Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.     

Impact of highly active antiretroviral therapy on anemia and relationship between anemia and survival in a large cohort of HIV-infected women: Women's Interagency HIV Study

BACKGROUND: Anemia is common in HIV-infected individuals and may be associated with decreased survival. OBJECTIVE: To ascertain the impact of highly active antiretroviral therapy (HAART) on anemia and the relationship between anemia and overall survival in HIV-infected women. METHODS: A prospective multicenter study of HIV-1 infection in women. Visits occurred every 6 months, including a standardized history, physical examination, and comprehensive laboratory evaluation. The setting was a university-affiliated clinic at 6 sites in the United States. Participants were 2056 HIV-infected women from the Women's Interagency HIV Study (WIHS). The outcome measure was anemia, defined as hemoglobin (Hb) <12 g/dL. Survival analysis was based on overall mortality during the follow-up period. RESULTS: Among HIV-infected women who were not anemic at baseline, 47% became anemic by 3.5 years of follow-up. On multivariate analysis, the use of HAART was associated with resolution of anemia even when used for only 6 months (odds ratio [OR] = 1.45; P < 0.05). In the multivariate model, a CD4 cell count <200 cells/microL (OR = 0.56; P < 0.001); HIV-1 RNA level > or =50,000 copies/mL (OR = 0.65; P < 0.001), and mean corpuscular volume (MCV) value <80 fL (OR = 0.40; P < 0.001) were also associated with an inability to correct anemia. Similarly, use of HAART for 12 months or more was associated with a protective effect against development of anemia (OR = 0.71; P < 0.001). Among HIV-infected women, anemia was independently associated with decreased survival (hazard ratio [HR] = 2.58; P < 0.001). Other factors associated with decreased survival included a CD4 cell count <200 cells/microL (HR = 5.83; P < 0.001), HIV-1 RNA level > or = 50,000 copies/mL (HR = 2.12; P < 0.001), and clinical diagnosis of AIDS (HR = 2.83; P < 0.001). CONCLUSIONS: Anemia is an independent risk factor for decreased survival among HIV-infected women. HAART therapy for as little as 6 months is associated with resolution of anemia.     

Feasibility study on the utilization of rubber latex effluent for producing bacterial biopolymers

Rubber latex effluent is a polluting source that has a high biochemical oxygen demand (BOD). It is estimated that about 100 million liters of effluent are discharged daily from rubber processing factories. Utilization of this effluent such as the use of a coupled system not only can reduce the cost of treatment but also yield a fermentation feedstock for the production of bioplastic. This study initially was carried out to increase the production of organic acids by anaerobic treatment of rubber latex effluent. It was found that through anaerobic treatment the concentration of organic acids did not increase. Consequently, separation of organic acids from rubber latex effluent by anion exchange resin was examined as a preliminary study of recovering acetic and propionic acids. However, the suspended solids (SS) content in the raw effluent was rather high which partially blocked the ion-exchange columns. Lime was used to remove the SS in the rubber latex effluent. After the lime precipitation process, organic acids were found to adsorb strongly onto the anion exchange resin. Less adsorption of organic acids onto the resin was observed before the lime precipitation. This was probably due to more sites being occupied by colloidal particles on the resin thus inhibiting the adsorption of organic acids. The initial concentration of organic acids in the raw effluent was 3.9 g/L. After ion exchange, the concentration of the organic acids increased to 27 g/L, which could be utilized for production of polyhydroxyalkanoates (PHA). For PHA accumulation stage, concentrated rubber latex effluent obtained from ion exchange resins and synthetic acetic acid were used as the carbon source. Quantitative analyses from fed batch culture via HPLC showed that the accumulation of PHA in Alcaligenes eutrophus was maximum with a concentration of 1.182 g/L when cultivated on synthetic acetic acid, corresponding to a yield of 87% based on its cell dry weight. The dry cell weight increased from 0.71 to 1.67 g/L. On the other hand, using concentrated rubber latex effluent containing acetic and propionic acids resulted in reduced PHA content by dry weight (14%) but the dry cell weight increased from 0.49 to 1.30 g/L. The results clearly indicated that the cells grow well in rubber latex effluent but no PHA was accumulated. This could be due to the high concentration of propionic acid in culture broth or other factors such as heavy metals. Thus further work is required before rubber latex effluent can be utilized as a substrate for PHA production industrially.     

Supra-maximal cycling efficiency assessed in humans by using a new protocol

This study proposed a non-invasive method to determine the gross (GE, no baseline correction), net (NE, resting metabolism as the baseline correction) and work (WE, unloaded cycling as the baseline correction) efficiencies during cycling at an intensity higher than the maximal aerobic power (MAP). Twelve male subjects performed two exercises consisting of 4 min at 50% MAP followed either by 8 min at 63% MAP or by 8 sequences of 60 s divided into 10 s at 130% MAP and 50 s at 50% MAP (i.e., 63% MAP on average). Oxygen uptake was continuously measured to calculate GE, NE and WE at 50%, 63% and 130% MAP, and the data presented as the means and standard deviations. The GE values were 18.2%, 19.1%, 22.7%, the NE values were 22.4%, 22.8%, 24.3% and the WE values were 34.2%, 31.4% and 27.2% at 50%, 63% and 130% MAP, respectively. The GE and NE increased (P<0.001) whereas the WE decreased (P<0.001) with each increment in power output. The GE was lower than the NE (P<0.001) at 50% and 63% MAP and than the WE (P<0.001) at all intensities. The NE was lower (P<0.001) than the WE at 50% and 63% MAP. These results showed that (1) efficiency index values obtained during supra-maximal exercise were consistent with previous proposals and (2) the efficiency-power output relationships were not limited to sub-maximal intensity levels but were confirmed at higher power output.     

Identification and characterization of human pulmonary dendritic cells

Dendritic cells (DC) are specialized antigen-presenting cells, linking innate and adaptive immune responses, and thus play an important role in immunologically mediated diseases, including pulmonary diseases such as asthma and respiratory viral infections. Although much is known about the characteristics of lung DC in animal models, very few data concerning human lung DC are available. The goal of our study was to identify and characterize dendritic cells in human lung by preparing single-cell suspensions from surgical resection specimens and subsequent labeling with the recently developed blood dendritic cell antigen (BDCA) markers. A straightforward isolation procedure was developed to avoid phenotypical and functional changes induced by extensive purification methods. In this way, human lung DC were directly identified without the need for an additional adherence step for further purification. For the first time, we demonstrate the presence of three previously unidentified DC subsets in human lung digests: myeloid DC type 1 (BDCA1+/HLA-DR+), myeloid DC type 2 (BDCA3+/HLA-DR+), and plasmacytoid DC (BDCA2+/CD123+). The presence of CD1a+ DC in the human lung was confirmed. The identification and characterization of different human pulmonary DC subtypes is of great importance for the future development of DC-based immunotherapies.     

Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

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