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Biomedical subjects

I Wilkinson

Publications and source records attributed to I Wilkinson.

At least 19 recordsLinked to original sources
PubMed2003

PEHO and PEHO-like syndromes: report of five Australian cases.

PEHO syndrome is a rare progressive infantile encephalopathy with onset within the first few months of life. Few patients fulfilling the diagnostic criteria for PEHO syndrome have been reported outside Finland. Affected infants have facial dysmorphism and suffer from severe hypotonia, profound mental retardation, convulsions (often with a hypsarrhythmic EEG pattern), transient or persistent peripheral oedema, and optic atrophy. Cerebellar and brainstem atrophy are usually present on neuroimaging. A PEHO-like syndrome has been described, in which the affected individuals have neither optic atrophy nor the typical neuroradiological findings. We report five Australian patients, the first with classical features of PEHO syndrome, and four who have a PEHO-like disorder. We compare their features with other published cases. We suggest that PEHO or a PEHO-like syndrome may affect more patients than are currently identified, based on the original diagnostic criteria for this disorder.

Brain Diseases, Metabolic, Inborn↗
PubMed2002

Effects of GH replacement on endothelial function and large-artery stiffness in GH-deficient adults: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening. DESIGN AND PATIENTS: In a randomized, double-blind, placebo-controlled study, we investigated the effects of GH replacement on endothelial function and large-artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19-64 years) over a 6-month period. Thirty-two age- and sex-matched healthy controls were also studied. MEASUREMENTS: Endothelial function was assessed using ultrasonic wall tracking to measure flow-mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured. RESULTS: At baseline, FMD (mean +/- SD) was impaired in GH-deficient subjects vs. controls (3.4 +/- 2.3 vs. 5.7 +/- 2.0%, P < 0.0001), although endothelium-independent dilatation was similar. The augmentation index was higher in GH-deficient subjects vs. controls (23 +/- 12 vs. 14 +/- 14%, P < 0.01). GH-deficient subjects had higher LDL cholesterol (4.1 +/- 0.8 vs. 3.5 +/- 0.8 mmol/l, P < 0.01) and lower HDL cholesterol (1.1 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P < 0.01). In GH-deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = -0.40, P < 0.05) and between FMD and the augmentation index (r = - 0.58, P < 0.01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0.0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5.0 +/- 2.6 vs. 2.8 +/- 1.9%, P < 0.01). There were decreases in central aortic systolic pressure (117 +/- 15 vs. 123 +/- 17 mmHg, P < 0.01), diastolic pressure (82 +/- 10 vs. 86 +/- 8 mmHg, P < 0.01) and the augmentation index (22 +/- 8% vs. 26 +/- 10%, P < 0.05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3.5 +/- 0.8 vs. 4.2 +/- 0.8 mmol/l, P < 0.01). There were no significant changes in the placebo group. CONCLUSIONS: Adult GHD is associated with endothelial dysfunction and increased large-artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.

Adult↗
PubMed2002

Pegvisomant: structure and function.

Pegvisomant is the pegylated form of mutant growth hormone (B2036). B2036 has increased affinity in one binding site and lowered affinity in its second binding site, it has been shown that this molecule still enables dimerisation of the growth hormone receptor at the cell surface but does not allow the necessary conformational changes for signalling. Pegylation decreases the antagonistic activity of B2036, however the rate of clearance of the pegylated B2036 is greatly reduced compared to the unpegylated form. Even though the antagonistic activity of pegvisomant is lower than B2036, the reduced rate of clearance makes it an effective clinical drug for the treatment of conditions such as acromegaly.

Binding Sites↗
PubMed2001

Fermi surface nesting in disordered Cu1-xPdx alloys.

The concentration-dependent position of the diffuse peaks in electron and x-ray diffraction patterns of Cu1-xPdx alloys in the disordered state is attributed to Fermi surface nesting. We present the first experimentally determined Fermi surfaces of Cu0.72Pd0.28 and Cu0.6Pd0.4, and show that they do indeed possess significant flat areas capable of nesting. Moreover, the magnitudes of the nesting vectors are in excellent agreement with those deduced from electronic structure calculations and diffraction experiments.

Journal Article↗
PubMed2001

Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.

Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder characterized by muscle weakness and the presence of nemaline bodies (rods) in skeletal muscle. Disease-causing mutations have been reported in five genes, each encoding a protein component of the sarcomeric thin filament. Recently, we identified mutations in the muscle alpha-skeletal-actin gene (ACTA1) in a subset of patients with NM. In the present study, we evaluated a new series of 35 patients with NM. We identified five novel missense mutations in ACTA1, which suggested that mutations in muscle alpha-skeletal actin account for the disease in approximately 15% of patients with NM. The mutations appeared de novo and represent new dominant mutations. One proband subsequently had two affected children, a result consistent with autosomal dominant transmission. The seven patients exhibited marked clinical variability, ranging from severe congenital-onset weakness, with death from respiratory failure during the 1st year of life, to a mild childhood-onset myopathy, with survival into adulthood. There was marked variation in both age at onset and clinical severity in the three affected members of one family. Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability, in clinical phenotype, among patients with different mutations in ACTA1 suggests that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggests that alpha-actin genotype is not the sole determinant of phenotype.

Actins↗
PubMed2001

Rotavirus encephalopathy: pathogenesis reviewed.

Two cases of rotavirus gastroenteritis associated with neurological involvement, one with encephalitis (defined by abnormal neurological signs, cerebrospinal fluid (CSF) pleocytosis and detection of rotavirus genomic nucleic acid in the CSF) and one with a non-inflammatory encephalopathy (defined by abnormal neurological signs, an entirely normal CSF and detection of rotavirus genomic nucleic acid in the CSF), are presented and used as a basis to review and explore potential pathogenetic mechanisms, including direct viral replication within neurons and indirect effects of the newly described rotavirus 'enterotoxin'.

Acyclovir↗
PubMed2001

The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review.

Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin alpha2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin alpha2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin alpha2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin alpha2. In addition, the use of multiple antibodies to different regions of laminin alpha2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.

Age of Onset↗
PubMed2000

Stable periodic vortex shedding studied using computational fluid dynamics, laser sheet flow visualization, and MR imaging.

Recirculating and detached flow patterns close to the carotid bifurcation are thought to play an important role in the development of carotid stenoses by promoting atherosclerosis. The aim of this study was to investigate a flow regime with strong transient characteristics, including vortex shedding and transport to develop methodologies appropriate to the analysis of carotid stenoses. The existence of a regular periodic vortex street behind a cylindrical flow obstruction was predicted and analysed in detail by Theodore van Karman in the early 20th century. This model was chosen in our study for both ease of phantom construction and of theoretical modelling using finite element computational fluid dynamics (CFD). The results of the theoretical calculations have been compared with two methods of flow visualization-laser sheet imaging and real-time echo planar magnitude MR imaging. Flow was investigated over a range of Reynold's number from 40 through 400 through which vortex shedding is predicted. Good overall agreement was obtained between the theoretical (16 mm-CFD) and experimental (16+/-2 mm-Laser, 17+/-2 mm-MRI) estimates of the Karman Vortex street wavelength for a Reynolds number of 200.

Carotid Arteries↗
PubMed2000

Antibody cross-linking of human CD9 and the high-affinity immunoglobulin E receptor stimulates secretion from transfected rat basophilic leukaemia cells.

Previous studies have shown that antibody cross-linking of the tetraspanin protein CD9 stimulates the degranulation of platelets and eosinophils, although the mechanism of activation is unclear. In this work we transfected human CD9 into the rat basophilic leukaemia (RBL-2H3) cell line and studied the stimulation of secretion from these cells in response to a panel of anti-CD9 antibodies. Intact immunoglobulin G1 (IgG1) antibodies activated transfected cells whereas F(ab')2 fragments of antibody and an intact IgG2a did not. Stimulation of secretion was inhibited by co-incubation with monomer murine immunoglobulin E (IgE) but not with an IgG1 isotype control, indicating that the response involves the endogenous high-affinity IgE receptor (FcepsilonRI). The anti-CD9 antibody activation curve was biphasic, and supraoptimal antibody concentrations stimulated little or no degranulation, indicating that multivalent binding of human CD9 molecules is necessary for the formation of an active complex with rat FcepsilonRI. Immunoprecipitation of FcepsilonRI under mild detergent conditions co-precipitated CD9, suggesting the presence of pre-existing complexes of CD9 and FcepsilonRI that could be activated by antibody cross-linking. These data are further evidence that tetraspanins are involved in FcepsilonRI signalling and may reflect the participation of tetraspanins in the formation of complexes with other membrane proteins that use components of Fc receptors for signal transduction.

Animals↗
PubMed2000

A study of three cases of familial related agenesis of the corpus callosum.

This paper provides data on a family in which three members, all female, have been diagnosed as having agenesis of the corpus callosum. That all three acallosal individuals came from the same family and showed relatively uniform neuropsychological impairment and could be compared in similar terms with their "callosal" siblings, also female, provides a unique sample. Inter-hemispheric transfer, psychometric measures, and motor and cognitive function were examined in the acallosal individuals, all of whom had borderline to low-average intelligence, with results compared to their non-acallosal siblings. The data indicated that all acallosal individuals exhibited deficits with the cognitive tests indicating difficulties of inter-hemispheric transfer of tactile information, difficulties in some areas of memory and, at least as far as the children are concerned, a marked difference in Verbal IQ and Performance IQ.

Adolescent↗
PubMed1999

A population-based study of children with cerebral tuberculosis in New South Wales.

OBJECTIVE: To determine the incidence of childhood cerebral tuberculosis (tuberculous meningitis [TBM] and tuberculoma) in a defined population. DESIGN: Retrospective, population-based study. SETTING AND PARTICIPANTS: All resident children aged up to 14 years in New South Wales diagnosed with cerebral tuberculosis, from 1982 to 1996. MAIN OUTCOME MEASURE: Population-based incidence of childhood TBM. RESULTS: 10 children with TBM and one with tuberculoma were identified in the 15 years. The incidence of TBM was 0.053 (95% CI, 0.025-0.097) per 100,000. Eight of the 10 TBM patients were born in Australia and five were of white European origin. Only one had been vaccinated with BCG vaccine. Three of the children died. CONCLUSIONS: The incidence of childhood TBM in New South Wales is low, and comparable with that in other First World countries.

Adolescent↗
PubMed1999

Diminished wave reflection in the aorta. A novel physiological action of insulin on large blood vessels.

Epidemiological data suggest that insulin may have direct effects on large-vessel function, but thus far insulin has only been shown, after prolonged infusions, to slowly decrease peripheral vascular resistance by increasing muscle blood flow. We determined whether physiological doses of insulin affect function of large arteries, before any changes in peripheral blood flow, in vivo using pulse wave analysis. Nine normal men were studied on 2 occasions: once during a 6-hour infusion of saline and once under normoglycemic hyperinsulinemic conditions (sequential 2-hour insulin infusions of 1, 2, and 5 mU/kg. min). Central aortic pressure waves were synthesized from those recorded in the periphery with the use of applanation tonometry and a validated reverse transfer function every 30 minutes. This allowed determination of central aortic augmentation (the pressure difference between early and late systolic pressure peaks) and augmentation index (augmentation expressed as a percentage of pulse pressure). Both augmentation and augmentation index decreased significantly within 1 hour after administration of insulin (P<0.001) but not saline. Systolic and diastolic blood pressure and heart rate remained unchanged for the first 2 hours. A significant increase in peripheral (forearm) blood flow was not observed until 2.5 hours after start of the insulin infusion. These data demonstrate that insulin, in normal subjects, rapidly decreases wave reflection in the aorta. This beneficial effect is consistent with increased distensibility or vasodilatation of large arteries. In contrast to the effect of insulin on peripheral blood flow, this action of insulin is observed under conditions in which both the insulin dose and duration of insulin exposure are physiological. Resistance to this action of insulin could provide a mechanism linking insulin resistance and conditions such as hypertension at the level of large arteries.

Adult↗
PubMed1999

Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity.

We tested the hypothesis that insulin has effects on large artery stiffness in addition to its slow vasodilatory effect on resistance vessels in skeletal muscle, and whether such an effect might be altered in obesity. Eight nonobese (aged 25 +/- 1 years, BMI 22.7 +/- 0.4 kg/m2) and eight obese (aged 27 +/- 2 years, BMI 30.6 +/- 0.9 kg/m2) men were studied under normoglycemic-hyperinsulinemic (sequential 2-h insulin infusions of 1 [step 1] and 2 [step 2] mU x kg(-1) x min(-1)) conditions, and another seven men participated in a saline control study. Central aortic pressure waves were synthesized from those recorded in the periphery using applanation tonometry and a validated reverse transfer function every 30 min. This allowed determination of augmentation (the pressure difference between early and late systolic pressure peaks) and the augmentation index (augmentation divided by pulse pressure), a measure of arterial stiffness. Whole-body glucose uptake was reduced by 48 (step 1) and 41% (step 2) (P < 0.01) in the obese subjects versus the nonobese subjects. Basal forearm blood flow averaged 2.5 +/- 0.2 and 2.6 +/- 0.2 ml x dl(-1) x min(-1) in the obese and nonobese subjects, respectively (NS). Insulin induced a significant increase in forearm blood flow after 2.5 h (3.6 +/- 0.4 ml x dl(-1) x min(-1), P < 0.05 vs. basal) in the nonobese subjects and after 4 h in the obese subjects (3.2 +/- 0.2, P < 0.05). In contrast to these slow changes in peripheral blood flow, augmentation and the augmentation index decreased significantly in the nonobese subjects after 1 h (-3.0 +/- 1.6 mmHg and -10.0 +/- 5.4%, respectively, P < 0.001 vs. basal), but remained unchanged until 3 h in the obese subjects. Percent fat (r = 0.86, P < 0.0001) and whole-body glucose uptake (r = -0.72, P < 0.01) correlated with the change in the augmentation index by insulin. These data demonstrate temporal dissociation in insulin's vascular actions. Insulin's effect to decrease arterial stiffness in nonobese subjects (a decrease in wave reflection) is observed under physiological conditions and precedes a slow vasodilatory effect in the periphery. In the obese subjects, insulin's normal effect to decrease central wave reflection is severely blunted. The degree of impairment in this novel vascular action of insulin is closely correlated with the degree of obesity and insulin action on glucose uptake.

Adult↗
PubMed1998

Improving communication between hospital and primary care increases follow-up rates for asthmatic patients following casualty attendance.

Despite adequate access to primary care facilities, there is a group of patients who habitually present to hospital accident and emergency (A&E) departments when their asthma deteriorates. In Nottingham 50% of these patients are discharged from the A&E department without admission to hospital and are advised to inform and see their general practitioner (GP), but many fail to do so. We instituted a system of identifying all patients seen and discharged from our A&E department with asthma and informing their GPs and practice nurses within one working day of the event by fax. To determine whether any action had been taken following receipt of our fax, we contacted each general practice 1 month after the A&E attendance in 100 consecutive cases. Full data were available for 66 patients. Our faxes increased the notification of A&E attendances to GPs from 47 to 89%. This resulted in an increase in the number of follow-up appointments initiated by the practice, from 15 to 31. However, 29% of patients were not asked to attend for follow-up, in spite of the practice being aware of a recent A&E visit. Improving communication between hospital and general practice increases the rate of follow-up by GPs for patients with asthma who have been discharged from A&E. This has the potential to improve asthma management for this group of patients.

Asthma↗
PubMed1998

Evidence of CNS impairment in HIV infection: clinical, neuropsychological, EEG, and MRI/MRS study.

OBJECTIVES: To identify by clinical examination, EEG, MRI, and proton spectroscopy, and neuropsychological assessment the prevalence of signs of CNS involvement in patients infected with HIV, and to relate such findings to the evidence of immunosuppression. METHODS: The design was a cross sectional analysis of a cohort of male patients with infected HIV with an AIDS defining diagnosis or low CD4 count (<350), and seropositive asymptomatic subjects, both groups being followed up in a longitudinal study. Control groups consisted of seronegative subjects from the same genitourinary medicine clinics. RESULTS: This report sets out the cross sectional findings at the seventh visit in the longitudinal study. Patients with AIDS had more signs of neurological dysfunction, poorer performance on a neuropsychological test battery, were more likely to have an abnormal EEG, and to have abnormalities on MRI. They more often had cerebral atrophy, abnormal appearing white matter, and abnormal relaxometry and spectroscopy. There was little evidence of abnormality in seropositive people who had a CD4 count >350 compared with seronegative people from a similar background. CONCLUSIONS: Detailed testing failed to disclose significant CNS impairment without immunosuppression in men infected with HIV. Findings from MRI and magnetic resonance spectroscopy (MRS) correlated with those of the neurological examination and neuropsychological assessment. A combination of such assessments offers a simple surrogate for studies of CNS involvement in HIV disease.

AIDS Dementia Complex↗
PubMed1998

Improved laboratory test selection and enhanced perception of test results as tools for cost-effective medicine.

Inconsistencies in the way physicians perceive and handle identical laboratory results have untoward effects on morbidity, mortality and cost of medical care. In this context, the selection of suitable tests to answer definite clinical questions, and the manner in which laboratory results are presented have great impact on the action taken by the clinician. This review addresses preferred methods to improve laboratory test selection, and examines methods that more effectively convey laboratory results to clinicians. It is anticipated that refined selection of tests, and presentation of the test results in a configuration that is easily perceived by the clinician, will facilitate interpretation of laboratory reports. Furthermore, any measures that promote the application of laboratory information in medical practice improve economics at the laboratory-clinical interface. The presently described methods to optimize test selection and interpretation are: likelihood ratios to provide estimates of the ability of a test to identify a clinical condition; consensus- and discriminant function-analysis to estimate the performance of tests in diagnosing a particular disease or condition; receiver operating characteristic (ROC) curves to assess discrimination capabilities. The methods which improve test result perception are expression of results as multiples of the upper normal limit, utilizing signal strength to provide prognostic probabilities, and presentation of results in graphic forms that display mutually interrelated functions, with a specific cluster of results being highly suggestive of a given condition. In addition, we discuss application of expert systems to provide rules based on knowledge and experience to analyze results of tests and suggest diagnosis and action, including additional tests when required. It is anticipated that judicious utilization of laboratory services by application of the reviewed methodologies will help to achieve medically justified responses at a lower cost and help to achieve a proper balance between cost of tests and their clinical usefulness.

Clinical Laboratory Techniques↗
PubMed1997

Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene.

We have isolated and characterized complete cDNAs for two isoforms (HSPDE4D4 and HSPDE4A5) encoded by the human PDE4D gene, one of four genes that encode cAMP-specific rolipram-inhibited 3',5'-cyclic nucleotide phosphodiesterases (type IVPDEs; PDE4 family). The HSPDE4D4 and HSPDE4D5 cDNAs encode proteins of 810 and 746 amino acids respectively. A comparison of the nucleotide sequences of these two cDNAs with those encoding the three other human PDE4D proteins (HSPDE4D1, HSPDE4D2 and HSPDE4D3) demonstrates that each corresponding mRNA transcript has a unique region of sequence at or near its 5'-end, consistent with alternative mRNA splicing. Transient expression of the five cDNAs in monkey COS-7 cells produced proteins of apparent molecular mass under denaturing conditions of 68, 68, 95, 119 and 105 kDa for isoforms HSPDE4D1-5 respectively. Immunoblotting of human cell lines and rat brain demonstrated the presence of species that co-migrated with the proteins produced in COS-7 cells. COS-cell-expressed and native HSPDE4D1 and HSPDE4D2 were found to exist only in the cytosol, whereas HSPDE4D3, HSPDE4D4 and HSPDE4D5 were found in both cytosolic and particulate fractions. The IC50 values for the selective PDE4 inhibitor rolipram for the cytosolic forms of the five enzymes were similar (0.05-0.14 microM), whereas they were 2-7-fold higher for the particulate forms of HSPDE4D3 and HSPDE4D5 (0.32 and 0.59 microM respectively), than for the corresponding cytosolic forms. Our data indicate that the N-terminal regions of the HSPDE4D3, HSPDE4D4 and HSPDE4D5 proteins, which are derived from alternatively spliced regions of their mRNAs, are important in determining their subcellular localization, activity and differential sensitivity to inhibitors.

3',5'-Cyclic-AMP Phosphodiesterases↗