Antiretroviral Therapy Outcomes in HIV-Infected Children after Adjusting Protease Inhibitor Dosing during Tuberculosis Treatment

Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir.A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6-24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB. Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons. Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29).Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation

Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries

Emilin1 gene and essential hypertension: a two-stage association study in northern Han Chinese population

<p>Abstract</p> <p>Background</p> <p>Elastogenesis of elastic extracellular matrix (ECM) which was recognized as a major component of blood vessels has been believed for a long time to play only a passive role in the dynamic vascular changes of typical hypertension. Emilin1 gene participated in the transcription of ECM's formation and was recognized to modulate links TGF-β maturation to blood pressure homeostasis in animal study. Recently relevant advances urge further researches to investigate the role of Emilin1 gene in regulating TGF-β signals involved in elastogenesis and vascular cell defects of essential hypertension (EH).</p> <p>Methods</p> <p>We designed a two-stage case-control study and selected three single nucleotide polymorphisms (SNPs), rs3754734, rs2011616 and rs2304682 from the HapMap database, which covered Emilin1 gene. Totally 2,586 subjects were recruited from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). In stage 1, all the three SNPs of the Emilin1 gene were genotyped and tested within a subsample including 503 cases and 490 controls, significant SNPs would enter into stage 2 including 814 cases with hypertension and 779 controls and analyze on the basis of testing total 2,586 subjects.</p> <p>Results</p> <p>In stage 1, single locus analyses showed that SNPs rs3754734 and rs2011616 had significant association with EH (P < 0.05). In stage 2, weak association for dominant model were observed by age stratification and odds ratio (ORs) of TG+GG vs. TT of rs3754734 were 0.768 (0.584-1.009), 0.985 (0.735-1.320) and 1.346 (1.003-1.806) in < 50, 50-59 and ≥ 60 years group and ORs of GA+AA vs. GG of rs2011616 were 0.745 (0.568-0.977), 1.013 (0.758-1.353) and 1.437 (1.072-1.926) in < 50, 50-59 and ≥ 60 years group respectively. Accordingly, significant interactions were detected between genotypes of rs3754734 and rs2011616 and age for EH, and ORs were 1.758 (1.180-2.620), P = 0.006 and 1.903 (1.281-2.825), P = 0.001, respectively. Results of haplotypes analysis showed that there weren't any haplotypes associated with EH directly, but the interaction of hap2 (GA) and age-group found to be significant after being adjusted for the covariates, OR was 1.220 (1.031-1.444), P value was 0.020.</p> <p>Conclusion</p> <p>Our findings don't support positive association of Emilin1 gene with EH, but the interaction of age and genotype variation of rs3754734 and rs2011616 might increase the risk to hypertension.</p

Thermal niche evolution and geographical range expansion in a species complex of western Mediterranean diving beetles

[Background] Species thermal requirements are one of the principal determinants of their ecology and biogeography, although our understanding of the interplay between these factors is limited by the paucity of integrative empirical studies. Here we use empirically collected thermal tolerance data in combination with molecular phylogenetics/phylogeography and ecological niche modelling to study the evolution of a clade of three western Mediterranean diving beetles, the Agabus brunneus complex.[Results] The preferred mitochondrial DNA topology recovered A. ramblae (North Africa, east Iberia and Balearic islands) as paraphyletic, with A. brunneus (widespread in the southwestern Mediterranean) and A. rufulus (Corsica and Sardinia) nested within it, with an estimated origin between 0.60-0.25 Ma. All three species were, however, recovered as monophyletic using nuclear DNA markers. A Bayesian skyline plot suggested demographic expansion in the clade at the onset of the last glacial cycle. The species thermal tolerances differ significantly, with A. brunneus able to tolerate lower temperatures than the other taxa. The climatic niche of the three species also differs, with A. ramblae occupying more arid and seasonal areas, with a higher minimum temperature in the coldest month. The estimated potential distribution for both A. brunneus and A. ramblae was most restricted in the last interglacial, becoming increasingly wider through the last glacial and the Holocene.[Conclusions] The A. brunneus complex diversified in the late Pleistocene, most likely in south Iberia after colonization from Morocco. Insular forms did not differentiate substantially in morphology or ecology, but A. brunneus evolved a wider tolerance to cold, which appeared to have facilitated its geographic expansion. Both A. brunneus and A. ramblae expanded their ranges during the last glacial, although they have not occupied areas beyond their LGM potential distribution except for isolated populations of A. brunneus in France and England. On the islands and possibly Tunisia secondary contact between A. brunneus and A. ramblae or A. rufulus has resulted in introgression. Our work highlights the complex dynamics of speciation and range expansions within southern areas during the last glacial cycle, and points to the often neglected role of North Africa as a source of European biodiversity.This work was supported by an FPI grant to AH-G and projects CGL2007-61665 and CGL2010-15755 from the Spanish government to IR. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

The Near-Infrared Spectrograph (NIRSpec) on the James Webb Space Telescope: I. Overview of the instrument and its capabilities

We provide an overview of the design and capabilities of the near-infrared spectrograph (NIRSpec) onboard the James Webb Space Telescope. NIRSpec is designed to be capable of carrying out low-resolution ($R\!=30\!-330$) prism spectroscopy over the wavelength range $0.6-5.3\!~\mu$m and higher resolution ($R\!=500\!-1340$ or $R\!=1320\!-3600$) grating spectroscopy over $0.7-5.2\!~\mu$m, both in single-object mode employing any one of five fixed slits, or a 3.1$\times$3.2 arcsec$^2$ integral field unit, or in multiobject mode employing a novel programmable micro-shutter device covering a 3.6$\times$3.4~arcmin$^2$ field of view. The all-reflective optical chain of NIRSpec and the performance of its different components are described, and some of the trade-offs made in designing the instrument are touched upon. The faint-end spectrophotometric sensitivity expected of NIRSpec, as well as its dependency on the energetic particle environment that its two detector arrays are likely to be subjected to in orbit are also discussed

The Near-Infrared Spectrograph (NIRSpec) on the James Webb Space Telescope: I. Overview of the instrument and its capabilities

We provide an overview of the design and capabilities of the near-infrared spectrograph (NIRSpec) onboard the James Webb Space Telescope. NIRSpec is designed to be capable of carrying out low-resolution ($R\!=30\!-330$) prism spectroscopy over the wavelength range $0.6-5.3\!~\mu$m and higher resolution ($R\!=500\!-1340$ or $R\!=1320\!-3600$) grating spectroscopy over $0.7-5.2\!~\mu$m, both in single-object mode employing any one of five fixed slits, or a 3.1$\times$3.2 arcsec$^2$ integral field unit, or in multiobject mode employing a novel programmable micro-shutter device covering a 3.6$\times$3.4~arcmin$^2$ field of view. The all-reflective optical chain of NIRSpec and the performance of its different components are described, and some of the trade-offs made in designing the instrument are touched upon. The faint-end spectrophotometric sensitivity expected of NIRSpec, as well as its dependency on the energetic particle environment that its two detector arrays are likely to be subjected to in orbit are also discussed

The clinical course of low back pain: a meta-analysis comparing outcomes in randomised clinical trials (RCTs) and observational studies.

BACKGROUND: Evidence suggests that the course of low back pain (LBP) symptoms in randomised clinical trials (RCTs) follows a pattern of large improvement regardless of the type of treatment. A similar pattern was independently observed in observational studies. However, there is an assumption that the clinical course of symptoms is particularly influenced in RCTs by mere participation in the trials. To test this assumption, the aim of our study was to compare the course of LBP in RCTs and observational studies. METHODS: Source of studies CENTRAL database for RCTs and MEDLINE, CINAHL, EMBASE and hand search of systematic reviews for cohort studies. Studies include individuals aged 18 or over, and concern non-specific LBP. Trials had to concern primary care treatments. Data were extracted on pain intensity. Meta-regression analysis was used to compare the pooled within-group change in pain in RCTs with that in cohort studies calculated as the standardised mean change (SMC). RESULTS: 70 RCTs and 19 cohort studies were included, out of 1134 and 653 identified respectively. LBP symptoms followed a similar course in RCTs and cohort studies: a rapid improvement in the first 6 weeks followed by a smaller further improvement until 52 weeks. There was no statistically significant difference in pooled SMC between RCTs and cohort studies at any time point:- 6 weeks: RCTs: SMC 1.0 (95% CI 0.9 to 1.0) and cohorts 1.2 (0.7to 1.7); 13 weeks: RCTs 1.2 (1.1 to 1.3) and cohorts 1.0 (0.8 to 1.3); 27 weeks: RCTs 1.1 (1.0 to 1.2) and cohorts 1.2 (0.8 to 1.7); 52 weeks: RCTs 0.9 (0.8 to 1.0) and cohorts 1.1 (0.8 to 1.6). CONCLUSIONS: The clinical course of LBP symptoms followed a pattern that was similar in RCTs and cohort observational studies. In addition to a shared 'natural history', enrolment of LBP patients in clinical studies is likely to provoke responses that reflect the nonspecific effects of seeking and receiving care, independent of the study design

Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV