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Biomedical subjects

J Kennedy

Publications and source records attributed to J Kennedy.

At least 91 records · Page 5Linked to original sources
PubMed1997

Simultaneous analysis of lignocaine and bupivacaine enantiomers in plasma by high-performance liquid chromatography.

A sensitive analytical procedure is described for the simultaneous determination of lignocaine and the enantiomers of bupivacaine in biological fluids using diazepam as an internal standard. After solvent extraction into hexane, the local anaesthetics were separated using an alpha1-acid glycoprotein (AGP) column and detected at 214 nm. Calibration curves were linear (r2>0.99) in the concentration range of 5 to 500 ng/ml for the enantiomers of bupivacaine and 12.5 to 1000 ng/ml for lignocaine. The corresponding limits of detection were 4 ng/ml and 10 ng/ml, respectively. The method was applied to the analysis of plasma from a healthy woman undergoing tubal ligation.

Anesthetics, Local↗
PubMed1997

ACV synthetase: expression of amino acid activating domains of the Penicillium chrysogenum enzyme in Aspergillus nidulans.

Fragments of ACV synthetase of Penicillium chrysogenum carrying partial activities of amino acid activation were expressed under the alcA promoter in an acvA-deletion mutant of Aspergillus nidulans. The 210 kDa domain A-beta-galactosidase fusion protein was partially cleaved to fragments of 200 and 97 kDa. The domain A fragment and the 312 kDa domain BC construct were identified by peptide specific antibodies and shown to catalyze alpha-aminoadipate-, cysteine-, and valine-dependent ATP/[32P]PPi exchange activity. Substrate specificities were investigated using amino acid analogues. Unexpectedly neither alpha-aminoadipate nor valine activation was exclusive, implying possible misactivations and proof reading functions. Both fragments were only expressed in limited amounts and found to be unstable.

Adenosine Triphosphate↗
PubMed1997

Further follow-up of New Zealand participants in United Kingdom atmospheric nuclear weapons tests in the Pacific.

We previously reported a study of deaths and cancer incidence in Royal New Zealand (RNZ) Navy personnel who participated in atmospheric nuclear weapons tests conducted by the United Kingdom in the Pacific in 1957-58. The study involved 528 men known to have participated in the tests, and a control group of 1,504 men who were in the RNZ Navy during the same period but were not involved in the tests. The original follow-up was carried out for the period 1957-87 with an observed increase in risk of leukemia and other hematologic cancers, but little or no increase of non-hematologic cancers or non-cancer deaths in test participants. Follow-up now has been extended for the period 1988-92. For the total follow-up period, there were 97 deaths in test participants and 256 deaths in controls, a relative risk (RR) of 1.1 (90 percent confidence interval [CI] = 0.9-1.3). The RR of death from causes other than cancer was 1.0 (CI = 0.8-1.3), whereas the RR of cancer death was 1.2 (CI = 0.8-1.7) and that of cancer incidence was 1.0 (CI = 0.8-1.4). For cancers other than hematologic malignancies, the RR was 1.0 (CI = 0.7-1.5) for mortality, and 1.0 (CI = 0.7-1.3) for incidence. However, there were eight deaths from hematologic cancers in test participants (RR = 3.8, CI = 1.4-10.8), including four leukemias (RR = 5.6, CI = 1.0-41.7). The RR for incidence of hematologic cancers was 1.9 (CI = 0.8-4.3), and that for leukemia was 5.6 (CI = 1.0-41.6). We concluded that the evidence is still consistent with the hypothesis that some leukemias and other hematologic cancers may have resulted from participation in the nuclear weapons test program, but the further follow-up strengthens the evidence that there is no increased risk for non-hematologic cancers or for causes of death other than cancer in the test participants.

Confidence Intervals↗
PubMed1997

Determinants of house dust mite allergen in homes in Wellington, New Zealand.

OBJECTIVES: To measure levels of the major Dermatophagoidespteronyssinus allergen (Der p 1) in homes in Wellington, New Zealand, and to examine factors which affect these levels. METHODS: As part of a study of risk factors for asthma among 474 8-10-year-old children, standard procedures were used to collect reservoir dust and to measure Der p 1 levels on the living room floor and child's bedroom floor and bedding. Der p 1 levels were analysed both as geometric mean microg/g of fine dust and as microg/m2. Questionnaires collected information about factors which might influence these levels, and an average relative humidity in the bed and on the bedroom floor was also measured. RESULTS: Similar geometric mean levels of Der p 1 were found at each floor site - 25.5 microg/g (95% CI: 22.8-28.5) in the living room and 26.4 microg/g (95% CI: 23.7-29.3) on the child's bedroom floor. The geometric mean level of Der p 1 in the child's bed was 46.6 microg/g (95% CI: 42.3-51.3). After controlling for possible confounders, geometric mean living room and bedroom floor Der p 1 levels were significantly higher in households with older carpet than households with no carpets or newer carpets, and higher in the autumn. Households with three or more children had higher levels of Der p 1 than households with fewer children. Bedding levels were significantly higher in beds with kapok or inner sprung mattresses, or wool underlays and at relative humidities above the mean (51%). CONCLUSION: The very high levels of house dust mite allergen (Der p 1) found in Wellington are likely to be due to a variety of life-style and climatic factors. However, the type and age of floor covering appears to be the single most important factor.

Allergens↗
PubMed1996

delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase is a rate limiting enzyme for penicillin production in Aspergillus nidulans.

The acvA gene from Aspergillus nidulans encoding delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) synthetase was overexpressed by replacing the wild-type acvA promoter with the ethanol dehydrogenase promoter, alcAp, from A. nidulans. The expression level of alcAp was determined using a strain in which the reporter gene, lacZ, is under the control of alcAp, and was found to be up to 100 times greater than that from the acvA promoter when induced in fermentation conditions. Penicillin yields were found to increase by as much as 30-fold when the acvA gene was overexpressed. Glucose, which strongly represses transcription from alcAp, also repressed penicillin biosynthesis in the overexpression strain. These results prove that ACV synthetase is a rate limiting enzyme for penicillin production in A. nidulans.

Alcohol Dehydrogenase↗
PubMed1996

Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: a potential method for monitoring clinical gene therapy.

Noninvasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression is possible with a clinical gamma camera and by single-photon emission tomography (SPECT) using 131I-labeled 2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodo-uracil (FIAU). Studies were performed in rats bearing s.c. tumors. Tumors were produced by injection of wild-type RG2 glioma or W256 mammary carcinoma cells into one flank and RG2TK+ glioma or W256TK+ mammary carcinoma cells (that had been transduced in vitro with the HSV1-tk gene) into the opposite flank. In some animals, HSV1-tk gene transduction of the pre-established wild-type tumors was accomplished in vivo by direct intratumoral injection of retroviral vector-producer cells. Imaging studies were performed 2 weeks after tumor transduction to allow time for production and spread of the retroviruses through the tumor and for sufficient growth and increase in size of the tumors to facilitate imaging. The gamma camera and SPECT images revealed highly specific localization of [131I]FIAU-derived radioactivity to areas of HSV1-tk gene expression at 24, 36, and 48 h after i.v. administration of 1.6-2.8 mCi of [131I]FIAU. Comparative analysis of quantitative autoradiographic images obtained from the same tumors confirmed that the high levels of [131I]FIAU-derived radioactivity (> 1% dose) were localized to areas of HSV1-tk gene expression demonstrated by immunohistochemical staining for HSV1-tk protein. In contrast, significantly lower levels of [131I]FIAU-derived radioactivity (< 0.01%) were observed in the surrounding nontransduced tumor tissue, contralateral wild-type tumors, and other tissues that showed no immunohistochemical staining for the HSV1-tk protein. The magnitude of FIAU accumulation in RG2TK+, W256TK+, and wild-type tumors corresponded to the in vitro ganciclovir sensitivity of the cell lines used to produce these tumors, which indicates that the magnitude of FIAU accumulation reflects the level of HSV1-tk gene expression. We suggest that "clinically relevant" levels of HSV1-tk gene expression in transfected tissue can be imaged with [131I]FIAU and a gamma camera or SPECT, and that a significant improvement in imaging sensitivity and resolution is expected with [124I]FIAU and PET.

Animals↗
PubMed1996

Ultrafast computed tomography as a diagnostic modality in the detection of coronary artery disease: a multicenter study.

BACKGROUND: Ultrafast computed tomography (CT), by acquiring images of the proximal coronary arteries, detects coronary calcifications and has been demonstrated to be highly sensitive for the detection of coronary artery disease in many small studies. The aim of this study was to determine the relationship between ultrafast CT scanning and coronary angiography in a large number of symptomatic patients. METHODS AND RESULTS: The study population consisted of 710 patients from six participating centers. A multivariate logistic regression model was used to evaluate the individual contributions of age, number of calcified vessels, and the calcium score for the probability of angiographically significant disease. Of the 710 patients enrolled, 427 patients had significant angiographic disease, and coronary calcification was detected in 404, yielding a sensitivity of 95%. Of the 23 patients without calcifications, 19 (83%) had single-vessel disease at angiography. Of the 283 patients without angiographically significant disease, 124 had negative ultrafast CT coronary studies, for a specificity of 44%. An increasing number of vessels with calcification present on ultrafast CT was found to increase specificity for the presence of obstructive coronary artery disease in at least one vessel (P < .0001). As the log of the calcium score increases, the probability of multivessel obstructive disease increases (P < .0001). CONCLUSIONS: Ultrafast CT scanning is an noninvasive, non-exercise-dependent test with an excellent sensitivity for the detection of coronary artery disease. The presence of calcifications in multiple vessels and in younger populations correlates with higher specificities for obstructive disease, making ultrafast CT coronary scanning a very useful diagnostic test.

Adult↗
PubMed1996

Febrile urinary infection in the institutionalized elderly.

PURPOSE: Bacteriuria is common among institutionalized elderly populations, but the contribution of urinary infection to febrile morbidity is unknown because of difficulties in clinical ascertainment. This study was undertaken to febrile morbidity using both clinical and serologic criteria. METHODS: Episodes of fever in residents of two long-term care institutions were identified prospectively for 2 years. Serum and urine specimens were obtained initially and at 4 weeks. The proportion of episodes attributable to urinary infection was determined by both standard clinical criteria proposed for use in these populations and serum antibody response to uropathogens. RESULTS: For 372 fewer episodes, 211 met clinical criteria for infection: 147 (40%) of the respiratory tract; 26 (7%) of the genitourinary tract; 25 (6%) of the gastrointestinal tract; and 13 (3%) of skin and soft tissue. Of the remaining 161 fever episodes, 2 (1%) were noninfectious and 159 (43%) were of unknown origin. The prevalence of bacteriuria for residents with nongenitourinary sources of fever varied from 32% to 75%. An antibody response meeting serologic criteria for urinary infection occurred in 26 (8.3%) of 314 episodes with paired sera obtained; 10 (43%) of 23 identified clinically as genitourinary infection, 14 (11%) of 132 unknown, 1 (4%) of 25 gastrointestinal, and 1 (0.8%) of 122 respiratory. The positive predictive value of bacteriuria for febrile urinary infection identified by clinical criteria was was 11% (95% confidence interval [CI] 4%, 18%) and identified by serologic criteria was 12% (95% CI 7%, 17%). CONCLUSIONS: Urinary infection contributes to less than 10% of episodes of clinically significant fever in this high-prevalence bacteriuric population. A restrictive clinical definition for genitourinary infection has poor sensitivity and specificity compared with serologic criteria for identification of fever of urinary source, and bacteriuria has a low predictive value for identifying febrile urinary infection.

Adult↗
PubMed1996

Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4-CD8-T cells.

A novel cytokine originally designated murine CTLA-8 was described as a cDNA isolated from an activated T cell hybridoma produced by fusing a mouse cytotoxic T cell clone and a rat T lymphoma. This cDNA, which contains mRNA instability sequences characteristic of many cytokines, encoded a putative secreted protein that was homologous to the ORF13 gene of Herpesvirus saimiri. The human homolog to this molecule has recently been identified as the proinflammatory cytokine IL-17. We describe the isolation of a cDNA encoding mouse IL-17 from a cDNA library generated from alpha beta TCR + CD4-CD8- thymocytes using a subtraction technique that enriched for activation specific genes. This cDNA shares 87.3% amino acid identity to the previously described murine CTLA-8. Comparison of murine CTLA-8 to a cDNA we isolated from activated rat splenocytes revealed that murine CTLA-8 is, in fact, the rat homolog of IL-17. Mouse IL-17 mRNA is specifically expressed by activated alpha beta TCR + CD4-CD8- T cells, a small subset with a potentially important role in immune regulation. Mouse, rat, and human IL-17 can induce IL-6 secretion in mouse stromal cells, indicating that all homologs can recognize the mouse receptor.

Animals↗
PubMed1996

Selective N-type calcium channel antagonist omega conotoxin MVIIA is neuroprotective against hypoxic neurodegeneration in organotypic hippocampal-slice cultures.

BACKGROUND AND PURPOSE: Neuroprotection by antagonists of both L-type and N-type calcium channels occurs in in vivo models of ischemia. The site of action of calcium channel antagonists is unclear, however, and it is likely that a combination of vascular and direct neuronal actions occurs. We have investigated the effects of blocking neuronal calcium channels using an organotypic hippocampal-slice model of ischemia. METHODS: Organotypic hippocampal-slice cultures prepared from 10-day-old rats were maintained in vitro for 14 days. Cultures were exposed to either 3 hours of oxygen deprivation (hypoxia) or 1 hour of combined oxygen and glucose deprivation (ischemia). Neuronal damage was quantified after 24 hours by propidium iodide fluorescence. RESULTS: Three hours of anoxia produced damage exclusively in CAT pyramidal cells. This damage was prevented by preincubation with omega conotoxin MVIIA, a selective N-type calcium channel blocker, and omega conotoxin MVIIC, which blocks N-type and other presynaptic neuronal calcium channels. The dihydropyridine nifedipine and the mixed calcium channel blocker SB201823-A were not protective. Furthermore, if addition of conotoxin MVIIA was delayed until after the hypoxic episode, a dose-dependent neuroprotective effect was observed, with an IC50 of 50 nmol/L. In contrast to hypoxia, none of the compounds was neuroprotective in the model of oxygen-glucose deprivation, although it was determined that extracellular calcium was essential for the generation of ischemic damage. CONCLUSIONS: These studies present clear evidence that neuroprotection by selective N-type calcium channel antagonists is mediated directly through neuronal calcium channels. In contrast, the neuroprotective effects of dihydropyridines may be mediated through vascular calcium channels or indirectly through actions in other brain regions.

Animals↗
PubMed1996

Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.

PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Voluntary, named testing for HIV in a community based antenatal clinic: a pilot study.

Despite the increasing advantages of identifying HIV infection in pregnant women, only some 12% of HIV positive women attending antenatal clinics in London have been identified by named testing. As virtually all antenatal care will be community based within the next two to three years, we assessed the problems of introducing named HIV testing during pregnancy into the primary care setting. Planning the service took a considerable time and required the production of educational material for both staff and pregnant women and some reorganisation of procedures. Over a one year period an uptake of 44% was noted. Several problems were encountered including an average of 21 minutes needed to give information on AIDS and HIV, an adverse effect on the midwife-mother relationship, and anxiety (affecting both women and midwives). Possible solutions to this difficult problem are discussed.

Attitude of Health Personnel↗
PubMed1995

Molecular cloning and functional characterization of human lymphotactin.

We describe the isolation of a cDNA that encodes human lymphotactin (Ltn), a new class of lymphocyte-specific chemokine. Human Ltn shows similarity to some members of the C-C chemokine family but has lost the first and third cysteine residues that are characteristic of the C-C and C-X-C chemokines. Ltn is chemotactic for lymphocytes but not for monocytes, a characteristic that makes it unique among chemokines. In addition, calcium flux desensitization studies indicate that Ltn uses a unique receptor. The human Ltn gene maps to a different chromosome than do the C-C and C-X-C chemokine families. Taken together, these characteristics indicate that Ltn is the first example of a new class of human chemokines with preferential effects on lymphocytes.

Amino Acid Sequence↗
PubMed1995

DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls.

The DRD4 dopamine receptor is thus far unique among neurotransmitter receptors in having a highly polymorphic gene structure that has been reported to produce altered receptor functioning. These allelic variations are caused by a 48-bp segment in exon III of the coding region which may be repeated from 2-10 times. Varying the numbers of repeated segments changes the length, structure, and, possibly, the functional efficiency of the receptor, which makes this gene an intriguing candidate for variations in dopamine-related behaviors, such as alcoholism and drug abuse. Thus far, these DRD4 alleles have been investigated for association with schizophrenia, bipolar disorder, Parkinson's disease, and chronic alcoholism, and all have been largely negative for a direct association. We evaluated the DRD4 genotype in 226 Finish adult males, 113 of whom were alcoholics, many of the early onset type with features of impulsivity and antisocial traits. Genotype frequencies were compared to 113 Finnish controls who were free of alcohol abuse, substance abuse, and major mental illness. In 70 alcoholics and 20 controls, we measured CSF homovanillic acid (HVA), the major metabolite of dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). No association was found between a particular DRD4 dopamine receptor allele and alcoholism. CSF concentrations of the monoamine metabolites showed no significant difference among the DRD4 genotypes. This study of the DRD4 dopamine receptor in alcoholics is the first to be conducted in a clinically and ethnically homogeneous population and to relate the DRD4 genotype to CSF monoamine concentrations. The results indicate that there is no association of the DRD4 receptor with alcoholism.

Adult↗
PubMed1995

Plasma clozapine levels and the treatment of L-DOPA-induced psychosis in Parkinson's disease. A high potency effect of clozapine.

The purpose of this study was to determine the plasma level of clozapine and its metabolite, N-desmethylclozapine, in Parkinson's disease patients with L-DOPA-induced psychosis responsive to clozapine. The psychotic symptoms of the three patients studied responded to low doses of clozapine with plasma levels of clozapine between 4.5 and 16.1 ng/ml and N-desmethylclozapine between 2.6 and 6.1 ng/ml, much below the plasma clozapine levels usually found in clozapine-treated refractory schizophrenia or affective disorders (range 100 to 687 ng/ml). Possible mechanisms that may account for clozapine's antipsychotic action in dopaminomimetic-induced psychosis in Parkinson's disease, including serotonin2A (5-HT2A) and dopamine D4 receptor blockade, at plasma levels that would be ineffective in refractory schizophrenia, are discussed. It is suggested that 5-HT2A receptor blockade is the most likely basis for the effectiveness of clozapine in L-DOPA psychosis.

Aged↗