The contribution of bipolar disorder (BD), a prevalent serious mental illness characterized by impulsivity and mood instability, to antiretroviral (ART) and psychiatric medication adherence among HIV-infected (HIV+) individuals is unknown. We examined medication adherence among 44 HIV+/BD+ persons as compared to 33 demographically- and medically-comparable HIV+/BD− persons. Classification of adherent (≥90%) or non-adherent (<90%) based on proportion of correctly taken doses over 30 days was determined using electronic medication monitoring devices. HIV+/BD+ persons were significantly less likely to be ART adherent (47.7%) as compared to HIV+/BD− (90.9%) persons. Within the HIV+/BD+ group, mean psychiatric medication adherence was significantly worse than ART medication adherence, although there was a significant correlation between ART and psychiatric adherence levels. Importantly, 30-day ART adherence was associated with plasma virologic response among HIV+/BD+ individuals. Given the high overlap of HIV and BD, and the observed medication adherence difficulties for these persons, specialized adherence improvement interventions are needed.
Medication Adherence; HIV/AIDS; Bipolar Disorder
The feasibility, use, and acceptability of text messages to track methamphetamine use and promote antiretroviral treatment (ART) adherence among HIV-infected methamphetamine users was examined. From an ongoing randomized controlled trial, 30-day text response rates of participants assigned to the intervention (individualized texting for adherence building (iTAB), n = 20) were compared to those in the active comparison condition (n = 9). Both groups received daily texts assessing methamphetamine use, and the iTAB group additionally received personalized daily ART adherence reminder texts. Response rate for methamphetamine use texts was 72.9% with methamphetamine use endorsed 14.7% of the time. Text-derived methamphetamine use data was correlated with data from a structured substance use interview covering the same time period (P < 0.05). The iTAB group responded to 69.0% of adherence reminder texts; among those responses, 81.8% endorsed taking ART medication. Standardized feedback questionnaire responses indicated little difficulty with the texts, satisfaction with the study, and beliefs that future text-based interventions would be helpful. Moreover, most participants believed the intervention reduced methamphetamine use and improved adherence. Qualitative feedback regarding the intervention was positive. Future studies will refine and improve iTAB for optimal acceptability and efficacy. This trial is registered with ClinicalTrials.gov NCT01317277.
Sestrin-2 is involved in p53-dependent antioxidant defenses and in the maintenance of metabolic homeostasis. We hypothesize that sestrin-2 expression is altered in the brains of subjects diagnosed with human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) due to neuronal oxidative stress. We studied sestrin-2 immunoreactivity in 42 isocortex sections from HIV-1-infected subjects compared to 18 age-matched non-HIV controls and 19 advanced Alzheimer's disease (AD) cases. With HIV infection, the sestrin-2 immunoreactivity pattern shifted from neuropil predominance (N) to neuropil and neuronal-soma co-dominance (NS) and neuronalsoma predominance (S; P < 0.0001, Chi-square test for linear trend). Among HIV cases showing the NS or S pattern, HAND cases were preferentially associated with the S pattern (n = 10 of 20) compared to cognitively intact cases (n = 1 of 11; P = 0.047, Fisher's exact test). In AD brains, sestrin-2 immunoreactivity was mostly intense in the neuropil and co-localized with phospho-Tau immunoreactivity in a subset of neurofibrillary lesions. Phospho-Tau-immunoreactive neurofibrillary lesions were rare in HIV cases and their occurrence was not associated with HAND. Levels of isocortical 8-hydroxy-deoxyguanosine (marker of nucleic acid oxidation) immunoreactivity were not significantly altered in HAND cases compared to cognitively intact HIV cases. In conclusion, the sestrin-2 immunoreactivity redistribution to neuronal soma in HAND suggests unique involvement of sestrin-2 in the pathophysiology of HAND, which is different from the role of sestrin-2 in AD pathogenesis. Alternatively, the difference in sestrin-2 immunoreactivity distribution between HAND and AD may be related to different degrees of severity or stages of oxidative stress.
Alzheimer's disease; HIV dementia; Neurofibrillary pathology; Oxidative stress; SESN2
Among English-speaking adults, HIV-associated neuropsychological (NP) impairments have been associated with problems in everyday functioning, including ability to function at work and drive an automobile. Latinos account for a disproportionate number of HIV/AIDS cases nationwide, and a significant segment of this population is primarily Spanish speaking. We have previously developed an assessment that evaluates English-speakers on a variety of instrumental activities of daily living. In this pilot study, we used Spanish-language translations of our functional battery to investigate the cultural relevance of such measures, and to explore relationships between NP status and ability to perform important everyday tasks in HIV-infected Spanish-speakers. Sixteen HIV-infected monolingual Spanish-speaking adults received comprehensive, Spanish language NP testing and functional assessments included the following domains: Medication Management, Cooking, Finances, Shopping, and Restaurant Scenario. Results revealed that most of the functional tasks appeared culturally relevant and appropriate with minor modifications. NP-impaired participants were significantly more functionally impaired compared to NP-normals (88% vs. 13%, p<.01). Performances on the functional assessment and the NP battery were also related to indicators of real world functioning, including employment status and quality of life. These results, though preliminary, suggest that Spanish language functional assessments are potentially valid tools for detecting everyday functioning deficits associated with NP impairments in HIV-infected Spanish-speakers.
Unemployment rates are high among chronic methamphetamine (MA) users and carry a significant economic burden, yet little is known about the neurocognitive and psychiatric predictors of employment in this vulnerable population.
The present study examined this issue in 63 participants with recent MA dependence and 47 comparison subjects without histories of MA use disorders. All participants completed a comprehensive neurocognitive, psychiatric and neuromedical evaluation. Individuals with HIV infection, severe neuropsychological or psychiatric conditions that might affect cognition (e.g., seizure disorder, schizophrenia), or a positive Breathalyzer or urine toxicology screen on the day of testing were excluded.
Consistent with previous research, a logistic regression revealed MA dependence as a significant, independent predictor of full-time unemployment status. Within the MA-dependent sample, greater impairment in global neurocognitive functioning and history of injection drug use emerged as significant independent predictors of unemployment status. The association between worse global cognitive functioning and unemployment was primarily driven by deficits in executive functions, learning, verbal fluency, and working memory.
These findings indicate that neurocognitive deficits play a significant role in the higher unemployment rates of MA-dependent individuals, and highlight the need for vocational rehabilitation and supported employment programs that assess and bolster cognitive skills in this population.
Functional status; Substance abuse; Cognitive impairment; Neuropsychological assessment; Employment
FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p<0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p=0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p=0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.
FKBP4; FKBP5; HIV dementia; Immunophilin; NR3C1
Episodic memory deficits are common in HIV infection and bipolar disorder, but patient insight into such deficits remains unclear. Thirty-four HIV-infected individuals without bipolar disorder l(HIV+/BD−) and 47 HIV+ individuals with comorbid bipolar disorder (HIV+/BD+) were administered the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised to examine objective learning/memory functioning. Subjective memory complaints were assessed via the memory subscale of the Patient’s Assessment of Own Functioning Inventory. HIV+/BD+ individuals performed poorer on tests of visual learning and visual/verbal recall compared to HIV+/BD− participants (ps<0.05). Memory complaints only predicted verbal learning (at a trend level, p=0.10) and recall (p=0.03) among the HIV+/BD− individuals. Memory complaints were not associated with memory performance within the HIV+/BD+ group (ps>0.10). Memory complaints were associated with affective symptoms in both groups. These complaints were also predictive of immunosuppression, higher unemployment, and greater dependence on Activities of Daily Living among the HIV+/BD+ individuals (ps<0.05). Awareness of memory abilities was particularly poor among HIV+/BD+ individuals (i.e., objective learning/memory did not correspond to reported complaints), which has important implications for the capacity of these individuals to engage in error-monitoring and compensatory strategies in daily life. Memory complaints are associated with depressed mood regardless of group membership. Among HIV+/BD+ individuals, these complaints may also signify worse HIV disease status and problems with everyday functioning. Clinicians and researchers should be cognizant of what these complaints indicate in order to lead treatment most effectively; use of objective neurocognitive assessments may still be warranted when working with these populations.
Self report; Infectious Diseases; Affective Disorders; Episodic Memory; Cognition
Persons infected with human immunodeficiency virus (HIV) have a high prevalence of insomnia (46%) and daytime drowsiness (30%). Factors associated with insomnia among patients with HIV infection include depression and increased waist size. Screening for sleep disturbances should be considered among HIV-infected persons.
Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited.
Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank.
Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0–142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4–5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7–.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly.
Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
During the last decade considerable attention has been focussed upon the development of new technologies and methodologies for detection of drug resistance in Mycobacterium tuberculosis. There is a growing acknowledgement that the redundancy in testing a full panel of first-line drugs is an unaffordable indulgence; since only resistance at baseline to either (or both) of the two most potent agents, isoniazid (H) and rifampicin (R), would usually prompt therapeutic modification there is a shift towards initial RH (or R alone for selected genotypic technologies) drug susceptibility testing (DST) followed, if necessary by further extended first and second line agent (currently phenotypic) DST. Most of the new drug susceptibility tests endorsed by the World Health Organization since 2007 deliver rapid RH (or R alone for selected genotypic technologies) DST. Targeting of patient groups with risk factors for drug resistance increases the proportion of tests that identify drug resistance, but in many settings at least as many patients with drug resistant disease will have no identifiable risk factors—equity of care demands that universal RH DST at baseline should be the goal. We review the bewildering array of choices facing TB program directors and attempt to provide objective information to help in deciding what tools may be best suited to different environments.
Difficulties with sustained attention have been found among both persons with HIV infection (HIV+) and bipolar disorder (BD). The authors examined sustained attention among 39 HIV+ individuals with BD (HIV+/BD+) and 33 HIV-infected individuals without BD (HIV+/BD−), using the Conners’ Continuous Performance Test–II (CPT–II). A Global Assessment of Functioning (GAF) score was also assigned to each participant as an overall indicator of daily functioning abilities. HIV+/BD+ participants had significantly worse performance on CPT–II omission errors, hit reaction time SE (Hit RT SE), variability of SE, and perseverations than HIV+/BD− participants. When examining CPT–II performance over the six study blocks, both HIV+/BD+ and HIV+/BD− participants evidenced worse performance on scores of commission errors and reaction times as the test progressed. The authors also examined the effect of current mood state (i.e., manic, depressive, euthymic) on CPT–II performance, but no significant differences were observed across the various mood states. HIV+/BD+ participants had significantly worse GAF scores than HIV+/BD− participants, which indicates poorer overall functioning in the dually-affected group; among HIV+/BD+ persons, significant negative correlations were found between GAF scores and CPT–II omission and commission errors, detectability, and perseverations, indicating a possible relationship between decrements in sustained attention and worse daily-functioning outcomes.
Leg exercise hemodynamics during single-leg knee extensions were compared among healthy groups of early perimenopausal (n = 15), late perimenopausal (n = 12), and early postmenopausal (n = 11) women. Femoral blood flow (FBF) and vascular conductance (FVC) at rest and during very light work rates (0 and 5 W) were similar among all three menopause stage groups. Vascular responses at 10 W (FBF) and 20 W (FBF and FVC) were significantly higher (P < 0.05) in early perimenopausal compared with late perimenopausal women. At 15 and 25 W, FBF and FVC were similar between late perimenopausal and early postmenopausal groups but higher (P < 0.05) in early perimenopausal women as compared with the other two menopausal groups. In the combined sample of all three menopause stage groups, follicle-stimulating hormone was significantly correlated with vascular conductance during submaximal (15 W) exercise (R = −0.56, P < 0.001), even after adjustment for age, fitness, LDL cholesterol, and abdominal fat (R = −0.46, P = 0.005). Collectively, these findings suggest that in middle-aged women, there is an association between menopause stage and leg vascular responsiveness during exercise.
exercise hyperemia; menopause transition; reproductive hormones
Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART).
Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204).
Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters.
Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt.
High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggests that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.
HIV; depression; suicide
HIV-associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral treatment (ART), and it is essential to have a sensitive and specific HAND screening tool.
Participants were 200 HIV-infected US military beneficiaries, managed early in the course of HIV infection, had few comorbidities, and had open access to ART. Participants completed a comprehensive, seven-domain (16-test), neuropsychological battery (∼120 min); neurocognitive impairment (NCI) was determined using a standardized score derived from demographically adjusted T-scores (global deficit score ≥0.5). Restricting the estimated administration time of the screening battery to < = 20 minutes, we examined the sensitivity and specificity of detecting NCI for all possible combinations of 2-, 3-, and 4- tests from the comprehensive battery.
Participants were relatively healthy (median CD4 count: 546 cells/mm3) with 64% receiving ART. Prevalence of NCI was low (19%). The best 2-test screener included the Stroop Color Test and the Hopkins Verbal Learning Test-Revised (11 min; sensitivity = 73%; specificity = 83%); the best 3-test screener included the above measures plus the Paced Auditory Serial Addition Test (PASAT; 16 min; sensitivity = 86%; specificity = 75%). The addition of Action Fluency to the above three tests improved specificity (18 min; sensitivity = 86%; specificity = 87%).
Combinations of widely accepted neuropsychological tests with brief implementation time demonstrated good sensitivity and specificity compared to a time intensive neuropsychological test battery. Tests of verbal learning, attention/working memory, and processing speed are particularly useful in detecting NCI. Utilizing validated, easy to administer, traditional neuropsychological tests with established normative data may represent an excellent approach to screening for NCI in HIV.
For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum (Cmax) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter; P = 0.05). The rifampin Cmax was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter; P < 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different Cmax results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (P < 0.001) and the time to maximum concentration of drug in serum (Tmax) at 2 h (P = 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.
Mild forms of HIV-associated neurocognitive disorders (HAND) remain prevalent in the era of combination antiretroviral therapy (cART). Although elevated LPS and immune activation are implicated in HAND pathogenesis, relationships of LPS and inflammatory markers to mild forms of HAND or impairment in specific cognitive domains are unknown. To examine these relationships, we compared plasma soluble CD14 (sCD14), CCL2, and LPS levels to neurocognitive test scores in a cART era cohort.
We analyzed plasma from HIV+ subjects (n=97) with nadir CD4 counts <300 and high frequency of HCV co-infection and illicit drug use for relationships between sCD14, CCL2, and LPS levels and neurocognitive test scores.
Plasma sCD14 levels were higher in subjects with test scores indicating global impairment (p=0.007), particularly in attention and learning domains (p=0.015 and p=0.03, respectively), regardless of HAND diagnosis. Plasma sCD14 levels correlated inversely with global, attention, and learning T scores (p=0.036, 0.047, and 0.007, respectively), and yielded higher AUROC values for predicting impaired scores than single-marker models based on plasma or CSF viral load or CD4 count (AUROC 0.71, 0.81, and 0.71, respectively), and in four-marker models based on plasma sCD14 and three conventional markers compared to the three-marker models.
Plasma sCD14 is a biomarker associated with impaired neurocognitive testing in attention and learning domains in HIV-infected individuals with advanced disease, suggesting involvement of cortical and limbic pathways by inflammatory processes in the cART era. Plasma sCD14 is a potential biomarker to monitor HAND progression and therapeutic responses.
HIV; AIDS; HIV-associated neurocognitive disorders; HCV; biomarkers; drug abuse
Memory and executive functioning are two important components of clinical neuropsychological (NP) practice and research. Multiple demographic factors are known to affect performance differentially on most NP tests, but adequate normative corrections, inclusive of race/ethnicity, are not available for many widely used instruments. This study compared demographic contributions for widely used tests of verbal and visual learning and memory (Brief Visual Memory Test-Revised, Hopkins Verbal Memory Test-Revised), and executive functioning (Stroop Color and Word Test, Wisconsin Card Sorting Test-64) in groups of healthy Caucasians (n = 143) and African-Americans (n = 103). Demographic factors of age, education, gender, and race/ethnicity were found to be significant factors on some indices of all four tests. The magnitude of demographic contributions (especially age) was greater for African-Americans than Caucasians on most measures. New, demographically corrected T-score formulas were calculated for each race/ethnicity. The rates of NP impairment using previously published normative standards significantly overestimated NP impairment in African-Americans. Utilizing the new demographic corrections developed and presented herein, NP impairment rates were comparable between the two race/ethnicities and unrelated to the other demographic characteristics (age, education, gender) in either race/ethnicity group. Findings support the need to consider extended demographic contributions to neuropsychological test performance in clinical and research settings.
Tuberculosis (TB) disease remains one of the highest causes of mortality in HIV-infected individuals, and HIV–TB coinfection continues to grow at alarming rates, especially in sub-Saharan Africa. Surprisingly, a number of important areas regarding coinfection remain unclear. For example, increased risk of TB disease begins early in the course of HIV infection; however, the mechanism by which HIV increases this risk is not well understood. In addition, there is lack of consensus on the optimal way to diagnose latent TB infection and to manage active disease in those who are HIV infected. Furthermore, effective point-of-care testing for TB disease remains elusive. This review discusses key areas in the epidemiology, pathogenesis, diagnosis, and management of active and latent TB in those infected with HIV, focusing attention on issues related to high- and low-burden areas. Particular emphasis is placed on controversial areas where there are gaps in knowledge and on future directions of study.
tuberculosis; HIV; diagnosis; management; epidemiology
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
Cognitive behavioural therapy (CBT) is the dominant psychological treatment for chronic pain. CBT covers a mixture of aims and a broad range of techniques, including attentional control, modification of maladaptive beliefs and coping strategies and flexible goal setting and acceptance. Patients are exposed to varying selections of these strategies, and a major challenge for clinical practice is to determine what works for whom in which context. We propose that incorporating laboratory research into translational behaviour medicine is a critical developmental step that will help optimizing CBT and provide examples of representative experimental research programs.
Pain; Psychology; Cognitive behavioural therapy; Experimental research
HIV-negative individuals with a family history of dementia (FHD) are more likely to develop dementia than those without a FHD. Whether FHD increases risk for neuropsychological (NP) impairment in HIV+ persons is unknown. As part of a multi-site study into HIV-Associated Neurocognitive Disorders (HAND), we captured FHD with a free-response, self-report question, and assessed NP performance with a comprehensive battery of tests. We examined HIV+ persons with (n=190) and without (n=916) self-reported FHD. Despite the fact that the FHD group had factors typically associated with better NP performance (e.g., higher CD4 counts and estimated verbal IQ [VIQ]), persons with FHD had significantly worse NP ability than those without FHD as measured by a Global Deficit Score (GDS) (FHD mean=0.66; No FHD mean=0.55; p<0.05). Thus, FHD appears to be a risk factor for HAND; the mechanism(s) underlying how FHD contributes to NP impairment among HIV+ persons warrants study.
HIV; AIDS; Cognition; Aging; Dementia
There is limited available data on the strain diversity of M tuberculosis in Peru, though there may be interesting lessons to learn from a setting where multidrug resistant TB has emerged as a major problem despite an apparently well-functioning DOTS control programme.
Spoligotyping was undertaken on 794 strains of M tuberculosis collected between 1999 and 2005 from 553 community-based patients and 241 hospital-based HIV co-infected patients with pulmonary tuberculosis in Lima, Peru. Phylogenetic and epidemiologic analyses permitted identification of clusters and exploration of spoligotype associations with drug resistance.
Mean patient age was 31.9 years, 63% were male and 30.4% were known to be HIV+. Rifampicin mono-resistance, isoniazid mono-resistance and multidrug resistance (MDR) were identified in 4.7%, 8.7% and 17.3% of strains respectively. Of 794 strains from 794 patients there were 149 different spoligotypes. Of these there were 27 strains (3.4%) with novel, unique orphan spoligotypes. 498 strains (62.7%) were clustered in the nine most common spoligotypes: 16.4% SIT 50 (clade H3), 12.3% SIT 53 (clade T1), 8.3% SIT 33 (LAM3), 7.4% SIT 42 (LAM9), 5.5% SIT 1 (Beijing), 3.9% SIT 47 (H1), 3.0% SIT 222 (clade unknown), 3.0% SIT1355 (LAM), and 2.8% SIT 92 (X3). Amongst HIV-negative community-based TB patients no associations were seen between drug resistance and specific spoligotypes; in contrast HIV-associated MDRTB, but not isoniazid or rifampicin mono-resistance, was associated with SIT42 and SIT53 strains.
Two spoligotypes were associated with MDR particularly amongst patients with HIV. The MDR-HIV association was significantly reduced after controlling for SIT42 and SIT53 status; residual confounding may explain the remaining apparent association. These data are suggestive of a prolonged, clonal, hospital-based outbreak of MDR disease amongst HIV patients but do not support a hypothesis of strain-specific propensity for the acquisition of resistance-conferring mutations.
Mannose binding lectin (MBL) activates complement pathway that leads to pathogen opsonization and phagocytosis. MBL deficiency is linked to HIV transmission and disease progression. We sought to determine the role of MBL in HIV encephalitis (HIVE) by evaluating its presence and distribution in the HIV-1-infected brain and by assessing its association with monocyte chemoattractant protein-1 (MCP-1) expression. This retrospective study utilized archived post-mortem brain tissues obtained from 35 individuals enrolled in a longitudinal study as part of the California NeuroAIDS Tissue Network. MBL, MCP-1 and brain cell markers in post-mortem brain tissues with or without HIVE were evaluated using immunocytochemistry, immunofluorescence, confocal microscopy, and western blots. MBL was expressed in neurons, astrocytes, microglia, and oligodendrocytes of the frontal cortex of the HIV-1-infected brain. Overall, there were 30% to 40% more MBL-positive brain cells in HIVE vs non-HIVE cases (P = 0.01, paired t-test). Specifically, there was an increased MBL expression in the neuronal axons of HIVE cases. Also, western blots showed 3- to 4-fold higher levels of 78 kD MBL trimers in HIVE vs non-HIVE cases. This MBL-HIVE link was further confirmed by MBL associated higher MCP-1 expression in HIVE vs non-HIVE cases. HIV negative healthy individuals and normal or the gp120 transgenic mice did not show any differential MBL expression. Increased MBL expression in the major brain cell types, specifically in the neuronal axons of HIVE brain, and MBL associated higher MCP-1 expression in HIVE suggest that MBL could cause neuroinflammation and neuronal injury through MBL complement activation pathway.
mannose binding lectin; HIV encephalitis; complement activation; neuroinflammation; neuroAIDS; MCP-1
Hepatitis C virus (HCV) is neurovirulent and has been shown to be associated with neuropsychological (NP) deficits in a subset of infected individuals. Despite these previous findings, little work has been done to examine neurobehavioral symptoms associated with HCV infection. We examined 34 HCV seropositive (HCV+) individuals and 35 healthy comparison participants (HCV−) with the self-rating form of the Frontal Systems Behavior Scale (FrSBe). Results showed that at the group level, only the FrSBe apathy subscale mean was clinically elevated (T-score >65) among HCV+ persons; executive dysfunction, disinhibition, and total subscale means were not clinically elevated. At the individual level, a significantly higher proportion of HCV+ individuals reported clinically elevated FrSBe T-scores as compared to HCV− individuals. Moreover, HCV+ individuals were nearly 3 times as likely to report clinically elevated FrSBe T-scores of apathy, executive dysfunction, and disinhibition as compared to HCV− participants. A multiple regression that included substance use disorders, neuropsychological impairment and age indicated that HCV status was an independent predictor of self-reported FrSBe total T-scores. Across all participants, small, yet significant, correlations were found between elevated self-reported FrsBe T-scores and dependence in activities of daily living. These results show that a subset of HCV infected individuals report clinically elevated behavioral symptoms. Clinical implications for the assessment and management of elevated behavioral symptoms in HCV are discussed.
Hepatitis; Executive functions; Prefrontal cortex; Apathy; Neuropsychology; Substance abuse
Tuberculosis (TB) destroys lung tissues and this immunopathology is mediated in part by Matrix Metalloproteinases (MMPs). There are no data on the relationship between local tissue MMPs concentrations, anti-tuberculosis therapy and sputum conversion.
Materials and Methods
Induced sputum was collected from 68 TB patients and 69 controls in a cross-sectional study. MMPs concentrations were measured by Luminex array, TIMP concentrations by ELISA and were correlated with a disease severity score (TBscore). 46 TB patients were then studied longitudinally at the 2nd, 8th week and end of treatment.
Sputum MMP-1,-2,-3,-8,-9 and TIMP-1 and -2 concentrations are increased in TB. Elevated MMP-1 and -3 concentrations are independently associated with higher TB severity scores (p<0.05). MMP-1, -3 and -8 concentrations decreased rapidly during treatment (p<0.05) whilst there was a transient increase in TIMP-1/2 concentrations at week 2. MMP-2, -8 and -9 and TIMP-2 concentrations were higher at TB diagnosis in patients who remain sputum culture positive at 2 weeks and MMP-3, -8 and TIMP-1 concentrations were higher in these patients at 2nd week of TB treatment.
MMPs are elevated in TB patients and associate with disease severity. This matrix-degrading phenotype resolves rapidly with treatment. The MMP profile at presentation correlates with a delayed treatment response.