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Biomedical subjects

L Sheppard

Publications and source records attributed to L Sheppard.

68 records · Page 4Linked to original sources
PubMed1987

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.

Administration, Oral↗
PubMed1987

1,2-Dimethyl-3-hydroxypyrid-4-one, an orally active chelator for treatment of iron overload.

Subcutaneous desferrioxamine, though effective in preventing or reducing iron overload in transfusion-dependent refractory anaemia, is expensive and inconvenient. One potentially cheaper and orally active alternative is 1,2-dimethyl-3-hydroxypyrid-4-one (L1). This drug has been tested in three multiply transfused patients with myelodysplasia. Gelatin capsules were taken at doses ranging from 0.5 g to 3.0 g. Urinary iron excretion increased substantially in all three patients and in the one tested was equal to that achieved with comparable doses of subcutaneous desferrioxamine. The amounts of iron excreted were related to the dose of L1 administered and the iron load of the patients. The urinary excretion of zinc, magnesium, and calcium did not increase, and the drug was well tolerated.

Administration, Oral↗
PubMed1987

Iron chelation studies using desferrioxamine and the potential oral chelator, 1,2-dimethyl-3-hydroxypyrid-4-one, in normal and iron loaded rats.

A novel iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one, and desferrioxamine were compared for their ability to remove iron and for their site of action in iron release in rats. Repeated intraperitoneal injections of the chelators in rats with widespread tissue labelling by 59Fe derived from transferrin showed comparable 59Fe mobilisation by each chelator in normal and iron loaded rats. Specific labelling of a chelatable "cold" iron pool in hepatocytes by 59Fe derived from ferritin showed this pool to be equally accessible to parenteral doses of both chelators and also to oral 1,2-dimethyl-3-hydroxypyrid-4-one, which is an effective oral iron chelating agent that removes iron from parenchymal cells. This and other alpha-ketohydroxypyridines need further development as potential therapeutic agents in human iron overload.

Animals↗
PubMed1987

New synthetic approach and iron chelating studies of 1-alkyl-2-methyl-3-hydroxypyrid-4-ones.

The major diseases of iron metabolism are iron deficiency anaemia, which could be treated using Fe2+ or Fe3+ salt supplements, and iron overload, which could arise either from an increased gastrointestinal absorption of iron or from recurrent blood transfusions. While the former form of iron overload could be treated by phlebotomy the latter requires the use of a chelator. Desferrioxamine is the only clinically available chelator for the treatment of iron overload but its use worldwide is limited because it is expensive and orally inactive. Several alpha-ketohydroxy heteroaromatic chelators have been synthesised and tested for their iron binding properties at physiological pH. The synthetic route involves the benzylation of the hydroxyl group of maltol using benzyl chloride, the conversion of the benzylated maltol to the 1-alkyl benzylated pyridine derivative by introducing the corresponding alkylamine in alkaline conditions and the cleavage of the benzyl group in acid to form the 1-alkyl-2-methyl-3-hydroxypyrid-4-one. All the chelators are water soluble and stable at a wide range of pH, forming stable, water soluble, coloured iron complexes with a molar ratio of approximately 3 chelator: 1 iron at pH 7.4 and lower molar ratio of chelators to iron complexes at acidic pH. When the 1-methyl, 1-ethyl and 1-propyl, -2-methyl-3-hydroxypyrid-4-ones were mixed at pH 7.4 with transferrin, ferritin and haemosiderin substantial amounts of iron were released.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Phenomena↗
PubMed1986

A review of ten years' experience with surgical equipment in international health programs.

The Johns Hopkins Program for International Education in Gynecology and Obstetrics (JHPIEGO) began in June of 1973 with financial assistance from the Agency for International Development (AID). The purpose of the organization was to provide training and medical equipment to physicians in developing countries to update their education in reproductive health. JHPIEGO began by offering courses in the United States and shortly thereafter began training at centers in the developing countries themselves. Because of its important contributions to gynecological diagnosis in addition to its use in fertility management, laparoscopic equipment has been a major item in JHPIEGO reproductive health training. This paper details the development and role of laparoscopic training in JHPIEGO's program. Laparoscopic training begins with selection of trainees from appropriate institutions. Training itself begins with a didactic session at Baltimore or an in-country center. Trainees then receive clinical training and perform a minimum number of procedures, after which the practitioner, if he or she has successfully completed the clinical practice, can be named eligible to receive medical equipment to be donated to his or her institution. When equipment is installed, a field visit is made by a JHPIEGO consultant to insure the proper use and upkeep of equipment, and the understanding and implementation of standards and procedures. JHPIEGO has trained almost 3000 physicians in laparoscopy techniques between 1973 and 1984.

Developing Countries↗
PubMed1985

Selective visceral angiography for unexplained acute gastrointestinal bleeding in a district general hospital.

Eleven patients are reported with unexplained gastrointestinal haemorrhage (GIH) presenting over a 2 year period in whom selective visceral angiography (SV A) was carried out after a negative endoscopy. SV A revealed the anatomical source of bleeding in all eleven patients and the aetiology in six of them. The latter comprised two tumours of the small bowel, an A-V malformation of the jejunum, enlarged pancreaticoduodenal vessels, angiodysplasia of the caecum and carcinoma of the rectum. Of the remaining five patients, four were seen to have active bleeding into the large bowel and one into the duodenum. Local surgical resection was carried out in nine patients, only one of whom rebled. There was one preoperative and one postoperative death. Experience with this technique has altered our management such that SV A is carried out sooner, saving the patient repeated admissions, investigations and transfusions. SV A is recommended as a pre-operative investigation for the surgeon managing acute unexplained GIH.

Acute Disease↗
PubMed1970

Observer variation in the clinical and radiological assessment of hepatosplenomegaly.

The size of the liver and spleen of 32 patients was assessed by four clinicians from a clinical examination and by four radiologists from a plain radiograph of the abdomen. The latter assessment was found to be subject to less variation than the former, particularly in regard to the liver. Large livers and spleens were more easily seen radiologically than small ones. Most of the variation among the radiologists arose because of the 6% and 24% of cases in which the liver and spleen, respectively, were poorly seen on the radiograph. It is concluded that a plain radiograph of the abdomen, including the diaphragm and with the costal margin indicated, is a useful adjunct to clinical examination.

Hepatomegaly↗
PubMedDate not supplied

Design considerations for estimation of exposure effects on disease risk, using aggregate data studies.

Previously we proposed an aggregate data study design for estimation of exposure effects from population-based disease rates and covariate data from risk factor surveys in each population group. A basic relative rate model specified for individuals is aggregated to produce a random effects relative rate model for the disease rates. Relative rate parameter estimates from aggregate data studies target the same parameters as individual-level studies but use between-group information in the data. We distinguish aggregate data studies from ecologic studies. Considerations in the design of aggregate studies are motivated by the need to gain clearer understanding of the role of diet in cancer aetiology. Simulation studies show that increasing the number of populations included in an aggregate data study from about 20 to 30-40 gives greater improvement in power than corresponding increases in the size of the survey sample in each population over an initial size of 100 individuals.

Aged↗
PubMedDate not supplied

Correcting for the effects of location and atmospheric conditions on air pollution exposures in a case-crossover study.

A limitation of most air pollution health effects studies is that they rely on monitoring data averaged over one or more ambient monitors to represent daily air pollution exposures for individuals. Such data analyses therefore implicitly require the assumption of a homogeneous spatial distribution for particulate matter (PM). This assumption may be suspected in the Pacific Northwest because of its hilly topography and local variations in wood burning. To examine the bias from substituting regional PM (i.e., the average of three ambient monitor measurements) for individual PM exposure, we conducted an exposure substudy to identify the influence of location factors, specifically urban versus suburban classification and topographic features ("upstream" versus "downstream"), on local ambient measurements. Using nephelometer measurements collected over 1 year in four locations, we developed regression models to predict local PM as a function of regional PM, atmospheric stagnation, temperature, and location. We found a significant interaction between atmospheric stagnation and topography, with the most upstream site having reduced PM levels on high stagnation days after controlling for regional PM. We also found a significant interaction with temperature at one downstream site thought to be heavily exposed to wood smoke in the winter. These results are consistent with the physics of surface radiation inversions. The interactions reordered the index versus referent exposures in a case-crossover analysis of out-of-hospital primary cardiac arrest for subjects living in specific locations, but did not meaningfully change the associations with PM from the analysis using regional PM as the exposure. The lack of change in these results may be due to limitations in the data used to correct the exposure estimates or to the absence of a PM effect among persons without prior heart disease who experienced a primary cardiac arrest.

Adult↗
PubMedDate not supplied

Health, symptoms, self-care, and dyadic adjustment in menopausal women.

OBJECTIVE: To determine the relationships among perceived health, menopausal symptoms, and self-care responses in perimenopausal and postmenopausal women. DESIGN: Descriptive, cross-sectional survey. SETTING: A large midwestern city in the United States. PARTICIPANTS: One-hundred-one menopausal women who were over age 40, used no hormones during the previous 6 months, and had an intact uterus. MAIN OUTCOME MEASURES: Four standardized survey instruments. RESULTS: Significant correlations were found between self-rated health and health perceptions (r = .44, p = .0004), self-rated health and total symptoms (r = -.30, p = .0023), self-rated health and worrisome symptoms (r = -.26, p = .0085), health perceptions and worrisome symptoms (r = .30, p = .0195), health perceptions and self-care responses (r = .43, p = .0009), and total symptoms and worrisome symptoms (r = .38, p = .0001). CONCLUSIONS: Health is related to menopausal symptoms and self-care. Dyadic adjustment is not related to health, menopausal symptoms, or self-care. Healthy menopausal women provide self-care and need not automatically be treated for menopause.

Adaptation, Psychological↗
PubMedDate not supplied

People with dementia use schemata to support episodic memory.

This paper describes two experiments which examine whether people with dementia use schemata, established knowledge stores associated with specific scenarios, to aid episodic memory. On all tests of memory, volunteers with dementia remembered less than their age-matched controls. There was evidence for an age-related decline in cognitive resources available for effortful memorizing. For people with dementia, errors of commission in free recall, false recognition scores and reconstruction data were consistent with the use of schema to guide retrieval of items from memory. We conclude that retrieval support improves memory performance for both the healthy and dementing elderly. More importantly, pre-established schemata remain intact well into the course of dementia and can support recall of newly acquired episodic information.

Aged↗