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Biomedical subjects

M Adams

Publications and source records attributed to M Adams.

At least 19 recordsLinked to original sources
PubMed1997

[Clinical value of somatostatin receptor scintigraphy. Studies of pre- and intraoperative localization of gastrointestinal and pancreatic tumors].

BACKGROUND: [111In-DTPA-D-Phe1]-pentetreotide scintigraphy is able to detect neuroendocrine tumors not shown by radiological methods. PATIENTS AND METHODS: In 270 patients with neuroendocrine gastroenteropancreatic tumors (GEP tumors) 400 somatostatin receptor scintigraphies were performed. 70 patients (38 female, 32 male, aged 28 to 74 [56 +/- 12.6] years) underwent surgery and follow-up over 2 years. The aim of the present study was the comparison of preoperative somatostatin receptor scintigraphy with radiological methods (sonography, CT) and intraoperative localization of GEP tumors with a hand-held gamma-probe. RESULTS: Somatostatin receptor scintigraphy was successful in localizing primary tumors in all patients. Liver- and lymph node metastases could be visualized with a sensitivity of 94 and 95 percent. In 7 patients 35 lesions could be identified by intraoperative tumor localization using a hand held gamma probe. Radiological methods identified only 11, surgical palpation 15 and preoperative somatostatin receptor scintigraphy 27 lesions. CONCLUSION: Somatostatin receptor scintigraphy improves detection of small and occult GEP tumors. Intraoperative probe counting with a hand-held gamma probe can identify tumors even when they are small and impalpable, but receptor positive.

Adult↗
PubMed1997

Infectious human herpesvirus 8 in a healthy North American blood donor.

BACKGROUND: Molecular studies have provided strong evidence for the association of human herpesvirus 8 (HHV-8) with Kaposi's sarcoma. These data have been supported by serological studies, which have also suggested that HHV-8 can be found in the healthy population. We report the presence of infectious HHV-8 in a healthy donor to a North American blood bank. METHODS: We examined the peripheral blood mononuclear cells or CD19 cells of blood donors by PCR for evidence of HHV-8 infection. The CD19 cells were separated from peripheral blood mononuclear cells by immunomagnetic-bead selection. To enhance detection of HHV-8, the CD19 cells from eleven unsystematically selected blood donors were activated with phorbol ester and recombinant interleukin-6; the culture fluid was filtered and inoculated onto HHV-8-negative target CD19 cells that had been prepared from phytohaemagglutinin-stimulated peripheral blood mononuclear cells. These inoculated target cells were cultured for 3 days and then analysed for HHV-8 sequences by PCR. Serum samples were tested for antibodies to HHV-8 by an indirect immunofluorescence assay. FINDINGS: One blood donor was consistently found to be infected with HHV-8 by PCR after the cell-culture activation procedure. He was seropositive for the virus. The HHV-8 recovered was infectious, as shown by a reverse-transcription-PCR technique that detected HHV-8 RNA in the inoculated target cells. INTERPRETATION: These data provide the first indication that HHV-8 can be recovered from the blood of a healthy individual, a blood donor, and that the virus is infectious. This observation suggests that HHV-8 could be transmitted by blood transfusion, a possibility that merits further study.

Adult↗
PubMed1997

Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site.

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) regulates transcription in response to prostanoid and thiazolidinedione ligands and promotes adipocyte differentiation. The amino-terminal A/B domain of this receptor contains a consensus mitogen-activated protein kinase site in a region common to PPARgamma1 and -gamma2 isoforms. The A/B domain of human PPARgamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (S84A) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by ERK2 and JNK, and this was markedly reduced in the S84A mutant. A wild type Gal4-PPARgamma(A/B) chimera exhibited weak constitutive transcriptional activity. Remarkably, this was significantly enhanced in the S84A mutant fusion. Ligand-dependent activation by full-length mouse PPARgamma2 was also augmented by mutation of the homologous serine in the A/B domain to alanine. The nonphosphorylatable form of PPARgamma was also more adipogenic. Thus, phosphorylation of a mitogen-activated protein kinase site in the A/B region of PPARgamma inhibits both ligand-independent and ligand-dependent transactivation functions. This observation provides a potential mechanism whereby transcriptional activation by PPARgamma may be modulated by growth factor or cytokine-stimulated signal transduction pathways involved in adipogenesis.

Animals↗
PubMed1997

A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.

The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Magnetic source imaging evidence of sex differences in cerebral lateralization in schizophrenia.

BACKGROUND: It has been postulated that schizophrenia represents a disorder of anomalous cerebral lateralization. This study is a replication of earlier preliminary findings using a multichannel neuromagnetometer, suggesting altered lateralization in schizophrenia in male subjects, with an extension of the findings to female subjects. METHODS: We used magnetoencephalography-based magnetic source imaging to estimate the intracranial location of the 100-millisecond latency auditory-evoked field component (M100) in both left and right hemispheres of 20 patients with paranoid schizophrenia and 20 controls without schizophrenia. Neuroanatomical data were obtained by means of magnetic resonance imaging, from which we segmented and computed volumes of both total brain and left and right superior temporal gyri. RESULTS: Locations of M100 source were compatible with neuronal generators located in the transverse gyri of Heschl on the superior temporal gyri in both study groups; M100 sources were asymmetric in all the control subjects. The male patient subgroup exhibited significantly less asymmetry than the control group, while the female patient subgroup actually showed significantly more asymmetry. The male patient subgroup generally had smaller superior temporal gyri than the control group. No evidence of total brain volume differences was observed. CONCLUSIONS: Our findings support previous magnetoencephalography-based studies suggesting anomalous cerebral lateralization in schizophrenia. Further, in extending our studies to female patients, our data suggest that the nature of this anomaly is sex specific, a finding that, to our knowledge, has not previously been reported.

Adult↗
PubMed1997

Oxaprozin and piroxicam, nonsteroidal antiinflammatory drugs with long half-lives: effect of protein-binding differences on steady-state pharmacokinetics.

The nonsteroidal antiinflammatory drugs (NSAIDs) oxaprozin and piroxicam have long elimination half-lives (t 1/2 approximately 55 hours), permitting once-daily dose regimens. The protein-binding characteristics of these drugs, however, vary widely. This study examines the effect of these binding differences on the drugs' disposition kinetics at steady state. A total of 52 participants (26 young healthy volunteers, and 26 elderly osteoarthritic patients, 15 men and 37 women (2 of them poor metabolizers of debrisoquine [CYP2D6]) completed the two-period, two-treatment, randomized, single-dose and 21-day, once-daily multiple-dose, cross-over study. Doses of oxaprozin and piroxicam were 1,200 mg once daily and 20 mg once daily, respectively. Mean single-dose kinetic parameters of oxaprozin versus piroxicam did not differ more than +/-14% (t1/2, 53.0 versus 57.4 hours; apparent oral clearance adjusted for 70-kg body weight [Clpo], 0.139 versus 0.121 L/hr; apparent volume of distribution adjusted for 70-kg body weight [Vd/F]; 10.2 L versus 9.13 L). Protein binding was plasma-concentration dependent with oxaprozin (range, 10-400 mg/L) but not with piroxicam (range, 1-30 mg/ L). Steady-state conditions were established within 3 days with oxaprozin but took almost 12 days with piroxicam. Compared with the single-dose values, steady-state Clpo (Clpo,ss) and Vd/F of total drug increased with oxaprozin by almost 127% but remained within +/-10% with piroxicam. Post-steady-state apparent t 1/2 of the total and unbound drugs of approximately 62 hours were similarly prolonged with piroxicam but differed substantially with oxaprozin (50.6 hours [total drug] versus 23.8 hours [unbound drug]). Single dose Clpo (Clpo,sd) values of both NSAIDs were significantly correlated in the study populations. With both NSAIDs, Clpo in the two poor metabolizers of debrisoquine was within +/-20% of mean values for the population. Clinically important age- and gender-dependent decreases were not observed in the weight-adjusted, Clpo,sd or Vd/F values of the total drug for either NSAID. Clearances of the two NSAIDs were significantly correlated, suggesting that a common P450 isozyme (most likely CYP2C9, in that piroxicam is a known substrate of this isozyme) may be at least partly involved in the oxidative metabolism of these NSAIDs.

Adult↗
PubMed1997

Alcohol-history taking by nurses and doctors--how accurate are they really?

The aim of this study was to look at how nurses and doctors record alcohol histories on the patients under their care and the frequency and appropriateness of the way they use an alcohol withdrawal scale in the acute hospital setting. To achieve these aims patient records were audited and compared at two points in time, in 1992 and 1994. Results of the study showed that nurses and doctors took alcohol histories from patients on approximately three-quarters of occasions and that this level of recording has not changed over time. The adequacy of alcohol-history taking has, however, increased for both nurses and doctors since 1992. At that time, 71% of the alcohol histories taken by nurses and 74% of alcohol histories taken by doctors were judged to be adequate. By 1994, however, 79% of alcohol histories taken by nurses and 77% of histories by doctors were rated as adequate. The increase in the adequacy of history taking by nurses was significant (chi 2 = 5.05; d.f. = 1; P < 0.05) and the increase by doctors was not significant (chi 2 = 1.03; d.f. = 1; P > 0.05). These results are seen as being positively associated with the major governmental nursing initiative in New South Wales, Australia, the New South Wales Strategic Plan for the Nursing Management of Alcohol and Other Drugs.

Aged↗
PubMed1997

Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass.

The haemostatic system and the use of heparin during cardiopulmonary bypass (CPB) have been studied extensively in adults but not in children. Results from adult trials cannot be extrapolated to children because of age-dependent physiologic differences in haemostasis. We studied 22 consecutive paediatric patients who underwent CPB at The Hospital for Sick Children, Toronto. Fibrinogen, factors II, V, VII, VIII, IX, XII, prekallikrein, protein C, protein S, antithrombin (AT), heparin cofactor II, alpha 2-macroglobulin, plasminogen, alpha 2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin-AT complexes (TAT), D-dimer, heparin (by both anti-factor Xa assay and protamine titration) and activated clotting time (ACT) were assayed perioperatively. The timing of the sampling was: pre heparin, post heparin, after initiation of CPB, during hypothermia, post hypothermia, post protamine reversal and 24 h post CPB. Plasma concentrations of all haemostatic proteins decreased by an average of 56% immediately following the initiation of CPB due to haemodilution. During CPB, the majority of procoagulants, inhibitors and some components of the fibrinolytic system (plasminogen, alpha 2 AP) remained stable. However, plasma concentrations of TAT and D-dimers increased during CPB showing that significant activation of the coagulation and fibrinolytic systems occurred. Mechanisms responsible for the activation of haemostasis are likely complex. However, low plasma concentrations of heparin (< 2.0 units/ml in 45% of patients) during CPB were likely a major contributing etiology. ACT values showed a poor correlation (r = 0.38) with heparin concentrations likely due to concurrent haemodilution of haemostatic factors, activation of haemostatic system, hypothermia and activation of platelets. In conclusion, CPB in paediatric patients causes global decreases of components of the coagulation and fibrinolytic systems, primarily by haemodilution and secondarily by consumption.

Adolescent↗
PubMed1996

A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer.

BACKGROUND: Human papillomavirus (HPV) infection, especially with type 16 or 18, is associated with cervical cancer. Two HPV proteins, E6 and E7, are consistently expressed in tumour cells. The objectives of the study were to examine the clinical and environmental safety and immunogenicity in the first clinical trial of a live recombinant vaccinia virus expressing the E6 and E7 proteins of HPV 16 and 18 (TA-HPV). METHODS: The study was an open label phase I/II trial in eight patients with late stage cervical cancer. The patients were vaccinated with a single dose of TA-HPV and kept in strict isolation to monitor local and systemic side-effects, environmental spread, and anti-E6/E7 immune responses. FINDINGS: Vaccination resulted in no significant clinical side-effects and there was no environmental contamination by live TA-HPV. Each patient mounted an antivaccinia antibody response and three of the eight patients developed an HPV-specific antibody response that could be ascribed to the vaccination. HPV-specific cytotoxic T lymphocytes, the effector mechanism most likely to be of therapeutic benefit, were detected in one of three evaluable patients. INTERPRETATION: Further studies to investigate the use ot TA-HPV for immunotherapy of cervical cancer are warranted.

Adult↗
PubMed1996

Regional assignment and tissue expression of twenty-three expressed sequence tags (ESTs) from human chromosome 5.

Regional localization and expression patterns are reported for 19 expressed sequence tags (ESTs) from human chromosome 5, two of which were derived from the same transcript. Two of the ESTs correspond to genes not previously characterized in humans: a stress-activated protein kinase and nicotinamide nucleotide transhydrogenase. Expression was determined by three methods: Northern blots, PCR from tissue-specific cDNA libraries, and sequence sampling from EST sequencing projects. Six of the ESTs show no expression, and EST01986 appears to be expressed predominantly in the brain by all methods tested.

Chromosome Mapping↗
PubMed1996

Mutation analysis in hereditary hemochromatosis.

The DNA of 147 patients of European origin clinically diagnosed with idiopathic hemochromatosis and 193 controls was examined for mutations of the HLA-H gene at nt 845 and nt 187. One hundred twenty-one (82.3%) of the hemochromatosis patients were homozygous and 10 (6.8%) heterozygous for the 845A (C282Y) mutation. All of the homozygous patients were also homozygous for nt 187C, and all 845A heterozygotes had at least one copy of 187C. Thus, the nt 845 and nt 187 mutations were in complete linkage disequilibrium; nt 187 was a C on all chromosomes with the 845A mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G(H63D). The excess of heterozygotes at both nt 187 and nt 845 suggested either the presence of as yet undiscovered mutations existing in trans with 845A and in linkage disequilibrium with 187G, or that the 187G itself is a deleterious mutation, which in concert with the 845A can give rise to hemochromatosis. None of the 193 normal controls were homozygous for 845A and 29/193 (15%) were heterozygous for 845A. Although 47/193 (24.3%) of normal controls were heterozygous for the 187G mutation only two of these carried the 845A mutation. If the 187G mutation complemented the 845A mutation with high penetrance in causing hemochromatosis, then the population frequency of the two genes would require that a high proportion of patients with hemochromatosis be heterozygous for 845A and 187G. Instead, the frequency of homozygotes for the 845A mutation was much higher than that of the 845A/187G genotype. Based on our data, the penetrance of the 845A/187G genotype is only 1.5% and based on the data of Feder et al. only 0.5%. In contrast, the penetrance of the homozygous 845A/845A genotype seems to be very high. Thus, screening for this genotype should be very useful.

Alleles↗
PubMed1996

Perioperative on-site haemoglobin determination: as accurate as laboratory values?

PURPOSE: This study assessed the accuracy of photometer based haemoglobin (Hb) determination technology (HemoCue) when used by different anaesthetists in situations of rapidly changing Hb values during anaesthesia. METHODS: (Part 1) In the laboratory, repeated measurements were done on 16 split samples of blood using both the Hematology Analyzer (CELL-DYN 3500 System, Abbot Laboratories, San Jose, California) and the photometer. (Part 2) Twelve patients had blood samples drawn from an arterial line for simultaneous Hb determination in the hospital laboratory and by the photometer. At the same time, capillary samples were taken from the patient's earlobe for Hb determination by the photometer. All sample collection and photometer measurements were done by the same operator. (Part 3) The Part 2 protocol was then repeated with different anaesthetists performing both the sampling and the photometer measurements. Statistical comparison was by ANOVA and a two-tailed paired t-test. RESULTS: (Part 1) Samples determined by the photometer and the laboratory were highly correlated (r2 = 1.0, P < 0.001). The average error of each method was similar ( < 4%). (Part 2) Using a 2-tailed paired t-test, the photometer arterial measurements were not different from the laboratory measurements, however the photometer capillary measurements were consistently approximately 8% higher (P = 0.003). (Part 3) When multiple operators performed the sampling there were no differences on arterial or capillary samples (r2 = 0.942, r2 = 0.851 respectively), although the variance was greater. CONCLUSIONS: The HemoCue haemoglobinometer has sufficient accuracy to support treatment decisions regarding blood transfusions.

Anesthesia↗
PubMed1996

Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels.

OBJECTIVES: This study sought to examine whether endothelial function is impaired in the large vessels of asymptomatic young adults with insulin-dependent diabetes and whether endothelial dysfunction is related to duration or control of diabetes, small-vessel disease or other vascular risk factors. BACKGROUND: Endothelial dysfunction is an early event in atherosclerosis, and large-vessel atherosclerotic disease is the major cause of morbidity and mortality in diabetes. METHODS: We compared 80 young adults with insulin-dependent diabetes (15 to 40 years old; mean [+/- SD] diabetes duration 13 +/- 8 years) with 80 matched nondiabetic control subjects. Using high resolution vascular ultrasound, we measured brachial artery responses to reactive hyperemia (with increased flow causing endothelium-dependent dilation) and sublingual glyceryltrinitrate (causing endothelium-independent dilation). RESULTS: Flow-mediated dilation was significantly impaired in diabetic subjects (5.0 +/- 3.7% vs. 9.3 +/- 3.8% in control subjects, p < 0.001). The ratio of flow-mediated dilation to glyceryltrinitrate-induced dilation was significantly lower in the diabetic subjects (p < 0.02), indicating that impaired dilation to increased flow was out of proportion to the impairment of the glyceryltrinitrate response in these subjects (15.6 +/- 5.6% vs. 19.7 +/- 6.6% in control subjects, p < 0.001). On multivariate analysis, flow-mediated dilation was inversely related to both duration of diabetes (r = -0.26, p < 0.05) and low density lipoprotein (LDL) cholesterol levels (r = -0.38, p < 0.005). CONCLUSIONS: Vascular reactivity is impaired in the systemic arteries of asymptomatic young adults with insulin-dependent diabetes and may represent early large-vessel disease. The degree of impairment is related to the duration of diabetes, and these patients appear particularly vulnerable to damage from LDL cholesterol, even at levels considered acceptable in nondiabetic subjects.

Adolescent↗
PubMed1996

Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.

OBJECTIVE: To compare low-molecular-weight preparations of heparin (LMWH) with standard heparin in children requiring anticoagulant treatment for thromboembolic disease. METHODS: We treated 25 children who required heparin, but were at significant risk of bleeding, with LMWH (enoxaparin, Rhone-Poulenc Rorer). The median age was 4 years (range, newborn to 17 years), with nine infants less than 2 months of age. Fourteen children had a deep vein thrombosis or pulmonary embolism, nine had thrombotic complications in the central nervous system, and two had complex congenital heart disease, for which they received prophylaxis at a lower dosage (0.5 mg/kg given subcutaneously twice a day). The remaining 23 children received an initial dose of 1 mg/kg, every 12 hours subcutaneously, with subsequent doses adjusted to achieve a 4-hour anti-factor Xa level between 0.5 and 1.0 unit/ml. RESULTS: Newborn infants had increased dose requirements; an average of 1.60 units/kg was required to achieve therapeutic heparin levels. For the remaining children, the initial dose of 1.0 mg/kg was sufficient. After the initial dose adjustment, LMWH was administered with twice-weekly monitoring. The median duration of therapy with LMWH was 14 days. Two children with previously documented gastrointestinal ulcers bled and required transfusion therapy. Therapy with LMWH was continued without further events. There were no new thrombotic events during the treatment with LMWH. The cost of administering LMWH compared with heparin was reduced by 30% because of decreased laboratory monitoring, blood sampling times, intravenous starts, and nursing time. Needle punctures were reduced with LMWH therapy by the placement of a subcutaneous catheter. CONCLUSION: These results provide the basis for a randomized, controlled trial comparing LMWH with standard heparin in pediatric patients.

Adolescent↗
PubMed1996

Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction.

Hyperhomocyst(e)inemia is associated with an increased risk of coronary artery disease and myocardial infarction. Both genetic and environmental factors influence the plasma level of homocysteine. One of the metabolic pathways for homocysteine involves the enzyme methylenetetrahydrofolate reductase (MTHFR), which regulates the conversion of homocysteine to methionine. A thermolabile variant of MTHFR is associated with reduced enzyme activity and increased plasma homocysteine levels. Recently, the cause of this variant of MTFHR has been identified as a single base change altering an alanine to a valine residue in the protein. Using a PCR-based assay to distinguish the normal and thermolabile variants of MTHFR in this study, we investigated whether the thermolabile variant is a genetic risk factor for myocardial infarction. In a study of 532 subjects (310 myocardial infarction patients and 222 population-based controls), we found no difference in either MTHFR genotype distribution (p = 0.57) or allele frequencies (p = 0.68) between cases and controls. The allele frequencies of the thermolabile variant were 0.34 and 0.35 in cases and controls, respectively. The age- and sex-stratified odds ratio for risk of myocardial infarction associated with homozygosity for the thermolabile variant was 0.85 (95% CI 0.50-1.50, p = 0.57) and that with carriage of the thermolabile allele was 1.06 (95% CI 0.73-1.52, p = 0.76). The odds ratios remained non-significant when restricted to young subjects (< 60 years) or males, and were not influenced by several other risk factors for myocardial infarction considered either singly or in combination. Interestingly, in both cases and controls, there was a trend toward a higher prevalence of hypertension in subjects carrying the normal allele, although as this is a post-hoc finding it needs to be interpreted with caution. The thermolabile variant of MTHFR is not a major risk factor for myocardial infarction and is unlikely to explain a significant proportion of the reported association of hyperhomocyst(e)inemia with coronary artery disease.

Adult↗