Massachusetts Justice Community Opioid Innovation Network (MassJCOIN).

A major driver of the U.S. opioid crisis is limited access to effective medications for opioid use disorder (MOUD) that reduce overdose risks. Traditionally, jails and prisons in the U.S. have not initiated or maintained MOUD for incarcerated individuals with OUD prior to their return to the community, which places them at high risk for fatal overdose. A 2018 law (Chapter 208) made Massachusetts (MA) the first state to mandate that five county jails deliver all FDA-approved MOUDs (naltrexone [NTX], buprenorphine [BUP], and methadone). Chapter 208 established a 4-year pilot program to expand access to all FDA-approved forms of MOUD at five jails, with two more MA jails voluntarily joining this initiative. The law stipulates that MOUD be continued for individuals receiving it prior to detention and be initiated prior to release among sentenced individuals where appropriate. The jails must also facilitate continuation of MOUD in the community on release. The Massachusetts Justice Community Opioid Innovation Network (MassJCOIN) partnered with these seven diverse jails, the MA Department of Public Health, and community treatment providers to conduct a Type 1 hybrid effectiveness-implementation study of Chapter 208. We will: (1) Perform a longitudinal treatment outcome study among incarcerated individuals with OUD who receive NTX, BUP, methadone, or no MOUD in jail to examine postrelease MOUD initiation, engagement, and retention, as well as fatal and nonfatal opioid overdose and recidivism; (2) Conduct an implementation study to understand systemic and contextual factors that facilitate and impede delivery of MOUDs in jail and community care coordination, and strategies that optimize MOUD delivery in jail and for coordinating care with community partners; (3) Calculate the cost to the correctional system of implementing MOUD in jail, and conduct an economic evaluation from state policy-maker and societal perspectives to compare the value of MOUD prior to release from jail to no MOUD among matched controls. MassJCOIN made significant progress during its first six months until the COVID-19 pandemic began in March 2020. Participating jail sites restricted access for nonessential personnel, established other COVID-19 mitigation policies, and modified MOUD programming. MassJCOIN adapted research activities to this new reality in an effort to document and account for the impacts of COVID-19 in relation to each aim. The goal remains to produce findings with direct implications for policy and practice for OUD in criminal justice settings.

Nuclear Focal Adhesion Kinase Controls Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia Through GATA4-Mediated Cyclin D1 Transcription.

RATIONALE: Neointimal hyperplasia is characterized by excessive accumulation of vascular smooth muscle cells (SMCs) leading to occlusive disorders, such as atherosclerosis and stenosis. Blood vessel injury increases growth factor secretion and matrix synthesis, which promotes SMC proliferation and neointimal hyperplasia via FAK (focal adhesion kinase). OBJECTIVE: To understand the mechanism of FAK action in SMC proliferation and neointimal hyperplasia. METHODS AND RESULTS: Using combined pharmacological FAK catalytic inhibition (VS-4718) and SMC-specific FAK kinase-dead (Myh11-Cre-ERT2) mouse models, we report that FAK regulates SMC proliferation and neointimal hyperplasia in part by governing GATA4- (GATA-binding protein 4) cyclin D1 signaling. Inhibition of FAK catalytic activity facilitates FAK nuclear localization, which is required for proteasome-mediated GATA4 degradation in the cytoplasm. Chromatin immunoprecipitation identified GATA4 binding to the mouse cyclin D1 promoter, and loss of GATA4-mediated cyclin D1 transcription diminished SMC proliferation. Stimulation with platelet-derived growth factor or serum activated FAK and redistributed FAK from the nucleus to cytoplasm, leading to concomitant increase in GATA4 protein and cyclin D1 expression. In a femoral artery wire injury model, increased neointimal hyperplasia was observed in parallel with elevated FAK activity, GATA4 and cyclin D1 expression following injury in control mice, but not in VS-4718-treated and SMC-specific FAK kinase-dead mice. Finally, lentiviral shGATA4 knockdown in the wire injury significantly reduced cyclin D1 expression, SMC proliferation, and neointimal hyperplasia compared with control mice. CONCLUSIONS: Nuclear enrichment of FAK by inhibition of FAK catalytic activity during vessel injury blocks SMC proliferation and neointimal hyperplasia through regulation of GATA4-mediated cyclin D1 transcription.

Extended-Release Naltrexone Improves Viral Suppression Among Incarcerated Persons Living With HIV With Opioid Use Disorders Transitioning to the Community: Results of a Double-Blind, Placebo-Controlled Randomized Trial.

OBJECTIVE: To determine whether extended-release naltrexone (XR-NTX) would improve or maintain viral suppression (VS) among prisoners or jail detainees with HIV and opioid use disorder (OUD) transitioning to the community. DESIGN: A 4-site, prospective randomized double-blind, placebo-controlled trial was conducted among prison and jail inmates with HIV and OUD transitioning to the community from September 2010 through March 2016. METHODS: Eligible participants (N = 93) were randomized 2:1 to receive 6 monthly injections of XR-NTX (n = 66) or placebo (n = 27) starting at release and observed for 6 months. The primary outcome was the proportion that maintained or improved VS (<50 copies/mL) from baseline to 6 months. RESULTS: Participants allocated to XR-NTX significantly improved to VS (<50 copies/mL) from baseline (37.9%) to 6 months (60.6%) (P = 0.002), whereas the placebo group did not (55.6% at baseline to 40.7% at 6 months P = 0.294). There was, however, no statistical significant difference in VS levels at 6 months between XR-NTX (60.6%) vs. placebo (40.7%) (P = 0.087). After controlling for other factors, only allocation to XR-NTX (adjusted odds ratio = 2.90; 95% confidence interval = 1.04 to 8.14, P = 0.043) was associated with the primary outcome. Trajectories in VS from baseline to 6 months differed significantly (P = 0.017) between treatment groups, and the differences in the discordant values were significantly different as well (P = 0.041): the XR-NTX group was more likely than the placebo group to improve VS (30.3% vs. 18.5%), maintain VS (30.3% vs. 27.3), and less likely to lose VS (7.6% vs. 33.3%) by 6 months. CONCLUSIONS: XR-NTX improves or maintains VS after release to the community for incarcerated people living with HIV with OUD.

Extended-release naltrexone for opioid use disorder started during or following incarceration.

A western Massachusetts county jail began initiating extended-release naltrexone (XR-NTX) prior to release from incarceration and linking participants to community treatment providers upon release. Program barriers prevented the start of XR-NTX prior to release for a subset. METHODS: This report consists of the initial 67 jail releasees with opioid dependence, 47 who received XR-NTX before release, and 20 after release. Utility of the program was assessed by determining medication addiction treatment (MAT) retention rates at 4, 8, and 24 weeks. RESULTS: Forty-seven commenced XR-NTX approximately 7 days prior to release, and 20 were referred to commence XR-NTX at outpatient treatment centers. Rate of retention at week 4 was higher in group with treatment initiation prior to release as compared to those started in community: week 4: 55% (24 XR-NTX+2 agonist MAT out of 47) versus 25% (4 XR-NTX+1 agonist MAT out of 20) (p=0.03); week 8: 36% (13 XR-NTX+4 agonist) versus 25% (3 XR-NTX+2 agonist) (p=0.41); week 24: 21% (6 XR-NTX+4 agonist) versus 15% (1 XR-NTX+2 agonist) (p=0.74). Three patients died, all in the pre-release group, all from overdose at 3-5months after release and 2.5 or more months after stopping XR-NTX, compared to none of 20 in community group (p=0.55). Limitations include that cohorts were non-random and observational; substance use could not be consistently determined; and overdose deaths in MA occurred partly in clusters, limiting historical comparisons. CONCLUSIONS: Receiving XR-NTX prior to jail release for opioid use disorder appears to increase the treatment retention rate as compared to commencing after release. The treatment attrition and striking rate of overdose deaths are concerning, and support expanded availability of opioid agonist treatments prior to release and other evidence-based supports and retention strategies in the community.

Pain is Associated with Missed Clinic Visits Among HIV-Positive Women.

Pain is highly prevalent among HIV-positive individuals, with women representing a large subset of those with pain. However, little is known about the relationship between pain and retention in HIV medical care. Among a cohort of HIV-positive women of color, we evaluated the association between pain and retention in care, as measured by missed clinic visits. The Health Resources and Services Administration's Women of Color Initiative was a multi-site observational cohort study evaluating demonstration projects to engage HIV-positive women in medical care. From November 2010 to July 2013, 921 women were enrolled in the study across nine U.S. sites; baseline interviews collected data on socio-demographic, clinical, and risk behavior characteristics. Pain was assessed at baseline based on number of days in pain over the last 30 days and was categorized as no pain (0 days), infrequent pain (1-13 days), and frequent pain (14-30 days), with 14 days being the median. Missed visits over the one-year follow-up period, evaluated by chart abstraction, were dichotomized as ≤1 missed visit versus >1 missed visit. We conducted multivariate logistic regression to assess the association between pain at baseline and missed visits, adjusting for pertinent covariates. Among our sample (N = 862), 52.2 % of women reported no pain, 23.7 % reported infrequent pain and 24.1 % reported frequent pain. Forty-five percent had >1 missed visit during the one-year follow-up period. Overall, we did not find a significant association between pain and missed visits (aOR 2.30; 95 % CI 1.00-5.25). However, in planned stratified analyses, among women reporting current substance use at baseline, reporting frequent pain was associated with a higher odds of missed visits as compared with reporting no pain (aOR 15.14; 95 % CI 1.78-128.88). In our overall sample, pain was not significantly associated with missed visits. However, frequent pain was associated with missed visits among HIV-positive women of color who reported substance use at baseline. A better understanding of the relationship between pain and missed visits could guide efforts to improve retention in care in this population.

Vascular smooth muscle cell contractile protein expression is increased through protein kinase G-dependent and -independent pathways by glucose-6-phosphate dehydrogenase inhibition and deficiency.

Homeostatic control of vascular smooth muscle cell (VSMC) differentiation is critical for contractile activity and regulation of blood flow. Recently, we reported that precontracted blood vessels are relaxed and the phenotype of VSMC is regulated from a synthetic to contractile state by glucose-6-phosphate dehydrogenase (G6PD) inhibition. In the current study, we investigated whether the increase in the expression of VSMC contractile proteins by inhibition and knockdown of G6PD is mediated through a protein kinase G (PKG)-dependent pathway and whether it regulates blood pressure. We found that the expression of VSMC-restricted contractile proteins, myocardin (MYOCD), and miR-1 and miR-143 are increased by G6PD inhibition or knockdown. Importantly, RNA-sequence analysis of aortic tissue from G6PD-deficient mice revealed uniform increases in VSMC-restricted genes, particularly those regulated by the MYOCD-serum response factor (SRF) switch. Conversely, expression of Krüppel-like factor 4 (KLF4) is decreased by G6PD inhibition. Interestingly, the G6PD inhibition-induced expression of miR-1 and contractile proteins was blocked by Rp-ß-phenyl-1,N2-etheno-8-bromo-guanosine-3',5'-cyclic monophosphorothioate, a PKG inhibitor. On the other hand, MYOCD and miR-143 levels are increased by G6PD inhibition through a PKG-independent manner. Furthermore, blood pressure was lower in the G6PD-deficient compared with wild-type mice. Therefore, our results suggest that the expression of VSMC contractile proteins induced by G6PD inhibition occurs via PKG1α-dependent and -independent pathways.

Prevalence and Predictors of Mental/Emotional Distress Among HIV+ Jail Detainees at Enrollment in an Observational Study.

This study evaluates the prevalence of mental/emotional distress and its specific correlates among people living with HIV/AIDS (PLWHA) in 20 jail systems across the United States. Of the 878 PLWHA jail detainees, 52% had high levels of mental/emotional distress, defined by the composite Addiction Severity Index score. High mental/emotional distress was found to be associated with the inmate living in a city with lower income inequality, lower health ranking, and higher degree of danger. Proximate variables included being female, bisexual orientation, poorer physical health, and increased severity of substance abuse. Inmates in jails with accredited health services and those satisfied with family support had lower mental/emotional distress scores. These findings indicate the need for expanded mental health assessment of PLWHAs entering jail.

Design and methods of a double blind randomized placebo-controlled trial of extended-release naltrexone for HIV-infected, opioid dependent prisoners and jail detainees who are transitioning to the community.

BACKGROUND: People with opioid dependence and HIV are concentrated within criminal justice settings (CJS). Upon release, however, drug relapse is common and contributes to poor HIV treatment outcomes, increased HIV transmission risk, reincarceration and mortality. Extended-release naltrexone (XR-NTX) is an evidence-based treatment for opioid dependence, yet is not routinely available for CJS populations. METHODS: A randomized, double-blind, placebo-controlled trial of XR-NTX for HIV-infected inmates transitioning from correctional to community settings is underway to assess its impact on HIV and opioid-relapse outcomes. RESULTS: We describe the methods and early acceptability of this trial. In addition we provide protocol details to safely administer XR-NTX near community release and describe logistical implementation issues identified. Study acceptability was modest, with 132 (66%) persons who consented to participate from 199 total referrals. Overall, 79% of the participants had previously received opioid agonist treatment before this incarceration. Thus far, 65 (49%) of those agreeing to participate in the trial have initiated XR-NTX or placebo. Of the 134 referred patients who ultimately did not receive a first injection, the main reasons included a preference for an alternative opioid agonist treatment (37%), being ineligible (32%), not yet released (10%), and lost upon release before receiving their injection (14%). CONCLUSIONS: Study findings should provide high internal validity about HIV and opioid treatment outcomes for HIV-infected prisoners transitioning to the community. The large number of patients who ultimately did not receive the study medication may raise external validity concerns due to XR-NTX acceptability and interest in opioid agonist treatments. CLINICAL TRIAL NUMBER: NCT01246401.

Transcriptional regulation of α1H T-type calcium channel under hypoxia.

The low-voltage-activated T-type Ca(2+) channels play an important role in mediating the cellular responses to altered oxygen tension. Among three T-type channel isoforms, α1G, α1H, and α1I, only α1H was found to be upregulated under hypoxia. However, mechanisms underlying such hypoxia-dependent isoform-specific gene regulation remain incompletely understood. We, therefore, studied the hypoxia-dependent transcriptional regulation of α1G and α1H gene promoters with the aim to identify the functional hypoxia-response elements (HREs). In rat pulmonary artery smooth muscle cells (PASMCs) and pheochromocytoma (PC12) cells after hypoxia (3% O2) exposure, we observed a prominent increase in α1H mRNA at 12 h along with a significant rise in α1H-mediated T-type current at 24 and 48 h. We then cloned two promoter fragments from the 5'-flanking regions of rat α1G and α1H gene, 2,000 and 3,076 bp, respectively, and inserted these fragments into a luciferase reporter vector. Transient transfection of PASMCs and PC12 cells with these recombinant constructs and subsequent luciferase assay revealed a significant increase in luciferase activity from the reporter containing the α1H, but not α1G, promoter fragment under hypoxia. Using serial deletion and point mutation analysis strategies, we identified a functional HRE at site -1,173cacgc-1,169 within the α1H promoter region. Furthermore, an electrophoretic mobility shift assay using this site as a DNA probe demonstrated an increased binding activity to nuclear protein extracts from the cells after hypoxia exposure. Taken together, these findings indicate that hypoxia-induced α1H upregulation involves binding of hypoxia-inducible factor to an HRE within the α1H promoter region.

An evaluation of hepatic enzyme elevations among HIV-infected released prisoners enrolled in two randomized placebo-controlled trials of extended release naltrexone.

Extended-release naltrexone (XR-NTX), an approved treatment for opioid or alcohol dependence, is a once-monthly injectable formulation of naltrexone. Hepatotoxicity concerns have limited its use, necessitating further investigation. This study aims to examine hepatic enzyme levels in participants of 2 randomized placebo-controlled trials (RCTs) of XR-NTX. Hepatic transaminases were measured in 85 patients enrolled in RCTs of XR-NTX among HIV-infected prisoners, transitioning to the community and receiving treatment for either dependence on alcohol (52.9%), opioids (44.7%) or both (16.5%). Baseline characteristics included HCV co-infection (55.7%), antiretroviral therapy (81%), mental illness (39%) and receiving psychiatric medications (34.1%). Levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were not statistically different between persons randomized to placebo (N=24) and XR-NTX (N=61) arms. These results confirm that XR-NTX is safe to use among opioid and alcohol dependent HIV-infected released prisoners receiving ART with high rates of co-morbid HCV infection and mental illness.

Screening for sexually transmitted diseases in short-term correctional institutions: summary of evidence reviewed for the 2010 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines.

Young persons entering US jails and youth detention facilities have high rates of sexually transmitted diseases (STDs). The Centers for Disease Control and Prevention added STD screening guidelines specific to correctional settings to the 2010 STD Treatment Guidelines. This article summarizes published evidence from 1990 to 2009 used to develop the recommendations. The literature supports routine screening of adolescents and young women (aged ≤35 years, or on the basis of local institutional prevalence data) for chlamydia and gonorrhea because of high prevalence and the subsequent risk of adverse reproductive outcomes. Chlamydia positivity among young women (aged <20 years) in juvenile detention facilities and adult facilities is more than 14%. Men in correctional settings are also at high risk for chlamydia and gonorrhea. Among boys in juvenile detention facilities, chlamydia positivity is estimated at 6.6%; among young men in adult facilities, positivity is 16.6%. Screening men (to reduce sequelae among women) should be considered based on local epidemiology and resource availability. Syphilis screening is not strongly supported in published literature because of low prevalence and is not routinely recommended; however, some screening may be warranted based on local prevalence. Although there is a great diversity in the organization of correctional facilities, implementation of screening recommendations is possible owing to improvements in test technology (urine specimens) and through integration of a standard screening protocol. Based on the high burden of disease and substantial opportunities to reach a high-risk population, correctional facilities are important venues to target efforts to control STDs.

Contribution of substance use disorders on HIV treatment outcomes and antiretroviral medication adherence among HIV-infected persons entering jail.

HIV and substance use are inextricably intertwined. One-sixth of people living with HIV/AIDS (PLWHA) transition through the correctional system annually. There is paucity of evidence on the impact of substance use disorders on HIV treatment engagement among jail detainees. We examined correlates of HIV treatment in the largest sample of PLWHA transitioning through jail in 10 US sites from 2007 to 2011. Cocaine, alcohol, cannabis, and heroin were the most commonly used substances. Drug use severity was negatively and independently correlated with three outcomes just before incarceration: (1) having an HIV care provider (AOR = 0.28; 95 % CI 0.09-0.89); (2) being prescribed antiretroviral therapy (AOR = 0.12; 95 % CI 0.04-0.35) and (3) high levels (>95 %) of antiretroviral medication adherence (AOR = 0.18; 95 % CI 0.05-0.62). Demographic, medical and psychiatric comorbidity, and social factors also contributed to poor outcomes. Evidence-based drug treatments that include multi-faceted interventions, including medication-assisted therapies, are urgently needed to effectively engage this vulnerable population.

Hypoxic depression of PKG-mediated inhibition of serotonergic contraction in ovine carotid arteries.

Chronic hypoxia attenuates soluble guanylate cyclase-induced vasorelaxation in serotonin (5-HT)-contracted ovine carotid arteries. Because protein kinase G (PKG) mediates many effects of soluble guanylate cyclase activation through phosphorylation of multiple kinase targets in vascular smooth muscle, we tested the hypothesis that chronic hypoxia reduces the ability of PKG to phosphorylate its target proteins, which attenuates the ability of PKG to induce vasorelaxation. We also tested the hypothesis that hypoxia attenuates PKG expression and/or activity. Arteries from normoxic and chronically hypoxic (altitude of 3,820 m for 110 days) fetal and adult sheep were denuded of endothelium and equilibrated with 95% O2-5% CO2 in the presence of nitro-l-arginine methyl ester (l-NAME) and N(G)-nitro-l-arginine (l-NNA) to inhibit residual endothelial nitric oxide synthase. Concentration-response relations for 5-HT were determined in the presence of prazosin to minimize activation of α-adrenergic receptors. The PKG activator 8-(p-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (8-pCTP-cGMP) reduced agonist binding affinity of the 5-HT receptor in a concentration-dependent manner that was attenuated by hypoxia. Expression and activity of PKG-I was not significantly affected by chronic hypoxia in either fetal or adult arteries, although PKG-I abundance was greater in fetal arteries. Pretreatment with the large conductance calcium-sensitive potassium channel (BK) inhibitor iberiotoxin attenuated the vasorelaxation induced by 8-pCPT-cGMP in normoxic but not chronically hypoxic arteries. These results support the hypothesis that hypoxia attenuates the vasorelaxant effects of PKG through suppression of the ability of PKG to activate large conductance calcium-sensitive potassium channels in arterial smooth muscle. The results also reveal that this hypoxic effect is greater in fetal than adult arteries and that chronic maternal hypoxia can profoundly affect fetal vascular function.

MicroRNA-145 restores contractile vascular smooth muscle phenotype and coronary collateral growth in the metabolic syndrome.

OBJECTIVE: Transient, repetitive occlusion stimulates coronary collateral growth (CCG) in normal animals. Vascular smooth muscle cells (VSMCs) switch to synthetic phenotype early in CCG, then return to contractile phenotype. CCG is impaired in the metabolic syndrome. We determined whether impaired CCG was attributable to aberrant VSMC phenotypic modulation by miR-145-mediated mechanisms, and whether restoration of physiological miR-145 levels in metabolic syndrome (JCR rat) improved CCG. APPROACH AND RESULTS: CCG was stimulated by transient, repetitive left anterior descending artery occlusion and evaluated after 9 days by coronary blood flow measurements (microspheres). miR-145 was delivered to JCR VSMCs via adenoviral vector (miR-145-Adv). In JCR rats, miR-145 was decreased late in CCG (≈ 2-fold day 6; ≈ 4-fold day 9 versus SD), which correlated with decreased expression of smooth muscle-specific contractile proteins (≈ 5-fold day 6; ≈ 10-fold day 9 versus SD), indicative of VSMCs' failure to return to the contractile phenotype late in CCG. miR-145 expression in JCR rats (miR-145-Adv) on days 6 to 9 of CCG completely restored VSMCs contractile phenotype and CCG (collateral/normal zone flow ratio was 0.93 ± 0.09 JCR+miR-145-Adv versus 0.12 ± 0.02 JCR versus 0.87 ± 0.02 SD). CONCLUSIONS: Restoration of VSMC contractile phenotype through miR-145 delivery is a highly promising intervention for restoration of CCG in the metabolic syndrome.

Adherence to HIV treatment and care among previously homeless jail detainees.

HIV-infected persons entering the criminal justice system (CJS) often experience suboptimal healthcare system engagement and social instability, including homelessness. We evaluated surveys from a multisite study of 743 HIV-infected jail detainees prescribed or eligible for antiretroviral therapy (ART) to understand correlates of healthcare engagement prior to incarceration, focusing on differences by housing status. Dependent variables of healthcare engagement were: (1) having an HIV provider, (2) taking ART, and (3) being adherent (≥95% of prescribed doses) to ART during the week before incarceration. Homeless subjects, compared to their housed counterparts, were significantly less likely to be engaged in healthcare using any measure. Despite Ryan White funding availability, insurance coverage remains insufficient among those entering jails, and having health insurance was the most significant factor correlated with having an HIV provider and taking ART. Individuals interfacing with the CJS, especially those unstably housed, need innovative interventions to facilitate healthcare access and retention.

Jails as an opportunity to increase engagement in HIV care: findings from an observational cross-sectional study.

Linkage, engagement, retention and adherence to care are necessary steps along the HIV care continuum. Progression through these steps is essential for control of the disease and interruption of transmission. Identifying and re-engaging previously diagnosed but out-of-care patients is a priority to achieve the goals of the National HIV/AIDS strategy. Participants in the EnhanceLink cohort who were previously diagnosed HIV+ (n = 1,203) were classified as not-linked to of care and non-adherent to medication prior to incarceration by self report. Results based on multivariate models indicate that recent homelessness as well as high degrees of substance abuse correlated with those classified as not-linked to care and non-adherent to medications while having insurance was associated with being linked to care and adherent to care. The majority of detainees reported being linked to care but not currently adherent to care confirming that jails are an important site for re-engaging HIV+ individuals.

Planning for success predicts virus suppressed: results of a non-controlled, observational study of factors associated with viral suppression among HIV-positive persons following jail release.

In the United States, jail frequently disrupts access to HIV care. EnhanceLink, a 10-site demonstration project promoting linkage to HIV primary care upon jail discharge, offered an opportunity to gauge how many releasees had favorable clinical outcomes. Individual level data were available on 1270 participants. Persons never discharged from the correctional environment were excluded. Multivariate logistic regression identified factors associated with viral suppression 6 months post discharge (6M-VL < 400). Among 1082 individuals eligible for follow-up evaluation, 25.7 % had 6M-VL < 400. 6M-VL < 400 was associated with case managers assessing whether help was needed for linkage to HIV-related medical services and clients keeping an appointment with a case manager. The adjusted odds ratio (aOR) of 6M-VL < 400 associated with attending a meeting with an HIV care provider within 30 days of release was 1.85. The results of this non-controlled, observational study support further development and rigorous evaluation of transitional care programs for HIV-positive jailed persons across the country.

Transcriptional and post-transcriptional regulation of cGMP-dependent protein kinase (PKG-I): pathophysiological significance.

The ability of the endothelium to produce nitric oxide, which induces generation of cyclic guanosine monophosphate (cGMP) that activates cGMP-dependent protein kinase (PKG-I), in vascular smooth muscle cells (VSMCs), is essential for the maintenance of vascular homeostasis. Yet, disturbance of this nitric oxide/cGMP/PKG-I pathway has been shown to play an important role in many cardiovascular diseases. In the last two decades, in vitro and in vivo models of vascular injury have shown that PKG-I is suppressed following nitric oxide, cGMP, cytokine, and growth factor stimulation. The molecular basis for these changes in PKG-I expression is still poorly understood, and they are likely to be mediated by a number of processes, including changes in gene transcription, mRNA stability, protein synthesis, or protein degradation. Emerging studies have begun to define mechanisms responsible for changes in PKG-I expression and have identified cis- and trans-acting regulatory elements, with a plausible role being attributed to post-translational control of PKG-I protein levels. This review will focus mainly on recent advances in understanding of the regulation of PKG-I expression in VSMCs, with an emphasis on the physiological and pathological significance of PKG-I down-regulation in VSMCs in certain circumstances.

KLF4 and SOX9 transcription factors antagonize ß-catenin and inhibit TCF-activity in cancer cells.

The transcriptional activator ß-catenin is a key mediator of the canonical Wnt signaling pathway. ß-catenin itself does not bind DNA but functions via interaction with T-cell factor (TCF)/lymphoid-enhancing factor (LEF) transcription factors. Thus, in the case of active Wnt signaling, ß-catenin, in cooperation with TCF/LEF proteins family, activates the expression of a wide variety of genes. To date, the list of established ß-catenin interacting targets is far from complete. In this study, we aimed to establish the interaction between ß-catenin and transcription factors that might affect TCF activity. We took advantage of EMSA, using TCF as a probe, to screen oligonucleotides known to bind specific transcription factors that might dislodge or antagonize ß-catenin/TCF binding. We found that Sox9 and KLF4 antagonize ß-catenin/TCF binding in HEK293, A549, SW480, and T47D cells. This inhibition of TCF binding was concentration-dependent and correlated to the in vitro TCF-luciferase functional assays. Overexpression of Sox9 and KLF4 transcription factors in cancer cells shows a concentration-dependent reduction of TCF-luciferase as well as the TCF-binding activities. In addition, we demonstrated that both Sox9 and KLF4 interact with ß-catenin in an immunoprecipitation assay and reduce its binding to TCF4. Together, these results demonstrate that Sox9 and KLF4 transcription factors antagonize ß-catenin/TCF in cancer cells.