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Dynamic contrast-enhanced magnetic imaging (DCE-MRI) is a useful method for detection and diagnosis of liver lesions. However, DCE-MRI using Gd-EOB-DTPA has some problems with arterial phase images. Radial volumetric imaging breath-holding examination (r-VIBE) with k-space weighted image contrast reconstruction (KWIC), which is a modification of Cartesian VIBE (c-VIBE), is a new 3D-gradient echo sequence with a number of advantages compared with c-VIBE, including lower motion sensitivity. This study was performed to evaluate image contrast, blurring, and temporal phase division effects of r-VIBE in comparison with c-VIBE. Image contrast using diluted Gd-EOB-DTPA aqueous solution showed no significant difference between r-VIBE and c-VIBE. Imaging was performed with r-VIBE and c-VIBE during injection of a Gd-EOB-DTPA solution into a serpentine tube. r-VIBE showed a smaller half-width of the signal intensity profile of the tube and less image artifacts by blurring when compared to c-VIBE. The arrival times and durations of the maximum signal strengths of r-VIBE and c-VIBE images during injection of Gd-EOB-DTPA solution into the tube were almost identical. r-VIBE improved the temporal resolution without degradation of liver DCE-MRI using Gd-EOB-DTPA.

Objectives: To investigate the superiority of radial volumetric breath-hold examination (r-VIBE) with k-space weighted image contrast reconstruction (KWIC) over Cartesian VIBE (c-VIBE) for reducing motion artefacts., Methods: We acquired r-VIBE-KWIC and c-VIBE images in 10 healthy volunteers. Each acquisition lasted 24 seconds. The volunteers held their breath for decreasing lengths of time during the acquisitions, from 24 to 0 seconds (protocols A-E). Magnetic resonance images at the level of the right portal vein and confluence of hepatic veins were assessed by two readers using a five-point scale with a higher number indicating a better study., Results: The mean scores for the complete r-VIBE-KWIC series (r-VIBEfull) and first r-VIBE-KWIC series (r-VIBE1) were not significantly lower than those for c-VIBE in any protocols. The mean scores for c-VIBE were lower than those for r-VIBEfull and r-VIBE1 in protocols C and D. The mean score for c-VIBE was lower than that for r-VIBEfull in protocol E. The mean score for the eighth r-VIBE-KWIC series (r-VIBE8) was lower than that for c-VIBE only in protocol B., Conclusion: r-VIBE-KWIC minimised artefacts relative to c-VIBE at any slice location. The r-VIBE-KWIC's sub-frame images during the breath-holding period were hardly affected by another failed breath-holding period., Key Points: • A two-reader study revealed r-VIBE-KWIC's advantages over c-VIBE • The image quality of r-VIBE-KWIC's sub-frame images was maintained during breath holding • Full-frame r-VIBE-KWIC images minimized motion artefacts caused by breathing • A complete breath holding over half the acquisition time is recommended for c-VIBE • c-VIBE was susceptible to respiratory motion especially in the subphrenic region.

Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.

Objectives: To compare radial volumetric imaging breath-hold examination with k-space weighted image contrast reconstruction (r-VIBE-KWIC) to Cartesian VIBE (c-VIBE) in arterial phase dynamic gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (DCE-MRI) of the liver., Methods: We reviewed 53 consecutive DCE-MRI studies performed on a 3-T unit using c-VIBE and 53 consecutive cases performed using r-VIBE-KWIC with full-frame image subset (r-VIBEfull) and sub-frame image subsets (r-VIBEsub; temporal resolution, 2.5-3 s). All arterial phase images were scored by two readers on: (1) contrast-enhancement ratio (CER) in the abdominal aorta; (2) scan timing; (3) artefacts; (4) visualisation of the common, right, and left hepatic arteries., Results: Mean abdominal aortic CERs for c-VIBE, r-VIBEfull, and r-VIBEsub were 3.2, 4.3 and 6.5, respectively. There were significant differences between each group (P < 0.0001). The mean score for c-VIBE was significantly lower than that for r-VIBEfull and r-VIBEsub in all factors except for visualisation of the common hepatic artery (P < 0.05). The mean score of all factors except for scan timing for r-VIBEsub was not significantly different from that for r-VIBEfull., Conclusions: Radial VIBE-KWIC provides higher image quality than c-VIBE, and r-VIBEsub features high temporal resolution without image degradation in arterial phase DCE-MRI., Key Points: Radial VIBE-KWIC minimised artefact and produced high-quality and high-temporal-resolution images. Maximum abdominal aortic enhancement was observed on sub-frame images of r-VIBE-KWIC. Using r-VIBE-KWIC, optimal arterial phase images were obtained in over 90 %. Using r-VIBE-KWIC, visualisation of the hepatic arteries was improved. A two-reader study revealed r-VIBE-KWIC's advantages over Cartesian VIBE.

Tramadol is an atypical opioid analgesic widely used in small animal practice. This study was designed to determine the effect of a single intravenous (IV) dose of tramadol on the minimum alveolar concentration (MAC) of sevoflurane in dogs. Six beagle dogs were anesthetized twice to determine the sevoflurane MAC with or without an administration of tramadol (4 mg/kg, IV) at 7 days interval. The sevoflurane MAC was determined using a tail clamp method in each dog ventilated with positive pressure ventilation. The tramadol administration produced a significant reduction in the sevoflurane MAC by 22.3 ± 12.2% (1.44 ± 0.28% with tramadol versus 1.86 ± 0.30% without tramadol, P=0.010). This MAC reduction had been determined from 122 ± 19 to 180 ± 41 min following the tramadol administration. During this period, the plasma concentrations of tramadol and its metabolite, O-desmethyltramadol (M1), decreased from 429 ± 64 to 332 ± 55 ng/ml and from 136 ± 24 to 114 ± 68 ng/ml, respectively, but these changes were not statistically significant. There was no significant difference in heart rate, mean arterial blood pressure and SpO2 between the control and tramadol treatment. The dogs that received tramadol treatment sometimes breathed spontaneously. Therefore, their respiratory rates significantly increased, and PETCO2 decreased during the MAC determination. In conclusion, the single IV dose of tramadol produced a significant reduction in the sevoflurane MAC in dogs.

Background: In Western medicine, the application of topical steroids and oral antihistaminic or antiallergic agents is the main treatment option for atopic dermatitis (AD). However, instead of these therapies the disease may remain intractable in some patients, resulting in long-term exposure to these chemical agents and consequently leading to concerns about possible adverse drug reactions., Methods: In the present open-label clinical study, the efficacy and safety of a novel multi component TCM therapy approach for AD was investigated. Therefore, 94 patients received the formula I (10 crude drugs) orally, combined with both the lotion II (7 crude drugs), and the ointment III (8 crude drugs). Each crude drug was extracted with boiling water in a defined manner, concentrated, and reworked into the preparations. Standardized scores were used for evaluating the severities of AD (clinical severity 0-4) and pruritus (pruritus score 0-4)., Results: Both scores had significantly improved at the end of a 12 month treatment (P<0.001). Eosinophil ratio and serum IgE levels, which were elevated in AD patients, were significantly reduced at the end of therapy (P<0.01). In 32 of 94 treated patients the condition markedly improved, in 59 cases AD improved, and in 3 patients there was a slight improvement with no case of ineffective treatment. There was no hint of renal or hepatic toxicity or any other adverse effects., Conclusion: The present study confirms that the 3 newly developed herbal TCM combination preparations are clinically efficacious on AD, accomplishing a significant reduction in both clinical and pruritus scores as well as in eosinophil ratios and serum IgE levels., (© 2013 S. Karger GmbH, Freiburg.)

Cardiovascular effects of tramadol were evaluated in dogs anesthetized with sevoflurane. Six beagle dogs were anesthetized twice at 7 days interval. The minimum alveolar concentration (MAC) of sevoflurane was earlier determined in each dog. The dogs were then anesthetized with sevoflurane at 1.3 times of predetermined individual MAC and cardiovascular parameters were evaluated before (baseline) and after an intravenous injection of tramadol (4 mg/kg). The administration of tramadol produced a transient and mild increase in arterial blood pressure (ABP) (P=0.004) with prolonged increase in systemic vascular resistance (SVR) (P<0.0001). Compared with baseline value, mean ABP increased significantly at 5 min (119% of baseline value, P=0.003), 10 min (113%, P=0.027), and 15 min (111%, P=0.022). SVR also increased significantly at 5 min (128%, P<0.0001), 10 min (121%, P=0.026), 30 min (114%, P=0.025), 45 min (113%, P=0.025) and 60 min (112%, P=0.048). Plasma concentrations of tramadol were weakly correlated with the percentage changes in mean ABP (r=0.642, P<0.0001) and SVR (r=0.646, P<0.0001). There was no significant change in heart rate, cardiac output, cardiac index, stroke volume, pulmonary arterial pressure, right atrial pressure and pulmonary capillary wedge pressure. In conclusion, the administration of tramadol produces a prolonged peripheral vascular constriction in dogs anesthetized with sevoflurane, which is accompanied with a transient and mild increase in arterial blood pressure. It also indicated that the degree of vasoconstriction might depend on the plasma concentration of tramadol.

Intraductal papillary neoplasm of the bile duct (IPNB) or liver is a recently noted rare disease, and its pathogenesis remains unclear. Here we present a case of IPNB with an interesting morphology, which was treated by resection of the right hemiliver and extrahepatic bile duct. A 79-year-old woman was found to have a high alkaline phosphatase level and slight dilatation of the right intrahepatic bile duct on imaging studies. The right intrahepatic bile duct became dilated over a 2-year period; however, no solid mass could be detected, and tumor markers were not elevated. Hepatic resection was scheduled because a mucin-producing bile duct carcinoma of the liver was suspected. A right hemihepatectomy was conducted, and the extrahepatic bile duct was also resected after malignant cells were found in the surgical stump of the right bile duct and in the bile itself. Macroscopically, diffuse dilatation of the intrahepatic bile duct was noted, but no solid component or mucin within the duct was found. Histopathological findings revealed carcinoma in situ, IPNB, in the majority of intrahepatic bile ducts, with no lymph node metastasis, and it extended continuously to the epithelium of the common bile duct. No tumor recurrence or biliary dilatation was observed at follow-up 2 years after surgery. It is important to consider malignancy in the presence of a dilated bile duct and in the absence of any cause of occlusion. Complete resection of IPNB results in a good prognosis and no recurrence.

Aims: To evaluate lung disease, pulmonary tissues should be fixed by inflation. However, many histological sections prepared after inflation fixation show wire-like alveolar septa with capillary collapse. We investigated the reason for this artefact., Methods: To evaluate the effect of fixatives, we used the following commercially available solutions: regular 10% neutral buffered formalin (NBF), 20% NBF, 10% and 5% formalin prepared by diluting the 20% NBF, modified formalin solution as a substitute for 10% NBF, and 10% formalin prepared by diluting the 100% formalin without any buffers., Results: The osmolarity of the fixative was found to be responsible for the collapse artefact. Ten per cent formalin, prepared by diluting 100% formalin, the commercially available substitute for 10% NBF, and 5% formalin prepared by diluting 20% NBF, yielded the best pulmonary tissue morphology, including that of the alveolar-capillary interface., Conclusions: Pulmonary physicians and pulmonary pathologists should use a suitable fixative solution for obtaining a better pulmonary architecture as well as to preserve the tissue block in optimal condition for future assessment of pulmonary diseases.

A 74-year-old woman presented with a microcystic meningioma which manifested as mental disturbance. A rapidly growing tumor in the left middle fossa had not been detected by examination 10 months before. The tumor was remarkably enhanced by contrast medium on both computed tomography and magnetic resonance imaging and was associated with massive perifocal edema. Cerebral angiography revealed that the tumor was mainly fed by the left middle meningeal artery, which was embolized preoperatively. The tumor was completely removed and no postoperative adjuvant therapy was administered. The histological diagnosis was microcystic meningioma with many mitotic figures and a MIB-1 labeling index of 12.8%. Four months later, the tumor recurred and invaded the paranasal sinus. Focal irradiation successfully controlled further regrowth. This case suggests that microcystic meningioma may have aggressive features, and close observation is necessary even after gross total removal.

Primary pulmonary artery sarcomas (PASs) are rare and lethal tumors. They are easily misdiagnosed as chronic pulmonary embolism, mediastinal mass or tumor emboli, which delay a proper treatment. Although the advanced technologies are now increasingly being used, their diagnosis is usually hard to establish preoperatively at the present time. We report here a case of a 68-year-old female with PAS with lung metastases, who firstly presented with symptoms of common cold and anemia. Although a PAS had been suspected, the final diagnosis of pulmonary intimal sarcoma was made only postoperatively by histological and immunohistochemical examination. The patient died 8 months after the operation because of tumor growth progression, despite adjuvant chemotherapy and radiation therapy. Although pulmonary intimal sarcomas are usually of poorly differentiated mesenchymal malignancy, most reported cases are immunohistochemically positive for vimentin, alpha-smooth muscle actin (SMA), and/or desmin, therefore resembling leiomyosarcomas. However, the diagnosis of leiomyosarcoma should not be made on the basis of immunostains in the absence of typical morphologic features, and PAS, like the present case, should be more appropriately classified as intimal sarcoma according to the new WHO Classification of Tumours of Soft Tissue and Bone published in 2002.

Keratinocyte growth factor (KGF), a mesenchymal cell derived paracrine growth factor that regulates normal epithelial cell proliferation, appears to be an essential mediator of steroids in various reproductive organs. The present study was designed to determine the expression and role of KGF and its receptor (KGFR) in human breast carcinoma tissues by immunohistochemistry. We also compared the results with the expression of estrogen receptor alpha(ERalpha), ERbeta, the proliferative activity assessed by the labeling index (LI) for the Ki-67 antigen, apoptotic frequency assessed by terminal dUTP nick end-labeling (TUNEL) index, and the expression of Bcl-2. All of KGF-positive cases were ERalpha- positive (p<0.05), but not that of ERbeta, while all of KGFR-positive cases were ERbeta-positive (p<0.05), but not that of ERalpha. The specimens with the coexpression of KGF and KGFR significantly correlated with a lower TUNEL index (p<0.05), but not with Ki-67 LI in breast cancer tissues. Further analysis at the cellular level revealed that Bcl-2 was colocalized in KGFR-positive cells, and these cells were almost negative for TUNEL staining. Bcl-2-positive cells were also associated with ERbeta, as expected. Therefore, the results indicate that ERalpha may be involved in KGF expression, and that the coexpression of KGF and KGFR may play an inhibitory role in the induction of apoptosis possibly through the up-regulation of Bcl-2 expression in human breast cancer.

Although estrogen is known to play a crucial role in the pathogenesis of breast cancer, the molecular mechanisms underlying the action of estrogen remain elusive. In the present study, we focused on keratinocyte growth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediating estrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependent tissues. First, using paraffin-embedded specimens from 42 breast cancer patients, we examined expression patterns of KGF and KGFR by both immunohistochemistry using newly generated antibodies and nonradioactive in situ hybridization with T-T dimerized synthetic oligonucleotide probes. We next compared the results with the expression of estrogen receptor (ER) alpha and beta, proliferative activity and apoptotic frequency (TUNEL staining). Also, the similar approaches were taken to analyze the expression and role of KGF in ER-positive (MCF7, ZR-75-1) and ER-negative (SK-BR-3, MDA-MB-231) human breast cancer cell lines in vitro. In the surgical specimens, KGF was expressed in cancer cells as well as stromal cells in 19/42 cases (45%), while KGFR was found in cancer cells in 24/42 cases (57%). The distribution of protein and mRNA in the analysis of both KGF and KGFR expression generally coincided. Moreover, KGF expression was closely associated with the expression of ER alpha, and the coexpression of KGF and KGFR significantly correlated with lower TUNEL index, but not with proliferative activity. In accordance with the in vivo findings, KGF expression was detected only in ER alpha-positive MCF7 and ZR-75-1 cells in vitro. And more importantly, we found the inhibitory effect of KGF upon the induction of apoptosis by anticancer drugs in MCF7 cells. Collectively, our results indicate that ER alpha may be involved in KGF expression, and that KGF may play antiapoptotic roles, rather than mitogenic, in human breast cancer.

Objective: To investigate the proliferative characteristics of fibroblasts cultured from emphysematous lungs., Methods: Fibroblasts were isolated and cultured from emphysematous lungs surgically resected as a consequence of lung volume reduction surgery and from non-cancerous areas of lungs obtained following resection for lung cancer as a non-emphysematous control. Their proliferative activities were compared, as was the effect of cigarette smoke extract (CSE) on fibroblast proliferation. After incubation with various concentrations of CSE, cells were harvested and cell numbers were counted. Growth curves were constructed and doubling time was calculated to compare the proliferative activity of fibroblasts from emphysematous and non-emphysematous lungs., Results: The proliferation of fibroblasts from emphysematous lungs cultured with normal medium appeared suppressed compared with non-emphysematous lungs. The addition of CSE to the medium induced more obvious growth inhibition in emphysematous lung fibroblasts. The growth of both fibroblast cultures was inhibited by CSE and this appeared to be concentration dependent., Conclusions: Fibroblasts from emphysematous lungs had lower proliferative activity and were more susceptible to cigarette smoke than those from non-emphysematous lungs. Cigarette smoke may play a critical role in the development and deterioration of pulmonary emphysema by suppressing the growth of lung fibroblasts.

Growth of the fetal lung has been monitored by left lung area (LLA), right lung area (RLA), and total lung area (TLA) from 14 to 41 weeks menstrual age in 116 normal Japanese fetuses. Growth of the fetal heart and chest has also been monitored by heart area (HA) and chest area (CA), respectively. Growth curves for these parameters have been determined by using a Rossavik growth model [p = c(t)k+s(t)]. R2 values of 95.3%, 90.3%, 89.0%, 88.7%, and 92.1% were obtained for CA, HA, LLA, RLA, and TLA, respectively. Variability analysis indicated a progressive increase in variability with fetal age for these five parameters. Variability data were used with the growth curve models to determine standard curves for these parameters. These standard curves provide a superior means for evaluating the normal fetal lung growth in the fetus and for identifying pulmonary hypoplasia in utero.

In the present study, we used the envelope method to divide patients with respiratory infections into two groups: a monotherapy group given imipenem/cilastatin sodium (IPM/CS) and a combination therapy group given imipenem/cilastatin sodium plus amikacin sulfate (AMK). We then compared the clinical efficacy and safety between groups. 1. Safety was evaluated in 83 patients in the IPM/CS group and 88 in the IPM/CS + AMK group while clinical efficacy was evaluated in 77 and 80 patients in the respective groups. 2. The overall efficacy rate was 84.4% in the IPM/CS group. Among the main infections, the efficacy rates were 82.7% in 52 cases of pneumonia (including lung abscess), 100% in cases of infected bronchiectasis, 66.7% in six cases of secondary infection of chronic respiratory disease, and 100% in four cases of chronic bronchitis. The overall efficacy rate was 83.8% in the IPM/CS + AMK group. Among the main infections, the efficacy rates were 88.1% in 59 cases of pneumonia (including lung abscess), 83.3% in 12 cases of infected bronchiectasis, and 60.0% in five cases of secondary infection of chronic respiratory disease. No significant differences in efficacies were seen between groups. 3. In the IPM/CS group, the efficacy rates were 92.3% for patients without prior antibiotic therapy in the IPM/CS group and 68.0% for those with prior therapy; in the IPM/CS + AMK group, the respective rates were 83.7% and 83.9%. In the IPM/CS group, there was a significant difference in the responses of patients with and without prior antibiotic therapy (P < 0.05). 4. Side effects were observed in six patients in the IPM/CS group (7.2%) and two patients in the IPM/CS + AMK group (2.3%). Abnormal laboratory test results were noted in 5 patients in the IPM/CS group (6.0%) and in 10 in the IPM/CS + f1p4group (11.4%). There was no significant difference in the incidence of side effects between groups and no severe adverse reactions in either group. These results indicate that IPM/CS alone produces of good response in moderate to severe respiratory infections while IPM/CS combined with AMK is useful in intractable respiratory infections.

A disk-supporting mechanism for a high-capacity 90-mm (3.5-in) flexible optical-disk system is studied for low-cost recording media and small drives. The mechanical characteristics are analyzed by a simple calculation of dynamic air pressure generated by pocket thrust bearings and by measurements of disk vibrations. The flexible disk rotates stably, supported by two thrust air bearings fabricated in a plastic cartridge, with disk tilt less than 5 mrad and disk acceleration less than 5 m/s(2) The feasibility of this system is confirmed by write-erase operations at a 2-µm track pitch.

The data reliability of a 90-mm flexible optical disk system with a phase-change rewritable disk is studied through accelerated tests of dust density for fabrication of low-cost, reliable flexible optical disks. A simple dust generator composed of a small loud speaker creates an extremely dusty environment in a chamber, with a dust density several times higher than in a normal environment. These accelerated tests indicate that a flexible optical disk contained in a semisealed cartridge will show no change in the number of errors over several years in a normal environment.

A high-capacity 90-mm flexible optical disk system with a phase-change rewritable disk is studied, aiming at low-cost recording media and small drives. The flexible disk rotates stably and is supported by two thrust air bearings fabricated in a plastic cartridge with a disk tilt of less than 5 mrad. A radial tracking-control precision of 0.2 microm is attained with a sample servo system by using photographically replicated square servo marks on the disk. The feasibility of this system is confirmed by write-erase operations in a 2-microm track pitch.

Paraquat is a herbicide known to cause pulmonary edema in its acute toxic phase. Many investigators showed that paraquat induces morphological changes of alveolar epithelial cells even in its early phase. Controversy still exists, however, as to whether pulmonary vascular endothelial cells are also morphologically vulnerable to paraquat. To test the direct toxicity and metabolic changes of pulmonary vascular endothelial cells after paraquat addition, porcine pulmonary artery endothelial cells (PPAEC) were cultured. Thrombin- or bradykinin-stimulated PGI2 production was enhanced significantly, and the angiotensin converting enzyme (ACE) activity of cell lysate of PPAEC was significantly suppressed after a 24-hour incubation with 10(-4) M of paraquat. No further thrombin-induced enhancement of PGI2 production was noted after a 48-hour incubation. The alterations in arachidonic acid metabolism and ACE activity mentioned above did not result from cytotoxicity of paraquat because LDH release into culture medium was not increased during 72 hours of incubation with paraquat. Longer incubation more than 48 hours, in turn, induces obvious toxic effects on PPAEC.

Ciprofloxacin (CPFX), a new pyridone carboxylic acid, was administered orally to the patients with chronic respiratory tract infection and its clinical efficacy and safety were studied in a multicenter open trial. The results and summarized as follows. 1. The efficacy rate for the patients with acute exacerbation as 52.5% (21/40) in 2 week-treatment, and 75.0% (24/32) in 4 week-treatment. 2. The efficacy rate for the patients with chronic phase was 23.1% (6/26) in 2 week-treatment, and 26.9% (7/26) in 4 week-treatment, but acute exacerbation was not observed in any of the patients. 3. CPFX was administered to 6 patients over 60 days for the prophylaxis of acute exacerbation. Only 2 patients had acute exacerbation in 2 and 3 months after the start of the therapy, respectively. 4. Bacteriological eradication rate was high except P. aeruginosa, for which the eradication rate was about 20%. 5. Side effects were observed in 3 patients, and abnormal findings of laboratory tests were observed in 5 patients, though they were not severe. These results show that CPFX is a useful antimicrobial agent for the treatment of chronic respiratory tract infections.