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Biomedical subjects

G K Brown

Publications and source records attributed to G K Brown.

At least 19 recordsLinked to original sources
PubMed2006

Pyruvate dehydrogenase E3 binding protein (protein X) deficiency.

Pyruvate dehydrogenase (PDH) deficiency is a major cause of neurological dysfunction and lactic acidosis in infancy and early childhood. The great majority of cases (>80%) result from mutations in the X-linked gene for the E1alpha subunit of the complex (PDHA1). Mutations in the genes for the other subunits have all been described, but only dihydrolipoamide dehydrogenase (E3) and E3 binding protein (E3BP) defects contribute significantly to the total number of patients with PDH deficiency. Although previously considered rare, with only 13 reported cases, we have found that mutations in PDX1, the gene for the E3 binding protein, are in fact relatively common. Clinical, biochemical, and genetic features of six new patients (four males, two females; age range 15mo-6y) with mutations in this gene are compared with previously reported cases. All patients with E3BP deficiency identified to date have mutations which completely prevent synthesis of the protein product. However, they are generally less severely affected than patients with PDHA1 mutations, although there is considerable overlap in clinical and neuroradiological features.

Child↗
PubMed2006

Detection of Anaplasma platys and Babesia canis vogeli and their impact on platelet numbers in free-roaming dogs associated with remote Aboriginal communities in Australia.

OBJECTIVE: To detect Anaplasma platys and Babesia canis vogeli infection, using polymerase chain reaction (PCR)-based assays, in free-roaming dogs associated with eight Aboriginal communities in remote areas of Australia and to determine the impact of infection through the assessment of platelet numbers. PROCEDURES: Blood samples from 215 dogs were screened by PCR for A platys and B canis vogeli using established genus-specific DNA primers for the 16S and 18S rRNA genes respectively. Both A platys DNA and B canis vogeli DNA were confirmed from the screening PCR either by sequencing or by the use of species-specific primers. Peripheral blood films from 92 of the 215 dogs were used to estimate platelet numbers through an indirect method. RESULTS: Of 215 dogs, 69 (32%) were positive for A platys, 22 (10%) for B canis vogeli and 24 (11%) for both. The two organisms were detected singularly and as coinfection in all communities. For the 92 dogs in which peripheral blood films were examined, the mean estimated platelet counts for the non-infected dogs was 318 x 10(9)/L, those infected with A platys alone was 256 x 10(9)/L, those with B canis vogeli alone was 276 x 10(9)/L and those infected with both parasites was 169 x 10(9)/L. In young dogs, infection produced significantly decreased mean platelet counts when compared to uninfected dogs. Thrombocytopenia (< 200 x 10(9)/L) was detected in 18 (51%) dogs infected with A platys alone, 3 (33%) dogs infected with B canis vogeli alone, 13 (72%) dogs coinfected, and 8 (27%) uninfected dogs. CONCLUSIONS: A platys and B canis vogeli infection, either singularly or together, was widespread in free roaming dogs associated with remote Aboriginal communities in the Northern Territory and north-western New South Wales. Moreover, both A platys and B canis vogeli infections were associated with a reduction in mean platelet numbers in dog populations, particularly in young dogs. The fact that 51% of dogs infected with A platys alone and 72% dogs coinfected were thrombocytopenic compared to 27% of uninfected dogs suggests that the organism alone or in combination with B canis vogeli has the potential to cause thrombocytopenia and perhaps contribute to a clinical bleeding disorder in infected dogs.

Anaplasma↗
PubMed2006

Mitochondrial cytopathies, phenotypic heterogeneity and a high incidence.

Mitochondrial respiratory chain disorders account for significant and varied presentations in paediatric practice. The true prevalence of these disorders in the paediatric population is still not well documented with predicted geographic variation. We report a retrospective analysis over a seven year period of cases presenting to a tertiary care centre and associated clinical features. The overall prevalence of mitochondrial disorders in our population is higher than expected (1/9,000 births), explained in part by multiple presentations in a consanguineous subgroup of the population (Irish travellers).

Humans↗
PubMed2005

Congenital brain malformations in mitochondrial disease.

The majority of patients with mitochondrial disease have some degree of neuropathology and this is usually degenerative in nature. However, in a subset of mitochondrial diseases there are additional specific and characteristic congenital malformations in the brain. These developmental abnormalities are not unique to mitochondrial diseases and their association with only some conditions suggests that they are not simply due to energy deprivation or accumulation of metabolites such as lactic acid. Pathogenic mechanisms are at present unknown, but interference with neurotransmitter homeostasis, in addition to altered energy metabolism, may be important. The postnatal evolution of the neuropathology in these conditions and the type and pattern of the malformations suggest secondary degeneration of specific brain structures during fetal life rather than primary interference with developmental pathways.

Brain↗
PubMed2004

Pyruvate dehydrogenase deficiency presenting as dystonia in childhood.

Two individuals with pyruvate dehydrogenase (PDH) deficiency due to missense mutations in the gene for the E1alpha subunit (PDHA1) presented during childhood with dystonia. The first patient, a male, presented at age 4 years with dystonia affecting the lower limbs, which responded to treatment with combined carbidopa and levodopa. The second patient, a female, was first investigated at age 6 years because of a dystonic gait disorder. In both patients, the main clue to the biochemical diagnosis was a raised concentration of lactate in the cerebrospinal fluid. PDH activity was significantly reduced in cultured fibroblasts in both cases. Dystonia is a previously unrecognized major manifestation of PDH deficiency and is of particular interest as the mutations in the PDHA1 gene in these patients have both been identified previously in individuals with typical presentations of the condition.

Child↗
PubMed2004

Marked increases in psychopathology found in a 30-year cohort comparison of suicide attempters.

BACKGROUND: Although several epidemiological studies have found increases in the percentages of people who have made a suicide attempt, few cohort comparisons have been conducted to determine changes within this population over time. The purpose of this investigation was to determine if there have been changes in the clinical profile of suicide attempters in recent decades. METHOD: Comparisons between a sample of 258 suicide attempters evaluated between 1970 and 1973 and a second sample of 179 suicide attempters evaluated between 1999 and 2002 were made on depression, hopelessness, suicide intent, drug use, history of suicide attempts and subsequent suicide attempts. RESULTS: Present-day suicide attempters were found to exhibit greater levels of depression (p = 0.031), hopelessness (p = 0.008), suicide intent (p < 0.001), and had much higher rates of illicit drug use (p < 0.001). Almost twice as many of the present-day suicide attempters had histories of four or more suicide attempts (p < 0.001), and the present-day suicide attempters made subsequent suicide attempts at close to four times the rate in the year following the index attempt (p < 0.001). CONCLUSIONS: The present-day suicide attempters exhibited greater levels of psychopathology on every major variable assessed. Replication is necessary and public health implications are discussed.

Adolescent↗
PubMed2004

Diagnostic difficulties with common SURF1 mutations in patients with cytochrome oxidase-deficient Leigh syndrome.

In three unrelated patients with systemic cytochrome oxidase deficiency resulting from mutations in the SURF1 gene, the same mutation in the splice donor site of intron 3 was identified. All three patients were compound heterozygotes, two for the common insertion/deletion mutation in exon 4. In all three cases, complete definition of the causative mutations was only resolved by combined analysis of cDNA and genomic DNA. Several factors were identified that contributed to the diagnostic difficulties: preferential amplification of deleted cDNA, significant formation of heteroduplexes in cDNA PCR amplification and unequal representation of heterozygous peaks in genomic DNA sequences. These patients emphasize the need to perform mutation analysis on both cDNA and genomic DNA wherever possible.

Alternative Splicing↗
PubMed2004

Lactic acidosis and developmental delay due to deficiency of E3 binding protein (protein X) of the pyruvate dehydrogenase complex.

Pyruvate dehydrogenase deficiency is an important cause of primary lactic acidosis. Most cases occur as a result of mutations in the gene for the E1 alpha subunit of the complex, with a small number resulting from mutations in genes for other components, most commonly the E3 and E3-binding protein subunits. We describe pyruvate dehydrogenase E3-binding protein deficiency in two siblings in each of two unrelated families from Kuwait. The index patient in each family had reduced pyruvate dehydrogenase activity in cultured fibroblasts and no detectable immunoreactive E3-binding protein. Both were homozygous for nonsense mutations in the E3-binding protein gene, one involving the codon for glutamine 266, the other the codon for tryptophan 5.

Acidosis, Lactic↗
PubMed2003

A pathogenic glutamate-to-aspartate substitution (D296E) in the pyruvate dehydrogenase E1 subunit gene PDHA1.

In a patient with fatal neonatal lactic acidosis due to pyruvate dehydrogenase deficiency, the only potential mutation detected was c.888C>G in PDHA1, the gene for the E1alpha subunit of the complex. This would result in a substitution of glutamate for aspartate (D296E). Pathogenicity of this minor alteration in amino acid sequence was demonstrated by expression studies. By comparing the mutant sequence with the known structures of the E1 components of pyruvate dehydrogenase and the closely related branched chain alpha-ketoacid dehydrogenase, an explanation for the profound consequences of the mutation can be proposed.

Amino Acid Substitution↗
PubMed2001

Synthesis of mitochondrial DNA in permeabilised human cultured cells.

The mechanisms that underlie the maintenance of and increase in mutant mitochondrial DNA (mtDNA) are central to our understanding of mitochondrial disease. We have therefore developed a technique based on saponin permeabilisation that allows the study of mtDNA synthesis in intact cells. Permeabilisation of cells has been extensively used in an established method both for studying transcription and DNA replication in the nucleus and for measuring respiratory chain activities in mitochondria. We have quantitatively studied incorporation of radiolabelled DNA precursors into mtDNA in human cell lines derived from controls and from patients with mitochondrial DNA disease. Total cell DNA is extracted, restriction digested and Southern blotted, newly synthesised mtDNA being proportional to the label incorporated in each restriction band. A rate of synthesis can then be derived by estimating the relative steady-state mtDNA after probing with full-length mtDNA. Where co-existing mutant and wild-type mtDNA (heteroplasmy) can be distinguished using restriction digestion, their rates of synthesis can be compared within a single cell line. This will be particularly useful in elucidating the pathophysiology of mtDNA diseases in which the distribution of mutant and wild-type mtDNA in cell lines in patient tissues may evolve with time.

Cell Culture Techniques↗
PubMed2001

A SURF1 gene mutation presenting as isolated leukodystrophy.

Mitochondrial respiratory chain defects are increasingly recognized in patients with leukodystrophy. We report the first case of leukodystrophy with systemic cytochrome oxidase deficiency caused by a loss of function mutation in the SURF1 gene in a 2-year-old girl presenting with failure to thrive, global neurodevelopmental regression, and lactic acidosis. Although all previously reported mutations in the SURF1 gene have been found in patients with cytochrome oxidase (COX)-deficient Leigh syndrome, the phenotype associated with SURF1 protein deficiency should be extended to include leukodystrophy.

Acidosis, Lactic↗
PubMed2001

High-risk management guidelines for elderly suicidal patients in primary care settings.

Older adults, especially older white men, are more likely to commit suicide than other age-groups. The assessment and management of suicide ideation and behavior for the elderly is especially relevant for primary care physicians because many patients visit their physician shortly before committing suicide. In 1993, the Agency for Health Care Policy and Research (AHCPR) released clinical practice guidelines for the treatment of depression in primary care settings. The AHCPR guidelines offered some assistance with respect to detecting and treating patients who are suicidal. However, these guidelines lacked detailed and specific instructions for managing high-risk patients within the context of intervention research. The current set of guidelines builds upon this previous work by describing (1) a general approach for interacting with suicidal patients; (2) structured assessments for determining the degree of risk for suicide; (3) crisis intervention strategies; and (4) ongoing management procedures for working with suicidal patients in primary care settings.

Aged↗
PubMed2001

The National Institutes of Health Clinical Center Digital Imaging Network, Picture Archival and Communication System, and Radiology Information System.

In this work, we describe the digital imaging network (DIN), picture archival and communication system (PACS), and radiology information system (RIS) currently being implemented at the Clinical Center, National Institutes of Health (NIH). These systems are presently in clinical operation. The DIN is a redundant meshed network designed to address gigabit density and expected high bandwidth requirements for image transfer and server aggregation. The PACS projected workload is 5.0 TB of new imaging data per year. Its architecture consists of a central, high-throughput Digital Imaging and Communications in Medicine (DICOM) data repository and distributed redundant array of inexpensive disks (RAID) servers employing fiber-channel technology for immediate delivery of imaging data. On demand distribution of images and reports to clinicians and researchers is accomplished via a clustered web server. The RIS follows a client-server model and provides tools to order exams, schedule resources, retrieve and review results, and generate management reports. The RIS-hospital information system (HIS) interfaces include admissions, discharges, and transfers (ATDs)/demographics, orders, appointment notifications, doctors update, and results.

Hospital Information Systems↗
PubMed2001

Psychometric properties of the Beck Self-Esteem Scales.

The psychometric characteristics of the Beck Self-Esteem Scales (BSE) are described for 360 psychiatric outpatients. Patients rated their evaluative beliefs about themselves (Self Scale) and their beliefs about how others evaluate them (Other Scale). Both measures consist of 18 pairs of adjectives, e.g., lovable-unlovable, that are rated using a 10-point scale. The coefficient alphas for the Self Scale (0.94) and the Other Scale (0.95) indicated high internal consistency. Both scales were positively associated with other measures of self-esteem and negatively associated with measures of anxiety and depression. As predicted by the cognitive theory of depression, patients with a principal mood disorder scored significantly lower on the BSE than patients with a principal anxiety disorder. In addition, the mean scores for patients with major depression and dysthymia on the Self Scale were significantly lower than the mean scores for the Other Scale.

Adult↗
PubMed2001

Dysfunctional beliefs discriminate personality disorders.

This study examines whether specific sets of dysfunctional beliefs are differentially associated with five personality disorders (PDs) as predicted by cognitive theory. Seven hundred fifty-six psychiatric outpatients completed the Personality Belief Questionnaire (PBQ) at intake and were assessed for PDs using a standardized clinical interview conducted by assessors who were blind to patients' PBQ responses. Findings showed that patients with avoidant, dependent, obsessive-compulsive, narcissistic, and paranoid PDs preferentially endorsed PBQ beliefs theoretically linked to their specific disorders. The study results support the cognitive theory of personality disorders. Suggestions are made regarding the clinical utility of the PBQ with personality-disordered patients and future research on the PBQ.

Adolescent↗
PubMed2001

Sequence variations in the NDUFA1 gene encoding a subunit of complex I of the respiratory chain.

NDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondrial complex I involved in the respiratory chain. The human NDUFA1 has been cloned, completely sequenced and mapped to Xq24. In the present study, we searched for sequence variations in NDUFA1 as causative defects in complex I deficiency using genomic DNA of 152 patients with various clinical phenotypes. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Germany and 98 patients (72 male and 26 female) with biochemically proven complex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter region of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 patients tested, no mutation was found that could be related to any of the disease phenotypes included. However, three single-nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt -71 and SNP T/C at nt -189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I-deficient patients. There was no significant difference between the control population, the LHON patients, or the severely affected patients with complex I deficiency, excluding an association of the polymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and complex phenotypes with complex I deficiency.

Alleles↗
PubMed2001

Response to cognitive therapy in depression: the role of maladaptive beliefs and personality disorders.

This study examined whether personality disorder status and beliefs that characterize personality disorders affect response to cognitive therapy. In a naturalistic study, 162 depressed outpatients with and without a personality disorder were followed over the course of cognitive therapy. As would be hypothesized by cognitive theory (A. T. Beck & A. Freeman, 1990), it was not personality disorder status but rather maladaptive avoidant and paranoid beliefs that predicted variance in outcome. However, pre- to posttherapy comparisons suggested that although patients with or without comorbidity respond comparably to "real-world" cognitive therapy, they report more severe depressive symptomatology at intake and more residual symptoms at termination.

Adolescent↗