Epidemiology of congenital hearing loss in Victoria, Australia

The aim of this study was to report the incidence, prevalence and clinical characteristics of congenital hearing loss sufficient to require hearing aid fitting in the first 6 years of life for the 1993 birth cohort of the state of Victoria (population 4.4 million), Australia. In 1993, 64,116 infants born in the state of Victoria survived the neonatal period. Subjects included all children with congenital hearing loss for which hearing aids were fitted, at any time up to and including 31 December 1999, when the youngest member of the cohort reached 6 years of age. Data on the degree, type and etiology of hearing loss were available from the Australian Hearing database for all subjects. Sociodemographic and health data were available from the Victorian Infant Hearing Screening Program (VIHSP) and parent questionnaires. The known prevalence of identified congenital hearing loss increased as the cohort aged. By the time the youngest member had reached the age of 6 years, 134 children (78 boys, 56 girls) had been fitted with hearing aids for permanent congenital hearing loss of any degree (2.09/1000). Fifty-four (40%) of these had known mild losses (20-40 dB HL). The prevalence of known moderate or greater loss (> 40 dB HL) was 1.12/1000; the data suggest that over 90% could have been detectable by neonatal hearing screening. A further seven children from the birth cohort were fitted with hearing aids due to acquired forms of hearing loss (0.11/1000). The etiology was known in only 57 (43%) congenital cases, with known non-syndromal genetic causes accounting for 21 (37%) of these. This study reports on the prevalence of congenital hearing loss requiring hearing aid fitting for an entire birth cohort. These data indicate the possible yield from neonatal screening, and hence the likely benefit of such screening. For a large proportion of cases, the etiology remains unknown. These data have implications for health service delivery and illustrate the usefulness of a population database in monitoring the prevalence of congenital hearing loss.     

Apolipoprotein E genotype, vascular risk and early cognitive impairment in an African Caribbean population

A reduced risk of Alzheimer's disease (AD) associated with the apolipoprotein E (APOE) epsilon4 allele is reported in populations of African origin. In order to clarify possible reasons for this, we examined the association between APOE genotype and early cognitive impairment in a community-based African Caribbean UK population aged 55-75 years. APOE genotype was available for 202 participants, 57 (28%) of whom were classified as having relative cognitive impairment on a battery of neuropsychological tests. Cognitive impairment was negatively associated with epsilon2 and positively but more weakly associated with epsilon4. Effects of both alleles increased markedly after age 70. The effect of epsilon4 was increased in combination with hypertension, diabetes or lower educational attainment, but these factors did not influence epsilon2 effects. Cholesterol and triglyceride levels partially explained effects of epsilon2, but did not account for those of epsilon4. A reduced association between epsilon4 and later AD in populations of African origin is unlikely to be explained by reduced cognitive effects or by differential mortality. However, it may be accounted for by vascular comorbidity. The different patterns of association between epsilon2 and epsilon4 alleles suggest different pathways of effect.     

Potent stimulation and inhibition of the CFTR Cl(-) current by phloxine B

The effects of the fluoresceine derivative, phloxine B, on the Cl(-) current through the cystic fibrosis transmembrane conductance regulator (CFTR) were examined in XENOPUS: oocytes expressing human CFTR. In whole oocytes, the CFTR Cl(-) current (I(CFTR)) was activated by superfusion with isobutylmethylxanthine and forskolin. I(CFTR) was stable during activation and deactivated rapidly upon washout of the activation solution. Phloxine B slowed deactivation and, at high concentrations, inhibited I(CFTR) weakly. In excised inside-out macropatches, I(CFTR) was activated by the catalytic subunit of protein kinase A (cPKA) and MgATP. Phloxine B (0.01 - 3 microM), applied after activation, increased I(CFTR) within 30 s followed by a slow decrease which became dominant at high concentrations. Slowing of deactivation of the CFTR was observed at all concentrations. The effect of phloxine B after 30 s had a bell-shaped concentration-dependence with midpoints at 45 and 1600 nM for the stimulatory and the inhibitory limb, respectively; maximum stimulation was about 1.8 times. The slow inhibitory component, measured after 6 min, occurred with an IC(50) value of approximately 1 microM. In the absence of cPKA, phloxine B did not stimulate I(CFTR). In the presence of cPKA and MgATP, the effects of phloxine B were more prominent at low (0.02 mM) than at high ATP (2 mM). The data show that phloxine B modulates I(CFTR) by increasing channel activity and slowing channel deactivation; at high concentrations inhibition dominates. The effects may be mediated by direct interactions with CFTR from the inside of the cell.     

Geographic variance in access to renal transplantation in Australia

BACKGROUND: Geographic disparities in access to transplantation in Australia during the past 15 years have been accentuated by the increasing size of the transplant waiting lists in each state and by low cadaveric donation rates. Access to dialysis treatment is similar in all states of Australia, although there are fewer elderly dialysis patients in South Australia. RESULTS: Access to the transplant waiting list varies significantly between the states, with one state having 39 per million population (pmp) on their list compared with the two most populous states at 113 pmp and 101 pmp. Patients between the ages of 25 and 54 years in one state had twice the chance of being on the waiting list compared with another.Transplantation rates reflect both the cadaveric donor rate (16.9 transplants pmp) and the large contribution from living donors (39% of all transplants in 2001). Transplantation with a kidney in Australia is dependent both upon age and the state of residence, with one state performing transplantations with 15% of their dialysis population each year but all other states achieving less than 10%, with an average of 8% for the country as a whole. CONCLUSIONS: Criteria for access to the transplantation waiting list in each state vary, depending perhaps upon whether a general community or individual patient perspective is the dominant policy. Access to transplantation on the other hand is reflective of each states' cadaveric donation rate modified by increasing use of living donors, especially in younger patients.     

Influenza a virus PB1-F2 protein

PB1-F2 protein (PB1-F2) is encoded by the alternative (+1) ORF in the PB1 gene of influenza A viruses (IAVs). This protein has a number of unique features, namely its absence from some animal IAV isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation, mitochondrial localization, and apoptotic or pro-apoptotic properties. Localization of PB1-F2 to mitochondria is mediated via C-terminal basic amphipathic alpha-helix. PB1-F2 affects apoptosis and may contribute to the pathogenicity and lethality of IAVs. Sequence analysis showed that, in addition to the strains with an ORF for full-length PB1-F2, there are some with an ORF for different truncated forms of PB1-F2. Several other viruses encode proteins with structure and function similar to PB1-F2 of IAVs.     

Techniques used by smokers during contingency motivated smoking reduction

This study investigated the smoking reduction strategies used by smokers who were not enrolled in formal treatment. Twenty-four smokers were interviewed following a study in which they were contingently reinforced for reductions in alveolar carbon monoxide levels but not provided with specific reduction strategies. Results indicated that smokers who consumed more food or liquids to avoid smoking and/or who avoided other related substances such as alcohol and coffee were more successful in reducing carbon monoxide levels than subjects who did not use these techniques (p < 0.05). Conversely, subjects who stated that they attempted to reduce without a specific plan were less successful in reducing carbon monoxide levels (p < 0.05).     

Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma

POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.     

Investigating the Role of Ischemia vs. Elevated Hydrostatic Pressure Associated with Acute Obstructive Uropathy

Obstructive uropathy can cause irreversible renal damage. It has been hypothesized that elevated hydrostatic pressure within renal tubules and/or renal ischemia contributes to cellular injury following obstruction. However, these assaults are essentially impossible to isolate in vivo. Therefore, we developed a novel pressure system to evaluate the isolated and coordinated effects of elevated hydrostatic pressure and ischemic insults on renal cells in vitro. Cells were subjected to: (1) elevated hydrostatic pressure (80 cm H₂O); (2) ischemic insults (hypoxia (0% O₂), hypercapnia (20% CO₂), and 0 mM glucose media); and (3) elevated pressure + ischemic insults. Cellular responses including cell density, lactate dehydrogenase (LDH) release, and intracellular LDH (LDH_i), were recorded after 24 h of insult and following recovery. Data were analyzed to assess the primary effects of ischemic insults and elevated pressure. Unlike pressure, ischemic insults exerted a primary effect on nearly all response measurements. We also evaluated the data for insult interactions and identified significant interactions between ischemic insults and pressure. Altogether, findings indicate that pressure may sub-lethally effect cells and alter cellular metabolism (LDH_i) and membrane properties. Results suggest that renal ischemia may be the primary, but not the sole, cause of cellular injury induced by obstructive uropathy.