Temperature homeostasis in transgenic mice lacking thyroid hormone receptor-alpha gene products

We studied temperature homeostasis in male mice lacking all thyroid hormone receptor-alpha gene products (TRalpha-0/0). As other TRalpha-deficient mice, TRalpha-0/0 mice have lower core body temperature (T(C)) than cognate wild-type controls. We found that obligatory thermogenesis is normal in TRalpha-0/0 and that the lower T(C) at room temperature (RT, 20-22 C) is caused by a down setting of the hypothalamic thermostat. However, TRalpha-0/0 mice are cold intolerant due to impaired facultative thermogenesis. Norepinephrine-induced brown adipose tissue (BAT) thermogenesis is blunted, even though BAT-relevant genes and T(4) deiodinase respond normally to cold stimulation, as do serum T(3), serum glycerol (marker of lipolysis), and heart rate. BAT normally contributes to maintain T(C) at RT, 9 C below thermoneutrality, yet TRalpha-0/0 mice do not show signs of being cold stressed at 20-22 C. Instead, oxygen consumption is greater in TRalpha-0/0 than in wild-type mice at RT, suggesting the recruitment of an alternate, cold-activated form of thermogenesis to compensate for the lack of BAT thermogenesis. These results indicate that TRalpha is necessary for T(3) to modulate the central control of T(C) and for an essential step in norepinephrine activation of BAT thermogenesis but not to sustain obligatory thermogenesis. In addition, the results provide evidence for an alternate form of facultative thermogenesis, which probably originates in skeletal muscle and that is less effective and more energy demanding than BAT thermogenesis.     

Spirituality,Social Support,and Survival in Hemodialysis Patients

Background and objectives: No studies have evaluated the relationship among spirituality, social support, and survival in patients with ESRD. This study assessed whether spirituality was an independent predictor of survival in dialysis patients with ESRD after controlling for age, diabetes, albumin, and social support.Design, setting, participants, & measurements: A total of 166 patients who had ESRD and were treated with hemodialysis completed questionnaires on psychosocial variables, quality of life, and religious and spiritual beliefs. The religious variables were categorized into three scores on a 0 to 20 scale (low to high levels): Spirituality, religious involvement, and religion as coping. Social support was assessed using the Multidimensional Scale for Perceived Social Support. Analyses were also performed including and excluding patients with HIV infection. Religious variables were categorized on the basis of means, medians, and tertiles.Results: In analyses that used religious variables, only the responses on the spirituality scale split at the mean were associated with survival. The association of other religious variables with survival did not reach significance. Social support correlated with spirituality, religion as coping, and religious involvement measures. Only social support and age were associated with survival when controlling for diabetes, albumin concentration, HIV infection, and spirituality.Conclusions: These data suggest that the effects of spirituality may be mediated by social support. Larger, multicenter, prospective studies that use well-validated tools to measure religiosity and spirituality are needed to determine whether there is an independent association of spirituality variables with survival in patients with ESRD.Relationships between spirituality and mortality have been investigated in medical populations but remain controversial (1–13). Variable associations have been found depending on definitions of spirituality and patient populations studied (1–11). Miller and Thoreson (12) explored nine different hypotheses regarding the relationship among religious beliefs, spirituality, and mortality. The only hypothesis that they found to be supported by persuasive evidence stated that “church/service attendance protects [only] healthy people against death.” Studies supporting a similar link in patients with chronic illnesses have also shown mixed results. Koenig et al. (14) evaluated approximately 4000 elderly patients to determine whether attendance at religious services during a 6-yr period was associated with survival. In adjusted analyses, there was a significantly lower mortality in patients who frequently attended church services.Many researchers have suggested a publication bias, whereby only the studies that indicate a significant relationship are published (13). Most studies cited the need for more research on the relationship between spirituality and mortality before any firm conclusions can be reached. In addition, the health dimensions of lack of belief have not been well explored.There also exists considerable debate on how to operationalize religiosity and spirituality. Whereas the first term often is associated with participation in social institutions and adherence to specific beliefs and practices, the latter is a broader term that typically pertains to life''s vital qualities and an overall broad belief in the immaterial features of life (12). Spirituality relates to transcendent values and relationships and the way people find meaning, purpose, and hope in life and in the midst of suffering (15). A person may be spiritual and not religiously observant or observe rituals without a spiritual focus.Few studies have specifically evaluated the potential association between spirituality and survival in patients with ESRD (16,17). We (18) previously showed that religious and spiritual beliefs are associated with decreased perception of burden of illness, decreased depressive affect, increased perception of social support, and higher satisfaction with life and perception of quality of life in an urban, predominantly black ESRD population. We also found that a “spiritual beliefs scale” correlated with several quality-of-life measures in patients with ESRD (19). Even though many of these psychosocial measures have been shown to be related to survival independently, no study to our knowledge has demonstrated a link between spirituality and survival in this population.We determined whether three variables related to spirituality, religious beliefs, and practices and faith (spirituality, religious involvement, and religion as a coping measure) were independently associated with survival in hemodialysis patients with ESRD. We then assessed the relationship between social support and survival, regardless of whether the spiritual variables were included in analyses. We hypothesized that spiritual variables would be associated with survival in patients with ESRD.     

The degree of kinship and its association with reciprocity and exchange in the relationships of visually impaired older adults

This study draws on an evolutionary model of exchange in relationships to examine the nature of perceived reciprocity in the context of kin and non-kin relationships among a sample of visually impaired older adults (age 63–99). Further, we examined the direct and moderating impact of functional impairment and adaptation to visual impairment on the nature of perceived reciprocity. Results showed that the greater the degree of genetic relatedness the more imbalanced the exchange. It was also found that degree of adaptation to visual impairment moderated the association between genetic relatedness and perceived exchange, such that the greater the degree of genetic relatedness the more people reported they gave rather than received except at very low levels of adaptation, when people received more than they gave the greater the degree of genetic relatedness. Thus, an evolutionary model was supported such that imbalanced exchange was found more with greater degrees of genetic relatedness, but the direction of exchange was different for high versus low levels of adaptation to vision impairment.     

Superiority of practolol versus propranolol in protection against ventricular fibrillation induced by coronary occlusion

The ability of practolol and propranolol to prevent ventricular fibrillation in experimental anterior myocardial infarction was compared in dogs subjected to ligation of the left anterior descending and first septal coronary arteries. This procedure, which causes ventricular fibrillation in 90 percent of animals within 30 minutes, was performed in control dogs and in dogs pretreated with propranolol (0.5 mg/kg body weight) or with practolol (1.5 to 2.5 mg/kg). These doses produced nearly equivalent shifts in isoproterenol-induced chronotropic dose-response curves, indicating equivalent degrees of beta adrenergic blockade. In 21 dogs with confirmed ligation, cardiogenic shock did not develop. Six of seven control dogs died with ventricular fibrillation. Six of seven dogs pretreated with propranolol also had fibrillation, whereas only one of the seven dogs pretreated with practolol manifested ventricular fibrillation during the 45 minute postligation observation period. Practolol afforded significant protection compared with no treatment or treatment with propranolol (P < 0.05).     

Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection

HIV type 1 (HIV-1) persists within resting CD4(+) T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10(-4)) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4(+) T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4(+) T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4(+) T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.     

Nonviral delivery of self-amplifying RNA vaccines

Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use. Taking advantage of the recent innovations in systemic delivery of short interfering RNA (siRNA) using lipid nanoparticles (LNPs), we developed a self-amplifying RNA vaccine. Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA. This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of nonviral technologies to deliver self-amplifying RNA vaccines is warranted.     

Bronchodilators in Heart Failure Patients With COPD: Is It Time for a Clinical Trial?

Chronic heart failure (HF) and chronic obstructive pulmonary disease (COPD) commonly coexist, and patients with both diseases fare worse than those with either disease alone. Several factors may contribute to worse outcomes, including an increased burden of care related to greater disease complexity, an overlap of symptoms resulting in misapplication of therapy, and the adverse effects of treatment for one disease on the symptoms and outcomes related to the other. For example, there are conflicting data about the cardiovascular risks of bronchodilators in HF patients who may experience worse outcomes with inhaled beta-2 agonists via arrhythmogenesis, ischemia, and/or attenuation of beta-blocker benefits. In contrast, the long-acting anticholinergic class of bronchodilators has a more reassuring safety profile. Anticholinergic bronchodilators may be the preferred first-line agents for COPD patients with comorbid HF, yet data supporting these recommendations are limited. Therapeutic trials in COPD patients have generally excluded patients with significant HF and vice-versa. This paper reviews bronchodilator therapy in HF and proposes a randomized trial designed to enroll patients with significant COPD and HF to determine the risks and/or benefits of adding a long-acting beta-2 agonist to patients currently taking a long-acting anticholinergic agent.