Biomedical subjects

R M Brown

Publications and source records attributed to R M Brown.

At least 19 recordsLinked to original sources

PubMed2006

Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials.

OBJECTIVE: To assess the use of n-of-1 trials for short-term choice of drugs for osteoarthritis, with particular reference to comparing the efficacy of sustained-release [SR] paracetamol with celecoxib in individual patients. METHODS: Evaluation of community-based patients undergoing n-of-1 trials which consisted of double-blind, crossover comparisons of celecoxib 200 or 400 mg/day with sustained-release paracetamol 1330 mg three times a day in three pairs of 2 week treatment periods per drug with random order of the drugs within pairs. Outcomes evaluated were pain and stiffness in sites nominated by the patient, functional limitation scores, preferred medication, side effects and changes in drug use after an n-of-1 trial. Participants were 59 patients with osteoarthritis in multiple sites (hip 6, knee 24, hand 6, shoulder/neck 8, back 14, foot 5), with pain for >or=1 month severe enough to warrant consideration of long-term use of celecoxib but for whom there was doubt about its efficacy. Forty-one n-of-1 trials were completed. RESULTS: Although on average, celecoxib showed better scores than SR paracetamol [0.2 (0.1) for pain, 0.3 (0.1) for stiffness and 0.3 (0.1) for functional limitation], 33 of the 41 individual patients (80%) failed to identify the differences between SR paracetamol and celecoxib in terms of overall symptom relief. Of the eight patients who were able to identify the differences, seven had better relief with celecoxib and one with SR paracetamol. In 25 out of 41 [61%] patients, subsequent management was consistent with their trial results. CONCLUSIONS: N-of-1 trials may provide a rational and effective method to best choose drugs for individuals with osteoarthritis. SR paracetamol is more useful than celecoxib for most patients of whom management is uncertain.

Acetaminophen↗

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↗

PubMed2005

Mice lacking the alpha4 nicotinic receptor subunit fail to modulate dopaminergic neuronal arbors and possess impaired dopamine transporter function.

Neuronal nicotinic acetylcholine receptors (nAChRs) at presynaptic sites can modulate dopaminergic synaptic transmission by regulating dopamine (DA) release and uptake. Dopaminergic transmission in nigrostriatal and mesolimbic pathways is vital for the coordination of movement and is associated with learning and behavioral reinforcement. We reported recently that the D2 DA receptor plays a central role in regulating the arbor size of substantia nigra dopaminergic neurons. Given the known effects of nAChRs on dopaminergic neurotransmission, we assessed the ability of the alpha4 nAChR subunit to regulate arbor size of dopaminergic neurons by comparing responses of wild-type and alpha4 nAChR subunit knockout [alpha4(-/-)] mice to long-term exposure to cocaine, amphetamine, nicotine, and haloperidol, and after substantia nigra neurotoxic lesioning. We found that dopaminergic neurons in adult drug-naive alpha4(-/-) mice had significantly larger terminal arbors, and despite normal short-term behavioral responses to drugs acting on pre- and postsynaptic D2 DA receptors, they were unable to modulate their terminal arbor in response to pharmacological manipulation or after lesioning. In addition, although synaptosome DA uptake studies showed that the interaction of the D2 DA receptor and the dopamine transporter (DAT) was preserved in alpha4(-/-) mice, DAT function was found to be impaired. These findings suggest that the alpha4 subunit of the nAChR is an independent regulator of terminal arbor size of nigrostriatal dopaminergic neurons and that reduced functionality of presynaptic DAT may contribute to this effect by impairing DA uptake.

Animals↗

PubMed2005

Congenital nodular multiple glomangioma: a case report.

A 13 year old girl presented with recurrent painful "varicosities" on her right calf. These lesions were subsequently clinically diagnosed as "cavernous haemangiomas" after normal duplex scanning and were excised. Histological examination revealed multiple glomangiomas (glomus tumours). A literature review revealed only two reported cases of nodular multiple glomangioma, so that this is the third case to be reported in the literature.

Adolescent↗

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

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↗

PubMed2004

Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature.

BACKGROUND: Wolcott-Rallison syndrome is a rare autosomal recessive condition characterized by early infancy onset diabetes mellitus and multiple epiphyseal dysplasia. So far, 17 children have been described in the world literature. Recently, mutations in the gene encoding EIF2AK3 have been shown to segregate with the syndrome in three affected families. AIMS: We aimed to describe the clinical characterization and mutation analysis of a further child, and full clinical and follow-up details on our first family including the longest surviving child. METHODS: Retrospective case notes review of three children presenting to the diabetic unit at our institution; mutation analysis of the EIF2AK3 gene in our most recent patient; and review of the literature on Wolcott-Rallison syndrome. RESULTS: Previously unreported phenotypic features in our patients included developmental regression after episodes of hepatic failure, and pachygyria on brain imaging. We have identified a novel 4-base pair deletion (nt 3021-3024 del GAGA) in exon 13, which results in a frameshift and premature stop codon (R908 F/S +22X), causing premature truncation of the protein and abolition of the carboxy-segment of the catalytic domain. CONCLUSIONS: Wolcott-Rallison syndrome causes early-onset diabetes and acute hepatic failure, before epiphyseal dysplasia is manifest. We have identified a novel mutation in EIF2AK3, and prenatal diagnosis may now be offered to affected families.

Adolescent↗

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↗

PubMed2002

A primary tumour of the oesophagus with both melanocytic and schwannian differentiation. Melanocytic schwannoma or malignant melanoma?

A 76 year old white woman presented with a four month history of dysphagia and weight loss. Clinical, radiological, and endoscopic examination revealed a pigmented mass in the lower third of the oesophagus. The preoperative diagnosis, including biopsy examination, was that of malignant melanoma. Following oesophageal resection, the mass was found to be a localised, relatively superficial tumour with light, electron microscopic, and immunohistochemical features common to both Schwann cells and melanocytes. The patient survived 46 months after surgery and died of a stroke, with no evidence of tumour recurrence. The tumour is presented as a case of melanocytic schwannoma, with unique features when compared with oesophageal melanotic schwannomas and malignant melanomas described in the literature. The differential diagnosis is discussed and an origin from a common precursor cell of neural crest origin is postulated.

Aged↗

PubMed2001

Correlation of immunohistochemical molecular staging of bladder biopsies and radical cystectomy specimens.

PURPOSE: To determine the relationship of p53, retinoblastoma (RB), and p16 expression between precystectomy transurethral resection bladder (TURB) biopsy and matched cystectomy specimens; and to determine the value of p53 immunoreactivity for predicting progression and survival in patients undergoing radical cystectomy. METHODS AND MATERIALS: We performed p53 immunohistochemical staining on matched archival TURB and cystectomy specimens taken from 40 patients. Twenty-seven and 26 of these patients were also evaluated for RB and p16 expression, respectively. RESULTS: Twenty-eight (70%) of the TURB and 22 (55%) of the cystectomy specimens stained positive for p53. RB and p16 protein expression were altered in 19 (70%) and 19 (73%) of the TURB specimens, respectively, and 19 (70%) and 19 (73%) of the cystectomy specimens, respectively. There was a strong correlation between p53, RB, and p16 expression and TURB and cystectomy specimens (all p < 0.001). In preoperative and postoperative multivariate analyses, biopsy p53 and cystectomy p53 were independently associated with disease progression (p = 0.049 and p = 0.034, respectively) and bladder cancer-related death (p = 0.044 and p = 0.037, respectively). CONCLUSION: p53, RB, and p16 expression patterns on TURB specimens correlate with cystectomy specimens. p53 immunoreactivity is an independent predictor of disease progression and bladder cancer survival. These data support the potential of prognostic staging using immunohistochemical analysis on bladder biopsy specimens prior to neoadjuvant or definitive therapy.

Adult↗

PubMed2001

The synthesis of megatubes: new dimensions in carbon materials.

Extremely large carbon tubes, some exceeding 5 microm in diameter, were produced with both laser and electric arc techniques using graphite, a transition metal catalyst, and a reactive third-body gas. We have named these structures carbon megatubes. They are the first carbonaceous tubes large enough to observe using optical microscopy. We also report the synthesis of what we believe to be the first self-assembled branched nanotubes. In addition to their extreme diameters and unique morphologies, X-ray photoelectron spectroscopy has shown that these tubes also contain a significant amount of nitrogen atom incorporation into the graphite lattice. Subsequently, these nitrogen functionalities were shown to interact with rhenium pentacarbonyl bromide and serve as anchor points to tether molecules to the surface of the tubules.

Journal Article↗

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

A putative plant homolog of the yeast beta-1,3-glucan synthase subunit FKS1 from cotton (Gossypium hirsutum L.) fibers.

A novel plant gene CFL1 was cloned from cotton (Gossypium hirsutum L.) fibers by expressed sequence tag (EST) database searching and 5'-RACE (rapid amplification of cDNA ends). This gene shows sequence homology with FKS1 which has been identified as the putative catalytic subunit of the yeast beta-1,3-glucan synthase. It encodes a protein (CFL1p) of 219 kDa with 13 deduced transmembrane helices and 2 large hydrophilic domains, one of which is at the N-terminus and the other in the internal region of the polypeptide. CFL1 displays 21% identity and 41% similarity to FKS1 at the amino acid level over its entire length, with 31% identity and 52% similarity for the hydrophilic central domain. Using RNA and protein blot analysis, CFL1 was found to be expressed at higher levels in cotton fibers during primary wall development. CFL1 also had a strong expression in young roots. Using a calmodulin (CaM)-gel overlay assay, the hydrophilic N-terminal domain of CFL1p was shown to bind to CaM, while the hydrophilic central domain did not. A putative CaM-binding domain, 16 amino acids long, was predicted in the hydrophilic N-terminal domain. Moreover, a product-entrapment assay demonstrated that a protein associated with an in vitro-synthesized callose pellet could be labeled by anti-CFL1 antibodies. Our finding suggests that CFL1 is a putative plant homolog of the yeast beta-1,3-glucan synthase subunit FKS1 and could be involved in callose synthesis.

Calmodulin-Binding Proteins↗

PubMed2001

5 a day fruit and vegetable intervention improves consumption in a low income population.

OBJECTIVE: This study evaluated the Michigan Farmers' Market Nutrition Program in one Michigan county to determine its effect on fruit and vegetable consumption behavior. SUBJECTS/SETTING: Subjects were selected from WIC and Community Action Agency populations: 564 low income women completed the pretest; 455 completed the posttest. Attrition rate was 19.3%. INTERVENTION: Subjects were assigned to one of 4 interventions: education about the use, storage and nutritional value of fruits and vegetables, distribution of farmers' market coupons, both education and coupons, or no intervention. DESIGN: Education-only and coupon and education groups were randomly assigned; clinic appointment timing determined assignment to no-intervention and coupon-only groups. MAIN OUTCOME MEASURES: A self-administered questionnaire before and after intervention measured attitudes about fruit and vegetable consumption and intake of fruits and vegetables. WIC records documented redemption of coupons. STATISTICAL ANALYSES: Data analysis included 2-way multivariate analysis of covariance, univariate analysis of covariance, logistic regression, and covariance structure modeling. RESULTS: Both the education interventions and the coupon interventions had positive effects. Coupons had a direct effect on increasing fruit and vegetable consumption behavior but no effect on attitudes. Education had a direct effect on attitudes and seemed to exert an effect on consumption behavior through attitudes. The maximum impact of the intervention was achieved through a combination of education and coupons. APPLICATIONS: This study demonstrated that a low-income population may be more likely to increase its fruit and vegetable consumption behavior when incentives such as coupons improve affordability.

Analysis of Variance↗

PubMed2001

Structure--function characterization of cellulose synthase: relationship to other glycosyltransferases.

A combined structural and functional model of the catalytic region of cellulose synthase is presented as a prototype for the action of processive beta-glycosyltransferases and other glycosyltransferases. A 285 amino acid segment of the Acetobacter xylinum cellulose synthase containing all the conserved residues in the globular region was subjected to protein modeling using the genetic algorithm. This region folds into a single large domain with a topology exhibiting a mixed alpha/beta structure. The predicted structure serves as a topological outline for the structure of this processive beta-glycosyltransferase. By incorporating new site-directed mutagenesis data and comparative analysis of the conserved aspartic acid residues and the QXXRW motif we deduce a number of functional implications based on the structure. This includes location of the UDP--glucose substrate-binding cavity, suggestions for the catalytic processing including positions of conserved and catalytic residues, secondary structure arrangement and domain organization. Comparisons to cellulose synthases from higher plants (genetic algorithm based model for cotton CelA1), data from neural network predictions (PHD), and to the recently experimentally determined structures of the non-processive SpsA and beta 4-galactosyltransferase retest and further validate our structure-function description of this glycosyltransferase.

Amino Acid Sequence↗

PubMed2001

E-cadherin expression predicts clinical outcome in carcinoma in situ of the urinary bladder.

OBJECTIVES: The clinical course of carcinoma in situ (CIS) of the bladder is highly variable. Our objective in this study was to describe E-cadherin expression patterns in CIS with and without papillary disease and to determine whether altered E-cadherin expression is associated with disease progression and survival in patients with CIS of the bladder. METHODS: Tumor specimens from 53 patients who had CIS in the absence of muscle-invasive carcinoma on bladder biopsy were identified. Formalin-fixed paraffin sections were processed using a hot citric acid antigen retrieval method, followed by immunostaining with anti-E-cadherin monoclonal antibody. Expression patterns were evaluated in a blinded fashion and scored as normal and abnormal, which included absent and various degrees of heterogeneous immunostaining. Outcomes analyzed were recurrence, progression, and survival. RESULTS: Loss of normal membrane E-cadherin immunoreactivity was found in 17 patients (32%). At a median follow-up of 131 months, abnormal E-cadherin expression was significantly associated with disease recurrence (P = 0.0087), disease progression (P = 0.0003), and bladder cancer-specific survival (P = 0.0285). In multivariate analyses, E-cadherin expression was independently associated with disease recurrence (P = 0.019, 95% confidence interval [CI] 1.342 to 5.940), disease progression (P = 0.002, 95% CI 2.049 to 17.989), and bladder cancer-specific survival (P = 0.025, 95% CI 1.179 to 10.432). CONCLUSIONS: Loss of E-cadherin expression in patients CIS with and without papillary disease of the bladder predicts disease recurrence, disease progression, and bladder cancer-specific death. CIS with and without papillary disease associated with abnormal E-cadherin expression may represent a biologically more aggressive cancer, requiring early definitive therapy. This hypothesis should be evaluated in larger studies and prospective clinical trials.

Adult↗

PubMed2001

"Nematic ordered cellulose": a concept of glucan chain association.

Native cellulose consists of a set of parallel chains composed of glucose. Most of the time, these chains are highly ordered and form a structure that is known as a microfibril. On the other hand, highly crystalline forms of cellulose are more difficult to process and often are unpredictable in their behavior. If an ordered but noncrystalline form of cellulose could be produced, this would greatly extend the possibilities of usage of cellulose to new areas. In this paper, we have produced such a new supermolecular structure of cellulose, called nematic ordered cellulose. The unique characteristics of this supermolecular structure of cellulose have been clarified using various kinds of physicochemical analyses. Using a high-resolution transmission electron microscopic approach, we have also imaged the single glucan chains, demonstrating the close but nonprecise association usually found in crystalline biopolymers.

Carbohydrate Conformation↗