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Biomedical subjects

R M Andrews

Publications and source records attributed to R M Andrews.

At least 19 recordsLinked to original sources
PubMed2001

Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

Leber hereditary optic neuropathy (LHON) is a major cause of inherited blindness in young males. Approximately 1 in 7 individuals with LHON harbor a mixture of mutated and wild-type (normal) mtDNA (heteroplasmy), and the risks of developing blindness in heteroplasmic LHON individuals are not well characterized. MtDNA is inherited exclusively down the maternal line, and although the risks of a relative within a homoplasmic LHON pedigree are relatively well established, the risks of transmission in heteroplasmic LHON pedigrees have not been studied in detail. We analyzed 17 independent pedigrees that harbor the most prevalent LHON mutation: G11778A. The pedigrees were influenced by incomplete ascertainment bias, which was reduced by omitting the affected probands from the analysis. We made the following observations: (1) The frequency of blindness in males was related to the mutation load in that individual's blood. (2) Mothers with < or = 80% mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift in these pedigrees. This study provides insights into the mutation load, or threshold, necessary for expression of the optic neuropathy, the relationship between mutation load in the mother and the risk of blindness in her children, and the complex inheritance of heteroplasmic mtDNA defects.

DNA, Mitochondrial↗
PubMed2001

The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease. The majority of LHON patients harbour one of three point mutations of the mitochondrial DNA (mtDNA) complex I, or NADH:ubiquinone oxidoreductase (ND) genes (G11778A in ND4, G3460A in ND1, T14484C in ND6). As a consequence, screening for these mutations has become part of the routine clinical investigation of young adults who present with bilateral optic neuropathy, and the absence of these mutations is interpreted as indicating there is a low likelihood that an optic neuropathy is LHON. However, there are many individuals who develop the clinical features of LHON but who do not harbour one of these primary LHON mutations. We describe two LHON pedigrees that harbour the same novel point mutation within the mtDNA ND6 gene (A14495G). This mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on two independent occasions. This is the seventh mutation in the ND6 gene that causes optic neuropathy, indicating that this gene is a hot spot for LHON mutations. Protein modelling studies indicate that all of these pathogenic mutations lie within close proximity to one another in a hydrophobic cleft or pocket. This is the first evidence for a relationship between a specific disease phenotype and a specific structural domain within a mitochondrial respiratory chain subunit. These findings suggest that the mtDNA ND6 gene should be sequenced in all patients with LHON who do not harbour one of the three common LHON mutations.

Adolescent↗
PubMed2001

Mitochondrial enteropathy: the primary pathology may not be within the gastrointestinal tract.

BACKGROUND: Mitochondrial DNA (mtDNA) defects are an important cause of disease. Although gastrointestinal symptoms are common in these patients, their pathogenesis remains uncertain. AIM: To investigate the role of the mtDNA defect in the production of gastrointestinal dysfunction. PATIENT: A 20 year old woman who presented at 15 years of age with recurrent vomiting and pseudo-obstruction, who did not respond to conservative management and ultimately had subtotal gastrectomy and Roux-en-y reconstruction. She subsequently presented with status epilepticus and was found to have a mitochondrial respiratory chain disorder due to a pathogenic mtDNA point mutation (A3243G). METHODS: Resected bowel was studied using light and electron microscopy and mtDNA analysed from both mucosal and muscular layers using polymerase chain reaction generated RFLP analysis. RESULTS: Histological and electron microscopic studies revealed no morphological abnormalities in the resected stomach, and molecular genetic analysis failed to identify the genetic defect in either the mucosal or muscle layers. CONCLUSION: This study suggests that in some individuals with gastrointestinal symptoms associated with established mitochondrial DNA disease, the primary pathology of the mitochondrial enteropathy lies outside the gastrointestinal tract.

Adolescent↗
PubMed2000

Analysis of European mtDNAs for recombination.

The standard paradigm postulates that the human mitochondrial genome (mtDNA) is strictly maternally inherited and that, consequently, mtDNA lineages are clonal. As a result of mtDNA clonality, phylogenetic and population genetic analyses should therefore be free of the complexities imposed by biparental recombination. The use of mtDNA in analyses of human molecular evolution is contingent, in fact, on clonality, which is also a condition that is critical both for forensic studies and for understanding the transmission of pathogenic mtDNA mutations within families. This paradigm, however, has been challenged recently by Eyre-Walker and colleagues. Using two different tests, they have concluded that recombination has contributed to the distribution of mtDNA polymorphisms within the human population. We have assembled a database that comprises the complete sequences of 64 European and 2 African mtDNAs. When this set of sequences was analyzed using any of three measures of linkage disequilibrium, one of the tests of Eyre-Walker and colleagues, there was no evidence for mtDNA recombination. When their test for excess homoplasies was applied to our set of sequences, only a slight excess of homoplasies was observed. We discuss possible reasons that our results differ from those of Eyre-Walker and colleagues. When we take the various results together, our conclusion is that mtDNA recombination has not been sufficiently frequent during human evolution to overturn the standard paradigm.

Africa↗
PubMed2000

Measles outbreak in young adults in Victoria, 1999.

OBJECTIVES: To describe an outbreak of measles in Victoria. DESIGN: Case series with cases identified through enhanced passive surveillance and outbreak-related active surveillance. SETTING: State of Victoria, 1999. MAIN OUTCOME MEASURES: Number of cases; epidemiological links and patterns of transmission; patient demographic features and vaccination status; complications. RESULTS: 75 cases were identified (74 laboratory-confirmed; and one epidemiologically linked to a laboratory-confirmed case), with onset between 11 February and 2 May 1999. The first case was in a 21-year-old woman who had recently holidayed in Bali and worked at a large cinema complex in Melbourne. Sixteen cases occurred in people who had contact with the index case at the cinema on one evening. The outbreak spread to regional Victoria and South Australia. Median age of patients was 22 years; 64 (85%) were born between 1968 and 1981, with only one patient in the age group targeted by the primary school component of the 1998 Australian Measles Control Campaign; this child had not been vaccinated. More than a third of patients (28) were hospitalised (total, 97 inpatient days), and five were healthcare workers. CONCLUSIONS: This outbreak was caused by international importation of measles virus. It highlights the change in epidemiology of measles in Australia, from a disease of childhood to one predominantly affecting young adults. A strong two-dose childhood vaccination program, vigilant surveillance, and rapid response to outbreaks will continue to be the basis of measles control, but better protection for young adults should be considered.

Adolescent↗
PubMed2000

Improving pneumococcal vaccination coverage among older people in Victoria.

Although pneumococcal vaccine is recommended by the National Health and Medical Research Council and is cost-effective in preventing invasive pneumococcal disease, it is the only vaccine on the standard schedule that is not nationally funded through public health grants to the States. In Victoria, the Department of Human Services has provided free pneumococcal vaccine to people aged 65 years and over since 1998. Pneumococcal vaccination was given in conjunction with the annual influenza vaccination program; 28.5% of the eligible cohort (95% CI, 24.8%-32.1%) received pneumococcal vaccine in 1998, giving an estimated cumulative coverage of 42% (13.4% had received it in 1997). We expect coverage will continue to increase over time, but revaccination every five years will present a substantial financial burden; access to vaccine is critical to improving coverage. Our experience in Victoria suggests that a nationally funded program, administered similarly to the influenza vaccination program, would dramatically increase pneumococcal vaccination coverage at a national level.

Adolescent↗
PubMed2000

Mitochondrial DNA haplogroups and susceptibility to AD and dementia with Lewy bodies.

The authors analyzed the relationship between nuclear genetic risk factors (apolipoprotein E genotype) and mitochondrial DNA (mtDNA) sequence variants in pathologically proved cases of AD (n = 185), dementia with Lewy bodies (DLB; n = 84), and control subjects (n = 179). Specific European mtDNA haplogroups and the A4336G mutation were not associated with an increased risk of AD. mtDNA haplogroup H was overrepresented in the DLB patients when compared with control subjects. Additional studies are needed to clarify the significance of the association.

Aged↗
PubMed2000

Enhanced measles surveillance during an interepidemic period in Victoria.

OBJECTIVE: To describe results of the first two years of enhanced measles surveillance in Victoria. DESIGN: Case series identified through enhanced measles surveillance. PARTICIPANTS AND SETTING: All measles cases notified to the Disease Control Section, Department of Human Services, Victoria, in 1997 and 1998. MAIN OUTCOME MEASURES: Proportion of notified cases laboratory confirmed as measles, rubella, or human parvovirus infection; identification of clusters (two or more linked cases of measles); and utility of the National Health and Medical Research Council clinical case definition for suspected measles. RESULTS: Rates of laboratory testing of notified cases improved after introduction of a paediatric phlebotomy service in July 1997, from 21 of 90 notified patients (23%) in the preceding six months, to 258 of 317 notified patients (81%) between July 1997 and December 1998. Of the 317, only 19 (6%) were laboratory confirmed with measles, while a further 26 (8%) were laboratory confirmed with human parvovirus infection (18) or rubella (8). Three clusters of measles, involving 11 cases, were identified during 1998. Use of the NHMRC case definition did not greatly improve the positive predictive value for diagnosis of measles above that of notification alone (14% versus 8%). CONCLUSIONS: Circulation of measles virus in Victoria in 1997 and 1998 appeared minimal. In this interepidemic period most notified cases of measles were not measles; to identify true cases, surveillance during an interepidemic period must include laboratory testing of notified cases.

Adolescent↗
PubMed2000

An outbreak of cryptosporidiosis in an urban swimming pool: why are such outbreaks difficult to detect?

OBJECTIVE: To describe an outbreak of Cryptosporidium gastroenteritis in a swimming pool in Melbourne in early 1998 that was not detected through routine surveillance, and discuss difficulties in identifying such outbreaks. METHODS: The Water Quality Study (WQS) was a large community-based study of gastroenteritis. Following suspicion of an outbreak of cryptosporidiosis within the study group, due to pool "X", a nested case control study was performed. Each case of Cryptosporidium gastroenteritis was matched with six controls and data from weekly Health Diaries from the WQS were reviewed. The Department of Human Services also instigated active surveillance among patrons at pool "X" using a systematic sample of 50 people from the pool's swim-school enrollment list. RESULTS: There were seven cases of Cryptosporidium gastroenteritis in the case control study. Five cases and eight controls swam at pool "X" during the outbreak period. The adjusted odds of developing cryptosporidial diarrhoea if an individual swam at pool "X" was 34.5 (CI 2.3-2548). DHS identified another 11 laboratory confirmed cases associated with pool "X" as well as cases not linked to pool "X". 125 cases were identified throughout Melbourne with the suspected involvement of seven swimming pools. CONCLUSIONS: Despite a high odds ratio of developing cryptosporidiosis this outbreak was not detected by routine surveillance methods. Current outbreak detection methods lack sensitivity, specificity or timeliness. IMPLICATIONS: Improved surveillance systems are required if outbreaks of gastroenteritis are to be detected early so an intervention can be instigated to reduce the amount of subsequent illness.

Animals↗
PubMed2000

Use of major therapeutic procedures: are Hispanics treated differently than non-Hispanic Whites.

OBJECTIVES: This study examines whether Hispanics and non-Hispanic White patients, hospitalized with one of a wide range of conditions, receive major therapeutic procedures at the same rates. METHODS: The study examined hospital stays of Hispanic and non-Hispanic White adults using 1993 discharge abstract data from the Healthcare Cost and Utilization Project State Inpatient Database for California, Florida and New York, states containing half the Hispanic population in the country. Logistic regression modeling was used to identify the effect of ethnicity on the likelihood of receiving a major therapeutic procedure separately for 63 conditions, controlling for age, gender, disease severity, health insurance, income level of patient's community, and hospital characteristics. RESULTS: Hispanics are less likely than non-Hispanic Whites to receive major therapeutic procedures for 38% of the 63 conditions examined and more likely for 6% of the conditions. CONCLUSIONS: This study identified many conditions with apparent variations in treatment based on patient ethnicity. Future studies should examine reasons for disparities between ethnic groups, why these disparities occur for some conditions and not others, and appropriateness of procedures received.

Adolescent↗
PubMed1999

Evaluation of bupivacaine-induced muscle regeneration in the treatment of ptosis in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome.

PURPOSE: Ptosis is common in patients with mitochondrial disease. Whilst surgical shortening of the levator muscle can mechanically elevate the lid, this procedure does not restore normal movement and leaves patients at risk of corneal exposure due to concomitant ophthalmoparesis. Recent studies have shown that bupivacaine-induced muscle regeneration is capable of reversing the molecular genetic and biochemical defect in patients with mitochondrial myopathies. This study was undertaken to assess the potential of this approach in restoring levator muscle function in patients with mitochondrial disease and ptosis. METHODS: The levator muscle of one eye in five patients with molecularly genetically confirmed mitochondrial DNA disease and ptosis was directly injected with 3 ml of bupivacaine hydrochloride (0.75%). Levator function was compared before and 3 months after the injection. RESULTS: No objective clinical improvement in levator function was detected following bupivacaine administration. DISCUSSION: The lack of functional recovery seen in our patients is most likely to result from a failure of bupivacaine to induce sufficient regeneration necessary to improve levator muscle function. This result indicates that consideration now needs to be given to the use of alternative and more potent myotoxic agents capable of inducing a more widespread regenerative response from the endogenous muscle satellite cells which contain low or undetectable amounts of mutant mitochondrial DNA.

Adult↗
PubMed1999

An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy.

A novel heteroplasmic 7587T-->C mutation in the mitochondrial genome which changes the initiation codon of the gene encoding cytochrome c oxidase subunit II (COX II), was found in a family with mitochondrial disease. This T-->C transition is predicted to change the initiating methionine to threonine. The mutation load was present at 67% in muscle from the index case and at 91% in muscle from the patient's clinically affected son. Muscle biopsy samples revealed isolated COX deficiency and mitochondrial proliferation. Single-muscle-fiber analysis revealed that the 7587C copy was at much higher load in COX-negative fibers than in COX-positive fibers. After microphotometric enzyme analysis, the mutation was shown to cause a decrease in COX activity when the mutant load was >55%-65%. In fibroblasts from one family member, which contained >95% mutated mtDNA, there was no detectable synthesis or any steady-state level of COX II. This new mutation constitutes a new mechanism by which mtDNA mutations can cause disease-defective initiation of translation.

Adult↗
PubMed1999

Histochemical localisation of mitochondrial enzyme activity in human optic nerve and retina.

AIMS: To demonstrate the quantitative distribution of mitochondrial enzymes within the human optic nerve and retina in relation to the pathogenesis of ophthalmic disease. METHODS: Enucleations were performed at the time of multiple organ donation and the optic nerve and peripapillary retina immediately excised en bloc and frozen. Reactivities of the mitochondrial enzymes cytochrome c oxidase and succinate dehydrogenase were demonstrated in serial cryostat sections using specific histochemical assays. RESULTS: In the optic nerve the unmyelinated prelaminar and laminar regions were rich in both cytochrome c oxidase and succinate dehydrogenase. Myelination of fibres as they exited the lamina cribrosa was associated with an abrupt reduction in enzyme activity. Within the retina, high levels of enzyme activity were found localised within the retinal ganglion cells and nerve fibre layer, the outer plexiform layer, inner segments of photoreceptors, and the retinal pigment epithelium. CONCLUSIONS: Mitochondrial enzyme activity is preserved in human optic nerve and retina retrieved at the time of multiple organ donation. The distribution of enzyme activity within the eye has implications for the understanding of the pattern of ophthalmic involvement seen in mitochondrial diseases and the site of ganglion cell dysfunction in those patients with optic nerve involvement.

DNA, Mitochondrial↗
PubMed1999

Mitochondrial DNA analysis: polymorphisms and pathogenicity.

The investigation of mtDNA disease can be relatively straightforward if a person has a recognisable phenotype and if it is possible to identify a known pathogenic mtDNA mutation. The difficulties arise when no known mtDNA defect can be found, or when the clinical abnormalities are complex and not easily matched to those of the more common mitochondrial disorders. We will describe here the difficulties that can be encountered during the identification of pathogenic mtDNA mutations and the approaches that can be used to confirm, or eliminate, a likely pathogenic role, in either single gene diseases or in multifactorial disorders.

Animals↗
PubMed1998

Vaccinating children with a history of serious reactions after vaccination or of egg allergy.

OBJECTIVE: To describe the results of vaccinating children with a history of serious adverse reactions after vaccination or of egg allergy at a special clinic established for that purpose. DESIGN: Retrospective case series. PATIENTS: Children who attended the clinic between 1 August 1994 and 31 July 1996 after being referred by vaccine providers. SETTING: A clinic conducted in the Emergency Department of The Canberra Hospital, Australian Capital Territory. MAIN OUTCOME MEASURES: Reasons for referral; vaccinations given; and subsequent adverse vaccination events. RESULTS: 91 children received 155 vaccinations at the clinic, and only one serious event--a hypotonic/hyporesponsive episode (HHE) after diphtheria-tetanus-whole-cell pertussis (DTPw), oral polio and Haemophilus influenzae type b vaccination--was subsequently reported; this child recovered spontaneously. Fifty-three children referred because of a previous serious adverse vaccination event were revaccinated at the clinic with whole-cell pertussis vaccine (47), combined diphtheria and tetanus vaccine (4), tetanus toxoid (1), and typhoid vaccine (1). Three children (referred because of previous meningitis, subdural haemorrhage or parental suspicion of allergy to DTPw) received their first dose of pertussis vaccine at the clinic. The remaining 35 children had a history of egg allergy and were given measles-mumps-rubella vaccine. CONCLUSIONS: We successfully vaccinated children with histories of serious reactions to vaccination, including HHEs, convulsions, apnoea, high temperatures and persistent screaming, as well as those with egg allergy. We believe special clinics can improve vaccination coverage.

Adolescent↗