Ana Puga

Virologic and Immunologic Outcomes after 24 Weeks in HIV Type 1-Infected Adolescents Receiving Highly Active Antiretroviral Therapy

BACKGROUNDnAdolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy.nnnMETHODSnWe studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy.nnnRESULTSnSubjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads.nnnCONCLUSIONSnAdolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.

Phosphorylation of Tuberin as a Novel Mechanism for Somatic Inactivation of the Tuberous Sclerosis Complex Proteins in Brain Lesions

Tuberous sclerosis complex is caused by mutations in tumor suppressor genes TSC1 or TSC2 and is characterized by the presence of hamartomas in many organs. Although tuberous sclerosis complex is a tumor suppressor gene syndrome with classic “second hits” detectable in renal tumors, conventional genetic analysis has not revealed somatic inactivation of the second allele in the majority of human brain lesions. We demonstrate a novel mechanism of post-translational inactivation of the TSC2 protein, tuberin, by physiologically inappropriate phosphorylation, which is specific to tuberous sclerosis complex-associated brain lesions. Additional analysis shows that tissue specificity is due to abnormal activation of the Akt and mitogen-activated protein kinase pathways in brain but not in renal tumors. These results have widespread implications for understanding the tissue specificity of tumor suppressor gene phenotypes.

Serologic response to hepatitis B vaccine in HIV infected and high-risk HIV uninfected adolescents in the REACH cohort

PURPOSEnTo evaluate hepatitis B (HBV) vaccine response rates in HIV infected and high-risk HIV uninfected youth and examine associations with responsiveness in the HIV infected group.nnnMETHODSnCohorts within the Reaching for Excellence in Adolescent Care and Health (REACH) study population were defined based on receipt of HBV vaccine both retrospectively and prospectively. Sero-responsiveness was determined by HBsAb measurements. Testing was done for HBsAg, HBsAb, and HBcAb. For HBsAb, a value of > 10 International Units per liter was considered a positive response, and the data were collected as either positive or negative from each of the reporting laboratories. Covariates of responsiveness were explored in univariate and multivariate models for each cohort.nnnRESULTSnSixty-one subjects had received a three-dose vaccination course at the time of entry into REACH. HIV uninfected subjects had significantly higher rates of response by serology compared with HIV infected subjects (70% vs. 41.1%; chi(2) = .05; RR = .586, 95% CI: .36-.96). By the time of an annual visit 43 subjects had received three vaccinations with at least one occurring in the study period. The rates of response were similar for the HIV infected and uninfected groups (37.1% vs. 37.5%) in this cohort. Univariate and multivariate analysis in the prospective HIV infected group (N = 35) found an association between elevated CD8(+)/CD38(+)/HLA-DR(+) T cells and lack of HBV vaccine responsiveness (6.7% vs. 60%; chi(2) = .03; RR = .12, 95% CI: .02- .55).nnnCONCLUSIONSnThe poor HBV vaccine response rate in the HIV uninfected high-risk adolescents was unexpected and suggests that HBV vaccination doses have not been optimized for older adolescents. This is the first report of decreased responsiveness in HIV infected subjects being associated with elevated CD8(+)/CD38(+)/HLA(-)DR(+) T cells and suggests that ongoing viral replication and concomitant immune system activation decreases the ability of the immune system in HIV infected subjects to respond to vaccination.

Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2.

Chordomas are rare sacrococcygeal/sacral, sphenooccipital/clivus, and spinal tumors whose molecular etiology remains relatively understudied. As several anecdotal reports had described chordomas in individuals with tuberous sclerosis complex (TSC), a multisystem hamartoma syndrome, we hypothesized that the genes that cause TSC may have an etiological role in chordomas. In two cases of sacrococcygeal chordomas in individuals with TSC, one with a germ‐line TSC2 mutation and the other with a germ‐line TSC1 mutation, we confirmed somatic inactivation of the corresponding wild‐type allele by loss of heterozygosity analysis and immunohistochemistry. These data provide the first evidence of a pathogenic role by TSC genes in sacrococcygeal chordomas.

Prospective study of 11 Brazilian patients with mucopolysaccharidosis II

OBJECTIVEnTo assess the progression of mucopolysaccharidosis II in 11 Brazilian patients over a 12-month period.nnnMETHODSnEleven Brazilian patients with mucopolysaccharidosis II were prospectively studied at the Division of Medical Genetics of Hospital de Clínicas de Porto Alegre. The initial assessment and the assessment at 12 months included: anamnesis, physical examination, abdominal nuclear magnetic resonance, echocardiogram, 6-minute walk test, audiometry, serum biochemical tests and urinary glycosaminoglycan concentration.nnnRESULTSnThe major findings after comparing the assessments were: 1) two patients had growth retardation; 2) two patients showed negative weight change; 3) one patient went from obese to overweight; 4) three patients revealed left ventricle hypertrophy; of these, two increased the number of cardiac valve lesions; 5) there was no statistically significant difference between the mean distances obtained on the 6-minute walk test; 6) there was splenic enlargement; 7) there was an increase in gamma-glutamyltransferase levels; 8) the urinary concentration of glycosaminoglycans remained unchanged.nnnCONCLUSIONSnIn general, echocardiographic findings were the only variable with deterioration and possible immediate clinical consequences. Although a 12-month period is too short to detect changes in most variables related to mucopolysaccharidosis II, its progressive nature should be taken into account when evaluating the efficiency of treatment protocols.

Psychiatric symptoms and antiretroviral nonadherence in US youth with perinatal HIV: a longitudinal study.

Objectives:The relationship of specific psychiatric conditions to adherence has not been examined in longitudinal studies of youth with perinatal HIV infection (PHIV). We examined associations between psychiatric conditions and antiretroviral nonadherence over 2 years. Design:Longitudinal study in 294 PHIV youth, 6–17 years old, in the United States and Puerto Rico. Methods:We annually assessed three nonadherence outcomes: missed above 5% of doses in the past 3 days, missed a dose within the past month, and unsuppressed viral load (>400u200acopies/ml). We fit multivariable logistic models for nonadherence using Generalized Estimating Equations, and evaluated associations of psychiatric conditions (attention deficit hyperactivity disorder, disruptive behavior, depression, anxiety) at entry with incident nonadherence using multivariable logistic regression. Results:Nonadherence prevalence at study entry was 14% (3-day recall), 32% (past month nonadherence), and 38% (unsuppressed viral load), remaining similar over time. At entry, 38% met symptom cut-off criteria for at least one psychiatric condition. Greater odds of 3-day recall nonadherence were observed at week 96 for those with depression [adjusted odds ratio (aOR) 4.14, 95% confidence interval (CI) 1.11–15.42] or disruptive behavior (aOR 3.36, 95% CI 1.02–11.10], but not at entry. Those with vs. without attention deficit hyperactivity disorder had elevated odds of unsuppressed viral load at weeks 48 (aOR 2.46, 95% CI 1.27–4.78) and 96 (aOR 2.35, 95% CI 1.01–5.45), but not at entry. Among 232 youth adherent at entry, 16% reported incident 3-day recall nonadherence. Disruptive behavior conditions at entry were associated with incident 3-day recall nonadherence (aOR 3.01, 95% CI 1.24–7.31). Conclusion:In PHIV youth, comprehensive adherence interventions that address psychiatric conditions throughout the transition to adult care are needed.

Neurocognitive Functioning in Antiretroviral Therapy–Naïve Youth With Behaviorally Acquired Human Immunodeficiency Virus

PURPOSEnYouth living with human immunodeficiency virus (HIV) account for over one third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. Human immunodeficiency virus-associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy. Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here, we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use.nnnMETHODSnA total of 220 participants, age 18-24xa0years, who were naive to treatment (except for prevention of mother-to-child HIV transmission; nxa0= 3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery.nnnRESULTSnSixty-seven percent of youth met criteria for HAND (96.4% were asymptomatic and 3.5% were syndromic); deficits in episodic memory and fine-motor skills emerged as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high-risk alcohol use were uniquely associated with neurocognitive deficits.nnnCONCLUSIONSnOver two thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e.g., nonadherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy.

Avaliação prospectiva de 11 pacientes brasileiros com mucopolissacaridose II

OBJETIVO: Avaliar a progressao da mucopolissacaridose II, durante um periodo de 12 meses, em 11 pacientes brasileiros. METODOS: Onze pacientes brasileiros com mucopolissacaridose II foram avaliados prospectivamente no Servico de Genetica Medica do Hospital de Clinicas de Porto Alegre. As avaliacoes realizadas na visita inicial e na de 12 meses foram: anamnese, exame fisico, ressonância nuclear magnetica abdominal, ecocardiograma, teste da caminhada em 6 minutos, audiometria, exames bioquimicos sericos e dosagem urina- ria de glicosaminoglicanos. RESULTADOS: Os principais achados relativos a comparacao entre as duas visitas foram: 1) dois pacientes apresentaram retardo de crescimento; 2) dois pacientes apresentaram variacao negativa em relacao ao peso; 3) um paciente apresentou variacao de obesidade para sobrepeso; 4) tres pacientes desenvolveram alargamento do ventriculo esquerdo; destes, dois aumentaram o numero de lesoes nas valvas cardiacas; 5) nao foi encontrada diferenca estatistica significativa entre a media das distâncias percorridas no teste da caminhada em 6 minutos; 6) houve aumento do volume esplenico; 7) ocorreu aumento dos niveis de gamaglutamiltransferase; 8) nao houve alteracao dos niveis urinarios de glicosaminoglicanos. CONCLUSOES: De uma maneira geral, a unica variavel que apresentou, no periodo estudado, piora com potencial repercussao clinica imediata foram os achados ecocardiograficos. Embora o periodo de 12 meses seja curto para medir alteracoes na maioria dos parâmetros comprometidos na mucopolissacaridose II, sua natureza progressiva deve ser levada em conta na avaliacao da eficacia dos protocolos de tratamento para essa condicao.

Cardiac Effects of in utero Exposure to Antiretroviral Therapy in HIV-Uninfected Children Born to HIV-Infected Mothers

Objectives:We evaluated the potential cardiac effects of in-utero exposures to antiretroviral drugs in HIV-exposed but uninfected (HEU) children. Design and methods:We compared echocardiographic parameters of left ventricular function (ejection fraction, fractional shortening, and stress–velocity index) and structure (left ventricular dimension, posterior wall/septal thickness, mass, thickness-to-dimension ratio, and wall stress) (expressed as Z-scores to account for age and body surface area) between HEU and HIV-unexposed cohorts from the Pediatric HIV/AIDS Cohort Studys Surveillance Monitoring for ART Toxicities study. Within the HEU group, we investigated the associations between the echocardiographic Z-scores and in-utero exposures to maternal antiretroviral drugs. Results:There were no significant differences in echocardiographic Z-scores between 417 HEU and 98 HIV-unexposed children aged 2–7 years. Restricting the analysis to HEU children, first-trimester exposures to combination antiretroviral therapy (a regimen including at least three antiretroviral drugs) and to certain specific antiretroviral drugs were associated with significantly lower stress–velocity Z-scores (mean decreases of 0.22–0.40 SDs). Exposure to combination antiretroviral therapy was also associated with lower left ventricular dimension Z-scores (mean decrease of 0.44 SD). First-trimester exposure to combination antiretroviral therapy was associated with higher mean left ventricular posterior wall thickness and lower mean left ventricular wall stress Z-scores. Conclusion:There was no evidence of significant cardiac toxicity of perinatal combination antiretroviral therapy exposure in HEU children. Subclinical differences in left ventricular structure and function with specific in-utero antiretroviral exposures indicate the need for a longitudinal cardiac study in HEU children to assess long-term cardiac risk and cardiac monitoring recommendations.

Neuronal ceroid lipofuscinoses: a clinical and morphological study of 17 patients from Southern Brazil

The neuronal ceroid lipofuscinoses (NCL) are a group of inherited progressive neurodegenerative disorders with presentation from infancy to adulthood. Three main childhood forms can be established on the basis of age of onset, clinical course, and ultrastructural morphology: infantile (INCL), late infantile (LINCL), and juvenile (JNCL). Several variant subtypes have been described. Genetic and biochemical analysis are helping to better understand, diagnose and classify these disorders. We report on clinical, neurophysiological, neuroradiological, and morphological data from 17 patients with different forms (infantile, late infantile, and juvenile ) of neuronal ceroid lipofuscinoses (NCL) evaluated at Hospital de Clínicas de Porto Alegre, Southern Brazil, during 6 years (1992-1997). Seven cases were infantile; 5 were late infantile; and 5 were juvenile NCL. Gender ratio was male:female, 11:6. Age at presentation varied from 2-24 months for INCL; 2,5 to 5 years for LINCL; and 4-10 years for the JNCL cases. Seizures (6 patients) and psychomotor retardation (1 patient) were the initial symptoms in the INCL group. All the patients in the group of LINCL had the usual findings. JNCL patients manifested different initial symptoms, although tending to follow a similar clinical picture within familial cases. Epidemiological data on the prevalence of NCLs in Brazil are not available, we expect this series of cases to contribute to further research in our population.