutrophil profiles intermediate between parental strains following a delay in viral replication during initial infection. Examination of FIV-PCenv proviral sequences recovered at week 11 post-infection revealed two changes compared to initial viral inoculum; the most significant being arginine to histidine in the integrase region of Pol at residue 813 (R813H). Pooled plasma from the initial in vivo study was used to inoculate a second cohort of cats to determine whether similar virulence and kinetics could be established following primary infection. Viral replication kinetics and immunocyte profiles were monitored in blood, bone marrow, and saliva over a one-year period. Passaged FIV-PCenv again displayed intermediate phenotype between parental strains, but unlike primary experiments, the onset of acute viremia was not delayed. CD4/8 alterations were noted in all groups of animals, though significant changes from controls were delayed in FIV-PPR infected animals compared to FIV-C36 and FIV-PCenv. In vivo passage of FIV-PCenv increased replication-competence relative to the initial molecularly-cloned chimera in association with one adaptive nucleotide change in the 5' end of the genome relative to primary tissue culture inoculum, while mutations in the 3' end of the genome were not detected. The results are consistent with the interpretation that 3' elements contribute to heightened virulence of FIV-C36, and that integrase residue 813 plays an important role in facilitating successful in vivo replication.