Nogo-66 Receptor Prevents Raphespinal and Rubrospinal Axon Regeneration and Limits Functional Recovery from Spinal Cord Injury

AbstractAxon regeneration after injury to the adult mammalian CNS is limited in part by three inhibitory proteins in CNS myelin: Nogo-A, MAG, and OMgp. All three of these proteins bind to a Nogo-66 receptor (NgR) to inhibit axonal outgrowth in vitro. To explore the necessity of NgR for responses to myelin inhibitors and for restriction of axonal growth in the adult CNS, we generated ngr−/− mice. Mice lacking NgR are viable but display hypoactivity and motor impairment. DRG neurons lacking NgR do not bind Nogo-66, and their growth cones are not collapsed by Nogo-66. Recovery of motor function after dorsal hemisection or complete transection of the spinal cord is improved in the ngr−/− mice. While corticospinal fibers do not regenerate in mice lacking NgR, regeneration of some raphespinal and rubrospinal fibers does occur. Thus, NgR is partially responsible for limiting the regeneration of certain fiber systems in the adult CNS

Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice

Mutations or deletions of the maternal allele of the UBE3A gene cause Angelman syndrome (AS), a severe neurodevelopmental disorder. The paternal UBE3A/Ube3a allele becomes epigenetically silenced in most neurons during postnatal development in humans and mice; hence, loss of the maternal allele largely eliminates neuronal expression of UBE3A protein. However, recent studies suggest that paternal Ube3a may escape silencing in certain neuron populations, allowing for persistent expression of paternal UBE3A protein. Here we extend evidence in AS model mice (Ube3am–/p+) of paternal UBE3A expression within the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Paternal UBE3A-positive cells in the SCN show partial colocalization with the neuropeptide arginine vasopressin (AVP) and clock proteins (PER2 and BMAL1), supporting that paternal UBE3A expression in the SCN is often of neuronal origin. Paternal UBE3A also partially colocalizes with a marker of neural progenitors, SOX2, implying that relaxed or incomplete imprinting of paternal Ube3a reflects an overall immature molecular phenotype. Our findings highlight the complexity of Ube3a imprinting in the brain and illuminate a subpopulation of SCN neurons as a focal point for future studies aimed at understanding the mechanisms of Ube3a imprinting

Cost-Effectiveness of World Health Organization 2010 Guidelines for Prevention of Mother-to-Child HIV Transmission in Zimbabwe

Background. In 2010, the World Health Organization (WHO) released revised guidelines for prevention of mother-to-child human immunodeficiency virus (HIV) transmission (PMTCT). We projected clinical impacts, costs, and cost-effectiveness of WHO-recommended PMTCT strategies in Zimbabwe. Methods. We used Zimbabwean data in a validated computer model to simulate a cohort of pregnant, HIV-infected women (mean age, 24 years; mean CD4 count, 451 cells/µL; subsequent 18 months of breastfeeding). We simulated guideline-concordant care for 4 PMTCT regimens: single-dose nevirapine (sdNVP); WHO-recommended Option A, WHO-recommended Option B, and Option B+ (lifelong maternal 3-drug antiretroviral therapy regardless of CD4). Outcomes included maternal and infant life expectancy (LE) and lifetime healthcare costs (2008 US dollars [USD]). Incremental cost-effectiveness ratios (ICERs, in USD per year of life saved [YLS]) were calculated from combined (maternal + infant) discounted costs and LE. Results. Replacing sdNVP with Option A increased combined maternal and infant LE from 36.97 to 37.89 years and would reduce lifetime costs from $5760 to$5710 per mother–infant pair. Compared with Option A, Option B further improved LE (38.32 years), and saved money within 4 years after delivery ($5630 per mother–infant pair). Option B+ (LE, 39.04 years; lifetime cost,$6620 per mother–infant pair) improved maternal and infant health, with an ICER of $1370 per YLS compared with Option B. Conclusions. Replacing sdNVP with Option A or Option B will improve maternal and infant outcomes and save money; Option B increases health benefits and decreases costs compared with Option A. Option B+ further improves maternal outcomes, with an ICER (compared with Option B) similar to many current HIV-related healthcare interventions

Core-Shell Gold Nanorod@Zirconium-Based Metal-Organic Framework Composites as in Situ Size-Selective Raman Probes.

Nanoparticle encapsulation inside zirconium-based metal-organic frameworks (NP@MOF) is hard to control, and the resulting materials often have nonuniform morphologies with NPs on the external surface of MOFs and NP aggregates inside the MOFs. In this work, we report the controlled encapsulation of gold nanorods (AuNRs) by a scu-topology Zr-MOF, via a room-temperature MOF assembly. This is achieved by functionalizing the AuNRs with poly(ethylene glycol) surface ligands, allowing them to retain colloidal stability in the precursor solution and to seed the MOF growth. Using this approach, we achieve core-shell yields exceeding 99%, tuning the MOF particle size via the solution concentration of AuNRs. The functionality of AuNR@MOFs is demonstrated by using the AuNRs as embedded probes for selective surface-enhanced Raman spectroscopy (SERS). The AuNR@MOFs are able to both take-up or block molecules from the pores, thereby facilitating highly selective sensing at the AuNR ends. This proof-of-principle study serves to present both the outstanding level of control in the synthesis and the high potential for AuNR@Zr-MOF composites for SERS

Routine HIV Screening in Portugal: Clinical Impact and Cost-Effectiveness

Objective: To compare the clinical outcomes and cost-effectiveness of routine HIV screening in Portugal to the current practice of targeted and on-demand screening. Design: We used Portuguese national clinical and economic data to conduct a model-based assessment. Methods: We compared current HIV detection practices to strategies of increasingly frequent routine HIV screening in Portuguese adults aged 18-69. We considered several subpopulations and geographic regions with varying levels of undetected HIV prevalence and incidence. Baseline inputs for the national case included undiagnosed HIV prevalence 0.16%, annual incidence 0.03%, mean population age 43 years, mean CD4 count at care initiation 292 cells/μL, 63% HIV test acceptance, 78% linkage to care, and HIV rapid test cost €6 under the proposed routine screening program. Outcomes included quality-adjusted survival, secondary HIV transmission, cost, and incremental cost-effectiveness. Results: One-time national HIV screening increased HIV-infected survival from 164.09 quality-adjusted life months (QALMs) to 166.83 QALMs compared to current practice and had an incremental cost-effectiveness ratio (ICER) of €28,000 per quality-adjusted life year (QALY). Screening more frequently in higher-risk groups was cost-effective: for example screening annually in men who have sex with men or screening every three years in regions with higher incidence and prevalence produced ICERs of €21,000/QALY and €34,000/QALY, respectively. Conclusions: One-time HIV screening in the Portuguese national population will increase survival and is cost-effective by international standards. More frequent screening in higher-risk regions and subpopulations is also justified. Given Portugal’s challenging economic priorities, we recommend prioritizing screening in higher-risk populations and geographic settings

A retrospective analysis of second-line chemotherapy in patients with advanced gastric cancer

<p>Abstract</p> <p>Background</p> <p>Because treatment of advanced gastric cancer (AGC) patients after failure with first-line chemotherapy remains controversial, we performed this retrospective analysis based on the data obtained from 1455 patients registered in a first-line treatment cohort with respect to receiving or not receiving subsequent chemotherapy.</p> <p>Methods</p> <p>The decision for administering second-line chemotherapy was, in most cases, at the discretion of the physician. Seven-hundred twenty-five (50%) received second-line chemotherapy after first-line failure. Univariate and multivariate analyses were performed on the recognized baseline parameters for survival.</p> <p>Results</p> <p>At the time of initiating second-line chemotherapy, the patients' median age was 56 years (range, 22 to 86) and 139 (19%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Seven (1%) complete and 108 (15%) partial responses to second-line chemotherapy were observed for an overall response rate of 16% (95% confidence interval [CI], 13 to 19%). The median progression-free and overall survivals, calculated from the start of second-line chemotherapy, were 2.9 months (95% CI, 2.6 to 3.3) and 6.7 months (95% CI, 5.8 to 7.5), respectively. Multivariate analysis revealed that low baseline hemoglobin level (hazard ratio [HR], 0.74; 95% CI 0.61–0.90) and a poor performance status (HR, 0.66; 95% CI, 0.52–0.83) were independent negative prognostic factors for overall survival.</p> <p>Conclusion</p> <p>Performance status, along with baseline hemoglobin level, could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy for AGC.</p

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.