A de novo mutation affecting human TrkB associated with severe obesity and developmental delay

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.     

Microtubules associated with postsynaptic ''thickenings''.

Summary Using a new albumin technique, microtubules can be seen closely related to or associated with the postsynaptic thickening of mature and immature central nervous synapses. Thus in conventionally fixed synapses (without albumin pretreatment) where microtubules cannot usually be observed running into the postsynaptic dense material, this material could perhaps, in part, consist of the debris ofin vivo microtubules. Smooth endoplasmic reticulum (ER) is often seen associated with the microtubules near the postsynaptic thickening. Microtubules, and possibly smooth ER, may have an important role in the initiation of synapse formation and in the maintenance of mature synapses.     

Can population differences explain the contrasting results of the Mwanza, Rakai, and Masaka HIV/sexually transmitted disease intervention trials?: A modeling study

OBJECTIVE: To determine whether population differences can explain the contrasting impacts on HIV observed in the Mwanza trial of sexually transmitted disease (STD) syndromic treatment (ST), the Rakai trial of STD mass treatment (MT), and the Masaka trial of information, education, and communication (IEC) with and without ST as well as to predict the effectiveness of each intervention strategy in each population. METHODS: Stochastic modeling of the transmission of HIV and 6 STDs was used with parameters fitted to demographic, sexual behavior, and epidemiological data from the trials and general review of STD/HIV biology. RESULTS: The baseline trial populations could be simulated by assuming higher risk behavior in Uganda compared with Mwanza in the 1980s, followed by reductions in risk behavior in Uganda preceding the trials. In line with trial observations, the projected HIV impacts were larger for the ST intervention in Mwanza than for the MT intervention in Rakai or the IEC and IEC + ST interventions in Masaka. All 4 simulated intervention strategies were more effective in reducing incidence of HIV infection in Mwanza than in either Rakai or Masaka. CONCLUSIONS: Population differences in sexual behavior, curable STD rates, and HIV epidemic stage can explain most of the contrast in HIV impact observed between the 3 trials. This study supports the hypothesis that STD management is an effective HIV prevention strategy in populations with a high prevalence of curable STDs, particularly in an early HIV epidemic.     

Synthesis and secretion of high- and low-molecular-weight forms of the enzyme-releasing peptide (ERP) from the macrophage-like cell line THP-1

Neutrophil enzymes have been implicated as a source of lung injury in patients with the adult respiratory distress syndrome (ARDS) and with emphysema. We studied a human alveolar macrophage-derived peptide messenger, the enzyme-releasing peptide (ERP), which causes neutrophils to secrete their enzymes. The secretion and synthesis of ERP was studied in human alveolar macrophages and in the macrophage-like cell lines THP-1, HL-60, and U937. All four cell types secrete an ERP-like peptide. THP-1 cells secrete a higher concentration of the peptide than do macrophages. The secretion of ERP by THP-1 is suppressed by the protein synthesis inhibitors actinomycin D and cycloheximide. While the macrophages secrete ERP, they do not synthesize it. These studies suggest that ERP is synthesized by an alveolar macrophage precursor and stored in the mature macrophage for later release. 12-O-tetradecanoylphorbol-13-acetate (TPA) suppresses ERP secretion by THP-1 cells, but it does not modify secretion in macrophages. Escherichia coli-derived lipopolysaccharide and dimethyl sulfoxide do not modify secretion in either cell type. The THP-1 cells secrete a high- and low-mass-ratio (Mr) form of ERP-like proteins. The low Mr but not the high Mr form stimulates neutrophils to secrete their granule enzymes. We conclude that human alveolar macrophages secrete ERP but do not synthesize it. It is likely that ERP is made by an alveolar macrophage precursor in a high Mr form that is cleaved prior to secretion by the macrophages.     

Maternal self-medication and provision of nevirapine to newborns by women in Rakai, Uganda

To assess the effectiveness of maternal self-administration of nevirapine for prevention of mother-to-child transmission (MTCT) of HIV, we conducted a program to provide maternal and newborn doses of nevirapine to pregnant women in rural Uganda. Women provided blood for HIV testing and were offered voluntary counseling and testing (VCT) during annual community HIV surveys. HIV-positive women who accepted VCT were offered nevirapine tablets and syrup. Blood samples were collected postpartum from women and their babies. Infants were tested for HIV by polymerase chain reaction (PCR), and a subsample of maternal and infant blood was assayed for nevirapine. Among the 981 women tested for HIV, 900 (91.7%) accepted VCT, of whom 105 (11.7%) were HIV-positive. Ninety-three women accepted nevirapine, of whom 81 (87.1%) were followed postpartum; 75 (92.6%) reported receipt of the drug, and 69 reported taking the tablets (85.2%). There were 81 liveborn babies (3 sets of twins), and 67 (84.8%) received the syrup. In a subsample of 25 mothers reporting receipt of the drug, nevirapine was detected in 22 (88.0%) and 24 (96.0%) babies tested. PCR of 67 infant blood samples identified 5 HIV-positive (MTCT rate = 7.5%, 95% confidence interval [CI]: 0.3%-16.6%). Mothers can administer nevirapine to themselves and their newborns and can achieve low rates of perinatal HIV infection.     

Macrophage-derived chemokine production by activated human T cells in vitro and in vivo: preferential association with the production of type 2 cytokines

Macrophage-derived chemokine (MDC), a potent chemoattractant for chronically activated Th2 lymphocytes, is constitutively expressed by dendritic cells, B cells, macrophages, and thymic medullary epithelial cells, whereas monocytes, NK cells, and T lymphocytes produce MDC only upon appropriate stimulation. In this study, we show in vitro MDC production also by activated T cells, which preferentially associate with the production of Th2 cytokines, IL-4, IL-5, and IL-6, and inversely correlate with the production of the Th1 cytokine, IFN-gamma. Moreover, high levels of MDC were detected in the sera of the great majority of subjects suffering from mycosis fungoides/Sézary syndrome or atopic dermatitis, which are considered as disorders characterized by the predominant expansion and activation of Th2 cells, respectively. By contrast, serum MDC levels in subjects with multiple sclerosis or Crohn's disease, which are characterized by a Th1 predominance, did not differ significantly from those of healthy controls. Finally, MDC expression was detected in the skin biopsy specimens of subjects with atopic dermatitis, where it was expressed by both dendritic cells and T lymphocytes. Taken together, these findings suggest that MDC production by activated T cells may occur both in vitro and in vivo, particularly in association with Th2 cytokines, thus providing an important amplification circuit for Th2-mediated responses.