Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Clarithromycin is postulated to possess immunomodulatory properties in addition to its antimicrobial activity. OBJECTIVE: To evaluate the effect of clarithromycin on serum and nasopharyngeal cytokine and chemokine concentrations in children with an acute exacerbation of recurrent wheezing. METHODS: Children with a history of recurrent wheezing or asthma and who presented with an acute exacerbation of wheezing were enrolled in a double-blind, randomized trial of clarithromycin vs placebo. Concentrations of tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, RANTES, eotaxin, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 were measured in serum and/or nasopharyngeal aspirates before, during, and after therapy. Mycoplasma pneumoniae and Chlamydophila pneumoniae infection were evaluated for by polymerase chain reaction and serologic testing. RESULTS: Nasopharyngeal concentrations of TNF-alpha, IL-1beta, and IL-10 were significantly and persistently lower in children treated with clarithromycin compared with placebo. There tended to be a greater effect of clarithromycin on nasopharyngeal cytokine concentrations in patients with evidence of M. pneumoniae or C. pneumoniae infection. No significant differences were detected in serum cytokines for children treated with clarithromycin compared with placebo. CONCLUSION: Clarithromycin therapy reduces mucosal TNF-alpha, IL-1beta, and IL-10 concentrations in children with an acute exacerbation of recurrent wheezing.     

Is fecundability associated with month of birth? An analysis of 19th and early 20th century family reconstitution data from The Netherlands

The relationship between fecundability and month of birth was investigated in a cohort of 1526 women who married between 1802 and 1929, using only women whose first marriage occurred before the age of 35 years. On the basis of their time to pregnancy (TTP, calculated as time between wedding and first birth minus gestational length), women were categorized into two groups: fecunds (TTP up to 12 months or prenuptial conceptions, n = 1348) and subfecunds (TTP >18 months, n = 118). By use of logistic regression, cosinor functions with a period of 1 year or 6 months and variable shift and amplitude were fitted through the monthly odds of subfecunds versus fecunds. The best fitting curve was unimodal, with a zenith in September (P = 0.13 for H0: no differences). Exclusion of childless women (n = 36, minimum follow-up 5 years) from the subfecunds led to a similar curve (P < 0.01), while childless women, as compared with fecunds, showed a birth distribution that was best represented with a bimodal curve with zeniths in January and July (P = 0.06). This study provides evidence for the existence of differences in fecundability by month of birth. The cause of this relationship is unclear, but may lie in a melatonin-dependent circannual variability of the quality of the oocyte.      

Mycoplasma pneumoniae induces host-dependent pulmonary inflammation and airway obstruction in mice

Respiratory tract infections result in wheezing in a subset of patients. Mycoplasma pneumoniae is a common etiologic agent of acute respiratory infection in children and adults that has been associated with wheezing in 20-40% of individuals. The current study was undertaken to elucidate the host-dependent pulmonary and immunologic response to M. pneumoniae respiratory infection by studying mice with different immunogenetic backgrounds (BALB/c mice versus C57BL/6 mice). After M. pneumoniae infection, only BALB/c mice developed significant airway obstruction (AO) compared with controls. M. pneumoniae-infected BALB/c mice manifested significantly elevated airway hyperresponsiveness (AHR) compared with C57BL/6 mice 4 and 7 d after inoculation as well as BALB/c control mice. Compared with C57BL/6 mice, BALB/c mice developed worse pulmonary inflammation, including greater peribronchial infiltrates. Infected BALB/c mice had significantly higher concentrations of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-1beta, IL-6, IL-12, KC (functional IL-8), and macrophage inflammatory protein 1alpha in the bronchoalveolar lavage fluid compared with infected C57BL/6 mice. No differences in IL-2, IL-4, IL-5, IL-10, and granulocyte/macrophage colony-stimulating factor concentrations were found. The mice in this study exhibited host-dependent infection-related AO and AHR associated with chemokine and T-helper type (Th)1 pulmonary host response and not Th2 response after M. pneumoniae infection.     

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Comparison of fixed concentration and fixed ratio options for dilution susceptibility testing of gram-negative bacilli to ampicillin and ampicillin/sulbactam

Ampicillin combined with sulbactam was tested at both fixed ratio (2:1 and 1:1) and fixed sulbactam concentrations (4 µg/ml, 8 µg/ml and 16 µg/ml) against 2440 consecutively isolated gram-negative bacilli. Sulbactam significantly enhanced the spectrum of ampicillin activity. Overall, at 8 µg/ml ampicillin inhibited 50 % of theEnterobacteriaceae isolates, whereas 69 % to 84 % of the isolates were inhibited by the various sulbactam combinations. The widest spectrum of activity for ampicillin/sulbactam was achieved by testing at a fixed sulbactam concentration of 16 µg/ml, followed by the 1:1 ratio and the fixed 8 µg/ml (84 %, 76 % and 74 % inhibited, respectively). The amount of sulbactam at the susceptible breakpoint concentrations of ampicillin markedly affected the percentage of susceptible strains. Combinations that include 8 µg/ml of sulbactam are suggested for consideration.     

Macrophages in immunity to syphilis: suppressive effect of concurrent infection with Mycobacterium bovis BCG on the development of syphilitic lesions and growth of Treponema pallidum in tuberculin-positive rabbits.

Paired groups of male rabbits were challenged with Treponema pallidum and Mycobacterium bovis BCG. One group had been sensitized to BCG by inoculation 3 weeks before challenge. All animals were challenged intradermally at multiple sites with T. pallidum alone, BCG alone, and both organisms into the same sites. The resulting lesions were followed clinically and histologically. BCG lesions enlarged more rapidly in sensitized rabbits, but they were otherwise no different from those in the controls. T. pallidum lesions enlarged and regressed simultaneously in both groups, but in the BCG-sensitized animals they became twice as large as those in the unsensitized rabbits. Mixed BCG-T. pallidum lesions showed the greatest differences in the two groups of animals. Like the pure BCG lesions, they enlarged more rapidly in the sensitized rabbits but began to recede after 1 week. The corresponding lesions in the controls enlarged more slowly and reached their maximum size after 3 weeks when the receding lesions in the sensitized animals were much smaller. The most marked histological-histochemical difference between the two groups of animals was in the number and activation of macrophages. These cells were more numerous in the mixed lesions of BCG-sensitized animals than in similar lesions of the controls and more activated as determined by beta-galactosidase staining. Although sparsely distributed, activated macrophages were more numerous in the pur T. pallidum lesions of sensitized animals than in those of control animals. Silver-stained sections revealed fewer treponemes in mixed lesions of sensitized animals than in the mixed lesions of control animals. Quantitation of treponemes in pure T. pallidum versus mixed lesions was determined in two groups of rabbits challenged intratesticularly. The total number of treponemes per testis in the mixed lesions of BCG-sensitized rabbits was significantly less than the number in the mixed lesions of control animals, and also less than the number in pure T. pallidum lesions of both groups of animals.     

An association study of the cholesteryl ester transfer protein TaqI B polymorphism with late onset Alzheimer's disease

Cholesteryl ester transfer protein (CETP) is reportedly able to affect the amount of cholesterol available for deposition and/or removal from peripheral tissues, in its capacity to mediate the transfer of cholesterol from high density lipoprotein (HDL) to very low density lipoprotein, in exchange for triacylglycerols from the latter. The TaqI B polymorphism of the human CETP gene has been associated with decreased CETP mass and an increase in HDL-cholesterol. While many studies have addressed the atherogenic or anti-atherogenic potential of this polymorphism, little is known about its effect on neurodegeneration, despite the fact that CETP is expressed in the brain and the disturbance of cholesterol homeostasis appears to be an important factor in the pathogenesis of Alzheimer's disease (AD). In this report, we have compared the distribution of the TaqI B polymorphism in an independent population of 102 clinically diagnosed late onset AD patients and a spousal control group of 97 individuals. We have also examined the possible interaction between this polymorphism and two other polymorphisms suspected of affecting cholesterol flux, namely apolipoprotein E APOE epsilon4, and lipoprotein lipase LPLS447X. No statistically significant differences have emerged with respect to either genotype or allele frequencies between the AD and control populations. CETP TaqI B did not interact significantly with either APOE epsilon4 or LPLS447X, in this study.