Mutation in the mitochondrial 12S rRNA gene in two families from Mongolia with matrilineal aminoglycoside ototoxicity.

Irreversible hearing loss is a catastrophic complication of treatment with aminoglycoside antibiotics such as streptomycin, gentamycin, and kanamycin. Many kindreds showing a matrilineal pattern of inheritance of this trait have been described in China where the widespread use of aminoglycoside antibiotics accounts for approximately 25% of profound deafness in some districts. Because of the characteristic inheritance pattern, mitochondrial DNA (mtDNA) mutations were postulated to be the cause of the deafness in these pedigrees. In 1993 it was shown that an A to G substitution at base pair 1555 of the mitochondrial 12S ribosomal RNA gene was the only mutation common to all the families with aminoglycoside ototoxicity. We ascertained three Mongolian pedigrees from the School for the Deaf and Blind in Ulaanbaatar, all of which contained multiple affected subjects with streptomycin induced deafness in a pattern consistent with matrilineal transmission. Amplified mtDNA, obtained from transformed lymphoblastoid cell lines using previously described primers, showed the A to G point mutation in the 12S rRNA gene in two of the three families by restriction analysis as well as direct sequencing. No other example of this substitution was found among 400 control samples from Mongolians with normal hearing. We have thus confirmed the clinical relevance of the 1555 A to G mitochondrial mutation in the 12S rRNA gene by identifying it in affected subjects with familial aminoglycoside ototoxicity in another ethnic group. In countries where aminoglycosides are widely used, genetic counselling and screening of high risk families before the use of these drugs could have a dramatic effect on the incidence of deafness.     

Interethnic genetic differentiation: HLA class I antigens in the population of Mongolia

A total of 1668 individuals representing 10 major Mongolian ethnic groups were serologically typed for HLA-A, -B, and -C antigens. Antigens A2, A24, B61, B51, B58, Cw3, Cw7, and Cw6 were the most frequent specificities in Mongolians and no case of B42 was noted in all ethnic groups. The cluster analysis of Principal Components I and II shows that Mongolian speaking groups form one cluster vs Turkic-speaking Kazakhs. The analysis reveals a low, but significant differentiation of Mongolian ethnic groups as measured by F_ST = 0.0100 (P < 0.001). Gene diversity analysis shows that the genetic diversity of the Mongolian population can be attributed largely to its ethnic component, which makes up 64% of total genetic variation. The low degree of interpopulation variation and high level of intrapopulation diversity can be explained by the nomadic way of life of this indigenous population. Three-locus haplotypes A24-B61-Cw3, A33-B58-Cw3 are the most common haplotypic associations in Mongolians. The presence of antigens characteristic of Mongoloid, Caucasoid, and Negroid populations in Mongolians suggests a unique genetic background of this indigenous population. The three-locus haplotype distribution among Mongolians relative to other world populations supports the migration of ancient people from Central Asia to the New World, Korean Peninsula, and Southeast Asia. Am. J. Hum. Biol. 11:603–618, 1999. © 1999 Wiley-Liss, Inc.     

Gap Junctional Coupling Between Retinal Astrocytes Exacerbates Neuronal Damage in Ischemia-Reperfusion Injury

PurposeRetinal astrocytes abundantly express connexin 43 (Cx43), a transmembrane protein that forms gap junction (GJ) channels and unopposed hemichannels. While it is well established that Cx43 is upregulated in retinal injuries, it is unclear whether astrocytic Cx43 plays a role in retinal ganglion cell (RGC) loss associated with injury. Here, we investigated the effect of astrocyte-specific deletion of Cx43 (Cx43KO) and channel inhibitors on RGC loss in retinal ischemia/reperfusion (I/R) injury and assessed changes in expression and GJ channel and hemichannel function that occur in I/R injury. The effect of Cx43 deletion on neural function in the uninjured retina was also assessed.MethodsCx43 expression, astrocyte density and morphology, and RGC death in wild-type and Cx43KO mice after I/R injury were determined using immunohistochemistry and Western blotting. Visual function was assessed using ERG recordings. GJ coupling and hemichannel activity were evaluated using tracer coupling and uptake studies, respectively.ResultsLoss of RGCs in I/R injury was accompanied by an increase of Cx43 expression in astrocytes. Functional studies indicated that I/R injury augmented astrocytic GJ coupling but not Cx43 hemichannel activity. Importantly, deletion of astrocytic Cx43 improved neuronal survival in acute ischemia but did not affect RGC function in the absence of injury. In support, pharmacologic inhibition of GJ coupling provided neuroprotection in I/R injury.ConclusionsThe increase in Cx43 expression and GJ coupling during acute I/R injury exacerbates RGC loss. Inhibition of astrocytic Cx43 channels might represent a useful strategy to promote RGC survival in pathologic conditions.     

Comparison of hepatitis B vaccine coverage and effectiveness among urban and rural Mongolian 2-year-olds

BACKGROUND: The prevalence of hepatitis B (HBV) carriage in Mongolia is reported to be 14%. Universal HBV immunization of newborns has been shown to decrease carriage in Asian populations. Mongolia began universal newborn vaccination in 1991. This evaluation of vaccine coverage and effectiveness compares the success of the program between urban and nomadic rural populations. METHODS: Using random cluster sampling, 148 Mongolian 2-year-olds from seminomadic rural families were compared with 127 2-year-olds from Ulaanbaatar, the capital city. RESULTS: More than 95% of all subjects received hepatitis B vaccine although rural subjects were less likely to complete the series than were urban subjects. Adequate vaccine response differed significantly: 94.2% of urban subjects versus only 70.2% of rural subjects had protective anti-HBs levels (P < 0.001). Overall the proportion of hepatitis B infection in both samples was lower than the historical Mongolian prevalence. However, unexpectedly 40% of subjects in rural Bayanhongor Aimag (Province) were found to be HBsAg positive. CONCLUSION: The Mongolian infant vaccination program for hepatitis B is successfully reducing the rate of chronic carriage in the immunized generation. However, vaccine response among rural subjects is less than that among urban. There appears to be a pocket of high disease prevalence in Bayanhongor that requires further study.     

Non-contrast cardiac CT immediately after percutaneous coronary intervention: does it predict the risk of left ventricular remodeling in patients with ST-elevation myocardial infarction?

To assess the clinical utility of non-contrast cardiac CT (CCT) immediately after successful percutaneous coronary intervention (PCI) for predicting the risk of left ventricle (LV) remodeling in the management of patients with acute myocardial infarction (AMI), 35 patients with AMI underwent non-contrast CCT immediately after PCI. Volume and transmural extent of myocardial delayed enhancement (DE) were assessed on non-contrast CCT. Serial echocardiography and serologic biomarkers were evaluated at baseline and at 2 and 12 months after AMI. Based on an increase in left ventricular end-diastolic volume (LVEDV) ≥20?% at 2 months, patients were classified into two groups: LV remodeling (group 1, n?=?14) and no LV remodeling (group 2, n?=?21). Clinical characteristics, imaging parameters, and serologic biomarkers were compared between the two groups. Higher incidence of hypertension, longer time to reperfusion, and higher Killip classification at admission were observed for group 1 than for group 2, but these differences were not statistically significant (P?>?0.05). Greater volume and transmural extent of DE on non-contrast CCT and poorer resolution of ST-segment elevation on ECG were observed in group 1 compared to group 2, but these results were not statistically significant (P?>?0.05). Measurement of biochemical markers showed that probrain natriuretic peptide (proBNP), initial high sensitivity C reactive protein (hs-CRP), and maximum troponin T level were significantly higher in group 1 than in group 2 (P?<?0.05) at 2 months. Based on the trend of greater volume and transmural extent of DE in group 1 compared to group 2, non-contrast CCT immediately after PCI, in combination with serologic biomarkers (proBNP, hs-CRP, and troponin T) might be useful for managing patients with AMI.     

New payment model for rural health services in Mongolia

This article describes experiences in Mongolia in designing and implementing a new method of payment for rural health services. The new method involves using a formula that allocates 65% of available funding on the basis of risk-adjusted capitation, 20% on the basis of asset costs, 10% on the basis of variations in distance-related costs, and 5% on the basis of satisfactory attainment of quality of care targets. Rural populations have inferior health services in most countries, whether rich or poor. Their situation has deteriorated in most transition economies, including Mongolia since 1990. One factor has been the use of inappropriate methods of payment of care providers. Changes in payment methods have therefore been made in most transition economies with mixed success. One factor has been a tendency to over-simplify, for example, to introduce capitation without risk adjustment or to make per case payments that ignored casemix. In 2002, the Mongolian government decided that its crude funding formula for rural health services should be replaced. It had two main components. The first was payment of an annual grant by the local government from its general revenue on the basis of estimated service population, number of inpatient beds, and number of clinical staff. The second was an output-based payment per inpatient day from the National Health Insurance Fund. The model was administratively complicated, and widely believed to be unfair. The two funding agencies were giving conflicting types of financial incentives. Most important, the funding methods gave few incentives or rewards for service improvement. In some respects, the incentives were perverse (such as the encouragement of hospital admission by the National Health Insurance Fund). A new funding model was developed through statistical analysis of data from routine service reports and opinions questionnaires. As noted above, there are components relating to per capita needs for care, capital assets, distance, and quality of care. The risk-adjusted capitation component determines needs classes by use of age, gender, and family income. The model was accepted by all concerned parties, and steps are now being taken to implement it under transitional arrangements. Many of the data used to parameterize the model are inaccurate and will need to be updated in the near future. However, the model is inherently valid, and procedures have been set in place that will ensure accuracy is improved on a continuing basis. An important reason why the government strongly supported implementation was its commitment to implement output-based budgeting across all government sectors. The new model provided a convenient way of applying output-based budgeting to one major component of the health sector.     

A low rate of hepatitis B virus vaccine breakthrough infections in Mongolia

A nation-wide hepatitis B virus (HBV) immunization program of all newborn babies was launched in Mongolia in 1991. However, the continuation of clinical icteric viral hepatitis infections in children led to the investigation to determine whether HBV breakthrough infections were occurring and if any were due to hepatitis B surface antigen (HBsAg) mutants. Hepatitis A virus (HAV) infections accounted for most of these cases with 3% of the jaundiced children shown to have acute hepatitis B. Hepatitis B vaccine protection was 93% against HBV infection and 97% against HBV carriage. A G145A "escape mutant" was found in one HBV carrier child only. Anti-HBs levels, however, were low with 85% having titers less than 100 IU/L, 46% of whom had levels less than 10 IU/L. The results from this study demonstrate that the HBV immunization program in Mongolia provides an effective level of protection. However, continued surveillance of breakthrough infections and close monitoring of "vaccine escape" mutants is required.