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Biomedical subjects

D Clarke

Publications and source records attributed to D Clarke.

At least 91 records · Page 5Linked to original sources
PubMed1998

Recombinant human respiratory syncytial virus (RSV) from cDNA and construction of subgroup A and B chimeric RSV.

Infectious human respiratory syncytial virus (RSV) was produced from a cDNA clone that contains 15,222 nucleotides of RSV genome derived from the A2 strain of subgroup A. Recovery of infectious RSV from cDNA required cotransfection of only three expression plasmids encoding the nucleoprotein (N), the phosphoprotein (P), and the major polymerase protein (L). Inclusion of the M2-1 plasmid was not required in the transfection reaction and if included did not significantly increase the rescue efficiency. However, a single nucleotide substitution in the RSV leader region (C to G at position 4 in the antigenomic sense), greatly increased the amount of infectious virus recovered from cDNA. A recombinant RSVA2 virus that expresses an additional structural G protein derived from a subgroup B RSV was also obtained. Both A2 and B strain G glycoproteins were expressed in cells infected with the chimeric RSV. A chimeric RSV that expresses a heterologous subgroup antigen in a live attenuated vaccine candidate may be important for prevention of diseases associated with both RSV subgroup A and subgroup B infection.

Animals↗
PubMed1998

Growth-related and antennular amputation-induced changes in the olfactory centers of crayfish brain.

Freshwater crayfish increase in size throughout their lives, and this growth is accompanied by an increase in the length of the appendages and number of mechanoreceptive and chemoreceptive sensilla on them. We find that in the Australian freshwater crayfish Cherax destructor, neuropil volumes of the olfactory centers increase linearly with body size over the entire size range of animals found in their natural habitat. The number of cell somata of two groups of interneurons associated with the olfactory centers (projection neurons and small local neurons) also increases linearly with the size of the animals. In contrast, axon counts of interneurons that represent a nonolfactory input to the olfactory centers show that these reach a total number in the very early adult stages that then remains constant regardless of the size of the animal. Only the axon diameter of these interneurons increases linearly with body size. Amputation of the antennule and olfactory sensilla reduces the number of projection and local interneurons on the amputated side. No change in the size of the olfactory centers occurs on the unamputated side. Amputation of the olfactory receptor neurons in crayfish therefore leads not only to a degeneration of the receptor cell endings in the olfactory lobe but also to a trans-synaptic response in which the number of higher order neurons decreases. Reconstitution of the antennule and olfactory receptor neurons in small adult crayfish is accompanied by the reestablishment of the normal number of interneurons and neuropil volume in the olfactory centers.

Aging↗
PubMed1998

Temporal architecture of violent incidents.

Five hundred five reports of violent incidents in British pubs and bars were studied by using logical pathway modeling to provide information on the processes underlying work-related violence. Logical pathway modeling is innovative in examining and mapping sequences in real incidents at a population level. The data reveal the most common pathway to be misbehavior by customers, intervention by staff (before any physically violent act), physical attack on staff, and injury to staff. The data also highlight the likelihood of further action after assailants have exited and identify stages in incidents at which most staff and customer injuries and damage to property occur. Results assist in the design of strategies to reduce the risk from future violence, particularly by training staff to recognize and to handle potentially violent situations and to maintain vigilance and security following problem incidents.

Accidents, Occupational↗
PubMed1998

Prader-Willi syndrome and psychotic symptoms: 1. Case descriptions and genetic studies.

Six people with Prader-Willi syndrome (PWS) who developed psychoses are described. Along with other literature reviewed in the present paper, the results imply an association between PWS and psychotic symptoms. Genetic studies were possible in five cases and SNRPN expression was examined in three cases. Maternal uniparental disomy and 15q11q13 deletions were found, demonstrating that psychotic symptoms are not associated with a single type of genetic abnormality.

Adolescent↗
PubMed1998

Prader-Willi syndrome and psychotic symptoms: 2. A preliminary study of prevalence using the Psychopathology Assessment Schedule for Adults with Developmental Disability checklist.

The Psychopathology Assessment Schedule for Adults with Developmental Disability (PAS-ADD) checklist was used to screen for psychotic symptoms among people with Prader-Willi syndrome (PWS) aged 16 years and over. The scoring instructions for the PAS-ADD checklist were modified to take account of knowledge about the behavioural phenotype of PWS. Using modified scoring, 6.3% of the 95 people for whom checklists were completed had a possible psychotic disorder in the month before the assessment was made. The results should be treated as a crude estimate of the prevalence of psychotic symptoms associated with PWS in adult life in view of potential biases in the sample reported. These findings lend some support to the hypothesis that PWS has a non-chance association with psychotic symptoms and that the association is not entirely accounted for by the increased prevalence of psychosis associated with intellectual disability.

Adolescent↗
PubMed1998

Long-term prognosis in unstable angina. The importance of early risk stratification using continuous ST segment monitoring.

AIMS: To assess the ability of clinical characteristics, admission ECG and continuous ST segment monitoring in determining long-term prognosis in unstable angina. METHODS: Two hundred and twelve patients with unstable angina (mean age 59 years), presenting within 24 h of an acute episode of angina were recruited at three hospitals and treated with standardized medical therapy. All patients kept chest pain charts and underwent ST segment monitoring for 48 h. The occurrence of death, myocardial infarction, and need for revascularization was assessed over a median follow-up of 2.6 years. RESULTS: The risk of death of myocardial infarction was greatest in the first 6-8 weeks after admission. Admission ECG ST depression and the presence of transient ischaemia predicted increased risk of subsequent death or myocardial infarction, whereas a normal ECG predicted a good prognosis. In 14 patients, ST segment monitoring provided the only evidence of recurrent ischaemia, and 72% of this group suffered an adverse event. Transient ischaemia and a history of hypertension were the most powerful independent predictors of death or myocardial infarction. CONCLUSIONS: Adverse events in unstable angina occur early after admission and can be predicted by clinical and ECG characteristics, and by the presence of transient ischaemia during ST segment monitoring. Risk stratification by these simple assessments can identify patients with unstable angina at high risk.

Adult↗
PubMed1998

Long-term (5 year) effects of transient (silent) ischaemia on left ventricular systolic function in stable angina. Clinical and radionuclide study.

AIMS: (a) to assess short (1 year) and long-term (5 year) changes in left ventricular ejection fraction in patients with stable coronary disease with or without ECG evidence of transient ischaemia during daily life on routine therapy, and (b) to assess whether patients with recurrent transient ischaemic episodes have a particular propensity to gradual deterioration in left ventricular ejection fraction in the absence of infarction. METHODS AND RESULTS: One hundred and forty eight patients (127 males; mean age 59 years), part of a natural history cohort of 172 patients who had undergone exercise testing, 48 h ambulatory ST monitoring, and resting radionuclide ventriculography at baseline, and who had not suffered any intervening cardiac event, underwent repeat radionuclide ventriculography at 1 year follow-up on identical or very similar medications. Furthermore, 56 patients (50 males; mean age 65 years) of this cohort, who had ischaemia both on exercise testing and ambulatory monitoring at baseline (n=33), or no ischaemia on either test at baseline (n=23), and who had suffered no intervening event, underwent repeat exercise testing, ambulatory monitoring and radionuclide ventriculography at a mean of 61.8 months follow-up. In 38 of these 56 cases, long-term testing mirrored baseline testing in terms of presence or absence of ischaemia (both tests +, n=25; both tests -, n=13). At one year there was no change in left ventricular ejection fraction, either for the whole group (n=148; left ventricular ejection fraction 47=11.6% - 47.13+11.07%, P=ns) or for subgroups with (n=62; left ventricular ejection fraction 48+12.1%-48.5+10.5%, P=ns) and without (n=86; left ventricular ejection fraction 46.2+10.4%-46.2+11.3%, P=ns) evidence of transient ischaemia at baseline. At 61 months, there was a small fall in mean left ventricular ejection fraction for the total study group (n=56; left ventricular ejection fraction 45.8+9.3%-42.1+8.8%, P<0.05); however, this fall was not significant for those patients with both baseline and 5 year evidence of transient ischaemia (n=25; left ventricular ejection fraction 44.9+8.7%-41.3+7.5%, P=0.056). CONCLUSION: In medically treated stable coronary patients who do not suffer any intervening cardiac event, recurrent transient (silent) ischaemic episodes do not, in themselves, lead to gradual deterioration in left ventricular systolic function over a 1-5 year period.

Adult↗
PubMed1998

Increased platelet responsiveness following coronary stenting. Heparin as a possible aetiological factor in stent thrombosis.

AIMS: Platelet activation may be a determinant of thrombotic and restenotic complications following intracoronary stenting. In order to measure the effect of stenting on platelet activation antigen expression we used whole blood flow cytometry in 18 patients undergoing Palmaz-Schatz stenting (treated with full anticoagulation) and compared these with a group of 18 patients undergoing elective angioplasty. The effects of low molecular weight heparin and unfractionated heparin on platelet behaviour were also studied, both in vitro and in vivo to determine the contribution of prolonged heparin therapy to platelet activation following stenting. METHODS AND RESULTS: Fibrinogen binding to activated GPIIb-IIIa, and surface expression of P-selectin, GPIb and GPIIb-IIIa antigens were measured in unstimulated peripheral blood samples (rest) and on stimulation with adenosine diphosphate (0.1-10 micromol x 1(-1)) and thrombin (0.02-0.16 U x ml(-1)). No changes were seen in resting samples following angioplasty or stenting. Agonist responsiveness was unaltered after angioplasty, but in stented patients antigen expression in response to thrombin was significantly reduced (P< or =0.04), whilst the adenosine diphosphate response was significantly increased (P=0.01). Similar effects were observed in patients with unstable angina treated with either low molecular weight heparin or unfractionated heparin in vivo. In vitro, both unfractionated and low molecular weight heparin inhibited thrombin-induced platelet activation, but stimulation of adenosine diphosphate responses was more marked with unfractionated than low molecular weight heparin. CONCLUSIONS: There was a significant increase in platelet responsiveness to adenosine diphosphate following intracoronary stenting in patients treated with conventional anticoagulants. This was probably a consequence of treatment with heparin. Activation of platelets by heparin may explain the increased rate of stent thrombosis in patients treated with anticoagulant therapy. Low molecular weight heparins stimulate platelets less than unfractionated heparin.

Adenosine Diphosphate↗
PubMed1998

Hyperbaric oxygen and thrombolysis in myocardial infarction: the 'HOT MI' randomized multicenter study.

In a previous pilot study, we demonstrated that adjunctive treatment with hyperbaric oxygen (HBO) appears to be feasible and safe in patients with acute myocardial infarction (AMI) and may result in an attenuated rise in creatine phosphokinase (CPK), more rapid resolution of pain and ST changes. This randomized multicenter trial was organized to further assess the safety and feasibility of this treatment in human subjects. Patients with an AMI treated with recombinant tissue plasminogen activator (rTPA) or streptokinase (STK), were randomized to treatment with HBO combined with either rTPA or STK, or rTPA or STK alone. An analysis included 112 patients, 66 of whom had inferior AMIs (p = NS). The remainder of the patients had anterior AMIs. The mean CPK at 12 and 24 h was reduced in the HBO patients by approximately 7.5% (p = NS). Time to pain relief was shorter in the HBO group. There were 2 deaths in the control and 1 in those treated with HBO. The left ventricle ejection fraction (LVEF) on discharge was 51.7% in the HBO group as compared to 48.4% in the controls (p = NS). The LVEF of the controls was 43.4 as compared to 47.6 for those treated, approximately 10% better (no significant difference). Treatment with HBO in combination with thrombolysis appears to be feasible and safe for patients with AMI and may result in an attenuated CPK rise, more rapid resolution of pain and improved ejection fractions. More studies are needed to assess the benefits of this treatment.

Adolescent↗
PubMed1998

Intra-adrenal factors are not involved in the differential control of cortisol and adrenal androgens in human adrenals.

The differential control of adrenal androgens and cortisol may be due to intra-adrenal factors, which may be age- or sex-related, or due to extra-adrenal factors, such as circulating hormones. The purpose of this study was to identify any intrinsic differences that may exist in steroidogenic production occurring within adrenals obtained from males and females, and any maturational differences that may evolve with age. Using human adrenals from 48 transplant donors (32 males, 16 females; ages 5-60 years), the influences of age and sex on basal production of and ACTH-stimulated cortisol, androstenedione and dehydroepiandrosterone (DHEA) were examined in freshly prepared adrenal cell suspensions. Basal and ACTH-stimulated cortisol, androstenedione and DHEA production were similar in adrenals from males and females and did not correlate significantly with age when the whole group was examined. When steroidogenesis in male and female adrenals was examined separately against age, a significant correlation was observed only for basal and ACTH-stimulated androstenedione in adrenals from males in the younger age group, 5-30 years (basal: r=0.84, P=0.0001; ACTH-stimulated: r=0.52, P=0.007). Examination of the relationships between the steroids disclosed that the basal and ACTH-stimulated cortisol/androgen ratios did not correlate significantly with age, but the androstenedione/DHEA ratio showed a significant direct relationship with age in males only (basal: r=0.53, P=0.006; ACTH-stimulated: r=0.5, P=0.01). These data suggest that the influences of sex and age are minor in the modulation of adrenal steroidogenesis and support the concept that extra-adrenal factors dominate in the differential modulation of adrenal androgens and cortisol. The relationship between the androstenedione/ DHEA ratio and increasing age in men is consistent with the recently reported stimulatory effect of testosterone on adrenal steroidogenesis by induction of the conversion of DHEA to androstenedione.

Adolescent↗
PubMed1998

Can C reactive protein or troponins T and I predict outcome in patients with intractable unstable angina?

OBJECTIVE: To determine whether a single blood test for the measurement of C reactive protein, or troponin I or T concentrations could be used to stratify patients with intractable unstable angina awaiting transfer for coronary angiography by correlating these values with coronary anatomy and transient myocardial ischaemia. DESIGN: Prospective study. SETTING: Tertiary cardiac unit. PATIENTS: All patients admitted to their local hospital with ischaemic chest pain, uncontrolled by medical treatment, in whom acute myocardial infarction had been excluded by serial measurement of creatine kinase and lack of Q waves on ECG. INTERVENTION: Coronary angiography and ST segment monitoring for 24 hours. MAIN OUTCOME MEASURES: Concentrations of C reactive protein, troponins T and I, coronary anatomy, presence of transient myocardial ischaemia. RESULTS: Median C reactive protein, troponin I, and troponin T concentrations were 17.1 mg/dl (4.8 to 203.9), 0.05 microgram/l (0 to 7.8), and 0.0 microgram/l (0 to 2.51), respectively. Seven patients (10%) had normal coronaries and 14, 20, and 31 had one, two, or three vessel coronary disease, respectively. Nineteen (26%) had transient myocardial ischaemia, 33 (46%) had complex lesion morphology, and six (8%) had intracoronary thrombus. Of the three markers, troponin T alone was higher in patients with multivessel disease (p < 0.05) and in those with transient myocardial ischaemia (p < 0.05), but there was no significant relation between C reactive protein, troponin T or I and lesion morphology or thrombus. CONCLUSIONS: In patients transferred to a tertiary centre with intractable chest pain, C reactive protein and troponin I are not predictive of transient myocardial ischaemia or lesion morphology, both of which are surrogate markers of outcome. Troponin T is, however, raised in patients with multivessel disease or transient myocardial ischaemia. These serum protein assays cannot be used to stratify the risk of patients with unstable angina who are awaiting transfer to the tertiary centre.

Adult↗
PubMed1998

Balanced affinity AT1/AT2 receptor nonpeptide binding site determinants on the AT1 angiotensin receptor.

Angiotensin II (Ang II), a potent modulator of cardiovascular homeostasis, mediates its effects through two Ang II receptor subtypes (AT1 and AT2) which share less than 30% amino acid homology and can be differentiated by specific nonpeptide ligands. We investigated the structural determinants of ligand binding to the AT1 receptor for L-163,017 which belongs to a newly developed class of nonpeptides that have equivalent affinities for AT1 and AT2 receptors. Nonpeptide binding affinities were determined in radioreceptor binding assays in membranes from COS cells transfected with wild-type and mutant receptor cDNAs. The amphibian AT receptor variant, xCM46, recognized L-163,017 with an affinity (IC50=8±2 nM) that was only 1.5-fold lower than for the rat AT1 receptor (IC50=5±1 nM) which is in striking contrast to the poor affinity of the amphibian xATa wild-type receptor (IC50 >50 µM). Analysis of single point rAT1 receptor mutants in which individual mammalian residues were replaced by the corresponding frog amino acids revealed significant overlap but also distinct differences in ligand binding interactions between dual receptor and subtype selective non-peptides. These data suggest that AT1-selective and dual receptor nonpeptides share overlapping but distinct binding pockets on the AT1 receptor. These findings may lead to improved therapeutics for the treatment of cardiovascular diseases involving both AT receptor subtypes.

Journal Article↗
PubMed1997

Pathophysiology of transient myocardial ischemia in acute coronary syndromes. Characterization by continuous ST-segment monitoring.

BACKGROUND: Transient ischemia in stable coronary disease peaks in the morning, reflecting increased myocardial oxygen demand and coronary vasomotor tone after walking. In acute coronary syndromes, however, ischemia may result from transient thrombus formation or coronary spasm at the site of a ruptured plaque. We report on the pathophysiological mechanisms underlying transient ischemia in acute coronary syndromes despite optimal therapy, on the basis of analysis of heart rate changes preceding ischemia and its circadian variation. METHODS AND RESULTS: Two hundred fifty-six patients with unstable angina or non-Q-wave myocardial infarction underwent continuous ST-segment monitoring for 48 hours while receiving maximal medical therapy. All ischemic episodes were characterized by their timing, duration, association with pain, and heart rate changes before the onset of ischemia. During 10,629 hours of monitoring, 44 patients (17.2%) had 176 episodes of transient ischemia. The mean heart rate at onset of ischemia was 68 +/- 12.8 bpm, and > 55% of ischemic episodes were not preceded by a significant increase in heart rate. Ischemic activity had a single nocturnal peak, with 64% of all episodes occurring between 10 PM and 8 AM, this nocturnal preponderance being evident for episodes with or without a preceding increase in heart rate. The characteristics and timing of transient ischemia were similar in unstable angina and non-Q-wave myocardial infarction, but transient ischemia was more frequent (27.3% versus 15.1%; P < .05) and prolonged (median, 20 versus 13.5 minutes; P < .01) in non-Q-wave myocardial infarction. CONCLUSIONS: In acute coronary syndromes, transient ischemia has a low threshold, occurs predominantly without an increase in myocardial oxygen demand, and is present mainly at night rather than in the morning. These findings in patients receiving maximal medical therapy suggest significant pathophysiological differences underlying transient ischemia compared with stable coronary disease.

Acute Disease↗
PubMed1997

Subacute and chronic oral toxicity of lornoxicam in cynomolgus monkeys.

Lornoxicam is a novel non-steroidal anti-inflammatory compound in the same chemical class as piroxicam and tenoxicam, with potent anti-inflammatory, antipyretic and analgesic activity. As part of the preclinical safety programme, its toxicity was evaluated in a dose-range-finding and 52-wk toxicity study in cynomolgus monkeys. In the dose-range-finding study, five groups of monkeys (two per sex per group) were dosed orally by gavage for 6 wk with 0, 0.25, 0.5, 1.0 or 2.0 mg lornoxicam/kg/day. Drug-related toxicity was observed in the 1.0 and 2.0 mg/kg/day dose groups only. This included mortality, diarrhoea, prostration, decreased body weight gain and food consumption, faecal occult blood, anaemia, leucocytosis, hypoalbuminaemia, gastrointestinal erosions and ulcerations. On the basis of these results, four groups of monkeys (six per sex per group) were given the compound orally by nasogastric intubation at dose levels of 0, 0.125, 0.25 or 0.5 mg/kg/day for 52 wk. The high-dose level was increased to 0.6 mg/kg/day from wk 39 to wk 52. Treatment was followed by a 4-wk recovery period for two animals per sex per group. Histologically, drug-related changes seen were gastrointestinal erosions, ulcerations and inflammation in males and females at 0.5/0.6 mg/kg/day. Treatment-related clinicopathological findings included decreased haematocrit and hypoproteinaemia (group 0.5/0.6 mg/kg/day males), and hypoalbuminaemia (group 0.5/0.6 mg/kg/day males and females). None of these changes were present after the recovery period, thus indicating reversibility. Plasma concentration of lornoxicam measured 2 hr after dosing increased in a dose proportional manner. The estimated area under the curve (AUC) at steady state increased in a dose-proportional manner and at 0.25 mg/kg was three- to fivefold higher than the human AUC following a 16 mg dose (8 mg b.i.d.). The no-observed-effect level in the chronic toxicity study was 0.25 mg/kg/day.

Administration, Oral↗
PubMed1997

Evaluation of chronic oral toxicity and carcinogenic potential of lornoxicam in rats.

As part of the preclinical development program for lornoxicam, a novel non-steroidal anti-inflammatory drug (NSAID), its chronic oral toxicity and carcinogenic potential was assessed in Sprague-Dawley rats. Male and female rats were administered lornoxicam by oral gavage at 0, 0.06, 0.16 or 0.40 mg/kg/day for 12 months or at 0, 0.01 or 0.06 mg/kg/day in a supplementary low-dose study of the same duration (main group: 20/sex/group; 4-wk recovery: five/sex/group; satellites for electrocardiography and toxicokinetics: five/sex/group). Drug-related toxicity mainly comprised mortality, reduced body weight gain, clinico-pathological changes indicative of anaemia resulting from blood loss, and renal damage, renal papillary necrosis and gastrointestinal mucosal lesions. The kidney-associated changes were not completely reversible during the recovery period. Toxicokinetic investigations demonstrated a dose-linear absorption of the drug. In female rats the terminal half-life was about twice that in males which led to a higher exposure of this gender to lornoxicam. A dose of 0.01 mg/kg/day was established as no-observed-effect level. In a 104-wk carcinogenicity study, lornoxicam was administered by oral gavage to male and female rats (50/sex/group) at 0 (control 1), 0 (control 2), 0.0625, 0.125 or 0.250 mg/kg/day. In females only, the high dose was reduced twice during the study due to toxicity observed (0.250 to 0.200 to 0.160 mg/kg/day). Drug-related changes were similar to those in the chronic studies and consistent with the anticipated side-effects of NSAIDs. No carcinogenic potential was revealed.

Animals↗
PubMed1997

A critical review of the origin and control of adrenal androgens.

The reticularis and fasciculata zones of the adrenal cortex are the predominant sources of dehydroepiandrosterone (DHEA) and DHEA-sulphate and contribute directly or indirectly 60-75% of androstenedione and testosterone in women. The specific control of adrenal androgens remains unclear. While ACTH stimulates adrenal androgen secretion, the dissociation of cortisol and androgens occurring during adrenarche and under pathological conditions suggests other factors are involved. Recent studies using human adrenal cells in vitro have demonstrated that the ratio of androgen to cortisol produced is substantially independent of the age and gender of the adrenal, indicating that extra-adrenal factors are of greater importance. beta-Endorphin and joining peptide have been shown to stimulate androgen production in human adrenal cells and to influence ACTH-stimulated steroidogenesis in a manner that promotes adrenal androgen production. The activity of these pro-opiomelanocortin-derived peptides may explain the physiological and pathological dissociations of androgens and cortisol.

Adrenal Cortex↗