Mycobacterial diseases and antitumour necrosis factor therapy in USA.

OBJECTIVE: In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown. METHODS: At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000-2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. RESULTS: Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). CONCLUSIONS: Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.

Efficacy and safety of antidepressant drug treatment in children and adolescents.

Depression and anxiety are common disorders in youth that can have profound influences on functioning and even mortality. In the late 1990s, large controlled trials began demonstrating the efficacy of selective serotonin reuptake inhibitors for these conditions in the pediatric population. By 2003, regulatory agencies began warning the public of unrecognized risk and misrepresented benefit. The current review article summarizes a series of published and unpublished efficacy and safety data regarding antidepressant use in children and adolescents. The resulting complex synthesis suggests that these medications may offer mild-to-moderate benefit, with notable exceptions depending on medication and indication, but they may also heighten the risk for suicidal ideation and parasuicidal behavior. However, reviewed epidemiological data does not demonstrate a relationship between newer antidepressant prescription and completed suicide in large populations of youth. In conclusion, this breadth of mixed research data is applied to clinical decision making.

Isolation of non-tuberculous mycobacteria from the sputum of patients with active tuberculosis.

We looked for non-tuberculous mycobacteria (NTM) in the sputum of patients diagnosed with pulmonary tuberculosis (TB) in Oregon in 2005-2006 (n = 141). Twenty (14%) patients had NTM isolated from sputum during TB treatment. Compared to those without NTM, TB patients with NTM were more likely to have cavitary disease (RR 2.7, 95%CI 1.2-6.0) and were more likely to be born in the United States (RR 2.4, 95%CI 1.1-5.3). Further study is needed to determine the clinical significance of simultaneous isolation of NTM and TB.

FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that has been implicated in the induction of differentiation of various cell types, including human uroepithelial cells. PPARgamma-mediated differentiation of normal human urothelial (NHU) cells in vitro requires coinhibition of epidermal growth factor receptor (EGFR) signalling and is characterised by de novo expression of late/terminal differentiation-associated genes, including uroplakins (UPK), over a 6-day period. We used gene microarrays to identify intermediary transcription factors induced in direct response to PPARgamma activation of EGFR-inhibited NHU cells. FOXA1 and IRF-1 contained consensus cognate binding sites in UPK1a, UPK2, and UPK3a promoters and transcripts were induced within 12 h of PPARgamma activation; transcription complex formation was confirmed by electromobility shift assays. In urothelium in situ, both FOXA1 and IRF-1 were nuclear and expressed in a differentiation-associated pattern. Knockdown by transient siRNA of either FOXA1 or IRF-1 abrogated PPARgamma-induced uroplakin expression in vitro. This is the first evidence that ligand activation of PPARgamma induces expression of intermediary transcription factors that mediate an epithelial differentiation programme and represents a new paradigm for understanding differentiation, regenerative repair and inflammation in epithelial tissues.

Pneumothorax, pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum and subcutaneous emphysema following diagnostic colonoscopy.

Colonic perforation is an unusual complication of colonoscopy. We present a case of pneumothorax, pneumomediastinum, pneumoperitoneum and extensive subcutaneous emphysema resulting from a diagnostic colonoscopy. To our knowledge, only two such cases have been described previously.

Modelling cell signalling and differentiation in the urothelium.

Urothelial cells line the bladder. If the urothelium is damaged, it is vital that it repairs itself quickly. Experimental results shedding light on how this repair process works are presented, revealing in particular the dependence of the response on the length of time for which the drug Troglitazone (TZ) is applied. A simple mathematical model for the basic mechanism (comprising ordinary differential equations) is then developed and analysed, seeking specifically to clarify and quantify the mechanisms governing the dependence of the cell differentiation response on the TZ administration time, rather than providing a comprehensive model of differentiation. Through biologically justified simplifications, analysis reveals that the model gives results in accord with the experimental observations, and suggests new experiments that may aid further understanding. Directions in which this preliminary modelling of the PPAR gamma (peroxisome proliferator activated receptor gamma) pathway could be usefully extended are also indicated.

Sudden death related to selected tricyclic antidepressants in children: epidemiology, mechanisms and clinical implications.

The association between tricyclic antidepressant (TCA) use in children and increased risk of sudden death is unclear, but still possible. There are suitable alternatives to TCAs for all of the indications in which they have shown efficacy. A prudent practice model for the utilisation of TCAs has been developed. This includes initial utilisation of alternative agents, with TCAs as secondary or tertiary choices; informed consent from patient and family, including mention of the possible relationship of TCA with sudden death; vigilance of the emerging literature; and finally, systematic monitoring of patients, including electrocardiograms, drug serum concentrations and vital signs. This protocol needs to be validated with regard to utility and the degree of assistance it provides in the management of children treated with TCAs.

Interleukin-1 beta induced synthesis of protein kinase C-delta and protein kinase C-epsilon in EL4 thymoma cells: possible involvement of phosphatidylinositol 3-kinase.

We present evidence here that the proinflammatory cytokine, interleukin-1 beta (IL-1 beta) stimulates a significant increase in protein kinase C (PKC)-epsilon and PKC-delta protein levels and increases PKC-epsilon, but not PKC-delta, transcripts in EL4 thymoma cells. Incubation of EL4 cells with IL-1 beta induced protein synthesis of PKC-epsilon (6-fold increase) by 7 h and had a biphasic effect on PKC-delta levels with peaks at 4 h (2-fold increase) and 24 h (4-fold increase). At the level of mRNA, PKC-epsilon, but not PKC-delta levels, were induced after incubation of EL4 cells with IL-1 beta. The signalling mechanisms utilized by IL-1 beta to induce the synthesis of these PKC isoforms were investigated. Two phosphatidylinositol (PI) 3-kinase-specific inhibitors, wortmannin and LY294002, inhibited IL-1 beta-induced synthesis of PKC-epsilon. However, the PI 3-kinase inhibitors had little effect on the IL-1 beta-induced synthesis of PKC-delta in these cells. Our results indicate that IL-1 beta induced both PKC-delta and PKC-epsilon expression over different time periods. Furthermore, our evidence suggests that IL-1 beta induction of PKC-epsilon, but not PKC-delta, may occur via the PI 3-kinase pathway.

Emergence of tics in children with attention deficit hyperactivity disorder treated with stimulant medications.

The emergence of tics in children treated with stimulant medication for attention deficit hyperactivity disorder (ADHD) was investigated. A retrospective chart review of the medical records of 555 subjects was performed to examine the emergence of tics in relation to treatment with a stimulant medication, dosage, duration of treatment, and age of subjects. A total of 7.8% of the subjects treated with stimulants developed tics: 8.3% of subjects treated with methylphenidate, 6.3% with dextroamphetamine, and 7.7% with pemoline. The subjects who developed tics were significantly younger than those who did not. Subjects treated with higher doses of stimulant medication were not more likely to develop tics. While the emergence of tics was common, these subjects may have developed tics irrespective of stimulant medication. Controversy remains as to the long-term risk of tics in relation to stimulant medication and to appropriate practice should tics emerge during the course of stimulant medication treatment.

Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure.

OBJECTIVES: To compare the hemodynamic effects of twice daily metoprolol tartrate (MT) and once daily metoprolol succinate (MS) in congestive heart failure patients. BACKGROUND: Adverse hemodynamic effects with MT demonstrated during initiation persist with drug readministration during chronic therapy. METHODS: Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally and the dose was gradually increased to a target of 50 mg twice a day or 100 mg once a day, respectively. Hemodynamic measurements were obtained at baseline and after three months of therapy--both before and after drug readministration. RESULTS: Long term metoprolol therapy produced significant functional, exercise and hemodynamic benefits with no difference in response between either metoprolol preparation in the 27 patients (MT [14], MS [13]). When full dose metoprolol was readministered during chronic therapy, there were parallel adverse hemodynamic effects in both drug groups. Cardiac index decreased by 0.6 liters/min/m2 (p < 0.0001) with MT and by 0.5 liters/min/m2 (p < 0.0001) with MS. Systematic vascular resistance increased by 253 dyne-sec-cm(-5) (p < 0.001) with MT and by 267 dyne-sec-cm(-5) (p < 0.0005) with MS. Stroke volume index decreased by 7.0 ml/m2 (p < 0.0005) with MT and by 6.5 ml/m2 (p < 0.0001) with MS, while SWI decreased by 6.2 g-m/m2 (p < 0.0005) with MT and by 6.0 g-m/m2 (p < 0.001) with MS. CONCLUSION: Metoprolol tartrate and MS produce similar hemodynamic and clinical effects acutely and chronically despite the fourfold greater starting dose of MS used in this study. A more rapid initiation with readily available starting doses of MS may offer distinct advantages compared with MT in treating chronic heart failure patients with beta-adrenergic blocking agents.

Sudden death of a child treated with imipramine. Case study.

Since 1990, there have been seven reported cases of sudden death in children treated with tricyclic antidepressants. This case study describes the sudden death of an additional child (8 years 9 months old, 29 kg in weight) treated with a tricyclic antidepressant, imipramine (100 mg orally, twice daily), and dextroamphetamine (10 mg orally every morning). Prior to death, there were signs of possible cardiovascular abnormalities after treatment was begun with imipramine. The report adds to the concern over the use of tricyclics in children.

Hepatocyte isolation stimulates formation of interferon stimulatory response element DNA-protein complexes.

We have examined the relationship between intracellular signalling pathways and loss of differentiated function during hepatocyte isolation and culture. We have shown that isolation induces the activation of the interferon stimulatory response element (ISRE). This activation was transient and peaked at 3 h before it returned to basal by 24 h of culture. Interferon regulatory factor-1 (IRF-1) was shown to be important for generation of ISRE complexes by electromobility shift assays and supershift intervention. IRF-1 was translocated to the nucleus in parallel with changes to ISRE complex formation. The p38 kinase inhibitor, SB 203580, diminished the formation of ISRE binding complexes. Hence p38 kinase may be involved in the activation and binding of IRF-1 or related proteins to the ISRE motif. Changes in ISRE activation levels in cultured hepatocytes may have important implications in primary hepatocyte differentiation and loss of function.

Short-term and long-term hemodynamic and clinical effects of metoprolol alone and combined with amlodipine in patients with chronic heart failure.

BACKGROUND: Initiation of beta-blocker therapy is often limited by worsening congestive heart failure, which may manifest as worsening hemodynamics. Deleterious hemodynamic effects might be mitigated with the vasodilation of combined calcium channel/beta-blocker therapy. METHODS AND RESULTS: This prospective, randomized study assessed the safety and efficacy of metoprolol alone or combined with amlodipine on hemodynamic parameters at baseline, 2 hours after the first dose of study medication, and after 12 weeks of therapy in patients receiving background triple therapy for mild to severe heart failure. Functional, exercise, and hormonal status were assessed at baseline and end of study. Twenty-nine patients (mean age 50 +/- 12.1 years) were enrolled; 21 completed 12 weeks of treatment. Mean ejection fraction at baseline was 13.4% +/- 5.7%; 79% of patients had heart failure classified as New York Heart Association class III, and 66% had heart failure of idiopathic origin. Heart rate and blood pressure did not change with short-term therapy in either group. The first dose of both regimens produced significant increases in systemic vascular resistance and significant decreases in cardiac output and index and stroke volume and stroke work indexes; combination therapy acutely yielded small but statistically significant increases in pulmonary artery, pulmonary capillary wedge, and right atrial pressures. Long-term therapy with both regimens produced significant decreases in heart rate, systemic vascular resistance, and pulmonary capillary wedge pressure and significant increases in cardiac output and index and stroke volume and stroke work indexes. Combination therapy produced significant long-term decreases in blood pressure. CONCLUSIONS: There was no further measurable benefit with the addition of amlodipine to metoprolol compared with the effects of metoprolol alone. Therapy with metoprolol alone and the combination of metoprolol and amlodipine was well tolerated in patients with mild to severe heart failure, as evidenced by a lack of adverse effects on hemodynamic parameters over the short term and clinical and hemodynamic improvement with long-term treatment.

Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure.

BACKGROUND: With beta-blocker use becoming more prevalent in treating chronic heart failure (CHF), the choice of drugs raises important theoretical and practical questions. Although the second-generation compound metoprolol is beta1-selective, the third-generation compound carvedilol is beta-nonselective, with ancillary pharmacological properties including alpha-blockade and antioxidant effects. A prospective comparison of these 2 agents can address the issue of optimal adrenergic blockade in selecting agents for therapy in CHF. METHODS AND RESULTS: Sixty-seven patients with symptomatic stable heart failure were randomly assigned to receive either carvedilol or metoprolol in addition to standard therapy for CHF. Measured variables included symptoms, exercise, ejection fraction, and thiobarbituric acid-reactive substances (TBARS) as an indirect marker of free radical activity. Metoprolol and carvedilol were well tolerated, and both patient groups showed beneficial effects of beta-blocker therapy in each of the measured parameters, with no between-group differences. Ejection fraction increased over 6 months from 18+/-6.3% to 23+/-8.7% (P<0.005) with metoprolol and from 19+/-8.5% to 25+/-9.9% (P<0.0005) with carvedilol (P=NS between groups). With metoprolol, TBARS values decreased from 4.7+/-0.9 nmol/mL at baseline to 4.2+/-1.5 nmol/mL at month 4 to 3.9+/-1.0 nmol/mL at month 6 (P<0.0001). With carvedilol, there was a parallel decline from 4.7+/-1.4 to 4.2+/-1.3 to 4.1+/-1.2 nmol/mL over the same time frame (P<0.025), with no between-group difference in these changes. CONCLUSIONS: Carvedilol and metoprolol showed parallel beneficial effects in the measured parameters over 6 months, with no relevant between-group differences in this heart failure population.

Activation of stress-activated protein kinases by hepatocyte isolation induces gene 33 expression.

Gene 33 is a putative immediate early gene and we have shown that mRNA encoding for gene 33 exhibits a transient increase as a result of the procedures used for hepatocyte isolation. The stress-activated protein kinases p46 JNK, p54 JNK, and p38 SAPK are activated by hepatocyte isolation and precede changes in gene 33 mRNA content. Although each SAPK isoform shows a distinctive profile of activity during isolation and subsequent hepatocyte culture, in each case the activation is transient and is largely reversed within 3 h of hepatocyte isolation. SB 203580, a p38 SAPK inhibitor, prevents the change to gene 33 expression in response to hepatocyte isolation. Given the possible role of gene 33 as an immediate early gene, the data presented here have general implications for control of hepatocyte proliferation and differentiation.

Prediction of stimulant response in children with attention-deficit/hyperactivity disorder.

Discrimination of stimulant-responding and nonresponding groups of children with attention-deficit/hyperactivity disorder (ADHD) on the basis of demographic, neurophysiologic, or behavioral variables would be beneficial for clinical and theoretical reasons. Previous researchers have identified many predictor variables, but relationships between predictor and criterion variables generally have been subtle. In addition, few investigations have considered the relative predictive power of the variables. The present study evaluated the multivariate relationship between several predictor variables and response to medication in 336 children with ADHD. Neurologic status, inattention, and overactivity were found to be most likely to predict good response to psychostimulants, whether rated by parents or teachers. Although a number of variables predicted a positive psychostimulant response, the strength of the predictive associations suggests only minimal clinical usefulness.

Effect of race in the response to metoprolol in patients with congestive heart failure secondary to idiopathic dilated or ischemic cardiomyopathy.

We sought to determine the effect of race in response to metoprolol in patients with dilated cardiomyopathy. We found no difference in exercise, hemodynamic, and neurohormonal responses to metoprolol based on race in patients with cardiomyopathy.

Acute hepatitis associated with Campylobacter jejuni bacteraemia.

A case of acute hepatitis associated with Campylobacter jejuni bacteraemia is reported. Transaminase levels were increased over 50-fold in a patient with clinical features of enteritis and septicaemia. Campylobacter jejuni was isolated from blood and faecal cultures. Other infective and noninfective causes of acute hepatitis were excluded. The patient's symptoms and liver function values improved after antimicrobial therapy. Hepatitis should be considered as a complication of human Campylobacter jejuni infection.

Interleukin-1beta-induced expression of protein kinase C (PKC)-delta and epsilon in NIH 3T3 cells.

NIH 3T3 cells express the alpha, delta, epsilon and zeta isoenzymes of protein kinase C(PKC). Following stimulation of cells (24 h) with the pro-inflammatory cytokine, interleukin 1beta (IL-1beta), we observed, by Western blotting, a dose-dependent effect on the levels of PKC-epsilon and delta, but not on alpha or zeta. Moreover, time course analysis revealed that the isoenzymes, PKC-delta and epsilon were induced by IL-1beta after 7 h. Again, no change in PKC-alpha or zeta levels after IL-1beta treatment were detected. Incubation with selective PKC inhibitor peptides blocked the PKC-alpha, delta, epsilon and zeta antibodies binding to their respective isoenzyme bands. We also observed that the addition of the tumour-promoting phorbol ester, Phorbol 12-myristate 13-acetate (PMA), downregulated PKC-alpha, delta and epsilon by 7 h in NIH 3T3 cells. PMA did not affect constitutively produced PKC-zeta protein levels even after 24-h treatment. In summary, these results demonstrate that IL-1beta induces protein synthesis of the Ca2+-independent PKC-delta and epsilon isoforms in NIH 3T3 cells. The differences observed here between PKC isoenzymes in response to IL-1beta suggest that each isoenzyme may have a unique role in the signal transduction pathways of IL-1beta and that such isoenzyme may have a unique role in the signal transduction pathways of IL-1beta and that such selective expression may influence the action of agents which require PKC for signal transduction acting in concert with IL-1.

Adult attention-deficit hyperactivity disorder: assessment guidelines based on clinical presentation to a specialty clinic.

Of 143 adults presenting for attention-deficit hyperactivity disorder (ADHD) evaluation, 46 (32%) clearly met diagnostic criteria, 46 (32%) clearly did not meet diagnostic criteria, and another 51 (36%) with current ADHD-like features did not meet criteria due to either a lack of childhood history and/or complicating severe psychiatric or substance abuse comorbidity. The three groups were similar in demographics, psychiatric diagnosis, psychiatric symptom severity, and functional impairment. Compared with the group not meeting ADHD criteria, patients with ADHD had more frequent histories of learning disability in childhood, poorer reading scores on the Wide-Range Achievement Test (WRAT), poorer scores on the Continuous Performance Test (CPT), and higher scores on the Wender-Utah Rating Scale (WURS) for ADHD. Patients in the ambiguous ADHD category had higher rates of current substance abuse than the other two groups. While this group resembled the non-ADHD group in having a low incidence of learning disability and normal reading scores, their poor performance on the CPT and high scores on the WURS more closely resembled those of ADHD patients. These findings suggest that there are a few rating scales, testing instruments, and lifetime history characteristics that help to clarify the difficult diagnostic distinction between adult patients who do and do not have ADHD.