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Biomedical subjects

T A Smith

Publications and source records attributed to T A Smith.

At least 19 recordsLinked to original sources
PubMed1995

Class I HLA antigens in two long-separated populations: Melanesians and South Amerinds.

Class I HLA antigens have been compared in 5,835 Melanesians of Papua New Guinea and 2,028 Amerindians of South America. The sample includes 50 PNGMel ethnolinguistic groups and 22 SAmInd groups. Both carry 15 serologically defined antigens and an undefined C allele. Except for A2 in Papua New Guinea and Cw1 in South America, these antigens are widely distributed in their respective populations. Nine (A2 and A24, B39, B60 and B62, and Cw1, Cw3, Cw4, and Cw7) are common to both. This commonality suggests that these two populations derive from an ancestral population with less polymorphism than modern East Asians. In both populations several theoretically possible haplotypes were absent, and other haplotypes were in positive disequilibrium in both. The parallels in disequilibria suggest that haplotypes are subject to selective forces acting on the level of allelic interaction. Based on three locus haplotype frequencies, the PNGMel groups form five clusters with internally typical linguistic and geographic characteristics and miscellaneous category, but SAmInd groups show no cluster.

Humans↗
PubMed1995

Study of the acute human health effects of intermediates in the synthesis of sodium cromoglycate.

Sodium cromoglycate is manufactured by a seven-stage synthetic process. There has been no previous documentation of toxicological effects of the intermediate compounds in its synthesis. This paper describes the health effects of acute exposure to the intermediates on the skin, eye and respiratory tract. With the exception of the product of the fourth stage, 2,6-dihydroxyacetophenone, no significant local effects arise at exposures of 10 mg m-3. Inhalation of dried 2,6-dihydroxyacetophenone produces nasal irritation and sneezing at short-term exposures of around 1 mg m-3.

Acetophenones↗
PubMed1995

In vivo gene delivery and expression of physiological levels of functional human factor VIII in mice.

Hemophilia A is caused by blood coagulation factor VIII (FVIII) deficiency and is an attractive target for gene therapy. However, features of FVIII physiology, such as the instability of the mRNA and protein, have provided obstacles to the design of a feasible strategy for the transfer and expression of the human FVIII gene in vivo. We have constructed a recombinant adenoviral vector, Av1ALH81, that contains the human FVIII cDNA from which the B-domain has been deleted (BDD FVIII) and extensively characterized this vector in vitro and in vivo. In vitro, HepG2, human hepatoma cells, transduced with Av1ALH81 secreted high levels of biologically active human BDD FVIII measured by the Coatest bioassay (> 2,400 mU per 10(6) cells per 24 hr). Administration of Av1ALH81 to mice, via tail vein, resulted in expression of human BDD FVIII in the mouse plasma at levels averaging 307 +/- 93 ng/ml 1 week post-injection, measured by a sensitive human FVIII-specific ELISA. Normal FVIII levels in humans are 100-200 ng/ml, and therapeutic levels are as low as 10 ng/ml. Purification of the human FVIII from the mouse plasma, and subsequent Coatest analysis, revealed that the human FVIII produced in the mice was biologically active. In addition, the duration of FVIII expression in vivo was followed, and high-level FVIII expression was sustained over a period of several weeks. The finding that an adenoviral vector can mediate high-level expression of human FVIII in an animal model provides the basis for the development of gene therapy for hemophilia A.

Adenoviridae↗
PubMed1995

Using a Delphi Technique in a needs assessment for an innovative approach to advanced general dentistry education.

The University of Kentucky College of Dentistry has been awarded a $500,000 grant to develop and test a university-based educational program leading to a graduate certificate in Advanced General Dentistry, by the use of "extended campus" and distance learning methods. As an aid in developing this curriculum, dentists in general practice in non-urban Kentucky were asked about their educational needs. A Delphi Technique approach to this assessment was adopted. Forty dentists in general practice in non-urban areas in eastern and southern Kentucky were sent four mailings in which they rated or re-rated 65 topics for inclusion in the curriculum. A total of 59 topics were voted to be essential or desirable for the curriculum, 40 of them by a 2/3 majority. The Delphi Technique was workable for involving students in curriculum design. The curriculum produced by this method has also proven to be attractive to the dentists and their colleagues.

Curriculum↗
PubMed1992

An Arabidopsis serine/threonine kinase homologue with an epidermal growth factor repeat selected in yeast for its specificity for a thylakoid membrane protein.

A number of molecules have recently been described that effect the correct transport and assembly of cytoplasmically synthesized proteins to cellular membranes. To identify proteins that bind or modify other proteins during the process of membrane translocation, we developed a yeast selection scheme that employs the yeast transcriptional activator GAL4. This selection facilitates the isolation of cDNAs that encode proteases and binding proteins for known target peptide sequences. We report the isolation of an Arabidopsis cDNA encoding a polypeptide that can interact with the amino terminus of a ligh-harvesting chlorophyll a/b-binding protein (LHCP), a cytoplasmically synthesized protein that is integral to the chloroplast thylakoid membrane. The cDNA was selected in yeast from an Arabidopsis expression library for its ability to inhibit a transcriptional activator GAL4-LHCP fusion protein, but not inhibit native GAL4 protein. The LHCP amino-terminal sequences included in the fusion protein are known to regulate LHCP biogenesis and function. The Arabidopsis cDNA encodes a 595-amino acid protein with at least two functional domains, one with similarity to the family of protein-serine/threonine kinases and another that contains an epidermal growth factor repeat. The identification of an EGF repeat in Arabidopsis indicates that the motif is conserved between the plant and animal kingdoms. Hybridization studies indicate that this gene is likely to be present in other genera of plants. Its mRNA is detected in green leaves but not in other plant tissues or in etiolated plants. The specificity in yeast and the expression pattern in plants together are suggestive of a role for this protein kinase in the assembly or regulation of LHCP.

Amino Acid Sequence↗
PubMed1992

The Malaria Vaccine Epidemiology and Evaluation Project of Papua New Guinea: rationale and baseline studies.

The range of possible malaria vaccines, against different species of Plasmodium and various stages in the life cycle of the parasite in both human host and mosquito vector, is reviewed. The importance, in a malaria-endemic area, of protection by a malaria vaccine against disease rather than infection is emphasized, and the ways by which disease prevention may be achieved are discussed. Mechanisms of production and presentation of vaccines are considered, including the importance of appropriate and more effective adjuvants. The variety of immune responses to malaria is set out and linked to both human and plasmodial genetic factors. Host genetics may also modify susceptibility to malaria through mechanisms which are not immunological. There is a need for entomological studies of the Anopheles vectors, especially but not only in preparation for transmission-blocking vaccines. This overall complexity justifies a multidimensional approach to epidemiology and field-site preparation. An iterative procedure is proposed for initial field evaluation, through adult male volunteers to community studies in immune adults and then to semi-immune school children, before evaluation in the principal target population of nonimmune young children. The outcome variables for epidemiological evaluation are specified. After this brief review of malaria vaccines, the baseline studies being undertaken by the Malaria Vaccine Epidemiology and Evaluation Project of the Papua New Guinea Institute of Medical Research in the Wosera area of East Sepik Province are discussed in some detail, and their rationale linked to the range and complexity of the malaria vaccines that have been reviewed. These studies are described under the headings of their principal components of epidemiology, parasitology, immunology, genetics and entomology.

Animals↗
PubMed1992

Age at menarche and associated nutritional status variables in Karimui and Daribi census divisions of Simbu Province.

Age at menarche was estimated from data on 310 girls and young women living in Karimui and Daribi census divisions of Simbu Province in 1987. The area has high malnutrition rates among children under five years of age and short adult female stature suggesting that onset of menses should be late. However, other work has shown young ages at the birth of first children and high overall fertility rates among women. The prediction of age at menarche from adult female height is not valid for this population; the actual age at which 50% of girls had commenced menstruating is approximately one and a half years earlier, at 15.8 years, than the predicted age. The nutritional status variables investigated and found to be associated with the age at menarche are height, weight and triceps skinfold thickness. At any given age girls whose nutritional status was better, particularly in terms of weight, were more likely to have commenced menstruation. Menarche appears to be followed closely by onset of reproductive function, with the age at the birth of first children estimated at 17.2 years. A consequence of early entry into reproduction, particularly for girls in areas where undernutrition is common, is a period of considerable nutritional stress during adolescence. Intervention programs should consider this and target these groups for additional health, family planning and nutritional advice.

Adolescent↗
PubMed1991

Direct selection for sequences encoding proteases of known specificity.

We have developed a simple genetic selection that could be used to isolate eukaryotic cDNAs encoding proteases that cleave within a defined amino acid sequence. The selection was developed by using the transcription factor GAL4 from Saccharomyces cerevisiae as a selectable marker, a cloned protease from tobacco etch virus (TEV), and an 18-amino acid TEV protease target sequence. In yeast, TEV protease cleaves its target even when the target is fused to internal regions of the GAL4 protein. This cleavage separates the DNA binding domain from the transcription activation domain of GAL4, rendering it transcriptionally inactive. The proteolytic cleavage can be detected phenotypically by the inability of cells to metabolize galactose. Cells expressing the TEV protease can also be selected on the suicide substrate 2-deoxygalactose. DNA binding studies show that the TEV protease decreases the activity of the GAL4/target fusion protein. Because another protease target sequence of 55 amino acids can be inserted into GAL4 without any loss of transcriptional activity, this assay offers the opportunity to use high-efficiency cDNA cloning and expression vectors to select coding sequences of other proteases from various species. The assay could also be used to help define both target specificities and functional domains of proteases.

Base Sequence↗
PubMed1991

The effect of intra-tumour heterogeneity on the distribution of phosphorus-containing metabolites within human breast tumours: an in vitro study using 31P NMR spectroscopy.

The concentration of phosphorus-containing metabolites was determined in extracts of multiple samples from six human breast tumours and in samples from normal and inflamed breast tissue. The degree of lymphoid infiltrate, necrotic fraction and tumour cell and normal tissue fraction were determined on sections taken from each of the tumour samples. In four of the tumours there was a very high degree of variation between samples in the absolute concentration of metabolites. Three of these tumours showed a high degree of intra-tumour variation in the distribution of tumour cells and of normal tissue. The other two tumours were relatively homogeneous with respect to both tumour cellularity and the distribution of phosphorus-containing metabolites. Samples from normal breast tissue was found to contain only low concentrations of phosphorus-containing metabolites. However one of the inflamed samples, which consisted predominantly of macrophages, contained high levels of such compounds. The effect of time delay between resection and freezing on the levels of metabolites in human breast tumours was also examined.

Breast↗
PubMed1991

A comparison of in vivo and in vitro 31P NMR spectra from human breast tumours: variations in phospholipid metabolism.

An in vivo 31P NMR spectrum was obtained from each of four human breast tumours. The phosphomonoester and phosphodiester region of each spectrum consisted of a broad peak. Chemical extracts from samples of each of the tumours obtained at resection were examined on a high field strength NMR system. The phosphomonoester region in the spectrum from each extract resolved into three peaks consisting of phosphocholine, phosphoethanolamine and a nucleoside monophosphate. The phosphodiester region resolved into two components, glycerophosphorylcholine and glycerophosphorylethanolamine. Comparing the in vivo and in vitro data from each tumour showed that the contribution of phosphodiester was much lower in the in vitro spectra. We believe this to be a consequence of phospholipid, which would not appear in the aqueous extract, contributing to the phosphodiester peak in vivo.

Breast Neoplasms↗
PubMed1991

The phosphocholine and glycerophosphocholine content of an oestrogen-sensitive rat mammary tumour correlates strongly with growth rate.

An oestrogen sensitive rat mammary tumour was grown in two groups of female and one group of male hooded rats. The male group and one of the female groups were supplemented with oestrogen. The tumours grew most rapidly in the female supplemented group. When the tumours reached 1.5 cm in diameter they were harvested and the cell cycle distribution and number of cells actively synthesising DNA (bromodeoxyuridine (BrdU) labelling index) determined in each case. Chemical extracts were prepared from each tumour and the concentration of phosphorus-containing metabolites determined using high resolution NMR spectroscopy. The concentration of phosphocholine was found to correlate strongly with the number of cells in S-phase and the number of cells labelled with BrdU, whilst a highly significant negative correlation was observed between these two parameters and glycerophosphocholine. The concentration of phosphoethanolamine did not correlate with either of these measures of proliferation rate. The concentration of glycerophosphorylethanolamine showed a weak negative correlation with the number of cells in S-phase.

Animals↗
PubMed1991

Relationships between growth and acute lower-respiratory infections in children aged less than 5 y in a highland population of Papua New Guinea.

One hundred fifty-six children in the highlands of Papua New Guinea aged less than 5 y, studied for a total of 7019 child-weeks, had an incidence of 1.3 episodes per child-year of acute lower-respiratory-tract infections (ALRIs). There was a marked age trend with an incidence of almost three times this average for children aged less than 6 mo. Those with low weight-for-age or low height-for-age had a higher ALRI incidence rate, with no evidence of cutoffs above which nutritional status had no effect; there was no association between low weight-for-height and increased risk of ALRI. A slow weight gain was not a significant risk factor in the short term but weight gain was reduced during episodes of ALRI.

Aging↗
PubMed1991

Repair of DNA single-strand breaks in lymphocytes from Alzheimer's disease patients.

We have studied DNA single-strand breaks (SSB) and their repair, after gamma-irradiation, in lymphocytes from patients with Alzheimer's disease (AD) and from normal, age-matched individuals, using alkaline sucrose gradient centrifugation. We have found that values for AD patients and normals are similar in each of the following: level of breaks in unirradiated cells, level in cells irradiated with 150 Gy and rate of repair. Also, preliminary results for young and old normal individuals showed no significant difference between their SSB levels in unirradiated cells, nor between levels in irradiated cells nor in repair rate. In all cases, post-irradiation repair appeared to be almost complete after 50 min incubation. We conclude that gamma-irradiation produces no gross difference in the initial number of SSB between lymphocytes from AD patients, old normals and young normals, and that their repair is equally proficient.

Aged↗
PubMed1991

Chemical peritonitis associated with intraperitoneal vancomycin.

A case of chemical peritonitis associated with intraperitoneal vancomycin is reported. A 23-year-old woman presented with signs and symptoms consistent with a chronic ambulatory peritoneal dialysis catheter exit-site infection. Intraperitoneal vancomycin (Vancoled) 1 g was given, followed by 25 mg/L into each subsequent exchange. On day 4 the patient developed abdominal pain and cloudy dialysis effluent. The vancomycin was discontinued, and the dialysate cleared by day 8. Fluid cultures were negative, and Staphylococcus aureus was isolated from the exit site. Subsequent intravenous vancomycin, and smaller intraperitoneal doses, failed to repeat the event. Fluid and serum white blood cell count, serum immunoglobulins and complement, culture results, and the temporal relationship are strongly suggestive of a vancomycin-induced chemical peritonitis.

Adult↗
PubMed1991

Treatment of snakebite poisoning.

The epidemiology, mechanics, prevention, pharmacology, clinical manifestations, and treatment of snakebites are reviewed. Poisonous snakes bite approximately 8000 persons annually in the United States, causing approximately 12-15 deaths per year. Pit vipers (rattlesnakes, copperheads, cottonmouths, and massasaugas) are responsible for 99% of all snakebite poisonings; coral snakes and other foreign exotic species are responsible for the additional 1%. Envenomation is characterized by pain, edema, and ecchymoses at or near the site of venom injection, followed by cardiac, hematologic, neurologic, renal, and pulmonary toxicity. The major clinical finding in most snakebite poisonings is local tissue necrosis. Immediate treatment for snakebite includes limiting movement and placing a constriction band proximal to the site of venom injection. If medical care is more than 30 minutes away, the wound may be incised and suctioned. Antivenin therapy is the mainstay of medical treatment of snakebite, along with administration of plasma expanders, pain medication, diazepam, tetanus toxoid, antiseptics, and antibiotics. Patients who have pain, swelling, ecchymoses, systemic symptoms, or abnormal laboratory findings within 30 minutes to one hour of a bite are probable candidates to receive antivenin therapy. Before receiving antivenin therapy, the patient must be tested for hypersensitivity to the antivenin. Antivenin therapy is most effective when given within four hours of the snakebite. Pharmacists--especially those serving rural areas--should be familiar with current snakebite treatments, both local and systemic, and should be prepared to provide important information and dispel any myths about snakebite poisoning.

Animals↗