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Biomedical subjects

D Marsden

Publications and source records attributed to D Marsden.

At least 19 recordsLinked to original sources
PubMed2006

X-linked creatine transporter defect: a report on two unrelated boys with a severe clinical phenotype.

We report two unrelated boys with the X-linked creatine transporter defect (CRTR) and clinical features more severe than those previously described with this disorder. These two boys presented at ages 12 and 30 months with severe mental retardation, absent speech development, hypotonia, myopathy and extra-pyramidal movement disorder. One boy has seizures and some dysmorphic features; he also has evidence of an oxidative phosphorylation defect. They both had classical absence of creatine peak on brain magnetic resonance spectroscopy (MRS). In one, however, this critical finding was overlooked in the initial interpretation and was discovered upon subsequent review of the MRS. Molecular studies showed large genomic deletions of a large part of the 3' end of the complete open reading frame of the SLC6A8 gene. This report emphasizes the importance of MRS in evaluating neurological symptoms, broadens the phenotypic spectrum of CRTR and adds knowledge about the pathogenesis of creatine depletion in the brain and retina.

Child, Preschool↗
PubMed2005

The knowledge gap in expanded newborn screening: survey results from paediatricians in Massachusetts.

Massachusetts currently offers an optional expanded newborn screening programme that tests for 20 biochemical genetic disorders in addition to the mandated newborn screening tests, including phenylketonuria (PKU) and nine other biochemical genetic disorders. We conducted a mail survey of 550 paediatricians listed in the 2000 Massachusetts Healthcare Directory to determine paediatricians' preparedness in discussing expanded newborn screening and its results with families, and to determine in what specific format physicians in Massachusetts would prefer to receive educational materials and updates. Of surveys mailed, 35% (190/550) were returned within the allotted 3 weeks: 25 paediatricians (14%) were unaware of expanded newborn screening; 78 respondents (42%) indicated feeling less than prepared talking about test results with families; 100 paediatricians (54%) indicated a lack of information about metabolic disorders; 134 (73%) preferred information sent in postal mailings, 62 (34%) preferred grand rounds, 60 (33%) preferred educational seminars, and 58 (32%) preferred websites. Other formats receiving preferences of less than 30% included e-mail (27%), phone calls (8%), video (6%), and distance learning (1%). Paediatricians are ill-prepared for expanded newborn screening for biochemical genetic disorders. To address this problem, paediatricians in Massachusetts indicated a preference for unsolicited periodic mailings including short reviews and brochures.

Attitude of Health Personnel↗
PubMed2003

X-linked creatine transporter defect: an overview.

In 2001 we identified a new inborn error of metabolism caused by a defect in the X-linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X-linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X-linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come from one metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.

Biological Transport↗
PubMed2001

Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation.

UNLABELLED: In eight patients with disorders of fatty acid oxidation, analysis of uric acid and creatine kinase served as indicators of the underlying disorder in episodes of acute metabolic imbalance. Six patients had deficiency of medium-chain acyl-CoA dehydrogenase, one had long-chain hydroxyacyl-CoA dehydrogenase deficiency, and one very long-chain acyl-CoA dehydrogenase deficiency. The most common presentation was with symptomatic hypoglycemia; there was one Reye-like presentation and one of rhabdomyolysis. The mechanism of the elevation of uric acid and creatine kinase appears to be the breakdown of tissue. CONCLUSION: it is concluded that uric acid and creatine kinase provide a useful alerting signal to the presence of a disorder of fatty acid oxidation. Maximal levels of uric acid in this series were 6.2-21.5 mg/dl and of creatine kinase 879-27,557 U/l.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2001

Detection of neonatal carnitine palmitoyltransferase II deficiency by expanded newborn screening with tandem mass spectrometry.

The introduction of tandem mass spectrometry to newborn screening has substantially expanded our ability to diagnose metabolic diseases in the newborn period. We report the first case of neonatal carnitine palmitoyltransferase deficiency II detected by expanded newborn screening with tandem mass spectrometry. The neonate presented with dysmorphic facial features, structural malformations, renal failure, seizures, and cardiac arrythmias and died on the third day of life. This experience illustrates the importance of expanded newborn screening to avoid missing a metabolic diagnosis in early infantile death.

Abnormalities, Multiple↗
PubMed2001

Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program.

BACKGROUND: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values. METHODS: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in approximately 1.9 min. Cutoffs for each marker were set at 6-13 SD above the population mean. RESULTS: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain acyl-CoA dehydrogenase deficiencies, 5 presumptive short-chain acyl-CoA dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 methylcrotonyl-CoA carboxylase deficiency, and 1 presumptive very-long chain acyl-CoA dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g. CONCLUSIONS: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns.

Amino Acid Metabolism, Inborn Errors↗
PubMed2000

Patterns of referral in patients with medically unexplained motor symptoms.

OBJECTIVE: To investigate the pattern and reasons for referrals in 64 patients with a stable diagnosis of motor conversion symptoms who had been assessed at the National Hospital for Neurology and Neurosurgery (NHNN). METHOD: Patients were interviewed on average 6 years after their original admission to the NHNN. Hospital notes and GP records were consulted. RESULTS: Psychiatrists at the NHNN saw 75% of patients. Treatment was initiated in 60% of these. During the 6-year follow up, many patients continued to be referred to neurologists and other specialists, but subsequent psychiatric referral was rare. Many changed their GP after discharge from the NHNN and a disproportionate number of re-referrals was made by GPs who had known their patients for less than 6 months. Psychological attribution of symptoms was rare and did not appear to be related to the pattern of referrals. CONCLUSION: The pattern of care of these patients was inconsistent and many felt dissatisfied with the treatment they received. This led to further referrals, unnecessary use of valuable resources and unnecessary exposure to iatrogenic damage. Further studies should aim to assist GPs and other clinicians in deciding when referral is likely to be beneficial.

Adult↗
PubMed1997

1995 survey of physics teaching efforts in radiation oncology residency programs.

A physics teaching survey was constructed and sent to the 83 radiation oncologist training programs. The survey requested program information regarding size, staffing, curriculum, lab/rotation programs, organization, requirements, instructor makeup, teaching materials, and board certification examination results. The surveys were sent to the physicist responsible for the physics program. Forty-nine (59%) institutions returned completed surveys, of which 43 (88%) were university-associated programs, and 27 (55%) were 4-year programs. On average, there were two residents/year. Most programs (39) taught physics exclusively during the first year (PG2). Some programs taught different subjects (or levels) to different year residents. Radiation dosimetry, treatment planning, and brachytherapy constituted nearly half of the teaching hours. On average the total classroom time expended by physicists was 61.4 h/year with a range of 24-118 h. The mean for laboratory/demonstration time was 27 h/year with 18 programs providing none. Physics orientation/rotations ranged from 1 to 480 h with a mean of 170 h for a physics rotation taking place in year 2 (PG3). Mandatory attendance was 80% for first-year residents and decreased in later years. Homework was assigned in 76% of the programs, and 65% of the programs were graded. The primary instructors averaged 18.2 years of experience, and the majority were ABR/ABMP certified. Khan's textbook was the most prevalent resource for most subjects. No correlation could be made between teaching hours and ABR physics percentile scoring. The survey results reveal enormous differences in national teaching efforts.

Curriculum↗
PubMed1996

Risk factors, falls, and fracture of the distal forearm in Manchester, UK.

OBJECTIVE: To determine the risk factors associated with fracture of the distal forearm, and to evaluate the influence of falls on these risks. DESIGN: This was a case-control study. SETTING: Manchester, UK. PARTICIPANTS: The cases were 62 white women aged 45-82 years who had sustained a fracture of the distal forearm and had attended local hospitals. Two control groups were studied - 50 women who had fallen onto the hand but had not sustained a fracture (recruited from the same source as those with fracture) and 116 women randomly selected from primary care age and sex registers in the catchment area of the hospitals. Both cases and controls were sent a letter inviting them to take part in the study. Data were collected by questionnaire completed by an interviewer. MAIN RESULTS: Compared with the population control group, those with fracture were more likely to walk at a brisk pace (odds ratio (OR) = 3.5; 95% confidence interval (CI) 1.3, 9.6) though they had undertaken less physical activity at home or work on a daily basis throughout life (OR = 0.4; 95% CI 0.2, 0.9). The risk associated with brisk walking was less marked when the cases were compared with fall controls. Other lifestyle factors including calcium intake, smoking, and alcohol consumption were not associated with fracture. Analysis of gynaecological and hormonal factors suggested that compared with population controls, those with fracture of the distal forearm had had fewer fertile years (OR = 0.4; 95% CI 0.1, 0.9) and were less likely to have used oral contraceptives (OR = 0.3; 95% CI 0.1, 0.9). CONCLUSIONS: The data highlight the need for caution when advising middle aged and elderly subjects about exercise. Such advice should be combined with practical information about the prevention of falls. Hormonal factors seem to be additional determinants of fracture. Other lifestyle interventions seem unlikely to play an important part in preventing distal forearm fracture.

Accidental Falls↗
PubMed1995

Differences in the characteristics of responders and non-responders in a prevalence survey of vertebral osteoporosis. European Vertebral Osteoporosis Study Group.

Men and women aged 50 years and over were recruited for participation in a population-based prevalence survey of vertebral osteoporosis from 36 centres in 19 European countries. All subjects were invited to attend by letter of invitation for a "lifestyle" interview and lateral spinal radiograph. The aim of this analysis was to investigate how far those who agreed to attend were representative of the target population and thus whether any important level of non-response bias existed. To address this a second invitation was sent to all non-responders and, in 20 centres, a sample of ultimate non-responders was contacted by mail, telephone or home visit and given a shortened version of the lifestyle questionnaire. Compared with the sample of non-responders, responders might be considered less at risk from osteoporosis in that as a group they took more exercise and were less likely to be current smokers. Other factors suggested the contrary in that they consumed less calcium and were more likely to have suffered a previous fracture. Amongst responders, these factors appeared also to be related to the timing of response. Thus compared with delayed responders, those who participated after a first letter of invitation took more exercise, were less likely to be smokers and more likely to have suffered a previous fracture. However, in contrast to the results suggested by the non-response survey early responders consumed more calcium than late responders. The magnitude of the differences between responders and non-responders was small (less than 10% for most of the categorical variables) and the differences were not consistently in the direction of an increased or decreased risk of osteoporosis. Additionally the size or direction of these differences was not consistently influenced by the response rate based on classifying centres into those with a high, medium or low response rate. This suggests that in this multicentre study response bias probably does not have a major influence on the prevalence estimates of vertebral fracture. In epidemiological studies of osteoporosis comparison of the lifestyle differences between early and late responders provides useful information concerning response characteristics.

Aged↗
PubMed1995

Survey response rates: national and regional differences in a European multicentre study of vertebral osteoporosis.

STUDY OBJECTIVE: This analysis aimed to compare the response rates of those invited to attend for screening in a multicentre, multinational study within Europe. DESIGN: This was a population survey. SETTING: Thirty four centres in 16 European countries. SUBJECTS: Men and women aged 50 years and over were recruited from population based sampling frames to participate in a prevalence survey of osteoporosis. Subjects were invited by post to attend for radiological screening and interview, and non-responders were followed up by repeat mailing. RESULTS: There was a substantial variation between centres in response rates: the mean was 49% and the range 5-83%. Adjusting for those known to have died or moved house did not affect the overall ranking. The response rates to each mailing also varied between centres: first mailing 45% (range 5-83%) and second mailing mean 10% (range 0-23%). The response rates varied in relation to age and sex and were higher in women than men. Rates fell gradually with age in women but rose in men until the age of 65 years. Response rates varied regionally. These were highest in countries from northern Europe and lowest in southern European countries, but there was wide variation both within regions and within countries. CONCLUSIONS: Multicentre, multinational studies within Europe will probably become increasingly popular. In this study, despite a standardised approach, the range in response rates between centres both within and between countries was substantial. Attempts at cross national standardisation in survey design can have only a limited effect on yielding uniformity in response.

Aged↗
PubMed1994

Syndrome of hypoparathyroidism, growth hormone deficiency, and multiple minor anomalies.

A 5 1/2-year-old Saudi Arabian girl presented with a syndrome of intrauterine growth retardation, minor anomalies, hypoparathyroidism, and growth hormone deficiency. She was the product of a consanguineous mating. Her minor anomalies and delayed development were similar to findings in a previously reported Saudi Arabian patients with hypoparathyroidism and growth deficiency. There were substantial differences in findings from a series of Kuwaiti children. Parathyroid hormone was undetectable, but the renal response to infused parathyroid hormone was normal, indicating primary hypoparathyroidism. In response to arginine stimulation, her GH rose to 5.8 ng/ml (5.8 micrograms/L) (nl > 10), and to 2.3 ng/ml (2.3 micrograms/L) after L-dopa. Following clonidine it rose to 15 ng/ml (15 micrograms/L) at 120 minutes. She responded normally to infusions of GHRH (GH rose to 22 ng/ml (22 micrograms/L) at 75 minutes) and TRH (TSH rose to 37 mu u/ml, 37 mIU/L). On treatment with recombinant human growth hormone, she showed an increase in height and weight. Hypocalcemia was well controlled with supplemental 1-alpha-cholecalciferol.

Abnormalities, Multiple↗