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Biomedical subjects

M G Pike

Publications and source records attributed to M G Pike.

At least 19 recordsLinked to original sources
PubMed2003

A cohort study of neurodevelopmental outcome in children with DiGeorge syndrome following cardiac surgery.

AIMS: To examine whether the learning difficulties seen in a proportion of children with DGS are secondary to cardiac pathology and treatment, or a feature of the DGS phenotype. METHODS: Cohort study of all patients with DGS and coexisting cardiac lesions within a region. Ten children with 22q11 deletion were assigned two controls each, matched for age, sex, cardiac lesion, and preoperative hemodynamic status but without DGS. The neurodevelopmental status was evaluated with the Ruth Griffiths test for babies and young children. RESULTS: Children with the 22q11 deletion showed a wide range of developmental quotient (DQ; mean 71, 95% CI 47 to 95) and subscale scores, but these as a group were significantly lower than those of the control group (DQ 113, 95% CI 108 to 118). Four of the DGS children had DQs below 60. Hypocalcaemia, prolonged postoperative ventilation, and abnormal neurology perioperatively were associated with a low DQ. CONCLUSIONS: A proportion of children with DGS have a very poor developmental outcome following cardiac surgery. This outcome is not attributable to the cardiac condition and its treatment alone, but represents either a pre-existing component of the syndrome or an interaction between the syndrome and its treatment.

Case-Control Studies↗
PubMed2002

Benign intracranial hypertension associated with arteriovenous malformation.

This is a report of a 9-year-old female with a clinical presentation of benign intracranial hypertension (BIH) who was found to have an unruptured pial arteriovenous malformation (AVM) with a significant fistula. The AVM was completely embolized using a recently developed liquid embolic system, Onyx, after which gradual clinical improvement followed. A few cases of BIH associated with AVM have been described in adults and adolescents. Possible causal relation is discussed.

Brain↗
PubMed2002

Fracture prevalence in Duchenne muscular dystrophy.

The objective of this study was to determine the prevalence, circumstances, and outcome of fractures in males with Duchenne muscular dystrophy (DMD) attending neuromuscular clinics. Three hundred and seventy-eight males (median age 12 years, range 1 to 25 years) attending four neuromuscular centres were studied by case-note review supplemented by GP letter or by interview at the time of clinic attendance. Seventy-nine (20.9%) of these patients had experienced fractures. Forty-one percent of fractures were in patients aged 8 to 11 years and 48% in independently ambulant patients. Falling was the most common mechanism of fracture. Upper-limb fractures were most common in males using knee-ankle-foot orthoses (65%) while lower-limb fractures predominated in independently mobile and wheelchair dependent males (54% and 68% respectively). Twenty percent of ambulant males and 27% of those using orthoses lost mobility permanently as a result of the fracture. In a substantial proportion of males, the occurrence of a fracture had a significant impact on subsequent mobility.

Activities of Daily Living↗
PubMed2001

Improved methods for determining the concentration of 6-thioguanine nucleotides and 6-methylmercaptopurine nucleotides in blood.

The conversion of the cytotoxic and immunosuppressive 6-mercaptopurine (6MP) to the active 6-thioguanine nucleotides (6TGN) is necessary for clinical efficacy of 6MP and its prodrug azathioprine. Another metabolite, 6-methylmercaptopurine nucleotide (6MMPN), is formed via a competing pathway by thiopurine methyl transferase. The concentrations of 6TGN and 6MMPN are measured in washed erythrocytes as a surrogate to the intracellular levels of these metabolites in the target tissues. Analysis of 6TGN and 6MMPN in multi-center clinical studies is more complicated because of the requirement to wash erythrocytes. In this investigation, we found no differences in the concentrations of 6TGN and 6MMPN in blood versus washed erythrocytes in samples obtained from patients taking therapeutic doses of oral 6MP or azathioprine for inflammatory bowel disease. We concluded that whole blood could be used for the analysis of these analytes, thus saving sample preparation time. We also found that the erythrocyte 6TGN concentration in blood at ambient temperature declined 2-4% per day, a loss that can be avoided by shipping blood samples frozen. The loss of 6TGN in blood stored at approximately -80 degrees C was 1% after 1 week and 12% after 24 weeks, indicating the analyte was moderately stable. 6MMPN in blood did not significantly change after 24 weeks of storage at approximately -80 degrees C. In addition, the sensitivity of the 6TGN assay was improved by modifying the HPLC conditions, which made the method more suitable for quantifying low levels of 6TGN in human intestinal biopsy samples and blood.

Chromatography, High Pressure Liquid↗
PubMed2001

Mycoplasma pneumoniae infection, meningoencephalitis, and hemophagocytosis.

Central nervous system manifestations are a common extrapulmonary complication of Mycoplasma pneumoniae infection, of which encephalitis is a well-recognized abnormality in children. In this report the first description of M. pneumoniae infection simultaneously complicated by meningoencephalitis and hemophagocytosis is presented.

Brain↗
PubMed2001

Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.

BACKGROUND: Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine. METHODS: We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count. RESULTS: Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r(s) = -0.09, p = 0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8 x 10(8) red blood cells; p = 0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts. CONCLUSIONS: In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted.

Adolescent↗
PubMed2001

Metabolism of a disulfiram metabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes.

S-Methyl N,N-diethyldithiocarbamate (MeDDC), a metabolite of the alcohol deterrent disulfiram, is converted to MeDDC sulfine and then S-methyl N,N-diethylthiocarbamate sulfoxide, the proposed active metabolite in vivo. Several isoforms of CYP450 and to a lesser extent flavin monooxygenase (FMO) metabolize MeDDC in the liver. The human kidney contains FMO1 and several isoforms of CYP450, including members of the CYP3A, CYP4A, CYP2B, and CYP4F subfamilies. In this study the metabolism of MeDDC by the human kidney was examined, and the enzymes responsible for this metabolism were determined. MeDDC was incubated with human renal microsomes from five donors or with insect microsomes containing human FMO1, CYP4A11, CYP3A4, CYP3A5, or CYP2B6. MeDDC sulfine was formed at 5 microM MeDDC by renal microsomes at a rate of 210 +/- 50 pmol/min/mg of microsomal protein (mean +/- S.D., n = 5) and by FMO1 at 7.6 +/- 0.2 nmol/min/nmol (n = 3). Oxidation of 5 microM MeDDC was negligible by all CYP450 tested (< or =0.03 nmol/min/nmol). Inhibition of FMO by methimazole or heat diminished MeDDC sulfine formation 75 to 89% in renal microsomes. Inhibition of CYP450 in renal microsomes by N-benzylimidazole or antibody to the CYP450 NADPH reductase had no effect on MeDDC sulfine production. Benzydamine N-oxidation, a probe for FMO activity, correlated with MeDDC sulfine formation in renal microsomes (r = 0.951, p = 0.013). The K(M) values for MeDDC sulfine formation by renal microsomes and recombinant human FMO1 were 11 and 15 microM, respectively. These results demonstrate a role for the kidney and FMO1 in the metabolism of MeDDC in humans.

Chromatography, High Pressure Liquid↗
PubMed2000

Intravenous azathioprine in severe ulcerative colitis: a pilot study.

OBJECTIVE: Azathioprine use in acute ulcerative colitis has been limited by its perceived long onset of action. The aim of this study was to determine the safety and clinical effect of an i.v. loading dose of azathioprine in the setting of severe steroid refractory ulcerative colitis. METHODS: Nine hospitalized patients with severe steroid refractory ulcerative colitis were enrolled. Patients 1-3 received 20 mg/kg i.v. azathioprine over 36 h. Patients 4-6 received 40 mg/kg i.v. azathioprine over 36 h. Patients 7-9 received 40 mg/kg i.v. azathioprine as three 8-h infusions over 3 days. Clinical remission was defined as steroid withdrawal and an Ulcerative Colitis Disease Activity Index score of 0. The Inflammatory Bowel Disease Questionnaire was obtained at each visit. White blood cell concentrations and erythrocyte concentrations of 6-thioguanine were obtained. RESULTS: Five of nine patients (56%) had a response and avoided colectomy. Three of nine patients (33%) met the definition for clinical remission. Response was seen within 4 wk. The mean 6-thioguanine concentration for those five patients at 12 wk after infusion was 148.2 pmol/8 x 10(8). Two patients had transient leukopenia and one had transient hepatotoxicity. CONCLUSIONS: Intravenous azathioprine appears to be safe and of clinical benefit in inducing response and avoiding colectomy in severe steroid refractory ulcerative colitis. Data from an i.v. azathioprine trial in Crohn's disease suggests oral dosing alone may obtain the same results. The role of oral dosing alone in severe ulcerative colitis and the role of azathioprine metabolite levels in monitoring efficacy should be investigated further.

Adult↗
PubMed1999

Inhibition of interleukin-1-stimulated NF-kappaB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity.

Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that regulates genes important in immunity and inflammation. The activity of NF-kappaB is highly regulated: transcriptionally active NF-kappaB proteins are sequestered in the cytoplasm by inhibitory proteins, IkappaB. A variety of extracellular signals, including interleukin-1 (IL-1), activate NF-kappaB by inducing phosphorylation and degradation of IkappaB, allowing nuclear translocation and DNA binding of NF-kappaB. Many of the stimuli that activate NF-kappaB by inducing IkappaB degradation also cause phosphorylation of the NF-kappaB RelA (p65) polypeptide. The transactivating capacity of RelA is positively regulated by phosphorylation, suggesting that in addition to cytosolic sequestration by IkappaB, phosphorylation represents another mechanism for control of NF-kappaB activity. In this report, we demonstrate that mesalamine, an anti-inflammatory aminosalicylate, dose-dependently inhibits IL-1-stimulated NF-kappaB-dependent transcription without preventing IkappaB degradation or nuclear translocation and DNA binding of the transcriptionally active NF-kappaB proteins, RelA, c-Rel, or RelB. Mesalamine was found to inhibit IL-1-stimulated RelA phosphorylation. These data suggest that pharmacologic modulation of the phosphorylation status of RelA regulates the transcriptional activity of NF-kappaB, independent of nuclear translocation and DNA binding. These findings highlight the importance of inducible phosphorylation of RelA in the control of NF-kappaB activity.

Base Sequence↗
PubMed1999

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Administration, Oral↗
PubMed1999

A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: The optimum initial dose of methotrexate for steroid-requiring inflammatory bowel disease is not known. AIM: To compare directly the efficacy and toxicity of methotrexate 15 and 25 mg/week, and to explore the value of methotrexate blood levels as predictors of outcome. METHODS: A 16-week randomized single-blind comparison of subcutaneous methotrexate 15 or 25 mg/week was performed in 32 patients with steroid-requiring Crohn's disease or ulcerative colitis. Patients who did not respond to methotrexate 15 mg/week were further studied for an additional 16 weeks on methotrexate 25 mg/week. Blood was drawn every 2 weeks for methotrexate levels. RESULTS: After 16 weeks, 17% of patients in each group achieved remission; 39% of patients randomized to 15 mg/week and 33% of patients randomized to 25 mg/week improved (P=N.S. ). Clinical status improved in four out of 11 patients after methotrexate dose escalation from 15 to 25 mg/week. Toxicity was not different between the treatment groups. Methotrexate blood levels did not predict efficacy or toxicity. CONCLUSIONS: For induction of remission in steroid-requiring inflammatory bowel disease, subcutaneous methotrexate at initial doses of 15 and 25 mg/week are equally efficacious. At these doses, response is not associated with blood methotrexate concentrations.

Adult↗
PubMed1999

Roles of FMO and CYP450 in the metabolism in human liver microsomes of S-methyl-N,N-diethyldithiocarbamate, a disulfiram metabolite.

BACKGROUND: The conversion of S-methyl-N,N-diethyldithiocarbamate (MeDDC) to MeDDC sulfine is the first step after methylation in the metabolic pathway of disulfiram, an alcohol deterrent, to its ultimate active metabolite. Various isoforms of CYP450 have recently been shown to catalyze this reaction, but the involvement of flavin monooxygenase (FMO) in this metabolism in humans has not been evaluated. In this study we examined the ability of recombinant human FMO3 in insect microsomes to metabolize MeDDC, and investigated the relative roles of FMO and CYP450 in the metabolism of MeDDC in human liver microsomes. METHODS: HPLC-mass spectrometry was used to identify the products of MeDDC formed by human liver microsomes and by recombinant human FMO3. MeDDC metabolism in human liver microsomes was studied by using either heat inactivation to inhibit FMO, or N-benzylimidazole (NBI) or antibodies to the CYP450 NADPH reductase to inhibit CYP450. RESULTS: We confirmed by HPLC-mass spectrometry that MeDDC sulfine was the major product of MeDDC formed by human liver microsomes and by FMO3. Recombinant FMO3 was an efficient catalyst for the formation of MeDDC sulfine (5.3+/-0.2 nmol/min/mg, mean+/-SEM, n = 6). Inhibition studies showed MeDDC was metabolized primarily by CYP450 in human liver microsomes at pH 7.4, with a 10% contribution from FMO (total microsomal activity 3.1+/-0.2, n = 17). In the course of this work, methyl p-tolyl sulfide (MTS), sulfoxidation of which is used by some investigators as a specific probe for FMO activity, was found to be a substrate for both FMO and CYP450 in human liver microsomes. CONCLUSIONS: Our results prove that MeDDC sulfine is the major product of MeDDC oxidation in human liver microsomes, MeDDC is a good substrate for human FMO3, and MeDDC is metabolized in human liver microsomes primarily by CYP450. We also showed that use of MTS sulfoxidation as an indicator of FMO activity in microsomes is valid only in the presence of a CYP450 inhibitor, such as NBI.

Adult↗
PubMed1997

Late presentation of biotinidase deficiency with acute visual loss and gait disturbance.

An unusual presentation of biotinidase deficiency is described. The disorder classically presents in infancy or early childhood with intractable seizures, hypotonia, ataxia, hearing loss, dermatitis, and alopecia. A 5-year-old girl developed acute visual loss associated with optic atrophy, and disturbance of gait with predominantly lower-limb pyramidal signs. She had no seizures, and skin, hair, hearing, and intellect were normal. Biotinidase deficiency was confirmed biochemically and she responded well to biotin therapy. A diagnosis of biotinidase deficiency should be considered in children with unexplained bilateral optic neuropathy, particularly when there is accompanying gait disorder.

Amidohydrolases↗
PubMed1994

Patterns of visual impairment associated with lesions of the preterm infant brain.

The visual function of 42 children with haemorrhagic and/or ischaemic cerebral lesions acquired before a gestational age of 35 weeks was examined and related to cranial ultrasound in the neonatal period and to MRI and neurodevelopmental status at follow-up. All 37 children with abnormal ultrasound scans and one of the five with normal ultrasound scans showed impairment of one or more aspects of visual function. While impaired acuity was more frequent among infants with MRI evidence of visual pathway damage, this was not an invariable finding. Normal or near-normal visual acuity did not preclude the presence of other functional visual deficits. The authors conclude that preterm cerebral insults may produce a variety of visual difficulties, the pattern and severity of which cannot be predicted on imaging. Each child therefore requires individual assessment of multiple aspects of visual function.

Brain↗
PubMed1991

Herpes simplex encephalitis with relapse.

Three children are described in whom herpes simplex encephalitis (HSE) followed a clearly biphasic course. The secondary deterioration may be due to a resurgence of the viral infection and calls into question the adequacy of current treatment regimens for HSE. Alternatively, a postinfectious neuroallergic process may be active in which case immunomodulatory treatment might be more appropriate than further antiviral treatment.

Acyclovir↗
PubMed1990

Congenital rubella syndrome associated with calcific epiphyseal stippling and peroxisomal dysfunction.

An infant girl had the clinical and immunologic findings of congenital rubella syndrome but also had arthrogryposis multiplex and calcific epiphyseal stippling. Spastic quadriparesis developed, and both physical and behavioral development were slow. Increased spasticity of the legs at 5 1/2 years was related not to progressive rubella encephalomyelopathy but to spinal cord compression by abnormal cartilaginous tissue. The presence of a peroxisomal disorder was demonstrated by a greatly increased level of phytanic acid and slightly increased levels of hexacosanoate in serum and by reduced activity of peroxisomal dihydroxyacetone phosphate acyltransferase and a slightly increased ratio of cytosolic to peroxisomal catalase activity in cultured fibroblasts. A reduction in the number and size of peroxisomes was demonstrated in cultured fibroblasts, and a needle biopsy specimen of the liver also showed the peroxisomes to have a smaller diameter than usual. We recommend that any child with epiphyseal stippling be assessed for peroxisomal disease and that the potential for spinal cord compression by dysplastic bone or cartilage be recognized. The association of peroxisomal dysfunction with congenital rubella has not been described previously. The interaction between rubella virus infection and peroxisomal function may need further investigation.

Calcinosis↗