Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy

OBJECTIVE: To examine the independent association of discordant virologic and immunologic responses to highly active antiretroviral therapy (HAART) with mortality. METHODS: A population-based study of 1527 treatment-naive individuals initiating HAART used Cox proportional hazards modeling to determine the independent association of treatment response at 3 to 9 months with nonaccidental mortality. Logistic regression was used to examine associations with discordant responses. RESULTS: Viral load (VL)/CD4 discordant responses were seen in 235 (15.4%) of subjects, and VL/CD4 responses were seen in 179 (11.7%) of subjects. In adjusted Cox regression models, discordant responses were found to be independently associated with an increased risk of mortality (VL/CD4: relative hazard [RH] = 1.87, 95% confidence interval [CI]: 1.15 to 3.04; VL/CD4: RH = 2.47, 95% CI: 1.54 to 3.95). VL/CD4 discordance was found to be associated with increasing age, baseline HIV RNA load <100,000 copies/mL, baseline CD4 counts <50 cells/muL, the use of lamivudine (3TC)/zidovudine (ZDV), and poor adherence to therapy. VL/CD4 discordance was associated with younger age; injection drug use; baseline HIV RNA load >100,000 copies/mL; the use of 3TC/ZDV, didanosine (ddI)/3TC, or ddI/stavudine; and poor adherence to therapy. CONCLUSION: Discordant responses are independently associated with an increased risk of mortality and are, in turn, associated with poor adherence to therapy.     

Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material

The expression and cellular localization of angiotensin II (Ang II) and AT(1) receptor proteins were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by immunohistochemistry. In the normal prostate, Ang II immunoreactivity was localized to the basal layer of the epithelium and AT(1) receptor immunostaining was found predominantly on stromal smooth muscle and also on vascular smooth muscle of prostatic blood vessels. Ang II immunoreactivity was markedly increased in hyperplastic acini in BPH compared with acini in the normal prostate (normal: 7.4+/-0.2%, n=5 vs. BPH: 22.7+/-1.9%, n=5, p<0.001). However, AT(1) receptor immunoreactivity was significantly decreased in BPH compared with the normal prostate [normal: 16.4+/-2.2%, n=4 vs. BPH: 9.4+/-1.3%, n=5, p<0.05 (p=0.025)]. The present study demonstrates the presence of Ang II peptide in the basal layer of the epithelium and AT(1) receptors on stromal smooth muscle, suggesting that Ang II may mediate paracrine functions on cellular growth and smooth muscle tone in the human prostate. Furthermore, AT(1) receptor down-regulation in BPH may be due to receptor hyperstimulation by increased local levels of Ang II in BPH. These data extend previous findings in support of the novel concept that overactivity of the renin-angiotensin system (RAS) may be involved in the pathophysiology of BPH.     

NCAM in developing mouse gonads and ducts

Summary The expression of theNeuralCell AdhesionMolecule, NCAM, in mouse gonads and ducts was studied from fetal life to maturity. The methods used were immunocytochemical staining and Western blotting. The immunocytochemical studies showed that the only structures that remain NCAM-positive throughout life were the mesonephric-derived rete ovarii and rete testis. Also in the fetal gonads some somatic cell lining the groups of differentiating germ cells were stained. In the immature as well as in the mature ovary the granulosa cells and oocytes of growing and large follicles — but not of small follicles — were stained. A particularly strong staining of the cytoplasm of the oocyte, healthy as well as atretic, was seen. All cells of the testis remained negative except for weakly stained residual bodies and late spermatids. At all ages the male ducts showed only weak staining, whereas in the female Müllerian duct the epithelium became strongly positive at puberty. The stroma of the Müllerian duct was positive during a transitory period around day 16 of fetal life in both sexes. One-dimensional gel immunoblotting of total protein from gonads, rete and ducts from immature and mature mice showed that only the two largest isoforms of NCAM (NCAM-A and NCAM-B) were present. The gonads and the rete of both sexes and the adult uterus expressed only NCAM-B, whereas NCAM-A was also detected in the adult epididymis. The present findings suggest that NCAM may be involved in the normal development and formation of both the gonads and ducts. In particular, NCAM may play a part in sustaining the integrity of the rete testis, thus ensuring the pathway for spermatozoa from the testis to the epididymis. Furthermore this cell adhesion molecule may also be important for follicular growth and differentiation.     

Electrophysiological analysis of a sensorimotor integration task

The present experiment aimed at investigating electrophysiologic changes observed as beta band asymmetry, by Quantitative Electroencephalography (qEEG), when individuals performed a reaching motor task (catching a ball in free fall). The sample was composed of 23 healthy individuals, of both sexes, with ages varying between 25 and 40 years old. All the subjects were right handed. A two-way ANOVA was applied for the statistical analysis, to verify the interaction between task moment (i.e., 2 s before and 2 s after ball's fall) and electrode (i.e., frontal, central and temporal regions). The first analysis compared electrodes placed over the somatosensory cortex. Central sites (C3–C4) were compared with temporal regions (T3–T4). The results showed a main effect for moment and position. The second analysis was focused over the premotor cortex, which was represented by the electrodes placed on the frontal sites (F3–F4 versus F7–F8), and a main effect was observed for position. Taken together, these results show a pattern of asymmetry in the somatosensory cortex, associated with a preparatory mechanism when individuals have to catch an object during free fall. With respect to task moment, after the ball's fall, the asymmetry was reduced. Moreover, the difference in asymmetry between the observed regions were related to a supposed specialization of areas (i.e., temporal and central). The temporal region was associated with cognitive processes involved in the motor action (i.e., explicit knowledge). On the other hand, the central sites were related to the motor control mechanisms per se (i.e., implicit knowledge). The premotor cortex, represented by two frontal regions (i.e., F3–F4 versus F7–F8), showed a decrease on neural activity in the contralateral hemisphere (i.e., to the right hand). This result is in agreement with other experiments suggesting a participation of the frontal cortex in the planning of the apprehension task. This sensorimotor paradigm may contribute to the repertoire of tasks used to study clinical conditions such as depression, alzheimer and Parkinson diseases.     

Melosis in holocentric chromosomes: Kinetic activity is randomly restricted to the chromatid ends of sex univalents inGraphosoma italicum (Heteroptera)

We have determined the number and location of the nucleolar organizing regions in spermatocytes ofGraphosoma italicum (2n=12A+ XY/XX) by means of silver impregnation, chromomycin A₃/distamycin A staining and fluorescencein situ hybridization. The identification of only one nucleolar organizing region located at one of the X chromosome ends has provided a suitable cytological marker to analyse the segregation of this univalent and that of the XY pseudobivalent during the first and second meiotic divisions respectively. Our results clearly show that at first meiotic metaphase the chromatids of the X chromosome are orientated with their long axes perpendicular to the polar axis. Although the kinetic activity is restricted to only one end in both X chromatids during the first meiotic division, both ends of the same chromatid have the same probability of showing such kinetic activity. In this sense, we also report that the chromatid segregation maybe initiated either at the same sister chromatid ends or at opposite ends in each chromatid. Thus, this indicates a sex chromatid independence as regards to the chromatid segregation during the first meiotic division. Throughout the second meiotic division both ends of the X chromatid are involved with the same probability in the end-to-end association to conform the XY pseudobivalent. This also implies a random localization of the kinetic activity at the ends opposite to those involved in the end-to-end association.accepted for publication by J. S. (Pat) Heslop-Harrison     

Effect of cysteamine on cytosolic somatostatin binding sites in rabbit duodenal mucosa

Administration of cysteamine in rabbits elicited a rapid depletion of both duodenal mucosa and plasma somatostatin. A significant reduction was observed within 5 min, returning toward control values by 150 min. The depletion of somatostatin was associated with an increase in the binding capacity and a decrease in the affinity of both high- and low-affinity binding sites present in cytosol of duodenal mucosa. Incubation of cytosolic fraction from control rabbits with 1 mM cysteamine did not modify somatostatin binding. Furthermore, addition of cysteamine at the time of binding assay did not affect the integrity of 125I-Tyr11-somatostatin. It is concluded that in vivo administration of cysteamine to rabbits depletes both duodenal mucosa and plasma somatostatin and leads to up-regulation of duodenal somatostatin binding sites.     

Effect of challenge method on sensitivity, reactivity, and maximal response to methacholine.

BACKGROUND: Recent data suggest that the tidal breathing method may produce methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20) values significantly lower than the dosimeter method; however, the effect of the challenge method on the shape of the concentration-response curve has not been investigated. OBJECTIVE: To determine the effect of the challenge method on sensitivity, reactivity, and maximal response to methacholine. METHODS: We measured airway responsiveness to methacholine using dosimeter and tidal breathing methods in 30 individuals with suspected asthma. Concentration-response curves were characterized by their PC20 (sensitivity), slope (reactivity), and, if possible, level of plateau. RESULTS: Dosimeter PC20 values were significantly higher than tidal breathing values (geometric mean, 8.9 and 5.2 mg/mL, respectively); the mean difference in PC20 values obtained using each method was 0.78 doubling concentrations (P = .01). The mean slopes were 22.7%/log mg/mL using the tidal breathing method and 24.9%/log mg/mL using the dosimeter method; the mean difference in the slopes obtained using each method was -2.17%/log mg/mL (P = .18). In 10 individuals who showed a plateau with the 2 methacholine challenge tests, the mean level of plateau was 19.8% using the tidal breathing method and 19.5% using the dosimeter method; the mean difference in the plateau values obtained with each method was 0.3% (P = .87). CONCLUSIONS: Although the tidal breathing method produces methacholine PC20 values significantly lower than the dosimeter method, both methods provide similar values for slope and level of plateau. These results suggest that the technical factors that affect methacholine sensitivity and the shape of the curve are different.     

Aboriginal status is a prognostic factor for mortality among antiretroviral naïve HIV-positive individuals first initiating HAART

Background  

Although the impact of Aboriginal status on HIV incidence, HIV disease progression, and access to treatment has been investigated previously, little is known about the relationship between Aboriginal ethnicity and outcomes associated with highly active antiretroviral therapy (HAART). We undertook the present analysis to determine if Aboriginal and non-Aboriginal persons respond differently to HAART by measuring HIV plasma viral load response, CD4 cell response and time to all-cause mortality.