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Biomedical subjects

I Smith

Publications and source records attributed to I Smith.

At least 199 records · Page 11Linked to original sources
PubMed1994

Outcome of treatment in young adults with phenylketonuria detected by routine neonatal screening between 1964 and 1971.

Intellectual status at 18 years is reported in 192 patients with phenylketonuria born in the UK between 1964 and 1971, together with their school progress. Mean IQs expressed as standard deviation scores (IQ-SDS) were significantly below estimated population norms, and showed a small decrease from 14 to 18 years of age (mean IQ-SDS -1.06 +/- 1.3 at 14 years and -1.28 +/- 1.07 at 18 years, t = 5.7, p < 0.0001). At 18 years, 27% of subjects had IQs over 2 SDs below the estimated population mean. IQ-SDS at 18 years, although significantly related to average phenylalanine control both between birth and 14 years, and between 14 and 18 years, was not independently related to either variable after allowing for IQ-SDS at 14 years. We conclude that general ability in young adults with early treated phenylketonuria, although reduced in comparison with their peers and closely related to phenylalanine control in early childhood, is not directly influenced by phenylalanine control in the four years preceding the 18th birthday. The apparent fall in IQ-SDS between 14 and 18 years may be due to methodological problems in the analysis of longitudinal IQ data without a control group, rather than providing evidence of intellectual decline.

Adolescent↗
PubMed1993

Cancer-cell traffic in the liver. II. Arrest, transit and death of B16F10 and M5076 cells in the sinusoids.

Fluorescent probes were used to detect BUdR-labelled B16F10 and M5076 cancer cells delivered to the livers of mice via intrasplenic injection. In liver sections stained for succinic dehydrogenase, which permits the periportal, acinar zone 1 to be distinguished from the pericentral zone 3, counts were made of the zonal distribution of fluorescent, intact cancer cells and, by default, the numbers of "lost" cells. Very few intact cancer cells leave the liver from the single bolus of the intrasplenic injection, and even fewer of these generate pulmonary lesions; therefore, within the time limits of these experiments, the liver is virtually a closed system. A dynamic view of intrahepatic cancer-cell traffic with respect to zones 1 (periportal) and 3 (pericentral) was obtained from static measurements of cell densities at different times after intrasplenic injection, by means of Markov chain probability analysis. This indicated that, during the first hour after arrival in zone 1 of the liver sinusoids, there is a 10% probability of a B16F10 cell remaining intact in zone 1, an 89% probability of cell death in zone 1 and only a 1% probability of the cell passing into zone 3. During the same period, there is a 77% probability of an M5076 cell remaining intact in zone 1, a 21% probability of death, and a 2% probability of relocation to zone 3. In both cell types, very few cells were lost from zone 3. Further proportional death in zone 1 diminished over the next 23 hr, concomitant with an increased proportion of cell death in zone 3. Our results indicate that, although there is considerable variation between the 2 cell types studied here, most (B16) or many (M5076) of these cancer cells entering the liver via the portal vein die within 1 hr in zone 1 of liver lobules. In addition, very few of the cells delivered to zone 1 travel along the sinusoids to zone 3, and few of these reach the lungs in a viable state.

Animals↗
PubMed1993

Plasma phenylalanine and tyrosine levels revisited in heterozygotes for hyperphenylalaninaemia.

We examined the value of the fasting plasma phenylalanine/tyrosine ratio obtained in an ordinary clinical setting for assessing the probability of being a heterozygote for hyperphenylalaninaemia. This biochemical test was found to be of little value in those with a high (66%) prior risk of heterozygosity, because it could not reduce the risk below 12%. However, in a population with a prior risk of only 2%, it discriminates the 3% with a 19% risk from the 97% with a risk of 1.5% or less. This simple method could usefully be applied to such a population, in order to select those at higher risk for further investigation using molecular genetics.

Amino Acid Metabolism, Inborn Errors↗
PubMed1993

Pipecuronium-induced prolongation of vecuronium neuromuscular block.

We have examined the prolongation of a maintenance dose of vecuronium after an intubating dose of pipecuronium in 45 patients who received either pipecuronium 70 micrograms kg-1 or vecuronium 200 micrograms kg-1 i.v. for tracheal intubation, followed by either pipecuronium 10 micrograms kg-1 or vecuronium 15 micrograms kg-1 for maintenance of neuromuscular block. The duration of the vecuronium maintenance dose was greater after pipecuronium (40 (SD 12) min) than after vecuronium (29 (9) min) (P = 0.02). The duration of pipecuronium after pipecuronium (49 (15) min) was similar to that of vecuronium after pipecuronium. We conclude that the duration of action of vecuronium is prolonged by prior administration of pipecuronium.

Adolescent↗
PubMed1993

Brain MRI changes in phenylketonuria. Associations with dietary status.

Following the introduction 30 years ago of neonatal screening and early dietary treatment for phenylketonuria there has been a dramatic decrease in the severity of neurological dysfunction associated with this disorder. However, there is evidence that subtle neurological impairment remains common in early treated subjects and in the last 3 years there have been a number of reports of overt neurological impairment with white matter abnormalities on MRI. The frequency of white matter changes in phenylketonuria, and the relation of these changes to dietary management, have remained unclear. The present study examines MRI findings in 34 subjects aged 8-33 years. Twenty-five subjects had been detected by routine neonatal screening and nine had been missed in the screening programme. At the time of the investigation 16 of the early treated and two of the late treated subjects were still receiving a diet low in phenylalanine. All but two of the 34 subjects showed abnormalities on MRI. In the early diagnosed group it could be shown that the severity of MRI changes (graded 1-5) was significantly and independently associated with phenylalanine concentrations at the time of investigation and the time since dietary treatment had been withdrawn. These data are consistent with studies in animals showing that hyperphenylalaninaemia increases myelin turnover in a dose dependent manner. It is suggested that the effects of phenylalanine on myelin pose a lifelong hazard to the nervous system.

Adolescent↗
PubMed1993

SinI modulates the activity of SinR, a developmental switch protein of Bacillus subtilis, by protein-protein interaction.

SinR, a 111-amino-acid DNA-binding protein, is a pleiotropic regulator of several late growth processes in Bacillus subtilis. It acts as a developmental switch, positively regulating genes for competence and motility and repressing aprE and stage II sporulation genes. It is encoded by the second gene in a two gene operon, but previous results have also indicated that these two genes are differently regulated. We show in this discussion that the product of sinI, the first open reading frame (ORF) of this operon, interferes with the function of SinR. In vivo experiments have demonstrated that overexpression of sinI results in phenotypes that are observed in cells with a null mutation of sinR. A chromosomal in-frame deletion of sinI gives rise to a phenotype associated with higher levels of SinR. Thus, SinI acts as an antagonist to SinR. In vitro experiments have shown that the interaction between these two proteins is a direct one. SinI prevents SinR from binding to its target sequence on aprE, and the two proteins form a complex that can be immunoprecipitated with antibodies to either SinR or SinI.

Amino Acid Sequence↗
PubMed1993

Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine.

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.

Child, Preschool↗
PubMed1993

Many peptides that are present in the external zone of the median eminence are not secreted into the hypophysial portal blood of sheep.

Apart from the well recognized factors that are produced by the hypothalamus and secreted into hypophysial portal blood to regulate pituitary function, there is a range of neuropeptides that are present in the median eminence and could be secreted to serve a modulatory function. In this study we have collected hypophysial portal blood and jugular venous blood from sheep in an attempt to identify which of these putative modulatory peptides might be secreted from the median eminence. We have measured neuropeptide Y (NPY), substance P (SP), galanin (GAL), neurokinin A (NKA), peptide histidine isoleucine (PHI), vasoactive intestinal peptide (VIP), neurotensin (NT) and cholecystokinin (CCK). We also examined the sheep median eminence using immunohistochemistry for NPY, SP and GAL and determined degradation profiles of NPY, SP, GAL and NKA in portal and jugular plasma. In no instance did we find that levels of the above peptides were consistently higher in portal blood than in peripheral blood. In some cases levels of peptide were lower in portal plasma e.g. for NPY (6/10 sheep). In one experimental series SP levels in portal plasma were significantly (p < 0.05) lower than levels in jugular plasma but this was not found in another experimental series. Galanin levels were significantly (p < 0.01) lower in portal plasma compared to levels in jugular plasma. We conducted in vitro studies to determine whether or not the above peptides are selectively degraded in portal blood but were unable to show any differences between the rates of degradation in portal and jugular plasma. Immunohistochemistry revealed projections into the external zone of the median eminence for NPY, GAL and SP. This study shows that none of the above peptides are secreted into the hypophysial portal blood of sheep. For some peptides e.g. GAL, enzymes from the endothelial cells of the portal vessels may enhance degradation. Projections into the external zone of the median eminence of neuronal systems containing these peptides may serve to modulate the secretion of the well recognized release and inhibiting factors by acting on the neurosecretory terminals.

Animals↗
PubMed1993

Tuberculosis control learning games.

In teaching health workers about tuberculosis (TB) control we frequently concentrate on the technological aspects, such as diagnosis, treatment and recording. Health workers also need to understand the sociological aspects of TB control, particularly those that influence the likelihood of diagnosis and cure. Two games are presented that help health workers comprehend the reasons why TB patients often delay in presenting for diagnosis, and why they then frequently default from treatment.

Attitude of Health Personnel↗
PubMed1993

Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population.

Accurate diagnosis and management of inborn errors of monoamine neurotransmitter and tetrahydrobiopterin metabolism depend on reliable reference ranges of key metabolites. Cerebrospinal fluid (CSF) was collected in a standardized way from 73 children and young adults with neurologic disease, with strict exclusions. In each specimen, concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), total neopterin, 7,8-dihydrobiopterin, and tetrahydrobiopterin (BH4) were measured using HPLC. There was a continuous decrement in CSF HVA, HIAA, and BH4 during the first few years of life; this was independent of height (or length). Age-related reference ranges for each metabolite are given. Extensive correlations between HVA, HIAA, 7,8-dihydrobiopterin, and BH4 were further analyzed by multiple regression. Age and CSF BH4 were significant explanatory variables for CSF HIAA, but CSF HVA had only HIAA as a significant explanatory variable.

Adolescent↗
PubMed1993

Muscle pain after outpatient laparoscopy--influence of propofol versus thiopental and enflurane.

The incidence and pattern of postoperative muscle pains was studied in 155 healthy women undergoing outpatient laparoscopic surgery who were assigned randomly to one of five treatment groups. Group 1 (control) received thiopental and succinylcholine, 1 mg/kg, followed by enflurane and nitrous oxide. Group 2 received d-tubocurarine, 3 mg, followed by succinylcholine, 1.5 mg/kg, but was otherwise similar to Group 1. Groups 3 and 4 were similar to Group 1, but received propofol instead of thiopental, and Group 4 also received a variable-rate propofol infusion instead of enflurane. Finally, Group 5 was similar to Group 3, but received atracurium instead of succinylcholine. Muscle fasciculations were often observed in Groups 1, 3, and 4, but were attenuated in Group 2 and absent in Group 5. Overall, postoperative shoulder pain occurred in 81%, 72%, and 29% of patients on the first, second, and third postoperative days, respectively. The incidence of this symptom did not differ among the five groups. Neck pain occurred less frequently than shoulder pain in each group, and also occurred less often in Group 5 than in Group 1. Muscle stiffness occurred less often than muscle pain, and also occurred less frequently in Group 5 than in Group 1. In conclusion, succinylcholine contributes to neck pain and muscle stiffness after laparoscopic procedures. Compared to thiopental and enflurane, the use of propofol for induction and/or maintenance of anesthesia failed to alter the incidence of postlaparoscopic muscle pain or stiffness.

Adult↗
PubMed1992

Cancer-cell traffic in the liver. I. Growth kinetics of cancer cells after portal-vein delivery.

Following the intrasplenic injection of B16F10 melanoma cells into mice, at first single cells, and later multicellular tumor foci were observed at different times in the liver. Cell numbers and tumor volumes were determined over the next 12 days, by confocal microscopy of thick liver sections. Fifteen minutes after injection, approximately 20% of the melanoma cells were identified in the liver microvasculature; after 48 hr, only 0.68% of these retained morphologic integrity; by 5 days only 0.13% of the originally detected cells incorporated BUdR; and, by 12 days, these subsequently grew into tumor nodules. Tumor volume changes with time were not exponential and, following a non-replicative period during the first 2 1/2 days, the volume doubling times increased from approximately 8 to 39 hr at 12 days. BUdR incorporation indicated that this was probably due to a diminishing proliferative fraction in the cancer-cell population. When animals were killed at 12 days, tumor foci were centered on the liver sinusoids and appeared to represent expansive growth of arrested cells, with no evidence of parenchymal invasion by migrating cancer cells, in spite of the absence of a subendothelial basement membrane. Our direct observations indicate that, in this model system, the post-delivery phase of hepatic colonization is characterized by high levels of inefficiency with respect to cancer-cell survival, growth and extravasation.

Animals↗
PubMed1992

Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment.

We have investigated the ability of tamoxifen to regulate members of the transforming growth factor beta (TGF-beta) family in human breast cancers in vivo. Using immunohistochemical techniques, we find that 3 months of tamoxifen treatment causes a consistent induction of extracellular TGF-beta 1 in breast cancer biopsies, compared with matched pretreatment samples from the same patient. The induced TGF-beta is localized between and around stromal fibroblasts and appears to be derived from these cells. Lower levels of TGF-beta 1,-beta 2, and -beta 3 seen in epithelial cells were not altered by tamoxifen treatment. The increased stromal staining of TGF-beta 1 occurred in estrogen receptor-negative as well as estrogen receptor-positive tumors. These results provide in vivo evidence for a novel, estrogen receptor-independent mechanism of action for tamoxifen, involving the stromal induction of a potent growth inhibitor for epithelial cells.

Biomarkers, Tumor↗
PubMed1992

Tryptophan and serotonin metabolism in familial erythrophagocytic lymphohistiocytosis.

Reduced concentrations of tryptophan and 5-hydroxyindoleacetic acid (the major CSF metabolite of serotonin) were found in the cerebrospinal fluid of two children with familial erythrophagocytic lymphohistiocytosis. This was associated with elevated cerebrospinal fluid neopterin concentrations indicating increased macrophage activity within the central nervous system. In one child, cytotoxic therapy induced a complete clinical remission and an increase of tryptophan and 5-hydroxyindoleacetic acid concentrations to normal; during a subsequent relapse, concentrations of these analytes again fell below normal. In the other child, in whom therapy produced only a transient improvement, tryptophan and 5-hydroxyindoleacetic acid concentrations remained low and the child died. It is likely that increased activity of indoleamine 2,3-dioxygenase induced by the activation of macrophages was responsible for the disturbance in serotonin and tryptophan homeostasis within the brain. Excessive tryptophan catabolism and the disturbance of serotonin turnover may play a role in the aetiology of the neurological symptoms seen in familial erythrophagocytic lymphohistiocytosis.

Aging↗
PubMed1992

Familial glucocorticoid deficiency with achalasia of the cardia associated with mixed neuropathy, long-tract degeneration and mild dementia.

This paper describes the progress of two previously reported brothers with familial glucocorticoid deficiency, achalasia of the cardia, and alacrima. In their early 'teens both boys developed polyneuropathy with sensory, motor and autonomic components, Parkinsonism, and signs of both dorsal column and pyramidal tract damage. The older boy also showed signs of dementia. Red cell folate levels were markedly reduced but plasma and CSF folate were normal. Serum B12 and erythrocyte concentrations were at or below the lower limit of normal CSF levels of homovanillic acid and 5-hydroxyindole acetic acid (the major metabolites of dopamine and serotonin in brain) were low, indicating impaired turnover of the two amines within the nervous system. Positron emission photometry scans in the older boy showed low binding of c-methyl-spiperone and reduced uptake of 18-F-L-fluorodopa in the striatum, confirming the impairment in dopamine metabolism and suggesting both reduced synthesis and reduced receptor density. Treatment with L-dopa up to 800 mg/day (along with carbidopa 200 mg/day) corrected the low CSF homovanillic acid levels and produced some improvement in the Parkinsonism but no other obvious clinical benefit. Empirical treatment with hydroxycobalamin (1000 micrograms three times a week) and folinic acid (15 mg/day) was without clinical effect. The cause of the neurological disorder, low red-cell folate concentrations, and amine disturbance remains unknown, as does the pathogenesis of the adrenocortical failure.

Adolescent↗
PubMed1992

The Fifth Edition of the Addiction Severity Index.

The Addiction Severity Index (ASI) is 12 years old and has been revised to include a new section on family history of alcohol, drug, and psychiatric problems. New items were added in existing sections to assess route of drug administration; additional illegal activities; emotional, physical, and sexual abuse; quality of the recovery environment; and history of close personal relationships. No changes were made in the composite scoring to maintain comparability with previous editions. This article discusses the clinical and research uses of the ASI over the past 12 years, emphasizing some special circumstances that affect its administration. The article then describes the rationale for and description of the changes made in the ASI. The final section provides "normative data" on the composite scores and severity ratings for samples of opiate, alcohol, and cocaine abusers as well as drug abusing inmates, pregnant women, homeless men, and psychiatrically ill substance abusers.

Adolescent↗