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Biomedical subjects

J Brown

Publications and source records attributed to J Brown.

At least 253 records · Page 14Linked to original sources
PubMed1999

SCH 57790: a novel M2 receptor selective antagonist.

As a decrease in cholinergic neurons has been observed in Alzheimer's Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.

Acetylcholine↗
PubMed1999

Identifying genes predisposing to atopic eczema.

BACKGROUND: Genetic and environmental factors are known to play a role in the development of atopic diseases, such as asthma, eczema, and rhinitis. However, the atopy gene (or genes) has yet to be defined. Studies of familial asthma have identified several regions that may contain genes predisposing to atopy, but the data for candidate regions do not show agreement, which may be due to heterogeneity, ascertainment bias, or stochastic factors. Factors such as an early age of onset, a positive family history, and a clearly defined phenotype favor a genetic origin and improve the chance of identifying genes that predispose to atopy. OBJECTIVE: We sought to define genes that predispose to the development of atopic eczema. METHODS: We have studied nuclear families with multiple cases of early-onset atopic eczema for involvement of the candidate regions on chromosomes 5q31 (IL gene cluster), 11q13 (high-affinity FCepsilon receptor), 14q11.2 (mast cell chymase), and 16p12 (IL-4 receptor alpha-chain, IL4RA gene). RESULTS: Using a recessive model, we find a maximum parametric log of the odds of linkage score of 2. 25 and nonparametric score of 2.54 (P =.006) for a region on chromosome 5q31, which we postulate contains a gene predisposing to atopic eczema, but lack of support for linkage to 11q13. Transmission disequilibrium tests do not support an association with candidate polymorphisms in the mast cell chymase and IL4RA genes. CONCLUSION: We have identified a clinically homogeneous cohort of patients with atopic eczema to identify genetic factors predisposing to the development of atopy. We postulate that there are certain loci that predispose to atopy in general and other loci that determine which of the atopic phenotypes is expressed.

Adolescent↗
PubMed1999

An international network for evaluating neuroprotective therapy after severe birth asphyxia.

Animal studies have shown great promise in their applicability to potentially neuroprotective therapies for severe birth asphyxia in human babies. It is now necessary to consider a strategy to evaluate some or all of these techniques within the context of human neonatal randomized control trials (RCT). We have set up a pilot study for an international RCT of mature babies with severe asphyxia (defined by an Apgar score of 5 or less at 10 minutes) and have shown that we can recruit from 120 centers in 17 countries an average of three babies a week, which is the required number to undertake a study over a 2-year period with sufficient power to show a significant improvement in outcome. Particular attention must be given in future studies to the size of improvement in outcome required, generalizability of entry criteria, and the appropriate measure of functional outcome in treated babies.

Animals↗
PubMed1999

Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized, controlled trial.

Previous data have suggested that rofecoxib, a cyclooxygenase (COX)-2-specific inhibitor, had analgesic effects similar to those of the nonsteroidal anti-inflammatory drugs when tested in the post-dental surgery pain model. The objective of this parallel-group, double-masked, randomized, placebo- and active comparator-controlled clinical trial was to assess more fully the analgesic efficacy of rofecoxib in the treatment of postoperative dental pain. After dental surgery, 151 patients (50.3% women; mean age, 18.3 years; 93.4% white) experiencing moderate-to-severe pain were to receive a single dose of placebo, rofecoxib 50 mg, or ibuprofen 400 mg. Analgesic efficacy was assessed for up to 24 hours postdose using self-administered questionnaires. Tolerability was assessed using spontaneous reports of adverse experiences, physical findings, and laboratory measurements. The results of this study demonstrated that rofecoxib 50 mg was more effective than placebo on all measures of analgesic efficacy. Rofecoxib 50 mg exhibited overall analgesic effects, onset of analgesia, and peak analgesic effects that were not significantly different from those of ibuprofen 400 mg, with a significantly longer duration of action (P < 0.05). We concluded that rofecoxib was efficacious in the treatment of postoperative dental pain and that COX-2-derived prostanoids play a role in treatment of the pain associated with dental surgery.

Adolescent↗
PubMed1999

Visual acuity impairment in patients with retinitis pigmentosa at age 45 years or older.

OBJECTIVE: To determine the severity of visual acuity impairment in patients, age 45 years or older, with either isolated or identifiable genetic subtypes of retinitis pigmentosa (RP) and Usher syndrome. DESIGN: Multicenter, retrospective, cross-sectional analysis. PARTICIPANTS: Visual acuity data were obtained on 999 patients with different genetic subtypes of RP and Usher syndrome, age 45 years or older, from 4 major eye care centers in the United States. INTERVENTION: The best-corrected visual acuity obtained on these patients from the eye with better vision on their most recent visit was used for the analysis. MAIN OUTCOME MEASURE: Best-corrected visual acuity was the main parameter analyzed for the study, and it was obtained with Snellen or Feinbloom low vision charts or with a B-VAT II monitor (Mentor). RESULTS: The final analyses were done on 982 patients (17 patients with a sector form of RP were analyzed separately). Of the 982 patients, 506 (52%) had a visual acuity of 20/40 or better, and 678 (69%) had a visual acuity of 20/70 or better in at least one eye. There were 243 (25%) patients who had a visual acuity of 20/200 or worse in both eyes. Five (0.5%) patients had no light perception in both eyes. The odds ratio for any patient having a visual acuity of 20/200 or worse in this population was 1.4 for each difference of 10 years of age. Similarly, the odds ratio of a patient having a visual acuity of 20/40 or better in at least one eye was 0.95 for a 10-year age difference. CONCLUSIONS: In this large population of patients with RP and Usher syndrome from four centers, it was rare for such patients to lose all vision in both eyes. One fourth of the patients had a visual acuity of 20/200 or worse in both eyes, and more than half of the population had a visual acuity of 20/40 or better in at least one eye. These data can be used to counsel such patients on the extent of potential visual acuity impairment from their disease.

Aged↗
PubMed1999

Inspiratory pressure threshold training for glottal airway limitation in laryngeal papilloma.

A single-subject design was used to determine if inspiratory pressure threshold training increases inspiratory muscle strength and reduces the sensation of dyspnea during exercise and speech. The subject was a 23-year-old female with congenital juvenile papilloma which has been in remission for 10 years. A 4-week inspiratory muscle training program was implemented using an inspiratory pressure threshold trainer. The pressure threshold of the trainer was set by the experimenter. The pressure threshold setting of the trainer was based on a percentage of the subject's maximum inspiratory pressure measured prior to training. The average range of the pressure threshold was 40 to 70 cmH2O. In order for inspiratory air to flow, the subject generated inspiratory pressure, independent of airflow rate. Maximum inspiratory pressure (MIP) was the dependent variable used as the index of inspiratory muscle strength. Exercise dyspnea was a dependent variable rated by the subject during a progressive treadmill test. Dyspnea associated with speech was rated following production of a comfortable and loud speech task. MIP increased by 57% following the training program with a 2-scale point reduction in the perception of dyspnea during exercise. Dyspnea during loud speech decreased from moderate to mild. The changes in dyspnea, both during exercise and speech, are directly related to inspiratory muscle strengthening. The results suggest that inspiratory muscle training may improve respiratory related function in patients with restrictive upper airway disorders.

Adult↗
PubMed1999

HLA-A typing by reference strand-mediated conformation analysis (RSCA) using a capillary-based semi-automated genetic analyser.

HLA typing of class I loci by reference strand-mediated conformation analysis (RSCA) using a slab gel genetic analyser has been described. This study adapted the method for use in the capillary based ABI PRISM 310. Control DNA samples were used to create a database of mobility values for 37 HLA-A alleles. The technique was validated by comparing RSCA and sequence-specific oligonucleotide probe (SSOP)/sequence-specific primer amplification (SSP) HLA-A locus typing results from 214 cord blood samples. Of the samples tested, 6.5% required confirmatory typing by SSP, compared with a repeat rate of 10-40% for SSOP. In 200 samples where no SSP was necessary, there was 100% concordance between RSCA and previous results. The ABI PRISM 310 RSCA method defines HLA-A types at medium resolution and is quick and easy to implement.

Electrophoresis, Capillary↗
PubMed1999

Skin bruising, adrenal function and markers of bone metabolism in asthmatics using inhaled beclomethasone and fluticasone.

Fluticasone propionate (FP) is generally considered to have twice the efficacy of beclomethasone dipropionate (BDP) on a weight-to-weight basis for the control of asthma, and may have lesser effects on adrenal function. However, the effects of FP and BDP on skin integrity and bone metabolism markers require further examination. Sixty-nine asthmatic subjects were enrolled in a double-blind crossover study in which, after a baseline period, they received BDP or FP (at half the dose of BDP) for two 4-month periods each. A questionnaire on skin bruising, a skin examination, tests of adrenal function and of markers of bone metabolism were performed after 2 months of each period. The number of asthma exacerbations was not significantly different for the two treatment periods (eight for BDP and nine for FP), nor were various indices of asthma control. Whereas the frequency of bruising reported by the questionnaire was not different, there were more bruises on examination for BDP (1.6+/-2.5) than for FP (1.2+/-2.3) (p=0.04). Although baseline serum cortisol was not significantly different for the two drugs, the increase in cortisol after cortrosyn was lower for BDP (357+/-158 micromol x dL(-1)) than for FP (422+/-144 micromol x dL(-1)) (p<0.01). Serum osteocalcin levels were significantly lower in subject on BDP (2.8+/-1.7 microg x mL(-1)) than on FP (3.5+/-1.9 ng x mL(-1)) (p=0.003). Other markers of bone metabolism were not significantly altered. The three major side-effects were loosely, but significantly correlated with the periods on BDP and FP. However, skin bruises, increase in cortisol after Cortrosyn and osteocalcin were not significantly correlated for the period on either BDP or FP. In conclusion, whereas fluticasone propionate used at half the dose of beclomethasone dipropionate has a comparable effect on the control of asthma, fluticasone propionate demonstrated fewer side-effects in terms of skin bruising, adrenal suppression and bone metabolism.

Administration, Inhalation↗
PubMed1999

Cytokine release by ovine macrophages following infection with Chlamydia psittaci.

Chlamydia psittaci is an obligate intracellular pathogen that causes abortion in both sheep and humans. The disease in sheep (but not humans) is characterized by a long-term persistent phase that appears to be under the control of interferon-gamma. However, nothing is known about cytokine induction that precedes the persistent phase in sheep. Primary alveolar lavage cells recovered from normal adult sheep were used to study cytokine production in the first 72 h of infection with C. psittaci. These cells were phenotypically characteristic of macrophages, being adherent, phagocytic, CD14+ and staining positive for non-specific esterase. In vitro infection of the macrophages with C. psittaci resulted in the release of IL-1beta, IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) as measured by ovine-specific ELISAs. Heat-treated chlamydiae (1 h at 65 degrees C) did not induce the release of IL-1beta, but the release of IL-8 was similar to that induced by untreated organisms. The cells from different sheep varied most notably in their patterns of GM-CSF release in response to heat-treated and untreated organisms.

Animals↗
PubMed1999

Lifetime treatment costs of beta-thalassaemia major.

Beta-thalassaemia major is a serious genetic disorder, which results in a considerable increase in both acute and chronic morbidity, and mortality. Although beta-thalassaemia major is a rare disease affecting approximately 600 people in the UK, treatment is intensive and predictions of the costs incurred may aid health care planning. In this report, the cost to the health service of providing treatment services for beta-thalassaemia major patients, over the course of a lifetime, is calculated in order to assist resource allocation decisions. A cost model was developed, incorporating data from disparate sources. The undiscounted lifetime cost of treating a beta-thalassaemia major patient was estimated to be pound 803,002, although when the costs were discounted at a rate of 6%, the lifetime cost was reduced to pound 219,068. Within sensitivity analyses, the discounted cost ranged from approximately pound 188,000 to pound 226,000. This report may act as a guide to those involved in the planning of health care provision with regard to the resources required to treat beta-thalassaemia major patients. Such information may also be incorporated into the decision-making process for the provision of antenatal screening programmes for beta-thalassaemia major.

Adolescent↗
PubMed1999

Influence of micronization method on the performance of a suspension triamcinolone acetonide pressurized metered-dose inhaler formulation.

The purpose of this study was to investigate the influence of micronization technique on performance and stability of the model drug formulated in a suspension-based pressurized metered-dose inhaler (pMDI). The model drug, triamcinolone acetonide (TAA), was subjected to ball milling or air-jet milling prior to formulation of the pMDI. The dose delivery characteristics of the emitted aerosol cloud were monitored for the ball-milled, air-jet-milled, and unmicronized TAA pMDI formulations prior to and after storage at 25 and 40 degrees C. Cascade impaction was used to determine the aerodynamic particle size distribution of the emitted dose. Both micronization techniques reduced the drug particle size distribution and the polydispersity of the drug particles to a similar extent, but the ball-milling technique reduced the crystallinity of the drug to a greater degree compared to the air-jet-milling technique. The air-jet-milled and unmicronized TAA pMDI displayed similar aerodynamic particle size distributions of the emitted aerosol and respirable fractions over the storage period. The ball-milled TAA resulted in a pMDI formulation with the smallest aerodynamically sized particles and the highest respirable fraction compared to the air-jet-milled or unmicronized TAA pMDI formulations. The micronization techniques significantly influenced the dose delivery characteristics as a result of different initial particle size distributions, amorphous contents, and surface energies.

Administration, Topical↗
PubMed1999

Enhanced anti-tumor effects with microencapsulated c-myc antisense oligonucleotide.

A phosphorothioate c-myc antisense oligonucleotide was complexed with zinc and encapsulated into injectable biodegradable microspheres. The efficacy of this novel formulation was compared with intravenous administration of the unencapsulated drug in human melanoma and leukemia xenografts in immunocompromised mice. The microencapsulated formulation was more effective as shown by reduced tumor growth, a decreased number of metastases, reduced c-myc expression, and increased survival in the melanoma model, and decreased metastatic potential and increased survival in the leukemia model. These results show that, as has been demonstrated previously with protein and peptide drugs, greater therapeutic efficacy can be obtained when antisense oligonucleotides are delivered from sustained-release formulations.

Animals↗
PubMed1999

Disease-specific and generic health outcomes: a model for the evaluation of long-term intrathecal opioid therapy in noncancer low back pain patients.

OBJECTIVE: The present study provided comprehensive characterization of the long-term outcomes of intrathecal opioid administration via a drug administration system (DAS) in chronic pain patients with predominantly low back pain. A conceptual framework based on multidimensional outcomes is proposed using both disease-specific and generic measures. DESIGN: Pre-post longitudinal data were collected in a retrospective fashion on 38 patients receiving intraspinal opioid therapy for a minimum of 36 months (average = 50 months). MAIN OUTCOME MEASURES: Disease-specific measures included magnitude of infused opioid, side effects/complications, pain ratings, McGill Pain Questionnaire, Beck Depression Inventory, Oswestry Disability Questionnaire, and patient estimated improvement in pain (0-100%). Generic measures of health included the Quality of Well-Being Scale, Medical Outcomes Study (MOS) Short Form 36 (SF-36), return to work, patient estimated improvement in functioning, overall patient satisfaction, and family opinion of patient improvement. RESULTS: Disease-specific outcomes. Patients receiving long-term intrathecal opioid administration showed a sixfold increase in morphine equivalents infusion rates across time. DAS patients showed a small but significant decrease in pain ratings from pre-treatment levels. Following 3 years or more of intrathecal opioid infusion, patients endorsed high pain levels on the McGill Pain Questionnaire, severe levels of disability via the Oswestry Disability Questionnaire, mild levels of depression based on the Beck Depression Inventory, and multiple side effects associated with the intrathecal opioids and complications related to the infusion system. On retrospective questioning, patients receiving long-term intrathecal opioid administration reported an average of 64% improvement in their pain and 48% improvement in functioning. Family members of patients reported that they observed on average a 61% improvement in patient's pain. Generic outcome measures. On the Quality of Well-Being Scale, patients reported significantly lower health-related quality of life than health maintenance organization enrollees with no known chronic condition and patients with rheumatoid arthritis (p < 0.001). On the MOS SF-36, patients reported significantly lower physical functioning than the U.S. general population, patients with uncomplicated medical conditions, diabetes-type II patients, and congestive heart failure patients. Mental functioning was comparable to the U.S. general population (p > 0.001). Fourteen percent of patients were working following implantation. Eighty-nine percent of patients reported good to excellent satisfaction with the long-term intrathecal opioid therapy. CONCLUSIONS: Results from this study revealed differences in findings across the outcome measures, highlighting the complexity of intrathecal opioid therapy. Generally, patients after 3 years or more of intrathecal opioid therapy can be characterized as hav ing substantially impaired physical functioning with a high prevalence of side effects. Despite poor physical functioning, patients endorsed relatively good mental health status with only mild depressive symptoms. Longitudinal pain ratings showed a modest decrease from pretreatment levels. On retrospective evaluation, patients and their family endorsed high levels of pain relief secondary to intrathecal therapy. Overall, findings support that intrathecal opioid therapy provides some therapeutic benefit although substantial physical impairment continues to cause debilitation in the patient population.

Female↗
PubMed1999

Pain during insertion of peripheral intravenous catheters with and without intradermal lidocaine.

Phase 1 of this study evaluated the perception of pain in 50 patients undergoing peripheral venous catheter insertion without the use of a local anesthetic. Phase 2 evaluated perceived pain in 50 patients who received intradermal lidocaine before the i.v. catheter was inserted. The researchers found that lidocaine injected intradermally before placement of an i.v. catheter resulted in significantly lower self-reported pain perceptions (p < 0.01). No additional time (determined in intervals of 15 minutes) was required for the study group. Based on these findings, the hospital policy was modified so that intradermal lidocaine would be offered to all patients requiring peripherally inserted i.v. catheters.

Anesthetics, Local↗
PubMed1999

Childhood abuse and neglect: specificity of effects on adolescent and young adult depression and suicidality.

OBJECTIVE: To investigate the magnitude and independence of the effects of childhood neglect, physical abuse, and sexual abuse on adolescent and adult depression and suicidal behavior. METHOD: A cohort of 776 randomly selected children was studied from a mean age of 5 years to adulthood in 1975, 1983, 1986, and 1992 during a 17-year period. Assessments included a range of child, family, and environmental risks and psychiatric disorders. A history of abuse was determined by official abuse records and by retrospective self-report in early adulthood on 639 youths. Attrition rate since 1983 has been less than 5%. RESULTS: Adolescents and young adults with a history of childhood maltreatment were 3 times more likely to become depressed or suicidal compared with individuals without such a history (p < .01). Adverse contextual factors, including family environment, parent and child characteristics, accounted for much of the increased risk for depressive disorders and suicide attempts in adolescence but not in adulthood (p < .01). The effects of childhood sexual abuse were largest and most independent of associated factors. Risk of repeated suicide attempts was 8 times greater for youths with a sexual abuse history (odds ratio = 8.40, p < .01). CONCLUSIONS: Individuals with a history of sexual abuse are at greater risk of becoming depressed or suicidal during adolescence and young adulthood. Adolescence is the most vulnerable period for those youths who may attempt suicide repeatedly. Many of the apparent effects of neglect, in contrast, may be attributable to a range of contextual factors, suggesting broader focus for intervention in these cases.

Adolescent↗