Contemporary treatment of heart failure: Is there adequate evidence to support a unique strategy for African-Americans? con position

Heart failure is a substantial cause of increased morbidity and mortality in the African-American population, with poorer prognosis versus white patients. Systolic heart failure is predominantly caused by poorly controlled hypertension in African-Americans. Overall, African-Americans remain underrepresented in morbidity and mortality heart failure trials, and further data are needed to confirm the potential benefit of present therapies and newer approaches to heart failure in African-Americans. Intensive blood pressure control and control of other risk factors, along with the appropriate application of evidence-based therapies including angiotensin converting enzyme (ACE) inhibitors and approved beta-blockers, are required to decrease racial disparities. Although some data suggest that contemporary treatment with ACE inhibitors and beta-blockers may be less effective in African-Americans in terms of reducing heart failure morbidity and mortality, there is not adequate evidence to support a unique strategy for this population. The use of evidence-based therapies should be equally applied to African-Americans as well as to other ethnic groups while awaiting further studies.     

A clinicopathological study of vascular progressive supranuclear palsy: a multi-infarct disorder presenting as progressive supranuclear palsy

BACKGROUND: Clinical features suggesting a diagnosis of progressive supranuclear palsy (PSP) include early falls, axial rigidity, vertical supranuclear ophthalmoplegia, and levodopa unresponsiveness. When these clinical features are present, the diagnosis is almost always PSP, yet vascular disease sometimes has a similar presentation, referred to as vascular PSP. OBJECTIVE: To evaluate clinical and pathologic features of cases of vascular PSP submitted to a PSP brain bank. DESIGN: Review of gross and microscopic neuropathological features, determination of tau haplotype, and medical record review of 4 patients with an antemortem diagnosis of PSP who did not meet the pathologic criteria for PSP and instead had vascular pathologic abnormalities. RESULTS: All patients had vertical supranuclear ophthalmoplegia, a history of falls, and a gradually progressive disease course. Falls began 1 year after symptom onset, and all patients had asymmetric findings on a neurological examination. A magnetic resonance imaging scan revealed lacunar basal ganglia infarcts in one patient and an increased T2-weighted signal in the corona radiata and centrum semiovale in another. Gross and microscopic neuropathological studies demonstrated infarcts in the cerebral cortex (n = 4), thalamus (n = 4), basal ganglia (n = 3), and cerebellum (n = 4). The brainstem was affected in one patient, but no infarcts were detected in the subthalamic nucleus or substantia nigra. Of the 4 patients, 3 carried an H2 tau haplotype, a rare occurrence in the general population. CONCLUSIONS: Asymmetric signs, falls after 1 year of symptom onset, vascular lesions on a magnetic resonance imaging scan, and an H2 tau haplotype may help differentiate vascular PSP from PSP. Thalamic and basal ganglia infarcts are common in patients with vascular PSP and, when present, may contribute to misdiagnosis.     

Hepatitis C virus envelope glycoproteins and potential for vaccine development

HCV envelope glycoproteins play an important role in the initiation of viral infection. The functional dichotomy of the individual HCV glycoproteins was investigated using VSV/HCV pseudotype virus. Surprisingly, VSV/HCV pseudotype virus generated from either E1 or E2 displayed infectivity of a number of mammalian cells. The use of pseudotyped virus has allowed us to better understand the similar and divergent properties of E1 and E2 glycoproteins decorating the envelope of HCV. The serum pseudotype virus neutralizing activity in patient sera did not exhibit a correlation with the infecting HCV genotype or virus load. HCV E2 glycoprotein induces a weak neutralizing antibody response, however the neutralization function was augmented by complement. Taken together, these observations suggest a role for both the glycoproteins in HCV attachment and entry into susceptible host cells. An understanding of HCV entry and strategies appropriate for mimicking cell surface molecules may help in the development of new therapeutic modalities against HCV infection. Furthermore, incorporation of the HCV glycoproteins in a candidate vaccine may offer protection, although additional work is necessary to enhance their immunogenicity.     

Assaying gene content in Arabidopsis

Arabidopsis has been popular as a model plant system for decades. Completion of the Arabidopsis genome and the availability of large expressed sequence-tag collections from other dicot species provides an opportunity to assess gene content in Arabidopsis, specifically by identifying genes from dicot test species that are absent from Arabidopsis. I report here results from these sorts of comparisons, carried out in part to assess the extent to which Arabidopsis is representative of dicot genomes and also the degree to which gene loss and novel gene acquisition has accompanied angiosperm speciation. More than 10% of the contigs from each of three dicot test species have no detectable homologue in Arabidopsis. By means of cross comparison among the test species, 154 specific cases of gene loss in the lineage leading to Arabidopsis were identified, including several well characterized enzymes and a group of proteins with strong homologs in the photosynthetic bacterium Synechocystis. These results show that although Arabidopsis is broadly representative of the other dicot genomes, there seems to be substantial variation even among relatively closely related genera. Further, although we cannot yet draw a causative link, variation in actual gene content seems appears to be a feature of angiosperm speciation.     

Punctuated evolution of mitochondrial gene content: high and variable rates of mitochondrial gene loss and transfer to the nucleus during angiosperm evolution

To study the tempo and pattern of mitochondrial gene loss in plants, DNAs from 280 genera of flowering plants were surveyed for the presence or absence of 40 mitochondrial protein genes by Southern blot hybridization. All 14 ribosomal protein genes and both sdh genes have been lost from the mitochondrial genome many times (6 to 42) during angiosperm evolution, whereas only two losses were detected among the other 24 genes. The gene losses have a very patchy phylogenetic distribution, with periods of stasis followed by bursts of loss in certain lineages. Most of the oldest groups of angiosperms are still mired in a prolonged stasis in mitochondrial gene content, containing nearly the same set of genes as their algal ancestors more than a billion years ago. In sharp contrast, other plants have rapidly lost many or all of their 16 mitochondrial ribosomal protein and sdh genes, thereby converging on a reduced gene content more like that of an animal or fungus than a typical plant. In these and many lineages with more modest numbers of losses, the rate of ribosomal protein and sdh gene loss exceeds, sometimes greatly, the rate of mitochondrial synonymous substitutions. Most of these mitochondrial gene losses are probably the consequence of gene transfer to the nucleus; thus, rates of functional gene transfer also may vary dramatically in angiosperms.     

Primary HIV infection

Primary HIV can be asymptomatic or result in a severe symptomatic illness. Common symptoms are pyrexia, pharyngitis, malaise, lethargy, maculopapular rash, mucous membrane ulceration, lymphadenopathy and headache. It can be reliably diagnosed by a positive virologic test in the absence of HIV-specific antibodies. Progression to late-stage disease is influenced by the severity of the symptoms in primary HIV infection, the duration of the illness, the presence of neurological symptoms and the presence of oral candidiasis. This stage is characterized by a very high viral load and infectiousness. Currently the experimental data are insufficient to recommend whether or not those diagnosed with primary HIV infection should routinely receive antiretroviral therapy.     

Neurobehavioral analysis of developmental iron deficiency in rats

Iron deficiency (ID) in early life alters the course of behavioral and cognitive development in humans, causing decreased physical activity and responsiveness to the environment. The effects of ID on behavior are similar in rats and hypothesized to be related to ID-related impairments in central dopamine pathways. The objective of this study was to examine the association between brain iron measures of dopamine function, and behavioral measures of activity and reactivity. Male and female weanling rats were fed either an iron deficient diet or control diet for 6 weeks. The iron deficient rats showed significantly decreased activity and increased anxiety-like behaviors. Iron deficient rats also showed significant decrements in brain iron content in the corpus striatum, prefrontal cortex, and midbrain and decreases in dopamine receptors and the transporter in the same areas. Multiple regression analysis showed ventral midbrain iron concentration and dopamine D(1) receptor density to be highly associated with exploration and repeated movements, respectively. In addition, the results showed anxiety-like behaviors to be related to prefrontal cortex dopamine transporter and dopamine D(1) receptor densities. We conclude from these analyses that iron concentration in dopamine containing regions and densities of dopamine receptors and the transporter, are significant predictors of measures of activity and reactivity. These observations also strengthen the argument that the Fe-dopamine link is fundamental to understanding biobehavioral difficulties seen in children with ID anemia.     

Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease

Patients with chronic hepatitis C virus (HCV) infection frequently report fatigue, lassitude, depression, and a perceived inability to function effectively. Several studies have shown that patients exhibit low quality-of-life scores that are independent of disease severity. We therefore considered whether HCV infection has a direct effect on the central nervous system, resulting in cognitive and cerebral metabolite abnormalities. Twenty-seven viremic patients with biopsy-proven mild hepatitis due to HCV and 16 patients with cleared HCV were tested with a computer-based cognitive assessment battery and also completed depression, fatigue, and quality-of-life questionnaires. The HCV-infected patients were impaired on more cognitive tasks than the HCV-cleared group (mean [SD]: HCV-infected, 2.15 [1.56]; HCV-cleared, 1.06 [1.24]; P =.02). A factor analysis showed impairments in power of concentration and speed of working memory, independent of a history of intravenous drug usage (IVDU), depression, fatigue, or symptom severity. A subgroup of 17 HCV-infected patients also underwent cerebral proton magnetic resonance spectroscopy (1H MRS). The choline/creatine ratio was elevated in the basal ganglia and white matter in this group. Patients who were impaired on 2 or more tasks in the battery had a higher mean choline/creatine ratio compared with the unimpaired patients. In conclusion, these preliminary results demonstrate cognitive impairment that is unaccounted for by depression, fatigue, or a history of IVDU in patients with histologically mild HCV infection. The findings on MRS suggest that a biological cause underlies this abnormality.     

Discriminative stimulus effects of ethanol in C57BL/6J and DBA/2J inbred mice

BACKGROUND: Two of the most widely used mouse strains for studying the behavioral effects of ethanol are C57BL/6J (B6) and DBA/2J (D2) mice. These strains exhibit marked differences in behavioral and physiological responses to ethanol. The subjective discriminative stimulus effects of ethanol may play a role in ethanol abuse, but the discriminative stimulus profile of ethanol has not been compared in B6 and D2 mice. Examination of the discriminative stimulus effects of ethanol in B6 and D2 mouse strains may enhance our understanding of the relationship between the subjective effects of ethanol and other ethanol-induced behavioral effects. METHODS: Twelve adult male C57BL/6J mice and 12 male DBA/2J mice were trained to discriminate 1.5 g/kg ethanol from saline in daily 15 min, milk-reinforced operant sessions. After training, ethanol substitution and response-rate suppression dose response curves were determined for ethanol, midazolam, diazepam, pentobarbital, pregnanolone, 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), dizocilpine, and morphine. RESULTS: D2 mice learned the ethanol discrimination significantly more quickly than did B6 mice. Ethanol, midazolam, pregnanolone, and dizocilpine fully substituted for ethanol in both strains. Pentobarbital was more potent in producing ethanol-like discriminative stimulus effects in D2 than B6 mice. Midazolam and diazepam were significantly more potent in suppressing response rates in D2 than B6 mice. Morphine failed to substitute for ethanol in either strain, but the ED50 for morphine suppression of responding was significantly lower in B6 than D2 mice. CONCLUSIONS: The initial stimulus effects of 1.5 g/kg ethanol may be more salient in D2 than B6 mice. This does not appear to result from differences in the neurotransmitter systems that mediate ethanol's discriminative stimulus effects. In both strains, gamma-aminobutyric acid-positive modulators and a noncompetitive NMDA antagonist substituted for ethanol. However, strain differences did exist in the potency of gamma-aminobutyric acid-positive modulators and morphine for suppressing operant responding.