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Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children 1 , 2 , 3 . Identification of four genes mutated in NPHP subtypes 1–4 (refs. 4 – 9 ) has linked the pathogenesis of NPHP to ciliary functions 9 . Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5 ), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10–20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.

Model Predictive Control (MPC) is a control method in which an optimal control problem for a future time-frame, called a prediction horizon, is solved at every time step. The first portion of the optimal control solution is applied to the system, and the process is repeated for the next time-step with the prediction horizon receding with real time. Although MPC is not an optimal control method (it approaches optimal control as the horizon extends to infinity), it is a highly performant heuristic method that has found success in a wide variety of application areas. MPC was first popularized in industrial process control because the prediction modeling is flexible (i.e., can handle high-order and multi-input multi-output systems), because the optimal control problem can be formulated to include constraints on the system state for safe operation and on the control inputs to maximize performance, and because the dynamics were slow enough to allow the optimization problem to be solved at every sampling interval. As computational power has improved, MPC has been introduced to more application areas. Themes in the MPC literature demonstrate the need to study algorithms, to achieve the desired combination of optimization accuracy and speed for strong control performance, and model design, to capture desired system behavior without inducing unwarranted computational burden. The overall goal of the dissertation is to contribute to the understanding of using MPC effectively in three application areas. The first contribution is the development of a simulation framework that can be used to prototype MPC algorithms and the effects of dynamics and constraint modeling, objective function design, and algorithm choice. The second contribution is a simulation study using MPC for nonlinear tracking control during an aero-assisted orbital maneuver. The final contribution is the application of MPC to real-time motion control.

To gather additional 28-day all-cause mortality and safety data among adult patients with severe sepsis who were treated with drotrecogin alfa (activated). Prospective, single-arm, multicenter clinical trial. Eighty-five study sites in the United States and two in Puerto Rico. Adult patients (273 patients) with a diagnosis of severe sepsis, which was defined as a systemic inflammatory response due to acute infection and one or more sepsis-induced organ dysfunctions present for ≤ 48 h, as in the recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Drotrecogin alfa (activated) [Xigris; Eli Lilly and Company; Indianapolis, IN], 24 μg/kg/h, as a continuous IV infusion for a duration of 96 ± 1 h. The primary end point was all-cause mortality, which was assessed 28 days after the start of the infusion of drotrecogin alfa (activated). Serious bleeding was monitored to day 28. Comparisons of mortality were made to treatment groups from two double-blind, placebo-controlled clinical trials (PROWESS United States and the Secretory Phospholipase A2 Inhibitor [sPLA2I] in Severe Sepsis trial) that used similarly defined patient populations from the United States. For the 273 adult patients enrolled in this study, the 28-day all-cause mortality rate was 26.4%. This mortality rate was 6% lower than that observed in the placebo groups in the PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of the group treated with drotrecogin alfa (activated) in the PROWESS US trial (24.4%). One nonfatal intracranial hemorrhage was reported in the Extended Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE US) [0.35%]. Serious bleeding events during the infusion period occurred in 11 patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US drotrecogin alfa (activated) treatment group. Despite the limitations associated with comparisons across trials, this study provides confirmatory evidence of the efficacy and safety of drotrecogin alfa (activated) documented in the PROWESS trial.

Background: Tuberculosis (TB) is a known public health threat to prison systems due to poor hygiene, crowded living conditions, poor health of inmates, and poor prison healthcare systems. The large population of HIV-infected people living in prisons is especially susceptible to increased TB transmission and higher mortality. In Northeastern Malaysia, there is no screening for active or latent TB infection (LTBI) in the prison system. Aims and Hypothesis: This study serves to measure the prevalence and correlates of LTBI and active TB symptoms in HIV-infected and non-HIV-infected prisoners in Northeastern Malaysia. Given the host of factors that contribute to TB transmission and burden in prisons, it is expected that the burden of LTBI is high. In studying a population of HIV-infected inmates who are not receiving antiretroviral therapy, it is expected that a significant number of inmates will display active TB symptoms. Methods: This is a cross sectional study design that uses Tuberculin Skin Testing (TST) to measure LTBI, and the World Health Organization (WHO) TB symptom survey to measure active TB symptom prevalence. A total of 266 prisoners in Penjara Pengkalan Chepa, Kelantan, Malaysia, were enlisted in the study. After consent, participants underwent two-step TST and were surveyed for active TB symptoms. Standardized cutoffs of ≥5mm and ≥10mm were used to define reactive TST among prisoners with and without HIV, respectively. Clinical and behavioral data were assessed with a questionnaire and HIV-infected prisoners were stratified by CD4 status. Results: LTBI prevalence in Penjara Pengkalan Chepa in July-August 2011 was 87.6%, with significantly lower TST-reactivity among HIV-infected compared to non-HIV-infected prisoners (83.6% vs. 91.5%; p<0.05); however, TB symptoms were similar (16.9% vs. 10.1%; p=0.105). On multivariate analysis, previous incarceration (AOR=4.61: 95%CI=1.76-12.1) was the only significant correlate of LTBI. Increasing age (AOR=1.07: 95%CI=1.01-1.13), lower body mass index (AOR=0.82: 95%CI=0.70-0.96) and having a negative TST (AOR=3.46: 95%CI=1.20-9.97) were correlated with TB symptoms. Conclusion: LTBI is highly prevalent, associated with previous incarceration, and suggests the need for routine TB screening at entry to Malaysian prisons as well as continued surveillance. The prevalence of LTBI symptoms among HIV-infected inmates is alarming and provides further justification for active screening measures. Treating LTBI in prisons is challenging, but new, shorter regimens hold promise for feasible treatment options in prisons.

Background: The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One interesting synapsin III single nucleotide polymorphism (SNP), –196G/A, has been identified in the promoter region. The –196A allele results in a 6/8 base match to the core recognition octamer sequence for Oct-1, a member of the POU family of transcription factors. Objective: To determine whether or not the –196 SNP is associated with either SZ or bipolar disorder (BD). Methods: A case control comparison was used to determine whether or not differences in allele or genotype distribution occurred in patients with SZ and BD. Electromobility gel shift assay (EMSA) was used to determine whether the –196 SNP affected protein binding. Results: A trend towards significance was detected when the allele distribution was analyzed in Caucasian patients with SZ (n = 145; 191 controls) and a cohort of subjects from the Czech Republic with BD (n = 82; 94 controls). No association was found in bipolar patients from the United States (n = 127) or in African-American patients with SZ (n = 124; 133 controls). EMSA showed that the region encompassing the –196 SNP binds to a brain protein in an allele-specific manner. Conclusions: These data, while inconclusive, suggest that –196 SNP should be further investigated as a candidate for 22q13-linked SZ.