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Biomedical subjects

S McLean

Publications and source records attributed to S McLean.

At least 91 records · Page 5Linked to original sources
PubMed1992

Prenatal diagnosis of Pallister-Killian syndrome: resolution of cytogenetic ambiguity by use of fluorescent in situ hybridization.

We report a case of Pallister-Killian syndrome initially diagnosed prenatally as tetrasomy 21. A 33-year-old primiparous woman was noted at 24 weeks' gestation to have moderate polyhydramnios. Ultrasonography showed diminished fetal stomach filling, hydronephrosis, and prominence of the cisterna magna. Cytogenetic analysis of cultured amniocytes was initially interpreted as mosaic tetrasomy 21: 46,XX/47,XX,+i(21q). The patient was then referred to our centre for genetic counselling. At 34 weeks' gestation, a dysmorphic infant was delivered and died within 30 min. Physical features were consistent with the Pallister-Killian syndrome. Renal, gastrointestinal, and central nervous system anomalies were found at post-mortem examination. Analysis of peripheral lymphocytes revealed 5 per cent of cells with a marker chromosome, while 92 per cent of cultured fibroblasts had this same marker. Fluorescent in situ hybridization (FISH) using an alpha-satellite probe for chromosomes 13 and 21 failed to hybridize to the marker, while a chromosome 12 centromeric probe unequivocally identified it as an i(12p). Use of FISH can provide rapid, specific prenatal diagnosis of ambiguous marker chromosomes and improve prenatal counselling.

Abnormalities, Multiple↗
PubMed1992

Is it dementia?

The recognition of early dementia remains a difficult task, calling on the clinician's alertness to subtle clues, skillful assessment and selective use of investigations. This approach may lead to earlier diagnosis, which can reduce carer stress, avoid unnecessary treatments and allow planning and management to begin. The diagnosis of dementia is not an end but the beginning of a partnership in which the general practitioner can greatly assist by adopting a caring and supportive role, while managing practical problems as they arise.

Aged↗
PubMed1991

Automated screening procedure using gas chromatography-mass spectrometry for identification of drugs after their extraction from biological samples.

A novel analytical screening procedure has been developed, using computer-controlled gas chromatography-mass spectrometry (GC-MS), to detect 120 drugs of interest to road safety. This paper describes GC-MS methodology suitable for use on extracts of biological origin, while extraction procedures will be the subject of a future communication. The method was devised to identify drugs in extracts of blood samples, as part of an investigation into the involvement of drugs, other than alcohol, in road accidents. The method could be adapted to screen for other substances. The method depends on a "macro" program which was written to automate the search of GC-MS data for target drugs. The strategy used was to initially search for each drug in the database by monitoring for a single characteristic ion at the expected retention time. If a peak is found in this first mass chromatogram, a peak for a second characteristic ion is sought within 0.02 min of the first and, if found, the ratio of peak areas calculated. Probable drug identification is based on the simultaneous appearance of peaks for both characteristic ions at the expected retention time and in the correct ratio. If the ratio is outside acceptable limits, a suspected drug (requiring further investigation) is reported. The search macro can use either full mass spectra or, for enhanced sensitivity, data from selected ion monitoring (which requires switching between groups of ions during data acquisition). Quantitative data can be obtained in the usual way by the addition of internal standards.

Drug Evaluation, Preclinical↗
PubMed1991

Metabolism of paracetamol and phenacetin in relation to debrisoquine oxidation phenotype.

The metabolism of paracetamol and phenacetin has been studied in subjects previously phenotyped as either extensive or poor metabolisers of debrisoquine (EM and PM, respectively), in order to examine the relationship between phenacetin and paracetamol activation and debrisoquine oxidation status. In separate experiments, paracetamol and phenacetin were administered orally to groups of 5 EM and 5 PM subjects, and the excretion of metabolites measured for 24 h. There were no differences between EM and PM subjects in the excretion of metabolites. After phenacetin, 0.82 of the dose was recovered in urine, mostly as paracetamol glucuronide (51%) and sulphate (30%), with smaller amounts of free paracetamol (4%) and the mercapturate (5%) and cysteine conjugates (5%), 2-hydroxyphenetidine (5%) and N-hydroxyphenacetin (0.5%). Following paracetamol, 0.87 of the dose was recovered, with similar proportions of paracetamol-derived metabolites. It is concluded that the debrisoquine oxidation phenotype is unrelated to either the metabolic activation of phenacetin and paracetamol, or to their overall metabolic clearance.

Acetaminophen↗
PubMed1991

Debrisoquine oxidation polymorphism in a Tasmanian population.

The debrisoquine hydroxylation phenotype was studied in 152 unselected healthy Tasmanian subjects, who were mostly Caucasians of British ancestry. Following a 10 mg oral dose of debrisoquine (D), the ratio of D/4-hydroxydebrisoquine excreted in 8-h urine (metabolic ratio, MR) was determined. MR values were bimodally distributed. Thirteen subjects (8.6%) had MR values from 13.8 to 93.3 and were considered to be poor metabolisers of D, while the others were extensive metabolisers with MR values of 0.04 to 5.4. The D hydroxylation phenotype was not associated with sex. These findings confirm the constancy of D polymorphism in a Caucasian population even after migration to another country.

Adolescent↗
PubMed1990

Thiazole as a carbonyl bioisostere. A novel class of highly potent and selective 5-HT3 receptor antagonists.

A novel structural class of highly potent and selective 5-HT3 receptor antagonists is described. The compounds in this new series contain a thiazole moiety linking an aromatic group and a nitrogen-containing basic region; the thiazole group appears to be acting as a carbonyl bioisostere in this system. An optimized member of this series, 4-(2-methoxyphenyl)-2-[[4(5)-methyl-5(4)-imidazolyl]methyl]thiazole (5), exhibits oral activity in the Bezold-Jarisch reflex paradigm comparable to or better than the standard agents ondansetron (1) and ICS-205-930 (2). Several of the structure-activity relationships are rationalized in terms of a computer pharmacophore model for 5-HT3 receptor binding.

Administration, Oral↗
PubMed1990

An initial three-component pharmacophore for specific serotonin-3 receptor ligands.

With computer modeling, an initial three-component pharmacophore for specific 5-HT3 receptor ligands ICS-205-930 (1), ondansetron (2), zacopride (3), and 3-[2-(guanidinylmethyl)-4-thiazolyl]indol (4) has been identified. Two parts represent electrostatic interactions, one as a hydrogen-bond-donating interaction and the other as a hydrogen-bond-accepting interaction. The third part is represented by a plane in which the lipophilic aromatic groups align. The generation of the pharmacophore relies on the interactions of these ligands with probe atoms representative of a possible hydrogen-bond donor or hydrogen-bond acceptor within the receptor. A carboxylate oxygen was used as a hydrogen-bond-accepting probe and a serine-like hydroxyl was utilized as a hydrogen-bond-donating probe.

Animals↗
PubMed1990

Synthesis, in vitro binding profile, and central nervous system penetrability of the highly potent 5-HT3 receptor antagonist [3H]-4-(2-methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole.

4-(2-Methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole (5) is a highly potent member of a structurally novel series of selective serotonin-3 receptor antagonists. The synthesis of tritiated 5 and its binding profile in neuroblastoma-glioma 108-15 cells are described. Furthermore, in vivo studies in rat with this radioligand indicate that it effectively penetrates the blood-brain barrier upon peripheral administration. Thus, 5 should be a useful pharmacological tool for both in vitro and in vivo studies of this class of compounds.

Animals↗
PubMed1990

In vitro cell-mediated immune responses to Plasmodium falciparum schizont antigens in adults from a malaria endemic area: CD8+ T lymphocytes inhibit the response of low responder individuals.

Plasmodium falciparum schizont extract and purified protein derivative were used to stimulate peripheral blood mononuclear cells obtained from healthy aparasitemic Gabonese individuals with lifelong exposure to malaria infection and non-Gabonese control subjects who have had had no clinical malaria. In vitro lymphoproliferation was measured by uptake of tritiated thymidine, while production of interleukin-2, interferon-gamma, and soluble CD8+ were measured by immunoenzymatic assays. Enumeration of interferon-gamma-producing cells was done using a modified immunoenzyme spot assay. Twenty-eight percent of Gabonese subjects were determined to be low responders in the lymphoproliferative assay, with a tritiated thymidine uptake of less than 6000 c.p.m. The proportions of T cell subsets and the kinetics of the proliferative response were similar in the low and the high responders. Removal of CD8+ T cells from mononuclear cells of low responders or culture of purified CD4+ T cells from the same individuals resulted in a 7-fold increase in the proliferative response to the schizont antigen but not to purified protein derivative (PPD). A similar increase in the proliferative response was seen in the low but not the high responder mononuclear cell cultures stimulated with the schizont antigen in the presence of exogenous interleukin 2 (IL-2) or in the presence of anti-HLA-DQ antibody. Low responder mononuclear cell cultures stimulated with schizont antigen but not PPD produced 3-fold less IL-2, 14-fold less interferon-gamma (IFN-gamma), and 3-fold more soluble CD8 than high responder mononuclear cell cultures. Removal of CD8+ T cells from low responder mononuclear cells resulted in a 2-fold increase in IL-2 production and a 4-fold increase in IFN-gamma production in response to schizont antigen. High responder mononuclear cells stimulated with schizont antigen contained four times as much IFN-gamma-producing cells as low responder cultures, with each IFN-gamma-producing cell producing three times the amount of IFN-gamma as that produced by an IFN-gamma-producing cell in low responder cultures. Removal of CD8+ T cells from low responder mononuclear cells led to a significant increase in the amount of IFN-gamma produced at the single cell level in response to schizont antigen stimulation. In such cultures, the amount of IFN-gamma produced by a single cell was similar between high and low responders. We conclude that in certain individuals, T cell responses to schizont antigen are actively down-regulated by activated schizont-specific CD8+ suppressor T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

HIV preventive medicine services and public health interventions: the Bethesda experience.

A basic Public Health approach to the Human Immunodeficiency Virus (HIV) epidemic has been considered by many to be the most appropriate initial strategy against the spread of this infection. Comprehensive Preventive Medicine services were implemented at Naval Hospital Bethesda, which utilized a sexually transmitted disease (STD) model and included: counseling and education; sexual contact interviews and spouse evaluations; Blood Bank Look Back tracking of donated blood; reporting of notifiable diseases; and screening of transfusion recipients, STD cases, and other at-risk populations. This coordinated approach is highly efficient and capable of evaluating the increasing numbers of HIV-positive individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Cross-linking of [125I]beta-endorphin to mu-opioid receptors during development.

Radioiodinated human beta-endorphin was cross-linked to opioid receptors from rat brain membranes using the bifunctional reagents bis-[2-(succinimidooxycarbonyloxy)ethyl] sulfone (BSCOES) and disuccinimidyl suberate (DSS). Major radiolabeled bands migrated with Mr values of 65,000, 55,000 and 33,000, however the presence of the 55 kDa band was variable. The 65 kDa band was characterized as the mu-receptor: the binding of [125I]beta-endorphin to this band was displaced by mu-selective ligands and blocked by alkylation of the receptor by mu-specific, but not delta-specific alkylating agents. The cross-linked receptor underwent alterations in mol. wt. during development. Early in development, embryonic day 18 and postnatal day 1, the [125I]beta-endorphin-labeled material migrated as a single band of mol. wt. 55 kDa. By day 21 postnatally the higher mol. wt. band of 65 kDa was present, as was material of 53, 47 and 43 kDa. Although the protein labeled early in development migrated with a mol. wt. of 55 kDa similar to the delta-receptor isolated from NG108-15 neuroblastoma-glioma cells, competition studies suggest this protein is not the delta-receptor. The 65 kDa band, tentatively identified as the mu-receptor, was present in adults but not detected in neonates, despite competition binding data indicating the presence of mu-sites. The results suggest that the 55 kDa band found in the 1-day-old neonate may be an immature form of the mu-opioid receptor that undergoes posttranslational modification, perhaps glycosylation, during development.

Alkylation↗
PubMed1989

Receptors and receptor binding methods in drug discovery.

Receptor binding methods provide the most direct measure of drug-receptor interaction currently available. They provide information, inexpensively, rapidly, and reliably on the interaction of chemical agents with receptors. Furthermore, receptor binding may be used to gain insight into receptor dysfunctions that may underlie a variety of diseases. Binding studies have been and will continue to be important in identifying the locus of action of psychotherapeutic drugs. This is not to suggest that in vivo testing should be supplanted by receptor binding assays, but that these assays represent a powerful weapon in the drug discovery team's armementarium and should not be overlooked.

Disease↗