Newer treatments for HIV in children.

Purpose Of Review: Several new antiretroviral agents have been introduced into pediatric and adult use. This review will summarize information about these new agents and other recent advances in the care of HIV-infected children.

Recent Findings: New drugs like tenofovir, emtricitabine, and enfuvirtide are being rapidly introduced into antiretroviral treatments for adult patients.

Growth velocity assessment in paediatric AIDS: smoothing, penalized quantile regression and the definition of growth failure.

The analysis of growth records in paediatric anti-HIV clinical trials plays an important role in trial evaluation. Growth failure may be a manifestation of progressive disease or treatment toxicity, and is commonly specified as a major trial outcome event indicating poor treatment performance. Despite new therapeutic advances against HIV proliferation in infected patients, accurate monitoring and interpretation of somatic growth in paediatric AIDS remains clinically important, in light of uncertainties regarding relationship between viral load reductions and achievement of favourable somatic growth profiles.

Mutations linked to drug resistance, human immunodeficiency virus type 1 biologic phenotype and their association with disease progression in children receiving nucleoside reverse transcriptase inhibitors.

Background: Few data are available concerning the impact of antiretroviral resistance in response to antiviral therapy in children. We evaluated the development of antiretroviral genotypic resistance and clinical outcome in a subgroup of children involved in a prospective antiretroviral therapy trial (Pediatric AIDS Clinical Trials Group Protocol 152).

Design: We studied 26 matched case/control pairs.

Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo.

Protein kinase C (PKC) modulates cardiomyocyte function by phosphorylation of intracellular targets including myofilament proteins. Data generated from studies on in vitro heart preparations indicate that PKC phosphorylation of troponin I (TnI), primarily via PKC-epsilon, may slow the rates of cardiac contraction and relaxation (+dP/dt and -dP/dt). To explore this issue in vivo, we employed transgenic mice [mutant TnI (mTnI) mice] in which the major PKC phosphorylation sites on cardiac TnI were mutated by alanine substitutions for Ser(43) and Ser(45) and studied in situ hemodynamics at baseline and increased inotropy.

Growth, survival and viral load in symptomatic childhood human immunodeficiency virus infection.

Background: The relationships among weight and height growth, viral load and survival in HIV-infected children remain unclear.

Objectives: To determine whether weight or height growth velocity independently predicts survival and to investigate associations of weight, height and head circumference growth velocities with viral loads in symptomatic HIV-infected children.

Methods: We analyzed data from a prospective antiretroviral study utilizing clinical endpoints (PACTG 152).

Genetic influence of CCR5, CCR2, and SDF1 variants on human immunodeficiency virus 1 (HIV-1)-related disease progression and neurological impairment, in children with symptomatic HIV-1 infection.

The role that host genetics plays in the modification of the rate of human immunodeficiency virus 1 (HIV-1)-related disease progression was evaluated in a seroprevalent cohort of 1049 children with symptomatic HIV-1 infection who participated in 2 clinical trials in the United States. Variants including CCR2-V64I, CCR5-wt/Delta32, CCR5-59029-G/A, CCR5-59353-T/C, CCR5-59356-C/T, and SDF1-3'-G/A were identified by polymerase chain-reaction genotyping. Children with the CCR5-wt/Delta32 genotype experienced significantly delayed disease progression, including less neurocognitive impairment.

Epileptiform activity in rat hippocampus strengthens excitatory synapses.

Although epileptic seizures are characterized by excessive excitation, the role of excitatory synaptic transmission in the induction and expression of epilepsy remains unclear. Here, we show that epileptiform activity strengthens excitatory hippocampal synapses by increasing the number of functional (RS)-alpha-amino-3hydroxy-5methyl-4-isoxadepropionate (AMPA)-type glutamate receptors in CA3-CA1 synapses. This form of synaptic strengthening occludes long-term potentiation (LTP) and enhances long-term depression (LTD), processes involved in learning and memory.

A comparison of height and weight velocity as a part of the composite endpoint in pediatric HIV.

Background: HIV adversely affects growth in children. Pediatric AIDS Clinical Trial Group (PACTG) protocols often use weight velocity [changes in weight z-score for age (WAZ)] as a part of the composite endpoint for phase II and III clinical trials. However, WAZ and height velocity (HAZ) have not been critically compared for their utility as part of the composite endpoint.

Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative.

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites.

N-methyl-D-aspartate receptor blockade during development lowers long-term potentiation threshold without affecting dynamic range of CA3-CA1 synapses.

During development, excitatory synapses in the CA1 region of the hippocampus undergo activity-dependent and N-methyl-D-aspartate (NMDA) receptor-dependent long-lasting changes in synaptic efficacy. These bidirectional changes occur between limits that determine the dynamic range within which synapses operate. It is unknown whether the dynamic range itself is also activity-dependent and NMDA receptor-dependent.

Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children.

The purpose of this study was to assess the population pharmacokinetics (PK) and pharmacodynamics (PD) of zidovudine (ZDV) in infants and children. This evaluation includes 394 subjects who participated in Pediatric AIDS Clinical Trials Group (PACTG) Study 152 and received either ZDV alone or in combination with didanosine. The most significant PK covariate was age, with infants < 2 years of age having reduced size-adjusted clearance.

Physiological and morphological plasticity induced by chronic treatment with NT-3 or NT-4/5 in hippocampal slice cultures.

Expression of neurotrophins (NTs) and their receptors is elevated in the adult CNS under several neuropathological conditions. We have investigated the anatomical and electrophysiological consequences of chronic NT-3 or NT-4/5 treatment on established organotypic hippocampal slice cultures maintained in vitro for > 14 days. Both NT-3 and NT-4/5 increased spontaneous, action potential-dependent excitatory synaptic activity (sEPSCs), but only NT-3 increased inhibitory synaptic activity (sIPSCs) in CA3 pyramidal cells.

Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1.

The adult mammalian CNS has a limited capacity for nerve regeneration and structural plasticity. The presence of glia-derived inhibitory factors myelin-associated glycoprotein (MAG) and Nogo-A have been suggested to provide a nonpermissive environment for elongating nerve fibers. In particular, Nogo-A, an integral membrane protein predominantly expressed by oligodendrocytes, has been demonstrated to impair neurite growth in vitro and in vivo.

The extreme N-terminus of the calcitonin-like receptor contributes to the selective interaction with adrenomedullin or calcitonin gene-related peptide.

The calcitonin (CT)-like (CL) receptor is a CT gene-related peptide (CGRP) receptor or an adrenomedullin (AM) receptor when co-expressed with receptor-activity-modifying proteins (RAMP) 1 or 2, respectively. The CL receptor shows 57% overall sequence identity with the CT receptor, but the homology is much lower in the extreme N-terminus. An N-terminal deletion mutant of the human (h) CL receptor (Delta18-hCL) and a chimeric receptor consisting of the N-terminal amino acids of the porcine (p) CT receptor fused to the Delta18-hCL receptor (pCT-hCL) were therefore analyzed.

Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes.

Administration of adenovirus (Ad) vectors to animals induces innate immune responses, typified by elevated interleukin-6 (IL-6). To assess innate responses to Ad vectors in humans, we evaluated serum IL-6 following administration of E1(-) E3(-) Ad vectors to different human hosts and the relationship among peak IL-6 and peak anti-Ad neutralizing antibodies. We administered: 1) Ad(GV)CFTR.

Trends in interventions to reduce perinatal human immunodeficiency virus type 1 transmission in North Carolina.

Background: Mother-to-child transmission of HIV has decreased in industrialized countries because of widespread use of antiretroviral therapy (ART) by HIV-infected pregnant women and perhaps to increased use of elective cesarean section. We evaluated changes in the use of ART and mode of delivery among HIV positive pregnant women in North Carolina.

Methods: We reviewed the medical records of HIV-exposed infants born in North Carolina between January 1, 1998, and December 31, 1999, who were tested for HIV DNA.

Predicting the occurrence of genetic adaptation to dioxinlike compounds in populations of the estuarine fish Fundulus heteroclitus.

A population of the nonmigratory estuarine fish species Fundulus heteroclitus (mummichog) indigenous to a polychlorinated biphenyl (PCB)-contaminated Superfund site (New Bedford Harbor, MA, USA) demonstrated an inherited tolerance to local, dioxinlike contaminants (DLCs). These findings suggest that DLCs have acted as selective agents, allowing the survival of only the most tolerant individuals, forming DLC-adapted populations. We hypothesized that DLC-tolerant mummichog populations would reside where local conditions are toxic to sensitive individuals, and that toxic environmental conditions could be predicted based on responses of sensitive early life stages to laboratory exposures of DLCs.

Using mussel isotope ratios to assess anthropogenic nitrogen inputs to freshwater ecosystems.

Stable nitrogen isotope ratios (delta15N) of freshwater mussels from a series of lakes and ponds were related to watershed land use characteristics to assess their utility in determining the source of nitrogen inputs to inland water bodies. Nitrogen isotope ratios measured in freshwater mussels from 19 lakes and ponds in Rhode Island, U.S.

Angiotensin II induced cardiac hypertrophy in vivo is inhibited by cyclosporin A in adult rats.

Recently, the calcium-calmodulin-dependent calcineurin pathway has been defined as a central pathway for the induction of cardiac hypertrophy. The purpose of this study was to determine if cardiac hypertrophy in animals chronically treated with angiotensin II (AngII), could be prevented by blocking this pathway with cyclosporin A (CsA). Female Wistar rats were treated with AngII by subcutaneous infusion and injected twice a day with CsA (25 mg/kg) for 7 days.

NMDA receptor activation limits the number of synaptic connections during hippocampal development.

Activity-dependent synaptic plasticity triggered by N-methyl-d-aspartate (NMDA) receptor activation is a fundamental property of many glutamatergic synapses and may be critical for the shaping and refinement of the structural and functional properties of neuronal circuits during early postnatal development. Using a combined morphological and electrophysiological approach, we showed that chronic blockade of NMDA receptors in hippocampal slice cultures during the first two weeks of postnatal development leads to a substantial increase in synapse number and results in a more complex dendritic arborization of CA1 pyramidal cells. Thus, the development of excitatory circuitry in the hippocampus is determined by two opposing processes: NMDA receptor-independent synapse formation and NMDA receptor-dependent attenuation of synaptogenesis.

Immune reconstitution in human immunodeficiency virus-infected children receiving highly active antiretroviral therapy: a cohort study.

Background: Highly active antiretroviral therapy (HAART) has brought about rapid declines in HIV-1 RNA concentrations and an increase in CD4+ counts in HIV-1-infected children. These changes are often accompanied by clinical improvement; however, the extent to which immune reconstitution occurs is not known.

Design: We compared two cohorts (n = 35) of HIV-1-infected children to evaluate the effects of HAART on immune recovery.

Successful prophylaxis against Pneumocystis carinii pneumonia in HIV-infected children using smaller than recommended dosages of trimethoprim-sulfamethoxazole.

Prophylaxis against Pneumocystis carinii pneumonia (PCP) is an essential part of the management of children with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). No dose-ranging studies were ever performed; therefore, the amount of trimethoprim-sulfamethoxazole (TMP-SMX) needed to suppress PCP in children with HIV/AIDS is not known. The dose recommended by the Centers for Disease Control (CDC) has been thought to be just above the threshold needed for prevention, based on anecdotal breakthrough PCP in cancer patients who were improperly dosed.