A distance learning program in advanced general dentistry.
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Computer-Assisted Instruction↗
Biomedical subjects
T A Smith
Publications and source records attributed to T A Smith.
Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants.
BACKGROUND: Malaria and anaemia, especially that due to iron deficiency, are two leading causes of morbidity worldwide. Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas. We undertook a randomised comparison of different strategies for control of anaemia and malaria in infants, including an assessment of the effect of iron supplementation on malaria susceptibility. METHODS: 832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October, 1995, were randomly assigned to group DI, receiving daily oral iron (2 mg/kg daily) plus weekly Deltaprim (3.125 mg pyrimethamine plus 25 mg dapsone); group IP, receiving iron plus weekly placebo; group DP, receiving daily placebo plus weekly Deltaprim; or group PP. supplementation was given from 8 to 24 weeks of age, and the weekly chemoprophylaxis from 8 to 48 weeks. The frequency of severe anaemia (packed-cell volume < 25%) and malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys. FINDINGS: The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron (0.62 vs 0.87 cases per person-year; protective efficacy 28.8% [95% CI 6.3-45.8). Iron supplementation had no effect on the frequency of malaria (0.87 vs 1.00 cases per person-year; protective efficacy 12.8% [-12.8 to 32.5]). The groups that received malaria prophylaxis had lower frequencies of both severe anaemia (0.45 vs 1.04 episodes per person-year; protective efficacy 57.3% [43.0-67.9]) and malaria (0.53 vs 1.34 episodes per person-year; protective efficacy 60.5% [48.2-69.9]) than the groups that did not receive prophylaxis. After the end of the intervention period, children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups (relative risks 2.2 [1.3-3.7] and 1.8 [1.3-2.6]). INTERPRETATION: Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity. Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria. Our findings support iron supplementation of infants to prevent iron-deficiency anaemia, even in malaria-endemic areas.
Adult↗
Focus on the effect of bednets on malaria morbidity and mortality.
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Comment↗
Archival fixed and analysed preimplantation human embryonic cells: a DNA resource for retrospective PCR analysis at the cellular level.
Biopsies of human embryonic cell preparations previously analysed by cytogenetic and/or fluorescent in-situ hybridization (FISH) chromosome probes provide a unique reference DNA resource for the archival preimplantation genetic diagnosis (PGD) of the transferred embryo. DNA polymerase chain reaction (PCR) may be utilized on these fixed cell preparations to verify equivocal FISH/PGD results. Retrospective PCR screens of the genotype of biopsied embryonic cell(s) may be of benefit in the case of a suspected genetic mutation. Currently, carrier detection or linkage analysis is often not possible because of early death of the fetus, or of patients with a lethal disease. Alternatively, fixed/stained 'failed fertilized' oocytes provide a resource to extend genetic analysis to infertile patients. A successful research is described which minimizes loss of individual analysed fixed/stained oocytes, metaphase chromosomes, and embryonic cell samples. Initial DNA amplification takes place in situ using a modified PCR protocol. Comparative cellular studies using primer sets previously used for PGD analyses show that 65% of the preparations amplified unequivocally using the modified protocol and primers for a CA repeat motif gene sequence, in comparison with 81% using the original PCR protocol. With further refinement and optimization, the methods outlined have the potential to retrospectively screen archival fixed chromosomes, gametes, and embryonic cells for clinical application, and enable the further study of the fixed human preimplantation embryo at the morphological, cell and molecular level.
Biopsy↗
Allergy to flour and fungal amylase in bakery workers.
The purpose of this study was to describe the prevalence of respiratory symptoms and skin prick test findings in a group of 383 employees in a plant bakery population who had the greatest regular exposure to ingredient dusts. The prevalence of positive skin prick tests to fungal amylase was 16%, in contrast to 6% to wheat flour, suggesting that the principal sensitiser is fungal amylase and not flour. Furthermore, the findings suggest that symptomatic allergy to bread-baking ingredients is uncommon (3.1%). In comparison, occasional short-lived symptoms which do not appear to have an allergic aetiology are relatively prevalent (17.2%). Where sensitisation to ingredients arises, fungal amylase present in bread improvers is the principal allergen.
Amylases↗
The role of low level Plasmodium falciparum parasitaemia in anaemia among infants living in an area of intense and perennial transmission.
Children under one year of age in an area of intense and perennial Plasmodium falciparum transmission were followed up for one year to establish to what extent chronic, low parasitaemia was associated with severe anaemia. There was a significant increase in the prevalence of anaemia (PCV < or = 25%) with increase in parasite density. PCV levels were related not only to concurrent parasite density but also decreased with densities measured one month previously. At any point in time, the mean PCV level in infants with low parasitaemia (< 1000 parasites/microliter) was higher than that of infants with intermediate (1000-9999/microliter) and high parasite densities (> or 10000/microliter). After the age of 7 months, infants with low parasite densities tend to recover, probably as a result of developing immunity. At the age of 12 months, they have similar PCV levels to infants with no detectable parasitaemia by microscopy. The maintenance of low parasite density appears crucial to the survival of infants in malaria endemic areas. The findings suggest that interventions which lower parasite densities in areas of intense transmission reduce the development of severe malarial anaemia and thus malaria-related mortality and morbidity in infants.
Anemia↗
Gene therapy for haemophilia.
Progress toward the development of a gene therapy protocol for the treatment of haemophilia has been substantial. Recent achievements include high level clotting factor expression in mice, dogs, and monkeys as well as phenotypic correction in both mouse and canine models of haemophilia. Studies using adenoviral vectors have contributed to much of the recent success. However, the repertoire of gene transfer vehicles being applied to the development of gene therapy strategies for haemophilia has expanded. In particular, encouraging data has been generated from studies using recombinant adeno-associated virus vectors. Progress toward human clinical trials has been inhibited by host immune responses to treatment which can limit the duration of therapy and prevent readministration. Several strategies have demonstrated the feasibility of circumventing host immune responses, but more effective, clinically applicable procedures remain to be developed. While direct in vivo gene therapy strategies have generated significant progress, the results from ex vivo strategies have not been as encouraging.
Journal Article↗
Duration of protection and age-dependence of the effects of the SPf66 malaria vaccine in African children exposed to intense transmission of Plasmodium falciparum.
The SPf66 synthetic vaccine is safe and partly efficacious against Plasmodium falciparum malaria among children 1-5 years old. The estimated vaccine efficacy [VE] for all clinical episodes over a period of 18 months after the third dose is 25% (95% confidence interval [CI], 1%-44%; P = .044). The observed temporal variations in efficacy could have been due to chance (likelihood ratio chi 2 = 13.8, 8 df; P = .086). Efficacy against clinical malaria did not vary significantly with age (chi 2 = 1.07, 4 df; P = .90). Overall parasite density was 21% lower in vaccine recipients than in the placebo group (95% CI, 0%-38%; P = .044). Further development of SPf66 may require trials to evaluate safety, immunogenicity, and efficacy when administered in the first year of life, together with other vaccines contained in the Expanded Programme of Immunization schedule.
Age Factors↗
Work-related asthma in a population exposed to grain, flour and other ingredient dusts.
The purpose of the study was to determine the prevalence and causation of work-related asthmatic symptoms in a population exposed to grain, flour and other ingredient dusts. Where workers complained of asthmatic symptoms which were the result of dust exposure, follow-up aimed to identify whether the symptoms were the result of sensitisation or of non-specific irritation. A questionnaire was presented to 3,450 workers who had exposure to dust during the course of flour milling (528), bread baking (1,756), cake baking (209) and other activities in food preparation (957). Those with positive responses were followed-up by taking a formal history, examination, skin prick testing and serial peak flow measurement. The overall prevalence of work-related asthmatic symptoms was 4.4% (153 out of 3,450). In the group who were followed-up (128 out of 153), non-specific respiratory irritation was thought to be the cause in 90 (2.6%), whilst sensitisation was responsible for symptoms in 12 (0.3%). Of the 12 cases due to sensitisation, the agents responsible were: fungal amylase (10 cases, all associated with bread baking), flour (one case, associated with flour packing), and grain (one case, associated with flour milling). Non-specific irritation is considerably more common than sensitisation as the cause of work-related asthmatic symptoms in flour milling, baking and other flour-based industries. The prevalence of sensitisation to flour is very low (less than 1 in 1,000) in all these industries. The principal sensitiser encountered in modern plant bakeries appears to be fungal amylase. The most important source of exposure to fungal amylase is probably the debagging, sieving, weighing and mixing of bread improvers.
Adult↗
Cytogenetic and fluorescent in-situ hybridization chromosomal studies on in-vitro fertilized and intracytoplasmic sperm injected 'failed-fertilized' human oocytes.
This study was undertaken to establish baseline data on the chromosomal status of 'failed-fertilized' oocytes derived from in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) procedures. A cytogenetic analysis was undertaken on 162 IVF and 51 ICSI oocytes. In all, 82.1% (133/162) of the IVF and 78.4% (40/51) of the ICSI oocytes had metaphase II (MII) plates, of which 50.4% of the IVF and 47.5% of the ICSI oocytes were analysed further. Chromosomes of the G-group (21-22) were identified with the majority of the anomalies. No overall significant difference in the aneuploidy rate was found for the IVF (37.3%) of ICSI (31.6%) oocytes, or with maternal age. However, chromosome anomalies, e.g. diploidy, fragmented and broken chromatids, single sperm and oocyte chromatids, were found in oocytes from IVF patients aged > 36 years and in the ICSI oocytes throughout the maternal age range (31-38 years). The status of the polar body chromatin indicated that there was no overall significant difference in the maturation of the IVF and ICSI oocytes. Evidence of successful sperm delivery was found in 72.5% (37/51) of the ICSI failed-fertilized oocytes. In this group there was a significant increase in the incidence of premature chromosome condensation: 19.6% (10/51) contained sperm chromosomes, 7.8% (4/51) had swollen sperm heads, and the remaining 45.0% had condensed sperm heads. The presence of both sperm and MII oocyte chromosomes was found in 19.6% (10/51) of the ICSI and 8.6% (14/162) of the IVF failed-fertilized oocytes. Specific fluorescent in-situ hybridization DNA probes were used to re-analyse the chromosomes of karyotyped 'failed-fertilized' IVF oocytes and, for the first time, applied to the karyotyped chromosomes of failed-fertilized ICSI oocytes. The hybridization efficiency was 86-95% for the centromere probe and 100% for probes 21 and 18.
Adult↗
Myxoid/round cell liposarcoma of the extremities. A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma.
Round cell liposarcoma, a high-grade sarcoma, is a poorly differentiated form of myxoid liposarcoma, which is low grade. It is not known, however, how much of a round cell component within an otherwise typical myxoid liposarcoma results in a neoplasm that behaves as a high-grade sarcoma. Twenty-nine cases of myxoid liposarcoma of the extremities with or without a component of round cell liposarcoma were studied to semiquantitate the amount of round cell component needed to adversely affect prognosis. An estimate of the percent of necrosis, round cell liposarcoma, myxoid liposarcoma, and transitional areas was obtained for each slide on all cases. Transitional areas were defined as those that displayed an increased cellularity compared with typical myxoid liposarcoma, but in which the cells remained spindled, did not have overlapping nuclear borders, and retained an easily discernible plexiform vascular pattern. The amount of necrosis was subtracted from the total material available for evaluation, and a composite estimate of the percent of round cell, myxoid, and transitional areas was obtained. Two tumors were located on the upper extremity, 27 on the lower extremity; tumor size ranged frm 3 to 30 cm (median, 14 cm). All 29 tumors had a myxoid component, with a range from 12 to 100% (median, 73%). The range of transitional component for all 29 tumors was 0 to 88% (median, 11%). Twenty-one tumors had transitional areas (range, 4-88%). The range of round cell component for all 29 tumors was 0 to 58% (median, 0%). Twelve tumors had round cell areas (range, 1-58%). Seventeen patients are either alive without disease, or died from unrelated causes at 24-202 months (median, 96 months). Twelve patients are either alive with metastases or died of disease at 10 to 180 months (median, 53 months). Patients with > 5% round cell component in their initial tumor had a statistically significant higher rate of metastasis or death due to disease than those with < or = 5% round cell liposarcoma (p = 0.05). In addition, patients with myxoid liposarcoma with transitional areas did not fare worse than those with myxoid liposarcoma alone. In conclusion, we found that a round cell component of > 5% portends a higher risk of metastasis or death from disease. Furthermore, transitional areas alone do not appear to alter the prognosis of myxoid liposarcoma. Thus, only those areas that are unequivocally round cell liposarcoma should be designated as high grade.
Adolescent↗
Lewy body disease.
Lewy bodies have historically been considered a histopathologic hallmark of idiopathic Parkinson's disease. Recently, it has become clear that Lewy bodies play a role in neurodegenerative processes other than idiopathic Parkinson's disease, including diffuse Lewy body disease and diffuse Lewy bodies with concomitant Alzheimer's disease changes. It is likely that these processes represent a spectrum of neurodegenerative change in which Lewy bodies play a pivotal role. Although much is known and has been written regarding the histopathology and pathophysiology of Lewy body diseases, specific criteria for their diagnosis remain problematic. Within the spectrum of Lewy body disease, overlap in clinical presentation and histopathologic findings has caused some to dismiss attempts at subcategorizing Lewy body disease as artificial. We present, in brief, current information and theories concerning the pathology and pathogenesis of Lewy body disease.
Alzheimer Disease↗
Evaluating a telemedicine delivery system.
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Computer Communication Networks↗
Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector.
The in vivo administration of adenovirus vectors frequently elicits a neutralizing antibody response which eliminates or substantially reduces the efficacy of subsequent treatments. Methods to overcome this significant barrier to repeat delivery will be required for the application of adenovirus-based gene therapy in the treatment of chronic disease. We have evaluated the relationship between the initial vector dose and the effectiveness of a second vector administration. C57BL/6 mice injected intravenously with up to 10(7) p.f.u. of a lacZ adenovirus vector, Av1lacZ4, expressed significant levels of human factor IX when injected with 2 x 10(8) p.f.u. of the factor IX vector, Av1H9F, 5 weeks later. An initial dose of 10(8) p.f.u. of Av1lacZ4 completely prevented expression of factor IX following the second administration due to the generation of neutralizing antibody. However, transient immunosuppression with deoxyspergualin (DSG) or cyclophosphamide at the time of initial exposure to 10(8) p.f.u. of Av1lacZ4 prevented the formation of anti-adenovirus neutralizing antibody and permitted an effective second administration of a factor IX vector. Furthermore, transient immunosuppression with cyclophosphamide concomitant with delivery of the factor IX vector enabled an effective administration of a third vector encoding human factor VIII. This approach, together with strategies to prolong the persistence of adenoviral vector expression, should permit long-term therapy with adenovirus-based vectors.
Adenoviruses, Human↗
Nicotine patch therapy in adolescent smokers.
OBJECTIVE: To evaluate the safety, tolerance, and efficacy of 24-hour nicotine patch therapy in adolescent smokers who were trying to stop smoking. DESIGN: Nonrandomized, open-label, 6-month clinical trial. SETTING: Five public high schools in the Rochester, MN, area. SUBJECTS: Twenty-two adolescent smokers, aged 13 through 17 years, with current smoking rate of 20 or more cigarettes per day (cpd). INTERVENTION: Daily nicotine patch therapy for 8 weeks (22 mg/d for 6 weeks followed by 11 mg/d for 2 weeks). Weekly individual behavioral counseling and group support continued for 8 weeks with follow up visits at 3 and 6 months and a mailed survey at 1 year. MAIN OUTCOME MEASURES: Self-reported smoking abstinence verified by expired air carbon monoxide of 8 ppm or less, nicotine withdrawal symptoms, adverse experiences, and blood cotinine levels. RESULTS: Subjects had a mean +/- SD smoking rate of 23.3 +/- 5.0 (range, 20 to 35) cpd at study entry and 2.6 +/- 1.6 years of smoking; the mean age was 15.9 +/- 1.2 (range 13 through 17) years, and 68% were girls. Of the 22 participants, 19 (86%) completed patch therapy, 3 (14%) had biochemically validated smoking cessation at week 8, and 1 continued to be smoke free at 3 and 6 months after patch initiation. There was a significant decrease from baseline in the mean nicotine withdrawal scores for days 4 and 7 of week 1 and the mean for weeks 2 through 8. Skin reactions were the most common adverse event. As the worst skin reactions, 55% had erythema only, 5% had erythema and edema, and 9% had erythema and vesicles, whereas 32% had no skin reactions. Other reported adverse events were headaches (41%), nausea and vomiting (41%), tiredness (41%), dizziness (27%), and arm pain (23%). None of these were considered serious, life threatening, or led to the discontinuation of patch therapy. In adults with comparable smoking rates, we found that the adolescents had lower blood cotinine levels. Those smoking 20 to 25 cpd had cotinine levels of 146 +/- 84 (adolescents) vs 260 +/- 98 (adults) ng/ml, and those smoking 26 to 35 cpd had levels of 169 +/- 73 vs 276 +/- 110 ng/ml, respectively. CONCLUSION: Nicotine patch therapy seems safe in adolescent smokers. Placebo-controlled trials are needed to establish the efficacy of nicotine patch therapy in adolescents.
Administration, Cutaneous↗
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↗
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↗
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↗