Citations

Abstract With the growing epidemic of obesity in an aging population, obstructive sleep apnea (OSA) is increasingly encountered in clinical practice. Given the acute cardiopulmonary stressors consequent to repetitive upper airway collapse, as well as evidence for cardiovascular homeostatic dysregulation in subjects with sleep apnea, there is ample biologic plausibility that OSA imparts increased cardiovascular risk, independent of comorbid disease. Indeed, observational studies have suggested strong associations with multiple disorders, such as systemic hypertension, heart failure, cardiac arrhythmias, and pulmonary hypertension. Further data in the form of longitudinal cohort studies and randomized controlled trials are accruing to add to the body of evidence. This review examines pathophysiologic mechanisms and explores current concepts regarding the impact of OSA and its treatment on selected clinical disease states.

ABSTRACTWe evaluated the participatory role of human HLA-DR molecules in control of virus from the central nervous system and in the development of subsequent spinal cord demyelination. The experiments utilized intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), a picornavirus that, in some strains of mice, results in primary demyelination. We studied DR2 and DR3 transgenic mice that were bred onto a combined class I-deficient mouse (beta-2 microglobulin deficient; β2m0) and class II-deficient mouse (Aβ0) of theH-2bbackground. Aβ0.β2m0mice infected with TMEV died within 18 days of infection. These mice showed severe encephalomyelitis due to rapid replication of virus genome. In contrast, transgenic mice with insertion of a single human class II major histocompatibility complex (MHC) gene (DR2 or DR3) survived the acute infection. DR2 and DR3 mice controlled virus infection by 45 days and did not develop spinal cord demyelination. Levels of virus RNA were reduced in HLA-DR transgenic mice compared to Aβ0.β2m0mice. Virus-neutralizing antibody responses did not explain why DR mice survived the infection and controlled virus replication. However, DR mice showed an increase in gamma interferon and interleukin-2 transcripts in the brain, which were associated with protection. The findings support the hypothesis that the expression of a single human class II MHC molecule can, by itself, influence the control of an intracerebral pathogen in a host without a competent class I MHC immune response. The mechanism of protection appears to be the result of cytokines released by CD4+T cells.

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection causes apoptosis of infected CD4 T cells as well as uninfected (bystander) CD4 and CD8 T cells. It remains unknown what signals cause infected cells to die. We demonstrate that HIV-1 protease specifically cleaves procaspase 8 to create a novel fragment termed casp8p41, which independently induces apoptosis. casp8p41 is specific to HIV-1 protease-induced death but not other caspase 8-dependent death stimuli. In HIV-1-infected patients, casp8p41 is detected only in CD4 + T cells, predominantly in the CD27 + memory subset, its presence increases with increasing viral load, and it colocalizes with both infected and apoptotic cells. These data indicate that casp8p41 independently induces apoptosis and is a specific product of HIV-1 protease which may contribute to death of HIV-1-infected cells.

Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide known to play a critical role in energy balance. We have previously reported that overexpression of MCH is associated with mild obesity. In addition, mice have substantial hyperinsulinemia and islet hyperplasia that is out of proportion with their degree of obesity. In this study, we further explored the role of MCH in the endocrine pancreas. Both MCH and MCHR1 are expressed in mouse and human islets and in clonal β-cell lines as assessed using quantitative real-time PCR and immunohistochemistry. Mice lacking MCH (MCH-KO) on either a C57Bl/6 or 129Sv genetic background showed a significant reduction in β-cell mass and complemented our earlier observation of increased β-cell mass in MCH-overexpressing mice. Furthermore, the compensatory islet hyperplasia secondary to a high-fat diet, which was evident in wild-type controls, was attenuated in MCH-KO. Interestingly, MCH enhanced insulin secretion in human and mouse islets and rodent β-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF)4α, and HNF1α. Together, these data provide novel evidence for an autocrine role for MCH in the regulation of β-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis.

AbstractOutcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.

Background— Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects ≈1 in 3000 persons, is 1 of the most common causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutations in LQTS in 1995, hundreds of mutations in 8 LQTS susceptibility genes have been identified. All 8 LQTS genotypes represent primary cardiac channel defects (ie, ion channelopathy) except LQT4, which is a functional channelopathy because of mutations in ankyrin-B. Approximately 25% of LQTS remains unexplained pathogenetically. We have pursued a “final common pathway” hypothesis to elicit novel LQTS-susceptibility genes. With the recent observation that the LQT3-associated, SCN5A -encoded cardiac sodium channel localizes in caveolae, which are known membrane microdomains whose major component in the striated muscle is caveolin-3, we hypothesized that mutations in caveolin-3 may represent a novel pathogenetic mechanism for LQTS. Methods and Results— Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, we performed open reading frame/splice site mutational analysis on CAV3 in 905 unrelated patients referred for LQTS genetic testing. CAV3 mutations were engineered by site-directed mutagenesis and the molecular phenotype determined by transient heterologous expression into cell lines that stably express the cardiac sodium channel hNa v 1.5. We identified 4 novel mutations in CAV3 -encoded caveolin-3 that were absent in >1000 control alleles. Electrophysiological analysis of sodium current in HEK293 cells stably expressing hNa v 1.5 and transiently transfected with wild-type and mutant caveolin-3 demonstrated that mutant caveolin-3 results in a 2- to 3-fold increase in late sodium current compared with wild-type caveolin-3. Our observations are similar to the increased late sodium current associated with LQT3-associated SCN5A mutations. Conclusions— The present study reports the first CAV3 mutations in subjects with LQTS, and we provide functional data demonstrating a gain-of-function increase in late sodium current.

Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele–dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.