A first-in-human study of the anti-inflammatory profibrinolytic TMS-007, an SMTP family triprenyl phenol.

AIMS: TMS-007, an SMTP family member, modulates plasminogen conformation and enhances plasminogen-fibrin binding, leading to promotion of endogenous fibrinolysis. Its anti-inflammatory action, mediated by soluble epoxide hydrolase inhibition, may contribute to its efficacy. Evidence suggests that TMS-007 can effectively treat experimental thrombotic and embolic strokes with a wide time window, while reducing haemorrhagic transformation. We aim to evaluate the safety, pharmacokinetics and pharmacodynamics of TMS-007 in healthy volunteers. METHODS: This was a randomized, placebo-controlled, double blind, dose-escalation study, administered as a single intravenous infusion of TMS-007 in cohorts of healthy male Japanese subjects. Six cohorts were planned, but only five were completed. In each cohort (n = 8), individuals were randomized to receive one of five doses of TMS-007 (3, 15, 60, 180 or 360 mg; n = 6) or placebo (n = 2). RESULTS: TMS-007 was generally well tolerated, and no serious adverse events were attributed to the drug. A linear dose-dependency was observed for plasma TMS-007 levels. No symptoms of bleeding were observed on brain MRI analysis, and no bleeding-related responses were found on laboratory testing. The plasma levels of the coagulation factor fibrinogen and the anti-fibrinolysis factor α2 -antiplasmin levels were unchanged after TMS-007 dosing. A slight increase in the plasma level of plasmin-α2 -antiplasmin complex, an index of plasmin formation, was observed in the TMS-007 group in cohort 2. CONCLUSIONS: TMS-007 is generally well tolerated and exhibits favourable pharmacokinetic profiles that warrant further clinical development.

Preclinical safety, toxicokinetics and metabolism of BIIB131, a novel prothrombolytic agent for acute stroke.

BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings. The BIIB131 was poorly metabolized in microsomes with no inhibition of CYPs. BIIB131-glucuronide, formed by UGT1A1, accounted for 21.5% metabolism in human hepatocytes and 28-40% in rat bile. In rats, excretion was primarily via the bile. BIIB131 inhibited the hERG and Nav1.5 cardiac channels by 39% but showed no effect on cardiovascular parameters in monkeys. Toxicology findings were limited to reversable hematuria, changes in urinary parameters and local effects. A MTD of 30 mg/kg was established in monkeys, the most sensitive species, at total plasma Cmax and AUC of 6- and 14-fold, respectively, greater than the NOAEL. The Phase 1 study started with intravenous 0.05 mg/kg and ascended to 6.0 mg/kg which corresponded to safety margins of 147- to 0.9-fold (for Cmax) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development.

Development of an In Vitro Chloroplast Splicing System: Sequences Required for Correct pre-mRNA Splicing.

Chloroplast genomes in land plants include approximately 20 intron-containing genes. Most of the introns are similar to the group II introns found in fungi, algae and some bacteria, but no self-splicing has been reported. To analyze splicing reactions in chloroplasts, we developed a tobacco (Nicotiana tabacum) chloroplast-based in vitro system. We optimized the splicing reaction using atpF precursor messenger RNA (pre-mRNA). Our system requires a high ATP concentration, whereas ATP is not necessary for self-splicing group II introns. Self-splicing group II introns possess two exon-binding sites (EBS1 and 2) complementary to two intron-binding sites (IBS1 and 2) in the 3' end of 5' exons, which are involved in 5' splice-site selection. Using our in vitro system and atpF pre-mRNA, we analyzed short sequences corresponding to the above EBSs and IBSs. Mutation analyses revealed that EBS1-IBS1 pairing is essential, while EBS2-IBS2 pairing is important but not crucial for splicing. The first 3' exon nucleotide determines the 3' splice sites of self-splicing introns. However, mutations to this nucleotide in atpF pre-mRNA did not affect splicing. This result suggests that the mechanism underlying chloroplast pre-mRNA splicing differs partly from that mediating the self-splicing of group II introns.

Transcriptome Analysis and Identification of a Transcriptional Regulatory Network in the Response to H2O2.

Hydrogen peroxide (H2O2) is a common signal molecule initiating transcriptional responses to all the known biotic and abiotic stresses of land plants. However, the degree of involvement of H2O2 in these stress responses has not yet been well studied. Here we identify time-dependent transcriptome profiles stimulated by H2O2 application in Arabidopsis (Arabidopsis thaliana) seedlings. Promoter prediction based on transcriptome data suggests strong crosstalk among high light, heat, and wounding stress responses in terms of environmental stresses and between the abscisic acid (ABA) and salicylic acid (SA) responses in terms of phytohormone signaling. Quantitative analysis revealed that ABA accumulation is induced by H2O2 but SA is not, suggesting that the implied crosstalk with ABA is achieved through ABA accumulation while the crosstalk with SA is different. We identified potential direct regulatory pairs between regulator transcription factor (TF) proteins and their regulated TF genes based on the time-course transcriptome analysis for the H2O2 response, in vivo regulation of the regulated TF by the regulator TF identified by expression analysis of mutants and overexpressors, and in vitro binding of the regulator TF protein to the target TF promoter. These analyses enabled the establishment of part of the transcriptional regulatory network for the H2O2 response composed of 15 regulatory pairs of TFs, including five pairs previously reported. This regulatory network is suggested to be involved in a wide range of biotic and abiotic stress responses in Arabidopsis.

The mechanism of persistent undermining of a sacral pressure ulcer: Experimental analyses using a deformable model and examination of skin mobility over different anatomical locations.

Undermining is an important issue in the treatment and care of deep pressure ulcers. The frequency of the undermining over different bony prominences varies. In particular, deep pressure ulcers over the sacrum exhibit undermining more frequently than those occurring over the heel. Although shear force has been suggested as a critical factor in undermining, the exact mechanism remains unclear due to ethical and technical reasons in clinical practice. To clarify this issue, a deformable model was constructed to recreate the physical and morphological properties of a pressure ulcer with persistent undermining. The model was constructed using urethane to recreate the physical properties of a pressure ulcer. To examine the clinical relevance of the model, mechanical properties of the skin and the model were measured using a durometer. The model was further mounted onto a phantom that was laid on a bed. Backrest elevation of the bed induced deformities in the urethane model, suggesting a mechanism of persistent undermining of the sacral pressure ulcer. Moreover, a simple palpation examination in elderly volunteers revealed that the skin over the sacrum was more mobile than the skin over the heel. Therefore, persistent undermining is likely caused by specific external forces and the characteristic skin mobility of the sacral region. These two different factors explain the frequent undermining that occurs in sacral pressure ulcers.

Type B and A monoamine oxidase and their inhibitors regulate the gene expression of Bcl-2 and neurotrophic factors in human glioblastoma U118MG cells: different signal pathways for neuroprotection by selegiline and rasagiline.

Type B monoamine oxidase (MAO-B) in glial cells has been considered to be associated with neuronal death in Parkinson's disease. MAO-B inhibitors, rasagiline and selegiline [(-)deprenyl], protect neurons in animal and cellular models of neurodegeneration. However, the role of MAO-B itself in the regulation of cell death processing remains elusive, whereas type A MAO (MAO-A) mediates the induction of anti-apoptotic Bcl-2 genes by rasagiline and selegiline. In this paper, the involvement of MAOs in the induction of neuroprotective genes by MAO inhibitors was investigated in human glioblastoma U118MG cells expressing mainly MAO-B. Selegiline significantly increased Mao-B, which was suppressed by Mao-A knockdown with short interfering (si)RNA, whereas rasagiline less markedly increased Mao-B, which was not affected by Mao-A knockdown. Mao-A mRNA was also markedly increased by rasagiline and selegiline, and Mao-B knockdown significantly enhanced the induction by selegiline, but not by rasagiline. Mao-B knockdown also significantly increased mRNA levels of Bcl-2, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Selegiline synergistically enhanced the expression of these genes in Mao-B knockdown cells, but Mao-A knockdown suppressed the increase. Rasagiline increased BDNF and GDNF, which Mao-B and Mao-A knockdown inhibited. These results show that MAO-B might function as a repressor and MAO-A as a mediator in the constitutional expression of pro-survival genes, and that MAO-B and MAO-A might regulate different signal pathways for rasagiline and selegiline to induce neuroprotective genes. The novel role of glial MAOs in the regulation of gene expression is discussed.

Neurotrophic function of phytochemicals for neuroprotection in aging and neurodegenerative disorders: modulation of intracellular signaling and gene expression.

Bioactive compounds in food and beverages have been reported to promote health and prevent age-associated decline in cognitive, motor and sensory activities, and emotional function. Phytochemicals, a ubiquitous class of plant secondary metabolites, protect neuronal cells by interaction with cellular activities, in addition to the antioxidant and anti-inflammatory function. In aging and age-associated neurodegenerative disorders, phytochemicals protect neuronal cells by neurotrophic factor-mimic activity, in addition to suppression of apoptosis signaling in mitochondria. This review presents the cellular mechanisms underlying anti-apoptotic function and neurotrophic function of phytochemicals in the brain. Phytochemicals bind to receptors of neurotrophic factors, and also receptors for γ-aminobutyric acid, acetylcholine, serotonin, and glutamate and estrogen, and activate downstream signal pathways. Phytochemicals also directly intervene intracellular signaling molecules to modify the brain function. Finally, phytochemicals enhance the endogenous biosynthesis of genes coding anti-apoptotic Bcl-2 and neurotrophic factors, such as brain-derived and glial cell line-derived neurotrophic factor. The gene induction may play a major role in the neuroprotective function of dietary compounds shown by epidemiological studies. Quantitative measurement of neurotrophic factors induced by phytochemicals in the serum, cerebrospinal fluid, and other clinical samples is proposed as a surrogate assay method to evaluate the neuroprotective potency. Development of novel neuroprotective compounds is expected among compounds chemically synthesized from the brain-permeable basic structure of phytochemicals.

Diagnostic Utility of Preserved Dried Umbilical Cord Polymerase Chain Reaction in Intrauterine Herpes Simplex Virus Infection: A Case Report and Literature Review.

INTRODUCTION: Intrauterine herpes simplex virus (HSV) infection is uncommon and challenging to diagnose, requiring detection of HSV in skin lesions within 48 h post-birth. CASE PRESENTATION: A preterm female infant presented with the typical triad of blisters, microcephaly, and chorioretinitis, but the initial diagnostic approach was elusive due to negative results for TORCH pathogens from vesicles/serum. Referred at 7 months for developmental delay and epilepsy, her brain imaging showed calcification and cortical dysplasia. Polymerase chain reaction (PCR) of her preserved dried umbilical cord detected HSV-2 DNA, diagnosing intrauterine HSV infection. HSV-2 was later found in relapsed blisters at 8 months but not in cerebrospinal fluid or brain tissue. A literature review identified 104 congenital/intrauterine HSV cases; 28.8% presented the typical triad, and 50% were diagnosed using specimens collected 48 h post-birth. CONCLUSION: This case marks the first retrospective diagnosis of intrauterine HSV infection via PCR on preserved umbilical cord, underscoring its diagnostic value.

Rasagiline and selegiline, inhibitors of type B monoamine oxidase, induce type A monoamine oxidase in human SH-SY5Y cells.

Type B monoamine oxidase (MAO-B) is proposed to be involved in the pathogenesis of neurodegenerative disorders, such as Parkinson's disease, through oxidative stress and synthesis of neurotoxins. MAO-B inhibitors, rasagiline and selegiline [(-)deprenyl], protect neuronal cells by direct intervention in mitochondrial death signaling and induction of pro-survival Bcl-2 and neurotrophic factors. Recently, type A MAO (MAO-A) was found to mediate the induction of anti-apoptotic Bcl-2 by rasagiline, whereas MAO-A increases in neuronal death and also serves as a target of neurotoxins. These controversial results suggest that MAO-A may play a decisive role in neuronal survival and death. This paper reports that rasagiline and selegiline increased the mRNA, protein and catalytic activity of MAO-A in SH-SY5Y cells. Silencing MAO-A expression with small interfering (si)RNA suppressed rasagiline-dependent MAO-A expression, but MAO-B overexpression in SH-SY5Y cells did not affect, suggesting that MAO-A, not MAO-B, might be associated with MAO-A upregulation. Rasagiline reduced R1, a MAO-A specific repressor, but selegiline did not. Mithramycin-A, an inhibitor of Sp1 binding, and actinomycin-D, a transcriptional inhibitor, reduced the rasagiline-dependent upregulation of MAO-A mRNA, indicating that rasagiline induced MAO-A transcriptionally through R1-Sp1 pathway, whereas selegiline by another non-defined pathway. These results are discussed in relation to the role of MAO-A and these MAO-B inhibitors in neuronal death and neuroprotection.

Type A monoamine oxidase is associated with induction of neuroprotective Bcl-2 by rasagiline, an inhibitor of type B monoamine oxidase.

Rasagiline and (-)deprenyl (selegiline), irreversible type B monoamine oxidase (MAO-B) inhibitors, protect neuronal cells through gene induction of pro-survival Bcl-2 and neurotrophic factors in the cellular models of neurodegenerative disorders. In this paper, the role of MAO in the up-regulation of neuroprotective Bcl-2 gene by these inhibitors was studied using type A MAO (MAO-A) expressing wild SH-SY5Y cells and the transfection-enforced MAO-B overexpressed cells. Rasagiline and (-)deprenyl, and also befloxatone, a reversible MAO-A inhibitor, increased Bcl-2 mRNA and protein in SH-SY5Y cells. Silencing MAO-A expression with short interfering (si) RNA suppressed Bcl-2 induction by rasagiline, but not by (-)deprenyl. MAO-B overexpression inhibited Bcl-2 induction by rasagiline and befloxatone, but did not affect that by (-)deprenyl, suggesting the different mechanisms behind Bcl-2 gene induction by these MAO-B inhibitors. The novel role of MAO-A in Bcl-2 induction by rasagiline is discussed with regard to the molecular mechanism underlying neuroprotection by the MAO inhibitors.

Congenital high airway obstruction syndrome in the breech presentation managed by ex utero intrapartum treatment procedure after intraoperative external cephalic version.

Congenital high airway obstruction syndrome (CHAOS) caused by laryngeal atresia was diagnosed by prenatal ultrasound in a male fetus at 26 weeks of gestation. Findings included massive ascites, subcutaneous edema, enlarged hyperechogenic lungs with diaphragmatic inversion, dilated trachea, polyhydramnios, and breech presentation. Those findings of CHAOS spontaneously returned to normal by 33 weeks of gestation. However, the placenta was localized to the anterior uterine wall. In addition, the fetal position had been breech until delivery. At 36 weeks of gestation, a planned ex utero intrapartum treatment (EXIT) procedure was performed following intraoperative external cephalic version (ECV) in which the fetus was approached from the posterior wall of the uterus. Laryngoscopy revealed the predicted laryngeal obstruction, and tracheostomy was placed. Intraoperative ECV may be a useful technique in breech presentation before EXIT procedure.

Diverse mutations in the ftsI gene in ampicillin-resistant Haemophilus influenzae isolates from pediatric patients with acute otitis media.

To clarify molecular changes in beta-lactamase-nonproducing, ampicillin-resistant (BLNAR) Haemophilus influenzae, which is increasing in pediatric patients with acute otitis media (AOM) in Japan, we identified amino acid (aa) substitutions in penicillin-binding protein 3 for the BLNAR strains. Of 191 H. influenzae strains isolated from middle ear fluid of pediatric AOM patients between October 2005 and March 2008, BLNAR strains determined by PCR accounted for 49.2%. Of the BLNAR strains, 91.5% possessed 4 aa substitutions: Met377Ile, Ser385Thr, Leu389Phe, and either Asn526Lys or Arg517His. Additionally, the emergence of BLNAR strains possessing a new aa substitution of Val329Ala in the conserved aa motif of Ser327-Thr-Val-Lys, or Val511Ala adjacent to the conserved aa motif of Lys512-Thr-Gly, was noted. Transformation of the ftsI gene into the Rd reference strain (ATCC 51907) demonstrated that these two aa substitutions reduced susceptibility to amoxicillin more than to cephalosporins. Pulsed-field gel electrophoretic profiles of BLNAR strains were highly diverse. These results suggested that inadequate antibiotic use may increase BLNAR strains by selecting mutations in the ftsI gene and that such use may have favored the new aa substitutions.

Systemic treatment of anti-CD4CD25 T cell monoclonal antibody exacerbates sialoadenitis in submandibular glands during the early life in lupus-prone female NZB x NZWF mice.

BACKGROUND: The maintenance mechanisms of peripheral tolerance by CD4(+)CD25(+) T cells before the development of sialoadenitis in secondary Sjögren's syndrome (sSS) are not well understood. The aim of the present study is to examine the effect of reduction of CD4(+)CD25(+) T cells on the development of sialoadenitis during the early life in female NZB x NZWF(1) (B/WF(1)) mice, a model for human sSS. METHODS: Female B/WF(1) mice at 3 days after birth were treated with either anti-mouse CD4(+)CD25(+) T cells rat IgG(1) monoclonal antibody (mAb) or Rat IgG(1)(control). At 25 weeks of age, autoantibodies against nucleus and cytoplasm of ductal epithelial and myoepithelial cells, and histpathology of submandibular glands were examined in the mAb-treated and control groups. Also the development of anti-Ro/SS-A antibodies was examined until 25 weeks of age in both groups. RESULTS: The mAb-treated group showed severe lesions with the development of autoantibodies compared to the control group. CONCLUSIONS: The present results suggest that peripheral CD4(+)CD25(+) T cells may, at least in part, contribute to down-regulate the development of sialoadenitis in submandibular glands of lupus-prone female B/WF(1) mice during their early life.

Microbial conversion of L-ascorbic acid to L-erythroascorbic acid.

We found that a strain of Penicillium sp. effectively converted L-ascorbic acid to a five-carbon analog, which was identified as L-erythroascorbic acid based on spectroscopic analysis. The conversion was achieved by growing culture or washed mycelia, with a yield of approximately 20-30% (mol/mol). The processes for the bioconversion and purification of the product are described.

Inhaled corticosteroid therapy reduces cytokine levels in sputum from very preterm infants with chronic lung disease.

AIM: To evaluate the effects of inhaled corticosteroid therapy and high-frequency oscillatory ventilation (oscillation) on preterm infants with chronic lung disease (CLD). METHODS: Ten infants with CLD who received inhaled corticosteroid therapy were enrolled. Week 1 was defined as the first week of therapy. The concentrations of interleukin (IL)-8, tumour necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, IL-10 and IL-12p70 in serial sputum specimens from the infants were determined using a cytometric bead array. RESULTS: The sputum concentrations of IL-8 obtained from the infants during week 3-4 were significantly lower than those obtained before therapy and during week 1-2. The sputum concentrations of TNF-alpha, IL-6 and IL-10 during week 3-4 were significantly lower than the concentrations during week 1-2. The ratio of IL-8 levels during week 1-2 to those before therapy in infants who received oscillation (n = 4) was significantly lower than in those who received intermittent mandatory ventilation (n = 6). CONCLUSION: Inhaled corticosteroids may be associated with a decrease in pro-inflammatory cytokine levels in sputum from infants with CLD from 2 weeks after the start of therapy. Our further investigations suggest that therapy with oscillation modulated airway inflammation earlier than therapy with intermittent mandatory ventilation.

Enhanced contact hypersensitivity by delayed T-helper 2 response in BALB/c mice.

T-helper (Th) 1/Th2 balance determines the direction of contact hypersensitivity (CHS). To clarify the immunopathogenesis of contact dermatitis, 2,4-dinitrofluorobenzene (DNFB)-induced CHS reaction was compared between the BALB/c and C57BL/6 mice. The two strains were sensitized with DNFB systemically and challenged with DNFB locally. The CHS reaction in BALB/c mice was intense compared with that in C57BL/6 mice at 24 and 48 hours post-DNFB challenge. The dermal lesions were characterized by infiltration of lymphocytes, eosinophils, neutrophils, and macrophages including CD4+ and CD8+ T cells, and interleukin (IL)-4-producing(+) and interferon (IFN)-gamma+ cells in BALB/c mice. In C57BL/6 mice, the composition of inflammatory cells was same as those in BALB/c mice except for eosinophils, CD4+ T cells, and IL-4+ cells. There was no increase in the number of mast cells in the two strains. Local and systemic productions of IL-4 and IFN-gamma in BALB/c mice were higher than those in C57BL/6 mice. Although blood IgE values increased in BALB/c mice, but not in C57BL/6 mice, at 48 hours postchallenge, its value was low. The delayed Th2-like response together with Th1-like response in BALB/c mice may induce strong CHS reaction compared with C57BL/6 mice, which may dominantly develop Th1-like reaction. Moreover, mast cell and IgE do not appear to be involved in delayed CHS.

Ultrastructure of myoepithelial cells as a target cell in sialoadenitis of submandibular glands of lupus-prone female NZBxNZWF1 mice.

The changes of myoepithelial cells of sialoadenitis in submandibular glands in lupus-prone female NZB x NZWF1 (B/WF1) mice, a model for human secondary Sjögren's syndrome (sSS), were examined ultrastructurally. Inflammatory foci consisting of mainly lymphoid cells (lymphocytes and plasma cells) in the interlobular interstitium began to develop from 18 weeks of ages, and those were found within acini from the age of 25 weeks. These were paralleled with the production of anti-double-stranded deoxyribonucleic acid and anti-Ro/SS-A antibodies with age. Infiltrated lymphoid cells consisted of CD4+ T cells and Ig+ (or IgG2a+) cells. Electron microscopy revealed destruction of myoepithelial cells with lysis of basement membranes contacted with either lymphocytes or plasma cells. These led to the destruction (degeneration and necrosis) of the epithelium in striated and intercalated ducts and acinar epithelium. Further destruction of those cells occurred by the invasion of lymphocytes into the epithelial layers. Small numbers of apoptotic myoepithelium and duct epithelium from the age of 25 to 36 weeks and an increase of those cells in survived mice at 44 weeks of age were observed. The present study suggests that the myoepithelium may be one of the target cells and that the destruction of myoepithelial cells by infiltrated lymphoid cells may precede the destruction of acinar ducts and epithelium in sialoadenitis in sSS.

Systemic administration of olygodeoxynucleotides with CpG motifs at priming phase reduces local Th2 response and late allergic rhinitis in BALB/c mice.

Oligodeoxynucleotides (ODN) with CpG motifs (CpG ODN) induce T helper (Th)1-type reaction. We aimed to evaluate the therapeutic effect of CpG ODN in the development of late allergic rhinitis induced by ovalbumin (OVA), which is one of Th2 diseaes, in BALB/c mice. Effects of a single dose of synthetic CpG-ODN (50 microg) intraperitoneally (i.p.) at the priming phase (on day 0) by OVA on the development of late eosinophilic rhinitis at respiratory areas were compared to the control mice treated with its vehicle (ODN without CpG motifs; 50 microg). Animals were again sensitized by OVA (on day 10) i.p., and 4 days after second sensitization animals were challenged by OVA intranasally (on day 14). Four days after challenge, eosinophilic reactions, nasal lesions and local cytokine values were examined. Compared to the control group, the CpG ODN-administration increased production of OVA-specific Th1 cytokine (interferon-gamma) and decreased productions of ovalubmin-specific Th2 cytokines [interleukin (IL)-5 and IL-13] in nasal cavity fluids, supernatants of splenocytes and/or sera. Also, eosinophilia and increased total IgE values were decreased in mice treated with the CpG ODN compared to the control group. Moreover, nasal lesions with infiltration of eosinophils were prominently reduced by the CpG ODN-treatment compared to the control mice. The present study suggests that the systemic administration of CpG ODN at the priming phase may reduce local OVA-specific Th2 responses, resulting in decreased nasal pathology in the late allergic eosinophilic rhinitis.

[Childhood bacterial meningitis trends in Japan from 2005 to 2006].

We surveyed pediatric bacterial meningitis epidemiology from January 2005 to December 2006 in Japan, with the following results. Bacterial meningitis cases numbered 246 -138 boys and 108 girls-, equivalent to 1.7-1.72 children of 1,000 hospitalized in pediatrics per year. The age distribution for infection was highest in those under 1 year of age and decreased with increasing age, Haemophilus influenzae was the most common infection causing the pathogen, followed by Streptococcus pneumoniae, group B streptococcus, and Escherichia coli. The relationship between causative pathogens and age distribution was as follows: group B streptococcus and E. coli were major pathogens in patients under 4 months old and H. influenzae and S. pneumoniae in those over 4 months old. Susceptibility tests at individual facilities showed 59.3% of H. influen- zae isolates and 69.3% of S. pneumoniae isolates in 2004 to be drug-resistant. Ampicillin and cephem antibiotics are effective against GBS, E. coli, and Listeria, so combined of ampicillin and cephem antibiotics are used as first-line antibiotics in many facilities in patients under 4 month old and combined of carbapenem antibiotics effective against PRSP and cephem effective against H. influenzae were the first choice against childhood bacterial meningitis in patients over 4 month old.

[Effectiveness of inhaled corticosteroids (ics) combination therapy; the addition of qvar to flutide].

PURPOSE: We recently reported treatment of asthmatic patients with a combination of FP-DPI 800 microg/day and BDP-HFA 400 microg/day. This regimen induced significant improvement in subjective symptoms and pulmonary function tests. This led us to study the additive effect of BDP-HFA 400 microg/day for seven unstable severe persistent bronchial asthma patients. RESULTS: PEF improved, daily (circadian) variation was minimized and FVC and FEV1.0 testing showed slight improvement. V25/height also revealed significant improvement. The more peripheral the airways are, the greater improvement was observed. The annual emergency admission rate of 4.6 times per patient decreased to 2.1 times after the addition of BDP-HFA 400 microg/day. All the three cases dependent on oral steroid medication could be removed from the drug and 6 out of 7 cases were able to lower the dose of anti-asthmatic drugs. CONCLUSIONS: The effectiveness of inhaled corticosteroids (ICS) differs based on the site reached in the bronchi and depending on the inhalation devices used. Addition of a second ICS has the potential to further alleviate symptoms of unstable asthmatics on conventional therapy with ICS and other drugs.