Biomedical subjects

J A Johnston

Publications and source records attributed to J A Johnston.

At least 19 recordsLinked to original sources

PubMed2007

Timing of drotrecogin alfa (activated) initiation in treatment of severe sepsis: a database cohort study of hospital mortality, length of stay, and costs.

INTRODUCTION: For patients with critical conditions including severe sepsis, minimizing the time from presentation to treatment is important to improving outcomes. Understanding the factors influencing high hospital mortality and resource utilization in severe sepsis continues to interest clinicians and researchers. This study examined the associations between timing of drotrecogin alfa (activated) (DrotAA) initiation and hospital mortality, length-of-stay, and costs. METHODS: We conducted a cohort study of adult patients (N = 1179) with intensive care unit stays from November 2001 to June 2003 who received DrotAA in US hospitals with data in the Solucient ACTracker database. We defined evident severe sepsis (ESS) as concurrent antibiotic plus ventilator and/or vasopressor use. We characterized the interval between ESS and DrotAA initiation as Same-day, Next-day, or Day 2+. We compared group characteristics and created multivariate models of hospital mortality, length-of-stay, and costs. RESULTS: Forty-three percent of patients received Same-day DrotAA, 30% Next-day, and 27% Day 2+. Same-day and Next-day patients had more organ dysfunctions at ICU admission than Day 2+ patients (1.1 +/- 0.9 and 1.2 +/- 0.8 vs. 1.0 +/- 0.8; p = 0.021 and p < 0.001, respectively), but from ESS to DrotAA initiation, organ dysfunctions for Day 2+ patients had increased more (+0.0 and +0.4 vs. +0.6, respectively; all p < 0.0001). Increased mortality was observed with administration later than Same-day, although only for the Day 2+ group did the association remain significant (p < 0.05) after adjusting for clinical and demographic factors. Only Next-day initiation was associated with significantly decreased costs (p = 0.0145). CONCLUSIONS: Timing of DrotAA initiation is associated with clinical and economic outcomes in severe sepsis. The potential impact of this timing on hospital mortality, length-of-stay, and costs deserves further study.

Adolescent↗

PubMed2006

Platelet beta-secretase activity is increased in Alzheimer's disease.

beta-Secretase activity is the rate-limiting step in Abeta peptide production from amyloid precursor protein. Abeta is a major component of Alzheimer's disease (AD) cortical amyloid plaques. beta-Secretase activity is elevated in post mortem brain tissue in AD. The current study investigated whether beta-secretase activity was also elevated in peripheral blood platelets. We developed a novel fluorimetric beta-secretase activity assay to investigate platelets isolated from individuals with AD (n=86), and age-matched controls (n=115). Platelet membrane beta-secretase activity (expressed as initial rate) varied over fourfold between individuals, raising important questions about in vivo regulation of this proteolytic activity. Nonetheless, we identified a significant 17% increase in platelet membrane beta-secretase activity in individuals with AD compared to controls (p=0.0003, unpaired t-test). Platelet membrane beta-secretase activity did not correlate with mini-mental state examination (MMSE) score in the AD group (mean MMSE=17.7, range 1-23), indicating that the increase did not occur as a secondary result of the disease process, and may even have preceded symptom onset.

Aged↗

PubMed2006

De-ubiquitinating enzymes: intracellular signalling and disease.

Ubiquitination is now accepted as an important process for regulating intracellular signalling and the realization that many known signalling molecules exhibit E3 ligase activity has led to great strides in our understanding of how these pathways are regulated. However, as most of the de-ubiquitinating enzymes have as yet no identified substrate, little is known about their potential role in the regulation of intracellular signalling. Here, we examine what is known about de-ubiquitinating enzymes and signalling, with particular emphasis on their role in the regulation of immune signalling and the initiation of DNA repair. In addition, we look at the evidence implicating these enzymes in the pathogenesis of diseases such as cancer and neurodegenerative diseases.

Animals↗

PubMed2005

Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease.

Several lines of evidence indicate that the Abeta peptide is involved at some level in the pathological process that results in the clinical symptoms of AD (Alzheimer's disease). The N-terminus of Abeta is generated by cleavage of the Met-Asp bond at position 671-672 of APP (amyloid precursor protein), catalysed by a proteolytic activity called beta-secretase. Two 'beta-secretase' proteases have been identified: BACE (beta-site APP-cleaving enzyme) and BACE2. The cause of sporadic AD is currently unknown, but some studies have reported elevated BACE/beta-secretase activity in brain regions affected by the disease. We have demonstrated that robust beta-secretase activity is also detectable in platelets that contain APP and release Abeta. This review considers the current evidence for alterations in beta-secretase activity, and/or alterations in BACE expression, in post-mortem brain tissue and platelets from individuals with AD.

Alzheimer Disease↗

PubMed2004

Bupropion as an aid to smoking cessation: a review of real-life effectiveness.

Clinical trials rigorously demonstrate the efficacy of new products and justify their marketing. However, it is only after use in real-life settings that the clinical value (effectiveness) of a new treatment is fully known. The purpose of this review was to summarise the effectiveness data for bupropion SR as an aid to smoking cessation. Available reports of effectiveness data for bupropion SR were obtained from the literature, presentations at smoking cessation meetings and from the manufacturer. Twelve sources of effectiveness data were found and included clinical practice trials, observational studies/surveys, motivational support programme results and employer-based cessation programme results. The 6-month point prevalence smoking cessation rates ranged from 25 to 49%. There is a growing body of evidence supporting the effectiveness of bupropion SR as an aid to smoking cessation. Real-life quit rates for bupropion SR are similar to those seen in the original clinical trial programme.

Bupropion↗

PubMed2003

Efficacy and safety of bupropion SR for smoking cessation: data from clinical trials and five years of postmarketing experience.

Bupropion SR was introduced for smoking cessation in the US in 1997. This review assesses the efficacy and safety of bupropion SR for treatment of tobacco dependence based on data from clinical trials and five years of postmarketing experience. Through June 2001, there were approximately 32 million patient exposures to bupropion (9 million for smoking cessation) in clinical practice, and more than 8000 patients have been studied in clinical trials for tobacco dependence. In clinical trials, bupropion SR was more effective than placebo at improving initial and long-term abstinence rates and preventing relapse. Bupropion SR is generally well tolerated. The most common adverse event in clinical trials or clinical practice is insomnia, which can also be a symptom of nicotine withdrawal. The two main risks of treatment with bupropion SR are major motor seizure and hypersensitivity reaction. Clinical trials data suggest that the incidence of seizure is approximately 0.1%, and that of serious cases of hypersensitivity approximately 0.12%. Benefit-risk assessment, assuming a 30% one-year quit rate demonstrates that for every 10,000 smokers treated with bupropion SR, 19 lives are saved and 86 cases of smoking-attributed morbidity are averted in a five-year period while the risk of experiencing one of the two potentially serious adverse events during treatment is 0.22%. These data further establish both the efficacy and safety of bupropion SR and its use in preventing the adverse health effects of chronic tobacco use.

Bupropion↗

PubMed2001

Sustained-release bupropion for pharmacologic relapse prevention after smoking cessation. a randomized, controlled trial.

BACKGROUND: Smoking relapse is common after successful pharmacologic treatment for smoking cessation. No previous studies have examined long-term drug therapy used expressly for prevention of smoking relapse. OBJECTIVE: To evaluate the efficacy of bupropion to prevent smoking relapse. DESIGN: Randomized, placebo-controlled trial. PARTICIPANTS: 784 healthy community volunteers who were motivated to quit smoking and who smoked at least 15 cigarettes per day. INTERVENTION: The participants received open-label, sustained-release bupropion, 300 mg/d, for 7 weeks. Participants who were abstinent throughout week 7 of open-label treatment were randomly assigned to receive bupropion, 300 mg/d, or placebo for 45 weeks and were subsequently followed for an additional year after the conclusion of the medication phase. Participants were briefly counseled at all follow-up visits. At the end of open-label bupropion treatment, 461 of 784 participants (58.8%) were abstinent from smoking. MEASUREMENT: Self-reported abstinence was confirmed by an expired air carbon monoxide concentration of 10 parts per million or less. RESULTS: The point prevalence of smoking abstinence was significantly higher in the bupropion group than in the placebo group at the end (week 52) of drug therapy (55.1% vs. 42.3%, respectively; P = 0.008) and at week 78 (47.7% vs. 37.7%; P = 0.034) but did not differ at the final (week 104) follow-up visit (41.6% vs. 40.0%). The median time to relapse was significantly greater for bupropion recipients than for placebo recipients (156 days vs. 65 days; P = 0.021). The continuous abstinence rate was higher in the bupropion group than in the placebo group at study week 24 (17 weeks after randomization) (52.3% vs. 42.3%; P = 0.037) but did not differ between groups after week 24. Weight gain was significantly less in the bupropion group than in the placebo group at study weeks 52 (3.8 kg vs. 5.6 kg; P = 0.002) and 104 (4.1 kg vs. 5.4 kg; P = 0.016). CONCLUSIONS: In persons who stopped smoking with 7 weeks of bupropion treatment, sustained-release bupropion for 12 months delayed smoking relapse and resulted in less weight gain.

Adult↗

PubMed2001

The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal.

Cytokines, such as interleukin-2 (IL-2), activate intracellular signaling pathways via rapid tyrosine phosphorylation of their receptors, resulting in the activation of many genes involved in cell growth and survival. The deubiquitinating enzyme DUB-2 is induced in response to IL-2 but as yet its function has not been determined. The results of this study show that DUB-2 is expressed in human T-cell lymphotropic virus-I (HTLV-1)-transformed T cells that exhibit constitutive activation of the IL-2 JAK/STAT (signal transducers and activators of transcription) pathway, and when expressed in Ba/F3 cells DUB-2 markedly prolonged IL-2-induced STAT5 phosphorylation. Although DUB-2 did not enhance IL-2-mediated proliferation, when withdrawn from growth factor, cells expressing DUB-2 had sustained STAT5 phosphorylation and enhanced expression of IL-2-induced genes cis and c-myc. Moreover, DUB-2 expression markedly inhibited apoptosis induced by cytokine withdrawal allowing cells to survive. Taken together these data suggest that DUB-2 can enhance signaling through the JAK/STAT pathway, prolong lymphocyte survival, and, when constitutively expressed, may contribute to the activation of the JAK/STAT pathway observed in some transformed cells.

Apoptosis↗

PubMed2001

A conditional form of Bruton's tyrosine kinase is sufficient to activate multiple downstream signaling pathways via PLC Gamma 2 in B cells.

BACKGROUND: Bruton's tyrosine kinase (Btk) is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-gamma2 (PLCgamma2) and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCgamma2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCgamma2-deficient DT40 B cell line. RESULTS: Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCgamma2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCgamma2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways, and apoptosis. In DT40 B cells deficient for PLCgamma2, Btk:ER activation failed to induce the signaling events described above with the consequence that the cells failed to undergo apoptosis. CONCLUSIONS: These data suggest that Btk:ER regulates downstream signaling pathways primarily via PLCgamma2 in B cells. While it is not known whether activated Btk:ER precisely mimics activated Btk, this conditional system will likely facilitate the dissection of the role of Btk and its family members in a variety of biological processes in many different cell types.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2001

Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release (SR), the nicotine patch, and the combination of these 2 treatments in patients who initially failed treatment. METHODS: This was a post hoc analysis of a multicenter, double-blind, randomized, placebo-controlled clinical trial in 893 smokers. Patients were randomly assigned to 9 weeks of treatment with placebo (n = 160), bupropion SR (n = 244), nicotine patch (n = 244), or a combination of nicotine patch and bupropion SR (n = 245). The study was originally designed with a follow-up period of 52 weeks. In this analysis, short-term success was defined as smoking cessation after 14 or 21 days of therapy and long-term success was defined as smoking cessation after >21 days of therapy. Patients who did not achieve short-term success were evaluated for long-term success at week 9 (end of treatment), 6 months, and 1 year after the start of the study. RESULTS: The mean age of the smokers was 44 years. The majority (93%) of patients were white, and 52% were female. The study subjects smoked an average of 27 cigarettes per day. Among the 467 patients who initially failed treatment in the first 3 weeks, treatment with bupropion SR alone and in combination with the nicotine patch produced significant increases in successful smoking cessation rates from weeks 4 to 9 (19% bupropion SR or combination, 7% nicotine patch, 7% placebo), at month 6 (11% bupropion SR, 13% combination, 2% nicotine patch, 3% placebo), and at month 12 (10% bupropion SR, 7% combination, 2% nicotine patch, 1% placebo) (P < 0.05 for bupropion SR and combination vs nicotine patch or placebo). CONCLUSION: Among patients who initially failed treatment, continued therapy with bupropion SR, either alone or in combination with the nicotine patch, resulted in significantly higher short- and long-term smoking cessation rates than treatment with the nicotine patch alone or placebo.

Administration, Cutaneous↗

PubMed2001

Feedback-dependent modulation of isometric force control: an EEG study in visuomotor integration.

The primary purpose of this investigation was to examine the cortical mechanisms underlying visuomotor integration in an experiment directly manipulating visual feedback (control-signal gain) as participants executed a grasping task. This was accomplished by assessing human electroencephalograms in both time and frequency domains and relating these measures to the performance accuracy of isometric force control. The basic experimental manipulation consisted of subjects controlling a grip dynamometer and the subsequent force trace displayed on a computer monitor at various magnitudes of force output and control-signal gain. Several findings from this study were of interest. First, the effects of control-signal gain and its interplay with the magnitude of force were most evident across the parietal and frontocentral electrode locations--areas specifically related to multi-modal sensory evaluation (parietal lobe) and higher-order movement control (supplementary and mesial premotor areas). Second, electroencephalography (EEG) measures in the time domain, i.e., slow-wave potentials, were sensitive to control-signal gain only during the ramp phase of force production (period of reaching the target force), not the static phase (period of maintaining the target force level). Third, EEG measures within the frequency domain (event-related desynchronization), unlike the slow-wave potential measures, were sensitive to control-signal gain during the static phase of force production--a sensitivity that was directly related to improvements in the accuracy of isometric force control. The findings of this investigation are described in relation to the existent literature on human visuomotor integration with special attention paid to the distinct spatial and temporal electrocortical patterns exhibited under varying degrees of visual feedback and magnitudes of force output during grasping.

Adult↗

PubMed2001

Signaling by type I and II cytokine receptors: ten years after.

Discovered during the past ten years, Janus kinases and signal transducers and activators of transcription have emerged as critical elements in cytokine signaling and immunoregulation. Recently, knockout mice for all the members of these families have been generated, with remarkably specific outcomes. Equally exciting is the discovery of a new class of inhibitors, the suppressor of cytokine signaling family. The phenotypes of mice deficient in these molecules are also striking, underscoring the importance of negative regulation in cytokine signaling.

Animals↗

PubMed2001

Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras.

Suppressors of cytokine signalling (SOCS, also known as CIS and SSI) are encoded by immediate early genes that act in a feedback loop to inhibit cytokine responses and activation of 'signal transducer and activator of transcription' (STAT). Here we show that SOCS-3 is strongly tyrosine-phosphorylated in response to many growth factors, including interleukin-2 (IL-2), erythropoietin (EPO), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). The principal phosphorylation sites on SOCS-3 are residues 204 and 221 at the carboxy terminus, and upon phosphorylation tyrosine 221 interacts with the Ras inhibitor p120 RasGAP. After IL-2 stimulation, phosphorylated SOCS-3 strongly inhibits STAT5 activation but, by binding to RasGAP, maintains activation of extracellular-signal-regulated kinase (ERK). A tyrosine mutant of SOCS-3 still blocks STAT phosphorylation, but also strongly inhibits IL-2-dependent activation of ERK and cell proliferation. Moreover, it also inhibits EPO- and PDGF-induced proliferation and ERK activation. Therefore, although SOCS proteins inhibit growth-factor responses, tyrosine phosphorylation of SOCS-3 can ensure cell survival and proliferation through the Ras pathway.

3T3 Cells↗

PubMed2001

Intimately linked or hardly speaking? The relationship between genotype and environmental gradients in a Louisiana Iris hybrid population.

Several models of hybrid zone evolution predict the same spatial patterns of genotypic distribution whether or not structuring is due to environment-dependent or -independent selection. In this study, we tested for evidence of environment-dependent selection in an Iris fulva x Iris brevicaulis hybrid population by examining the distribution of genotypes in relation to environmental gradients. We selected 201 Louisiana Iris plants from within a known hybrid population (80 m x 80 m) and placed them in four different genotypic classes (I. fulva, I. fulva-like hybrid, I. brevicaulis-like hybrid and I. brevicaulis) based on seven species-specific random amplified polymorphic DNA (RAPD) markers and two chloroplast DNA haplotypes. Environmental variables were then measured. These variables included percentage cover by tree canopy, elevation from the high water mark, soil pH and percentage soil organic matter. Each variable was sampled for all 201 plants. Canonical discriminant analysis (CDA) was used to infer the environmental factors most strongly associated with the different genotypic groups. Slight differences in elevation (-0.5 m to +0.4 m) were important for distinguishing habitat distributions described by CDA, even though there were no statistical differences between mean elevations alone. I. brevicaulis occurred in a broad range of habitats, while I. fulva had a narrower distribution. Of all the possible combinations, I. fulva-like hybrids and I. brevicaulis-like hybrids occurred in the most distinct habitat types relative to one another. Each hybrid class was not significantly different from its closest parent with regard to habitat occupied, but was statistically unique from its more distant parental species. Within the hybrid genotypes, most, but not all, RAPD loci were individually correlated with environmental variables. This study suggests that, at a very fine spatial scale, environment-dependent selection contributed to the genetic structuring of this hybrid zone.

Altitude↗

PubMed2001

Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation.

A population pharmacokinetic and pharmacodynamic analysis evaluated the relationships of dose, plasma concentrations of bupropion and metabolites, and patient covariates with the safety and efficacy of bupropion sustained release (SR) for smoking cessation. A total of 519 outpatient chronic cigarette smokers were randomized to one of three bupropion SR doses: 100, 150, or 300 mg/day or placebo. The bupropion plasma concentration time data were fit and subject-specific bayesian estimates of clearance were obtained. Logistic regression analyses evaluated the role of dose, concentrations, and covariates in predicting efficacy and safety endpoints. For the evaluation of efficacy, patients were classified as quitters or non-quitters on the basis of a 4-week quit variable (defined as complete abstinence for weeks 4-7 of the study). For the evaluation of safety, patients were classified into two categories for each adverse event evaluated, corresponding to whether the patient ever experienced the adverse event during the course of the study or never experienced the event, regardless of whether the event was treatment-emergent. The efficacy of bupropion SR in facilitating smoking cessation was found to be related to dose and a mean metabolite concentration, and quitting in general was found to be related to the number of cigarettes smoked per day at baseline. Smoking cessation was 1.42, 1.69, and 2.84 times more likely in patients receiving 100, 150, and 300 mg/day of bupropion SR, respectively, as compared to placebo (p = 0.0001). As the baseline number of cigarettes smoked per day increased, the likelihood of quitting decreased regardless of the treatment condition. Insomnia and dry mouth were positively associated with mean metabolite concentrations, and dry mouth was inversely related to patient weight. Anxiety was inversely related to predicted steady-state concentration (Cpss), suggesting a positive effect on this withdrawal symptom. Bupropion SR exhibits a statistically significant dose/plasma level-response relationship for smoking cessation. Dry mouth and insomnia, related to concentrations, may be managed with dose reduction, with the realization that smoking cessation may be impaired.

Adolescent↗

PubMed2001

Environment-dependent performance and fitness of Iris brevicaulis, I. fulva (Iridaceae), and hybrids.

We tested the relative fitness of two Louisiana Iris species (Iris brevicaulis and I. fulva) and their first-generation backcross hybrids in three experimental watering treatments: dry, field capacity, and flooded. Leaf area expansion rate, gas exchange (A(max), g(s), c(i)), and biomass at final harvest were measured for each species and hybrid class in all three environmental treatments. Fitness (based on total biomass) of the four genotypic classes differed significantly with environment. All genotypic classes performed most poorly in the dry treatment. The fitness ranking of genotypic class also changed across environments (significant genotypic class by treatment interaction) with hybrid genotype fitness shifting relative to parental genotypes. Integrating over all treatments, backcrosses to I. fulva showed the lowest fitness, whereas backcrosses to I. brevicaulis outperformed I. fulva. The differences in fitness were apparently achieved by a combination of differences in photosynthesis and allocation. In this system, hybrids are not necessarily less fit than their parents, and the relationship between hybrid and parental fitness is influenced by environmental conditions, lending support to the Hybrid Novelty model of hybrid zone evolution.

Journal Article↗

PubMed2000

Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis.

Deposition of aggregated protein into neurofilament-rich cytoplasmic inclusion bodies is a common cytopathological feature of neurodegenerative disease. How-or indeed whether-protein aggregation and inclusion body formation cause neurotoxicity are presently unknown. Here, we show that the capacity of superoxide dismutase (SOD) to aggregate into biochemically distinct, high molecular weight, insoluble protein complexes (IPCs) is a gain of function associated with mutations linked to autosomal dominant familial amyotrophic lateral sclerosis. SOD IPCs are detectable in spinal cord extracts from transgenic mice expressing mutant SOD several months before inclusion bodies and motor neuron pathology are apparent. Sequestration of mutant SOD into cytoplasmic inclusion bodies resembling aggresomes requires retrograde transport on microtubules. These data indicate that aggregation and inclusion body formation are mechanistically and temporally distinct processes.

Animals↗

PubMed2000

The effect of bupropion on nicotine craving and withdrawal.

RATIONALE AND OBJECTIVES: Bupropion has demonstrated efficacy for smoking cessation. Given the importance of nicotine craving and withdrawal in the smoking cessation process, the current study examined the effects of bupropion on these parameters during smoking abstinence. METHODS: During a 2-day Baseline phase with ad lib smoking, 91 non-depressed smokers (who were not trying to quit permanently) were administered measures of nicotine craving, withdrawal symptoms, and timed measures of cognitive performance five times daily. Participants were then assigned randomly to a 14-day treatment regimen with bupropion 300 mg/day, bupropion 150 mg/day, or placebo. Thereafter, the above measures were re-administered during 3 days of abstinence on a closed research ward. RESULTS: Relative to placebo, 300 mg bupropion significantly reduced abstinence-associated increases in rated depression, difficulty concentrating, and irritability, and attenuated a decrease in positive affect. The results also suggested that bupropion might have a positive effect on performance measures during the withdrawal period. No effects were observed on craving, anxiety, restlessness, or hunger. The lack of findings on craving measures may be explained by a floor effect; except on the first day of abstinence, neither drug nor placebo groups showed much craving elevation during abstinence. CONCLUSIONS: Study results indicate that bupropion ameliorates some nicotine withdrawal symptoms.

Adult↗