HIV-1 Tat Dysregulates the Hypothalamic-Pituitary-Adrenal Stress Axis and Potentiates Oxycodone-Mediated Psychomotor and Anxiety-Like Behavior of Male Mice.

Human immunodeficiency virus (HIV) is associated with co-morbid affective and stress-sensitive neuropsychiatric disorders that may be related to dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis. The HPA axis is perturbed in up to 46% of HIV patients, but the mechanisms are not known. The neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), may contribute. We hypothesized that HPA dysregulation may contribute to Tat-mediated interactions with oxycodone, a clinically-used opioid often prescribed to HIV patients. In transgenic male mice, Tat expression produced significantly higher basal corticosterone levels with adrenal insufficiency in response to a natural stressor or pharmacological blockade of HPA feedback, recapitulating the clinical phenotype. On acute exposure, HIV-1 Tat interacted with oxycodone to potentiate psychomotor and anxiety like-behavior in an open field and light-dark transition tasks, whereas repeated exposure sensitized stress-related psychomotor behavior and the HPA stress response. Pharmacological blockade of glucocorticoid receptors (GR) partially-restored the stress response and decreased oxycodone-mediated psychomotor behavior in Tat-expressing mice, implicating GR in these effects. Blocking corticotrophin-releasing factor (CRF) receptors reduced anxiety-like behavior in mice that were exposed to oxycodone. Together, these effects support the notion that Tat exposure can dysregulate the HPA axis, potentially raising vulnerability to stress-related substance use and affective disorders.

Secuelas neurológicas en pacientes con infección congénita por citomegalovirus / Neurological sequelae in patients with congenital citomegalovirus

INTRODUCCIÓN: La infección por citomegalovirus es la infección congénita más frecuente en los países desarrollados y una de las principales causas de retraso psicomotor y sordera neurosensorial de origen infeccioso. El presente estudio tiene como objetivos describir las características clínico-analíticas y de neuroimagen de los pacientes con secuelas neurológicas secundarias a la infección congénita por citomegalovirus y compararlas con el grupo de pacientes con infección congénita por citomegalovirus que no presentaron clínica neurológica durante su seguimiento. Material y MÉTODOS: Estudio de cohortes retrospectivo, observacional. Se incluyeron todos los casos de infección congénita por citomegalovirus desde 2003 hasta 2018 y se evaluaron las secuelas neurológicas a corto-medio plazo. Se compararon datos prenatales, perinatales y posnatales de los pacientes con secuelas neurológicas frente a los que no las presentaron. RESULTADOS: En el periodo descrito se registraron 60 pacientes con infección congénita por citomegalovirus: un 65% presentó afectación neurológica durante su periodo de seguimiento (retraso psicomotor 62,2%; microcefalia 61,5%, hipoacusia 46,2%; trastornos motores 27,8%; epilepsia 20,5% y coriorretinitis 5,6%). En el grupo de pacientes que presentó secuelas, la presencia de clínica en el periodo neonatal así como las alteraciones en el estudio de neuroimagen fueron más frecuentes y ambas fueron estadísticamente significativas respecto al grupo asintomático. Los pacientes con afectación neurológica también presentaron mayor puntuación en la escala de neuroimagen según Noyola et al. CONCLUSIONES: La sintomatología al nacimiento y ciertos hallazgos en la neuroimagen, como la presencia de alteraciones de la sustancia blanca o trastornos de la migración neuronal, podrían predecir las secuelas neurocognitivas en los pacientes con infección congénita por citomegalovirus

INTRODUCTION: The infection due to cytomegalovirus is the most common congenital infection in developed countries, and on of the main causes of psychomotor impairment and neurosensory hearing loss of infectious origin. The present study has its objectives to describe the clinical-analytical and neuroimaging of patients with secondary neurological sequelae secondary to the congenital cytomegalovirus infection and then compare them with the group of patients with a congenital cytomegalovirus infection that did not have neurological symptoms during their follow-up. MATERIAL AND METHODS: A retrospective, observational, cohort study was conducted that included all the cases of congenital cytomegalovirus infection from 2003 until 2018 and the short-medium term neurological sequelae were evaluated. Prenatal, perinatal, and postnatal data of patients with neurological sequelae were compared against those that did not present with any. RESULTS: A total of 60 patients with congenital cytomegalovirus infection were recorded during the study period, with 65% having neurological involvement during their follow-up period (62.2% with psychomotor impairment, 61.5% with microcephaly, 46.2% loss of hearing, 27.8% motor disorders, 20.5% epilepsy, and 5.6% with chorioretinitis). In the patient group that had sequelae, the presence of clinical symptoms during the neonatal period, as well as changes in the neuroimaging study, were the most common, with both being statistically significant compared to the asymptomatic group. The patients with neurological involvement also had a higher score on the Noyola et al. neuroimaging scale. CONCLUSIONS: The symptoms at birth, and certain findings in the neuroimaging, like the changes in the white matter or neuronal migration disorders, could predict neurocognitive sequelae in patients with congenital cytomegalovirus infection

[Neurological sequelae in patients with congenital cytomegalovirus]. / Secuelas neurológicas en pacientes con infección congénita por citomegalovirus.

INTRODUCTION: The infection due to cytomegalovirus is the most common congenital infection in developed countries, and on of the main causes of psychomotor impairment and neurosensory hearing loss of infectious origin. The present study has its objectives to describe the clinical-analytical and neuroimaging of patients with secondary neurological sequelae secondary to the congenital cytomegalovirus infection and then compare them with the group of patients with a congenital cytomegalovirus infection that did not have neurological symptoms during their follow-up. MATERIAL AND METHODS: A retrospective, observational, cohort study was conducted that included all the cases of congenital cytomegalovirus infection from 2003 until 2018 and the short-medium term neurological sequelae were evaluated. Prenatal, perinatal, and postnatal data of patients with neurological sequelae were compared against those that did not present with any. RESULTS: A total of 60 patients with congenital cytomegalovirus infection were recorded during the study period, with 65% having neurological involvement during their follow-up period (62.2% with psychomotor impairment, 61.5% with microcephaly, 46.2% loss of hearing, 27.8% motor disorders, 20.5% epilepsy, and 5.6% with chorioretinitis). In the patient group that had sequelae, the presence of clinical symptoms during the neonatal period, as well as changes in the neuroimaging study, were the most common, with both being statistically significant compared to the asymptomatic group. The patients with neurological involvement also had a higher score on the Noyola et al. neuroimaging scale. CONCLUSIONS: The symptoms at birth, and certain findings in the neuroimaging, like the changes in the white matter or neuronal migration disorders, could predict neurocognitive sequelae in patients with congenital cytomegalovirus infection.

Preconception screening for cytomegalovirus: an effective preventive approach.

Congenital cytomegalovirus (CMV) is the leading infectious cause of sensorineural hearing loss and delayed psychomotor development. Viral transmission to the fetus is far more likely to occur following a primary than a secondary maternal infection. Primary prevention seems to be the best means to reduce the burden of congenital CMV due to the lack of treatment options during pregnancy. We evaluated this approach on a cohort of 500 women planning pregnancy who attended our fertility clinic. Of the 444 who underwent CMV screening, 18 (4.1%) had positive IgM serology for CMV; of these, IgG avidity was high in 12 (remote infection) and low in 6 (recent infection). The latter were advised to delay pregnancy. All women who were seroimmune for CMV (366/444, 82.4%), including the 12 with remote infection, continued fertility treatment. The remaining patients (72/444, 16.2%), who were not immune to CMV at the initial screen, were advised to minimize CMV exposure by improving personal hygiene and to continue fertility treatment. None of the 69/72 (95.8%) women who were followed for one year were infected with CMV. Cytomegalovirus testing and counselling at preconception seemed effective in reducing CMV exposure in pregnancy.

Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy--a case-control study of the outcome in children.

BACKGROUND: Primary cytomegalovirus (CMV) infection early in gestation causes severe disease. METHODS: Case patients were 32 congenitally infected children aged 1-5 years who had either hearing deficit and/or psychomotor retardation and whose mothers had a confirmed or probable primary CMV infection at ≤ 20 weeks' gestation. Control subjects were 32 congenitally infected normal children whose mothers had a confirmed primary infection at ≤ 20 weeks' gestation. Case patients and control subjects were matched by the weeks of maternal gestation (± 1 week) at the mother's infection and by the child's age (± 1 year) at evaluation. RESULTS: For the case patients and control subjects, the mean age was 3.0 years. The mean number of weeks of gestation at maternal infection was 11 weeks. The only risk factor for an affected child was the mother not receiving immunoglobulin (P = .001). Of the 32 case patients, only 4 mothers received CMV immunoglobulin, compared with 27 of the 32 mothers of control infants (adjusted odds ratio, 14 [95% confidence interval, 1.7-110]). The rate of both psychomotor retardation and hearing deficit decreased with immunoglobulin. CONCLUSIONS: These results support the efficacy of immunoglobulins for decreasing the severity of disabilities caused by fetal CMV infection after a primary maternal infection during pregnancy.

Implications of HAM/TSP functional incapacity in the quality of life.

OBJECTIVE: To identify the functional status and quality of life of HAM/TSP patients. METHOD: We evaluated prospectively 30 HAM/TSP patients (20 females) seen in the Neuroinfection Clinic of the HUGG. The functional capacity was analyzed by the functional independence measure (FIM), the expanded disability status (EDSS) scale and the Osame's motor disability score (OMDS). The quality of life was assessed by the Short-Form Health Survey 36 (SF-36)TM. RESULTS: All patients need assistance device. The FIM, OMDS and EDSS scores classified 70%, 67% and 67% of the patients as dependent, respectively. The lowest scores of the SF-36 survey were found in the domains related to the physical health (D1, D2), role-emotional functioning (D7) and social functioning (D6). CONCLUSION: Our data suggest that the HAM/TSP physical impairment has an impact in the emotional and social issues, considering the limitation in the daily activities.

Implications of HAM/TSP functional incapacity in the quality of life / Implicações da incapacidade funcional na qualidade de vida de pacientes com HAM/TSP

OBJECTIVE: To identify the functional status and quality of life of HAM/TSP patients. METHOD: We evaluated prospectively 30 HAM/TSP patients (20 females) seen in the Neuroinfection Clinic of the HUGG. The functional capacity was analyzed by the functional independence measure (FIM), the expanded disability status (EDSS) scale and the Osame's motor disability score (OMDS). The quality of life was assed by the Short-Form Health Survey 36 (SF-36)TM. RESULTS: All patients need assistance device. The FIM, OMDS and EDSS scores classified 70 percent, 67 percent and 67 percent of the patients as dependent, respectively. The lowest scores of the SF-36 survey were found in the domains related to the physical health (D1, D2), role-emotional functioning (D7) and social functioning (D6). CONCLUSION: Our data suggest that the HAM/TSP physical impairment has an impact in the emotional and social issues, considering the limitation in the daily activities.

OBJETIVO: Avaliar a capacidade funcional e sua interferência na qualidade de vida de pacientes com HAM/TSP. MÉTODO: Foram analisados prospectivamente 30 casos (20 mulheres) de HAM/TSP, atendidos no Ambulatório de Neuroinfecção do HUGG. As escalas para avaliação da capacidade funcional consistiram em: medida de independência funcional (FIM), escala de incapacidade expandida (EDSS) e pontuação da incapacidade motora de Osame (OMDS). A qualidade de vida foi analisada pelo Short-Form 36 Health Survey (SF-36)TM. RESULTADOS: Todos os pacientes necessitavam de assistência para deambular. As escalas FIM, OMDS e EDDS classificaram 70 por cento, 67 por cento e 67 por cento dos pacientes como dependentes, respectivamente. A avaliação pelo SF-36 demonstrou menores escores nos domínios físico (D1, D2), emocional (D7) e social (D6). CONCLUSÃO: Os achados sugerem que a limitação nas atividades diárias decorrentes do envolvimento físico comprometem aspectos emocionais e sociais na HAM/TSP.

Longitudinal psychomotor speed performance in human immunodeficiency virus-seropositive individuals: impact of age and serostatus.

Older human immunodeficiency virus-seropositive (HIV+) individuals (greater than age 50 years) are twice as likely to develop HIV dementia compared to younger HIV+ individuals. The objective of this study was to examine the impact of both age and serostatus on longitudinal changes in psychomotor speed/executive functioning performance among HIV+ and HIV− individuals. Four hundred and seventy-seven HIV+ and 799 HIV− individuals from the Multicenter AIDS Cohort Study (MACS) were subdivided into three age groups: (1) <40 years, (2) 40-50 years, and (3) >50 years. Psychomotor speed/executive functioning test performance was measured by the Symbol Digit Modalities Test (SDMT) and the Trail Making (TM) Test Parts A and B. Changes in performance were compared among the three age groups for both HIV+ and HIV− individuals. Among HIV+ individuals, on the TM Test Part B the younger group demonstrated improvement in performance over time (P = .007). The older and middle age groups demonstrated decline in performance over time (P = .041 and .030). The older group had a significantly different trajectory relative to the younger group (P = .046). Among the HIV− individuals, there was no effect of age on longitudinal performance. In conclusion, older HIV+ individuals show greater decline over time than younger HIV+ individuals on the TM Test Part B. Our results suggest that both HIV serostatus and age together may impact longitudinal performance on this test. Mild neurocognitive changes over time among older HIV+ individuals are likely to reflect age associated pathophysiological mechanisms including cerebrovascular risk factors.

Theiler's virus infection chronically alters seizure susceptibility.

PURPOSE: Central nervous system infections greatly increase the risk for the development of seizures and epilepsy (recurrent unprovoked seizures). We have previously shown that Theiler's murine encephalomyelitis virus (Theiler's virus or TMEV) infection causes acute symptomatic seizures in C57BL/6 (B6) mice. The objective of the present study was threefold: (1) to assess pathologic changes associated with acute TMEV infection and infection-induced seizures, (2) to determine whether Theiler's virus infection and associated acute seizures lead to chronically altered seizure susceptibility, and (3) to determine whether genetic background influences seizure susceptibility following Theiler's virus infection. METHODS: Immunohistochemical techniques were used to assess Theiler's virus antigen localization in the brain and associated neuronal cell death. A battery of electroconvulsive threshold (ECT) tests and corneal kindling studies were conducted to assess whether there were chronic alterations in seizure susceptibility and kindling development. Studies were conducted in both B6 and SJL/J mice to assess strain-dependent effects. RESULTS: Histopathologic analyses indicate that TMEV has specific tropism for limbic structures and causes widespread cell death in these regions. Results from ECT studies demonstrate that B6 mice that displayed acute symptomatic seizures have significantly reduced seizure thresholds and kindle faster than either control mice or infected mice without acute seizures. Furthermore, these effects were mouse-strain dependent, since SJL/J mice displayed a different seizure threshold spectrum. DISCUSSION: These findings indicate that Theiler's virus infection leads to chronically altered seizure susceptibility in mice. It is important to note that Theiler's virus infection of B6 mice represents a novel model to study postinfection hyperexcitability.

Cognitive slowing in cognitive-motordisorder associated to type 1 humanimmunodeficiency virus: tr and P300

Introduction. Reaction time (RT) deficit exhibited by HIV-1 asymptomatic seropositive individuals cannot alwaysbe explained by the effect of a cognitive slowing single factor.Evidence exists that decisional and peripheral componentsof RT may have differential slowing.Objectives. To assess the hypothesis of a cognitive slowing single factor as the main responsible for RT slowingin these subjects. Methodology. Thirty two (32) HIV-1 neurologically asymptomatic seropositive individuals were compared to 29 seronegative controls in two discriminative reaction time tasks (DRT) having increased cognitive difficulty but equal motorresponse demands. P300 component of the event-related potential was recorded simultaneously. RT, PPI, errors, and P300 latency were assessed using ANOVA. Results: Seropositives were slower than controls in RT,made more errors and showed delayed latencies of P300 in both tasks. However, while the increase of RT from the easier to the more difficult task was additive, the increase of P300 latencies was multiplicative. Conclusions. These results reveal differences in patternsof slowing between central and motor information processing mechanisms. Such results suggest that a singlecommon factor is not enough to explain cognitive slowing in HIV-1 seropositive subjects(AU)

Introducción. Los déficit de tiempo de reacción (TR) en los sujetos infectados por el virus de inmunodeficienciahumana tipo 1 (VIH-1) en las etapas iniciales de la infección no parecen siempre comprensibles por la acciónde un factor general de enlentecimiento cognitivo. Existen evidencias que indican que los componentes dela decisión y periféricos del TR pueden lentificarse diferencialmente.Objetivos. Evaluar la acción de un factor general de enlentecimiento cognitivo como causa principal de incrementodel TR en estos sujetos. Métodos. Treinta y dos sujetos seropositivos al VIH-1 neurológicamente asintomáticos fueron comparados con 29 controles seronegativos en dos tareas de tiempo de reacción discriminativo (TRD) de dificultad creciente, perocon iguales demandas de respuesta. Simultáneamente se registró el componente P300 del potencial evocadopor las tareas. El TR, el IPP, los errores y la latencia del componente P300 fueron comparados mediante ANOVA.Resultados. Los seropositivos fueron más lentos, cometieron más errores y exhibieron latencias más prolongadasque los controles, pero mientras que el incremento del TR entre tareas fue aditivo, el de latencia de P300 fuemultiplicativo. Conclusiones. Los resultados revelan una disociaciónen el patrón de enlentecimiento de los mecanismos centrales y los de producción de respuesta. Tales resultadossugieren que un factor general no es suficiente paraexplicar el enlentecimiento cognitivo de estos(AU)

Cognitive slowing in cognitive-motor disorder associated to type 1 human immunodeficiency virus: TR and P300.

INTRODUCTION: Reaction time (RT) deficit exhibited by HIV-1 asymptomatic seropositive individuals cannot always be explained by the effect of a cognitive slowing single factor. Evidence exists that decisional and peripheral components of RT may have differential slowing. OBJECTIVES: To assess the hypothesis of a cognitive slowing single factor as the main responsible for RT slowing in these subjects. METHODOLOGY: Thirty two (32) HIV-1 neurologically asymptomatic seropositive individuals were compared to 29 seronegative controls in two discriminative reaction time tasks (DRT) having increased cognitive difficulty but equal motor response demands. P300 component of the event-related potential was recorded simultaneously. RT, PPI, errors, and P300 latency were assessed using ANOVA. RESULTS: Seropositives were slower than controls in RT, made more errors and showed delayed latencies of P300 in both tasks. However, while the increase of RT from the easier to the more difficult task was additive, the increase of P300 latencies was multiplicative. CONCLUSIONS: These results reveal differences in patterns of slowing between central and motor information processing mechanisms. Such results suggest that a single common factor is not enough to explain cognitive slowing in HIV-1 seropositive subjects.

Effects of hepatic function and hepatitis C virus on the nervous system assessment of advanced-stage HIV-infected individuals.

OBJECTIVES: To examine the effects of liver function and hepatitis C virus (HCV) serostatus on neurological, neuropsychological, and psychiatric abnormalities in an advanced-stage HIV-infected cohort. DESIGN: A correlational analysis of baseline data accumulated on 137 participants in the Manhattan HIV Brain Bank, a longitudinal study of HIV-infected individuals. METHODS: Patients underwent a battery of neuropsychological tests, a semi-structured psychiatric interview, and a neurological examination. The resulting diagnostic data were correlated with biochemical indices of hepatic function and HCV serostatus. RESULTS: Biochemical indices of liver function correlated with motor dysfunction determined by neurological evaluation, but not with neuropsychological or psychiatric disorders. Discrete neurological diagnostic entities showed no relationship with biochemical indices, with one exception: patients with cryptococcal leptomeningitis had worse liver function than those without. HCV had no relationship with any neurological disorder or symptom complex. In contrast, HCV serostatus was related to neuropsychological and psychiatric abnormalities, and indices of liver function were not. HCV-seropositive patients were more likely to have histories of opiate, cocaine or stimulant dependency, to have greater impairment in executive functioning, and to meet diagnostic criteria for AIDS dementia, compared with HCV-negative individuals of similar immunological and virological status. CONCLUSIONS: HCV and biochemical indices of liver function associate differentially with nervous system abnormalities in this HIV-infected population. Neurological abnormalities correlate with biochemical indices of liver function, whereas neuropsychological and psychiatric dysfunction are linked to HCV infection. We postulate that multifactorial impacts of HCV and liver disease on HIV-related nervous system disorders may originate in different anatomical and cellular compartments.

Early psychomotor slowing predicts the development of HIV dementia and autopsy-verified HIV encephalitis.

OBJECTIVES- To ask if slowed motor speed predicts later human immunodeficiency virus (HIV) dementia and HIV encephalitis. METHODS- In 100 deceased acquired immunodeficiency syndrome (AIDS) patients prior results from repeated testing of the movement reaction time test were correlated with later clinical signs of HIV dementia and with neuropathological signs of HIV encephalitis. Autopsy was performed in 72 patients. RESULTS- Movement reaction time 1-2 years prior to death, or at the time of clinical AIDS diagnosis predicted both development of HIV dementia (P<0.05) and HIV encephalitis at autopsy (P<0.01). CONCLUSION- Testing for early psychomotor slowing may be used to identify patients at risk of HIV dementia and HIV encephalitis.

Psychomotor slowing in HIV infection: a predictor of dementia, AIDS and death.

The objective of this study was to determine if sustained decline in psychomotor speed tests is associated with an increased risk of progression to dementia, acquired immunodeficiency syndrome (AIDS), or mortality in human immunodeficiency virus (HIV)-1-infected homosexual men in the Baltimore site of the Multicenter AIDS Cohort-Study (MACS). Clinical and neuropsychological data were obtained on 291 HIV+ homosexual men seen semi-annually over a nine year period (1986-1994). A proportional hazards model was used to assess the predictive value of sustained psychomotor slowing (defined as a 2.0 standard deviation (s.d.) decline in performance on either the Symbol Digit Modalities test or Trailmaking test at two consecutive evaluations). Time-dependent co-variates included in the model were sustained psychomotor slowing, number of attended visits, CD4+ lymphocyte count, hemoglobin and antiretroviral medication use. HIV+ participants with and without sustained psychomotor slowing were compared. Outcome variables were the development of dementia, AIDS and death. HIV+ subjects with sustained psychomotor slowing had an increased hazard of dementia (Risk ratio (RR) = 5.0, P = 0.008), AIDS (RR = 2.4, P = 0.02), and death (RR = 2.0, P = 0.04). A similar analysis using sustained cognitive decline in one domain from a more extensive neuropsychological test battery failed to show any predictive value. Sustained decline in psychomotor performance in HIV infection was predictive of dementia, AIDS and death. This brief neuropsychological test battery may be useful for early detection of HIV+ individuals with a poorer prognosis who may benefit from more aggressive treatment to prevent HIV dementia.