Epidermal growth factor receptor function in the human urothelium.

PURPOSE: Epidermal growth factor receptor (EGFr)-targeted therapy may be used in subgroups of patients with urinary bladder cancer. Here we assessed the role of EGFr in urothelial proliferation and migration in a two- and three-dimensional cell culture system. METHODS: UROtsa cells derived from normal urothelium and malignant T24 cells were cultured in a Type I collagen gel. Proliferation and migration of urothelial cells, in the absence and presence of the EGFr inhibitor cetuximab, were assessed with a proliferation test (ATCC) and with the Axioplan 2 imaging microscope with a motorized stage (Carl Zeiss), respectively. The expressions of cytokeratin (CK) 17, CK20, EGFr, pEGFr, laminin, occludin and zonula occludens 1 (ZO-1) were assessed with immunohistochemistry and/or western blot. RESULTS: UROtsa spheroids were formed after 7 days in culture, while T24 cells did not form spheroids. UROtsa expressed CK20 but not laminin or CK17 and consequently resembled umbrella cells. In UROtsa and T24, cetuximab inhibited urothelial proliferation, induced cleavage of EGFr and/or pEGFR but did not affect urothelial migration. The tight junction protein occludin was cleaved, and the formation of cellular spheroids was inhibited in UROtsa by the presence of cetuximab. CONCLUSIONS: EGFr modulates urothelial proliferation and the formation of the three-dimensional structure of the urothelium possibly by interfering with occludin. The present data also show a cell culture technique enabling phenotypically normal urothelial cells to form epithelial structures in contrast to malignant urothelial cells.

The Role of Sex Work Pay in Moderating the Effect of Mobile Phone Solicitation on Condom Practices: An Analysis of Female Sex Workers in India.

Mobile phones remain a largely untapped resource in the ongoing challenge to address Female Sex Worker (FSW) health, including HIV prevention services, in India. An important step towards designing effective mobile phone-based initiatives for FSWs is clarifying the contextual influences of mobile phone solicitation on sexual risk behavior. In this paper, we extend previously identified associations between mobile phone solicitation and condom practices by examining whether this association is moderated by sex work pay and offer key considerations for future research and implementation. Specifically, we conducted an analysis among 589 Indian FSWs, where FSWs who did not use mobile phones to solicit clients had the lowest mean sex work pay (INR 394/ USD 6.54) compared to FSWs who used both mobile and traditional strategies (INR 563/ USD 9.34). Our analysis indicate low paid FSWs who used mobile phones concurrently with traditional strategies had 2.46 times higher odds of inconsistent condom use compared to low paid FSWs who did not use mobile phones for client solicitation. No such effect was identified among high paid FSWs. These findings also identified group level differences among FSWs reporting different mobile phone solicitation strategies, including violence, client condom use and HIV status. Our results indicate that low pay does moderate the association between mobile phone solicitation and condom practices, but only among a sub-set of low paid FSWs. These findings also demonstrate the utility of classification by different mobile phone solicitation strategies for accurate assessment of sexual risk among mobile phone soliciting FSWs. In turn, this paves the way for novel approaches to utilize mobile phones for FSW HIV prevention. We discuss one such example, a mobile phone-based rapid screening tool for acute HIV infection targeting Indian FSWs.

Developing a scalable training model in global mental health: pilot study of a video-assisted training Program for Generalist Clinicians in Rural Nepal.

BACKGROUND: In low- and middle-income countries, mental health training often includes sending few generalist clinicians to specialist-led programs for several weeks. Our objective is to develop and test a video-assisted training model addressing the shortcomings of traditional programs that affect scalability: failing to train all clinicians, disrupting clinical services, and depending on specialists. METHODS: We implemented the program -video lectures and on-site skills training- for all clinicians at a rural Nepali hospital. We used Wilcoxon signed-rank tests to evaluate pre- and post-test change in knowledge (diagnostic criteria, differential diagnosis, and appropriate treatment). We used a series of 'Yes' or 'No' questions to assess attitudes about mental illness, and utilized exact McNemar's test to analyze the proportions of participants who held a specific belief before and after the training. We assessed acceptability and feasibility through key informant interviews and structured feedback. RESULTS: For each topic except depression, there was a statistically significant increase (Δ) in median scores on knowledge questionnaires: Acute Stress Reaction (Δ = 20, p = 0.03), Depression (Δ = 11, p = 0.12), Grief (Δ = 40, p < 0.01), Psychosis (Δ = 22, p = 0.01), and post-traumatic stress disorder (Δ = 20, p = 0.01). The training received high ratings; key informants shared examples and views about the training's positive impact and complementary nature of the program's components. CONCLUSION: Video lectures and on-site skills training can address the limitations of a conventional training model while being acceptable, feasible, and impactful toward improving knowledge and attitudes of the participants.

Adherence to Antiretroviral Therapy Among Children Living with HIV in South India.

Adherence to ART, fundamental to treatment success, has been poorly studied in India. Caregivers of children attending HIV clinics in southern India were interviewed using structured questionnaires. Adherence was assessed using a visual analogue scale representing past-month adherence and treatment interruptions >48 h during the past 3 months. Clinical features, correlates of adherence and HIV-1 viral-load were documented. Based on caregiver reports, 90.9 % of the children were optimally adherent. In multivariable analysis, experiencing ART-related adverse effects was significantly associated with suboptimal adherence (p = 0.01). The proportion of children who experienced virological failure was 16.5 %. Virological failure was not linked to suboptimal adherence. Factors influencing virological failure included running out of medications (p = 0.002) and the child refusing to take medications (p = 0.01). Inclusion of drugs with better safety profiles and improved access to care could further enhance outcomes.

Differences in testing, stigma, and perceived consequences of stigmatization among heterosexual men and women living with HIV in Bengaluru, India.

Approximately 2.4 million people in India are living with HIV. Gender inequality affects HIV prevention, detection, and management. The purpose of this paper was to describe gender differences in the experience of living with HIV in Bengaluru, India. A subsample of n = 313 (159 men and 154 women) from a larger cohort was used for these analyses. Participants were recruited through AIDS service organizations. They completed an interviewer-administered survey assessing HIV testing experience, types of stigma, and perceived consequences of stigmatization. The majority of men (67%) reported getting HIV tested because of illness, while women were more likely to be tested after learning their spouse's HIV-positive status (42%). More men (59%) than women (45%, p<0.05) were tested in private care settings. Men reported significantly higher mean levels of internalized stigma (men: M=0.71, SD = 0.63; women: M=0.46, SD = 0.55; p<0.001), whereas the women reported significantly higher scores for enacted stigma (men: M=1.30, SD = 1.69; women: M=2.10, SD = 2.17; p<0.001). These differences remained significant after controlling for potential socio-demographic covariates. Following their diagnosis, more women reported moving out of their homes (men: 16%; women: 26%; p<0.05). More men (89%) than women (66%; p<0.001) reported to have modified their sexual behavior after being diagnosed. These findings suggest that the experience of living with HIV and HIV stigma varies by gender in this population. Suggestions for a gender-based approach to HIV prevention and stigma reduction are provided.

Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice.

We generated mitochondrial late-onset neurodegeneration (MILON) mice with postnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histological changes during the first 5 months of life. The MILON mice display reduced levels of mitochondrial DNA and mitochondrial RNA from 2 and 4 months of age, respectively, and severely respiratory chain-deficient neurons from 4 months of age. Surprisingly, these respiratory chain-deficient neurons are viable for at least 1 month without showing signs of neurodegeneration or major induction of defenses against oxidative stress. Prolonged neuronal respiratory chain deficiency is thus required for the induction of neurodegeneration. Before developing neurological symptoms, MILON mice show increased vulnerability to excitotoxic stress. We observed a markedly enhanced sensitivity to excitotoxic challenge, manifest as an abundance of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactive cells after kainic acid injection, in 4-month-old MILON mice, showing that respiratory chain-deficient neurons are more vulnerable to stress. At approximately 5-5.5 months of age, MILON mice start to show signs of disease, followed by death shortly thereafter. The debut of overt disease in MILON mice coincides with onset of rapidly progressive neurodegeneration and massive cell death in hippocampus and neocortex. This profound neurodegenerative process is manifested as axonal degeneration, gliosis, and abundant TUNEL-positive nuclei. The MILON mouse model provides a novel and powerful tool for additional studies of the role for respiratory chain deficiency in neurodegeneration and aging.

Gay men report high rates of unprotected anal sex with partners of unknown or discordant HIV status.

OBJECTIVE: To examine patterns and factors that correlate with unprotected anal intercourse (UAI) practices among San Francisco gay men, including UAI with partners of unknown or different HIV antibody status. DESIGN: A longitudinal cohort recruited for the San Francisco Young Men's Health Study in 1992; re-assessed annually. PARTICIPANTS AND METHODS: A sample of 510 unmarried gay men who were 18 to 29 years at baseline were originally recruited as part of a larger population and referral-based sample. Subjects participated in four consecutive waves of data collection. RESULTS: The prevalence of reported unprotected anal intercourse (UAI) increased from 37% to 50% between 1993-1994 and 1996-1997. Almost half of all men who reported UAI in 1996-1997 indicated that it occurred with a partner of unknown or discordant HIV antibody status. This high-risk practice correlated with greater numbers of male sex partners, use of nitrite inhalants, sex in commercial sex environments, perceived difficulty controlling sexual risk-taking, and negative emotional reactions following UAI. CONCLUSIONS: These data on increasing rates of sexual risk-taking further confirm trends in sexual behavior previously suggested by rising rates of rectal gonorrhea in this population. Additional and sustained prevention efforts are urgently needed in light of the very high background rates of HIV infection found among gay men in San Francisco.

Traditional Balinese youth groups as a venue for prevention of AIDS and other sexually transmitted diseases.

OBJECTIVES: Our aims were to assess the feasibility of conducting peer-led educational interventions against AIDS and other sexually transmitted diseases (STDs) through traditional Balinese youth groups and to gather information on sexual risk-taking and its correlates among Balinese youth. DESIGN: A cross-sectional survey was conducted, with follow-up questionnaires for pilot intervention participants. SUBJECTS AND METHODS: A self-administered questionnaire was given to 375 subjects (aged 16-25 years) from 12 youth groups representing four main resort areas in Bali. Post-intervention data were collected from 97 of these subjects who had taken part in pilot educational programs. Focus groups supplemented survey data in evaluating the intervention and understanding risk behaviors. RESULTS: In a cross-sectional survey, one-quarter of males and few females reported sexual activity; subsequent focus groups suggested under-reporting by females. While knowledge and worries about HIV/AIDS were high, only 10% of sexually active males and no females reported consistent condom use. The mean age of first sexual intercourse was highly correlated with first alcohol consumption (P = 0.0003). Peer educators from selected youth groups planned and implemented interventions for their own groups. Post-intervention data indicated significant increases in communication about sexual issues with friends and parents. Condom attitudes became less negative and efficacy increased. Participants reported this as a first experience with peer-led health education, preferred interactive activities to adult-led lectures and recommended follow-up educational sessions. CONCLUSIONS: Peer educators from traditional youth groups can plan and conduct prevention programs for HIV/STDs that are well-received by their group memberships. Using such venues may be an efficient way to reach a wide range of pre-sexual Balinese youth, as well as those already at risk for HIV/STD due to unprotected sex, alcohol consumption and multiple sexual partners.

PIP: In a 1995 survey of Balinese youth, 75% expressed a desire to discuss sexual issues and AIDS/sexually transmitted diseases (STDs) with their peers. A cross-sectional survey of 375 young people 16-25 years of age assessed the feasibility of using traditional Balinese youth groups as a vehicle for peer-led AIDS education. In Bali virtually all youth, regardless of educational level or socioeconomic status, join the youth group in their neighborhood at puberty and remain members until they marry. The average age at first intercourse reported in the baseline survey was 18.8 years for males and 20.0 years for females. For 46% of sexually active males, intercourse was accompanied by alcohol consumption. Although youth had adequate knowledge of AIDS before the intervention, only 10% of sexually active males reported consistent condom use. Follow-up interviews with 97 young people from 3 resort areas of Bali who were exposed to the peer-led intervention revealed significant increases in communication about sexual matters with friends and family, more positive attitudes toward condoms, and increased condom use. Exposed youth who participated in focus group discussions expressed a preference for peer-led interactive activities over lectures and indicated they felt more comfortable asking their peers questions about sex. Use of peer educators from Balinese youth groups appears to represent an efficient way to reach young people before the initiation of sexual activity as well as those at high risk of AIDS and other STDs as a result of unprotected sex, alcohol consumption, and multiple sexual partners.

Actual versus perceived HIV status, sexual behaviors and predictors of unprotected sex among young gay and bisexual men who identify as HIV-negative, HIV-positive and untested.

OBJECTIVES: To compare the prevalence and predictors of HIV sexual risk behavior among young gay and bisexual men who perceived themselves to be HIV-negative, HIV-positive, or who were untested. DESIGN: Population-based sample of young gay and bisexual men. METHODS: Using multi-stage probability sampling, 408 gay and bisexual men aged 18-29 years in San Francisco were recruited and interviewed, and blood samples for HIV-testing from 364 participants were obtained. RESULTS: HIV prevalence was 18.7%, although 25% of the men who were HIV-positive did not know it. Thirty-seven per cent reported engaging in unprotected anal intercourse during the past year, including 59% of the men who knew they were HIV-positive, 35% of the men who perceived themselves HIV-negative and 28% of the untested men. Logistic regressions found similar predictors of unprotected intercourse for HIV-negatives and HIV-positives, including sexual impulsivity, substance use, sexual enjoyment and communication problems. CONCLUSIONS: The high rates of unprotected intercourse, particularly among the HIV-positive men, attest to the urgent need for HIV-prevention interventions for young gay and bisexual men. The findings suggest that many of the important variables to target in interventions are similar for both HIV-positive and HIV-negative men.

Differences in sexual behavior among HIV discordant and concordant gay men in primary relationships.

We investigated differences in unprotected anal intercourse among gay men in HIV concordant and discordant primary relationships. Individuals were recruited in 1992 from household- and bar-based samples of gay/bisexual men in Portland, Oregon, and Tucson, Arizona. Respondents were men who reported that they were in primary relationships of > or = 1 month and who reported their own and their partner's HIV status (n = 785). Comparisons were made between three groups: (a) HIV + respondents/HIV + partners; (b) HIV- respondents/HIV- partners; and (c) respondents whose partner's HIV status was different from their own (discordant), on sexual behavior, psychosocial, and demographic variables. Men in HIV concordant relationships reported significantly higher rates of unprotected anal intercourse (54% for +2 and 48% for --) than discordant couples (17%). HIV- men in concordant relationships were more likely to be monogamous (58%) and younger (22% < or = 25 years) than the other two groups. There were no significant differences among the groups regarding the kind of sexual behaviors they engaged in with nonprimary partners. The substantially lower rate of unprotected anal intercourse among men in discordant relationships compared to men in concordant relationships suggests that individuals and couples make judgments about sex and behavior based on knowledge of one's own and one's partner's HIV status.

Differences between gay men in primary relationships and single men: implications for prevention.

This study describes psychological and behavioral differences between gay men in primary relationships and single men from 1985 through 1989. In addition, differences in sexual behavior, relationship status, and relationship quality between HIV positive and HIV negative men were investigated. Data are from the San Francisco Men's Health Study and included only men who were gay identified and who participated in the longitudinal surveys in 1985, 1987 and 1989 (N = 452). Participants were stratified by relationship status and by HIV status. HIV positive men were less likely than HIV negative men to be in primary relationships (38.9% vs. 52.9%, respectively in 1989). In addition, men in relationships had higher rates of unprotected anal intercourse than single men (32.6% vs. 17.0%, respectively in 1989). Differences in psychosocial and behavioral variables were found and have considerable implications for prevention programs and mental health services trying to meet the needs of the gay men's community.

Decisions to get HIV tested and to accept antiretroviral therapies among gay/bisexual men: implications for secondary prevention efforts.

The objective of this study was to report prevalence rates of adherence by HIV-seropositive individuals to medical recommendations for the treatment of HIV infection, a behavioral pattern referred to as AIDS secondary prevention. We report cross-sectional data (n = 2,593) from two household-based and two bar-based samples of gay/bisexual men, gathered in 1992 in Tucson, Arizona, and Portland, Oregon. The main outcome variables were prevalence of HIV antibody testing and adherence to recommended secondary prevention behaviors to prevent onset of AIDS symptoms. Approximately one-third of the gay/bisexual men in these samples do not know their current HIV status. Of the gay/bisexual men who do know that they are HIV-seropositive, approximately three-fourths adhere to each of the secondary prevention recommendations, as appropriate to their stage of disease progression. In a multivariate logistic model, three variables distinguished between HIV-seropositive men who did and did not adhere: perceived antiviral treatment norms (OR = 1.4, CI = 1.1-1.7), perceived efficacy of secondary prevention treatments (OR = 1.4, CI = 1.1-1.7), and quality of the relationship with one's health-care provider (OR = 2.5, CI = 1.6-4.0). These findings indicate that efforts to support AIDS secondary prevention behaviors can occur not only through health education to change the perceptions of at-risk communities about the options available to delay the onset of opportunistic infections among HIV-seropositive individuals but also by enhancing effective doctor/patient communication.

Are bisexually identified men in San Francisco a common vector for spreading HIV infection to women?

OBJECTIVES: This article examines sexual risk taking among self-identified bisexual men in San Francisco and whether risk reduction has occurred, with respect to both homosexual and heterosexual behaviors, among human immunodeficiency virus (HIV) antibody-positive and HIV antibody-negative men. It also examines psychosocial correlates of unprotected anal and vaginal intercourse. METHODS: The participants were members of a population-based longitudinal cohort of 1034 single men aged 25 through 54 years recruited from the 19 census tracts in San Francisco that had the greatest prevalence of the acquired immunodeficiency syndrome in 1984. Of the total sample, 140 subjects initially identified themselves as bisexual; 85% of these men remained in the study. RESULTS: The participants reported dramatic reductions in sexual risk taking. Prevalences of unprotected anal sex with men were similar among HIV-positive bisexual men (89% in 1984-1985 and 18% in 1988-1989) and those who were HIV negative (65% and 20%). The prevalence of unprotected vaginal sex was much lower for HIV-positive men (16% in 1984-1985 and 2% in 1988-1989) than for HIV-negative men (35% and 20%). Unprotected intercourse was associated primarily with situational and interpersonal factors. CONCLUSIONS: Striking reductions in risk behaviors were reported. This subgroup of single, bisexually identified men appears unlikely to be a common vector for spreading HIV infection to women.

Depressive symptoms and CD4 lymphocyte decline among HIV-infected men.

OBJECTIVE: To investigate whether high levels of depressive symptomatology at baseline predict more rapid decline of CD4 lymphocyte counts and progression of clinical disease in persons infected with the human immunodeficiency virus (HIV). DESIGN: Prospective cohort study with semiannual data collection waves and up to 66 months of follow-up. SETTING: Population-based probability sample of single men in areas of San Francisco with high case rates of the acquired immunodeficiency syndrome (AIDS). SUBJECTS: All 330 homosexual or bisexual men who by January 1985 had serological evidence of HIV infection but had not had an AIDS diagnosis. Analysis of CD4 lymphocyte change was performed for 277 subjects (83.9%) who had three or more CD4 lymphocyte counts recorded during the study period January 1985 through July 1990. OUTCOME MEASURES: Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression scale (CES-D). All subjects were classified according to two indicators of depression: (1) as overall depressed using a cut point of 16 or higher on the complete CES-D, and (2) as affectively depressed using a cut point of more than 1 SD above the mean on a subscale of the CES-D measuring affective depression. Laboratory and symptom measures, antiretroviral use, demographics, and behavioral measures were also used. The primary outcome measure was the rate of change of the CD4 lymphocyte count. Secondary outcomes were AIDS-free survival and mortality. RESULTS: At baseline 65 subjects (19.7%) were classified as depressed on the overall scale and 53 (16.1%) were classified as depressed on the affective scale. The unadjusted mean rate of CD4 change was 38% greater for overall depressed subjects than for the overall nondepressed (-0.0812 vs -0.0588 x 10(9)/L [-81.2 vs -58.8/microL per year; P = .07) and 34% greater for affectively depressed subjects than for the affectively nondepressed (-0.0804 vs -0.0598 x 10(9)/L per year; P = .06). In hierarchical multivariate analysis controlling for antiretroviral use, symptoms, and other predictors, baseline overall depression was associated with an excess decline in CD4 count of -0.0285 x 10(9)/L per year (95% confidence interval, -0.0496 to -0.0073), and baseline affective depression was associated with an excess decline in CD4 count of -0.0236 x 10(9)/L per year (95% confidence interval, -0.0464 to -0.0008). Neither overall depression nor affective depression was significantly associated with earlier AIDS diagnosis or earlier mortality. CONCLUSIONS: Overall depression and affective depression predicted a more rapid decline in CD4 lymphocyte counts; this association was not attributable to baseline physiological differences. While the mechanism of the association remains unknown and cannot be addressed directly by this study, the data suggest that it can be explained neither as simply a reflection of perceived somatic symptoms nor as the result of differences in recreational drug and alcohol use. Further study is necessary to determine whether treating depression can alter the course of HIV infection.

Relationship between drug use and sexual behaviors and the occurrence of sexually transmitted diseases among high-risk male youth.

BACKGROUND AND OBJECTIVES: Sexually active adolescents, especially those in detention, are at high risk for acquisition of sexually transmitted diseases (STDs), including HIV infection. Yet little information is available that describes their risk behaviors associated with STDs. The overall objective was to define the relationship between risk behaviors and STD acquisition among adolescents. GOALS OF THIS STUDY: The first goal was to characterize drug use and sexual behaviors that place a population of adolescent male detainees at STD/HIV risk. The second goal was to define possible interrelationships between drug use, especially alcohol use, and risky sexual behaviors with STD acquisition. STUDY DESIGN: The study group consisted of 414 adolescent male detainees 12 to 18 years of age who participated in an interview and a clinical assessment. Two hundred sixty-nine of the 414 subjects agreed to STD laboratory tests, including serologic testing for hepatitis B and syphilis, and urethral cultures to screen for chlamydial and gonorrheal urethritis. RESULTS: Results showed that 15% had current evidence of at least one STD, and 34% had a history or current evidence of at least one STD (STD occurrence). The subjects were frequently engaging in risky sexual and drug use behaviors. Two multivariate models described three factors that significantly place the male adolescent in detention at risk for STDs: multiple sexual partners, inconsistent condom use, and the quantity of alcohol consumed per week. CONCLUSION: Youth in detention place themselves at risk for STDs including HIV because of their risky sexual behavior and drug use. Addressing alcohol use and barriers to condom use appear to be essential components of any STD prevention program targeting this largely minority youth population.

Safer sex among gay men: what is the ultimate goal?

PIP: Sex between homosexual partners in anything other than a mutually monogamous relationship between 2 HIV-negative people involves some risk of virus transmission; a condom must be used during anal intercourse to be considered safe. People, however, have the right to take risks and harm reduction is a long-term, stepwise process. Gay men receive multiple messages which either advocate risk-taking or preach that their sexual needs are bad. Instead of blaming people who occasionally engage in unprotected anal intercourse, people should be trained in skills to reduce their risk; safe sex should be eroticized; and attention should be given to interpersonal or social conditions which may lead to unsafe sex. Society must be challenged to support the messages of risk reduction and the sexual needs of all members of society. The authors further call for the recognition of various risk reduction strategies such as negotiated safety taken by gay men despite the potential problem of this strategy which relies upon the ability of sex partners to reveal their serostatus. The authors also stress that while the goal of eliminating unsafe sex and new HIV infections must be upheld, it is untenable. The understanding that this goal will never be realized, however, does not mean that efforts should not continue to educate and convince people to take better care of themselves. While no infringing upon individual rights, researchers should help prevent all future HIV infections.^ieng