Corticotropin releasing factor: basic studies and clinical applications

Corticotropin releasing factor (CRF) is a newly sequenced peptide first isolated from sheep hypothalami and thought to be an important modulator of both the pituitary-adrenal axis and the sympathetic nervous system. We administered intravenous, intramuscular, and intracerebroventricular CRH to non-human primates and measured plasma ACTH, beta endorphin, cortisol, GH and PRL responses to CRF. In addition, we determined the pharmacokinetic properties of I125 in these primates. We administered CRF as an intravenous bolus or as a continuous infusion to normal volunteers and as an intravenous bolus to patients with disorders of the hypothalamic-pituitary-adrenal axis, such as Cushing's syndrome and adrenal insufficiency, and patients with endogenous depression and mild hypercortisolism, and assessed their plasma ACTH, cortisol, GH and PRL responses. In addition, we determined the pharmacokinetic properties of CRF in man by measuring CRF immunoreactivity in plasma. CRF given intravenously to primates or man is a slowly metabolized, long-acting, secretagogue of ACTH, beta-endorphin and cortisol. When given intracerebroventricularly to primates it stimulates the hypothalamic-pituitary-adrenal axis without escaping into the plasma and it is actively cleared in the CNS. It does not cross the blood brain barrier appreciably when given intravenously. CRF given to primates and men as an intravenous continuous infusion has only mild ACTH stimulating effects and this may be due to an intact cortisol negative feedback system. Finally, CRF causes characteristic plasma hormone responses in patients with Cushing's disease, adrenal insufficiency and depression.     

Effects of dorsolateral frontal cortex lesions and discrimination-alternation training on regional acetylcholinesterase activity in monkey

Twenty adult female rhesus monkeys (Macaca mulatta) were divided into 4 treatment groups of 5 subjects each; nonlesioned-nontrained (NLNT), nonlesioned-trained (NLT), lesioned-nontrained (LNT), and lesioned-trained (LT). All lesions were bilateral ablations of dorsolateral frontal cortex. The training consisted of color discrimination and delayed alternation. AChE activity was determined for 19 brain regions in each subject. Significant changes in AChE activity due to the lesion were found in orbital cortex, caudate nucleus and pons while training procedures produced significant changes only in the orbital cortex. The 3 brain areas in which significant AChE changes were found bear a close anatomical and functional relationship to the lesioned prefrontal cortex.     

Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection -- a prospective cross-sectional study

AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore, these mutations may also affect the course of HIV/HCV coinfection. METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTES-IN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n = 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes. RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%, P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1: 19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002; 1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls. CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.     

Proxy sources for information on nursing home residents' quality of life

OBJECTIVES: This study explores how well staff and family proxies' reports on selected quality-of-life (QOL) domains (comfort, dignity, functional competence, privacy, meaningful activity, food enjoyment, relationships, security, and autonomy) correspond to residents' own reports. METHODS: We compared QOL domain scores for nursing home residents and 1,326 staff proxies and 989 family proxies at the individual and facility level using means, Pearson correlation statistics, and intraclass correlations. Regression models adjusted for residents' age, gender, length of stay, ability to perform activities of daily living, and cognition. RESULTS: For each domain in more than half the cases, proxy means were within 1 SD of the resident means. Resident and family proxy individual reports for selected domains were correlated at 0.14 to 0.46 (all p <.000). Resident and staff proxy individual reports were correlated at 0.13 to 0.37 (all p <.000). Correlation of mean levels by facility for staff proxies was 0.26 to 0.64 (generally p <.05) and for family proxies 0.13 to 0.61 (p <.01 except for one domain). DISCUSSION: Although staff and family proxy domain scores are significantly correlated with resident scores, the level of correlation suggests they cannot simply be substituted for resident reports of QOL. Determining how proxy reports can be used for residents who cannot be interviewed at all remains an unresolved challenge.     

Treatment outcomes in depression: comparison of remote treatment through telepsychiatry to in-person treatment

OBJECTIVE: Telepsychiatry is an increasingly common method of providing psychiatric care, but randomized trials of telepsychiatric treatment compared to in-person treatment have not been done. The primary objective of this study was to compare treatment outcomes of patients with depressive disorders treated remotely by means of telepsychiatry to outcomes of depressed patients treated in person. Secondary objectives were to determine if patients' rates of adherence to and satisfaction with treatment were as high with telepsychiatric as with in-person treatment and to compare costs of telepsychiatric treatment to costs of in-person treatment. METHOD: In this randomized, controlled trial, 119 depressed veterans referred for outpatient treatment were randomly assigned to either remote treatment by means of telepsychiatry or in-person treatment. Psychiatric treatment lasted 6 months and consisted of psychotropic medication, psychoeducation, and brief supportive counseling. Patients' treatment outcomes, satisfaction, and adherence and the costs of treatment were compared between the two conditions. RESULTS: Hamilton Depression Rating Scale and Beck Depression Inventory scores improved over the treatment period and did not differ between treatment groups. The two groups were equally adherent to appointments and medication treatment. No between-group differences in dropout rates or patients' ratings of satisfaction with treatment were found. Telepsychiatry was more expensive per treatment session, but this difference disappeared if the costs of psychiatrists' travel to remote clinics more than 22 miles away from the medical center were considered. Telepsychiatry did not increase the overall health care resource consumption of the patients during the study period. CONCLUSIONS: Remote treatment of depression by means of telepsychiatry and in-person treatment of depression have comparable outcomes and equivalent levels of patient adherence, patient satisfaction, and health care cost.     

Erythropoietin stimulates vasculogenesis in neonatal rat mesenteric microvascular endothelial cells

Human breast milk is a rich source of growth factors, including erythropoietin (Epo), the endogenous hormonal stimulant of erythropoiesis. Recombinant human Epo (rhEpo) has been shown to stimulate 1) angiogenesis, the process of new blood vessel growth from preexisting vessels; 2) vasculogenesis, tubule formation from single-cell suspensions; and 3) endothelial cell proliferation in immortalized endothelial cells and vessel explants. We hypothesized that Epo would induce mitogenesis and stimulate vasculogenesis in primary cultures of microvascular endothelial cells (MVECs) from neonatal rat mesentery. Isolation, purification, characterization, and culture of MVECs were performed. Cell proliferative effects of rhEpo were studied by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in cultured MVECs. Vasculogenic effects of rhEpo were examined on cultured MVECs plated on either hormone-rich Matrigel substratum or the extracellular matrix protein, type I collagen. Our findings show that MVECs are isolated and purified, and that rhEpo stimulates MVEC proliferation, with maximal proliferation seen with a concentration of 50 IU/mL rhEpo. Tubule formation assays reveal that an rhEpo concentration of 50 IU/mL produces maximal tubule formation after 12 h on both Matrigel and the simple substratum, type I collagen. Our study is the first to examine the effects of rhEpo on the endothelium of the neonatal gastrointestinal tract. These data suggest that Epo may have a trophic effect on the vasculature of the gastrointestinal tract early in development. Furthermore, as Epo has been measured in breast milk, and its receptor has been shown to exist on the mucosa and gastrointestinal vasculature, Epo may be an endogenous stimulant of vessel growth during neonatal gastrointestinal development.     

Immunity,autoimmunity, and the aging process: complex interactions

Immune deficiency is not an age-related process, but rather a progressive process where predominantly cellular immune response is gradually, but never totally, replaced by antibody response. Cellular immune response appears to be associated with the intrinsic mechanisms of pathological aging. Cellular immunity resulting from induction of macrophage stimulation and cytokine secretion appears to involved. These immuno-inflammatory changes mimic the effects of pathological aging in the different organs. Are they essential factors or simply accessory phenomena? Switching towards an antibody response appears to be a mechanism of adaptation rather than a mechanism of deterioration. Immune status provides a good means of assessing general status in an elderly subject. An attempt should be made to identify the cause of any immune deficiency since age is not in itself an underlying cause. Etiological treatment is indicated.