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Biomedical subjects

T M Cowan

Publications and source records attributed to T M Cowan.

At least 19 recordsLinked to original sources
PubMed2004

The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia type I.

Glutaric acidemia type I (GA-1) is a progressive neurodegenerative inborn error of metabolism that typically manifests acutely in infants during an intercurrent illness. The diagnosis is established biochemically by the detection of glutaric acid and 3-hydroxy glutaric acid in urine and glutarylcarnitine in plasma. However, some patients excrete only small amounts of glutaric acid and may be overlooked, especially if the plasma concentration of glutarylcarnitine is not elevated. To test the hypothesis that measuring the excretion of glutarylcarnitine may improve the recognition of GA-1 patients without significant glutaric aciduria, urine glutarylcarnitine was analyzed in 14 cases. Five of them lacked significant glutaric aciduria, 9 (of 10 available) had a normal plasma glutarylcarnitine concentration. As controls, we also evaluated 54 subjects with glutaric aciduria secondary to other causes (16-7509 mmol/mol creatinine; reference range: <15; no significant amounts of 3-hydroxy glutaric acid detectable). The excretion of glutarylcarnitine was significantly elevated in all GA-1 patients (14-522 mmol/mol creatinine; reference range: <5.2) and in none of the controls with glutaric aciduria. These findings suggest that the urinary excretion of glutarylcarnitine is a specific biochemical marker of GA-1 which could be particularly useful in the work up of patients with suggestive clinical manifestations but without glutaric aciduria and with normal plasma acylcarnitine profiles.

Carnitine↗
PubMed2002

Selective photothermal interaction using an 805-nm diode laser and indocyanine green in gel phantom and chicken breast tissue.

Laser immunotherapy, a novel therapy for breast cancer, utilises selective photothermal interaction to raise the temperature of tumour tissue above the cell damage threshold. Photothermal interaction is achieved with intratumoral injection of a laser-absorbing dye followed by non-invasive laser irradiation. When tumour heating is used in combination with immunoadjuvant to stimulate an immune response, antitumour immunity can be achieved. In this study, the selective photothermal effect was investigated using gel phantom and chicken breast tissue. An 805-nm diode laser and indocyanine green (ICG) were used. An ICG-containing gelatin phantom was constructed to simulate targeted tumour tissue. The target gel was buried inside chicken breast tissue and the tissue-gel construct was irradiated by the laser. Temperatures at different locations in the construct were measured during the laser irradiation. For comparison, the thermal effect of an Nd:YAG laser on the tissue-gel construct was also investigated. Selective heating of target gel containing 0.27% ICG and buried 1 cm below the chicken tissue surface was achieved with the 805-nm diode laser using a power of 0.85 W and beam radius of 1 cm. The target gel experienced a temperature increase of more then 6 degrees C whereas the surrounding chicken breast tissue experienced only a minor temperature increase. The feasibility of this experimental set-up has been shown. It will be used in the future to optimise treatment parameters such as laser power, laser beam radius, and dye concentration.

Animals↗
PubMed2001

A PCR-based method for detecting known mutations in the human UDP galactose-4'-epimerase gene associated with epimerase-deficiency galactosemia.

Epimerase-deficiency galactosemia results from impairment of the human enzyme UDP galactose-4'-epimerase (GALE). We report a rapid, internally controlled PCR-based method for detection of nine naturally occurring point mutations in human GALE associated with epimerase deficiency. These mutations were derived from patients whose clinical presentations ranged from mild to severe; all but one of these mutations have been reported previously. The tests described here work well on both cDNA and genomic samples and require no specialized equipment beyond a thermal cycler and an agarose gel electrophoresis system. Finally, although these tests in no way replace the need for biochemical diagnosis in epimerase-deficiency galactosemia, they do provide the possibility of additional molecular information to support a biochemical diagnosis and facilitate the possibility of more accurate carrier testing, should that option be desired.

Base Sequence↗
PubMed2000

A missense mutation in the OCTN2 gene associated with residual carnitine transport activity.

Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation caused by defective carnitine transport. This disease can present early in life with hypoketotic hypoglycemia and acute metabolic decompensation, or later in life with skeletal or cardiac myopathy. Mutations abolishing the function of OCTN2, an organic cation/carnitine transporter with twelve putative transmembrane spanning domains, were recently demonstrated in patients with early- and late-onset (up to seven years of age) presentation of this syndrome. Most of the reported mutations are null alleles. Here we evaluate the OCTN2 gene in a male patient who presented at seven years of age with severe dilated cardiomyopathy. Plasma carnitine levels were undetectable and carnitine transport by his fibroblasts was reduced to about 3% of normal controls. This patient was homozygous for a single base pair change in exon 8 of the OCTN2 gene (1354G>A) converting the codon for Glu 452 to Lys (E452K) in the predicted intracellular loop between transmembrane domains 10 and 11. Stable expression of the mutant E452K-OCTN2 cDNA in Chinese hamster ovary (CHO) cells caused a partial increase in carnitine transport to 2-4% of the levels measured in the wild type transporter. This reduced transport activity was associated with normal Km toward carnitine (3.1 +/- 1.1 microM), but markedly reduced Vmax. These results indicate that primary carnitine deficiency can be caused by mutations encoding for carnitine transporters with residual activity, and that the E452K affects a domain not involved in carnitine recognition.

Adult↗
PubMed2000

Are clinical practice guidelines valid for primary care?

Development of evidence-based clinical practice guidelines has emphasized treatment efficacy under methodologically rigorous conditions; internal validity (i.e., efficacy) has been assessed well. Despite their experimental foundations, guidelines originally were considered physician education tools relevant to singular, idealized encounters. Now, in rushing to generalize, quantify, and regulate quality, guidelines are being applied to whole populations as quality review criteria. Clinical guidelines do not make operational how, or even make clear whether they should be so used. We studied the external validity, the generalizability and measurability for primary care, of a guideline for treatment of systolic heart failure. Patient and clinical factors reducing generalizability were examined. Imprecise definition and reliance on single measures of recommendations were studied as limits to measurability. Patient, physician, organizational, and system factors influenced guideline validity. Attention to myriad invalidity sources undermining implementation and evaluation of efforts to improve quality and outcomes of primary care is critical.

Heart Failure↗
PubMed2000

The ultrasound-assisted physical examination in the periodic health evaluation of the elderly.

BACKGROUND: Except for specific procedures such as blood pressure measurement, the conventional physical examination (PE) does not have sufficient sensitivity to be useful as part of the periodic health evaluation. Ultrasound has demonstrated greater sensitivity and specificity in numerous studies but has been too expensive to be widely employed in health screening. The purpose of our study was to determine whether an examination in which conventional and ultrasound techniques are blended and applied by a primary care physician might be feasible and useful in the periodic health evaluations of senior citizens. METHODS: Seventy-two patients presenting to a community-based family physician for periodic health evaluations received an ultrasound-assisted physical examination (USA-PE) from a second family physician. The results were reported to the primary physician, and the outcomes were tracked for periods of up to 2 years. RESULTS: Twenty-two of the 72 patients (31%) had abnormalities found by the USA-PE that were not apparent during the conventional PE. Five of these patients (7%) had serious conditions that received prompt treatment with apparent benefit. Findings included endometrial carcinoma, abdominal aortic aneurysm, carotid stenosis, hydronephrosis, and urinary retention. CONCLUSIONS: The USA-PE found more abnormalities in this group of patients than conventional PE. Whether it can improve outcomes for senior citizens undergoing periodic health evaluations in a cost-effective manner is yet to be determined.

Aged↗
PubMed1999

Readiness for Medicaid managed care reform initiatives: a profile of rural family physicians.

Medicaid managed care is now an important factor in the financing of rural health care delivery. The participation of rural family physicians in Medicaid managed care is vital for the rural poor to access health services. This study examined 855 family physicians practicing in nonmetropolitan counties across the United States to determine their readiness to participate in Medicaid managed care. Physicians were asked about their experience with prepaid programs and the factors that would influence their participation in such a program. A shortage of health care providers and low reimbursement rates were most frequently cited as barriers to successful implementation. Physicians who had participated in prepaid programs in the past but were no longer participating had the most negative opinions about the potential for Medicaid managed care programs to enhance care for the poor in their communities. Overall, physicians reported potential for the program to improve access and quality of care, but they also expressed reservations about the financial and administrative effects on their practices. These results reveal that negative attitudes were associated with prepaid programs that failed to meet expectations, but physicians also expressed an optimism about the potential to serve the poor within a managed care model.

Analysis of Variance↗
PubMed1999

Heart failure in primary care: measuring the quality of care.

BACKGROUND: Concerns exist about the quality of care provided to heart failure patients by primary care physicians. Using an evidence-based clinical guideline, we evaluated the care given to patients with systolic heart failure. METHODS: We retrospectively reviewed the medical records of 420 patients from 25 primary care practices in upstate New York who had received a diagnosis of heart failure. Chart documentation confirmed the diagnosis (n = 395). We excluded patients with noncardiogenic volume overload or correctable valvular disease (n = 338). Performance profiles measured use of diagnostic tests, left ventricular ejection fraction (LVEF) measurement, patient education, and prescription of angiotensin-converting enzyme (ACE) inhibitors. For treatment recommendations, patients were classified according to LVEF status. RESULTS: Only 82% of the patients studied had an LVEF test result documented in their charts. Of these, 49% had an LVEF < or = 40%. ACE inhibitor use was greater among patients with low LVEF (91%) than among those with a normal LVEF (62%). Among patients with systolic heart failure taking ACE inhibitors, 87% were at target doses. Adherence measures were low for laboratory evaluation and patient-education criteria. CONCLUSIONS: Heart failure with normal LVEF was as prevalent as systolic heart failure in these primary care practices. Performance profiles for the physicians' prescriptions of ACE inhibitors exceeded those published in the literature. Patients who did not have a documented measure of LVEF, however, received lower quality of care as measured by this disease-specific guideline. This underscores the importance of measuring LVEF.

Aged↗
PubMed1998

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life.

OBJECTIVE: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1998

Molecular characterization of a unique patient with epimerase-deficiency galactosaemia.

Inherited deficiencies of UDP-galactose 4-epimerase (GALE) have been associated with two distinct phenotypes. The vast majority of North American patients are clinically asymptomatic, are identified through newborn screening programmes for classical galactosaemia, and are of African-American descent. At least two symptomatic patients have been reported, one Pakistani and the other Asian Muslim, both with severe complications in the neonatal period and subsequent mental retardation. Through newborn screening, we have identified a GALE-deficient patient who is of mixed Pakistani/caucasian ancestry. He was clinically well in the neonatal period on a lactose-containing diet, and biochemical studies, including urine reducing sugars and galactitol, were consistent with a diagnosis of peripheral GALE deficiency. Although early developmental milestones were met normally, he now shows significant developmental delays in both motor and language skills. Mutational analysis revealed this patient to be a compound heterozygote at the GALE locus, with mutations N34S and L183P identified in the patient and confirmed in the parents. This report represents the first characterization of specific mutations in a GALE-deficient patient in conjunction with biochemical and clinical phenotype, and facilitates further studies of the GALE enzyme and its role in the different clinical forms of epimerase-deficiency galactosaemia.

Child, Preschool↗
PubMed1998

Patient-centered clinical decisions and their impact on physician adherence to clinical guidelines.

BACKGROUND: This study was undertaken to assess the impact of traditionally unmeasured patient-centered factors on primary care physicians' decisions to adhere to an evidence-based clinical practice guideline for heart failure. METHODS: Experimental and control scenarios were developed to test three patient-centered factors hypothesized to influence physician nonadherence to a heart failure guideline: patient concerns about finances, quality of life, and location of care. Each factor represented an implicit patient goal potentially in conflict with a goal of the guideline recommendations. A control scenario for one factor and an experimental scenario for a second were placed within a cross-sectional survey and questionnaires were mailed by random assignment to 978 Upstate New York family physicians. Experimental and control responses were compared by chi square. RESULTS: The response rate was 47% (n = 456). Each hypothetical patient-centered factor resulted in significant reductions in physicians' predicted adherence. Reductions in reported pharmaceutical usage and testing of left ventricular (LV) function were associated with patient financial difficulties (P < .01). The poor quality-of-life scenario was associated with reduced testing for LV function but increased discussion of advance directives (P < .01). The clinical scenario limiting access to services for a rural patient was associated with decreases in physician choice of LV function tests and cardiology referrals (P < .05). CONCLUSIONS: Patient-specific factors are associated with physician decisions to comply with guideline recommendations. These findings suggest that performance profiles measuring physician adherence to guidelines should be interpreted with caution, and that current case-mix methodologies may not adequately control for patient-centered factors that may influence health care quality.

Aged↗
PubMed1997

Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase.

UDP-galactose-4-epimerase (GALE) is a highly conserved enzyme that catalyzes the interconversion of UDP-galactose and UDP-glucose. Impairment of this enzyme in humans results in one of two clinically distinct forms of epimerase-deficiency galactosemia-one benign, the other severe. The molecular and biochemical distinction between these disorders remains unknown. To enable structural and functional studies of both wild-type and patient-derived alleles of human GALE (hGALE), we have developed and applied a null-background yeast expression system for the human enzyme. We have demonstrated that wild-type hGALE sequences phenotypically complement a yeast gal10 deletion, and we have biochemically characterized the wild-type human enzyme isolated from these cells. Furthermore, we have expressed and characterized two mutant alleles, L183P-hGALE and N34S-hGALE, both derived from a patient with no detectable GALE activity in red blood cells but with approximately 14% activity in cultured lymphoblasts. Analyses of crude extracts of yeast expressing L183P-hGALE demonstrated 4% wild-type activity and 6% wild-type abundance. Extracts of yeast expressing N34S-hGALE demonstrated approximately 70% wild-type activity and normal abundance. However, yeast coexpressing both L183P-hGALE and N34S-hGALE exhibited only approximately 7% wild-type levels of activity, thereby confirming the functional impact of both substitutions and raising the intriguing possibility that some form of dominant-negative interaction may exist between the mutant alleles found in this patient. The results reported here establish the utility of the yeast-based hGALE-expression system and set the stage for more-detailed studies of this important enzyme and its role in epimerase-deficiency galactosemia.

Alleles↗
PubMed1997

Family physicians' attitudes about and use of clinical practice guidelines.

BACKGROUND: The use of clinical guidelines is one strategy intended to improve health care quality, rein in costs, and standardize medical practice. Clinical guideline development has been prodigious, while less effort has been expended on the guidelines' dissemination and implementation. This study examines family physician attitudes toward and perceived uses of clinical guidelines in practice. METHODS: A survey questionnaire was sent to 978 family physicians in Upstate New York to assess their confidence in clinical guidelines developed or endorsed by organizations and the perceived usefulness of such guidelines in practice. Descriptive analyses, chi-square tests, and comparison of means (one-way ANOVA) were conducted. RESULTS: After two mailings, the response rate was 43%. Most respondents perceived clinical guidelines as effective educational tools that should improve the quality of patient care, but were concerned about their potential regulatory intrusion into practice. Solo practitioners expressed more negative attitudes regarding clinical guidelines than physicians in non-solo practices. Respondents had greater confidence in clinical guidelines developed or endorsed by their professional society, the Centers for Disease Control and Prevention, the United States Preventive Services Task Force, and the National Institutes of Health, but less in those by insurance companies or state health departments. The reported adoption rate of clinical guidelines was low. The most preferred methods for adoption were continuing medical education and practice interventions. CONCLUSIONS: Family physicians found clinical guidelines to be valuable educational tools but were divided on their potential regulatory role. If clinical guidelines are to improve quality in practice, they must be more effectively disseminated and implemented. To broaden physicians' adoption of clinical guidelines, further research into dissemination and implementation methods is warranted, along with wider endorsement of guidelines by those whom family physicians trust.

Attitude of Health Personnel↗
PubMed1994

Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenesis VII--and their population frequency.

Phosphofructokinase (PFK) catalyzes the rate-limiting step of glycolysis. Deficiency of the muscle enzyme is manifested by exercise intolerance and a compensated hemolytic anemia. Case reports of this autosomal recessive disease suggest a predominance in Ashkenazi Jews in the United States. We have explored the genetic basis for this illness in nine affected families and surveyed the normal Ashkenazi population for the mutations we have found. Genomic DNA was amplified using PCR, and denaturing gradient-gel electrophoresis was used to localize exons with possible mutations. The polymorphic exons were sequenced or digested with restriction enzymes. A previously described splicing mutation, delta 5, accounted for 11 (61%) of 18 abnormal alleles in the nine families. A single base deletion leading to a frameshift mutation in exon 22 (delta C-22) was found in six of seven alleles. A third mutation, resulting in a nonconservative amino acid substitution in exon 4, accounted for the remaining allele. Thus, three mutations could account for all illness in this group, and two mutations could account for 17 of 18 alleles. In screening 250 normal Ashkenazi individuals for all three mutations, we found only one delta 5 allele. Clinical data revealed no correlation between the particular mutations and symptoms, but male patients were more symptomatic than females, and only males had frank hemolysis and hyperuricemia. Because PFK deficiency in Ashkenazi Jews is caused by a limited number of mutations, screening genomic DNA from peripheral blood for the described mutations in this population should enable rapid diagnosis without muscle biopsy.

Adult↗
PubMed1993

Intrafamilial variability in Hurler syndrome and Sanfilippo syndrome type A: implications for evaluation of new therapies.

Intrafamilial variability has not been reported previously in Hurler syndrome or Sanfilippo syndrome type A. We describe two families in which sibs with comparable deficiencies of alpha-iduronidase (Hurler) or sulfamidase (Sanfilippo type A) activities in vitro nonetheless have divergence in clinical severity and disease progression. These cases underscore the need for caution in counseling as well as the limitations of using sibs as controls in evaluating the outcome of treatment.

Adolescent↗
PubMed1992

Lay and professional knowledge of methods for emergency management of avulsed teeth.

Proper treatment during the first 30 minutes offers the best prognosis for traumatically avulsed teeth. This study sought to determine both lay people's and dental professionals' knowledge of and attitude to emergency procedures. A 12-question survey was administered to 5 groups: (a) parents of learner swimmers and (b) coaches of college sports teams (lay); (c) State Dental Nurses, (d) dentists and (e) dental nurse/receptionists (professional). Respondents totalled 184 (a 32, b 86, c 24, d 18, e 24) i.e. 118 lay and 66 professional. Data revealed that group b had the greatest personal experience of avulsed teeth and groups c and e the least. Public hospital accident and emergency services (A & E) were perceived by all groups as most available. 18% of lay groups could not cite an emergency service. Lay people thought first of A & E for management whereas profession groups preferred the victim's own dentist. Most professional people would replant avulsed permanent teeth and about 1/3 would replant deciduous teeth: 1/2 lay people would replant permanent teeth and 1/8 deciduous teeth. Where treatment was not straightforward lay people would seek advice before acting. Half of the lay groups would transport an avulsed tooth dry. All the professionals had had advice on management of avulsed teeth but only 1/4 of the lay groups. This study highlighted the need for educational campaigns aimed at members of the lay public likely to be involved in the emergency management of traumatically avulsed teeth.

Attitude of Health Personnel↗