Literacy,Social Stigma,and HIV Medication Adherence

BACKGROUND  Prior studies have linked limited literacy to poorer HIV medication adherence, although the precise causal pathways of this relationship have only been initially investigated. OBJECTIVE  To examine whether social stigma is a possible mediator to the relationship between literacy and self-reported HIV medication adherence. DESIGN  Structured patient interviews with a literacy assessment, supplemented by medical chart review, were conducted among patients receiving care at infectious disease clinics in Shreveport, Louisiana and Chicago, Illinois. Literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), while stigma was measured using items taken from the Patient Medication Adherence Questionnaire (PMAQ). PARTICIPANTS  Two hundred and four consecutive patients participated. RESULTS  Approximately one-third of the patients (30.4%) were less than 100% adherent to their regimen, and 31.4% had marginal (7th–8th grade) or low (≤ 6th grade) literacy. In multivariate analyses, patients with low literacy were 3.3 times more likely to be non-adherent to antiretroviral regimens (95% CI 1.3–8.7; p < 0.001). Perceived social stigma was found to mediate the relationship between literacy and medication adherence (AOR 3.1, 95% CI 1.3–7.7). CONCLUSIONS  While low literacy was a significant risk factor for improper adherence to HIV medication regimens in our study, perceived social stigma mediated this relationship. Low literacy HIV intervention strategies may also need to incorporate more comprehensive psychosocial approaches to overcome stigma barriers.     

Micropatterning of costimulatory ligands enhances CD4+ T cell function

Spatial organization of signaling complexes is a defining characteristic of the immunological synapse (IS), but its impact on cell communication is unclear. In T cell–APC pairs, more IL-2 is produced when CD28 clusters are segregated from central supramolecular activation cluster (cSMAC)-localized CD3 and into the IS periphery. However, it is not clear in these cellular experiments whether the increased IL-2 is driven by the pattern itself or by upstream events that precipitate the patterns. In this article, we recapitulate key features of physiological synapses using planar costimulation arrays containing antibodies against CD3 and CD28, surrounded by ICAM-1, created by combining multiple rounds of microcontact printing on a single surface. Naïve T cells traverse these arrays, stopping at features of anti-CD3 antibodies and forming a stable synapse. We directly demonstrate that presenting anti-CD28 in the cell periphery, surrounding an anti-CD3 feature, enhances IL-2 secretion by naïve CD4⁺ T cells compared with having these signals combined in the center of the IS. This increased cytokine production correlates with NF-κB translocation and requires PKB/Akt signaling. The ability to arbitrarily and independently control the locations of anti-CD3 and anti-CD28 offered the opportunity to examine patterns not precisely attainable in cell–cell interfaces. With these patterns, we show that the peripheral presentation of CD28 has a larger impact on IL-2 secretion than CD3 colocalization/segregation.     

A target site for template-based design of measles virus entry inhibitors

Measles virus (MV) constitutes a principal cause of worldwide mortality, accounting for almost 1 million deaths annually. Although a live-attenuated vaccine protects against MV, vaccination efficiency of young infants is low because of interference by maternal antibodies. Parental concerns about vaccination safety further contribute to waning herd immunity in developed countries, resulting in recent MV outbreaks. The development of novel antivirals that close the vaccination gap in infants and silence viral outbreaks is thus highly desirable. We previously identified a microdomain in the MV fusion protein (F protein) that is structurally conserved in the paramyxovirus family and constitutes a promising target site for rationally designed antivirals. Here we report the template-based development of a small-molecule MV inhibitor, providing proof-of-concept for our approach. This lead compound specifically inhibits fusion and spread of live MV and MV glycoprotein-induced membrane fusion. The inhibitor induces negligible cytotoxicity and does not interfere with receptor binding or F protein biosynthesis or transport but prevents F protein-induced lipid mixing. Mutations in the postulated target site alter viral sensitivity to inhibition. In silico docking of the compound in this microdomain suggests a binding model that is experimentally corroborated by a structure-activity analysis of the compound and the inhibition profile of mutated F proteins. A second-generation compound designed on the basis of the interaction model shows a 200-fold increase in antiviral activity, creating the basis for novel MV therapeutics. This template-based design approach for MV may be applicable to other clinically relevant members of the paramyxovirus family.     

Effects of age on responses to isometric exercise. Isometric handgrip in noninvasive screening for cardiovascular disease.

Isometric handgrip (IHG) imposes an acutely increased afterload on the left ventricle. Utilizing systolic time intervals, we studied various responses to IHG, measured as changes from resting values with near-maximum IHG, in old normal (ON) subjects, young normal (YN) subjects, and old patients with hypertensive heart disease (HHD) and patients with coronary artery disease (CAD). There were no differences in responses to IHG between ON and patients with HHD or patients with CAD. However, there were clear differences between the responses of ON and YN subjects. Increase in heart rate (HR) was much more prominent in YN (ON vs. YN = +11.6 +/- 2.6 vs. +15.6 +/- 5.7 beats per minute p less than 0.001). Pre-ejection period (PEP) end isovolumic contraction time (IVCT) increased in ON but decreased in YN (PEP + 6.2 +/- 1.7 vs. -11.0 +/- 3.7 msec., p less than 0.001; IVCT +8.1 +/- 2.2 vs. -13.8 +/- 3.4 msec., p less than 0.001. Shortening of LVET was much more marked in YN (-6.5 +/- 4.1 VS. -63.3 +/- 9.9 msec. p less than 0.001), but this was entirely due to the HR differences since there was no difference in ejection time index (+ 5.1 +/- 3.4 vs. -0.4 +/- 7.3 msec. p greater than 0.5). IHG produced no significant differences between ON and YN in the timing of the "mitral" component of the first heart sound (q-Im), in the ratio PEP/LVET, or in pulse transmission time (PTT). By contrast, resting control PTT was markedly short in ON, especially those with CAD. Resting PTT in ON was 27.1 +/- 2.6 msec.; in YN 43.7 +/- 1.4 msec.; in CAD patients 20.7 +/- 1.3 msec. We conclude that even near-maximal IHG does not seem to be an adequate noninvasive screening test for cardiovascular disease in that age alone seems to have the most significant influence on the responses.     

Mechanism of the effect of coronary artery stenosis on coronary flow in the dog

The hemodynamic mechanism of the effect of coronary artery stenosis on coronary flow was studied in the circumflex artery of 10 open-chest dogs by simultaneously measuring coronary flow, aortic pressure, and coronary artery pressure distal to an adjustable constrictor; while the distal coronary bed was intermittently maximally vasodilated by intracoronary injections of angiographic contrast media (Hypaque-M, 75 per cent). For each stenosis, the pressure gradient across the stenosis varied directly with the flow through the stenosis (r = 0.99), the slope of the regression indicating the severity of the stenosis. An important observation was that this regression line did not intercept the flow axis at zero flow, but at a positive flow, meaning that for a given regression line slope the pressure gradient was much less than expected. At rest, distal bed resistance decreased as progressive stenosis lowered the distal bed pressure, maintaining flow at control level until the distal bed pressure dropped below 60 mm. Hg. However, at maximum hyperemia, distal bed resistance was at a fixed minimum value such that flow was directly proportional to distal bed pressure. Hence, progressive stenosis decreased the ratio of hyperemic to resting flow by: (1) causing the vasodilatory reserve to be used to maintain resting flow, decreasing that available for hyperemia, and (2) dropping the distal bed pressure relatively more for smaller increases in flow. This study provides a hemodynamic explanation for the known fact that progressive stenosis initially limits the maximum hyperemic flow, and only after this flow is decreased almost to resting level, does resting flow fall.     

Physiological responses to prompt and sustained squatting. Measurement by systolic time intervals.

Ten healthy men, ages 22 to 35, were studied non-invasively standing (control), at the onset of squatting ('prompt squat'), and at two minutes of squatting. Squatting produced decreases in heart rate, isovolumic contraction time, pre-ejection period, and pulse transmission time from onset of depolarisation to the first heart sound, left ventricular ejection time, and the ejection time index. These results of systolic time intervals are consistent with the bradycardia and increased ventricular filling induced by squatting. Major changes from control measurements were found at the onset of squatting, showing the impact of prompt squat of left ventricular performance.     

The Potential Application of Mitochondrial Medicine in Toxicologic Poisoning

The advancement of biomolecular techniques has continued to advance in the area of mitochondrial medicine. This has allowed clinicians and researchers to more effectively study the bioenergetics of the mitochondria in various disease states. One potential technique in mitochondrial medicine is the generation of cytoplasmic hybrids. A cytoplasmic hybrid or cybrid are created by introducing mitochondrial DNA (mtDNA) of interest into cells depleted of mtDNA. A cybrid is therefore a hybrid cell that mixes the nuclear genome from one cell with the mitochondrial genes from another cell. Cybrids are currently utilized in mitochondrial research to demonstrate mitochondrial involvement in a wide range of diseases that include diabetes, Parkinson’s disease and inherited diseases. At this time the use of cybrids to study toxicologic poisoning is limited and offers a potential avenue of research in this area.     

Impact of calcium entry blockers on glomerular injury in experimental hypertension

Summary A major problem for patients with kidney disease and their physicians is that most chronic renal diseases progress to global glomerular sclerosis and end-stage renal failure. Studies in experimental models of hypertension and renal insufficiency have advanced our understanding of the pathogenesis of progressive kidney damage. In a number of settings, sclerosis has been related to the presence of intrarenal hypertension, a consequence of the hemodynamic adaptation to a reduction in the number of functioning nephrons. A growing body of evidence also supports the hypothesis that kidney and glomerular hypetrophy constitute an independent risk factor for glomerular sclerosis. Recent studies suggest that calcium antagonists can reduce glomerular injury in experimental hypertension. Renal protection may be related to the ability of these agents to inhibit compensatory renal growth.