Inherited anxiety-related parent-infant dyads alter LHPA activity.

The pathogenesis of post-traumatic stress disorder (PTSD) is incompletely understood. We hypothesize that disruptions in mother-child relations may be a key contributor to development of PTSD. A normal and healthy separation-individuation process requires adaptations of self- and interactive contingency in both the mother and her child, especially in early childhood development. Anxious mothers are prone to overprotection, which may hinder the individuation process in their children. We examined long-term stress hormones and other stress markers in subjects three generations removed from the Holocaust, to assess the long-term consequences of inherited behavioral and physiological responses to prior stress and trauma. Jewish subjects who recalled overprotective parental behavior had higher hairsteroid-concentrations and dampened limbic-hypothalamic-pituitary-adrenal (LHPA) axis reactivity compared to German and Russian-German subjects with overprotective parents. We suggest that altered LHPA axis activity in maternally overprotected Jewish subjects may indicate a transmitted pathomechanism of "frustrated individuation" resulting from cross-generational anti-Semitic experiences. Thus measurements of hairsteroid-concentrations and parenting practices may have clinical value for diagnosis of PTSD. We propose that this apparent inherited adaptivity of LHPA axis activity could promote higher individual stress resistance, albeit with risk of an allostatic overload.

Adjunctive therapies for HIV-1 associated neurologic disease.

In the past decade we have seen a milder phenotype and decreased incidence of HIV-1 associated dementia (HAD), largely due to the widespread use of combination chemotherapy to reduce viral burden. However, the prevalence of neurologic disease in people living with HIV-1 has actually increased, raising significant concerns that new therapeutic strategies, directed at restoring neuronal and glial homeostasis and signaling in the central nervous system (CNS), as opposed to directly interfering with the life cycle of HIV-1, must be developed. In this review, we focus briefly on previous Phase 1 clinical trials for adjunctive (i.e., chemotherapeutic agents that do not have a primary antiretroviral mechanism of action) therapy in patients with HAD, followed by an overview of key molecular events in the neuropathogenesis of HAD, and then discuss in more detail our rationale for investigating the effects of therapeutic agents that restore impaired mitochondrial bioenergetics in the CNS. Specifically, we focus on agents that either work in part through K-ATP channels, present in both mitochondria and plasma membranes, and agents that work to weakly uncouple the respiratory capacity of the electron transport chain in mitochondria from ATP production. We propose these agents may be complementary to currently available antiretroviral agents and may significantly improve the capacity of CNS infected with HIV-1 to meet increased bioenergetic demands involved in normal synaptic communication.

Psychotherapy adherence of therapists treating HIV-positive patients with depressive symptoms.

Adherence monitoring, a technology to specify research psychotherapies, was used in the NIMH Treatment of Depression Collaborative Research Program (TDCRP). The authors present adherence data from a similar randomized treatment trial of 56 depressed HIV-positive patients, comparing 16-week interventions with cognitive-behavioral therapy, interpersonal psychotherapy, and supportive psychotherapy alone or with imipramine. Therapists were certified in manualized treatments. Blind independent raters rated randomly selected taped sessions on an adaptation of the NIMH scale, yielding adherence scores for interventions and for therapist "facilitative conditions" (FC). All therapists were rated adherent. Interrater reliability was 0.89-0.99. The scale discriminated among the four treatments (P<0.0001), with each scoring highest on its own scale. FC, which might measure therapist competence independent of treatment technique, varied by intervention but did not predict treatment outcome. This study demonstrates the ability to reliably train adherence monitors and therapists able to deliver specified treatments. Its adherence findings provide the first replication of those from the landmark NIMH TDCRP study.

Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system.

HIV-1 infection of the brain results in chronic inflammation, contributing to the neuropathogenesis of HIV-1 associated neurologic disease. HIV-1-infected mononuclear phagocytes (MP) present in inflammatory infiltrates produce neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosis. Neurologic disease is correlated with the relative number of MP in and around inflammatory infiltrates and not viral burden. It is unclear whether these cells also play a neuroprotective role. We show that the chemokine, fractalkine (FKN), is markedly up-regulated in neurons and neuropil in brain tissue from pediatric patients with HIV-1 encephalitis (HIVE) compared with those without HIVE, or that were HIV-1 seronegative. FKN receptors are expressed on both neurons and microglia in patients with HIVE. These receptors are localized to cytoplasmic structures which are characterized by a vesicular appearance in neurons which may be in cell-to-cell contact with MPs. FKN colocalizes with glutamate in these neurons. Similar findings are observed in brain tissue from an adult patient with HIVE. FKN is able to potently induce the migration of primary human monocytes across an endothelial cell/primary human fetal astrocyte trans-well bilayer, and is neuroprotective to cultured neurons when coadministered with either the HIV-1 neurotoxin platelet activating factor (PAF) or the regulatory HIV-1 gene product Tat. Thus focal inflammation in brain tissue with HIVE may up-regulate neuronal FKN levels, which in turn may be a neuroimmune modulator recruiting peripheral macrophages into the brain, and in a paracrine fashion protecting glutamatergic neurons.

Weight assignment for adaptive image restoration by neural networks.

This paper presents a scheme for adaptively training the weights, in terms of varying the regularization parameter, in a neural network for the restoration of digital images. The flexibility of neural-network-based image restoration algorithms easily allow the variation of restoration parameters such as blur statistics and regularization value spatially and temporally within the image. This paper focuses on spatial variation of the regularization parameter.We first show that the previously proposed neural-network method based on gradient descent can only find suboptimal solutions, and then introduce a regional processing approach based on local statistics. A method is presented to vary the regularization parameter spatially. This method is applied to a number of images degraded by various levels of noise, and the results are examined. The method is also applied to an image degraded by spatially variant blur. In all cases, the proposed method provides visually satisfactory results in an efficient way.

Platelet-activating factor receptor activation. An initiator step in HIV-1 neuropathogenesis.

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system results in neuronal apoptosis. Activated HIV-1-infected monocytes secrete high levels of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the phospholipid mediator platelet-activating factor (PAF). TNF-alpha and PAF are elevated in the central nervous system of patients with HIV-1-associated dementia. We now demonstrate that conditioned media from activated HIV-1-infected monocytes induces neuronal apoptosis, which can be prevented by co-incubation with PAF acetylhydrolase, the enzyme that catabolizes PAF in the central nervous system. Preceding apoptosis is a TNF-alpha-induced increase in neuronal ceramide levels. TNF-alpha-mediated neuronal apoptosis can also be blocked by co-incubation with PAF acetylhydrolase, or a PAF receptor antagonist. Blocking pathologic activation of PAF receptors may therefore be a pivotal step in the treatment of HIV-1-associated dementia.

Treatment of depressive symptoms in human immunodeficiency virus-positive patients.

BACKGROUND: This randomized clinical trial compared 16-week interventions with interpersonal psychotherapy, cognitive behavioral therapy, supportive psychotherapy, and supportive psychotherapy with imipramine for human immunodeficiency virus (HIV)-positive patients with depressive symptoms. METHODS: Subjects (N = 101; 85 male, 16 female) with known HIV seropositivity for at least 6 months were randomized to 16 weeks of treatment. Inclusion criteria were 24-item Hamilton Depression Rating Scale score of 15 or higher, clinical judgment of depression, and physical health sufficient to attend outpatient sessions. Therapists were trained in manualized therapies specific for HIV-positive patients. Treatment adherence was monitored. RESULTS: Subjects randomized to interpersonal psychotherapy (n = 24) and supportive psychotherapy with imipramine (n = 26) had significantly greater improvement on depressive measures than those receiving supportive psychotherapy (n = 24) or cognitive behavioral therapy (n = 27). Similar results appeared in the completer subsample. CONCLUSIONS: Depressive symptoms appear treatable in HIV-positive patients. Interpersonal psychotherapy may have particular advantages as a psychotherapy for patients who have experienced the significant life events of HIV infection.

Simultaneous in situ detection of apoptosis and necrosis in monolayer cultures by TUNEL and trypan blue staining.

A method for simultaneously detecting membrane permeability (characteristic of necrosis) and DNA fragmentation (characteristic of apoptosis) is described. By combining a common dye-exclusion method (Trypan Blue) with a commercially available terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) labeling kit, we have succeeded in developing a novel methodology for obtaining permanently mounted slides of monolayer cell cultures double-labeled for DNA fragmentation and cell lysis. This method should facilitate in situ studies of cell death by allowing for a more accurate quantification of total toxicity in monolayer cell cultures and perhaps further enhance our understanding of the different mechanisms of cell death as well.

The impact of multiple bereavement in a gay male sample.

The effect of experiencing multiple close losses on a variety of psychological symptoms was examined in a sample of HIV positive and HIV negative gay men over 1 year. Symptoms assessed included depression, intrusive and avoidant thoughts and images, anxiety, and general distress. It was found that on average, experiencing two or more losses in the year prior to the initial interview was associated with significantly higher levels of distress in follow-up assessment over 1 year. Comparisons between subjects with two or fewer losses versus three or more losses produced the largest differences in emotional symptoms. HIV positive subjects showed higher levels of distress symptoms on all measures, except for intrusive and avoidant thoughts and images. These findings indicate that the experience of multiple close losses, which is rather common among HIV-infected gay men, chronically exacerbates their emotional distress.

Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia.

Human immunodeficiency virus (HIV) infection is commonly associated with neurological disease that occurs in the apparent absence of extensive infection of brain cells by HIV, suggesting that indirect mechanisms account for neuropathogenesis in the CNS, perhaps including changes in the normal neuroprotective functions of astrocytes. To test this hypothesis, we examined the effect of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFalpha), produced by HIV-1-infected macrophages and microglia, on glutamate transport by primary human fetal astrocytes (PHFAs). A dose-dependent inhibition of high affinity glutamate uptake sites was observed 12-24 h after addition of exogenous recombinant human TNFalpha to PHFAs. This effect was specific since it was blocked by a neutralizing monoclonal antibody directed against TNFalpha. Furthermore, the inhibitory effect was reproduced by a monoclonal antibody that is an agonist at the 55-kDa TNF receptor. These results suggest that the neurotoxic effects of TNFalpha may be due in part to its ability to inhibit glutamate uptake by astrocytes, which in turn may result in excitotoxic concentrations of glutamate in synapses.

Memory performance among women with parental abuse histories: enhanced directed forgetting or directed remembering?

Performance on a directed forgetting task was assessed in 24 individuals with borderline personality disorder and early life parental abuse, 24 borderline individuals with no history of abuse, and 24 healthy nonclinical controls under conditions of explicit and implicit memory. In the explicit memory condition, individuals with abuse histories showed greater differential recall of "to-be-remembered" versus "to-be-forgotten" material compared to the 2 comparison groups. Implicit memory performance was equivalent for all 3 groups. The enhanced selective memory in the abused group was the result of better recall for "remember" and not poorer recall for "forget" information, indicating that abused individuals have an enhanced ability to sustain attention to designated "remember" information. Because most people with childhood abuse recall their abuse, enhanced remembering of designated events (e.g., information not associated with abuse) may be a coping strategy.

Distress reduction during the structured clinical interview for DSM-III-R.

In an attempt to assess the influence of standardized diagnostic interviews on psychological distress in research volunteers, the Visual Analogue Scale (VAS) was used to measure anxiety and depression during the Structured Clinical Interview for DSM-III-R, Non-patient version (SCID). Subjects were 50 adults with concerns related to the human immunodeficiency virus who were seeking testing and treatment in research trials. Repeated measures analysis of variance showed significant decreases in distress by the end of the interview: 72% of subjects reported diminished anxiety, and 54% reported diminished depression. Thus, the SCID appeared to provide a positive interview experience, a finding that may serve to reassure subjects, their families, and review boards regarding participation in studies that employ structured interviews.

Individual psychotherapies for depressed HIV-positive patients.

OBJECTIVE: The authors present preliminary data from two treatment modalities of a randomized clinical trial in which they compared 16-week interventions of interpersonal psychotherapy to supportive psychotherapy. METHOD: HIV-positive patients who were not acutely medically ill and had scores of 15 or higher on the Hamilton Depression Rating Scale were randomly assigned to one of four treatment modalities. They were assessed by the Hamilton scale and Beck Depression Inventory at 8 and 16 weeks. Most subjects who underwent either interpersonal psychotherapy (N = 16) or supportive psychotherapy (N = 16) were male, gay or bisexual, white, and college educated. RESULTS: Results of last-observation-carried-forward and completer analyses showed that scores on the Hamilton scale and Beck Depression Inventory decreased significantly for both treatments. Differential improvement for interpersonal psychotherapy appeared by midtreatment (week 8) and persisted at termination. CONCLUSIONS: This is the first controlled study of individual psychotherapies for depressed HIV-positive patients. Results suggest that a specific antidepressant psychotherapy, interpersonal psychotherapy, has advantages over a supportive therapy.

Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy.

The pathogenesis of human immunodeficiency virus type 1 (HIV-1) associated dementia in adults involves neuronal loss from discrete areas of the neocortex and subcortical regions, but the mechanism for neuronal death is poorly understood. Gene-directed cell death resulting in apoptosis is thought to be a normal feature of neuronal development, but little is known about neuronal apoptosis in disease states. We investigated whether HIV-1 infection of the central nervous system is spatially associated with apoptosis of neurons. Using an in situ technique to identify newly cleaved 3'-OH ends of DNA as a marker for apoptosis, we demonstrate the presence of apoptotic neurons in cerebral cortex and basal ganglia of children that had HIV-1 encephalitis with progressive encephalopathy. Furthermore, an association was observed between the localization of apoptotic neurons and perivascular inflammatory cell infiltrates containing HIV-1 infected macrophages and multinucleated giant cells. Apoptotic neurons and p24-positive macrophages were observed infrequently in cerebral cortex and basal ganglia in children with HIV-1 infection without encephalitis or clinical encephalopathy. In nine control (HIV-1 negative) brains, ranging from the first post-natal month of life to 16.5 years of age, infrequent neuronal apoptosis was observed in three cases. These findings suggest that neuronal apoptosis is unlikely to be associated with post-natal development except in early post-natal germinal matrix, and that it may instead represent the end result of specific pathological processes, such as HIV-1 encephalitis.

Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA.

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.

Serosurvey of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infection among hospital-based surgeons. Serosurvey Study Group.

BACKGROUND: Because occupational blood contact places health-care workers at risk for infection with bloodborne pathogens, we wanted to estimate the prevalence of infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) among hospital-based surgeons and correlate the results with occupational and nonoccupational risk factors. STUDY DESIGN: All surgeons in training or in practice in general surgery, obstetrics and gynecology, or orthopedics at 21 hospitals in moderate to high AIDS incidence areas were eligible to participate in a voluntary, anonymous serosurvey. Serum samples were tested for HIV antibody, for HCV antibody, and for markers of HBV infection: hepatitis B surface antigen, total antibody to hepatitis B core antigen, and antibody to hepatitis B surface antigen. RESULTS: Of 2,887 eligible surgeons, 770 (27 percent) participated in the study. One of 740 surgeons not reporting nonoccupational risk factors was HIV seropositive (0.14 percent, upper limit 95 percent confidence interval [CI] equals 0.64 percent). None of 20 participants reporting nonoccupational HIV risk factors and none of ten not responding to the question on nonoccupational risk factors were HIV positive. Of 129 (17 percent) participants with past or current HBV infection, three (0.4 percent) had chronic HBV infection; all were negative for hepatitis B e antigen. Risk factors for HBV infection included not receiving hepatitis B vaccine (odds ratio [OR] 14.7, 95 percent CI 8.3 to 26.0) and practicing surgery at least ten years (OR 2.2, 95 percent CI 1.3 to 3.8). Seven (0.9 percent) participants had anti-HCV. CONCLUSIONS: Although not necessarily generalizable to all surgeons in moderate to high AIDS incidence areas, these results do not indicate a high rate of previously undetected HIV infection among surgeons who trained or practiced in these areas, or both. Hepatitis B virus posed the highest risk of infection with a bloodborne pathogen, followed by HCV and HIV.

Self-disclosure of HIV infection to sexual partners after repeated counseling.

This study, with the objective of examining voluntary self-disclosure of HIV infection after repeated counseling, was conducted in a private setting, and designed to operate in conjunction with HIV testing. Counseling was provided at entry, and then at 3 months, 6 months, and every six months thereafter. The study was conducted among 129 HIV-positive adults; the primary risk factor was history of: males having sex with males (n = 104); injection drug use (n = 19); or heterosexual contact (n = 6). Results showed that after a mean of 2.3 years since initial HIV-positive notification, 29 percent of subjects had not disclosed the HIV infection to any present partner, and 30 percent to any past sex partner. Casual sex and lower perceived social support were significantly associated with nondisclosure. The authors conclude that even after repeated individual counseling and at least several months to inform others, about one-third of the sexually active subjects did not disclose their HIV infection to any present sex partner. Clinical and public health implications are covered.