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A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities in pancreatic pain. The event was held on July 21, 2021, and structured into 4 sessions: (1) pathophysiology; (2) biomarkers, mediators, and pharmacology of pain; (3) pain assessment; and (4) pain treatment challenges and opportunities. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to better understand the underlying mechanisms of pain in pancreatic diseases, the relationship of visceral neural pathways and central pain centers, the role of behavioral factors and disorders on the perception of pain, and differences in pain perception and processes in children when compared with adults. In addition, the role of genetic risk factors for pain and the mechanisms and role of placebos in pain treatment were discussed. Methods of pain assessment including quantitative sensory testing were examined, as well as the process of central sensitization of pain. Finally, newer approaches to pain management including cognitive behavioral therapy, nerve stimulation, experimental (nonopioid) drugs, and cannabinoid compounds were covered.

Studies suggest that inflammation might be involved in the pathogenesis of depression. Individuals with human immunodeficiency virus (HIV) have a higher risk of depression and elevated inflammatory profiles. Despite this, research on the link between inflammation and depression among this high-risk population is limited. We examined a sample of men who have sex with men from the Multicenter AIDS Cohort Study in prospective analyses of the association between inflammation and clinically relevant depression symptoms, defined as scores >20 on Center for Epidemiological Studies Depression Scale. We included 1,727 participants who contributed 9,287 person-visits from 1984 to 2010 (8,218 with HIV (HIV+) and 1,069 without (HIV−)). Exploratory factor analysis (EFA) was used to characterize underlying inflammatory processes from 19 immune markers. Logistic regression with generalized estimating equations was used to evaluate associations between inflammatory processes and depressive symptoms stratified by HIV serostatus. Three EFA-identified inflammatory processes (EIPs) were identified. EIP-1 scores—described by soluble tumor necrosis factor receptor 2 (sTNF-R2), soluble interleukin-2 receptor α (sIL-2Rα), sCD27, B-cell activating factor, interferon γ-induced protein 10 (IP-10), soluble interleukin-6 receptor (sIL-6R), sCD14, and sGP130—were significantly associated with 9% higher odds of depressive symptoms in HIV+ participants (odds ratio = 1.09; 95% confidence interval: 1.03, 1.16) and 33% higher odds in HIV− participants (odds ratio = 1.33; 95% confidence interval: 1.09, 1.61). Findings suggest that immune activation might be involved in depression risk among both HIV+ and HIV− men who have sex with men.

Background Although cocaine use may induce/accelerate HIV-associated comorbidities in HIV-infected individuals on antiretroviral therapy (ART), and that HIV itself may accelerate aging, the issue of whether cocaine use plays a role in HIV-associated aging in HIV-infected cocaine users has not been reported. The goals of this study were (1) to explore factor(s) associated with peripheral blood leukocyte telomere length, a marker of cellular replicative history, and telomere shortening in HIV-infected individuals, and (2) to assess whether cocaine use plays a role in accelerating telomere shortening in cocaine users with HIV infection. Methods Between June 2010 and December 2016, 147 HIV-infected participants in Baltimore, Maryland, were enrolled in a cross-sectional study investigating factor(s) associated with telomere length. Of these 147, 93 participated in a follow-up study to examine factor(s) associated with telomere shortening. Robust regression model was used to analyze cross-sectional data and the generalized estimating equation approach was used to analyze follow-up data. Results Cross-sectional analyses demonstrated that (1) both daily alcohol consumption and use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were independently associated with telomere length, and cocaine use modified the associations of daily alcohol use and NNRTI use with telomere length. Longitudinal analyses suggested that both daily alcohol consumption and duration of NNRTI use were independently associated with telomere shortening, and (2) cocaine use induced/accelerated telomere shortening in HIV-infected individuals. Conclusions Our findings suggest that cocaine use may promote premature aging in HIV-infected individuals who are on ART. Our results emphasize the importance of cocaine abstinence/reduced use, which may retard HIV-associated premature aging.

Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population. It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances.

Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Background It has been recognized that myocardial and hepatic steatosis may be more prevalent in HIV-infected individuals on antiretroviral therapy (ART); however, factors associated with these conditions have not been thoroughly investigated. The goals of this study were (1) to identify the risk factors for myocardial and hepatic steatosis in HIV-infected African Americans (AAs) and explore whether ART use is independently associated with myocardial and hepatic steatosis, and (2) to examine whether and how cocaine use influences any associations of ART use with myocardial and hepatic steatosis. Methods Between June 2010 and December 2013, 220 HIV-infected AAs in Baltimore, Maryland, were enrolled in a study investigating HIV/ART-associated myocardial and hepatic damage. Proton magnetic resonance spectroscopy was performed to quantify myocardial and hepatic triglyceride contents. Sociodemographic, medical and laboratory data were also obtained. Robust regression model was employed to perform primary statistical analysis. Results Robust regression analyses showed that (1) duration of protease inhibitor (PI) use was independently associated with myocardial and hepatic triglyceride contents, (2) duration of PI use was independently associated with myocardial triglyceride in cocaine users (p = 0.025), but not in cocaine never-users (p = 0.84), and (3) duration of PI use was independently associated with hepatic triglyceride in cocaine users, but not in cocaine never-users (p = 0.52). Conclusions Cocaine use may trigger/exacerbate the toxicity of PI in ART-associated myocardial and hepatic steatosis, suggesting that cocaine abstinence/reduced use may retard these ART-associated comorbidities. Clinical trials should be conducted to examine whether reduced cocaine use improves HIV/AIDS-associated myocardial and hepatic steatosis.

Introduction Mental health care may mitigate negative consequences related to substance use and bolster engagement in care for drug dependence. Despite the increased risk of depression among people who inject drugs (PWID), the longitudinal relationship of depression symptoms with depression and drug treatment utilization in this population remains uncharacterized. Methods Data on depressive symptoms and depression treatment from current and former PWID in the ALIVE (AIDS Linked to the IntraVenous Experience) community-based cohort who had ≥3 study visits from July 2005 to June 2016 were included. We used logistic regression analysis with generalized estimating equations to examine factors associated with depression treatment in the 12 months following reported major depressive symptoms (CES-D ≥ 23) in the absence of treatment. We further examined the association between depression, depression treatment, and subsequent engagement in drug treatment among those with active substance use or alcohol dependence. Results Of the 1544 participants, 34% were female, the median age was 51 years, and 91% were African-American. PWID reported major depressive symptoms at 22% of study visits. In adjusted analysis, acute emergency care, suicidal ideation, and recent alcohol or drug treatment were positively associated with initiating depression treatment. Depression was positively associated with subsequent treatment for substance dependence among those actively using (aOR = 1.30, 95% CI: 1.10–1.53). Conclusions PWID experience a high burden of depressive symptoms with significant unmet need of treatment for depression. Our findings suggest that mental health providers should bolster connections to chronic disease and alcohol and drug treatment providers.

Mobile devices, digital technologies, and web-based applications—known collectively as eHealth (electronic health)—could improve health care delivery for costly, chronic diseases such as schizophrenia. Pharmacologic and psychosocial therapies represent the primary treatment for individuals with schizophrenia; however, extensive resources are required to support adherence, facilitate continuity of care, and prevent relapse and its sequelae. This paper addresses the use of eHealth in the management of schizophrenia based on a roundtable discussion with a panel of experts, which included psychiatrists, a medical technology innovator, a mental health advocate, a family caregiver, a health policy maker, and a third-party payor. The expert panel discussed the uses, benefits, and limitations of emerging eHealth with the capability to integrate care and extend service accessibility, monitor patient status in real time, enhance medication adherence, and empower patients to take a more active role in managing their disease. In summary, to support this technological future, eHealth requires significant research regarding implementation, patient barriers, policy, and funding.

ObjectivesCenter of Epidemiologic Studies-Depression Scale (CES-D) provides a snapshot of symptom severity at a single point in time. However, the best way of using CES-D to classify long-term depression is unclear.MethodTo identify long-term depression among HIV-infected and HIV-uninfected 50+ year-old men who have sex with men (MSM) with at least 5years of follow-up, we compared sensitivities and specificities of CES-D-based metrics (baseline CES-D; four consecutive CES-Ds; group-based trajectory models) thresholded at 16 and 20 to a clinician's evaluation of depression phenotype based on all available data including CES-D history, depression treatment history, drug use history, HIV disease factors, and demographic characteristics.ResultsA positive depressive phenotype prevalence was common among HIV-infected (prevalence = 33.1%) and HIV-uninfected MSM (prevalence = 23.2%). Compared to the depressive phenotype, trajectory models of CES-D≥20 provided highest specificities among HIV-infected (specificity = 99.9%, 95% Confidence Interval [CI]:99.4%-100.0%) and HIV-uninfected MSM (specificity = 99.0%, 95% CI:97.4%-99.7%). Highest sensitivities resulted from classifying baseline CES-D≥16 among HIV-infected MSM (sensitivity = 75.0%, 95% CI:67.3%-81.7%) and four consecutive CES-Ds≥16 among HIV-uninfected MSM (sensitivity = 81.0%, 95% CI:73.7%-87.0%).ConclusionChoice of method should vary, depending on importance of false positive or negative rate for long-term depression in HIV-infected and HIV-uninfected MSM.

OBJECTIVES Cardiac steatosis is a manifestation of ectopic fat deposition and is associated with obesity. The impact of chronic cocaine use on obesity measures and on the relationship between obesity measures and cardiac steatosis is not well-characterized. The objectives of this study were to compare obesity measures in chronic cocaine users and nonusers, and to explore which factors, in addition to obesity measures, are associated with myocardial triglyceride in African Americans, using noninvasive magnetic resonance spectroscopy. METHODS Between June 2004 and January 2014, 180 healthy African American adults without HIV infection, hypertension, and diabetes were enrolled in an observational proton magnetic resonance spectroscopy and imaging study investigating factors associated with cardiac steatosis. RESULTS Among these 180 participants, 80 were chronic cocaine users and 100 were nonusers. The median age was 42 (interquartile range, 34-47) years. Obesity measures trended higher in cocaine users than in nonusers. The median myocardial triglyceride was 0.6% (interquartile range, 0.4%-1.1%). Among the factors investigated, years of cocaine use, leptin, and visceral fat were independently associated with myocardial triglyceride. Body mass index and visceral fat, which were significantly associated with myocardial triglyceride in noncocaine users, were not associated with myocardial triglyceride content in cocaine users. CONCLUSIONS This study shows (1) cocaine users may have more fat than nonusers and (2) myocardial triglyceride is independently associated with duration of cocaine use, leptin, and visceral fat in all subjects, whereas leptin and high-density lipoprotein cholesterol, but not visceral fat or body mass index, in cocaine users, suggesting that chronic cocaine use may modify the relationships between obesity measures and myocardial triglyceride.

The advent of highly active antiretroviral therapy has prolonged the life expectancy of HIV patients and decreased the number of adults who progress to AIDS and HIV-associated dementia. However, neurocognitive deficits remain a pronounced consequence of HIV/AIDS. HIV-1 infection targets the central nervous system in subcortical brain areas and leads to high rates of delirium, depression, opportunistic central nervous system infections, and dementia. Long-term HIV replication in the brain occurs in astrocytes and microglia, allowing the virus to hide from antiviral medication and later compromise neuronal function. The associated cognitive disturbance is linked to both viral activity and inflammatory and other mediators from these immune cells that lead to the damage associated with HIV-associated neurocognitive disorders, a general term given for these disturbances. We review the severity and prevalence of the neuropsychiatric complications of HIV including delirium, neurobehavioral impairments (depression), minor cognitive-motor dysfunction, and HIV-associated dementia.

Questionnaires of depressive symptoms assess symptom severity at one timepoint. However, we can evaluate the ability of metrics to identify individuals at risk of more clinically relevant long-term depression. Using a depressive phenotype (derived from a review of all relevant depression indicators) as a gold standard, we examined sensitivities and specificities of CES-D–based metrics (baseline CES-D; four consecutive CES-Ds; group-based trajectory models) thresholded at 16 and 20 in HIV-infected and HIV–uninfected older men who have sex with men (MSM). Compared to the depressive phenotype, trajectory models of CES-D≥20 provided highest specificities among HIV-infected (specificity=99.9%, 95% Confidence Interval [CI]:99.4%–100.0%) and HIV-uninfected MSM (specificity=99.0%, 95% CI:97.4%–99.7%). Highest sensitivities resulted from classifying baseline CES-D≥16 among HIV-infected MSM (sensitivity=75.0%, 95% CI:67.3%–81.7%) and four consecutive CES-Ds≥16 among HIV-uninfected MSM (sensitivity=81.0%, 95% CI:73.7%–87.0%). Choice of method depends on importance of false positive or negative rate for long-term depression.

Background The key objectives of this study were to examine whether HIV infection itself is associated with subclinical coronary atherosclerosis and the potential contributions of cocaine use and antiretroviral therapies ( ART s) to subclinical coronary artery disease ( CAD ) in HIV ‐infected persons. Methods and Results Between June 2004 and February 2015, 1429 African American ( AA ) adults with/without HIV infection in Baltimore, Maryland, were enrolled in an observational study of the effects of HIV infection, exposure to ART , and cocaine use on subclinical CAD . The prevalence of subclinical coronary atherosclerosis was 30.0% in HIV ‐uninfected and 33.7% in HIV ‐infected ( P =0.17). Stratified analyses revealed that compared to HIV ‐uninfected, HIV ‐infected ART naïve were at significantly lower risk for subclinical coronary atherosclerosis, whereas HIV ‐infected long‐term ART users (≥36 months) were at significantly higher risk. Thus, an overall nonsignificant association between subclinical coronary atherosclerosis and HIV was found. Furthermore, compared to those who were ART naïve, long‐term ART users (≥36 months) were at significantly higher risk for subclinical coronary atherosclerosis in chronic cocaine users, but not in those who never used cocaine. Cocaine use was independently associated with subclinical coronary atherosclerosis. Conclusions Overall, HIV infection, per se, was not associated with subclinical coronary atherosclerosis in this population. Cocaine use was prevalent in both HIV ‐infected and ‐uninfected individuals and itself was associated with subclinical disease. In addition, cocaine significantly elevated the risk for ART ‐associated subclinical coronary atherosclerosis. Treating cocaine addiction must be a high priority for managing HIV disease and preventing HIV / ART ‐associated subclinical and clinical CAD in individuals with HIV infection.

This study described characteristics, psychiatric diagnoses and response to treatment among patients in an outpatient HIV clinic who screened positive for depression. Depressed (25 %) were less likely to have private insurance, less likely to have suppressed HIV viral loads, had more anxiety symptoms, and were more likely to report current substance abuse than not depressed. Among depressed, 81.2 % met diagnostic criteria for a depressive disorder; 78 % for an anxiety disorder; 61 % for a substance use disorder; and 30 % for co-morbid anxiety, depression, and substance use disorders. Depressed received significantly more treatment for depression and less HIV primary care than not depressed patients. PHQ-9 total depression scores decreased by 0.63 from baseline to 6-month follow-up for every additional attended depression treatment visit. HIV clinics can routinely screen and treat depressive symptoms, but should consider accurate psychiatric diagnosis as well as co-occurring mental disorders.

Persons over age 50 are not only aging with human immunodeficiency virus (HIV) infection but also represent a high proportion of new HIV infections. Neuropsychiatric symptoms, including depression, cognitive impairment, and substance abuse, are very common in individuals infected with HIV. However, there is little understanding of the relationship between these HIV-related comorbid conditions in newly infected elderly patients compared to uninfected elderly and those who have survived after 20 years of HIV/AIDS. We summarize the current theories and research that link aging and HIV with psychiatric illnesses and identify emerging areas for improved research, treatment, and patient care.

HIV infection, depression, and cocaine use are independently associated with increased inflammatory signal production. There is increasing evidence about the role of inflammation in depression. In HIV disease, cocaine use may increase disease progression as well as alter T cell functioning resulting in cytokine activation and thereby increasing susceptibility to depression. We examined the association between cocaine use and depression among 447 African American persons infected with HIV who were frequent cocaine users or non-users, enrolled in an observational study in Baltimore, Maryland, between August 2003 and December 2012. The overall prevalence of depression was 40.9 % (183 of 447) participants. Among persons who were depressed, the prevalence of cocaine use was 81.4 % (149 of 183), compared to 69.3 % among persons who were not depressed (183 of 264), P = 0.004. Cocaine use was associated with nearly twofold increased odds of depression, unadjusted odds ratio (OR) 1.94, (95 % CI 1.23, 3.06); P = 0.004, compared to never using cocaine, and OR 1.02, (95 % CI 1.10, 1.05); P = 0.04 in adjusted analysis. A dose-response relationship between increasing duration of cocaine use and depression was observed. Frequency and duration of cocaine use may be associated with depression. We speculate that depression among cocaine users with HIV may involve an inflammatory component that needs further examination.

Major depressive disorder is the most common neuropsychiatric complication in human immunodeficiency virus (HIV) infections and is associated with worse clinical outcomes. We determined if detectable cerebrospinal fluid (CSF) HIV ribonucleic acid (RNA) at threshold ≥50 copies/ml is associated with increased risk of depression. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort is a six-center US-based prospective cohort with bi-annual follow-up of 674 participants. We fit linear mixed models (N = 233) and discrete-time survival models (N = 154; 832 observations) to evaluate trajectories of Beck Depression Inventory (BDI) II scores and the incidence of new-onset moderate-to-severe depressive symptoms (BDI ≥ 17) among participants on combination antiretroviral therapy (cART), who were free of depression at study entry and received a minimum of three CSF examinations over 2496 person-months follow-up. Detectable CSF HIV RNA (threshold ≥50 copies/ml) at any visit was associated with a 4.7-fold increase in new-onset depression at subsequent visits adjusted for plasma HIV RNA and treatment adherence; hazard ratio (HR) = 4.76, (95 % CI 1.58–14.3); P = 0.006. Depression (BDI) scores were 2.53 points higher (95 % CI 0.47–4.60; P = 0.02) over 6 months if CSF HIV RNA was detectable at a prior study visit in fully adjusted models including age, sex, race, education, plasma HIV RNA, duration and adherence of CART, and lifetime depression diagnosis by Diagnostic Statistical Manual (DSM-IV) criteria. Persistent CSF but not plasma HIV RNA is associated with an increased risk for new-onset depression. Further research evaluating the role of immune activation and inflammatory markers may improve our understanding of this association.

Psychiatric disorders, particularly major depression, have a profound affect on the use of and adherence to highly active antiretroviral therapy (HAART) among patients with human immunodeficiency virus (HIV) infection. Because some of the symptoms of HIV infection are similar to those of major depression, efforts to diagnose and treat major depression are further complicated. Moreover, major depression increases vulnerability to HIV infection by provoking high-risk behaviors, and it interferes with a patient's ability to comply with protocols for the prevention and treatment of HIV infection. HIV infection itself can disguise, help initiate, or exacerbate major depression. In this report, the interrelation between major depression and HIV infection is evaluated, the impact of this interrelation on adherence to HAART is described, and methods for effective treatment of psychiatric conditions in HIV-infected persons are discussed.

Objectives Clinical and epidemiological evidence suggests that cocaine use is associated with an increased risk of premature atherosclerosis. The objectives of this study were to explore (1) whether cocaine abstinence is associated with a reduced marker of endothelial dysfunction, (2) whether cocaine abstinence is associated with a slower coronary plaque progression, and (3) whether reduction in cocaine use is associated with a reduced marker of endothelial dysfunction in African American chronic cocaine users with contrast-enhanced coronary CT angiography-confirmed less than 50% coronary stenosis. Methods Between March and June 2014, a total of 57 African American cocaine users with contrast-enhanced CT angiography-confirmed less than 50% coronary stenosis in Baltimore, Maryland, were enrolled in a 6-month follow-up study to investigate whether cocaine abstinence or reduction in cocaine use is associated with decreased endothelin-1 (ET-1) levels and coronary plaque progression at the 6-month follow-up. A voucher-based incentive approach was used to systematically reinforce cocaine abstinence, and urine benzoylecgonine test was implemented to confirm cocaine use. Results Among the 57 participants, 44 were HIV-infected. The median of duration of cocaine use was 18 (interquartile range, 7-30) years. According to generalized estimating equation analyses, both cocaine abstinence and reduction in cocaine use in the 6 months were independently associated with decreased ET-1. The incidence of coronary plaque progression was 7.4/100 person-years and 23.1/100 person-years in those who were totally abstinent from cocaine and those who continued to use cocaine, respectively. However, the difference in the incidence between these 2 groups was not significant (exact P = 0.30). Conclusions The findings of this study revealed a possible association of cocaine abstinence/reduction with lowered ET levels, which suggests that such changes in cocaine use might be beneficial for preventing endothelial damage. Further studies should be conducted to investigate whether ET-1 could be used as a marker for cocaine abstinence and reduction in cocaine use.

Patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome have high rates of psychiatric illness. The effective management of these psychiatric conditions can improve a patient's quality of life and may improve antiretroviral adherence. Care providers for patients with HIV infection frequently encounter clinical situations in which psychotropic medications are needed or are being used. Those clinical situations require familiarity with the broad category of medications termed "psychotropic." That familiarity should include a basic understanding of indications, adverse effects, and drug interactions. In particular, it is very important to recognize the many potential interactions based on cytochrome P450 metabolism, which is common to many psychotropics, the protease inhibitors, and the nonnucleoside reverse-transcriptase inhibitors. In a brief review of the use of psychotropic medications in patients with HIV infection, we discuss indications, adverse effects, and drug interactions for commonly used antidepressants, mood stabilizers, anxiolytics, antipsychotics, psychostimulants, and drugs of abuse.

Detectable human immunodeficiency virus (HIV) RNA in the cerebrospinal fluid (CSF) is associated with central nervous system (CNS) complications. We developed the CSF HIV risk score through prediction modeling to estimate the risk of detectable CSF HIV RNA (threshold >50 copies/mL) to help identify persons who might benefit most from CSF monitoring. We used baseline data from 1,053 participants receiving combination antiretroviral therapy who were enrolled in the 6-center, US-based CNS HIV Antiretroviral Therapy Effects Research (CHARTER) prospective cohort in 2004–2007. Plasma HIV RNA, CNS penetration effectiveness, duration of combination antiretroviral therapy, medication adherence, race, and depression status were retained correlates of CSF HIV RNA, displaying good discrimination (C statistic = 0.90, 95% confidence interval (CI): 0.87, 0.93) and calibration (Hosmer-Lemeshow P = 0.85). The CSF HIV risk score ranges from 0 to 42 points, with a mean of 15.4 (standard deviation, 7.3) points. At risk scores greater than 25, the probability of detecting CSF HIV RNA was at least 42.9% (95% CI: 36.6, 49.6). For each 1-point increase, the odds of detecting CSF HIV RNA increased by 26% (odds ratio = 1.26, 95% CI: 1.21, 1.31; P < 0.01). The risk score correlates with detection of CSF HIV RNA. It represents an advance in HIV management and monitoring of CNS effects, providing a potentially useful tool for clinicians.

This study assessed HIV risk behaviors and their association with psychiatric disorders among women prisoners.HIV risk behaviors practiced in the five years before incarceration were ascertained with the Risk Behavior Assessment interview for 177 inmates at the Maryland Correctional Institution for Women. The Structured Clinical Interview for the DSM-IV was used to determine the occurrence of posttraumatic stress disorder (PTSD), major depression, and dysthymic disorder among the women. Regression models were used to determine the association between HIV risk behavior and psychiatric disorders.HIV risk behaviors in the five years before incarceration included never or rarely having used condoms (56 percent of the women), injection drug use (42 percent), sexual intercourse with a partner who used injection drugs (42 percent), prostitution (30 percent), needle sharing (30 percent), receptive anal sex (19 percent), and having more than 100 sex partners (7 percent). After the analysis adjusted for age, education, race, HIV status, and addictive disorders, a lifetime occurrence of PTSD was associated with the practice of anal sex (odds ratio=1.7; 95 percent confidence interval=1.26 to 2.16; p.02) and prostitution (OR=1.56; 95% CI=1.17 to 1.95; p.03).HIV risk behaviors before incarceration were highly prevalent among the women in this study. Rates of PTSD, depression, and dysthymic disorder were also high. PTSD was associated with prostitution and receptive anal sex, and the disorder may contribute to high rates of risky sexual behavior. Targeted HIV risk reduction efforts among women prisoners should include evaluation for PTSD; conversely, women prisoners with a diagnosis of PTSD should be evaluated for prior HIV sexual risk behaviors.

Great strides have been achieved in recent years in the detection and treatment of major depressive disorder (MDD) in primary care settings. Little is known about the types or patients with MDD seen in primary care as compared with those seen in psychiatric office practice. Few studies have compared clinical outcomes after treatment with antidepressants in these two settings. In Argentina, the authors conducted an open-label treatment study of MDD patients in primary care (n = 469) and psychiatric office practice (n = 299). The patients were compared on baseline sociodemographic and clinical variables. These same patients were treated with sertraline 50-100 mg per day for 8 weeks. At baseline, the patients in psychiatric office practice were younger, more likely to abuse alcohol, less likely to have comorbid medical disorders, and more likely to have failed a prior treatment for depression during the current episode. The two groups did not differ significantly on depression severity or in depressive symptom profile on the Hamilton Depression Rating Scale (Ham-D). After 8 weeks of treatment, mean Ham-D scores were reduced comparably in both groups, from about 25 to about 10. Rates of adverse events were 14%-29%, depending on the follow-up interval. Adherence with treatment was high in both groups (over 95%). The patients in primary care and psychiatry office practice are similar in several ways. Significant reductions in depressive symptoms are possible in both settings, in large numbers of patients, by using doses of sertraline in the 50-100 mg range.

The study sought to determine the effectiveness of a model program of psychiatric care for human immunodeficiency virus (HIV)-infected patients. This was a cohort study of 126 HIV-positive outpatients referred for psychiatric evaluation and treatment (average follow up of 14 months) in a HIV-dedicated primary-care outpatient clinic in the inner city. A global outcome measure (encompassing symptom relief, functioning, and HIV-risk behaviors), and a measure of abstinence from alcohol and illicit substances were used. Fifty percent of patients improved, with 19% "nearly well" at follow-up. Abstinence was achieved 48% of the time. Good compliance with treatment and the absence of injection drug use were the primary predictors of good outcomes. Of the compliant patients, 94% improved, with 45.7% being nearly well. Psychiatric treatment of HIV-infected patients is effective when located in the HIV primary-care setting and administered by a multidisciplinary team under the direction of a psychiatrist, using evidence-based interventions.

This article reviews the literature on the classification and treatment of psychiatric morbidity associated with infection from the human immunodeficiency virus (HIV). The psychiatric disorders seen in HIV-infected patients are formulated by using one of the following four perspectives as treatment guides: 1) the syndromal or disease perspective, 2) the dispositional or personality perspective, 3) the behavioral or addictive perspective, and 4) the life story perspective.

Since an automobile accident in 2005, patient FL has reported difficulty retaining information from one day to the next. During the course of any given day, she describes her memory as normal. However, memory for each day disappears during a night of sleep. She reports good memory for events that occurred before the accident. Although this pattern of memory impairment is, to our knowledge, unique to the medical literature, it was depicted in the fictional film “50 First Dates”. On formal testing, FL performed moderately well when trying to remember material that she had learned during the same day, but she exhibited no memory at all for material that she knew had been presented on a previous day. For some tests, unbeknownst to FL, material learned on the previous day was intermixed with material learned on the same day as the test. On these occasions, FL’s memory was good. Thus, she was able to remember events from earlier days when memory was tested covertly. FL performed differently in a number of ways from individuals who were instructed to consciously feign her pattern of memory impairment. It was also the impression of those who worked with FL that she believed she had the memory impairment that she described and that she was not intentionally feigning amnesia. On the basis of her neuropsychological findings, together with a normal neurological exam, normal MRI findings, and psychiatric evaluation, we suggest that FL exhibits a unique form of functional amnesia and that its characterization may have been influenced by knowledge of how amnesia was depicted in a popular film. She subsequently improved (and began retaining day-to-day memory) at Johns Hopkins University where she was in a supportive in-patient environment and was shown how to take control of her condition by interrupting her sleep at 4-hour intervals.

Background: Psychiatric disorders are common in HIV patients, and previous work suggests that these patients experience delays in treatment with highly active antiretroviral therapy (HAART). We investigated whether a current psychiatric disorder (1) affected the time to initiation of HAART, (2) predicted the likelihood of being prescribed HAART for at least 6 months, and (3) affected survival in urban AIDS patients. Methods: We conducted a retrospective cohort study of AIDS patients with no prior history of HAART who were enrolled and followed at the Johns Hopkins University HIV clinic between January 1996 and January 2002. Patients were stratified based on the presence of a psychiatric disorder. Cox proportional hazards regression models estimated the relative risk of receiving HAART and survival, whereas multivariate logistic regression models estimated the relative odds of remaining on HAART. Results: During the study period, 549 patients with AIDS anc no prior antiretroviral treatment were enrolled in the clinic. Eighteen percent (n = 100) were defined as having a current psychiatric disorder, 39% (n = 215) were defined as having no psychiatric disorder, and 43% (n = 34) were indeterminate. Patients with a psychiatric disorder were 37% more likely to receive HAART (Cox adjusted hazard ratio [95% confidence interval (CI)]: 1.37 [1.01-1.87]), had greater than twice the odds of being prescribed HAART for at least 6 months (adjusted odds ratio [95% CI]: 2.14 [1.24-3.69]), and were 40% more likely to survive (Cox adjusted hazard ratio [95% CI]: 0.61[0.37-0.99]) as compared with those without a psychiatric disorder. Conclusion: Patients with psychiatric disorders are receiving HAART and are able to reap the survival benefit by remaining on it.

Psychiatric disorders increase the risk of acquiring human immunodeficiency virus (HIV) and increase morbidity from HIV-related illness by impeding treatment. The response to highly active antiretroviral therapies is impaired by poor patient adherence, a substantial component of which is related to mental illness and substance use disorders. The recognition of psychiatric disorders in most HIV clinics is an issue of utmost importance. We outline diagnostic and treatment issues for major depression, bipolar disorder, personality disorder, substance use disorders, and demoralization as seen in patients with HIV. Our experience at the Johns Hopkins Moore (HIV) Clinic has led us to conclude that treatment of these disorders greatly improves patient adherence to treatment and outcomes of HIV infection.

The interaction between the Ca2+-binding protein, calmodulin, and guanyl nucleotides was investigated in a rat striatal paniculate fraction. We found that the ability of calmodulin to stimulate adenylate cyclase in the presence of guanyl nucleotides depends upon the type and concentration of the guanyl nucleotide. Adenylate cyclase activity measured in the presence of calmodulin and GTP reflected additivity at every concentration of these reactants. On the contrary, when the activating guanyl nucleotide was the nonhydrolyzable analog of GTP, guanosine-5′-(3,7-imido)triphosphate (GppNHp), calmodulin could further activate adenylate cyclase only at concentrations less than 0.2 p.M GppNHp. Kinetic analysis of adenylate cyclase by GppNHp was compatible with a model of two components of adenylate cyclase activity, with over a 100-fold difference in sensitivity for GppNHp. The component with the higher affinity for GppNHp was competitively stimulated by calmodulin. The additivity between calmodulin and GTP in the striatal particulate fraction suggests that they stimulate different components of cyclase activity. The cal-modulin-stimulatable component constituted 60% of the total activity. Our two-component model does not delineate, at this point, whether there are two separate catalytic subunits or one catalytic subunit with two GTP-binding proteins. The finding that GTP was unable to activate the calmodulin-sensitive component suggests that this component has either a different mode of binding to a GTP-binding protein or inherently higher GTPase activity than has the calmodulin-insensitive component. The results suggest there are two components of adenylate cyclase activity that can be differentiated by their sensitivities to calmodulin and guanyl nucleotides.

In rat striatum, the activation of adenylate cyclase by the endogenous Ca2+-binding protein, calmodulin, is additive with that of GTP but is not additive with that of the nonhydrolyzable GTP analog, guanosine-5′-(β, γ-imido)triphosphate (GppNHp). One possible mechanism for this difference could be an effect of calmodulin on GTPase activity which has been demonstrated to “turn-off” adenylate cyclase activity. We examined the effects of Ca2+ and calmodulin on GTPase activity in EGTA-washed rat striatal particulate fractions depleted of Ca2+ and calmodulin. Calmodulin inhibited GTP hydrolysis at concentrations of 10−9–10−6M but had no effect on the hydrolysis of 10−5 and 10−6M GTP, suggesting that calmodulin inhibited a low Km GTPase activity. The inhibition of GTPase activity by calmodulin was Ca2+-dependent and was maximal at 0.12 μM free Ca2+. Maximal inhibition by calmodulin was 40% in the presence of 10−7M GTP. The IC50 for calmodulin was 100 nM. In five tissues tested, calmodulin inhibited GTP hydrolysis only in those tissues where it could also activate adenylate cyclase. Calmodulin could affect the activation of adenylate cyclase by GTP in the presence of 3,4-dihydroxyphenylethylamine (DA, dopamine). Calmodulin decreased by nearly 10-fold the concentration of GTP required to provide maximal stimulation of adenylate cyclase activity by DA in the striatal membranes. The characteristics of the effect of calmodulin on GTPase activity with respect to Ca2+ and calmodulin dependence and tissue specificity parallel those of the activation of adenylate cyclase by calmodulin, suggesting that the two activities are closely related. Inhibition of a low Km GTPase activity by calmodulin could represent an action of calmodulin in increasing the association of a GTP-binding protein with the catalytic subunit activity resulting in a reduction of the “turn-off” GTPase activity.

The effect of germ cells or germ cell fractions on adenylate cyclase (AC) activity in membrane preparations from cultured rat Sertoli cells has been examined. Whole germ cells or 30,000 X g pellet or supernatant fractions of germ cells have the ability to stimulate Sertoli cell AC to levels comparable to those measured in follicle-stimulating hormone-stimulated Sertoli cell membranes. Treatment at 100 degrees C but not 60 degrees C for 1 min abolished the ability of germ cell preparations to stimulate Sertoli AC. Germ cell stimulation of Sertoli cell AC was not calcium dependent, was not blocked by propranolol, and was observed to be dose dependent.

Suuunary--Chronic treatment of rats with haloperidol causes behavioral supersensitivity to dopaminergic agonists and an increase in the sensitivity of adenylate cyclase activity in the striatum to stimulation by dopamine. In this study the authors examined whether chronic treatment with haloperidol could elicit a change in sensitivity of adenylate cyclase in the striatum of the rat for guanyl nucleotides and the endogenous Ca 2+-binding protein, calmodulin. These agents increase the activation of adenylate cyclase activity by dopamine but act beyond the level of the dopamine receptor. Male, Sprague-Dawley rats were injected subcutaneously with either 0.6 mg/kg haloperidol or vehicle for 14 days. Four days after the last injection, the animals were sacrificed and the activity of adenylate cyclase was measured in a EGTAwashed particulate preparation of the striatum. There was an increase in the activation of adenylate cyclase activity by calmodulin and GppNHp but not by guanosine triphosphate (GTP) in particulate fractions of the striatum from rats treated with haloperidol as compared to controls. The sensitivity of adenylate cyclase to calmodulin was increased S-fold in particulate fractions from rats treated with haloperidol as opposed to vehicle-treated rats. The lack of change in activation by GTP was not due to an altered activity of GTPase in rats treated with haloperidol. In animals treated for 14 days but not withdrawn from haloperidol there was no statistically significant increase in the sensitivity of adenylate cyclase to calmodulin. There was no change in activation of the enzyme by GppNHp or GTP as compared to control. The activation of adenylate cyclase by calmodulin was not affected when haloperidol was added in vitro to the assay or after the acute injection of rats with haloperidol. These results demonstrate that the development of dopaminergic supersensitivity after withdrawal from chronic blockade of dopamine receptors resulted in increased sensitivity of post-receptor coupling mechanisms, as well as in changes in the receptor-mediated activity. In previous studies, increases in DA-stimulated adenylate cyclase activity were found with this treatment regimen. In this study it was shown that although basal activity was not changed, there was a selective increase in the sensitivity of adenylate cyclase to stimulation by calmodulin and GppNHp after chronic receptor blockade. These findings support previous observations suggesting a regulatory role for calmodulin in dopaminestimulated adenylate cyclase activity.

It is not yet apparent how Sertoli cell functions are regulated to coordinate and support differentiation of the adjacent germ cells (GC) in the seminiferous tubules of the testis. Studies have shown that FSH binding and response by cells of the seminiferous tubule,'.2 as well as activities of specific enzyme^,^ can be correlated with the stage of spermatogenesis existing within isolated tubule segments. Because the hormonal milieu of the testis is essentially constant, these observations support the hypothesis of a mechanism within the seminiferous tubule for localized regulation of morphological and biochemical event^.^ GC may directly affect Sertoli cell function by essentially the same series of biochemical events as the FSH response mechanism.'-3 To examine the possibility of direct GC effects on Sertoli function, we have studied the effects of GC and GC fractions of adenylyl cyclase (AC) activity in membrane preparations from highly enriched populations of rat Sertoli cells. We observe stimulation of AC by GC and GC fractions. Basal AC activity of membranes from Sertoli cells cultured for three days in hormone and serum-free medium was found to be low, ranging from 2 to 14 pmoles cAMP/min/mg protein. When the Sertoli membranes were treated with FSH or isoproterenol in the presence of 1 p M GTP, conditions that elicit maximal AC responses, AC was stimulated to average rates of 104 and 76 pmoles CAMP/ midmg, respectively (FIGURE la). If freshly prepared GC (50-150 pg protein/ assay) instead of hormone were added to Sertoli membranes, AC activity was measured to average 62 pmoles cAMP/min/mg Sertoli protein. When GC alone were assayed, they were found to exhibit no AC activity under the conditions employed. GC were also separated into membrane and cytosol fractions. Both fractions were able to stimulate AC activity of Sertoli membranes to levels significantly higher than basal (FIGURE Ib). The results did not offer any clear evidence concerning the subcellular localization of the GC factor that was activating Sertoli AC . The possibility of the activation being due to calmodulin was considered. Because calmodulin has been shown to be heat stable with a half-life of 7 min at 100°C,4 the effect of heat on the GC fractions' ability to activate Sertoli AC was examined (FIGURE Ic). Treatment at 60°C did not diminish the capacity of GC preparations to activate AC. However, 100°C for 1 min abolished completely the ability of GC preparations to activate AC. The results indicate that the stimulatory activity associated with the GC possesses limited heat stability and cannot be attributed to the heat-stable activator calmodulin.

Adenylate cyclase activity in bovine retina is highly responsive to Ca2+ and the endogenous Ca2+-binding protein, calmodulin (CaM). CaM stimulated adenylate cyclase activity in washed particulate fractions of bovine retina by 6.6-fold in a Ca2+-dependent manner. Activation of adenylate cyclase activity by CaM was maximal at 0.12 microM free Ca2+. The apparent Ka for calmodulin stimulation of adenylate cyclase was 67 nM and the apparent Vmax was 116 pmol/min/mg of protein above basal activity. Adenylate cyclase activity in bovine retina was stimulated approximately 50% by guanosine 5′-triphosphate (GTP), but the nonhydrolyzable GTP analogue, guanosine-5′-(beta, gamma- imido)triphosphate (Gpp(NH)p), was able to activate the enzyme nearly 5- fold. CaM and Gpp(NH)p appeared to be partially competitive activators of adenylate cyclase in the retina particulate fraction. Dopamine stimulated adenylate cyclase activity in the presence of GTP with an apparent Ka of 1.0 microM and an apparent Vmax of 66 pmol/min/mg of protein. Ca2+ and CaM increased the apparent Vmax of the dopamine- stimulated adenylate cyclase activity more than 2-fold to a level of 146 pmol/min/mg of protein but did not alter the apparent Ka. This suggests that CaM is an endogenous modulator of dopamine-stimulated adenylate cyclase activity in the retina. CaM-stimulated adenylate cyclase activity may be a common component to retina since we found this activity in retinas from rabbit, rat, and goldfish as well as cow.

Calmodulin, an endogenous calcium-binding protein, can modulate the intracellular concentration of adenosine 3',5'-cyclic monophosphate (cyclic AMP] by stimulating membrane-bound adenylate cyclase activity and soluble phosphodiesterase (PDE) activity.' There is increasing evidence that calmodulin can modulate the effects of calcium at both preand postsynaptic sites in some areas of brain. Calmodulin is enriched in rat brain synaptic membranes2 and has been located in postsynaptic densities in mouse basal ganglia3 and canine cerebral ~ o r t e x . ~ Previous studies have suggested that calmodulin is involved with dopamine IDA)-sensitive adenylate cyclase activity in rat striaturn. Gnegy et aL5 found that depletion of calmodulin t'rom striatal membranes results in a decreased ability of DA to stimulate adenylate cyclase activity. Furthermore, the calmodulin content in the striaturn was increased under conditions of dopamine supersensitivity.6 Rats treated chronically with cataleptogenic antipsychotic drugs and then withdrawn from the drugs hail increased calmodulin content in their striatal membranes. These animals exhibited behavioral supersensitivity to apomorphine and their striatal adenylate cyclase had an increased affinity for dopamine as demonstrated by a 3to 4-foid increase in dopamine sensitivity. The increase in calmodulin could positively affect DA-sensitive adenylate cyclase activity and thus contribute to dopaminergic: supersensitivity. The increased calmodulin in the striatal membranes of the supersensitive rats seems to be more tightly bound to its membrane binding protein^.^ In the brain, calmodulin can be hound to membrane proteins in a calcium-dependent and calcium-independent manner.' Calmodulin has been shown to hind to Caz+dependent PDE' and Caz+-sensitive adenylate cyclase'o as well as other proteins. Vandermeers et (11." have demonstrated a correlation between increased ['ZSI]calmodulin binding and activation of adenylate cyclase activity in guinea pig membranes. In this work we investigate more directly whether calmodulin can affect DA-sensitive activity in rat striatal membranes. We found that calmodulin could affect both the maximal velocity of the reaction and the sensitivity to DA. We studied the binding of calmodulin to striatal membranes in order to further investigate the relationship between calmodulin interaction with adenylate cyclase activity. We showed specific binding of ['251]calmodulin to striatal membranes that was competitively inhibited by trifluoperazine, an antipsychotic drug that binds to calmodulin and inhibits its action." We have also shown that the ability of the calmodulin content to increase could be specific for dopaminergic supersensitivity in the striatum.