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Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia.

A highly pathogenic avian influenza virus, H5N1, caused disease outbreaks in poultry in China and seven other east Asian countries between late 2003 and early 2004; the same virus was fatal to humans in Thailand and Vietnam. Here we demonstrate a series of genetic reassortment events traceable to the precursor of the H5N1 viruses that caused the initial human outbreak in Hong Kong in 1997 (refs 2-4) and subsequent avian outbreaks in 2001 and 2002 (refs 5, 6). These events gave rise to a dominant H5N1 genotype (Z) in chickens and ducks that was responsible for the regional outbreak in 2003-04. Our findings indicate that domestic ducks in southern China had a central role in the generation and maintenance of this virus, and that wild birds may have contributed to the increasingly wide spread of the virus in Asia. Our results suggest that H5N1 viruses with pandemic potential have become endemic in the region and are not easily eradicable. These developments pose a threat to public and veterinary health in the region and potentially the world, and suggest that long-term control measures are required.

Animals↗

Vitamin A deficiency and xerophthalmia among school-aged children in Southeastern Asia.

OBJECTIVE: To determine provisional estimates of the extent of vitamin A (VA) deficiency and xerophthalmia among school-aged children. DESIGN: Literature search of published, unpublished and website-based population survey and study reports, with country-specific imputation of prevalence rates and numbers of children affected by: (1) VA deficiency based on measured or imputed distributions of serum retinol concentration < 0.70 micromol/l (equivalent to < 20 microg/dl) and (2) xerophthalmia, by country. SETTING: Countries within the WHO South-East Asian Region. SUBJECTS: The target group for estimation was children 5-15 y of age. INTERVENTIONS: None. RESULTS: The estimated prevalence of VA deficiency is 23.4%, suggesting that there are approximately 83 million VA-deficient school-aged children in the region, of whom 10.9% (9 million, at an overall prevalence of 2.6%) have mild xerophthalmia (night blindness or Bitot's spot). Potentially blinding corneal xerophthalmia appears to be negligible at this age. CONCLUSIONS: VA deficiency, including mild xerophthalmia, appears to affect large numbers of school-aged children in South-East Asia. However, nationally representative data on the prevalence, risk factors and health consequences of VA deficiency among school-aged children are lacking within the region and globally, representing a future public health research priority.

Adolescent↗

Analysis of FMR1 (CGG)n alleles and FRAXA microsatellite haplotypes in the population of Greenland: implications for the population of the New World from Asia.

The fragile X syndrome is caused by the expansion of a polymorphic (CGG)n tract in the promoter region of the FMR1 gene. Apparently the incidence of fragile X syndrome is rare in the population of Greenland. In order to examine population-related factors involved in stability of the (CGG)n sequence, DNA samples obtained randomly from the Greenlandic population were analysed for size and AGG interspersion pattern of the FMR1 (CGG)n region and associated DXS548-FRAXAC1 haplotypes. In addition a large Greenland family with unstable transmission in the premutation range was analysed. The (CGG)n allele sizes in the Greenland population showed a narrow distribution similar to that reported for Asian populations. DNA sequencing of alleles with 36 CGG repeats revealed an AGG(CGG)6 insertion previously reported exclusively in Asian populations and a high frequency of alleles with a (CGG)10AGG(CGG)9AGG(CGG)9 or (CGG)9AGG(CGG)9AGG(CGG)6AGG(CGG)9 sequence pattern was found. Thus the data confirm the Asian origin of the Greenlandic (Eskimo) population and indicates that some (CGG)n alleles have remained stable for 15-30,000 years, since the population of the New World arrived from Asia via the Bering Strait.

Alleles↗

Analysis of FMR1 (CGG)(n) alleles and DXS548-FRAXAC1 haplotypes in three European circumpolar populations: traces of genetic relationship with Asia.

Fragile X syndrome, the most common form of inherited mental retardation, is caused by expansion of a (CGG)(n) repeat located in the FMR1 gene. The molecular factors involved in the mutation process from stable (CGG)(n) alleles towards unstable alleles are largely unknown, although family transmission studies and population studies have suggested that loss of AGG interruptions in the (CGG)(n) repeat is essential. We have analysed the AGG interspersion pattern of the FMR1 (CGG)(n) repeat and the haplotype distribution of closely located microsatellite markers DXS548 and FRAXAC1, in three circumarctic populations: Norwegians, Nenets and Saami. The data confirm the conservation, reported in all human populations studied so far, of an AGG interruption for each 9-10 CGG and support the stabilising effect of AGG interruptions. The data also indicate the existence of chromosomes of Asian origin in the Saami and Nenets population, thereby confirming a genetic relationship between Northern Europe and Asia. DXS548-FRAXAC1 haplotype frequencies were compared between 24 Norwegian fragile X males and 119 normal males. Significant linkage disequilibrium were found between the fragile X mutation and haplotype 6-4 and between normal (CGG)(n) alleles and haplotype 7-3.

Alleles↗

A complement receptor-1 polymorphism with high frequency in malaria endemic regions of Asia but not Africa.

Complement receptor-1 (CR1) is a ligand for rosette formation, a phenomenon associated with cerebral malaria (CM). Binding is dependent on erythrocyte CR1 copy number. In Caucasians, low CR1 expressors have two linked mutations. We determined the Q981H and HindIII RFLP distribution in differing population groups to ascertain a possible role in adaptive evolution. We examined 194 Caucasians, 180 Choctaw Indians, 93 Chinese-Taiwanese, 304 Cambodians, 89 Papua New Guineans (PNG) and 366 Africans. PCR/RFLP used HindIII for CR1 expression and BstNI for the Q981H mutation. DNA sequencing and pyrosequencing were performed to resolve inconclusive results. Gene frequencies for the L allele were 0.15 in Africans, 0.16 in Choctaws, 0.18 in Caucasians, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.58 in PNG. Allelic frequency for 981H were 0.07 in Africans, 0.15 in Caucasians, 0.18 in Choctaws, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.54 in PNG. The Q981H polymorphism correlates with the HindIII RFLP in most groups except West Africans and appears to be part of a low CR1 expression haplotype. The gene frequency for the haplotype is highest in the malaria-endemic areas of Asia, suggesting that this haplotype may have evolved because it protects from rosetting and CM.

Africa↗

Intercontinental genetic divergence of Castanea species in eastern Asia and eastern North America.

Castanea is one of the many plant genera with a disjunct distribution pattern between eastern Asia and eastern North America. Five species from three sections of the genus were investigated to examine genetic divergence between eastern Asian and eastern North American species. A total of 62 native populations were sampled for allelic variation at isozyme loci. The Chinese chestnut C. mollissima had the highest genetic variability, while the American C. dentata had the lowest genetic variability. The highest intracontinental genetic identities were observed between the Allegheny and Ozark chinkapins (0.931) and between C. mollissima and C. seguinii (0.870), while lower identities were detected between the American C. pumila and C. dentata (0.720-0.729). In intercontinental comparisons, genetic identities of 0.505, 0.495 and 0.507 were observed between the American chestnut and the Chinese C. mollissima, C. seguinii and C. henryi, respectively, whereas the Ozark chinkapin C. pumila var. ozarkensis had lower identities of 0.469, and 0.435 with C. mollissima and C. seguinii, respectively, but a slightly higher identity of 0.520 with C. henryi, the Chinese chinkapin. Divergence times were estimated at 10-13 million years before present between C. dentata and C. mollissima, and C. pumila var. ozarkensis and C. henryi.

Biological Evolution↗

Stigmatization of obesity in medieval times: Asia and Europe.

OBJECTIVE: To describe the stigmatization of obesity in medieval times in Asia and in Europe. DESIGN: Literature review. RESULTS: Obesity was stigmatized in medieval Japan in part, at least, because it was viewed as the karmic consequence of a moral failing in a Buddhist context. The stigma in Europe was based on the Christian deadly sin of gluttony. CONCLUSION: Stigmatization of obesity is not new. It was foreshadowed centuries ago by attitudes deriving from then extant theories of the origins of obesity.

Asia↗

Prevalence, awareness, treatment and control of hypertension in North America, North Africa and Asia.

Results from national surveys of prevalence, awareness, treatment and control provide the most meaningful basis for assessing the burden of hypertension in the community. National surveys conducted in a variety of countries in North America, Europe, Australia, Asia and Africa have identified a strikingly similar relationship between age and blood pressure (BP), with a progressive and steep increase in systolic BP throughout adult life and a less steep increase in diastolic BP from adolescence until the fifth or sixth decade. In most countries surveyed, there was a high prevalence of hypertension. Approximately, one quarter of all adults in the United States and Egypt had hypertension (systolic BP>/=140 mmHg or diastolic BP>/=90 mmHg or use of antihypertensive medication) in national surveys conducted in 1988-1991 and 1991-1993, respectively. The corresponding percentage was somewhat lower (14.4%) for adults surveyed in China during 1991, but temporal trends indicate that the prevalence of hypertension is increasing rapidly in that country. In the 1988-1991 national survey, more than 25% of US adults were unaware of their diagnosis, only 55% were being treated with antihypertensive medication and only 29% were on antihypertensive medication with a systolic/diastolic BP >140/90 mmHg. The situation was much worse in Egypt and China, with only 8% and <5% of adults with hypertension, respectively, being treated with antihypertensive medication and having a systolic/diastolic BP <140/90 mmHg. These survey results underscore the fact that hypertension is highly prevalent, poorly treated and controlled, and an escalating health challenge in economically developing countries.

Africa, Northern↗

SCAR markers and multiplex PCR-based identification of isomorphic species in the Anopheles dirus complex in Southeast Asia.

The Anopheles dirus Peyton & Harrison complex of mosquitoes (Diptera: Culicidae) comprises seven known species, including important malaria vectors in Southeast Asia. Specific identification of each species of the complex, which cannot be distinguished using morphological characters, is crucial for understanding vector ecology and implementing effective control measures. Derived from individual random amplified polymorphic DNA (RAPD) markers, sequence characterized amplified regions (SCAR) were analysed for the design of specific paired-primers. Combination of six SCAR primers resulted in the development of a simple, robust, single multiplex PCR able to identify three important malaria vectors among the four most common species (A, B, C, D) of the complex: species A from several Southeast Asian countries, species B from Perlis, Malaysia, and species C and D from Thailand.

Animals↗

The determinants of dust mite allergen and its relationship to the prevalence of symptoms of asthma in the Asia-Pacific region.

The role that house dust mites play in the primary causation of asthma is controversial. Approximately thirty-six 10-yr-old children in each of 10 centres in the Asia-Pacific region participated. Researchers collected dust from mattresses and living room floors using standardized procedures. Der p1 and Der f1 were analysed using a double monoclonal antibody enzyme-linked immunosorbent assay. Geometric mean allergen levels were calculated for each centre. An ecological analysis was conducted to show the regression of the geometric mean allergen level, using the highest household level, against asthma symptom and severity prevalence data from the International Study of Asthma and Allergies in Childhood, Phase I. Among children aged 13-14 yr, the change in asthma symptom prevalence was associated with per unit change in Der p1 microg/g (1.08, 95% CI 0.10-2.06) and Der 1 microg/g (Der p1 + Der f1) (0.64, 95% CI 0.02-1.26). The change in having four or more attacks of asthma in the last 12 months was associated with per unit change in Der p 1 microg/g (0.29, 95% CI -0.02 to 0.60) and Der 1 microg/g (0.20, 95% CI 0.01-0.38). There was no effect for total Der p1 or Der f1 (total or microg/g). Among children aged 6-7 yr, neither allergen was related to symptoms or severity prevalence. While our findings suggest that Dermatophagoides pteronyssinus may have a role in the primary causation of asthma, the complexity of this association reinforces the need for prospective studies.

Adolescent↗

A multiplex PCR-based method derived from random amplified polymorphic DNA (RAPD) markers for the identification of species of the Anopheles minimus group in Southeast Asia.

Effective control of Anopheles minimus s.l., an important malaria vector in Southeast Asia, is based on the accurate identification of species within An. minimus complex, which cannot be distinguished using morphological characters. Derived from individual random amplified polymorphic DNA markers, sequence characterized amplified regions were analysed for the design of species-specific paired-primers. Combination of these primers resulted in the development of a simple, robust multiplex PCR able to identify both species An. minimus A and C belonging to the complex, hybrids AC, and three sympatric and closely related species, An. aconitus, An. pampanai and An. varuna. Hybrids AC do not possess alleles of both parents but exhibit novel adaptive potentials resulting from recombination among parental genes leading to hybrizyme.

Animals↗

Epidemiology of hepatitis A in Asia and experience with the HAV vaccine in Hong Kong.

Hepatitis A and hepatitis B infections are prevalent throughout Asia. Patients infected with hepatitis B virus (HBV) have a higher morbidity and mortality if superinfected with hepatitis A virus (HAV). In Hong Kong, adolescents and young adults are particularly prone to severe hepatitis infection. Hepatitis A vaccination of patients with or without chronic HBV infection has been shown to be efficacious and associated with a good safety profile.

Adolescent↗

Spatial pattern of chloroplast DNA variation of Cyclobalanopsis glauca in Taiwan and East Asia.

This study examined the spatial pattern of chloroplast DNA (cpDNA) variation in Cyclobalanopsis glauca (Thunb. ex Murray) Oerst. (Fagaceae) in 140 trees from Taiwan (25 populations), Japan (three), Ryukyus (two), Hong Kong (one) and Mainland China (one). By sequencing three cpDNA intergenic spacer fragments using universal primers (trnT-trnL, trnV-trnM, including the trnV intron, and petG-trnP), we found a total of 1,980 bp and 15 polymorphic sites. Among them, 12 sites were caused by point mutation, and three resulted from insertion. This gives rise to a total of 13 cpDNA haplotypes. The level of differentiation among the populations studied is relatively high (GST = 0.612). Two ancestral haplotypes (A and B) are distributed widely in East Asia. Interestingly, all the derived cpDNA variations are found only in Taiwan but not in other areas. The Central Mountain Ridge (CMR) of Taiwan creates an unsurpassed barrier to the east-west gene flow of C. glauca. Among the populations on the west of CMR, only three separated populations, Yangmingshan, Wushe and Chinshuiying, have high haplotype diversity, each consisting of sister haplotypes all mutated from the same ancestral haplotype. Thus, they have probably originated from de novo mutation after the last glaciation. This inference agrees with the observation that no spatial autocorrelation existed on the west side. Two unrelated dominant lineages on the east of the CMR (haplotypes D and F) showed significant spatial genetic structure. Estimate of NST - GST was -0.090 and differed significantly from zero. Thus at the local scale, the phylogeographical component of the genetic structure is significant on the east of the CMR. Accompanied by published palynological records of the last glaciation, this study suggests the possibility that these two types were colonized northward from the southeastern part of Taiwan. 'Star-like' genealogy is characterized, with all the haplotypes coalescing rapidly and as a general outcome of population expansion (Page & Holmes 1998). A neutrality test also suggested a demographic expansion recovered from a bottleneck. We therefore inferred that the southeastern part of Taiwan might be a potential refugium for C. glauca.

DNA, Chloroplast↗

Case report and review of disseminated histoplasmosis in South-East Asia: clinical and epidemiological implications.

The South-East Asian region is not known to be a major endemic area for histoplasmosis. We have recently diagnosed several cases of disseminated histoplasmosis in patients from this region. We report on a well documented indigenous case of disseminated histoplasmosis in a 62-year-old poultry farmer and review the literature for other reported cases of clinical histoplasmosis in the South-East Asian region. Sporadic cases of indigenous chronic pulmonary and non-meningeal disseminated histoplasmosis in immunocompetent hosts have been reported as well as examples of disseminated histoplasmosis in immunocompromised hosts. These reports suggest that histoplasmosis is endemic to certain areas in South-East Asia and that there may be a large number of undiagnosed and subclinical cases. The recent advances in diagnostic tests for histoplasmosis are also reviewed with reference to the experience of using these tests in the reported case.

Amphotericin B↗

Spiders of medical importance in the Asia-Pacific: atracotoxin, latrotoxin and related spider neurotoxins.

1. The spiders of medical importance in the Asia-Pacific region include widow (family Theridiidae) and Australian funnel-web spiders (subfamily Atracinae). In addition, cupboard (family Theridiidae) and Australian mouse spiders (family Actinopodidae) may contain neurotoxins responsible for serious systemic envenomation. Fortunately, there appears to be extensive cross-reactivity of species-specific widow spider antivenom within the family Theridiidae. Moreover, Sydney funnel-web antivenom has been shown to be effective in the treatment of mouse spider envenomation. 2. alpha-Latrotoxin (alpha-LTx) appears to be the main neurotoxin responsible for the envenomation syndrome known as "latrodectism" following bites from widow spiders. This 120 kDa protein binds to distinct receptors (latrophilin 1 and neurexins) to induce neurotransmitter vesicle exocytosis via both Ca2+-dependent and -independent mechanisms, resulting in vesicle depletion. This appears to involve disruption to a process that normally inhibits vesicle fusion in the absence of Ca2+. Precise elucidation of the mechanism of action of alpha-LTx will lead to a major advancement in our understanding of vesicle exocytosis. 3. delta-Atracotoxins (delta-ACTX) are responsible for the primate-specific envenomation syndrome seen following funnel-web spider envenomation. These peptides induce spontaneous repetitive firing and prolongation of action potentials in excitable cells. This results from a hyperpolarizing shift of the voltage-dependence of activation and a slowing of voltage-gated Na+ channel inactivation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 on insect and mammalian voltage-gated Na+ channels in a manner similar, but not identical, to scorpion alpha-toxins and sea anemone toxins. delta-Atracotoxins provide us with highly specific tools to study Na+ channel structure and function 4. omega- and Janus-faced ACTX, from funnel-web spider venom, are novel neurotoxins that show selective toxicity to insects. In particular omega-ACTX define a new insecticide target due to a specific action to block insect voltage-gated Ca2+ channels. Both these ACTX show promise for the development of baculoviral recombinant biopesticides expressing these toxins for the control of insecticide-resistant agricultural pests. In addition, they should provide valuable tools for the pharmacological and structural characterization of insecticide targets.

Amino Acid Sequence↗

Treatment of chronic hepatitis B virus infection: an Asia-Pacific perspective.

Chronic hepatitis B infection is a serious health threat in the Asia-Pacific area. A consensus meeting on the treatment of chronic hepatitis B infection was conducted in Hong Kong, in August 1997. It was generally agreed that treatment of chronic hepatitis B infection should be based on the understanding of the natural history of chronic hepatitis B infection. To date, interferon alpha is the only Food and Drug Administration (FDA)-approved form of therapy for chronic hepatitis B infection. The overall response in Asian patients is unsatisfactory: approximately 15-20% will clear hepatitis B e antigen, but less than 5% will clear hepatitis B surface antigen. Newer immunomodulatory therapies are under trial. In contrast, nucleoside analogues, such as lamivudine (pending FDA approval) and famciclovir, have been shown to be potent suppressors of hepatitis B viral replication; however, their role as monotherapy in the treatment of chronic hepatitis B infection remains to be defined. Also, the issues of resistance to nucleoside analogues and withdrawal rebound need to be carefully studied. The future direction of therapy in chronic hepatitis B infection is probably a combination of nucleoside analogues or nucleoside analogues with immunomodulatory therapy.

2-Aminopurine↗

The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region.

Mutations in the haemochromatosis (HFE) gene cause most of the cases of hereditary haemochromatosis among people of Northern European ancestry while remaining a rare cause of iron overload among indigenous persons of the Asia-Pacific region. Advances in understanding of the role of the HFE protein product and other recently cloned iron transporters signify an exciting period, as previously unknown components of the iron metabolism pathway are revealed one by one. Epidemiological studies have shown that this gene is more widespread than its phenotypic expression would suggest and that the heterozygous state may be implicated in the expression of other diseases of the liver such as porphyria cutanea tarda, hepatitis C virus infection and non-alcoholic steatohepatitis. The diagnosis, management and ethical implications for clinical practice in the aftermath of this discovery are discussed.

Asia↗

Changing disease burden and management issues for esophageal cancer in the Asia-Pacific region.

The changing epidemiology of esophageal cancer in developed countries is from squamous cell type to adenocarcinomas arising from Barrett's epithelium and the gastric cardia. This has implications for management of this disease. Earlier diagnosis of cancer from screening high-risk patients with Barrett's esophagus is potentially possible, and mucosal ablation together with acid-suppressive therapies have been investigated to revert Barrett's epithelium in its premalignant stage. When a cancer has developed, the strategies of staging methodology and surgical approaches also differ from those applicable for squamous cell cancers located in more proximal locations of the esophagus. By contrast, in the Asia-Pacific region (with the exceptions of Australia and New Zealand), squamous cell cancers in the middle portion of the esophagus remain the main cell type seen. An overall increase in life expectancy has led to more elderly patients presenting with carcinoma of the esophagus. This is of particular importance when surgical resection is contemplated. Advances in surgical management, multimodality programs, and endoscopic therapies are most marked in recent years. Treatment for patients with esophageal cancer should be individualized. The choice depends on expertise and facilities available, tumor and patient factors, and local economics.

Asia↗