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Biomedical subjects

S H Jackson

Publications and source records attributed to S H Jackson.

At least 19 recordsLinked to original sources
PubMed2001

IFN-gamma is effective in reducing infections in the mouse model of chronic granulomatous disease (CGD).

Chronic granulomatous disease (CGD) is a genetic disorder characterized by recurrent bacterial and fungal infections and tissue granuloma formation. CGD phagocytes are unable to generate superoxide because of mutations in any of four proteins of the phagocyte NADPH oxidase. Prophylactic recombinant human interferon-gamma (IFN-gamma) has been shown to reduce the frequency and severity of infections in CGD patients, but its mechanism(s) remains undefined, and its benefit has been questioned. We investigated the prophylactic effect of IFN-gamma in the mouse model of the major autosomal recessive (p47(phox)) form of CGD. In a prospective, randomized, placebo-controlled study, we compared IFN-gamma, 20,000 U administered subcutaneously (s.c.) three times weekly, to placebo in 118 p47(phox-/-) mice. By 6 weeks of study, there were 3 infections in the IFN-gamma group compared with 13 infections in the placebo group (77% reduction in infections, p<0.01). By 18 months of study, there were 7 infections in the IFN-gamma group compared with 18 infections in the placebo group (39% reduction in infections, p<0.01). Two animals receiving IFN-gamma had seizures after 7 months in the study. No other toxicities were observed. Peripheral blood phagocytes from IFN-gamma treated p47(phox-/-) mice produced no superoxide, excluding restoration of the oxidative burst as a mechanism for the IFN-gamma effect. There were no differences in either peritoneal macrophage nitrate production or thioglycollate-induced peritoneal exudate between treatment groups. This animal model demonstrates a prophylactic benefit of IFN-gamma similar to that seen in humans and provides an opportunity to investigate the mechanism(s) of action for IFN-gamma in CGD.

Abscess↗
PubMed2001

Functional magnetic resonance imaging of odor identification: the effect of aging.

BACKGROUND: Sense of smell declines with age and impairment in olfaction has been observed in some neurodegenerative disorders such as Alzheimer's disease. Functional neuroimaging techniques enable researchers to observe brain regions activated by olfactory stimuli. METHODS: We gave three mainly olfactory-mediated odors (limonene, methylsalicylate, and eugenol) to six young and six elderly subjects and observed the areas activated by using blood oxygen level dependent contrast functional magnetic resonance imaging. RESULTS: The group mapping of young subjects showed extensive activation in the orbitofrontal cortex, commonly believed to be the olfactory cortex, some limbic areas (the hippocampus and the thalamus), regions involved with gustatory sensation (the anterior insula and the inferior postcentral gyrus), superior and inferior temporal gyri, and cerebellum. In the elderly group, only the left inferior temporal gyrus and the primary visual cortex reached accepted significance levels. CONCLUSIONS: We have therefore confirmed previous reports of brain regions involved in olfactory processing in young volunteers and demonstrated decreased activation in elderly volunteers.

Adult↗
PubMed2000

Development of an indicator to identify inappropriate use of benzodiazepines in elderly medical in-patients.

Studies reporting the quantity of benzodiazepines used are purely descriptive and cannot comment on the quality or appropriateness of prescribing benzodiazepines. An indicator to assess the appropriateness of prescribing benzodiazepines was developed from published literature. The applicability of the indicator was discussed in a multidisciplinary forum. The indicator uses clinical data currently available to the prescriber. The indicator, in the form of an algorithm, was applied to assess the appropriateness of prescribing of benzodiazepines to medical in-patients aged < or =65 years at 17 hospitals in England and Wales. Prescribing data were collected on 1391 patients. Appropriateness of prescribing of 311 benzodiazepines were assessed. Benzodiazepines were prescribed appropriately for 110/311 (35%) prescriptions and inappropriately for 201/311 (65%) prescriptions. Initiation of benzodiazepine for no acceptable indication was the commonest reason for inappropriate prescribing. The instrument identifies the appropriateness of prescribing of benzodiazepines and can be utilised by non-physicians.

Aged↗
PubMed1999

Human atrial repolarization: effects of sinus rate, pacing and drugs on the surface electrocardiogram.

OBJECTIVES: We studied the effects of rate and some cardioactive drugs on the atrial surface electrocardiogram (ECG). BACKGROUND: In atrioventricular block, atrial surface ECG is unmasked. The effect of rate alone permits detection of the effect of other exogenous stimulations such as drugs in the presence of rate alterations. METHODS: High fidelity, high gain ECG leads I, II and III were recorded from 51 patients with heart block. Durations of P and Ta waves and the total PTa interval were measured from nonconducted atrial events. RESULTS: No relationship was found between sinus cycle length and PTa, P or Ta in 31 patients. In 20 patients, progressively decreasing the atrial pacing cycle length from 853 ms to 381 ms resulted in a linear reduction of the PTa interval from 444 to 291 ms (rho = 0.76, slope = 0.24). This was largely due to shortening of Ta. A linear rate correction formula was derived: corrected PTa = PTa - 0.24 (PP - 1000). Atropine (0.02 mg/kg) shortened the PP interval (p < 0.001) and the PTa interval (p < 0.01). Propranolol (0.1 mg/kg) prolonged the PP interval (p < 0.001) but did not alter the PTa interval. Neither disopyramide (2.0 mg/kg) nor flecainide acetate (2.0 mg/kg) altered the PP interval, but both prolonged the PTa interval (p < 0.001). This was largely due to P wave lengthening after flecainide (p < 0.001) and to Ta prolongation after disopyramide (p < 0.001). CONCLUSIONS: In heart block, PTa, P and Ta waves can be measured reliably. The effects of pacing and some antiarrhythmic drugs on the atrial myocardium are similar to those known at the ventricular level.

Adult↗
PubMed1999

The role of stress in anaesthetists' health and well-being.

Stress is an inevitable part of our personal and professional lives. When poorly managed, stress will accumulate to levels that become injurious to our health and well-being. Burnout is one such consequence. However, because stress is an active process, with the proper knowledge and skills, we can learn to better manage and control its level of intensity. This paper examines the stress cycle and especially those aspects that are unique to the practice of medicine and anaesthesia. Sleep deprivation and physical fatigue are analyzed as key stressors. The role of the medical marriage and dual-career relationships are scrutinized. The importance of retaining the humanistic essence of medicine is emphasized. Stress management strategies and coping responses, including self-care and humor, are discussed.

Anesthesiology↗
PubMed1999

Single dose pharmacodynamics of thioridazine and remoxipride in healthy younger and older volunteers.

Phenothiazines are widely used in older patients, but little experimental work has been carried out in this age group. Two groups of healthy volunteers, a younger group (Y: six males and six females, aged 20-42 years) and an older group (O: six males and eight females, aged 65-77 years) took part in a randomized double-blind three-period crossover study in which they received by mouth single doses of thioridazine (Y: 50 mg; O: 25 mg) remoxipride (Y: 100 mg; O: 50 mg) or placebo. Measures of central nervous system (CNS) and haemodynamic function were carried out before drug administration and at 1.5-h intervals up to 9 h post-dose, and blood samples were collected over a 24-h period. No significant differences in dose-corrected pharmacokinetic variables were found between the two groups. There was evidence of marked CNS depressant effects of thioridazine from both objective and subjective measures. The effects for remoxipride were similar, though generally less marked. After allowance was made for dose, there was little indication of any difference in degree of CNS depression between the two age groups. Haemodynamic measures showed orthostatic reductions in blood pressure with thioridazine which were particularly marked in the older group, who also showed lower compensatory increases in pulse rate. These results indicate potential problems with orthostatic hypotension with thioridazine in older patients. CNS depression may also be a problem, especially in patients with compromised cholinergic function.

Adult↗
PubMed1999

Characterization of immortalized osteoclast precursors developed from mice transgenic for both bcl-X(L) and simian virus 40 large T antigen.

We recently developed an immortalized osteoclast (OCL) precursor cell line that forms large numbers of OCLs. This cell line was derived from mice doubly transgenic for bcl-X(L) and large T antigen that was targeted to cells in the OCL lineage (bcl-X(L)/Tag cells). We have now characterized these cells in terms of their surface and enzymatic phenotype, responsiveness to osteotropic factors, and differentiation potential. The bcl-X(L)/Tag cells expressed interleukin-1 receptors 1 and 2, gelatinase B (MMP9), as well as Mac-1, CD16/CD32 (Fcgamma receptors), CD45.2 (common leukocyte marker), CD86 (costimulatory molecule expressed on B cells, follicular dendritic cells, and thymic epithelium), major histocompatibility complex I, and nonspecific esterase when cocultured with MC3T3E1 cells. However, they did not express the antigens for F4/80 (mature macrophage/dendritic cell marker) by immunostaining. Treatment of bcl-X(L)/Tag cells, cocultured with MC3T3E 1 cells, with the combination of 1,25-dihydroxyvitamin D3 and dexamethasone induced high levels of OCL formation. The bcl-X(L)/Tag cells formed large numbers of OCLs when cultured with RANK ligand and macrophage colony-stimulating factor in the absence of feeder cells. In the absence of RANK ligand and a feeder cell layer, 100% of the cells differentiated into F4/80-positive cells. However, neither PTH nor PTH-related protein enhanced OCL formation by bcl-X(L)/Tag cells even when they were cocultured with primary osteoblasts, suggesting that they differ from primary mouse bone marrow cells in their responsiveness to PTH/PTH-related protein. Thus, bcl-X(L)/Tag cells have many of the properties of primary mouse OCL precursors and should be very useful for studies of OCL differentiation and divergence of OCL precursors from the macrophage lineage.

Animals↗
PubMed1999

Ibuprofen stereochemistry: double-the-trouble?

Racemic ibuprofen is an important NSAID used in the treatment of pain and inflammation in a variety of musculoskeletal and rheumatic disorders. The metabolism of ibuprofen, and that of a number of the related 2-arylpropionic acid NSAIDs, involves chiral inversion of the relatively inactive R-enantiomers to their active S-antipodes, together with other potentially stereoselective conjugative and oxidative pathways. Enantiospecific analytical methodology suitable for the determination of both the drug and its metabolites is essential in order to evaluate the significance of stereoselectivity both in terms of drug action and disposition. Recent investigations have also indicated that the R-enantiomers of these agents may not be totally devoid of useful biological activity, that the formation of acyl-coenzyme A derivatives results in interactions with lipid biochemistry, and has provided new insights into the disposition of these drugs in man. Ibuprofen represents a classical example of a drug where stereochemical considerations are essential for an understanding of its biological properties.

Acyl Coenzyme A↗
PubMed1998

Psychomotor performance: investigating the dose-response relationship for caffeine and theophylline in elderly volunteers.

OBJECTIVE: The aim of the study was to investigate the dose-response relationship for psychomotor performance, caffeine and theophylline in healthy elderly volunteers. METHODS: In a randomized, double-blind, placebo-controlled, six-period cross-over study we compared the effect of three doses of theophylline (predicted peak concentrations of 3, 6 mg. 1(-1) and 12 mg . 1(-1), two doses of caffeine (predicted peak concentrations of 4.5 mg. 1(-1) and 9 mg. 1 (-1) and placebo on ten healthy elderly volunteers. Psychomotor performance was measured using a continuous attention task, symbol digit substitution test and choice reaction time. Subjective effects were assessed using visual analogue scales. Following drug administration, subjects received the test battery at 30-min intervals, up to 150 min. Maximum and mean effects from baseline on each variable were included in the analysis. RESULTS: Significant improvement on the continuous attention task was seen at the lowest concentration of caffeine and theophylline used, while at higher concentrations there was a non-significant trend towards placebo scores. There was little effect of either drug on the subjective effects measured by visual analogue scales. CONCLUSION: Caffeine and theophylline increase psychomotor performance measures of attention at low plasma concentrations in healthy elderly volunteers. This effect is not increased by higher drug concentrations and there is trend towards a return to placebo scores. The lack of effect of both caffeine and theophylline on subjective measures is consistent with previous studies of caffeine in the elderly.

Aged↗
PubMed1998

The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women.

OBJECTIVE: Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults. METHODS: Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan during a randomized, double-blind, placebo-controlled study. Blood pressure, heart rate, ECG, and central nervous system effects were monitored, and pharmacokinetic parameters of zolmitriptan and its metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had little effect on systolic blood pressure in the young adults. In the elderly, mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg higher in both age groups. These changes were transient. Postural changes in blood pressure were unaffected. There was a dose-related increase in sedation, but the magnitude of the effects was small. Mean observed peak plasma concentration (Cmax) and area under the plasma concentration-time profile [AUC(0-infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in both age groups but higher in young women than in young men. Metabolite/parent ratios probably the result of greater first-pass metabolism in young men. Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to 2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N-oxide, and the indole acetic acid metabolites were higher in the elderly, associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well tolerated, with an effect of age on its effects on blood pressure and the pharmacokinetics of its metabolites. The data suggest no need for dose adjustment for age. In young subjects, concentrations were higher in women than in men, but the differences were insufficient to justify dosage adjustment.

Adult↗
PubMed1998

Validity and sensitivity of visual analogue scales in young and older healthy subjects.

BACKGROUND: Previous findings from studies on the acute effects of drugs indicate that older subjects report less change on visual analogue scales than do younger subjects, when the observed drug effects on objective performance measures are as great or greater. AIM: To validate the use of visual analogue scales independently of internal perceptions. SUBJECTS AND METHODS: 50 younger and 50 older subjects rated attributes of four animals--tortoise, crow, tiger and wasp--on a series of 10 cm lines. The attributes rated included physical qualities (size, noise) and psychological aspects (danger). RESULTS: Ratings were generally similar for the two groups, although older subjects tended to rate slightly greater differences between animals, but the variability was also slightly greater. Thus the mean difference between tiger and wasp for size was 60.1 (SD 15.6) in the younger group and 68.8 (SD 18.4) in the older group. CONCLUSIONS: These results support the validity of the use of visual analogue scales in both groups. Explanations for the previously observed discrepancy may need to be sought in terms of an effect of age on the perception of internal changes rather than on any difference in the use of the scales.

Adult↗
PubMed1998

Functional imaging of the brain in the evaluation of drug response and its application to the study of aging.

Functional neuroimaging techniques including single photon emission computerised tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (FMRI) can provide insight into the functional connectivity of the human brain in both health and disease, including the effects of aging and drugs on brain function. Neuroimaging measurement techniques can either be direct, using radio-specific ligands, or indirect, using the neurophysiological consequences of pharmacological interventions. Both approaches can be combined with sensorimotor or cognitive activation to examine the interaction between the targeted receptor function and the sensorimotor or cognitive process implicit in the study design. Using radionuclides, PET can provide absolute measurement of cerebral blood flow to regions of interest and can measure changes in cerebral metabolism using labelled fluorodeoxyglucose. PET offered the first opportunity to image brain activation caused by a variety of stimuli and hence to measure the effect of drugs on brain activation. PET also enables the study of drug disposition within the brain. SPECT has been used to study relative changes in cerebral blood flow associated with disease processes and also receptor occupancy. FMRI, by contrast, does not involve ionising radiation and has better spatial and temporal resolution. It is still a relatively new technique and limited by its ability to only measure haemodynamic changes through the blood oxygen level-dependent (BOLD) signal. The effects of aging on drug responsiveness and the effects of drug treatment of diseases associated with old age are relatively unexplored areas of functional neuroimaging research.

Aging↗
PubMed1997

Stereospecific analysis of the major metabolites of ibuprofen in urine by sequential achiral-chiral high-performance liquid chromatography.

A sequential achiral-chiral HPLC method has been developed for the stereospecific analysis of the two major urinary metabolites of ibuprofen, namely hydroxyibuprofen and carboxyibuprofen. Achiral analysis was carried out using a Partisil column (250x4.6 mm, 5 microm) and a mobile phase of hexane:ethanol (98.2:1.8, v/v) containing trifluoroacetic acid (TFA; 0.05%, v/v) at a flow-rate of 2.0 ml/min. The HPLC eluate containing the two metabolites was separately collected, evaporated under nitrogen and the residue dissolved in the mobile phase used for chiral chromatography. Chiral-phase analysis was carried out using a Chiralpak AD CSP (250x4.6 mm, 10 microm) with a mobile phase of hexane:ethanol (92:8, v/v) containing TFA (0.05%, v/v) at a flow-rate of 1.0 ml/min. In both assays the analytes were quantified by ultraviolet detection at a wavelength of 220 nm. Modification of the mobile-phase composition allowed the resolution of all six analytes in a single chromatographic run but with an increase in run time and consequent band broadening. The analytical method described allows the direct quantitation of the stereoisomers of both metabolites of ibuprofen in urine following the administration of therapeutic doses of the racemic drug to man.

Adult↗
PubMed1997

Enhanced host defense after gene transfer in the murine p47phox-deficient model of chronic granulomatous disease.

The p47phox-/- mouse exhibits a phenotype similar to that of human chronic granulomatous disease (CGD) and, thus, is an excellent model for the study of gene transfer technology. Using the Moloney murine leukemia virus-based retroviral vector MFG-S encoding the human form of p47phox, we performed ex vivo gene transfer into Sca-1+ p47phox-/- marrow progenitor cells without conditioning of donors with 5-fluorouracil. Transduced progenitors were transplanted into moderately irradiated (500 cGy), G-CSF preconditioned sibling p47phox-/- mice. Using the fluorescent probe dihydrorhodamine 123 (DHR), in vivo biochemical correction of the superoxide-generating NADPH oxidase system was detected by flow cytometry in 12.3% +/- 0.9% of phorbol myristate acetate-stimulated peripheral blood neutrophils at 4 weeks and 2.6% +/- 1.0% at 14 weeks after transplantation. Following gene therapy, mice were challenged with the CGD pathogen Burkholderia (formerly Pseudomonas) cepacia and bacteremia levels were assessed at 24 hours and 7 days after inoculation. At both time points, bacteremia levels in gene corrected p47phox-/- mice were significantly lower than untreated p47phox-/- mice (0.89 +/- 0.30 colonies v 237.7 +/- 83.6 colonies at 24 hours, P < .02; 4.0 +/- 2.0 colonies v 110.2 +/- 26.5 colonies at 7 days, P < .0014). More importantly, Kaplan-Meier survival analysis showed a significant survival advantage of gene corrected versus untreated p47phox-/- mice (P < .001). Thus, stem-cell-directed ex vivo gene therapy is capable of restoring phagocyte oxidant-dependent host-defense function in this mouse model of a human immune-system disorder.

Animals↗