COX-2 inhibition attenuates cough reflex sensitivity to inhaled capsaicin in patients with asthma.

BACKGROUND AND OBJECTIVE: Cyclooxygenase (COX) is an enzyme that converts arachidonic acid to prostanoids. There are two isoforms of COX, namely COX-1 and COX-2. COX-2 is highly inducible by several stimuli and is associated with inflammation. Recent studies have shown that COX-2 is upregulated in the airway epithelium of patients with asthma but little is known about the role it plays in cough, a common symptom of bronchial asthma. This study was designed to investigate the role of COX-2 in cough reflex sensitivity in patients with asthma. PATIENTS AND METHODS: The effect of etodolac, a potent COX-2 inhibitor, on cough response to inhaled capsaicin was examined in 17 patients with stable asthma in a randomized, placebo-controlled crossover study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting 5 or more coughs, was measured as an index of airway cough reflex sensitivity. RESULTS: The geometric mean (geometric SEM) cough threshold was significantly increased after a 2-week treatment program with oral etodolac (200 mg twice a day) compared with placebo (36.7 [1.2] vs 21.6 [1.2] gM, P<.02). CONCLUSIONS: These findings indicate that COX-2 may be a possible modulator augmenting airway cough reflex sensitivity in asthmatic airways.

Monitoring of Epstein-Barr virus load and killer T cells in pediatric renal transplant recipients.

AIM: The aim of this study is to establish a monitoring method to prevent Epstein-Barr virus (EBV)-associated symptoms including post-transplant lymphoproliferative disorder (PTLD) that occur after pediatric renal transplantation. SUBJECTS AND METHODS: Circulating EBV loads were quantified by real-time PCR every 1 - 3 months after grafting in 22 pediatric recipients (13 EBV-seronegative [R(-)] and 9 EBV-seropositive [R(+)] recipients before grafting). The peripheral blood cell populations of non-specific activated killer cells (CD8+HLA-DR+ phenotype) in 13 R(-) recipients and EBV-specific cytotoxic T cells (CTLs) reactive with a tetramer expressing HLA-A24-restricted EBV-specific antigens in 8 of 13 R(-) recipients were determined by flow cytometry. RESULTS: EBV-associated symptoms including PTLD (2 cases) were found in 4 R(-) and none of the R(+) recipients. The maximum of EBV load in the R(-) group was significantly higher that in the R(+) group. In R(-) recipients, 4 symptomatic cases had significantly more EBV genome than asymptomatic cases. EBV-specific CTLs were detected in 6 of the 8 R(-) recipients, but these CTLs could not be detected in 1 of the 2 cases at onset of PTLD. The percentage of CD8+HLA-DR+ cells was significantly higher in asymptomatic recipients than in recipients with EBV-associated symptoms whose EBV loads were over 400 copies/microg DNA. CONCLUSION: Monitoring of killer T cells and EBV loads may allow assessment of the risk of EBV-associated symptoms, and high EBV loads and low EBV-specific and/or non-specific CTL responses may be predictive for development of EBV-associated symptoms such as PTLD.

Ambroxol for the prevention of acute upper respiratory disease.

Although acute upper respiratory diseases (AURDs) such as common cold and influenza are common, few interventions have been proven to be effective in their prevention and treatment. The aim of this study was to assess the efficacy of ambroxol for preventing AURD. Fifty-four patients were randomly divided into 3 groups: a rebamipide (non-mucoactive drug) group (300 mg/day), carbocisteine group (1500 mg/day) and ambroxol group (45 mg/day). The study was divided into 2 terms, the first half-year (summer season) and the second half-year (winter season). In the preceding winter, only 19.5% of the patients had been vaccinated against influenza viruses (flu). The primary goal of this study was to evaluate the effectiveness of mucoactive drugs in decreasing the frequency of AURD. Treatment with ambroxol, but not carbocisteine, significantly reduced the median number of AURD episodes (P=0.0049 vs. rebamipide). Thirty-three patients without vaccination against flu were assessed especially during the second half-year. Treatment with ambroxol also significantly reduced the median number of AURD episodes in this assessment (P=0.0028 vs. rebamipide in the second half-year). In conclusion, ambroxol may be useful for preventing AURD.

Role of protein kinase C in central muscarinic inhibitory mechanisms regulating voiding in rats.

To evaluate the role of protein kinase C in central muscarinic mechanisms regulating voiding, cystometry was performed in conscious rats. Oxotremorine methiodide, a muscarinic agonist was injected i.c.v. in a dose (0.1 microg/rat) shown previously to alter voiding function. Oxotremorine methiodide was also tested after i.c.v. injection of chelerythrine chloride (a protein kinase C inhibitor, 2 microg/rat) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7, a protein kinase inhibitor, 5 nmol/rat). In untreated rats, oxotremorine methiodide elicited a bimodal response consisting of an initial increase in bladder capacity, maximal voiding pressure, pressure threshold and post voiding intravesical pressure, but reduced voiding efficiency and bladder compliance. The second response consisted of a decrease in bladder capacity and bladder compliance, increases in maximal voiding pressure and post voiding intravesical pressure, but no change in pressure threshold or voiding efficiency. However, approximately 20 min after pre-treatment with chelerythrine chloride or H-7 in doses that did not alter voiding function, oxotremorine methiodide decreased bladder capacity, increased maximal voiding pressure, but did not change pressure threshold or voiding efficiency. These results indicate that inhibitory and facilitatory muscarinic mechanisms in the brain that control voiding function involve different second messenger systems. Inhibitory mechanisms which are blocked by chelerythrine chloride or H-7 must involve protein kinase C and normally be inactive because the protein kinase inhibitors alone did not alter voiding. On the other hand, facilitatory muscarinic mechanisms which previous studies showed were tonically active are not mediated by chelerythrine chloride or H-7 sensitive signaling pathways.

A partial involvement of histamine in ultrasonically nebulized distilled water-induced bronchoconstriction in guinea-pigs.

1. Inhalation of ultrasonically nebulized distilled water (UNDW) can induce bronchoconstriction only in asthmatics, but mechanisms of the response are not well known. We recently reported a guinea-pig model of UNDW-induced bronchoconstriction (UNDW-IB) in which UNDW induces bronchoconstriction when UNDW is inhaled 20 min after a challenge with aerosolized ovalbumin (OA) in passively sensitized, anaesthetized and artificially ventilated guinea-pigs. 2. To elucidate the role of histamine in the UNDW-IB, we examined the effects of antihistamines, diphenhydramine hydrochloride (DH) and chlorpheniramine maleate (CP), and measured histamine content in bronchoalveolar lavage fluid (BALF) in the animal model. 3. DH in doses of 0.1, 1.0 and 10 mg kg(-1) and CP in doses of 0.01, 0.1 and 1.0 mg kg(-1) administered intravenously 15 min after the OA challenge partially reduced the UNDW-IB at 1 and 2 min after the UNDW inhalation in a dose-dependent manner. Histamine content in BALF recovered 10 min after the UNDW inhalation following the OA provocation was significantly increased compared with that after saline inhalation and before the UNDW inhalation following the OA challenge. 4. Intravenous atropine in a dose of 0.5 mg kg(-1) or inhaled disodium cromoglycate in concentrations of 1 and 10 mg ml(-1) did not alter the UNDW-IB. 5. These results suggest that histamine is involved in part in the UNDW-IB in our animal model.

A case of cigarette smoking-induced acute eosinophilic pneumonia showing tolerance.

It has been proposed that acute eosinophilic pneumonia (AEP), which is characterized by the absence of recurrence, is associated with cigarette smoking (CS), because Japanese patients with AEP are young and have a high incidence of short-term smoking history. However, there has been no direct evidence that CS causes AEP. We hypothesized that tolerance might develop against repeated resumption of smoking cigarettes in CS-induced AEP cases. In this connection, we challenged a patient with CS-induced AEP with repeated resumption of CS, and it was demonstrated that CS induced AEP in conjunction with tolerance to repeated resumption of smoking.

Enuresis in an adult female with obstructive sleep apnea.

Adult onset enuresis accompanied by obstructive sleep apnea has been reported rarely. A female patient was referred to our clinic with complaints of of a 15-year history of loud snoring and sleep apnea as well as enuresis, which was treated successfully with imipramine and acetazolamide. The mechanism of enuresis and its relationship to upper airway obstruction are reviewed here with reference to the findings of polysomnography and sleep cystometry.

No involvement of lipid mediators in a guinea pig model of ultrasonically nebulized distilled water-induced bronchoconstriction.

An inhalation of ultrasonically nebulized distilled water (UNDW) induces bronchoconstriction only in asthmatics, but the mechanism underlying the response is not fully understood. We have reported that bronchoconstriction occurs immediately after UNDW is inhaled 20 min after an antigen challenge in guinea pigs. Our aim was to examine the role of lipid mediators in this response. Passively sensitized guinea pigs were anesthetized and artificially ventilated. A sulfidopeptide leukotriene receptor antagonist, KCA-757, and platelet-activating factor antagonists, Y-24180 and E6123, were administered i.v. 15 min after an aerosolized antigen challenge, and UNDW was inhaled 5 min later. KCA-757, Y-24180, or E6123 did not, significantly alter the UNDW-induced bronchoconstriction. Together with our previous data that thromboxane A2 receptor antagonists did not influence the UNDW-induced bronchoconstriction, the present results suggest that lipid mediators are not involved in the UNDW-induced bronchoconstriction in our guinea pig model.

In vivo airway eosinophil accumulation does not enhance antigen- or propranolol-induced bronchoconstriction in guinea pigs.

BACKGROUND: Chronic airway eosinophil accumulation is characteristic of asthma. However, it remains unclear whether airway eosinophils enhance or reduce release of chemical mediators and/or action of the released mediators in the airways in vivo, because previous investigators have indicated that eosinophil-derived factors such as histaminase and arylsulfatase may alter the allergic reaction by metabolizing chemical mediators. Recently, we have developed a guinea pig model of propranolol-induced bronchoconstriction (PIB), which is mediated by lipid mediators such as thromboxane A2 (TxA2), cysteinyl leukotrienes (cLTs) and platelet activation factor (PAF). This study was conducted to explain the influence of airway eosinophil accumulation on antigen-induced bronchoconstriction and the following PIB, both of which are mediated by lipid mediators. METHODS: Guinea pigs were transnasally treated with 75 microg/kg of polymyxin-B or vehicle twice a week for a total of 3 weeks. Guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated 24 h after the last administration of polymyxin-B or vehicle followed by passive sensitization. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. RESULTS: The proportion of eosinophils in bronchoalveolar lavage fluid obtained 15 min after the propranolol inhalation was significantly increased in guinea pigs treated with polymyxin-B compared with the vehicle. The polymyxin-B treatment did not affect antigen-induced bronchoconstriction or the following PIB. CONCLUSIONS: We conclude that eosinophils accumulated in the airways by polymyxin-B does not affect release of chemical mediators induced by antigen or propranolol inhalation, or action of released mediators in vivo.

Additive effect of continuous low-dose ofloxacin on erythromycin therapy for sinobronchial syndrome.

It has been established that long-term low-dose erythromycin therapy (EM therapy) is very effective for sinobronchial syndrome, a common condition in Japan characterized by chronic upper and lower airway inflammation. The effect does not result from its bacteriocidal activity and the detailed mechanisms are not known. It takes 3-6 months for EM therapy to improve the symptoms. This study was designed to evaluate the additive effect of continuous low dosage or intermittent usual dosage of ofloxacin (OFLX) on EM therapy in patients with sinobronchial syndrome. Patients with sinobronchial syndrome were randomly allocated to receive one of the following four regimens. Patients in Group A received both low-dose OFLX and EM therapy daily for 6 months. Patients in Group B received EM therapy and intermittent treatment of OFLX for 6 months. Patients in Group C underwent EM therapy for 6 months. Patients in Group D received neither OFLX nor EM therapy. All patients were given carbocystein for more than 2 months before starting each treatment and during the study period. In patients receiving OFLX and/or EM therapy, these antimicrobial agents were well-tolerated during the treatment period. Amount of sputum in the morning was significantly less in Group C than in Group D after 3-6 months, and decreased significantly in Group A as compared with Group B after 2 weeks, Group C after 2 weeks to 2 months, and Group D after 2 weeks to 6 months. Other symptoms such as number of expectorations, difficulty of expectoration and severity of cough also improved rapidly in Group A. These findings suggest that it is useful to add low-dose OFLX to EM therapy for sinobronchial syndrome, especially within 1-2 months from starting treatment, and it may be cost-effective as this combination therapy can shorten the treatment period of EM therapy.

Necrotizing bronchial aspergillosis as a cause of hemoptysis in sarcoidosis.

The case history is presented of a patient with recurrent massive hemoptysis caused by necrotizing bronchial aspergillosis associated with sarcoidosis. The involved segments (right IX and X) were resected for treatment of the life-threatening hemoptysis. Histologic examination of the resected specimen confirmed the diagnosis. Necrotizing bronchial aspergillosis is a rare variant form of invasive pulmonary aspergillosis and has not been described previously as a cause of hemoptysis in sarcoidosis.

Effect of thromboxane synthase inhibitor, CS-518, on propranolol-induced bronchoconstriction in guinea pigs.

Beta-adrenoreceptor antagonists, such as propranolol, can provoke severe bronchoconstriction in asthmatic subjects. Recently we developed an animal model of propranolol-induced bronchoconstriction and investigated the involvement of chemical mediators in this reaction. The purpose of this study was to elucidate the role of thromboxane A2 in the development of propranolol-induced bronchoconstriction after allergic bronchoconstriction. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride and were then artificially ventilated. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. A potent and selective thromboxane A2 synthase inhibitor, CS-518, in doses of 0.01, 0.1 and 1 mg/kg and vehicle were administered intravenously 15 min after the antigen challenge. Another study was performed in naive guinea pigs; ascending doses of methacholine (12.5, 25, 50, 100 and 200 microg/ml) were inhaled for 20 sec at 5-min intervals, 10 min after intravenous administration of CS-518. Propranolol inhaled 20 min after the antigen challenge caused bronchoconstriction in sensitized guinea pigs. CS-518 administered 15 min after the antigen challenge significantly inhibited propranolol-induced bronchoconstriction in a dose-dependent manner, while CS-518 did not influence the dose-dependent response to inhaled methacholine in naive guinea pigs. We conclude that thromboxane A2 contributes to the development of propranolol-induced bronchoconstriction following allergic reaction in our guinea pig model.

A clinical study on patients with urinary tract infection due to coagulase-negative staphylococci.

To assess the clinical significance of coagulase-negative staphylococci (CNS) in patients with urinary tract infection (UTI), the clinical characteristics of a total of 117 patients (106 complicated UTI patients, 11 uncomplicated UTI patients) from whom CNS were isolated at urinary colony counts of 10(5) or more per ml were studied. Of the complicated UTI patients, 95 patients (89.6%) suffered from no symptoms while 11 (10.4%) had fever of 38 degrees C or greater, which was strongly suspected to be due to genitourinary tract infections. Six of these patients were managed by indwelling urinary catheters. On the other hand, all of the patients with uncomplicated UTI were young women and had typical symptoms of acute cystitis. These results suggest that CNS, which hitherto have been considered mere contaminants or benign colonization rather than true pathogens, can also cause complicated UTI requiring chemotherapy under certain conditions such as indwelling urinary catheterization and acute cystitis in sexually active women.

[The use of intravesical oxybutynin hydrochloride in patients with neurogenic bladder managed by intermittent catheterization].

Nine patients with persistent urinary incontinence due to neurogenic bladder and intolerable systemic side effects on oral anticholinergic agents were treated with intravesical instillation of oxybutynin hydrochloride. Two tablets (6 mg) dissolved in 10 ml of physiological saline or sterile water were instilled into the bladder two times daily via self intermittent catheterization. The mean bladder capacity increased from 128 to 212 ml 1 month after intravesical instillation of oxybutynin hydrochloride, although this difference was not significant. The bladder was augmented more efficaciously in patients with overactive detrusor than patients with an underactive detrusor. Subjective improvement was recognized in 4 patients. Among 5 patients who discontinued therapy due to ineffective results, maximum urethral closure pressure below 50 cmH2O was seen in 4. Intravesical instillation of oxybutynin hydrochloride was considered to be ineffective clinically in patients with underactive detrusor and low urethral closure pressure. Although no systemic side effects were observed, a decrease of bladder capacity was recognized in 2 patients.

[Experimental study of voiding dysfunction induced by cerebral infarction in rats].

BACKGROUND: Although clinical reports concerning voiding dysfunction after cerebrovascular disease are observed, no experimental studies have been carried out using an animal model. This study was performed to establish an animal model to evaluate neurogenic voiding dysfunction associated with cerebral infarctions. METHODS: Male Sprague-Dawley (S-D) rats weighing between 250 to 350 g were used. To induce regional cerebral infarction in rats, 4-0 monofilament nylon thread was introduced through the left internal carotid artery into the origin of the left middle cerebral artery. Cystometric examination was performed in conscious rats through a catheter chronically implanted into the bladder dome. Changes in body weight and bladder capacity were studied. The effects of intravenous oxybutynin hydrochloride, atropine and nifedipine on the conscious rat bladder were examined. By measuring the contractile response to field stimulation with added atropine and alpha, beta-methylene-ATP, the proportion of muscarinergic and purinergic innervation was compared between them. RESULTS: Bladder capacity in cerebral infarcted rats was significantly decreased just after middle cerebral artery occlusion, and 14, 21 and 28 days after occlusion reached less than half that in sham operated and untreated rats. Bladder capacity correlated with the area of infarcted lesion determined by triphenyltetrazolium chloride staining. In the cerebral infarcted rats, bladder capacity significantly increased at low concentrations of oxybutynin hydrochloride, while in the sham operated rats bladder capacity did not increase. Although an increase in bladder capacity was observed after administration of atropine both in cerebral infarcted and sham operated rats, a significant increase of residual urine was found and considered to be caused by decreased detrusor contraction pressure. Nifedipine increased bladder capacity in the cerebral infarcted rats without increasing residual urine. There was no significant difference in the proportion of muscarinergic and purinergic innervation between the cerebral infarcted and sham operated rats. CONCLUSION: These results indicate that calcium channel blocking agents may operate especially on the central nervous system rather than peripheral neuromuscular system, resulting in augmentation of the bladder capacity in the cerebral infarcted rats. Hitherto, the action of oxybutynin hydrochloride on the peripheral neuromuscular system is considered to be the most important, but in the cerebral infarcted rats its action on the central nervous system should also be considered. This type of animal model is believed to be useful to study neurogenic voiding dysfunction of human subjects with cerebrovascular disease.

[A case of adenocarcinoma complicated with massive leukocytosis and hypercalcemia].

A 66-year-old man was admitted to our hospital complaining of non-productive cough and low-grade fever. Chest X-ray examination revealed a mass shadow in the right hilum. Transbronchial lung biopsy of the tumor mass yielded a diagnosis of adenocarcinoma. Despite repeated chemotherapy using CDDP and VDS, metastasis to the right adrenal gland and right femur occurred, and was accompanied by hypercalcemia and hypophosphatemia. Serological study revealed elevated levels of PTH-rP and G-CSF. Six months after adenocarcinoma was diagnosed, multiple skin metastases of the cancer were observed. Immunohistochemical staining for PTH-rP and G-CSF indicated that production of cytokines had caused a paraneoplastic syndrome including hypercalcemia and leukocytosis. It appeared that the elevation of G-CSF was induced by IL-6 produced from PTH-rP in cancer tissue. Documentation of similar cases is required.

[A case of unilateral primary adrenal nodular hyperplasia with elevated plasma adrenocorticotropin (ACTH)].

A 57-year-old woman was admitted to our hospital with occipital headache and nausea. She had severe hypertension (192/122mmHg), hypokalemia (2.8mEq/l) and fasting hyperglycemia (127 mg/dl). Further examination revealed elevated plasma ACTH (124pg/ml) and cortisol (26.5 mu g/dl) with a lack of diurnal rhythm. Plasma ACTH or cortisol did not increase by injection of corticotropin releasing hormone (CRH). Rapid ACTH test resulted in an exaggerated response of plasma cortisol. Abdominal MRI scan showed a left adrenal tumor. Since the bilateral adrenal venous blood sampling revealed a significant increase of cortisol on the left, left adrenalectomy was performed. Histological examination of the resected adrenal gland revealed marked cortical hyperplasia. Postoperative investigations revealed that despite a small dose of steroid replacement for only 20 days, plasma ACTH level was decreased for a period of 6 months. Both plasma ACTH and cortisol increased by a CRH injection 38 days after surgery. CRH test during bilateral inferior petrosal sinus sampling indicated that this patient had no functioning pituitary tumor. Although the exact mechanism of high plasma ACTH level in this case was unknown, these findings suggest that any substance secreted from primary adrenal nodular hyperplasia adrenal nodular hyperplasia may stimulate pituitary ACTH production. This is a very rare case of Cushing's syndrome due to unilateral primary adrenal nodular hyperplasia with elevated plasma ACTH.

Multinodular deposition of AA-type amyloid localized in the adrenal glands of an old man.

Multinodular amyloid deposits localized in non-neoplastic adrenal glands were found incidentally at autopsy in an 83-year-old Japanese man. Clinically, the patient lacked evident deficiency of adrenal hormones. The nodules of the stromal amyloid deposits were scattered in the adrenal cortex, where the parenchymal cells were compressed and atrophic. The deposits were confirmed to be amyloid by Congo red staining and polarization microscopy. Amyloid fibrils were also demonstrated in the deposits by electron microscopy. The amyloid deposits were permanganate-sensitive and showed immunohistochemical staining for serum amyloid P component and serum amyloid A protein (SAA), implying that they were AA amyloid. There have been no reports describing localized amyloid deposits of the AA type in non-neoplastic adrenal glands. The pathogenesis and clinical significance of the amyloid deposition in the present case remain only speculative.