Search

Context: Caregivers managing symptoms of family members with cancer during home hospice care, often feel ill-prepared and need patient care coaching., Objectives: This study tested the efficacy of an automated mHealth platform that included caregiver coaching on patient symptom care and nurse notifications of poorly controlled symptoms. The primary outcome was caregiver perception of patients' overall symptom severity throughout hospice care and at weeks one, two, four, and eight. Secondary outcomes compared individual symptom severity., Methods: Caregivers (n = 298) were randomly assigned to the Symptom Care at Home (SCH) intervention (n = 144) or usual hospice care (UC) (n = 154). All caregivers placed daily calls to the automated system that assessed the presence and severity of 11 end-of-life patient physical and psychosocial symptoms. SCH caregivers received automated coaching on symptom care based on reported patient symptoms and their severity. Moderate-to-severe symptoms were also relayed to the hospice nurse., Results: The SCH intervention produced a mean overall symptom reduction benefit, over UC, of 4.89 severity points (95% CI 2.86-6.92) (P < 0.001), with a moderate effect size (d = 0.55). The SCH benefit also occurred at each timepoint (P < 0.001- 0.020). There was a 38% reduction in days reporting moderate-to-severe patient symptoms compared to UC (P < 0.001) with 10/11 symptoms significantly reduced in SCH compared to UC., Conclusion: Automated mHealth symptom reporting by caregivers, paired with tailored caregiver coaching on symptom management and nurse notifications, reduces cancer patients' physical and psychosocial symptoms during home hospice, providing a novel and efficient approach to improving end-of-life care., (Copyright © 2023 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the agreement of SUV metrics across the different clinical PET reading software platforms available at our institution., Methods: PET/CT images were reviewed on four different FDA-approved software platforms: syngoMMWP VE36A and syngo.via VB30A (Siemens), Intellispace Portal 9.0 (Philips), and Encore 6.7 (MIM Software). A total of thirty SUV measurements were derived from ten 18F-FDG PET/CT oncology studies. A volume of interest (VOI) was drawn around the primary tumor to determine lesion SUV max and a 3 cm diameter spherical VOI was placed in the right lobe of the liver to determine liver SUV mean and liver SUV max ., Results: For lesion SUV max , statistically significant differences were found for syngoMMWP VE36A vs syngo.via VB30A (p = 0.002), syngoMMWP VE36A vs Intellispace Portal 9.0 (p = 0.002), and syngoMMWP VE36A vs Encore 6.7 (p = 0.001), respectively. For liver SUV max , a statistically significant difference was found for syngoMMWP VE36A vs syngo.via VB30A (p = 0.033) only, whereas for liver SUV mean , no statistically significant differences were determined. A small systematic bias was found between syngoMMWP VE36A and all other platforms for lesion SUV max ., Conclusion: Significant differences and systematic biases were observed when measuring lesion SUV max using different reader software systems. Although these differences may not be clinically significant, this bias could confound outcomes for quantitative, precision-research protocols. Hence, it is important for nuclear medicine departments to take SUV metric agreement into consideration, especially when transitioning to a new clinical platform., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Neurotensin receptor-3 or sortilin is a vacuolar protein sorting 10 protein domain (Vps10p) has been firstly discovered in the human brain, it acts as receptor or co-receptor of the cell and traffics different proteins within the cell. Sortilin deregulation contributes to the development of several diseases, including neurological diseases and cancer. On the other hand, neurotrophins which are a family of proteins essential for the nervous system development, function and plasticity. The first discovered member is the nerve growth factor; other members are brain-derived growth factor, neurotrophin-3 and neurotrophin-4. Nerve growth factor and brain-derived growth factor are the common neurotrophins that have a role in cancer. Neurotrophins initiate their signals through interaction with tyrosine receptor kinases TrkA, TrkB, and TrkC; each member has an affinity for a specific receptor to stimulate cell survival, while the interaction with p75 NTR initiates cell apoptosis pathway by forming a complex with sortilin and neurotrophin precursors. A number of therapeutic approaches are emerging to target the neurotrophins pathway as well as sortilin., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: HIV treatment as prevention is effective for reducing the risk of HIV transmission and the messaging campaign, undetectable = untransmittable, is gaining recognition. As youth living with HIV (YLWH) who have condomless sex may acquire and potentially transmit other sexually transmitted infections (STIs), the purpose of this study was to assess potential differences in transmission risk of HIV and other STIs among YLWH to inform subsequent HIV and STI prevention efforts., Methods: A cohort of 600 HIV behaviorally infected youth aged 13-24 years who were engaged in medical care completed an audio computer-assisted self-interview including questions about demographics, HIV disclosure, mental health, substance use, and sexual behaviors and beliefs. HIV viral loads and the presence of other STIs were abstracted from medical records. A viral load <200 copies/mL was considered undetectable. Univariate and bivariate analyses were conducted to examine differences by viral load and STIs., Results: Participants were categorized into four groups: (1) undetectable without STIs (55.2%); (2) undetectable with STIs (14.2%); (3) detectable without STIs (22.8%); and (4) detectable with STIs (7.8%). In comparison to the other three groups, youth in the undetectable group with STIs reported more favorable sexual risk reduction attitudes and beliefs, internet use for finding sex partners, anal sex with male partners, and condomless anal sex with male partners., Conclusions: YLWH with undetectable viral loads and other STIs engaged in higher risk behaviors. To realize the promise of the messaging campaign, undetectable = untransmittable, efforts must focus on sustained viral suppression and prevention of STIs among YLWH., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Malaria remains a significant public health problem worldwide with an estimated annual global incidence of 200 million and an estimated 450,000 annual deaths. Among the five known human malarial species, Plasmodium falciparum is the deadliest and most resistant to antimalarials. Hence, there is a need for new antimalarial targets. The rational design of a drug is usually based on biochemical and physiological differences between pathogens and their hosts. In view of their high rate of replication, parasites require very active nucleic acid synthesis which necessitates large supplies of the indispensable pyrimidine nucleotides. Consequently, delineation of P. falciparum pyrimidine metabolic pathways may reveal potential targets for the chemotherapy of malaria. Previous studies reported the existence of pyrimidine de novo pathways in this organism. The present results demonstrate the presence of enzymes of the pyrimidine salvage pathways in P. falciparum and indicate that this parasite is capable of pyrimidine salvage. Furthermore, some of the pyrimidine salvage enzymes, e.g., dTMP kinase, phosphoribosyltransferase, and uridine phosphorylase could be excellent targets for chemotherapeutic intervention against this parasite., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We explored potential barriers and facilitators for prostate cancer screening choices among high-risk Black men. In our sample of 264 Black men over 45 years of age living in the U.S. who met the American Cancer Society criteria for screening, we found that only 49.6% had ever been screened. We investigated potential barriers including screening intention, access to care, medical mistrust, and fatalism. Potential facilitating factors investigated were provider-patient conversations encompassing the pros and cons of screening, ethnicity taken into account, insurance, and previous prostate cancer screening. Recommendations and resources are suggested to increase screening of high-risk Black men.

Purpose: Linkage of HIV-negative youth to prevention services is increasingly important with the development of effective pre-exposure prophylaxis that complements behavioral and other prevention-focused interventions. However, effective infrastructure for delivery of prevention services does not exist, leaving many programs to address HIV prevention without data to guide program development/implementation. The objective of this study was to provide a qualitative description of barriers and facilitators of linkage to prevention services among high-risk, HIV-negative youth., Design: Thematic analysis of structured interviews with staff implementing linkage to prevention services programs for youth aged 12-24 years., Methods: Twelve adolescent medicine HIV primary care programs as part of larger testing research program focused on young sexual minority men of color. The study included staff implementing linkage to prevention services programs along with community-based HIV testing programs. The main outcomes of the study were key barriers/facilitators to linkage to prevention services., Results: Eight themes summarized perspectives on linkage to prevention services: (1) relationships with community partners, (2) trust between providers and youth, (3) youth capacity to navigate prevention services, (4) pre-exposure prophylaxis specific issues, (5) privacy issues, (6) gaps in health records preventing tailored services, (7) confidentiality of care for youth accessing services through parents'/caretakers' insurance, and (8) need for health-care institutions to keep pace with models that prioritize HIV prevention among at-risk youth. Themes are discussed in the context of factors that facilitated/challenged linkage to prevention services., Conclusions: Several evidence-based HIV prevention tools are available; infrastructures for coordinated service delivery to high-risk youth have not been developed. Implementation of such infrastructures requires attention to community-, provider-, and youth-related issues., (Copyright © 2017 The Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

A wide range of central nervous system (CNS) disorders, particularly those related to sleep, are associated with the abnormal function of orexin (OX) receptors. Several orexin receptor antagonists have been reported in recent years, but currently there are no imaging tools to probe the density and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomography (PET) radiotracer development could be used to elucidate the association of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compounds based on diazepane orexin receptor antagonists previously described. One of the synthesized compounds, [(11)C]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR imaging. PET scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [(11)C]CW4 exhibited fast kinetics and high nonspecific binding, as determined after co-administration of [(11)C]CW4 and unlabeled CW4. These properties indicate that [(11)C]CW4 has excellent brain penetrance and could be used as a lead compound for developing new CNS-penetrant PET imaging probes of orexin receptors., (© 2013.)

Using cultured cortical neurons, we show that the blockade of protein phosphatase 2A (PP2A), either pharmacologically by okadaic acid or by short hairpin RNA (shRNA)-mediated silencing of PP2A catalytic subunit, inhibited basal autophagy and autophagy induced in several experimental settings (including serum deprivation, endoplasmic reticulum stress, rapamycin, and proteasome inhibition) at early stages before autophagosome maturation. Conversely, PP2A upregulation by PP2A catalytic subunit overexpression stimulates neuronal autophagy. In addition, PP2A blockade resulted in the activation of the negative regulator of autophagy mammalian target of rapamycin complex 1 and 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) and led to intraneuronal accumulation of p62- and ubiquitin-positive protein inclusions, likely due to autophagy downregulation. These data are consistent with previous findings showing that specific invalidation of the autophagy process in the nervous system of mouse resulted in the accumulation of p62- and ubiquitin-positive protein inclusion bodies. Furthermore, we showed that PP2A inhibition alters the distribution of the microtubule-associated protein 1 light chain(LC) 3-I (MAP LC3-I), a key component of the autophagy molecular machinery. Whether MAP LC3-I distribution in the cell accounts for autophagy regulation remains to be determined. These data are important to human neurodegenerative diseases, especially Alzheimer's disease, because they provide links for the first time between the pathological features of Alzheimer's disease:PP2A downregulation, autophagy disruption, and protein aggregation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Genomic testing, including single-nucleotide polymorphism-based microarrays and whole-genome sequencing, can detect long stretches of the genome that display homozygosity. The presence of these segments, when distributed across multiple chromosomes, can indicate a familial relationship between the proband's parents. This article describes the detection of possible consanguinity by genomic testing and the factors confounding the inference of a specific p-arental relationship. It is designed to guide the documentation of suspected consanguinity by clinical laboratory professionals and to alert laboratories to the need to establish a reporting policy in conjunction with their ethics review committee and legal counsel.

Gold nanostars offer unique plasmon properties that efficiently transduce photon energy into heat for photothermal therapy. Nanostars, with their small core size and multiple long thin branches, exhibit high absorption cross-sections that are tunable in the near-infrared region with relatively low scattering effect, making them efficient photothermal transducers. Here, we demonstrate particle tracking and photothermal ablation both in vitro and in vivo. Using SKBR3 breast cancer cells incubated with bare nanostars, we observed photothermal ablation within 5 minutes of irradiation (980-nm continuous-wave laser, 15 W/cm2). On a mouse injected systemically with PEGylated nanostars for 2 days, extravasation of nanostars was observed and localized photothermal ablation was demonstrated on a dorsal window chamber within 10 minutes of irradiation (785-nm continuous-wave laser, 1.1 W/cm2). These preliminary results of plasmon-enhanced localized hyperthermia are encouraging and have illustrated the potential of gold nanostars as efficient photothermal agents in cancer therapy., From the Clinical Editor: Gold nanostars are tunable in the near-infrared region with low scattering, thus enable photothermal therapy. Encouraging preliminary results of plasmon-enhanced localized hyperthermia both in vitro and in vivo demonstrate that Au nanostars may be efficient photothermal agents for cancer therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The expanding use of GSM devices has resulted in public concern. Chaperone-mediated autophagy (CMA) is a way for protein degradation in the lysosomes and increases under stress conditions as a cell defense response. α-synuclein, a CMA substrate, is a component of Parkinson disease. Since GSM might constitute a stress signal, we raised the possibility that GSM could alter the CMA process. Here, we analyzed the effects of chronic exposure to a low GSM-900MHz dose on apoptosis and CMA. Cultured cerebral cortical cells were sham-exposed or exposed to GSM-900MHz at specific absorption rate (SAR): 0.25W/kg for 24 h using a wire-patch cell. Apoptosis was analyzed by DAPI stain of the nuclei and western blot of cleaved caspase-3. The expression of proteins involved in CMA (HSC70, HSP40, HSP90 and LAMP-2A) and α-synuclein were analyzed by western blot. CMA was also quantified in situ by analyzing the cell localization of active lysosomes. 24 h exposure to GSM-900MHz resulted in ∼0.5°C temperature rise. It did not induce apoptosis but increased HSC70 by 26% and slightly decreased HSP90 (<10%). It also decreased α-synuclein by 24% independently of CMA, since the localization of active lysosomes was not altered. Comparable effects were observed in cells incubated at 37.5°C, a condition that mimics the GSM-generated temperature rise. The GSM-induced changes in HSC70, HSP90 and α-synuclein are most likely linked to temperature rise. We did not observe any immediate effect on cell viability. However, the delayed and long term consequences (protective or deleterious) of these changes on cell fate should be examined., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Malnutrition is an indicator of a poor prognosis in patients with cystic fibrosis (CF). Previous body-composition (BC) studies in children with CF used 2-component models (2CMs) to assess fat mass (FM) and fat-free mass (FFM), but to our knowledge no study has used the gold-standard 4-component model (4CM), which allows for a more accurate evaluation of the nature of both elements., Objective: We measured BC by using the 4CM in 6-12-y-old children with CF to 1) compare findings with those of healthy, matched control children and reference data; 2) relate BC to lung spirometry [forced expired volume in 1 s (FEV₁)]; and 3) compare findings with those from more commonly used 2CM techniques., Design: One hundred clinically stable children with CF (57% girls) aged 6-12 y were measured by using the 4CM. Children with CF underwent spirometry (FEV₁)., Results: Girls with CF had significantly less FM than did healthy girls, even after adjustment for height and pubertal status; boys with CF had higher body mass index SD scores than did healthy boys. FM in girls was positively associated with the FEV₁ percentage predicted. The 2CM FM was significantly different from the 4CM FM, with differences dependent on sex and condition, although most techniques identified a relation between FM and FEV₁ in girls., Conclusions: Although shorter than healthy children, boys with CF were heavier and had a BC within the normal range; however, girls with CF had lower FM than did healthy girls, and this was associated with poorer lung function. Given the worse prognosis in girls, this finding merits more attention. The reliability of 2CM techniques varied with sex and health status.

Understanding the demographic and risk profiles of youth with recent HIV infection offers insight for imputing the dynamics of the epidemic and targeting prevention efforts. Three hundred forty-two HIV-positive youth were tested using a Sensitive/Less Sensitive strategy; 33% were classified as recently infected; with the majority (51%) occurring within African Americans., (Copyright 2010 Society for Adolescent Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: QT interval prolongation and Torsade de Pointes (TdP) arrhythmias are recognised as a potential risk with many drugs, most of which delay cardiac repolarization by inhibiting the rapidly activating K(+) current (I(Kr)). The objective of this study was to compare the effects of compounds on cardiac action potentials recorded from guinea-pig ventricular myocytes and dog Purkinje fibres., Methods and Results: Effects of dofetilide, sotalol, cisapride, terfenadine, haloperidol and sparfloxacin, compounds known to cause QT prolongation (positive controls), and nifedipine and verapamil, not associated with QT prolongation (negative controls) were studied on intracellular action potentials recorded from guinea-pig isolated ventricular myocytes (VM) and dog isolated Purkinje fibres (PF). Prolongation of action potential duration (APD) by sotalol, dofetilide and sparfloxacin was concentration-dependent and of greater magnitude in dog PF compared to guinea-pig VM. The maximum prolongation of APD in guinea-pig VM at 0.5 and 1 Hz was approximately 25% and this was associated with complete inhibition of I(Kr) by dofetilide. Effects on APD of cisapride and haloperidol in both preparations, and terfenadine in guinea-pig VM, were biphasic, consistent with inhibition of multiple ion channels. There was no effect of terfenadine on APD in dog PF. Haloperidol increased APD by more than 25% in guinea-pig VM, consistent with effects on additional repolarizing currents. The negative controls shortened APD to a greater extent in guinea-pig VM compared to dog PF. In general, the positive control drugs increased action potential triangulation (APD(40-90)) to a greater extent than APD(90)., Conclusion: Guinea-pig isolated VM may be more sensitive for detecting APD prolongation with compounds inhibiting multiple ion channels and action potential triangulation (APD(40-90)). Effects on repolarizing currents other than I(Kr) were also distinguished in guinea-pig VM.

Hhex is required for early development of the liver. A null mutation of Hhex results in a failure to form the liver bud and embryonic lethality. Therefore, Hhex null mice are not informative as to whether this gene is required during later stages of hepatobiliary morphogenesis. To address this question, we derived Hhex conditional null mice using the Cre-loxP system and two different Cre transgenics (Foxa3-Cre and Alfp-Cre). Deletion of Hhex in the hepatic diverticulum (Foxa3-Cre;Hhex(d2,3/-)) led to embryonic lethality and resulted in a small and cystic liver with loss of Hnf4alpha and Hnf6 expression in early hepatoblasts. In addition, the gall bladder was absent and the extrahepatic bile duct could not be identified. Loss of Hhex in the embryonic liver (Alfp-Cre;Hhex(d2,3/-)) caused irregular development of intrahepatic bile ducts and an absence of Hnf1beta in many (cystic) biliary epithelial cells, which resulted in a slow, progressive form of polycystic liver disease in adult mice. Thus, we have shown that Hhex is required during multiple stages of hepatobiliary development. The altered expression of Hnf4alpha, Hnf6 and Hnf1beta in Hhex conditional null mice suggests that Hhex is an essential component of the genetic networks regulating hepatoblast differentiation and intrahepatic bile duct morphogenesis.

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. Correlating genotypes with phenotypes should facilitate the disease management of tuberous sclerosis complex.

Background: Antioxidant nutrient deficiencies may hasten the progression of HIV disease by impairing antioxidant defenses., Objective: The objective of the study was to determine whether HIV infection is associated with poor selenium status and low antioxidant protection by glutathione and glutathione peroxidase (GPX)., Design: In a cross-sectional study of 365 HIV-positive and HIV-negative adolescents and young adults, we examined the relation of plasma selenium, whole-blood glutathione, and whole-blood GPX to HIV status, disease severity, immune activation, and oxidative damage., Results: Selenium deficiency (plasma selenium < 0.070 microg/mL) was not seen in any subjects, and plasma selenium in 244 HIV-positive subjects (0.120 +/- 0.0013 microg/mL) did not differ significantly (P = 0.071) from that in 121 HIV-negative subjects (0.125 +/- 0.0020 microg/mL) . However, multiple regression analysis after adjustment for covariates showed a significant (P = 0.002) negative association between HIV-associated immune activation (plasma neopterin) and plasma selenium concentrations. GPX activity was highest in HIV-positive subjects taking antiretroviral therapy (median: 14.2; 25th, 75th percentiles: 11.1, 18.7 U/mL; n = 130), intermediate in HIV-positive subjects not taking antiretroviral therapy (11.8; 9.4, 15.1 U/mL; n = 114), and lowest in HIV-negative subjects (10.6; 8.6, 12.7 U/mL; n = 121; P < 0.05 for all comparisons). GPX was also positively associated with malondialdehyde, a marker of oxidative damage., Conclusions: Subjects had adequate selenium status, although HIV-related immune activation was associated with lower plasma selenium concentrations. GPX activity appears to have been induced by the oxidative stress associated with HIV infection and use of antiretroviral therapy. Thus, young, well-nourished subjects can mount a compensatory antioxidant response to HIV infection.

Hhex encodes a homeodomain-containing protein that functions as both a transcriptional repressor and activator, and is necessary for normal embryonic development. We previously reported that a null mutation of Hhex leads to abnormalities in vasculogenesis and have focused on identifying the transcriptional targets of Hhex necessary for vascular development. Here we report that the expression of ESM-1, a cysteine-rich protein expressed in the endothelium, is increased in Hhex(-/-) embryos. Overexpression of Hhex in endothelial cells down-regulates ESM-1. The results from transient cotransfection assay, electrophoretic-mobility shift assay, site-directed mutagenesis, and chromatin immunoprecipitation assay demonstrate that Hhex can directly bind to and repress ESM-1 via an evolutionarily conserved Hhex response element (HRE) 1. These findings indicate that ESM-1 is a direct target of Hhex and that Hhex functions as a transcriptional repressor of ESM-1. We speculate that Hhex-mediated repression of ESM-1 is critical for the normal function of the vascular endothelium and for tumor vasculogenesis.

Background: Dual-energy X-ray absorptiometry (DXA) is widely used to assess body composition in research and clinical practice. Several studies have evaluated its accuracy in healthy persons; however, little attention has been directed to the same issue in patients., Objective: The objective was to compare the accuracy of the Lunar Prodigy DXA for body-composition analysis with that of the reference 4-component (4C) model in healthy subjects and in patients with 1 of 3 disease states., Design: A total of 215 subjects aged 5.0-21.3 y (n = 122 healthy nonobese subjects, n = 55 obese patients, n = 26 cystic fibrosis patients, and n = 12 patients with glycogen storage disease). Fat mass (FM), fat-free mass (FFM), and weight were measured by DXA and the 4C model., Results: The accuracy of DXA-measured body-composition outcomes differed significantly between groups. Factors independently predicting bias in weight, FM, FFM, and percentage body fat in multivariate models included age, sex, size, and disease state. Biases in FFM were not mirrored by equivalent opposite biases in FM because of confounding biases in weight., Conclusions: The bias of DXA varies according to the sex, size, fatness, and disease state of the subjects, which indicates that DXA is unreliable for patient case-control studies and for longitudinal studies of persons who undergo significant changes in nutritional status between measurements. A single correction factor cannot adjust for inconsistent biases.

Background: Vitamin D status affects immune function and thus may affect the progress of HIV infection., Objectives: Our goals were to assess vitamin D intake and status in subjects with HIV infection and in matched control subjects and to determine whether HIV infection was associated with vitamin D insufficiency., Design: Plasma 25-hydroxyvitamin D [25(OH)D] concentrations and vitamin D intake were measured in a cross-sectional study of members of the Reaching for Excellence in Adolescent Health (REACH) cohort., Results: The subjects were aged 14-23 y; 74% were female, and 72% were black. Mean (+/-SE) vitamin D intake from food was 30% greater (P = 0.023) in HIV-positive subjects (295 +/- 18 IU/d; n = 237) than in HIV-negative subjects (227 +/- 26 IU/d; n = 121). The prevalence of vitamin D supplement use was 29% (104 of 358 subjects) and did not differ significantly by HIV status (P = 0.87). Mean plasma 25(OH)D did not differ significantly (P = 0.62) between the HIV-positive (20.3 +/- 1.1 nmol/L; n = 238) and HIV-negative (19.3 +/- 1.7 nmol/L; n = 121) subjects, nor was HIV status a significant predictor of plasma 25(OH)D when multiple regression analysis was used to adjust for other variables. The prevalence of vitamin D insufficiency [plasma 25(OH)D < or = 37.5 nmol/L] in the subjects was 87% (312 of 359 subjects)., Conclusions: HIV infection did not influence vitamin D status. The prevalence of vitamin D insufficiency in both HIV-positive and HIV-negative REACH subjects was high, perhaps because these disadvantaged, largely urban youth have limited sun exposure.

Background: Oxidative stress during HIV infection may impair immune function, cause more rapid disease progression, and increase requirements for dietary antioxidants such as vitamins C and E., Objectives: The study had 2 principal objectives. The first was to ascertain whether HIV infection and immune activation were associated with lower plasma concentrations of ascorbate, urate, and alpha- and gamma-tocopherols and with total antioxidant status (TAS). The second objective was to ascertain whether these antioxidants were associated with protection against oxidative damage., Design: This was a cross-sectional study involving 241 HIV-positive and 115 HIV-negative subjects aged 14-23 y. Subjects were primarily female (76%) and African American (70%), and 21% were Hispanic., Results: Plasma ascorbate was significantly lower, but gamma-tocopherol and TAS were significantly higher in subjects with HIV infection when the analysis was adjusted for dietary intake and sex. Plasma alpha-tocopherol did not differ significantly by HIV status. Plasma gamma-tocopherol also was higher in subjects with oxidative damage than in those without such damage. More than 90% of subjects had adequate plasma concentrations for both ascorbate and alpha-tocopherol, although alpha-tocopherol concentrations were lower than expected on the basis of third National Health and Nutrition Examination Survey data., Conclusions: Low plasma ascorbate concentrations in HIV-positive subjects suggest that vitamin C requirements are significantly higher in those with HIV infection. Plasma tocopherol concentrations were not depressed by HIV infection and may be maintained by compensatory mechanisms such as the activity of alpha-tocopherol transfer protein.

Objective: To examine the relationships among dietary quality, weight status, and human immunodeficiency virus (HIV) infection in US adolescents and young adults., Design: This cross-sectional study was embedded in the Reaching for Excellence in Adolescent Care and Health cohort study of HIV-infected and HIV-uninfected, at-risk youth. Biochemical, clinical, and sociodemographic data were available. Dietary intake was collected using the Block Food Frequency Questionnaire and a modified Healthy Eating Index was calculated to measure diet quality., Subjects/setting: Participants included 264 HIV-infected and 127 HIV-uninfected youth 13 to 23 years old (75.2% women, 67.3% African American/non-Hispanic, 20.5% Hispanic, 12.3% other) at 14 clinic sites., Statistical Analyses Performed: Determinants of obesity and the modified Healthy Eating Index were tested using logistic and generalized linear regression., Results: About half (51.7%) of participants were overweight or obese. Obesity was positively associated with being a woman, living independently, watching television >or=3 hours per day, previous dieting, and being from the northeastern or southern United States. Youth who were HIV uninfected or HIV infected with CD4 + T cells >or=500 cells/microL had similar obesity rates; overweight (25%) and obesity (20%) was prevalent among women even with CD4 + T cells <200 cells/microL. The modified Healthy Eating Index score was 56.2+/-0.6, reflecting a diet needing improvement. HIV infection, watching television >or=3 hours/day, and being from the Chicago, IL, area were associated with a lower-quality diet., Conclusions: Obesity is a common nutrition problem for both HIV-infected and uninfected youth; however, HIV-infected youth are at increased risk of developing metabolic abnormalities. Culturally appropriate, client-focused nutrition education will help youth improve their diet and increase physical activity to reduce health consequences associated with both obesity and HIV infection.

Objective: We examined the association between micronutrient intakes and human immunodeficiency virus (HIV) infection in youths who were at increased nutritional risk because of the demands of growth and disease as well as poor dietary habits., Design: This was a cross-sectional study to collect dietary intake data using the Block Food Frequency Questionnaire (98.2). Anthropometric, biochemical, clinical, and sociodemographic data were available.Subjects/Setting Participants included 264 HIV-infected and 127 HIV-uninfected adolescents and young adults from the Reaching for Excellence in Adolescent Care and Health network, a multisite observational study on HIV progression. Statistical analyses CD4(+) T cells were stratified for HIV-infected youths: >/=500, 200 to 499, and <200 cells/microL. Micronutrient intakes were compared by presence of HIV infection, using two-sample Student's t tests. Categoric analyses used chi(2) test. Generalized linear regression determined predictors of vitamins A, C, and E; iron; and zinc intakes., Results: Almost half (49.0%) of the HIV-infected participants had CD4(+) T cells >/=500 cells/microL. After controlling for other factors, HIV-infected participants with CD4(+) T cells >/=500 had decreased iron intake (P<.05) and tended to be associated with lower intakes of vitamins C and E (P<.10) compared with those with more advanced disease and HIV-uninfected youths. Among those youths with CD4(+) T cells between 200 and 499 cells/microL, a high anxiety score was associated with a sixfold increase in vitamin A intake as compared with those with a low score.Applications/conclusions Given the increased micronutrient requirements, nutrition counseling with HIV-infected youths should focus on early increase of intake of foods rich in micronutrients to improve growth, slow disease progression, and increase survival.

Membrane type-I metalloproteinase (MT1-MMP) is a transmembrane metalloproteinase that is critical for tumor cell invasion. MT1-MMP can degrade extracellular matrix (ECM) proteins directly and/or indirectly by activating soluble MMPs such as pro-MMP-2. Although MT1-MMP is upregulated in malignant melanoma, the biological consequences of elevated MT1-MMP expression for tumor progression are not entirely understood. In the current study, we have utilized the Bowes melanoma line for evaluating MT1-MMP in invasion and growth. Our studies extend the earlier observations to demonstrate that MT1-MMP expression in Bowes melanoma cells promotes selective invasion into matrigel but not matrices consisting of type-I collagen. Furthermore, MT1-MMP expressing melanoma cells exhibit increased migration in response to laminin 1 but not to type-I or type-IV collagen. MT1-MMP expression results in enhanced 3 dimensional growth in agarose gels and in long-term cultures within matrigel. The hydroxymate inhibitor BB94 inhibits MT1-MMP enhanced invasion and growth in 3 dimensional culture systems, but had no effect on increased motility. We demonstrated that MT1-MMP expression significantly facilitated tumorigenicity and growth by intradermal injection. The results suggest a more general role for elevated MT1-MMP in promoting both the selective invasion and increased growth of malignant melanoma in vivo.

Hyaluronan (HA), a secreted glycosaminoglycan component of extracellular matrices, is critical for cellular proliferation and motility during development. However, elevated circulating and cell-associated levels correlate with various types of cancer, including prostate. We have previously shown that aggressive PC3M-LN4 prostate tumor cells synthesize excessive HA relative to less aggressive cells, and express correspondingly higher levels of the HA biosynthetic enzymes HAS2 and HAS3. Inhibition of these enzymes by stable transfection of PC3M-LN4 cells with anti-sense HAS2 or HAS3 expression constructs diminishes HA synthesis and surface retention. In this report, we used these HA-deficient cell lines to examine the role of HA in tumorigenicity. Subcutaneous injection of SCID mice with hyaluronan synthase (HAS) antisense-transfected cells produced tumors threefold to fourfold smaller than control transfectants. Tumors from HAS antisense transfectants were histologically HA-deficient relative to controls. HA deficiency corresponded to threefold reduced cell numbers per tumor, but comparable numbers of apoptotic and proliferative cells. Percentages of apoptotic cells in cultured transfectants were identical to those of control cells, but antisense inhibition of HA synthesis effected slower growth rate of cells in culture. Quantification of blood vessel density within tumor sections revealed 70 to 80% diminished vascularity of HAS antisense tumors. Collectively, the results suggest HAS overexpression by prostate tumor cells may facilitate their growth and proliferation in a complex environment by enhancing intrinsic cell growth rates and promoting angiogenesis. Furthermore, this is the first report of a role for inhibition of HA synthesis in reducing tumor growth kinetics.

Purpose: To describe baseline prevalence of oral mucosal diseases among HIV infected adolescents in relationship to biological and behavioral risk factors., Methods: Participants in Reaching for Excellence in Adolescent Care and Health (REACH), a multicenter longitudinal observational study of HIV/AIDS in adolescents, received physical examinations, blood tests, and oral examinations at 3-month intervals. We evaluated participants for oral conditions commonly seen in relationship to HIV, and explored the association of the most common lesion with selected biological and behavioral variables at baseline using contingency tables and Fisher's Exact test., Results: Among 294 HIV infected adolescents recruited between March 1996 and March 1999, the majority were female (75%), aged 17 to 18 years (69%), and African-American (73%). More than 90% had a CD4(+) T-lymphocyte count > 200 cells/mm(3) at baseline and 57% had a plasma HIV-1 RNA concentration

Purpose: To evaluate hepatitis B (HBV) vaccine response rates in HIV infected and high-risk HIV uninfected youth and examine associations with responsiveness in the HIV infected group., Methods: Cohorts within the Reaching for Excellence in Adolescent Care and Health (REACH) study population were defined based on receipt of HBV vaccine both retrospectively and prospectively. Sero-responsiveness was determined by HBsAb measurements. Testing was done for HBsAg, HBsAb, and HBcAb. For HBsAb, a value of > 10 International Units per liter was considered a positive response, and the data were collected as either positive or negative from each of the reporting laboratories. Covariates of responsiveness were explored in univariate and multivariate models for each cohort., Results: Sixty-one subjects had received a three-dose vaccination course at the time of entry into REACH. HIV uninfected subjects had significantly higher rates of response by serology compared with HIV infected subjects (70% vs. 41.1%; chi(2) = .05; RR = .586, 95% CI: .36-.96). By the time of an annual visit 43 subjects had received three vaccinations with at least one occurring in the study period. The rates of response were similar for the HIV infected and uninfected groups (37.1% vs. 37.5%) in this cohort. Univariate and multivariate analysis in the prospective HIV infected group (N = 35) found an association between elevated CD8(+)/CD38(+)/HLA-DR(+) T cells and lack of HBV vaccine responsiveness (6.7% vs. 60%; chi(2) = .03; RR = .12, 95% CI: .02- .55)., Conclusions: The poor HBV vaccine response rate in the HIV uninfected high-risk adolescents was unexpected and suggests that HBV vaccination doses have not been optimized for older adolescents. This is the first report of decreased responsiveness in HIV infected subjects being associated with elevated CD8(+)/CD38(+)/HLA(-)DR(+) T cells and suggests that ongoing viral replication and concomitant immune system activation decreases the ability of the immune system in HIV infected subjects to respond to vaccination.

Overview: This review presents the findings of published research in the Reaching for Excellence in Adolescent Care and Health (REACH) Project on sexually transmitted infections (STIs) within the context of the project's scientific agenda. Methods employed in the study for specimen collection, management, and laboratory analysis are presented. This review presents published analyses of cross-sectional data; longitudinal analyses are underway. In addition, baseline prevalence data on selected STIs and sexual risk profiles of the subjects in REACH are presented. High STI rates were evident in both human immunodeficiency virus (HIV) infected and uninfected youth of both genders regardless of sexual orientation. High infection rates at baseline suggest that prevention-oriented programs for risk reduction among adolescents should focus on both HIV infected and at-risk, uninfected youth.

Purpose: To characterize sexual behaviors and sociodemographic factors that are associated with douching among geographically diverse adolescent women with and without HIV infection., Methods: HIV infected subjects recruited preferentially and behaviorally comparable high-risk HIV uninfected subjects were enrolled in a prospective HIV study from 15 sites in 13 U.S. cities. Baseline interview data from 1996 to 1999 for females aged 12 to 19 years were analyzed using one-way analysis of variance and multiple logistic regression., Results: Among the 342 females/young women, 74.9% were black (non-Hispanic), 11.1% Hispanic/Latina, and 14.0% white or other race/ethnicity; 63.5% were HIV infected. Young women who had dropped out of high school comprised 23.4% of subjects. In the 3 months before the interview, 179 (52.3%) adolescents had douched at least once. In a multivariable logistic regression model, recent douching was more common among sexually active females (OR = 2.2; 95% CI: 1.2-4.2), Blacks (OR = 2.2; 95% CI: 1.2-4.1 vs. Hispanics/Whites/others), females who dropped out of high school (OR = 2.1; 95% CI: 1.2-3.7), and HIV infected females (OR = 1.7; 95% CI: 1.04-2.7)., Conclusions: In this nationwide study, adolescents who are sexually active, African-American, dropped out of high school, and HIV infected were most likely to douche. Interventions to discourage douching should pay special attention to these populations.

Purpose: To examine the prevalence of anergy in HIV-infected adolescents and factors associated with its occurrence., Methods: Anergy was defined as less than 2mm induration to each of three intradermally applied antigens (Candida albicans, tetanus toxoid, and mumps) between 24 and 96 hours in a population of HIV-infected adolescents aged 12-18 at entry in a national multicenter study of HIV disease progression. CD4(+) T-cell counts and plasma HIV-1 RNA were measured in quality controlled laboratories. Factors associated with the probability of anergy were examined with contingency table comparisons, tree-structured classification, and logistic regression analyses., Results: Overall prevalence of anergy in this clinic-based population of 167 was 11% [7% in males and 12% in females (p = 0.57)]. The sole significant predictor of anergy was decreased CD4(+) T-cell count (p = 0.005)., Conclusion: The prevalence of anergy is low in this HIV-infected population compared to older infected cohorts. The occurrence of differential rates of anergy in particular age and sex groupings that may be related to intrinsic immunologic differences requires further study.

Purpose: To describe the Reaching for Excellence in Adolescent Care and Health (REACH) Project of the Adolescent Medicine Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) Research Network, a unique collaborative effort to conceive and implement a research design intended to examine HIV pathogenesis, pubertal hormonal variation, and the effects of sexually transmitted disease comorbidity in HIV-infected youth to improve their health care., Methods: This multidisciplinary team has drawn on basic science and clinical experience to produce a study design with relevant and feasible study aims and testable hypotheses. Particular attention has been paid to centralized training and quality control practices. Standardized measurements include direct and computer interviews, physical examination, laboratory analysis, and medical chart abstraction. The protocol has been approved by local institutional review boards., Results: A highly standardized and quality control monitored protocol has been implemented at 16 sites throughout the United States collecting historical, observational, and laboratory data in a group of HIV-infected adolescents and HIV-negative controls. Preliminary data collected on subjects are consistent with published reports of the sociodemographic and clinical characteristics of the HIV epidemic in sexually active youth, thus supporting the integrity of the protocol development process. The study population is, for the most part, in older adolescence, predominantly minority and female, and with publicly financed or no health insurance., Conclusions: The REACH Project is positioned to address questions about the clinical course, immunologic profile, and viral dynamics in HIV-positive youth, and thus is able to inform drug development and management strategies for this understudied population.

A 41-year-old man who presented with a history of sudden loss of consciousness suffered two further episodes during which asystole was documented. Subsequent investigations included exercise stress testing, thallium scintigraphy, electrophysiological studies, CT-scan of chest, Kveim test and a gallium-67 scan, which led to a presumptive diagnosis of averted sudden death as a first presentation of sarcoidosis with primary cardiac involvement.

Of consecutive patients seen with first myocardial infarction (88 of whom were treated out-of-hospital by mobile coronary care staff), 139 received 30 units of intravenous anistreplase at a mean of 101 minutes (range 35-180) from onset of symptoms. Thrombolysis in myocardial infarction patency grade 2 or 3 was found in 76/91 (83.5%) patients. At 3-4 months after hospital discharge, the mean global left ventricular ejection fraction and mean infarct-related regional third ejection fraction declined with increasing delay to anistreplase. For the first, second and third hour administrations, global ejection fraction was 54%, 50% and 45% (P = 0.002) and for regional third ejection fractions 49%, 43% and 41% (P = 0.02) respectively. Of the patients, 130 were reviewed at approximately 1 year: reinfarction had occurred in 9, 6 had undergone coronary angioplasty and 1 had coronary arterial bypass grafting performed since discharge. Mean global left ventricular ejection fraction was 52% and mean infarct-related regional third ejection fraction was 51%. Thus, intravenous anistreplase induces high rates of arterial patency. Global and regional third ejection fractions decline with increasing delay in the time of administration of anistreplase. Mortality and morbidity is low in the first year.

We describe a nonviral transformation strategy for the establishment of permanent cell lines derived from the progeny of individual mouse splenic macrophage (M phi) progenitors. These colony stimulating factor-1 (CSF-1)-dependent cell lines possess many features of mature M phi s, including antibody-dependent phagocytic and cellular cytotoxic activities, ability to secrete lysozyme, and expression of the Mac-1 antigen and mRNA for the CSF-1 receptor. It was also possible to immortalize selected clones of splenic M phi s differing in their constitutive antigen-presenting activities with the retention of the antigen-presenting phenotype in the resultant cell lines. The approach described in this report should be useful in obtaining additional cell lines of M phi s expressing other phenotypes of interest.

Free radical production may cause myocardial damage during reperfusion of ischaemic myocardial tissue; when free radicals interact with polyunsaturated fatty acids or their esters, lipid peroxides are produced. A product of lipid peroxidation, malondialdehyde, was measured in 10 subjects with stable angina who underwent angioplasty of a proximal high-grade stenosis (over 90%) of the left anterior descending coronary artery. In all subjects the duration of balloon occlusion was 60 s. Blood was withdrawn from the great cardiac vein immediately before balloon inflation (T0), immediately after balloon deflation (T60), 15 s after balloon deflation (T75), and 1 min after balloon deflation (T120). There was a significant increase in malondialdehyde at T60 compared with T0 for the first balloon inflation (mean increase 0.3 mumol/l [95% confidence limits 0.1, 0.5]), and at both T60 (0.31 mumol/l [0.15, 0.47]) and T75 (0.22 mumol/l [0.04, 0.40]) for the second balloon inflation. This model could be used to assess antioxidant effects of drugs.

The reported studies have shown that alpha-DL-amino [1-14C]adipic acid is metabolized to radioactive alpha-ketoadipic acid and then to 14CO2 in rat and beef liver homogenates. It was also demonstrated that alpha-keto [1-14C]adipic acid is decarboxylated to 14CO2. The effects of several co-factors and other variables, i.e. alpha-ketoglutarate, pyridoxal phosphate, NAD, thiamine pyrophosphate (TPP), FAD, LA, and pH have also been delimited. These reactions and the effects of the co-factors were also established in freshly drawn leukocytes. Using the methods outlined, a technique for studying the metabolism of alpha-amino-adipate and alpha-ketoadipate in the leukocytes from 10 ml of blood was developed.

The effects of strain, sex, hypophysectomy and hormone treatment on mouse submandibular gland renin, kallikrein, S2266 hydrolase, and BAEe esterase activities have been examined. Renin activity is determined by the Rnr locus on mouse Chromosome 1. Female SWR/J mice (Rnrs/Rnrs) have 1000-fold higher submandibular gland renin activity than C57BL/6J mice (Rnrb/Rnrb). Both strains have similar kallikrein activity. Renin, BAEe esterase, and S2266 hydrolase are substantially higher in male mice compared to females of the same strain whereas kallikrein is not. Dihydrotestosterone and/or thyroxine treatment induces renin, BAEe esterase, and S2266 hydrolase in female mice with little effect on kallikrein. All four enzyme activities are profoundly reduced by hypophysectomy. Dihydrotestosterone and thyroxine are both required to restore renin, BAEe esterase, and S2266 hydrolase to induce levels. Dihydrotestosterone and/or thyroxine restores kallikrein to control levels. We conclude that renin and kallikrein in the mouse submandibular gland are under different genetic and endocrine control. In addition, the synthetic substrate S2266 is not a specific substrate for kallikrein activity in mouse submandibular gland cytosol.

Patients receiving midazolam, temazepam or zopiclone by mouth as premedication for minor gynaecological surgery were pretreated with either ranitidine or an inert tablet. Pretreatment with ranitidine was associated with a greater degree of drowsiness at 20 and 40 min after midazolam, and a shorter mean time to peak hypnotic effect than in the non-pretreated group. Ranitidine did not affect the degree of drowsiness in the patients receiving temazepam or zopiclone.