Evaluation of LBM415 (NVP PDF-713), a novel peptide deformylase inhibitor, for treatment of experimental Mycoplasma pneumoniae pneumonia

Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. We evaluated the efficacy of LBM415, a novel peptide deformylase inhibitor antimicrobial agent, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were intranasally inoculated once with 10(7) CFU of M. pneumoniae. Groups of mice were treated with LBM415 (50 mg/kg of body weight) or placebo subcutaneously daily for 13 days, starting 24 h after inoculation. Groups of mice were evaluated at the baseline; at days of treatment 1, 3, 6, and 13; and at 7 days after treatment. The MIC of LBM415 against M. pneumoniae was <0.005 microg/ml. LBM415-treated mice had significantly lower bronchoalveolar lavage fluid M. pneumoniae concentrations than placebo-treated mice on days 6 and 13 of treatment. Compared with placebo treatment, therapy with LBM415 significantly decreased lung histopathology scores at days 3, 6, and 13 of treatment and at 7 days after treatment. Airway obstruction was significantly lower in LBM415-treated mice than in placebo-treated mice on days 1, 3, and 6 of treatment and after 7 days of therapy, while airway hyperresponsiveness was significantly lower only on day 3 of therapy. The bronchoalveolar lavage fluid concentrations of tumor necrosis factor alpha, gamma interferon (IFN-gamma), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, monokine induced by IFN-gamma, and IFN-inducible protein 10 were significantly reduced in LBM415-treated mice compared with the levels in placebo-treated mice. There were no differences in the bronchoalveolar lavage fluid concentrations of granulocyte-macrophage colony-stimulating factor, IL-1beta, IL-2, IL-4, IL-5, and IL-10 between the two groups of mice. LBM415 therapy had beneficial microbiologic, histologic, respiratory, and immunologic effects on acute murine M. pneumoniae pneumonia.     

Pharmacodynamics of vancomycin for the treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis

With the emergence of beta-lactam antibiotic resistance among strains of Streptococcus pneumoniae, vancomycin has assumed an important role in the treatment of bacterial meningitis. Using the rabbit meningitis model, we evaluated the pharmacokinetics and pharmacodynamics of vancomycin in this setting. Animals were given 80 mg/kg of body weight daily in two or four divided doses to determine the penetration and activity of vancomycin in cerebrospinal fluid (CSF); each regimen was administered with and without dexamethasone. Mean peak (2 h) concentrations in CSF that were four- to eightfold higher than the minimum bactericidal concentration (MBC; 0.5 microgram/ml) for the pathogen were adequate for bacterial clearance. In both groups concentrations in CSF remained higher than the MBC for greater than 80% of the respective dosing intervals, and the penetration of vancomycin into CSF was 20%. Mean concentrations in CSF at 24 to 36 h of therapy were lower than those achieved during the first 12 h, consistent with a decline in the level of antibiotic entry into CSF as inflammation wanes. Rates of bacterial clearance were similar for the two regimens, and for all animals cultures of CSF were sterile by 36 h. The coadministration of dexamethasone significantly reduced the penetration of vancomycin into CSF by 29% and significantly lowered the rate of bacterial clearance during the first 6 h in animals receiving 20-mg/kg doses of vancomycin. For animals receiving 40-mg/kg doses, therapeutic peak concentrations in CSF were obtained even with steroid use, suggesting that the effect of steroids may be circumvented by the use of larger daily doses of vancomycin.     

The pain vigilance and awareness questionnaire (PVAQ): further psychometric evaluation in fibromyalgia and other chronic pain syndromes

In chronic pain patients, preoccupation with or attention to pain is associated with pain-related fear and perceived pain severity. The current study investigated psychometric properties of the pain vigilance and awareness questionnaire (PVAQ). An exploratory factor analysis on Dutch fibromyalgia patients indicated that a two-factor solution was most suitable. The first factor could be referred to as attention to pain and the second factor was interpreted as attention to changes in pain. A confirmatory factor analysis, testing three different factor structures in two independent samples (Dutch fibromyalgia patients and American pain patients with various diagnoses) showed that the goodness-of-fit indicators for all models were satisfactory. The existence of the previously reported intrusion subscale of the PVAQ as a unique construct within the PVAQ was discussed. This subscale should be further extended by non-reverse-keyed items. With regard to the convergent validity, the PVAQ was highly correlated with related constructs such as the pain catastrophizing scale (PCS), pain anxiety symptoms scale (PASS), and Tampa scale of kinesiophobia (TSK). The attention to pain subscale was significantly stronger associated with these pain-related measures than the attention to changes in pain subscale, indicating that attention to changes in pain is a distinctive construct. The uniqueness of the attention to changes in pain subscale was also supported by an exploratory factor analysis on all items of the PVAQ, PCS, PASS, and TSK which showed that all items from that scale loaded on one separate factor. Overall, the PVAQ showed good internal consistency. Implications for future research and treatment interventions are discussed.     

Cost comparison of catheter ablation and medical therapy in atrial fibrillation

Introduction: There is emerging evidence for clinical superiority of catheter ablation over rate and rhythm control strategies in paroxysmal atrial fibrillation (PAF). The objective of this study was to compare costs related to medical therapy versus catheter ablation for PAF in Ontario (Canada).
Methods: Costs related to medical therapy in the analysis included the cost of anticoagulation, rate and rhythm control medications, noninvasive testing, physician follow-up visits, and hospital admissions, as well as the cost of complications related to this management strategy. Costs related to catheter ablation were assumed to include the cost of the ablation tools (electroanatomic mapping or intracardiac echocardiography-guided pulmonary vein ablation), hospital and physician billings, and costs related to periprocedural medical care and complications. Costs related to these various elements were obtained from the Canadian Registry of Atrial Fibrillation (CARAF), government fee schedules, and published data. Sensitivity analyses looking at a range of initial success rates (50–75%) and late attrition rates (1–5%), prevalence of congestive heart failure (CHF) (20–60%), as well as discounting varying from 3% to 5% per year were performed.
Results: The cost of catheter ablation ranged from $16,278 to $21,294, with an annual cost of $1,597 to $2,132. The annual cost of medical therapy ranged from $4,176 to $5,060. Costs of ongoing medical therapy and catheter ablation for PAF equalized at 3.2–8.4 years of follow-up.
Conclusion: Catheter ablation is a fiscally sensible alternative to medical therapy in PAF with cost equivalence after 4 years.     

Direct Health Care Costs for Children with Pervasive Developmental Disorders: 1996–2002

We compared direct costs of treatment of Pervasive Developmental Disorder (PDD), asthma, and diabetes in children aged 3–17 years. A retrospective, claims-based study was conducted using the California Medicaid (Medi-Cal) database (1996–2002). Seven hundred and thirty-one children with PDD were identified and matched for sex with an equal number of randomly selected children with asthma and diabetes. Mean total health care costs for PDD were two- to threefold higher than for asthma and diabetes post-diagnosis ($4,815 vs. $1,469 vs. $2,404, respectively, P < 0.0001). Children with PDD incur significantly greater health care costs when compared with children with other chronic pediatric diseases.     

Systemic cytokine profile in children with community-acquired pneumonia

OBJECTIVES: Characterization of the systemic cytokine response in community-acquired pneumonia (CAP) may facilitate our understanding of the host immune response and provide a prognostic as well as diagnostic tool. Systemic cytokine characterization of CAP has been limited largely to a few integral cytokines in adults. METHODS: Analyses were performed to investigate whether significant relationships existed between an expanded serum cytokine profile and etiologies, manifestations, and outcomes of pediatric CAP. The serum concentrations of 15 cytokines were investigated in 55 hospitalized children with well-characterized CAP. RESULTS: Comparison of median cytokine concentrations among patients with CAP caused by Mycoplasma pneumoniae or Chlamydophila pneumoniae, Streptococcus pneumoniae, viruses, mixed infections, or unidentified pathogens revealed significant differences in IFN-alpha, IL-6, IL-17, GM-CSF, and TNF-alpha concentrations. The mixed infections category had significantly elevated concentrations of IFN-alpha, IL-6, GM-CSF, and TNF-alpha. There were significant correlations between concentrations of IL-6 and markers of disease severity (white blood cell band-forms, procalcitonin, and unequivocal consolidation). No single cytokine could reliably differentiate the etiologic cause of pneumonia. CONCLUSIONS: IL-6 is the only one of 15 serum cytokines studied that correlated with indicators of disease severity in childhood CAP. The applicability of cytokine profiles to identify microbiologic etiologies of pneumonia remains to be defined.     

Parent versus teacher ratings of attention-deficit/hyperactivity disorder symptoms in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS)

OBJECTIVE: To assess parent-teacher concordance on ratings of DSM-IV symptoms of attention-deficit/hyperactivity disorder (ADHD) in a sample of preschool children referred for an ADHD treatment study. METHODS: Parent and teacher symptom ratings were compared for 452 children aged 3-5 years. Agreement was calculated using Pearson correlations, Cohen's kappa, and conditional probabilities. RESULTS: The correlations between parent and teacher ratings were low for both Inattentive (r = .24) and Hyperactive-Impulsive (r = .26) symptom domains, with individual symptoms ranging from .01-.28. Kappa values for specific symptoms were even lower. Conditional probabilities suggest that teachers are only moderately likely to agree with parents on the presence or absence of symptoms. Parents were quite likely to agree with teachers' endorsement of symptoms, but much less likely to agree when teachers indicated that a symptom was not present. CONCLUSIONS: Results provide important data regarding base rates and concordance rates in this age group and support the hypothesis that preschool-aged children at risk for ADHD exhibit significant differences in behavior patterns across settings. Obtaining ratings from multiple informants is therefore considered critical for obtaining a full picture of young children's functioning.     

Correlates of accommodation of pediatric obsessive-compulsive disorder: parent, child, and family characteristics

ObjectivePediatric obsessive-compulsive disorder (OCD) is a chronic, impairing condition associated with high levels of family accommodation (i.e., participation in symptoms). Understanding of factors that may engender accommodation of pediatric OCD is limited. This study conducted exploratory analyses of parent-, child-, and family-level correlates of family accommodation, considering both behavioral and affective components of the response.MethodThe sample included 65 youths (mean age 12.3 years, 62% male) with OCD and their parents who completed a standardized assessment battery composed of both clinical and self-report measures (e.g., Children's Yale-Brown Obsessive-Compulsive Scale, Brief Symptom Inventory).ResultsFamily accommodation was common, with the provision of reassurance and participation in rituals the most frequent practices (occurring on a daily basis among 56% and 46% of parents, respectively). Total scores on the Family Accommodation Scale were not associated with child OCD symptom severity; however, parental involvement in rituals was associated with higher levels of child OCD severity and parental psychopathology and with lower levels of family organization. Comorbid externalizing symptomatology and family conflict were associated with parent report of worse consequences when not accommodating.ConclusionsAlthough these findings must be interpreted in light of potential type I error, they suggest that accommodation is the norm in pediatric OCD. Family-focused interventions must consider the parent, child, and family-level variables associated with this familial response when teaching disengagement strategies.