Examination of pituitary adenylate cyclase-activating polypeptide in Parkinson’s disease focusing on correlations with motor symptoms

GeroScience - The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson’s disease (PD)...     

AsymptomaticH. pylori infection impairs pH inhibition of gastrin and acid secretion during second hour of peptone meal stimulation

H. pylori infection is associated with acid-peptic disease, although its role in the pathogenesis is unclear. The purpose of this study was to determine if chronic infection in asymptomatic subject impairs the inhibition of meal-stimulated gastrin and acid secretion that is observed normally at low intragastric pH. Presence of infection was determined by both C-14 urea breath test and serology. Acid secretion was measured under basal conditions and in response to peptone meal stimulation and pentagastrin. Plasma gastrin concentrations were determined by radioimmunoassay under basal conditions and during peptone meal stimulation. Intragastric titration with 1% peptone during the first hour, and 8% peptone during the second hour, was performed at both pH 7.0 and 2.5 on different days to compare the inhibition of gastrin and acid secretion. Compared to noninfected subjects, asymptomatic individuals infected withH. pylori had significantly increased: (1) basal gastrin values (P<0.005); (2) 8% peptone-stimulated gastrin responses at both pH 7.0 and 2.5 (P<0.05); and (3) 8% peptone-stimulated acid output at pH 2.5 (P=0.01). During the second hour of peptone-stimulation, subjects infected withH. pylori had significantly decreased inhibition of gastrin (52% vs 95%) (P=0.002) and acid (30% vs 81%) (P=0.01) secretion from pH 7.0 to 2.5. Thus, chronic infection withH. pylori results in impaired inhibition of gastrin and acid secretion at low intragastric pH during the second hour of peptone meal stimulation. These defects may be unrelated to the pathogenesis of acid-peptic disease, since they occur in asymptomatic subjects infected withH. pylori.Work supported in part by Veterans Affairs Medical Research Funds. Dr. Tarnasky was recipient of a 1990 Research Fellowship stipend sponsored by the American Gastroenterological Association.Work presented in part at the annual meeting of the American Gastroenterological Association in New Orleans, Louisiana (May 20, 1991), and published in abstract form (Gastroenterology 100:A845, 1991).     

Effect of menstrual cycle on HIV-1 levels in the peripheral blood and genital tract. WHS 001 Study Team

OBJECTIVE: To assess the variation in HIV-1 over the menstrual cycle, including RNA levels in the female genital tract, plasma HIV-1-RNA levels, CD4 cell counts, and culturable virus. DESIGN: A prospective analysis of 55 HIV-1-infected women. METHODS: Blood and genital tract specimens were collected weekly over 8 weeks, spanning two complete menstrual cycles. Applying repeated-measures models that used menses as the reference level, the variation in viral RNA levels was compared in endocervical canal fluid and cells (collected by Sno-strips and cytobrush, respectively) and ectocervicovaginal lavage (CVL) fluid. Repeated-measures models were also used to assess the variation in plasma CD4 cell counts and viral load. RESULTS: Shedding patterns differed among the three sampling methods, independent of genital tract co-infections. Genital tract HIV-1-RNA levels from CVL fluid and endocervical canal cytobrush specimens were highest during menses and lowest immediately thereafter (P = 0.001 and P = 0.04). The HIV-1-RNA level in endocervical canal fluid was highest in the week preceding menses (P = 0.003). The menstrual cycle had no effect on blood levels of RNA (P = 0.62), culturable virus (P = 0.34), or CD4 cell counts (P = 0.55). HIV-1-RNA levels were higher in endocervical canal fluid than in peripheral blood plasma during the late luteal phase (P = 0.03). CONCLUSION: HIV-1-RNA levels vary with the menstrual cycle in the female genital tract but not the blood compartment. HIV-1-RNA levels are higher in endocervical canal fluid than in blood plasma. These findings may have important implications for sex-specific pathogenesis, heterosexual transmission, and contraceptive hormone interventions in HIV-1-infected women.     

Physical Functioning,Mental Health,and Quality of Life in Different Congenital Heart Defects: Comparative Analysis in 3538 Patients From 15 Countries

BackgroundWe compared physical functioning, mental health, and quality of life (QoL) of patients with different subtypes of congenital heart disease (CHD) in a large international sample and investigated the role of functional class in explaining the variance in outcomes across heart defects.MethodsIn the cross-sectional Assessment of Patterns of Patient-Reported Outcome in Adults with Congenital Heart Disease-International Study (APPROACH-IS), we enrolled 4028 adult patients with CHD from 15 countries. Diagnostic groups with at least 50 patients were included in these analyses, yielding a sample of 3538 patients (median age: 32 years; 52% women). Physical functioning, mental health, and QoL were measured with the SF-12 health status survey, Hospital Anxiety and Depression Scale (HADS), linear analog scale (LAS) and Satisfaction with Life Scale, respectively. Functional class was assessed using the patient-reported New York Heart Association (NYHA) class. Multivariable general linear mixed models were applied to assess the relationship between the type of CHD and patient-reported outcomes, adjusted for patient characteristics, and with country as random effect.ResultsPatients with coarctation of the aorta and those with isolated aortic valve disease reported the best physical functioning, mental health, and QoL. Patients with cyanotic heart disease or Eisenmenger syndrome had worst outcomes. The differences were statistically significant, above and beyond other patient characteristics. However, the explained variances were small (0.6% to 4.1%) and decreased further when functional status was added to the models (0.4% to 0.9%).ConclusionsSome types of CHD predict worse patient-reported outcomes. However, it appears that it is the functional status associated with the heart defect rather than the heart defect itself that shapes the outcomes.     

Transformation of human androgen receptors to the deoxyribonucleic acid-binding state

The transformation of [3H]dihydrotestosterone-androgen receptor complexes to the nuclear binding state was studied in fibroblasts cultured from human genital skin, using binding of the androgen-receptor complex to DNA-cellulose as a measure of transformation. Transformation of cytosolic dihydrotestosterone-receptor complexes proceeded slowly at 0 C, and heating to 25 C caused rapid transformation that was essentially complete within 15 min. Sodium molybdate (up to 10 mM) slowed the rate of transformation in a concentration-dependent fashion; low concentrations of molybdate (0.5-1 mM) prevented transformation at 0 C, but transformation of up to 70% of the total cytosolic hormone-receptor complexes could be achieved in the presence of high concentrations of molybdate by appropriately prolonged heating at 25 C. Molybdate appeared to exhibit a dual effect, increasing the total amount of androgen-receptor complex recoverable in cytosol and prolonging the time course of heat-induced transformation. Treatment of cytosolic dihydrotestosterone-receptor complexes with 0.5 M NaCl caused a degree of transformation similar to that seen after heat treatment but was unaffected by 10 mM molybdate. Transformation was accompanied by disappearance of the 7S form of the receptor on sucrose density gradients, but there was no reciprocal increase in a smaller size binding moiety on low ionic strength sucrose density gradients. The heat-transformed receptor could be detected, however, as a 3S binding peak on gradients containing 0.3 M NaCl, suggesting that transformation was accompanied by a structural alteration of the hormone-receptor complex.     

Zidovudine in patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. A phase II randomized, placebo-controlled trial

STUDY OBJECTIVE: To evaluate the toxicity, effects on immune function, antitumor effects, antiretroviral effects, and pharmacokinetics of zidovudine therapy in patients with early human immunodeficiency virus (HIV) infection and Kaposi sarcoma. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: National Institutes of Health, a referral-based research institution (single site). PATIENTS: Physician-referred volunteer patients with HIV infection, Kaposi sarcoma, CD4+ lymphocyte counts greater than 0.2 x 10(9)/L, and no systemic symptoms or history of opportunistic infection. Of 41 patients enrolled, 4 had not met all entry criteria and were therefore not evaluable. INTERVENTIONS: Patients were randomized to one of four treatment groups for an initial 12-week treatment period: oral placebo (9 patients); zidovudine, 250 mg orally every 4 hours (9 patients); zidovudine, 0.5 mg/kg body weight intravenously every 4 hours (9 patients); and zidovudine, 2.5 mg/kg intravenously every 4 hours (10 patients). After at least 12 weeks of therapy at their assigned dose, patients were treated with oral zidovudine, generally 250 mg every 4 hours, with a mean 42-week follow-up. MEASUREMENTS AND MAIN RESULTS: Anemia and granulocytopenia were the major toxicities. Significant increases in platelet counts and declines in serum HIV antigen and IgG and IgM levels occurred in treated patients. Treated patients were more likely than those on placebo to clear HIV from the cerebrospinal fluid. There were no differences in tumor progression or CD4+ or CD8+ lymphocyte counts among the groups. CONCLUSIONS: Zidovudine was well tolerated and had antiretroviral activity in patients with early HIV infection and Kaposi sarcoma but it had no significant effect on the extent of Kaposi sarcoma or on immune function.     

The relationship between virus load response to highly active antiretroviral therapy and change in CD4 cell counts: A report from the Women's interagency HIV study

The relationship between the pattern of virus load response to highly active antiretroviral therapy (HAART) and CD4 lymphocyte response was assessed in a cohort of 249 human immunodeficiency virus (HIV) type 1-infected women at 3 times: 1 before and 2 after initiation of therapy, with follow-up of 6-12 months. Patients with a durable response to HAART (i.e., >1 log decrease in HIV-1 RNA sustained for the study periods) had a continuous and significant increase in CD4 cell counts over time, whereas those with no response (<0.5 log decrease in HIV-1 RNA) had a slight decline. Patients with a mixed response (initial decrease >1 log, followed by a subsequent decrease <0.5 log) had an increase in CD4 cell count, followed by a plateau. The trend in CD4 cell count differed significantly by response to HAART, with those patients who experienced a durable response having significantly higher CD4 cell counts than others.     

Effect of Gamma Knife Radiosurgery on a Pituitary Gonadotroph Adenoma: A Histologic,Immunohistochemical and Electron Microscopic Study

The morphologic findings in a pituitary macroadenoma removed from a 65-year old man by the transsphenoidal approach 9 months after gamma knife surgery are reported. The tumor was immunoreactive for FSH and showed ultrastractural features consistent with an oncocytic gonadotroph adenoma. Accumulation of connective tissue separating small groups of adenoma cells was evident. Several dilated vessels and numerous vascular endothelial growth factor immunopositive adenoma cell were noted. By electron microscopy the endothelial linings frequently showed discontinuities with platelet accumulation attached to the gaps. Several vessels were severely injured showing necrosis of endothelial cells. It can be concluded that gamma knife surgery caused severe alterations in pituitary adenoma microcirculation indicating that vascular injury plays a crucial role in tumor shrinkage.     

Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults

Multifocal cerebral microhemorrhages (CMHs, also known as “cerebral microbleeds”), which are associated with rupture of small intracerebral vessels, have been recognized as an important cause for cognitive decline in older adults. Although recent studies demonstrate that CMHs are highly prevalent in patients 65 and older, many aspects of the pathogenesis and clinical significance of CMHs remain obscure. In this longitudinal observational study, a case of a 77-year-old man with multifocal CMHs is described, in whom the rupture of intracerebral vessels could be linked to repeatedly performing extended Valsalva maneuvers. This patient was initially seen with acute aphasia after performing a prolonged Valsalva maneuver during underwater swimming. T2-weighted magnetic resonance imaging revealed a left acute frontal intracerebral hemorrhage (ICH) with multiple CMHs. The aphasia was resolved and no cognitive impairment was present. Two years later, he developed unsteadiness and confusion after performing two prolonged Valsalva maneuvers during underwater swimming separated by about 12 days. Repeat brain imaging revealed an acute right and a subacute left ICH, with a marked interval increase in the number of CMHs. The patient also exhibited manifest memory loss after the second admission and was diagnosed with dementia. These observations suggest that prolonged Valsalva maneuver is potentially a common precipitating cause of both CMHs and symptomatic ICHs. The Valsalva maneuver both increases the systolic arterial pressure and gives rise to a venous pressure wave transmitted to the brain in the absence of the competent antireflux jugular vein valves. This pressure increase is superimposed on existing hypertension and/or increases in blood pressure due to exercise and increased venous return due to immersion of the body in water. We advocate that further studies are needed to distinguish between CMHs with arterial and venous origins and their potential to lead to ICH induced by Valsalva maneuver as well as to determine whether these lesions have a predilection for a particular location.