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Biomedical subjects

D K Bowden

Publications and source records attributed to D K Bowden.

At least 19 recordsLinked to original sources
PubMed2006

A randomized, double-blind, placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia.

Beta-thalassaemia major is associated with low bone mass and fractures. We conducted a 2 year randomized controlled trial of zoledronic acid 4 mg administered intravenously every 3 months or placebo in the treatment of beta-thalassaemia-associated osteopenla. We recruited 23 subjects from 2 university hospitals with a T score of less than -1.0 at either the lumbar spine or hip, and 23 subjects completed the study (17 M, 6 F). Treatment groups did not differ significantly with respect to bone mineral density (BMD), age, height, weight and body mass index (BMI) at baseline. BMD was assessed at baseline, 12 months and 24 months by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, femoral reek, total hip and total body. After two years average lumbar spine BMD was 8.9% greater (95%CI 2.3-15.5%, P = 0.011), average femoral neck BMD was 9.1% greater (95%CI 5.5-12.7%, P < 0.0001), average total hip BMD was 9.6% greater (95%CI 6.5-12.6%, P < 0.0001) and average total body BMD was 4.7% greater (95%CI 2.7-6.8%, P < 0.0001) in the treated group compared to placebo. The absolute change in BMD from baseline to 2 years and the annualized rate of change of BMD was significantly greater in treated patients at all four sites. Age, gender, height, weight and BMI did not interact with the effect of treatment and so unadjusted data was used. The serum total ALP decreased 45% by 12 months (P = 0.004) and urinary deoxypyridinoline/creatinine ratio decreased 47% by 3 months (NS). We conclude that zoledronic acid (4 mg i.v. 3 monthly) suppresses bone turnover and increases BMD in beta-thalassaemia-associated osteopenia.

Adolescent↗
PubMed2004

HLA class-I and class-II allele frequencies and two-locus haplotypes in Melanesians of Vanuatu and New Caledonia.

HLA class-I and class-II allele frequencies and two-locus haplotypes were examined in 367 unrelated Melanesians living on the islands of Vanuatu and New Caledonia. Diversity at all HLA class-I and class-II loci was relatively limited. In class-I loci, three HLA-A allelic groups (HLA-A*24, HLA-A*34 and HLA-A*11), seven HLA-B alleles or allelic groups (HLA-B*1506, HLA-B*5602, HLA-B*13, HLA-B*5601, HLA-B*4001, HLA-B*4002 and HLA-B*2704) and four HLA-C alleles or allelic groups (HLA-Cw*04, HLA-Cw*01, HLA-Cw*0702 and HLA-Cw*15) constituted more than 90% of the alleles observed. In the class-II loci, four HLA-DRB1 alleles (HLA-DRB1*15, HLA-DRB1*11, HLA-DRB1*04 and HLA-DRB1*16), three HLA-DRB3-5 alleles (HLA-DRB3*02, HLA-DRB4*01 and HLA-DRB5*01/02) and five HLA-DQB1 alleles (HLA-DQB1*0301, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*0601 and HLA-DQB1*0602) constituted over 93, 97 and 98% of the alleles observed, respectively. Homozygosity showed significant departures from expected levels for neutrality based on allele frequency (i.e. excess diversity) at the HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB3/5 loci on some islands. The locus with the strongest departure from neutrality was HLA-DQB1, homozygosity being significantly lower than expected on all islands except New Caledonia. No consistent pattern was demonstrated for any HLA locus in relation to malaria endemicity.

Ethnicity↗
PubMed2000

DNA testing for haemochromatosis: diagnostic, predictive and screening implications.

Since 1996, the identification of the HFE gene has enabled DNA testing for hereditary haemochromatosis (HH). The range of DNA testing available includes: (1) diagnostic, (2) predictive (also called presymptomatic testing) and (3) screening. Access to DNA testing has been facilitated by an Australian Medicare rebate, the first available for genetic disorders. Despite the availability of HFE DNA testing in HH, it remains necessary to interpret results in the context of the clinical picture. Traditional markers based on phenotype (transferrin ferritinsaturation, and liver biopsy) are still required in some circumstances. We report our experience with HFE DNA testing using a semi-automated approach, which allows multiplexing for the two common mutations (C282Y and H63D). Screening a cohort of beta-thalassaemia major and sickle cell anaemia patients of predominantly Mediterranean origin showed that these individuals do not have the common C282Y mutation. This excluded C282Y as a factor in the pathogenesis of iron overload in these haemoglobinopathies. It also showed that the C282Y mutation is of limited value when investigating HH in certain ethnic groups. An Australian family studied illustrated the relative contribution of C282Y and H63D in iron overload. A recently reported third mutation (S65C) in the HFE gene was detected in a low frequency in the populations tested.

Aged↗
PubMed1999

Evidence for mitochondrial DNA recombination in a human population of island Melanesia.

Mitochondrial DNA (mtDNA) analysis has proved useful in studies of recent human evolution and the genetic affinities of human groups of different geographical regions. As part of an extensive survey of mtDNA diversity in present-day Pacific populations, we obtained sequence information of the hypervariable mtDNA control region of 452 individuals from various localities in the western Pacific. The mtDNA types fell into three major groups which reflect the settlement history of the area. Interestingly, we detected an extremely rare point mutation at high frequency in the small island of Nguna in the Melanesian archipelago of Vanuatu. Phylogenetic analysis of the mtDNA data indicated that the mutation was present in individuals of separate mtDNA lineages. We propose that the multiple occurrence of a rare mutation event in one isolated locality is highly improbable, and that recombination between different mtDNA types is a more likely explanation for our observation. If correct, this conclusion has important implications for the use of mtDNA in phylogenetic and evolutionary studies.

Biological Evolution↗
PubMed1999

Reduced soluble transferrin receptor concentrations in acute malaria in Vanuatu.

Soluble transferrin receptor (sTfR) concentration is a sensitive index of iron deficiency when used in conjunction with ferritin measurements in adults. One advantage of this assay is that unlike ferritin it does not appear to be affected by a range of infectious and inflammatory conditions or by pregnancy, rendering it a promising adjunct to the diagnosis of iron deficiency in tropical populations. We have measured plasma sTfR concentrations in a group of malaria patients (n = 21) and asymptomatic (18) and aparasitemic (76) controls in Vanuatu. Plasma sTfR concentration was significantly reduced in individuals with acute malaria (P = 0.003). While this observation provides evidence that erythropoeitic suppression may be an important etiologic component in malarial anemia, it also suggests that malaria may be a confounding factor when interpreting sTfR concentrations in such populations. The role of sTfR in the diagnosis of iron deficiency in tropical populations remains to be established.

Adolescent↗
PubMed1997

Studies to detect carriers of haemophilia A in German shepherd dogs using diagnostic DNA polymorphisms in the human factor VIII gene.

The current study investigated whether the DNA polymorphisms in the human FVIII gene, that are used for the diagnosis of carriers of haemophilia A, were diagnostically useful in dogs. Genomic DNA from 20 German Shepherd dogs (13 females, three normal males and four haemophilic males) was tested using five restriction site polymorphisms [HindIII/F8 (exon 17-18), Taq I/ST14.1, BclI/ST14.1, BclI F8 (exon 17-18) and Bgl II/DX13]. The DNA probes (with the exception of DX13) all hybridized to the canine DNA at high stringency, indicating significant homology between the human and canine FVIII gene. A BclI polymorphism (13.5/13.5 + 12.8 kb) was detected with the ST14.1 probe.

Animals↗
PubMed1997

Plasmodium vivax: a cause of malnutrition in young children.

We studied the aetiology of malnutrition in a cohort of 1511 children < 10 years old in Espiritu Santo, Vanuatu. Malnutrition was categorized using standard anthropometric criteria as: underweight [weight-for-age (WA) Z score < -2], wasting [weight-for-height (WH) Z < -2], or stunting [height-for-age (HA) Z < -2]. On multiple logistic regression analysis, the only factors significantly associated with wasting were age < 5 years [OR (95% CI) 1.8 (1.2-2.9), p = 0.01] and having suffered one or more episodes of clinical P. vivax malaria in the 6 months preceding nutritional assessment [OR 2.4 (1.3-4.4), p = 0.006]. The incidence of P. vivax infection was significantly higher during the 6 months preceding assessment in underweight vs. non-underweight children [incidence rate ratio (IRR) 2.6 (1.5-4.4), p < or = 0.0001). These groups had similar incidences of clinical P. falciparum infection during the same period [IRR 1.1 (0.57-2.1) p = 0.8] and of either species during the 6 months following assessment [IRR P. vivax 1.3 (0.9-2.0) p = 0.2; IRR P. falciparum 1.3 (0.9-1.9) p = 0.2]. In these children, P. vivax malaria was a major predictor of acute malnutrition; P. falciparum was not. Wasting neither predisposed to nor protected against malaria of either species. Although P. vivax malaria is generally regarded as benign, it may produce considerable global mortality through malnutrition.

Age Factors↗
PubMed1996

High incidence of malaria in alpha-thalassaemic children.

The alpha+-thalassaemias are the commonest known human genetic disorders, affecting up to 80 per cent of some populations. Although there is good evidence from both epidemiological and clinical studies that these gene frequencies reflect selection by, and protection from, malaria, the mechanism is unknown. We have studied the epidemiology of malaria in childhood on the southwestern Pacific island of Espiritu Santo in Vanuatu and here we report that, paradoxically, both the incidence of uncomplicated malaria and the prevalence of splenomegaly, an index of malaria infection, are significantly higher in young children with alpha+-thalassaemia than in normal children. Furthermore, this effect is most marked in the youngest children and for the non-lethal parasite Plasmodium vivax. The alpha+-thalassaemias may have been selected for their ability beneficially to increase susceptibility to P. vivax, which, by acting as a natural vaccine in this community, induces limited cross-species protection against subsequent severe P. falciparum malaria.

Animals↗
PubMed1996

Red blood cell phenotypes in the alpha + thalassaemias from early childhood to maturity.

The alpha+ thalassaemias are the most common single gene disorders of humans, yet little is known about their haematological characteristics in childhood. Blood samples have been collected randomly from more than 2000 individuals in village communities in Vanuatu in the South West Pacific and analysed for alpha thalassaemia and associated haematological changes. Here we describe the haematological effects of the alpha+ thalassaemias from early childhood through to maturity in this population. Mean cell volume (MCV) and mean cell haemoglobin (MCH) levels in individuals of normal, heterozygous and homozygous genotype differed significantly from one another throughout the entire age range (2P < 0.05). In contrast, haemoglobin levels in heterozygous and homozygous individuals were well maintained throughout development. Adults of normal genotype attain Hb levels which are indistinguishable from Caucasian reference values, a finding made all the more remarkable given the high frequency of clinical malaria in this population. It is clear from these findings that haematological data are valuable in screening for carriers of alpha+ thalassaemia in this population. MCH is clearly the most sensitive discriminator. None of the homozygous adults tested had an MCH of > 27 pg, whereas < 10% of normals had a value of < 27 pg. These data provide reference values for areas in which the alpha+ thalassaemias are common and often confused with iron-deficiency anaemia.

Adolescent↗
PubMed1995

DNA fingerprinting to determine paternity in laboratory rat sperm competition experiments.

Prior to this study a significant amount of research had been undertaken in the field of sperm competition in mammals. However, males of different strains have been required in each of these studies to enable paternity assignment through gene expression, which has consequently resulted in problems with differential fertilising capacity being encountered. In this study paternity assignment of progeny from sperm competition experiments with Sprague Dawley rats was achieved by multilocus DNA fingerprinting using band locus matching of individual specific banding patterns between progeny and parents. Trials with 4 restriction enzymes and 5 digoxygenin labelled probes (4 oligonucleotide and 1 cloned) achieved the highest levels of DNA fingerprint heterozygosity using AluI(CAC)5 and HinfI(CAC)5 combinations; however, paternity could not be determined in all offspring, due to a higher than expected degree of inbreeding within the rat population used in this study. This was demonstrated in subsequent comparisons of genetic diversity of three laboratory rat breeding populations from two different animal breeding facilities. Data from the rat mating study showed that, under conditions of direct sperm competition, second males given access to a mated oestrus female either 0.5 or 6.0 h after the first mating consistently required less time than the first to ejaculate: 7.6 min vs. 19.5 min (0.5 h delay ); 7.8 min vs. 19.5 min (6.0 h delay). A second males siring advantage was identified using DNA fingerprinting in both delay groups for those offspring on which paternity could be determined: 0.5 h delay, 1st = 39%, 2nd = 61%; 6 h delay, 1st = 34%, 2nd = 66%.

Animals↗
PubMed1995

Thalassaemia in Vanuatu, south-west Pacific: frequency and haematological phenotypes of young children.

The archipelago of Vanuatu situated in the South-West Pacific has a high frequency of alpha + thalassaemia and additionally on some of the islands there is a high frequency of beta thalassaemia. As part of a large cohort study to investigate the clinical effect of thalassaemia on malaria on the islands of Espiritu Santo and Maewo in Vanuatu, the gene frequencies of the thalassaemias were determined and blood counts were performed on a cohort of infants from birth to 3 years. The haematological phenotypes of the different thalassaemic genotypes are compared, providing a detailed description of the clinical manifestations of alpha + thalassaemia during early development. In addition, cross-sectional surveys of the population of the two islands were performed to establish the frequency of thalassaemia and other red cell polymorphisms and their geographical distribution.

Child, Preschool↗
PubMed1995

Short stature in homozygous beta-thalassaemia is due to disproportionate truncal shortening.

BACKGROUND AND OBJECTIVE: Growth failure in homozygous beta-thalassaemia has been recognized for many years, and has persisted despite major treatment advances. In this cross-sectional study, sitting and standing height were measured to determine whether growth failure was disproportionate. DESIGN: Patient data were analysed in three age groups, 2-10 years, 11-18 years and 19 and over. Sitting height and subischial leg length were also determined in a cohort of parents (n = 19) and normal Greek adolescents (n = 32). PATIENTS AND MEASUREMENTS: Of the known 156 patients with homozygous beta-thalassaemia in the State of Victoria, 154 (98.7%) attend our institution. Sitting and standing heights were measured, using Harpenden stadiometers, in 57 of 60 (95%) patients aged 2-18 years and in a random selection of 51 of 89 patients aged 19 and over (57%). Measurements are expressed as mean +/- SDS. Other data analysed included serum concentrations of ferritin, zinc, copper, FSH, LH, oestradiol and testosterone, according to standard laboratory assays, together with pubertal status and bone age in patients aged less than 19 years. RESULTS: Standing height standard deviation scores in the 2-10 age group were -0.687 +/- 0.861 (n = 9), in the 11-18 age group were -1.838 +/- 1.413 (n = 48) and in the age group 19 and over were -1.175 +/- 1.126. In individuals aged 2-10 years, sitting height standard deviation scores (SDS) were -1.56 +/- 1.02, in individuals 11-18 years were -3.76 +/- 1.51 (n = 48), and in individuals 19 years and over were -2.77 +/- 1.20 (n = 51), compared with subischial leg length SDS which were, in individuals aged 2-10 years 0.214 +/- 0.91; in 11-18 years, -0.063 +/- 1.347, and in individuals 19 and over, 0.37 +/- 1.18. These data show that the reduction in standing height was the result of truncal shortening. Mean sitting height SDS was significantly lower in children with homozygous beta-thalassaemia, compared with their parents (P < 0.001), and in a subgroup of Greek adolescents with homozygous beta-thalassaemia compared with age and sex matched normal Greek adolescents (P < 0.001). No correlation was found between truncal shortening and other clinical and biochemical variables measured. CONCLUSIONS: Short stature in our patients with homozygous beta-thalassaemia is due to disproportionate truncal shortening. The aetiology of truncal shortening in this patient group is likely to be multifactorial, although hypogonadism and chelation therapy may be contributory factors.

Adolescent↗
PubMed1995

Multiple glucose 6-phosphate dehydrogenase-deficient variants correlate with malaria endemicity in the Vanuatu archipelago (southwestern Pacific).

In studying the relationship between genetic abnormalities of red blood cells and malaria endemicity in the Vanuatu archipelago in the southwestern Pacific, we have found that of 1,442 males tested, 98 (6.8%) were G6PD deficient. The prevalence of GdPD deficiency varied widely (0%-39%), both from one island to another and in different parts of the same island, and generally correlated positively with the degree of malaria transmission. The properties of G6PD from GdPD-deficient subjects were analyzed in a subset of 53 samples. In all cases the residual red-blood-cell activity was < 10%. There were three phenotypic patterns. PCR amplification and sequencing of the entire coding region of the G6PD gene showed that the first of these patterns corresponded to G6PD Union (nucleotide 1360C-->T; amino acid 454Arg-->Cys), previously encountered elsewhere. Analysis of samples exhibiting the second pattern revealed two new mutants: G6PD Vanua Lava (nucleotide 383T-->C; amino acid 128Leu-->Pro) and G6PD Namoru (nucleotide 208T-->C; amino acid 70Tyr-->His); in three samples, the underlying mutation has not yet been identified. Analysis of the sample exhibiting the third pattern revealed another new mutant: G6PD Naone (nucleotide 497G-->A; amino acid 166Arg-->His). Of the four mutations, G6PD Union and G6PD Vanua Lava have a polymorphic frequency in more than one island; and G6PD Vanua Lava has also been detected in a sample from Papua New Guinea. G6PD deficiency is of clinical importance in Vanuatu because it is a cause of neonatal jaundice and is responsible for numerous episodes of drug-induced acute hemolytic anemia.

Adolescent↗
PubMed1993

DNA fingerprinting in relation to male dominance and paternity in a captive colony of tammar wallabies (Macropus eugenii).

The tammar wallaby has a polygynous mating system in which the dominant male usually controls initial access to oestrous females by mating first and then guarding the female from the advances of other subordinate males. In this study we used DNA fingerprinting with a human 3' hypervariable region (HVR) alpha globin probe to examine the paternity of pouch young progeny from 13 female tammars that were given continual access during the breeding season to a group of four sexually mature males. Constant individual-specific DNA profiles were observed for each animal. Paternity for 22 pouch young was successfully assigned using visual and computer-based analyses. However, no statistical difference was observed between the number of young sired by any of the four males (chi 2 = 2, d.f. = 3, P > 0.1). Mate guarding by the dominant male in our captive breeding group was not, therefore, sufficient to prevent successful subsequent matings by subordinates nor to enhance the genetic contribution of this male to the next generation. In each analysis, visual and computer assignments of paternity coincided, and these concurred with the results of a relatedness test which found that a large number of DNA bands were shared by sires and their progeny. The results from this paternity study show that first mating and subsequent mate guarding by the dominant male tammar wallaby in our captive group do not significantly skew the outcome of paternity towards this male and away from other males that subsequently mate with each female.

Animals↗
PubMed1992

A PCR-based strategy to detect the common severe determinants of alpha thalassaemia.

A rapid and inexpensive polymerase chain reaction (PCR) based strategy is described which detects the three common, severe alpha thalassaemia determinants observed in southeast Asia (--SEA) and the Mediterranean (--MED and -(alpha)20.5). Oligonucleotide primers have been chosen which allow specific identification of both normal (alpha alpha) and abnormal (--) chromosomes using identical conditions in either the same or parallel PCR reactions. This strategy should be useful in the development of screening programmes to identify carriers of alpha thalassaemia (--/alpha alpha) and prenatal diagnosis of the Hb Bart's hydrops fetalis syndrome (--/--) for those populations in which this represents a major cause of perinatal death.

Base Sequence↗
PubMed1990

Globin genes in Micronesia: origins and affinities of Pacific Island peoples.

DNA polymorphisms and copy-number variants of alpha-, zeta-, and gamma-globin genes have been studied in seven Micronesian island populations and have been compared with those in populations from Southeast Asia, Melanesia, and Polynesia. Micronesians are not significantly different from Polynesians at these loci and appear to be intermediate between Southeast Asians and Melanesians. There is evidence of significant Melanesian input into the Micronesian gene pool and of substantial proto-Polynesian contact with Melanesia.

Black People↗