Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment

In a consanguineous Turkish family, a locus for autosomal recessive nonsyndromic hearing impairment (ARNSHI) was mapped to chromosome 2q31.1-2q33.1. Microsatellite marker analysis in the complete family determined the critical linkage interval that overlapped with DFNB27, for which the causative gene has not yet been identified, and DFNB59, a recently described auditory neuropathy caused by missense mutations in the DFNB59 gene. The 352-amino acid (aa) DFNB59 gene product pejvakin is present in hair cells, supporting cells, spiral ganglion cells, and the first three relays of the afferent auditory pathway. A novel homozygous nonsense mutation (c.499C>T; p.R167X) was detected in the DFNB59 gene, segregating with the deafness in the family. The mRNA derived from the mutant allele was found not to be degraded in lymphocytes, indicating that a truncated pejvakin protein of 166 aa may be present in the affected individuals. Screening of 67 index patients from additional consanguineous Turkish families with autosomal recessive hearing impairment revealed a homozygous missense mutation (c.547C>T; p.R183W) that segregates with the hearing impairment in one family. Furthermore, in a panel of 83 Dutch patients, two additional novel mutations (c.509_512delCACT; p.S170CfsX35 and c.731T>G; p.L244R), which were not present in ethnically matched controls, were found heterozygously. Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population.     

The targeting,docking and anti-proteolysis functions of the secretin chaperone PulS

The Klebsiella oxytoca lipoprotein PulS might function as either or both a pilot and a docking factor in the outer membrane targeting and assembly of the Type II secretion system secretin PulD. In the piloting model, PulS binds to PulD monomers and targets them to the outer membrane via the lipoprotein sorting pathway components LolA and LolB. In this model, PulS also protects the PulD monomers from proteolysis during transit through the periplasm. In the docking model, PulS is targeted alone to the outer membrane, where it acts as a receptor for PulD monomers, allowing them to accumulate and assemble specifically in this membrane. PulS was shown to dissociate from and/or re-associate freely with PulD multimers in zwitterionic detergent, making it difficult to determine whether PulS remains associated with PulD dodecamers in the outer membrane by co-purification. However, PulD protomers in the dodecamer were shown to be stable in the absence of PulS, indicating that PulS is only required to protect the protease-susceptible monomer. DegP was identified as one of the proteases that could contribute to PulD degradation in the absence of PulS. Studies on the in vitro assembly and targeting of PulD into Escherichia coli membrane vesicles demonstrated its strong preference to insert into the inner membrane, as is the case in vivo in the absence of PulS. However, PulD could be targeted to outer membrane fragments in vitro if they were preloaded with PulS, indicating the technical feasibility of the docking model. We conclude that both modes of action might contribute to efficient outer membrane targeting of PulD in vivo, although the piloting function is likely to predominate.     

Glutathione levels modulate domoic acid induced apoptosis in mouse cerebellar granule cells.

Exposure of mouse cerebellar granule neurons (CGNs) to domoic acid induced cell death, either by apoptosis or by necrosis, depending on its concentration. Necrotic damage predominated in response to domoic acid above 0.1 microM. In contrast, cell injury with apoptotic features (assessed by Hoechst staining and DNA laddering assay) was evident after exposure to lower concentrations of domoic acid (< or = 0.1 microM). The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-sulfamoylbenzo [f] quinoxaline, but not the N-methyl-D-aspartate receptor antagonist MK-801, prevented domoic acid-induced apoptosis. To evaluate the role of oxidative stress in domoic acid-induced apoptosis, experiments were carried out in CGNs isolated from wild-type mice (Gclm (+/+)) and mice lacking the modifier subunit of glutamate-cysteine ligase, the first and rate-limiting step of glutathione (GSH) biosynthesis (Gclm (-/-)). CGNs from Gclm (-/-) mice have very low levels of GSH and were more sensitive to domoic acid-induced apoptosis and necrosis than Gclm (+/+) CGNs. The antioxidant melatonin (200 microM) and the membrane-permeant GSH delivery agent GSH ethyl ester (2.5 mM) prevented domoic acid-induced apoptosis. Domoic acid increased formation of reactive oxygen species but did not affect intracellular GSH levels. Domoic acid also increased cytosolic and mitochondrial calcium levels, increased oxidative stress in mitochondria, and altered mitochondrial membrane potential, which ultimately caused cytochrome c release, activation of caspase-3, and degradation of poly (ADP-ribose) polymerase. These results indicate that low concentrations of domoic acid cause apoptotic neuronal cell death mediated by oxidative stress.     

A decade of inequality in maternity care: antenatal care,professional attendance at delivery,and caesarean section in Bangladesh (1991–2004)

Background  

Bangladesh is committed to the fifth Millennium Development Goal (MDG-5) target of reducing its maternal mortality ratio by three-quarters between 1990 and 2015. Since the early 1990s, Bangladesh has followed a strategy of improving access to facilities equipped and staffed to provide emergency obstetric care (EmOC).     

The changing role of amputation for soft tissue sarcoma of the extremity in adults.

The role of amputation in soft tissue sarcoma of the extremity has decreased at Memorial Sloan-Kettering Cancer Center during the last 20 years. In an attempt to determine the reasons for this change in therapy, an analysis of two separate databases involving 1,057 patients compiled during the periods of 1968 to 1978 and 1982 to 1990 was performed. The patients requiring amputation for soft tissue sarcoma of the extremity in the two databases (n = 233) were compared in an attempt to determine any significant differences between the two time periods. The groups were specifically compared for differences in risk factors, indications for amputations and the effect a decreasing incidence of amputation in the 1982 to 1990 group had on local recurrence and overall survival between the two groups. Despite similarity of risk factors and indications for amputation, the decreased incidence of amputation during the 1982 to 1990 period was associated with a significant decrease in local recurrence after amputation and no significant change in overall survival compared with the 1968 to 1978 group. Absence of local recurrence was associated with significant improvement in survival. Possible reasons for the shift in therapy, as well as the present and future role of amputation in soft tissue sarcoma of the extremity, are discussed.     

Political economy of tobacco control in low-income and middle-income countries: lessons from Thailand and Zimbabwe. Global Analysis Project Team

Crucial to the success of the proposed Framework Convention on Tobacco Control will be an understanding of the political and economic context for tobacco control policies, particularly in low-income and middle-income countries. Policy studies in Thailand and Zimbabwe employed the analytical perspective of political economy and a research strategy that used political mapping, a technique for characterizing and evaluating the political environment surrounding a policy issue, and stakeholder analysis, which seeks to identify key actors and to determine their capacity to shape policy outcomes. These policy studies clearly revealed how tobacco control in low-income and middle-income countries is also being shaped by developments in the global and regional political economy. Hence efforts to strengthen national control policies need to be set within the context of globalization and the international context. Besides the transnational tobacco companies, international tobacco groups and foreign governments, international agencies and nongovernmental organizations are also playing influential roles. It cannot be assumed, therefore, that the tobacco control strategies being implemented in industrialized countries will be just as effective and appropriate when implemented in developing countries. There is an urgent need to expand the number of such tobacco policy studies, particularly in low-income and middle-income countries. Comprehensive guidelines for tobacco policy analysis and research are required to support this process, as is a broader international strategy to coordinate further tobacco policy research studies at country, regional and global levels.     

Precocious cervical ripening and preterm labor

A group of 8303 women was studied to determine the timing of cervical ripening. It was confirmed that these signs of cervical change can be observed several weeks before preterm births. The precocious signs of external ripening can be recognized during a vaginal examination and may be useful in predicting preterm labor.