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Biomedical subjects

A Smith

Publications and source records attributed to A Smith.

At least 415 records · Page 23Linked to original sources
PubMed1999

Specificity of starch synthase isoforms from potato.

In higher plants several isoforms of starch synthase contribute to the extension of glucan chains in the synthesis of starch. Different isoforms are responsible for the synthesis of essentially linear amylose chains and branched, amylopectin chains. The activity of granule-bound starch synthase I from potato has been compared with that of starch synthase II from potato following expression of both isoforms in Escherichia coli. Significant differences in their activities are apparent which may be important in determining their specificities in vivo. These differences include affinities for ADPglucose and glucan substrates, activation by amylopectin, response to citrate, thermosensitivity and the processivity of glucan chain extension. To define regions of the isoforms determining these characteristic traits, chimeric proteins have been produced by expression in E. coli. These experiments reveal that the C-terminal region of granule-bound starch synthase I confers most of the specific properties of this isoform, except its processive elongation of glucan chains. This region of granule-bound starch synthase I is distinct from the C-terminal region of other starch synthases. The specific properties it confers may be important in defining the specificity of granule-bound starch synthase I in producing amylose in vivo.

Amino Acid Sequence↗
PubMed1999

The diagnosis of Prader-Willi syndrome.

The methylation test can make the diagnosis of Prader-Willi syndrome (PWS) in approximately 99% of patients and is confirmed as a reliable, robust screening test. In a patient with PWS, methylation analysis does not provide the mechanism, for which other different genetic tests are required. Appropriate tests are available in each Australian state.

Adolescent↗
PubMed1999

Application of interphase FISH on direct bone marrow smears for evidence of chimerism in pediatric sex mismatched bone marrow transplantation.

We report here our experience in the management of four children undergoing sex mismatched allogeneic bone marrow transplantation (BMT) who showed evidence of poor engraftment post BMT. Fluorescence in situ hybridisation (FISH) was performed on direct bone marrow smears with the X centromere and Y heterochromatin probes, to ascertain chimerism. Of 16 hybridisations, only one was unsuccessful, whereas routine bone marrow cytogenetics performed at the same time failed in five of eight cultures. The FISH results were available in one to two days. The FISH findings provided a valuable aid in the early management of these children.

Bone Marrow Examination↗
PubMed1999

Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage.

We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P</=.05 were then taken through to the second stage, with an additional 184 families. This second stage confirmed evidence of linkage for markers on chromosome 11q. Additional markers from this region were then typed to create a denser map. We obtained a maximum single-point LOD score, at D11S901, of 2.40 (P=.0004) and a maximum multipoint-LOD score of 3.15, between markers D11S1358 and D11S35. A subset of 196 of the 481 families, comprising affected female sibling pairs, generated a corrected LOD score of 2.54 (P=.0003) for marker D11S901, with evidence for linkage extending 12 cM proximal to this marker. When we stratified for affected male sibling pairs there was no evidence of linkage to chromosome 11. Our data suggest that a female-specific susceptibility gene for idiopathic osteoarthritis is located on chromosome 11q.

Arthroplasty, Replacement↗
PubMed1999

Fluorescein kinetics in interstitial fluid harvested from diabetic skin during fluorescein angiography: implications for glucose monitoring.

BACKGROUND: Glucose monitoring based on sampling skin interstitial fluid (ISF) is being developed as an alternative to fingerstick blood glucose monitoring. Time delays between rapidly changing levels of glucose in blood and interstitial fluid have been reported in the literature to be between 5 and 20 minutes. This study investigated the time delay between the injection of a small molecular weight fluorescent tracer into the circulation and interstitial fluid. METHODS: Diabetic subjects undergoing fluorescein angiography were studied. Skin ISF was sampled using a proprietary microporation and harvesting process. ISF was drawn through micropores created in the stratum corneum. After intravenous injection of sodium fluorescein, samples of ISF were drawn from 2 sites for 30 seconds over a period of 20 minutes. Fluorescence levels in ISF were measured with a fluorometer and used to create ISF fluorescein concentration versus time profiles. RESULTS: The ISF fluorescein versus time profiles were characterized by a rapid rise followed by a slow decay. The time to peak of the ISF fluorescein concentration ranged from 2-4 minutes for the patients studied. CONCLUSIONS: Intravenous injection of a bolus of low molecular weight fluorescent tracer was used to estimate the time delay between changing glucose levels in blood and ISF. The results indicate that the ISF sampling technology utilized here is capable of tracking rapidly rising levels of blood glucose.

Adult↗
PubMed1999

The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase.

The protein kinase gene LKB1 has recently been identified as the gene mutated in the Peutz-Jeghers cancer predisposition syndrome. This condition is characterized by inherited susceptibility to a range of cancers but in particular those of the gastrointestinal tract. Here we have characterized the mouse Lkb1 gene. The mouse Lkb1 gene consists of 10 exons covering approximately 15 kb in length, maps to mouse chromosome 10 and encodes a protein showing strong sequence similarity to human LKB1. The 3" end of Lkb1 in the mouse is in very close proximity to the 3" end of an apparently unrelated gene R29144/1 and it seems probable that overlapping transcripts of the two genes are produced. Using transfection of Lkb1 cDNAs we have shown that Lkb1 is most likely a nuclear protein and have defined a nuclear localization signal within the protein sequence. Thus the defect in Peutz-Jeghers syndrome may directly result in changes in gene expression in the nucleus of target cells.

AMP-Activated Protein Kinases↗
PubMed1999

Dose-rate effects of ethylene oxide exposure on developmental toxicity.

In risk assessment, evaluating a health effect at a duration of exposure that is untested involves assuming that equivalent multiples of concentration (C) and duration (T) of exposure have the same effect. The limitations of this approach (attributed to F. Haber, Zur Geschichte des Gaskrieges [On the history of gas warfare], in Funf Vortrage aus den Jahren 1920-1923 [Five lectures from the years 1920-1923], 1924, Springer, Berlin, pp. 76-92), have been noted in several studies. The study presented in this paper was designed to specifically look at dose-rate (C x T) effects, and it forms an ideal case study to implement statistical models and to examine the statistical issues in risk assessment. Pregnant female C57BL/6J mice were exposed, on gestational day 7, to ethylene oxide (EtO) via inhalation for 1.5, 3, or 6 h at exposures that result in C x T multiples of 2100 or 2700 ppm-h. EtO was selected because of its short half-life, documented developmental toxicity, and relevance to exposures that occur in occupational settings. Concurrent experiments were run with animals exposed to air for similar periods. Statistical analysis using models developed to assess dose-rate effects revealed significant effects with respect to fetal death and resorptions, malformations, crown-to-rump length, and fetal weight. Animals exposed to short, high exposures of EtO on day 7 of gestation were found to have more adverse effects than animals exposed to the same C x T multiple but at longer, lower exposures. The implication for risk assessment is that applying Haber's Law could potentially lead to an underestimation of risk at a shorter duration of exposure and an overestimation of risk at a longer duration of exposure. Further research, toxicological and statistical, are required to understand the mechanism of the dose-rate effects, and how to incorporate the mechanistic information into the risk assessment decision process.

Administration, Inhalation↗
PubMed1999

Pilot trial of infusional 5-fluorouracil, interleukin-2, and subcutaneous interferon-alpha for advanced renal cell carcinoma.

The authors developed an outpatient, three-drug combination regimen for advanced renal cell carcinoma. Treatment was administered for 5 days each week for 4 weeks, followed by 2-week rests. Each weekly treatment consisted of 5-fluorouracil 1,750 mg/m2 continuous intravenous infusion for 24 hours followed by interleukin-2 6 mIU/m2 per day continuous intravenous infusion for 4 days, and interferon-alpha2b 6 mU/m2 subcutaneously on days 1, 2, and 5. This trial was undertaken to assess tolerability to this regimen and obtain a preliminary assessment of its effectiveness. Most patients required some dose adjustments (especially of cytokines), treatment interruptions, or both. Toxicities were as would be expected from individual drug profiles with only mild to moderate hematologic toxicities. Among 16 patients with renal cell carcinoma treated, four had major (clinical partial response) responses, one of which was demonstrated to be a pathologic clinical response after surgical resection of a residual mass. Estimated median survival time of all patients was 93 weeks. Response and survival were correlated with known clinical risk factors. Responding patients were noted to be significantly older in age (X = 61.75 years) than nonresponders (X = 48.92 years). There was no correlation between age and other clinical risk factors, treatment tolerance, or survival. The authors conclude that this three-drug regimen is a practical, tolerable, and promising regimen for further study in renal cell carcinoma.

Adult↗
PubMed1999

Sleep and behavior problems among preschoolers.

This study described the relationship between amount of sleep and behavior problems among preschoolers. Participants were 510 children aged 2 to 5 years who were enrolled through 68 private pediatric practices. Parents reported on the amount of sleep their child obtained at night and in 24-hour periods. With demographic variables controlled, regression models were used to determine whether sleep was associated with behavior problems. The relationship between less sleep at night and the presence of a DSM-III-R psychiatric diagnosis was significant (odds ratio = 1.23, p = .026). Less night sleep (p < .0001) and less sleep in a 24-hour period (p < .004) were associated with increased total behavior problems on the Child Behavior Checklist; less night sleep (p < .0002) and less 24-hour sleep (p < .004) were also associated with more externalizing problems on that measure. Further research is needed to ascertain whether sleep is playing a causal role in the increase of behavior problems.

Child Behavior Disorders↗
PubMed1999

Hepatic sarcoidosis and renal carcinoma.

Sarcoidosis is a relatively common, chronic, multisystem disease of unknown origin. It most commonly affects young adults and usually manifests with bilateral hilar lymphadenopathy or pulmonary infiltrates. Alternatively, it may present with protean manifestations. It has been documented in all organs of the body, with the exception of the adrenal gland. We describe a male patient who presented with hepatic sarcoidosis, with a sclerosing cholangitis-like picture, but without any pulmonary involvement. He was treated with prednisolone and cyclophosphamide, the latter as a steroid-sparing agent. A few years later, renal adenocarcinoma developed. We postulate that this could be related to cyclophosphamide treatment. We present this case history for two reasons: (1) sarcoidosis, selectively affecting the liver and lymph nodes but not the lung, with its hepatic involvement mimicking sclerosing cholangitis, has not previously been reported: and (2) although long-term cyclophosphamide treatment is known to be associated with malignancy, there is only one previous report of its association with a renal adenocarcinoma.

Carcinoma, Renal Cell↗
PubMed1999

Chloramphenicol pharmacokinetics in infants less than three months of age in the Philippines and The Gambia.

BACKGROUND: The broad antimicrobial spectrum and affordable price of chloramphenicol make it an attractive first line treatment option for children with severe illnesses in developing countries. Little is known, however, about its pharmacokinetics in young infants in these settings. METHODS: We studied infants younger than 3 months of age hospitalized in Manila, Philippines and The Gambia with possible severe bacterial infections likely to benefit from treatment with chloramphenicol. Infants in the first week of life received intramuscular doses of 25 mg/kg chloramphenicol once daily, twice daily in the second through fourth week of life and three times daily from 5 to 12 weeks of age. Blood samples were taken at 0.5, 1, 2 and 3 h after the first dose, 1 h before the second dose and before the repetition doses on subsequent days. In the Philippines a second group of infants was treated with oral chloramphenicol according to the same dosage schedule. RESULTS: Thirty-eight infants received intramuscular chloramphenicol, and 20 received oral drug. Intramuscular administration resulted in therapeutic concentrations (10 to 25 microg/ml) in 73 to 86% of children in each of the three age groups in the first 6 h and in 50 to 80% on Days 2 and 3. Between 33 and 38% of children had potentially toxic values on Days 2 and 3. In contrast, after oral administration, only about one-half of the children reached therapeutic values in serum at any time up to Day 3 after start of treatment. CONCLUSIONS: Intramuscular chloramphenicol can be used as a second line drug for the treatment of severe infections in infants younger than 90 days of age, where third generation cephalosporins are not available. It quickly achieves therapeutic values in a high proportion of children. However, severe infections should not be treated with oral chloramphenicol in this age group, because therapeutic serum concentrations were inconsistently achieved.

Administration, Oral↗
PubMed1999

Colorectal cancer and the Muir-Torre syndrome in a Gypsy family: a review.

OBJECTIVES: The Muir-Torre syndrome (MTS) is characterized by an autosomal dominant predilection to sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas, in concert with the cancer phenotype of hereditary nonpolyposis colorectal cancer (HNPCC). Proof that patients showing a familial aggregation of MTS's cutaneous signs in combination with a specific pattern of visceral cancers which are consonant with an HNPCC diagnosis has been buttressed by the discovery of hMSH2 and hMLH1 germ-line mutations in such families. Our purpose in this investigation was to determine the germ-line mutation in a Gypsy family with MTS in concert with HNPCC cancer features, and to provide genetic counseling. An added objective for this paper is to review the literature on MTS. METHODS: We describe a Gypsy family with MTS in concert with HNPCC cancer features, as well as the molecular genetic and genetic counseling procedures used in the interest of improved compliance with cancer control recommendations. We review the clinical phenotype, natural history, and molecular genetics involved in the MTS variant HNPCC. RESULTS: An hMSH2 germ-line mutation was identified as the culprit germ-line mutation in this family. CONCLUSIONS: The presence of the hMSH2 germ-line mutation in this family provides powerful predictability of colorectal and other HNPCC integral cancers. The gastroenterologist must assume an important role in the diagnosis and management of MTS.

Adult↗
PubMed1999

African runners exhibit greater fatigue resistance, lower lactate accumulation, and higher oxidative enzyme activity.

Nine African and eight Caucasian 10-km runners resident at sea level volunteered. Maximal O2 consumption and peak treadmill velocity (PTV) were measured by using a progressive test, and fatigue resistance [time to fatigue (TTF)] was measured by using a newly developed high-intensity running test: 5 min at 72, 80, and 88% of individual PTV followed by 92% PTV to exhaustion. Skeletal muscle enzyme activities were determined in 12 runners and 12 sedentary control subjects. In a comparison of African and Caucasian runners, mean 10-km race time, maximal O2 consumption, and PTV were similar. In African runners, TTF was 21% longer (P < 0.01), plasma lactate accumulation after 5 min at 88% PTV was 38% lower (P < 0.05), and citrate synthase activity was 50% higher (27.9 +/- 7.5 vs. 18.6 +/- 2.1 micromol. g wet wt-1. min-1, P = 0.02). Africans accumulated lactate at a slower rate with increasing exercise intensity (P < 0.05). Among the entire group of runners, a higher citrate synthase activity was associated with a longer TTF (r = 0.70, P < 0.05), a lower plasma lactate accumulation (r = -0.73, P = 0.01), and a lower respiratory exchange ratio (r = -0.63, P < 0.05). We conclude that the African and Caucasian runners in the present study differed with respect to oxidative enzyme activity, rate of lactate accumulation, and their ability to sustain high-intensity endurance exercise.

Adolescent↗
PubMed1999

Signaling mechanisms regulating self-renewal and differentiation of pluripotent embryonic stem cells.

An ability to propagate pluripotent embryonic cells in culture is the foundation both for defined germline modification in experimental rodents and for future possibilities for broad-based cellular transplantation therapies in humans. Yet, the molecular basis of the self-renewing pluripotent phenotype remains ill-defined. The relationship between factors that influence embryonic stem cell propagation in vitro and mechanisms of stem cell regulation operative in the embryo is also uncertain. In this article we discuss the role of intracellular signalling pathways in the maintenance of pluripotency and induction of differentiation in embryonic stem cell cultures and the mammalian embryo.

Animals↗
PubMed1999

Microchimerism of maternal origin persists into adult life.

Recent studies indicate that fetal cells persist in maternal blood for decades after pregnancy. Maternal cells are known to engraft and persist in infants with immunodeficiency, but whether maternal cells persist long-term in immunocompetent offspring has not specifically been investigated. We developed sensitive human leukocyte antigen-specific (HLA-specific) PCR assays and targeted nonshared maternal HLA genes to test for persistent maternal microchimerism in subjects with scleroderma and in healthy normal subjects. Nonshared maternal-specific DNA was found in 6 of 9 scleroderma patients. In situ hybridization with double labeling for X and Y chromosome-specific sequences revealed female cells in peripheral blood samples from 2 male scleroderma patients. HLA-specific PCR also frequently revealed persistent maternal microchimerism in healthy control subjects. The mean age of all subjects with maternal microchimerism was 28 years (range: 9-49 years). With few exceptions, mothers of subjects with persistent maternal microchimerism were HLA incompatible with subjects for class I and class II alleles. These results clearly indicate that HLA-disparate maternal cells can persist in immunocompetent offspring well into adult life. The biological significance of maternal microchimerism and whether it might contribute to autoimmune disease requires further investigation.

Adolescent↗
PubMed1999

The effects of idazoxan on reaction times, eye movements and the mood of healthy volunteers and patients with upper respiratory tract illnesses.

An experiment was carried out to determine whether idazoxan, a drug which increases the turnover of central noradrenaline, removes the malaise (reduced alertness, slower psychomotor performance) associated with upper respiratory tract illness (URTI). Eighty-one volunteers were tested when healthy and 17 returned to the laboratory when they developed URTIs. Those who remained healthy were then recalled as a control group. Volunteers were tested before and after receiving either idazoxan (40mg) or a lactose placebo. Idazoxan removed the URTI-induced slowing in a simple reaction time task and this group performed at a comparable level to the healthy group. No significant stimulant effect of idazoxan was found in the healthy subjects. The results suggest that at least part of the malaise induced by URTIs may reflect reductions in central noradrenaline and that this can be reversed by compounds such as idazoxan.

Adrenergic alpha-Antagonists↗