Measuring ART Adherence Among Young Adults with Perinatally Acquired HIV: Comparison Between Self-report, Telephone-Based Pill Count, and Objective Pharmacologic Measures.

Tenofovir diphosphate (TVF-DP) can be quantified in red blood cells (RBCs) and dried blood spots (DBS) and can objectively measure ART adherence and predict viral suppression. Data on the association of TFV-DP with viral load are very limited in adolescents and young adults (AYA) living with perinatally-acquired HIV (PHIV), as are data comparing TFV-DP to other measures of ART adherence, such as self-report and unannounced telephone pill count. Viral load and ART adherence (self-report, TFV-DP and unannounced telephone pill count) were assessed and compared among 61 AYAPHIV recruited from an ongoing longitudinal study (CASAH) in New York City.

Longitudinal trajectories of neurocognitive test performance among individuals with perinatal HIV-infection and -exposure: adolescence through young adulthood.

There are an estimated 2.1 million youth less than 15 years of age living with HIV globally (the majority perinatally HIV-infected [PHIV]) and millions more perinatally HIV-exposed uninfected (PHEU) youth who are expected to survive through adolescence and into adulthood. Transitioning from adolescence to young adulthood requires adaptation to more demanding social interactions, academic pressures, and individual responsibilities which place distinct demands on neurocognitive functions. This study examined longitudinal trajectories of neurocognitive test performance in the domains of processing speed (PS), working memory (WM), and executive functioning (EF) among PHIV and demographically similar PHEU from adolescence through young adulthood. Data for this paper come from four time points, spanning approximately 10 years, within the Child and Adolescent Self-Awareness and Health Study (CASAH). Youth age ranged from 15 to 29 years. Longitudinal linear mixed effect models were computed for each test. Few differences in performance were found on tests of EF and WM between PHIV and PHEU youth as they aged, though PHEU youth showed significantly better PS as they aged than PHIV youth. Future research is needed to understand these vulnerable youth's neurocognitive trajectories as a function of HIV infection and -exposure, biological functions and psychosocial stressors.

Patterns of a Rectal Microbicide Placebo Gel Use in a Preparatory Stage for a Phase I Trial Among Young Men Who Have Sex with Men.

We examined young gay, bisexual, and other men who have sex with men's (YGBMSM) usage patterns of a pre-coital, applicator-administered rectal placebo gel. An ethnically diverse sample of 94 YGBMSM (aged 18-30 years) were asked to insert hydroxyethylcellulose placebo gel rectally before receptive anal intercourse (RAI) and report their gel use through an interactive voice response system (IVRS) across 12 weeks. We used trajectory analyses to characterize participants' use of the rectal gel over the 12 weeks, and examine whether these trajectories varied based on participants' sociodemographic characteristics, sexual behaviors, application and insertion behaviors, and experiences using the placebo gel. A cubic model was the best fit for these longitudinal data, with two distinct trajectories of gel use observed. The first trajectory ('High with Varying Gel Use per Week') represented YGBMSM (N = 38; 40.3%) who reported using the rectal gel on several occasions per week. The second trajectory ('Low and Consistent Gel Use per Week') represented participants (N = 56; 59.7%) who reported a consistent average use of one gel per week. Participants in the High with Varying Gel Use Trajectory reported trying out a greater number of positions when inserting the gel across the 12-weeks than peers in the Low and Consistent Gel Use Trajectory. YGBMSM reporting more RAI occasions during the trial were more likely be present in the High with Varying Gel Use Trajectory than peers in the Low and Consistent Gel Use Trajectory. Future research examining how to facilitate gel application and adherence among YGBMSM is merited.

Changes in Substance Use Symptoms Across Adolescence in Youth Perinatally Infected with HIV.

The paper utilizes data collected at three time points in a longitudinal study of perinatally HIV-infected (PHIV+) and a comparison group of perinatally exposed but HIV-uninfected (PHEU) youths in the United States (N = 325). Using growth curve modeling, the paper examines changes in substance use symptoms among PHIV+ and PHEU youths as they transition through adolescence, and assesses the individual and contextual factors associated with the rate of change in substance use symptoms. Findings indicate that substance use symptoms increased over time among PHIV+ youths, but not among PHEU youths. The rate of change in these symptoms was positively associated with an increasing number of negative life events. Study findings underscore the need for early, targeted interventions for PHIV+ youths, and interventions to reduce adversities and their deleterious effects in vulnerable populations.

Emtonjeni-A Structural Intervention to Integrate Sexual and Reproductive Health into Public Sector HIV Care in Cape Town, South Africa: Results of a Phase II Study.

Integration of sexual and reproductive health within HIV care services is a promising strategy for increasing access to family planning and STI services and reducing unwanted pregnancies, perinatal HIV transmission and maternal and infant mortality among people living with HIV and their partners. We conducted a Phase II randomized futility trial of a multi-level intervention to increase adherence to safer sex guidelines among those wishing to avoid pregnancy and adherence to safer conception guidelines among those seeking conception in newly-diagnosed HIV-positive persons in four public-sector HIV clinics in Cape Town. Clinics were pair-matched and the two clinics within each pair were randomized to either a three-session provider-delivered enhanced intervention (EI) (onsite contraceptive services and brief milieu intervention for staff) or standard-of-care (SOC) provider-delivered intervention. The futility analysis showed that we cannot rule out the possibility that the EI intervention has a 10 % point or greater success rate in improving adherence to safer sex/safer conception guidelines than does SOC (p = 0.573), indicating that the intervention holds merit, and a larger-scale confirmatory study showing whether the EI is superior to SOC has merit.

Behavioral Outcomes of a Pragmatic Early Childhood Caries Management Trial.

OBJECTIVES: To evaluate a preventative behavioral intervention for managing early childhood caries (ECC) in a cohort of high-risk children. METHODS: This pragmatic trial of the MySmileBuddy Program (MSB) evaluated preventive behavioral outcomes in a 1-y community health worker-delivered intervention to prevent ECC progression. Pre-/postintervention surveys assessed parent-reported child engagement in therapeutic toothbrushing (i.e., adult-assisted brushing with fluoridated toothpaste twice daily) and caries-related dietary behaviors and barriers. Generalized linear model with identity link for continuous variables and logit link for dichotomous outcomes evaluated pre-/postintervention comparisons and generalized estimating equations accounted for within-participant correlation (α = 0.05). RESULTS: Among 1,130 children with postintervention data, the average age was 3.97 y, 99% were Medicaid insured, and 88% were Hispanic. Most parents (95%) were mothers/grandmothers, married or in a committed partnership (75%), unemployed (62%), and with modest education (80% high school degree or less). The odds of reported therapeutic brushing nearly doubled (n = 864; odds ratio [OR] = 1.79, 95% confidence interval [CI] = 1.46, 2.20, P < 0.001); day and night bottle/sippy cup frequencies dropped 0.29 units (n = 871; 95% CI = -0.37, -0.33, P < 0.001) and 0.22 units (n = 1,130; 95% CI = -0.30, -0.15, P < 0.001); nighttime breastfeeding reduced 0.15 units (n = 870; 95% CI = -0.21, -0.10, P < 0.001); sharing utensils reduced 0.30 units (n = 572; 95% CI = -0.39, -0.21, P < 0.001); not using sugary foods to calm child improved 0.37 units (n = 664; 95% CI = 0.31, 0.44, P < 0.001); odds of eating meals and snacks at a table increased (n = 572; OR = 1.57, 95% CI = 1.28, 1.93, P < 0.001; n = 572; OR = 1.80, 95% CI = 1.50, 2.15, P < 0.001) respectively; and reducing barriers to behaviors improved 0.38 units for toothbrushing (n = 666; 95% CI = 0.31, 0.44, P < 0.001) and 0.33 units for diet (n = 668; 95% CI = 0.29, 0.38, P < 0.001). CONCLUSION: Despite limitations inherent to pragmatic trials, significant behavioral changes suggest that MSB yielded an important salutary impact. Forthcoming mediation analyses will explore causal pathways. Findings support integration of MSB's behavior change program in caries management initiatives. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by clinicians, public health leaders, and researchers to inform the development and implementation of community-based, preventative behaviorally focused early childhood caries prevention programs. Study findings may enhance the understanding of the impact of behavioral interventions that engage parents of young children and could lead to more effective prevention for populations at high-risk of caries.

To Use a Rectal Microbicide, First Insert the Applicator: Gel and Applicator Satisfaction Among Young Men Who Have Sex With Men.

We examined how experiences with a rectal placebo gel and applicator used with receptive anal intercourse (RAI) related to young men who have sex with men's (YMSM) likelihood of using a rectal microbicide gel and applicator in the future. An ethnically diverse sample of 95 YMSM (aged 18 to 30 years) were asked to insert hydroxyethylcellulose (HEC) placebo gel rectally before RAI during 12 weeks and report the product's acceptability (i.e., satisfaction with applicator and gel, respectively; perceived gel side effects; and sexual satisfaction when gel was used) and likelihood of future microbicide use. Main and interaction effects predicting future use intentions were tested using linear regression. We found a positive association between future use intentions and applicator satisfaction (b = .33, p < .001). In a subsequent interaction effects model, we found that greater gel satisfaction was associated with increased future use intentions; however, the strength of this relationship was magnified when YMSM reported greatest satisfaction with the rectal applicator. Applicator satisfaction may be a salient factor in YMSM's decision-making to use a rectal microbicide in the future. Although the importance of developing a satisfactory rectal microbicide gel for YMSM is undeniable for its future use, our results also emphasize the importance of developing strategies that increase YMSM's comfort and skill when using a rectal applicator. Future research examining how to optimize the design, properties, and characteristics of a rectal applicator as a strategy to promote greater satisfaction and use among YMSM is merited.

Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway.

Overexpression of epidermal growth factor receptor (EGFR) and establishment of transforming growth factor alpha (TGF alpha)/EGF autocrine system are frequently detected in tumor cells. In addition to mitogenic ability, we demonstrate in this report that EGF protects a human esophageal carcinoma (CE) cell line, CE81T/VGH, from staurosporine-induced apoptosis. The anti-apoptotic signal of EGF is alleviated by a MEK inhibitor PD98059 or an ERK2 dominant negative mutant but not by a phosphatidylinositol-3'-kinase (PI-3K) inhibitor wortmannin. Furthermore, v-raf blocks apoptosis induced by staurosporine. This evidence implies that the survival signal of EGF is mediated via the Raf-MEK-ERK pathway but not the PI3-K pathway. The survival effect of EGF is coincident with the induction of mcl-1, an antiapoptotic gene in the bcl-2 family. PD98059 also suppresses the induction of Mcl-1 by EGF, implying that EGF may up-regulate Mcl-1 via the MAP kinase pathway. Overexpression of mcl-1 is sufficient to protect against apoptosis, while transfection of a mcl-1 antisense plasmid causes cell death. The expression of mcl-1 antisense plasmid also suppresses the anti-apoptotic effect of EGF. Taken together, these results indicate that EGF may up-regulate Mcl-1 through the MAP kinase pathway to suppress apoptosis.

Histomorphometric evidence for echistatin inhibition of bone resorption in mice with secondary hyperparathyroidism.

Echistatin, an RGD-containing peptide, was shown to inhibit the acute calcemic response to exogenous PTH or PTH-related protein (PTH-rP) in thyroparathyroidectomized rats, suggesting that echistatin inhibits bone resorption. In this study: 1) we present histological evidence for echistatin inhibition of bone resorption in mice with secondary hyperparathyroidism, and show that 2) echistatin binds to osteoclasts in vivo, 3) increases osteoclast number, and 4) does not detectably alter osteoclast morphology. Infusion of echistatin (30 microg/kg x min) for 3 days prevented the 2.6-fold increase in tibial cancellous bone turnover and the 36% loss in bone volume, produced by a low calcium diet. At the light microscopy level, echistatin immunolocalized to osteoclasts and megakaryocytes. Echistatin treatment increased osteoclast-covered bone surface by about 50%. At the ultrastructural level, these osteoclasts appeared normal, and the fraction of cells containing ruffled borders and clear zones was similar to controls. Echistatin was found on the basolateral membrane and in intracellular vesicles of actively resorbing osteoclasts. Weak labeling was found in the ruffled border, and no immunoreactivity was detected at the clear zone/bone surface interface. These findings provide histological evidence for echistatin binding to osteoclasts and for inhibition of bone resorption in vivo, through reduced osteoclast efficacy, without apparent changes in osteoclast morphology.

The integrin ligand echistatin prevents bone loss in ovariectomized mice and rats.

Integrins that bind RGD (arginine-glycine-aspartic acid) containing peptides, especially the vitronectin receptor alpha(v)beta3, have been implicated in the regulation of osteoclast function. Echistatin, an RGD-containing snake venom peptide with high affinity for beta3 integrins, as well as nonpeptide RGD mimetics, were shown to inhibit osteoclastic bone resorption in vitro and in vivo. To evaluate the role of RGD-binding integrins in bone metabolism, we examined by several methods the effects of echistatin on ovariectomy (OVX)-induced bone loss in mice and rats. First, we confirmed that echistatin binds in vitro with high affinity (Kd, 0.5 nM) to alpha(v)beta3 integrin purified from human placenta and established a competitive binding assay to measure echistatin concentrations in serum. We find that echistatin infused for 2 or 4 weeks at 0.36 microg/h x g body weight (approximately 50 nmol/day x mouse) completely prevents OVX-induced cancellous bone loss in the distal femora of ovariectomized mice. Echistatin has no effect on uterine weight, body weight, and femoral length changes induced by OVX, nor does it cause any apparent changes in major organs other than bone. In OVX rats, echistatin infusion at 0.26 microg/h x g for 4 weeks effectively prevents bone loss, evaluated by dual energy x-ray absorptiometry of the femur, by femoral ash weight, and by bone histomorphometry of the proximal tibia. At effective serum concentrations of 20-30 nM, measured at the end of the infusion period, echistatin maintains histomorphometric indices of bone turnover at control levels but does not decrease osteoclast surface. In conclusion, these results provide in vivo evidence, at the level of bone histology, that RGD-binding integrins, probably alpha(v)beta3, play a rate-limiting role in osteoclastic bone resorption and suggest a therapeutic potential for integrin ligands in the suppression of bone loss.

Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist.

Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported.

A multivariate method for estimating mortality rates among children under 5 years from health and social indicators in Iraq.

BACKGROUND: Many reports on Iraq suggest that a rise in rates of death and disease have occurred since the Gulf War of January/February 1991 and the economic sanctions that followed it. METHODS: Four preliminary models, based on unadjusted projections, were developed. A logistic regression model was then developed on the basis of six social variables in Iraq and comparable information from countries in the State of the World's Children report. Missing data were estimated for this model by a multiple imputation procedure. The final model depends on three socio-medical indicators: adult literacy, nutritional stunting of children under 5 years, and access to piped water. RESULTS: The model successfully predicted both the mortality rate in 1990, under stable conditions, and in 1991, following the Gulf War. For 1996, after 5 years of sanctions and prior to receipt of humanitarian food via the oil for food programme, this model shows mortality among children under 5 to have reached an estimated 87 per 1000, a rate last experienced more than 30 years ago. CONCLUSIONS: Accurate and timely estimates of mortality levels in developing countries are costly and require considerable methodological expertise. A rapid estimation technique like the one developed here may be a useful tool for quick and efficient estimation of mortality rates among under 5 year olds in countries where good mortality data are not routinely available. This is especially true for countries with complex humanitarian emergencies where information on mortality changes can guide interventions and the social stability to use standard demographic methods does not exist.

Partial agonist/antagonist properties of androstenedione and 4-androsten-3beta,17beta-diol.

Androgens play important endocrine roles in development and physiology. Here, we characterize activities of two "Andro" prohormones, androstenedione (A-dione) and 4-androsten-3beta,17beta-diol (A-diol) in MDA-MB-453 (MDA) and LNCaP cells. A-dione and A-diol, like cyproterone acetate, were partial agonists of transfected mouse mammary tumor virus (MMTV) and endogenous prostate-specific antigen (PSA) promoters. Different from bicalutamide but similar to CPA, both are inducers of LNCaP cell proliferation with only mild suppression of 5alpha-dihydrotestosterone (DHT)-enhanced cell growth. Like bicalutamide and cyproterone acetate, A-dione and A-diol significantly antagonized DHT/R1881-induced PSA expression by up to 30% in LNCaP cells. Meanwhile, in MDA cells, EC(50)s for the MMTV promoter were between 10 and 100nM. Co-factor studies showed GRIP1 as most active for endogenous androgen receptor (AR), increasing MMTV transcription by up to five-fold, without substantially altering EC(50)s of DHT, A-dione or A-diol. Consistent with their transcriptional activities, A-dione and A-diol bound full-length endogenous AR from MDA or LNCaP cells with affinities of 30-70nM, although binding to expressed ligand-binding domain (LBD) was >20-fold weaker. In contrast, DHT, R1881, and bicalutamide bound similarly to LBD or aporeceptor. Together, these data suggest that A-dione and A-diol are ligands for AR with partial agonist/antagonist activities in cell-based transcription assays. Binding affinities for both are most accurately assessed by AR aporeceptor complex. In addition to being testosterone precursors in vivo, either may impart its own transcriptional regulation of AR.

Clinical relative biological effectiveness of low-energy x-rays emitted by miniature x-ray devices.

Several groups are developing ultra-miniature x-ray machines for clinical use in radiation therapy. Current systems are for interstitial radiosurgery and for intravascular insertion for irradiation to prevent re-stenosis. Typical generating voltages are low, in the 20 to 40 kV range. It is well established that the biological effectiveness of such low-energy photons is large compared with higher-energy gamma rays, because of the dominance of photoelectric absorption at low energies. We have used microdosimetric analyses to estimate RBEs for such devices, both at low doses and clinically relevant doses, relative to radiations from 60Co, 192Ir, 125I and 90Sr/90Y. The RBEs at clinically relevant doses and dose rates for these low-energy x-ray sources are considerably above unity, both relative to 60Co and to 192Ir photons, and also relative to 125I and 90Sr/90Y brachytherapy sources. As a function of depth, the overall effect of the change in dose and the change in beam spectrum results in beams whose biologically weighted dose (dose x RBE) decreases with depth somewhat more slowly than does the physical dose. The estimated clinically relevant RBEs are sufficiently large that they should be taken into account during the treatment design stage.

[The practicability of preceptorship in the curriculum of medical education].

Physicians who have graduated from traditional medical education curriculum focus on technological and organ system training, and are deficient in modern community health care concepts and skills. A preceptorship course integrates at various medical educational periods is one of the important goals at education reform in America. In this study, we attempt to ascertain the opinions of family physicians about the current family medicine curriculum and the practicability of preceptorship in Taiwan. The result can be a reference for future medical curriculum design. Two hundreds and thirty-five (40.8%) questionnaires were collected and analyzed. They showed most respondents were dissatisfied with the current curriculum of family medicine, and most agree that primary care physicians involvement would be helpful in producing efficient and well-qualified physicians. They suggested that preceptorship should best be first integrated in a basic knowledge course. We suggest that faculties who are responsible for curriculum design should evaluate the current curriculum and the appropriateness of preceptorship in Taiwan. Prior to the reform, faculty development and evaluation are the essential and crucial tasks.

GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy.

OBJECTIVE: The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1 gene, encoding the glucose transporter type 1 (GLUT1), for mutations in a group of 95 European patients with familial IGE. METHODS: The affected individuals were examined clinically by EEG and brain imaging. The coding regions of SLC2A1 were sequenced in the index cases of all families. Wild-type and mutant transporters were expressed and functionally characterized in Xenopus laevis oocytes. RESULTS: We detected a novel nonsynonymous SLC2A1 mutation (c.694C>T, p.R232C) in one IGE family. Nine family members were affected mainly by absence epilepsies with a variable age at onset, from early childhood to adulthood. Childhood absence epilepsy in one individual evolved into juvenile myoclonic epilepsy. Eight affected and 4 unaffected individuals carried the mutation, revealing a reduced penetrance of 67%. The detected mutation was not found in 846 normal control subjects. Functional analysis revealed a reduced maximum uptake velocity for glucose, whereas the affinity to glucose and the protein expression were not different in wild-type and mutant transporters. CONCLUSION: Our study shows that GLUT1 defects are a rare cause of classic IGE. SLC2A1 screening should be considered in IGE featuring absence epilepsies with onset from early childhood to adult life, because this diagnosis may have important implications for treatment and genetic counseling.

Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT.

The aim of this study was to assess the frequency of potential drug-drug interactions (pDDIs) and adverse drug events (ADEs) associated with antimycotics in hospitalized patients with hematopoietic SCT (HSCT). Of the 120 HSCT recipients evaluated, 36 received antimycotics. A total of 124 ADEs were recorded in 32 of the 36 patients treated, with 54 ADEs being possibly and 9 probably related to antimycotics. Of the treatments with amphotericin B, 93% were associated with one or more possible and 36% with probable ADEs. The corresponding figures for lipid-based amphotericin B were 100% and 7%, for voriconazole 68% and 11% and for caspofungin 70% and 0%. A total of 57 potentially severe DDIs associated with antimycotics were detected in 31 of the 36 patients. Of these, 14 DDIs were a possible cause of an ADE and 5 (4 times a combination of voriconazole with CYA and once a combination of CYA with conventional amphotericin B) were probably related. Although the prevalence of pDDIs and ADEs is high in HSCT patients, ADEs related with a high probability to treatment with antimycotics are rare. Regarding the high prevalence of pDDIs, our findings underscore the importance of close monitoring of laboratory and clinical parameters, as well as dose adjustment for critical drugs, in patients with HSCT.

Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis.

Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.