The application of latent variable models to the assessment of determinants of HIV risk behavior

Studies on the relationship between psychosocial determinants and HIV risk behaviors have produced little evidence to support hypotheses based on theoretical relationships. One limitation inherent in many articles in the literature is the method of measurement of the determinants and the analytic approach selected. ^ To reduce the misclassification associated with unit scaling of measures specific to internalized homonegativity, I evaluated the psychometric properties of the Reactions to Homosexuality scale in a confirmatory factor analytic framework. In addition, I assessed the measurement invariance of the scale across racial/ethnic classifications in a sample of men who have sex with men. The resulting measure contained eight items loading on three first-order factors. Invariance assessment identified metric and partial strong invariance between racial/ethnic groups in the sample. ^ Application of the updated measure to a structural model allowed for the exploration of direct and indirect effects of internalized homonegativity on unprotected anal intercourse. Pathways identified in the model show that drug and alcohol use at last sexual encounter, the number of sexual partners in the previous three months and sexual compulsivity all contribute directly to risk behavior. Internalized homonegativity reduced the likelihood of exposure to drugs, alcohol or higher numbers of partners. For men who developed compulsive sexual behavior as a coping strategy for internalized homonegativity, there was an increase in the prevalence odds of risk behavior. ^ In the final stage of the analysis, I conducted a latent profile analysis of the items in the updated Reactions to Homosexuality scale. This analysis identified five distinct profiles, which suggested that the construct was not homogeneous in samples of men who have sex with men. Lack of prior consideration of these distinct manifestations of internalized homonegativity may have contributed to the analytic difficulty in identifying a relationship between the trait and high-risk sexual practices. ^

An update on pathobiologic roles of anti-glycan antibodies in Guillain-Barré syndrome.

Anti-glycan antibodies directed against gangliosides are now considered the major immune effectors that induce damage to intact nerve fibers in some variants of the monophasic neuropathic disorders that comprise Guillain-Barré syndrome. Recent experimental studies elucidating the complexity of anti-glycan antibody-mediated pathobiologic effects on intact and injured nerves undergoing repair are discussed.

Enforced expression of Tbx1 in fetal thymic epithelial cells antagonizes thymus organogenesis

Enforced expression of Tbx1 in fetal thymic epithelial cells antagonizes thymus organogenesis Kim T. Cardenas The thymus and parathyroid glands originate from organ-specific domains of 3rd pharyngeal pouch (PP) endoderm. At embryonic day 11.5 (E11.5), the ventral thymus and dorsal parathyroid domains can be identified by Foxn1 and Gcm2 expression respectively. Neural crest cells, (NCCs) play a role in regulating patterning of 3rd PP endoderm. In addition, pharyngeal endoderm influences fate determination via secretion of Sonic hedgehog (Shh), a morphogen required for Gcm2 expression and generation of the parathyroid domain. Gcm2 is a downstream target of the transcription factor Tbx1, which in turn is positively regulated by Shh. Although initially expressed throughout pharyngeal pouch endoderm, Tbx1 expression is excluded from the thymus-specific domain of the 3rd PP by E10.5, but persists in the parathyroid domain. Based on these observations, we hypothesized that Tbx1 expression is non-permissive for thymus fate specification and that enforced expression of Tbx1 in the fetal thymus would impair thymus development. To test this hypothesis, we generated knock-in mice containing a Cre-inducible allele that allows for tissue-specific Tbx1 expression. Expression of the R26iTbx1 allele in fetal and adult thymus using Foxn1Cre resulted in severe thymus hypoplasia throughout ontogeny that persisted in the adult. Thymic epithelial cell (TEC) development was impaired as determined by immunohistochemical and FACS analysis of various differentiation markers. The relative level of Foxn1 expression in fetal TECs was significantly reduced. TECs in R26iTbx1/+ thymi assumed an almost universal expression of Plet-1, a marker associated with a TEC stem/progenitor cell fate. In addition, embryonic R26iTbx1/+ mice develop a perithymic mesechymal capsule that appears expanded compared to control littermates. Interestingly, thymi from neonatal and adult R26iTbx1/+ but not R26+/+ mice were encased in adipose tissue. This thymic phenotype also correlated with a decrease in thymocyte cellularity and aberrant thymocyte differentiation. The results to date support the conclusion that enforced expression of Tbx1 in TECs antagonizes their differentiation and prevents normal organogenesis via both direct and indirect effects.

Crack and powder cocaine federal legislation: A sentencing disparity and potential for policy improvement

Since its introduction into the United States in the 1980s, crack cocaine has been a harsh epidemic that has taken its toll on a countless number of people. This highly addictive, cheap and readily available drug of abuse has permeated many demographic sectors, mostly in low income, lesser educated, and urban communities. This epidemic of crack cocaine use in inner city areas across the Unites States has been described as an expression of economic marginality and “social suffering” coupled with the local and international forces of drug market economies (Agar 2003). As crack cocaine is a derivative of cocaine, it utilizes the psychoactive component of the drug, but delivers it in a much stronger, quicker, and more addictive fashion. This, coupled with its ready availability and cheap price has allowed for users to not only become very addicted very quickly, but to be subject to the stringent and sometimes unequal or inconsistent punishments for possession and distribution of crack-cocaine. ^ There are many public health and social ramifications from the abuse of crack-cocaine, and these epidemics appear to target low income and minority groups. Public health issues relating to the physical, mental, and economic strain will be addressed, as well as the direct and indirect effects of the punishments that come as a result of the disparity in penalties for cocaine and crack-cocaine possession and distribution. ^ Three new policies have recently been introduced into the United Stated Congress that actively address the disparity in sentencing for drug and criminal activities. They are, (1) Powder-Crack Cocaine Penalty Equalization Act of 2009, (HR 18, 111th Cong. 2009), (2) The Drug Sentencing Reform and Cocaine Kingpin Trafficking Act of 2009, (HR 265, 111th Cong. 2009) and (3) The Justice Integrity Act of 2009, (111th Cong. 2009). ^ Although they have only been initiated, if passed, they have potential to not only eliminate the crack-cocaine disparity, but to enact laws that help those affected by this epidemic. The final and overarching goal of this paper is to analyze and ultimately choose the ideal policy that would not only eliminate the cocaine and crack disparity regardless of current or future state statutes, but will provide the best method of rehabilitation, prevention, and justice. ^

THE DISCHARGED PSYCHIATRIC PATIENT: POST-HOSPITAL ADJUSTMENT AND FACTORS AFFECTING REHOSPITALIZATION

Discharged psychiatric patients were studied six months post-discharge to determine those demographic, social and clinical characteristics affecting positive or negative adjustment and the degree to which the use of mental health services and medication compliance mediated the effects. With the exception of those with primary or secondary diagnoses of OBS, substance abuse or mental retardation, sixty-three psychiatric subjects between the ages of eighteen and sixty-four were chosen from all admissions into the hospital and interviewed six months after discharge using a specially designed questionnaire.^ The subjects' adjustment to community living was found to be marginal. Although not engaged in destructive activities, over half were living with their family members who supported them financially and emotionally. Most were unemployed and had been so for a long time. Others worked sporadically and frequently changed residences. Most did have substantial social ties with extended family and with friends with whom they interacted regularly, but one-fourth were socially isolated. Almost three-quarters continued to obtain regular mental health services after discharge and followed medication instructions under the supervision of their physician. The use of mental health services after discharge and the use of medication did not appear to affect the subjects' community adaption or their rate of rehospitalization.^ Forty percent of those discharged were rehospitalized by the end of the follow-up period. Four levels of risk of rehospitalization emerged. The highest risk was associated with a history of five or more prior hospitalizations, living alone, and social isolation. One third or more of the subjects expressed a need for more counseling, leisure time activities, case-manager assistance, vocational guidance, supervised housing, and placement into a transitional residential treatment program.^ Recommendations were made to enhance the ability to predict recidivism, to develop interorganizational casework management programs linking the patient and family to the community mental health system and to create computerized tracking and monitoring programs that systematically report patient treatment regimen and progress cross-sectionally and longitudinally. ^

Biological effects of PEA3 expression in {\it HER-2\/}/{\it neu\/}-overexpressing human cancer cells and the molecular mechanisms of PEA3-mediated transcriptional repression on {\it HER-2\/}/{\it neu\/}

HER-2/neu is a receptor tyrosine kinase highly homologous with epidermal growth factor receptor. Overexpression and/or amplification of HER-2/neu has been implicated in the genesis of a number of human cancers, especially breast and ovarian cancers. Transcriptional upregulation has been shown to contribute significantly to the overexpression of this gene. Studies on the transcriptional regulation of HER-2/neu gene are important for understanding the mechanism of cell transformation and developing the therapeutic strategies to block HER-2/neu-mediated cancers. PEA3 is a DNA binding transcriptional factor and its consensus sequence exists on the HER-2/neu promoter. To examine the role of PEA3 in HER-2/neu expression and cell transformation, we transfected PEA3 into the human breast and ovarian cancer cells that overexpress HER-2/neu and showed that PEA3 dramatically represses HER-2/neu transcription. PEA3 suppresses the oncogenic neu-mediated transformation in mouse fibroblast NIH 3T3 cells. Expression of PEA3 selectively blocks the growth of human cancer cells that overexpress HER-2/neu and inhibits their colony formation. It does not occur in the cancer cells expressing basal level of HER-2/neu. Further studies in the orthotopic ovarian cancer model demonstrated that expression of PEA3 preferentially inhibits growth and tumor development of human cancer cells that overexpress HER-2/neu, the tumor-bearing mice survived significantly longer if treated by injection of the PEA3-liposome complex intraperitoneally. Immunoblotting and immunohistochemical analysis of the tumor tissues indicated that PEA3 mediates the tumor suppression activity through targeting HER-2/neu-p185. Thus, PEA3 is a negative regulator of HER-2/neu gene expression and functions as a tumor suppressor gene in the HER-2/neu-overexpressing human cancer cells.^ The molecular mechanisms of PEA3 mediated transcriptional repression were investigated. PEA3 binds specifically at the PEA3 site on HER-2/neu promoter and this promoter-binding is required for the PEA3 mediated transcriptional repression. Mutation of the PEA3 binding site on HER-2/neu promoter causes decreased transcriptional activity, indicating that the PEA3 binding site is an enhancer-like element in the HER-2/neu-overexpressing cells. We therefore hypothesized that in the HER-2/neu-overexpressing cells, PEA3 competes with a transactivator for binding to the PEA3 site, preventing the putative factor from activating the transcription of HER-2/neu. This hypothesis was supported by the data which demonstrate that PEA3 competes with another nuclear protein for binding to the HER-2/neu promoter in vitro, and expression of a truncated protein which encodes the DNA binding domain of PEA3 is sufficient to repress HER-2/neu transcription in the HER-2/neu-overexpressing human cancer cells. ^