The first nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy. Part 1: a general view of antibacterial susceptibility.

The Japanese Society of Chemotherapy (JSC) conducted the first nationwide surveillance of bacterial respiratory pathogens during the period from January to August 2006. With the cooperation of 32 medical institutions throughout Japan, a total of 924 strains belonging to seven clinically relevant bacterial species were collected from adult patients with well-diagnosed respiratory tract infections (RTIs). Antimicrobial susceptibility testing of the 887 evaluable strains (205 Staphylococcus aureus, 200 Streptococcus pneumoniae, 9 Streptococcus pyogenes, 165 Haemophilus influenzae, 91 Moraxella catarrhalis, 74 Klebsiella pneumoniae, and 143 Pseudomonas aeruginosa) to 42 antibacterial agents was conducted at the Central Laboratory of the Research Center for Anti-infective Drugs of the Kitasato Institute, according to recommendations issued by the Clinical and Laboratory Standards Institute (CLSI). The antibacterial agents employed were 25 beta-lactams, three aminoglycosides, four macrolides (including one azalide and one ketolide), one lincosamide, one tetracycline, two glycopeptides, five fluoroquinolones, and one oxazolidinone. The incidence of methicillin-resistant S. aureus (MRSA) was 63.4%, and the incidences of penicillin-intermediately resistant S. pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP) were 35.0% and 4.0%, respectively. Among H. influenzae, 21.2% of the strains were found to be beta-lactamase-nonproducing ampicillin (ABPC)-intermediately resistant (BLNAI), 29.1% to be beta-lactamase-nonproducing ABPC-resistant (BLNAR), and 4.8% to be beta-lactamaseproducing ABPC-resistant (BLPAR) strains. The incidence of extended-spectrum beta-lactamase-producing K. pneumoniae was 2.7% (2 of 74 strains). Three (2.1%) of the 143 P. aeruginosa strains were found to be metallo-beta-lactamaseproducing, including 1 (0.7%) multidrug-resistant strain. Through the nationwide surveillance, we obtained fundamental antimicrobial susceptibility data of clinically relevant bacterial pathogens in adult RTI to various antibacterial agents. These data will be a useful reference for future periodic surveillance studies, as well as for investigations to control antimicrobial-resistant pathogens.

Association of susceptibility to the development of pneumonia in the older Japanese population with haem oxygenase-1 gene promoter polymorphism.

BACKGROUND: Oxidative stresses including cigarette smoking are implicated in the pathogenesis of cerebrovascular diseases, which are associated with pneumonia because of frequent aspiration. Haem oxygenase-1 (HO-1) acts in cytoprotection against oxidants, provides anti-inflammatory effects, and inhibits atherogenesis. A (GT)(n) dinucleotide repeat in the human HO-1 promoter modulates HO-1 gene expression and shows length polymorphism, which is grouped into three classes: class S (<27 repeats), class M (> or = 27, <33 repeats), and class L (> or = 33 repeats) alleles. OBJECTIVE: To investigate the correlation between the HO-1 gene polymorphism and development of pneumonia in elderly Japanese. METHODS: The length of the (GT)n repeats was analysed in 200 elderly patients with pneumonia and 200 control subjects. The association of the HO-1 gene polymorphism with risk of pneumonia was estimated by logistic regression. RESULTS: The proportion of allele frequencies in class L, and the proportion of genotypic frequencies in the L-allele carriers (L/L, L/M, and L/S), was significantly higher in patients with pneumonia than in controls (20% v 10% in class L, and 34% v 18% in L-allele carriers). After adjustment for potentially confounding factors, both cerebrovascular disorders and HO-1 gene L-allele carriers were significant and independent risk factors for pneumonia. The adjusted odds ratio for L-allele carriers v non-L-allele carrier was 2.1 (95% confidence interval, 1.2 to 3.6). CONCLUSIONS: The large size of a (GT)n repeat in the HO-1 gene promoter may be associated with susceptibility to pneumonia in the older Japanese population.

A resuscitated case from asphyxia by large bronchial cast.

A 62-year-old woman with bronchiectasis suffered from asphyxia due to a large bronchial cast that obstructed the bronchial tree. Immediate bronchoscopic suction of a bronchial cast of 17 cm in length through the intubated tube relieved the patients without any complications. Large bronchial casts appear to be rare in this century but it should be considered in patients with acute exacerbation of excessive sputa not only in patients with asthma or allergy but also in patients with respiratory tract infection.

Absence of association of alpha1-antichymotrypsin polymorphisms with Alzheimer's disease: a report on autopsy-confirmed cases.

alpha1-Antichymotrypsin (ACT) polymorphisms were examined in 79 cases with autopsy-confirmed Alzheimer's disease (AD) as well as in 28 cases with autopsy-confirmed nonneurological diseases to test the hypothesis that ACT polymorphisms confer a risk to an individual to develop AD. Neither ACT genotype frequency nor ACT allele frequency in the AD group was significantly different from the control group. The ACT polymorphic pattern was essentially the same among apolipoprotein E (apoE) epsilon4 carriers and noncarriers. The age at onset of AD was not significantly affected by the inherited dose of ACT/A allele. Taking together, our observations do not confirm the effect of the ACT/A allele as a risk factor for developing AD in addition to the ApoE epsilon4 allele.

A model of latent adenovirus 5 infection in the guinea pig (Cavia porcellus).

A model of adenovirus 5 (Ad5) infection was developed in guinea pigs to begin to study its role in the pathogenesis of peripheral lung inflammation. Forty animals were inoculated intranasally with 10(7.0) pfu of Ad5/animal, and 15 animals inoculated with sterile culture media served as controls. Viral titres were 10(4.4), 10(6.1), 10(5.2), and 10(2.9) pfu/animal, on days 1, 3, 4, and 7 after infection, respectively. In situ hybridization to viral DNA and immunocytochemistry for Ad5 E1A protein localized the virus to airway and alveolar epithelial cells. Histologic examination showed an extensive inflammatory cell infiltration around the airways, with epithelial necrosis and an alveolar exudate that caused localized alveolar collapse in the infected areas. Immunocytochemistry identified the cells in the infiltrate as cytotoxic T cells. Although all animals 20 and 47 days after infection had seroconverted to Ad5, virus was not detected in these groups either by viral plaque assay or in situ hybridization. Ad5 E1A DNA was detected by polymerase chain reaction in five of six animals 20 days after infection and in five of five animals 47 days after infection. In these same animals, E1A protein was detected 20 days after infection in two and 47 days after infection in one while persistent bronchiolitis was observed in four and three animals 20 and 47 days after infection, respectively. These results demonstrate that the guinea pig provides a useful model to study the role of Ad5 infection in chronic airway inflammation.

Peripheral airway hyperresponsiveness in the choline-deficiently fed rat.

Rats fed with choline-deficient diets are known as a model of aging and learning impairments due to acetylcholine (ACh) deficiency in the brain which may be associated with a decrease in acetylcholinesterase (AChE; EC 3.1.1.7). To determine the role of AChE in bronchial responsiveness, we examined the contractile response of isolated lung parenchymal strips to ACh in control rats and rats fed with choline-deficient diets. Concentration-response curves to ACh shifted to the lower concentrations and the maximum response to ACh was greater in rats fed with choline-deficient diets than in control rats (P < 0.01). Physostigmine (10(-6) M) mimicked effects of choline-deficient diets on the contractile response to ACh. However, concentration response curves to carbachol and 5-hydroxytryptamine did not differ between control rats and rats fed with choline-deficient diets. Choline-deficient diets significantly decreased the AChE activity from homogenates of lung parenchymal tissues (P < 0.01). These results suggest that a decrease in AChE activity of lung tissues may relate to airway hyperresponsiveness to ACh.

Late asthmatic response causes peripheral airway hyperresponsiveness in dogs treated with metopirone.

To determine if late asthmatic response (LAR) is associated with hyperresponsiveness of airway smooth muscle itself, we performed antigen challenge in dogs treated with Metopirone. We studied the contractile response to acetylcholine (ACh) in isolated bronchial and bronchiolar segments 8 h after either saline inhalation (the control group) or antigen challenge in dogs demonstrating immediate asthmatic response (IAR) alone and in dogs demonstrating both IAR and LAR. Airway responses to Ascaris suum antigen were assessed by changes in respiratory resistance measured with the forced oscillation technique at 3 Hz. Concentration-response curves of bronchial preparations to ACh did not differ significantly among three groups consisting of the control, IAR and LAR. However, the contractile response of bronchiolar preparations to ACh was significantly greater in the LAR group when compared to the control and IAR groups at the concentrations of ACh ranging from 10(-6) to 3 x 10(-4) M (p < 0.01). SQ 29548, a receptor antagonist of thromboxane A2 and prostaglandin D2 (PGD2), inhibited LAR-induced hyperresponsiveness to ACh in a concentration-dependent fashion. The bronchiolar preparations obtained from dogs showing LAR contained a significantly higher amount of PGD2 than those obtained from dogs showing IAR alone (p < 0.01, n = 6). These results suggest that LAR is associated with hyperresponsiveness of peripheral airway smooth muscle to ACh, and this augmented response to ACh mediates via PGD2 released during LAR.

Evidence that an atypical beta-adrenoceptor mediates the prejunctional inhibition of non-adrenergic non-cholinergic contraction in guinea-pig bronchi.

We investigated the effect of the putative beta 3 agonist BRL 35135 on non-adrenergic non-cholinergic (NANC) contractions in guinea-pig bronchial strips. BRL 35135 (10(-9) to 10(-6) M) did not alter the baseline tension but reduced NANC contractions induced by electrical field stimulation (EFS) in a concentration-dependent fashion without having a significant effect on the contraction induced by substance P (10(-6) M). BRL 35135 (10(-6) M) also reduced the contraction induced by capsaicin (10(-7) M). Likewise, BRL 37344 (10(-9) to 10(-6) M) reduced NANC contractions induced by EFS in a concentration-dependent fashion. While BRL 37344 up to concentrations of 10(-8) M did not alter the contraction induced by SP (10(-6) M), BRL 37344 (10(-8) M) significantly inhibited NANC contractions induced by EFS and capsaicin (10(-7) M), (P less than 0.01). The inhibitory effect of BRL 35135 (10(-6) M) on NANC contractions induced by EFS was not significantly altered by the non-selective beta-adrenoceptor antagonists, propranolol and pindolol (P greater than 0.10), by the beta 1-selective antagonists, atenolol and metoprolol (P greater than 0.20) (10(-8) to 10(-6) M), or by the alpha-adrenoceptor antagonist, phentolamine (10(-7) to 10(-5) M) (P greater than 0.50). These results suggest that beta 3 agonists exert a prejunctional inhibitory action on NANC contractions.

gamma-Aminobutyric acid-induced response in rat dissociated paratracheal ganglion cells.

1. The pharmacologic properties of gamma-aminobutyric acid (GABA)-induced Cl- current (ICl) were studied in the paratracheal ganglion cells freshly dissociated from 7- to 10-day-old rat trachea in a whole-cell recording mode by the use of a conventional patch-clamp technique. 2. GABA- and muscimol-induced currents increased sigmoidally in a concentration-dependent manner, and both currents reversed at approximately -3 mV, which was close to the Cl- equilibrium potential (ECl). 3. Strychnine (STR) at low concentration and bicuculline (BIC) inhibited GABA response competitively, whereas STR at the higher concentrations, benzylpenicillin (PCG), or picrotoxin (PTX) inhibited noncompetitively. Inhibition of GABA response by PCG but not other antagonists was voltage dependent, indicating that PCG acts as a Cl- channel blocker. 4. The concentration-response curve of pentobarbital sodium (PB)-induced ICl was bell shaped. At concentrations higher than 10(-3) M, both the peak and plateau currents decreased, and a transient "hump" current appeared immediately after washing out PB. In the presence of PB, the concentration-response curve of GABA shifted toward left without changing the maximum response. 5. Although diazepam (DZP) at concentration used did not induce a response, it potentiated the GABA response in a concentration-dependent manner between 10(-8) and 10(-6) M. DZP also caused a parallel shift toward left in the concentration-response curve of GABA. 6. PB or DZP further enhanced the GABA response in the presence of the other agent. 7. It is concluded that the properties of GABAA receptors in the paratracheal ganglion cells are essentially similar to those reported in other preparations.

The role of cyclic AMP in non-adrenergic non-cholinergic contraction in guinea-pig bronchi.

1. We investigated the role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in non-adrenergic non-cholinergic (NANC) contraction in guinea-pig bronchial strips. 2. Forskolin (3 nM to 1 microM) reduced NANC contraction induced by electrical field stimulation (EFS) in a concentration-dependent fashion (-log EC50 was 7.22 +/- 0.12 M and maximum inhibition was 100 +/- 0.01%). However, forskolin (less than 1 microM) did not alter the contraction induced by substance P (SP, 1 microM). 3. Dibutyryl cyclic AMP (1 mM) also reduced NANC contractions induced by EFS (100 +/- 0.01%) without significant effect on SP (1 microM)-induced contractions. In contrast, dibutyryl cyclic GMP (1 mM) was without effect against either NANC or SP-induced contractions. 4. Both the beta 2-adrenoceptor agonist, procaterol (0.1 nM to 3 nM) and theophylline (100 nM to 1 mM) concentration-dependently reduced EFS-induced NANC contractions without significant effect on SP (1 microM)-induced contractions. 5. In contrast to forskolin, procaterol and theophylline, both sodium nitroprusside and cromakalim inhibited the EFS-induced contractions only at those concentrations that similarly reduced the contractions induced by SP (1 microM). 6. These results suggest that cyclic AMP may mediate pre-junctional inhibition of NANC contractions in guinea-pig bronchi.

Pre- and postjunctional muscarinic receptor subtypes in dog airways.

To examine muscarinic receptor subtypes involved in cholinergically mediated contractions of the airway, we studied the effects of the M1-selective antagonist, pirenzepine, the M2-selective antagonist, AF-DX 116, the M3-selective antagonist, 4-diphenyl-acetoxy-N-methylpiperidine (4-DAMP) methiodide, and the non-selective antagonist, atropine, on acetylcholine (ACh)- and electrically induced contractions in dog bronchi and bronchioles. The relative potencies of the antagonists based on IC50 values of each antagonist for contractions induced by the two concentrations of ACh that produced 50% of the maximum (ED50) and the maximum (EDmax) contractions and the pA2 values were atropine greater than or equal to 4-DAMP methiodide greater than pirenzepine = AF-DX 116 in both the bronchi and bronchioles. The IC50 and pA2 values of each antagonist did not differ significantly between the bronchi and bronchioles. 4-DAMP methiodide significantly inhibited the contractile response to electrical field stimulation (EFS) at 5 Hz at concentrations that did not alter the contractile responses to exogenous ACh in both the bronchi and bronchioles, whereas pirenzepine, AF-DX 116 and atropine inhibited the EFS-induced contraction only at the concentrations that reduced the contraction induced by exogenous ACh. The present results suggest that the cholinergic contraction is mediated via the postsynaptic receptor M3, based on functional potencies of muscarinic antagonists and presynaptic receptor auto-facilitatory M3, based on the suppression of the contractile response to EFS by 4-DAMP methiodide in central and peripheral airways.

Permanent brain damage possibly caused by theophylline in two elderly patients with airway obstruction.

Two aged patients with bronchial asthma and chronic obstructive pulmonary disease who suffered convulsions that resulted in permanent brain damage during treatment with the recommended therapeutic dose of theophylline are presented here. A dose or concentration of theophylline lower than the recommended one should be considered in the treatment of some aged patients with pulmonary obstructive disease.

Prolonged hypoxemia after 10 min walking exercise in aged patients with chronic obstructive pulmonary disease.

Although the behavior and factors of exercise tolerance have been studied during exercise in patients with chronic obstructive pulmonary disease (COPD), little attention has been paid to the after-effects of such activity. Arterial oxygen saturation (SaO2) was monitored during and after a 10 min walking exercise in aged patients with COPD. Neither baseline SaO2 nor mean SaO2 during exercise correlated to the 10 min walking distance. However, the recovery time of SaO2 to the baseline value shows significant correlation to the 10 min walking distance. Careful attention should be paid to prolonged hypoxemia after exercise in severe cases of COPD.