Surgical antimicrobial prophylaxis in Japanese hospitals: Real status and challenges.

BACKGROUND: Information regarding the status of surgical antimicrobial prophylaxis (SAP) in Japanese hospitals is lacking. This study aimed to explore the status of SAP prescriptions for surgeries and adherence to Japanese SAP guidelines. METHODS: From February to July 2020, a 1-day multicentre point prevalent survey was conducted at 27 hospitals in Aichi Prefecture, Japan. Patients prescribed SAP were included in this study. The appropriateness of the SAP was evaluated based on the guidelines for selection of antimicrobials and their duration. Surgery was defined as appropriate when all the items were appropriate. RESULTS: A total of 728 patients (7.1 %; 728/10,199) received antimicrobials for SAP. Among them, 557 patients (76.5 %, 557/728) underwent the surgeries described in the guidelines. The overall appropriateness of all surgeries was 33.9 % (189/557). The appropriate selection of antimicrobial before/during and after surgery and their durations were 67.5 % (376/557), 67.5 % (376/557), and 43.3 % (241/557), respectively. The overall appropriateness ranged from 0 % (0/37, oral and maxillofacial surgery) to 58.7 % (88/150, orthopaedic surgery) and 27.7 % (36/130, community hospitals with 400-599 beds) to 47.2 % (17/36, specific hospitals). Cefazolin was the most prevalent antimicrobial prescribed before/during (55.5 %, 299/539), and after (45.1 %, 249/552) surgery. In total, 101 oral antimicrobials were prescribed postoperatively. CONCLUSIONS: SAP adherence by specific surgical fields and hospitals was shown in this study. Intensive intervention and repeated surveillance are necessary to improve SAP prescriptions in Japanese hospitals.

Predictors and impact of time to clinical stability in community-acquired pneumococcal pneumonia.

BACKGROUND: A clinical stability (CS) evaluation is thought to be important in community-acquired pneumonia (CAP) treatment, but evidence concerning the time to CS (TCS) remains lacking. METHODS: Among consecutive patients hospitalized with pneumococcal pneumonia, relationships between TCS and other clinical outcomes were examined, and predictors and a predictive TCS score were derived from patient characteristics on admission. RESULTS: A total of 144 patients were enrolled, including 46% and 27% with moderate and severe pneumonia, respectively, defined by the pneumonia severity index (PSI). The median TCS was 2 days, and was significantly correlated with the length of hospital stay (r = 0.595); a longer TCS was significantly associated with the more presence of poor clinical outcomes and ICU stays (adjusted odds ratios: 1.359 and 1.366, respectively). A multivariate Cox proportional hazard model revealed an absence of bilateral pneumonia (hazard rate (HR): 2.107) or bacteremia (HR: 2.520), and mild or moderate pneumonia (HR: 2.798 and 2.515, respectively, versus severe) as predictors of CS. A predictive score had moderate discriminating power for the prolonged TCS (area under the curve: 0.76), and provided similar predictive values for poor clinical outcomes and ICU stays. A score of 3 or more points indicated the prolonged TCS, with a sensitivity and specificity of 73.3% and 70.9%, respectively. CONCLUSIONS: Because TCS has a significant relationship with other clinical outcomes of pneumococcal CAP, the prediction of TCS might lead to the prevention of complications or an earlier transition to oral therapy. Future studies are warranted to validate these results.

Re-expansion pulmonary edema: evaluation of risk factors in 173 episodes of spontaneous pneumothorax.

BACKGROUND: The precise incidence and clinical features of re-expansion pulmonary edema (RPE) are unclear, and they vary among reports. In this study, we assessed the incidence, risk factors, and outcomes of patients with RPE over a 3-yr period in a general hospital, with the goal of proposing a primary intervention for pneumothorax. METHODS: We retrospectively reviewed records of inpatients with spontaneous pneumothorax treated by tube thoracostomy between October 2007 and December 2010. RESULTS: A total of 173 episodes of spontaneous pneumothorax occurred in 156 patients. The incidence of RPE was 27/173 (15.6%). Symptom duration and pneumothorax size were significant risk factors for RPE, and the occurrence of RPE was independent of primary treatment of spontaneous pneumothorax. Among the patients with RPE, 18 (67%) were symptomatic. Five patients (18.5%) were treated with temporary oxygen, however, 21 patients (78%) did not need any treatment. All patients survived and none required mechanical ventilation. The occurrence of RPE did not influence the clinical outcome. CONCLUSIONS: The risk of developing RPE increases with an increased duration or size of pneumothorax. Our results suggest that the methods of primary intervention, including prompt suction, do not affect the onset of RPE. Close observation is always required regardless of the intervention because of the potentially fatal complications.

Diagnostic management of patients with suspected ocular sarcoidosis.

BACKGROUND: Ophthalmologists often refer patients with suspected ocular sarcoidosis to pulmonologists for diagnostic examination of sarcoidosis. However, no recommendation has been proposed for managing such patients. This study aims to prospectively evaluate the diagnostic values of examinations and propose the management of patients with suspected ocular sarcoidosis. METHODS: Consecutive patients with suspected ocular sarcoidosis were prospectively investigated according to type of ocular lesions, measurement of serum ACE, and findings of chest radiography, chest CT, bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB). Diagnostic values were calculated on the basis of pathological results. RESULTS: Forty-two patients were included (female, 71.4%; mean age, 56.2±14.8 years), of whom 64.3% was diagnosed with sarcoidosis. Patient characteristics and ocular lesions did not differ significantly, regardless of the presence of sarcoidosis. Chest CT had low specificity and very high sensitivity for detecting sarcoidosis; in contrast, chest radiography and direct findings of bronchofiberscopy had high specificity and low sensitivity. Serum ACE and BAL did not have high diagnostic value. A flow chart was proposed to diagnose sarcoidosis, and this chart reduced the requirement of TBLB to 50% in our population. During the median follow-up of 51 months, 7 patients in the sarcoidosis group (25.9%) developed new lesions. CONCLUSIONS: Application of our flow chart appears to detect avoidable TBLB. Development of a more comprehensive flow chart including survey of ocular findings is warranted.

Paradoxical infarct in tuberculous meningitis: a case report.

We describe a case of 78-year-old woman with a 1-week history of fever and left hemiparesis. Head magnetic resonance imaging showed a small infarct. After admission, she showed altered consciousness and another small infarct. She finally had diagnoses of miliary tuberculosis (miliary-TB) and tuberculous meningitis (TBM). She recovered after receiving anti-tuberculous therapy (ATT) with prednisolone. However, 5 weeks later, we found another infarct. This is a rare case of TBM with recurrent infarcts in atypical lesions in spite of ATT. We suggest the possibility that the new infarct after ATT was due to a paradoxical reaction.

Prospective evaluation of the relationship between acute exacerbations of COPD and gastroesophageal reflux disease diagnosed by questionnaire.

BACKGROUND: Little is known about the relationship between acute exacerbations of COPD (AECOPD) and gastroesophageal reflux disease (GERD). The aim of this study was to investigate the effects on AECOPD of GERD diagnosed by a questionnaire. METHODS: The subjects were 221 consecutive patients with stable COPD who were evaluated using the Frequency Scale for Symptoms of GERD (FSSG) and a prospective survey of AECOPD for one year. Patients taking drugs for acid suppression were excluded. The association between the frequency of AECOPD and the presence of GERD or FSSG score was examined. RESULTS: Based on the FSSG, the prevalence of GERD was 26.7%. AECOPD and hospitalization due to AECOPD were significantly more frequent in patients with GERD than in those without GERD, with crude relative risks of 3.42 and 3.66, respectively. Multivariate analyses showed that GERD and COPD stage IV were significant predictors of hospitalization due to AECOPD, independent of respiratory therapies or patient characteristics. The severity of GERD symptoms, as measured by the FSSG score, was significantly correlated with the frequencies of AECOPD and hospitalization due to AECOPD. Similar correlations were seen for the FSSG subscores for acid reflux and gastric dysmotility. CONCLUSIONS: This prospective cohort study showed that GERD appears to be a predictive factor for hospitalization due to AECOPD and that severer GERD symptoms may be associated with more frequent AECOPD. Thus, further studies are warranted to evaluate the preventive effect of the therapy for GERD on AECOPD.

[A case of six metachronous primary malignancies].

Recently, the early detection and the advances in therapy for malignant diseases have contributed to prolonged survival of patients, resulting in an increment of multiple primary malignancies. We describe a 55-year-old man, at the first presentation, with six malignancies over 14 years(malignant lymphoma, gastric cancer, ureteral cancer, small cell lung cancer, bladder cancer, and squamous cell lung cancer). A case of six primary malignancies is extremely rare and, as far as we know, this is the 16th case of its kind reported in Japan. The overlapping of many malignant diseases resulted in some difficulties with treatment. Whereas the ureteral cancer and small cell lung cancer were synchronous, considering the therapeutic duration of lung cancer, we proceeded with the operation for ureteral cancer and had to delay the start of chemotherapy for small cell lung cancer for more than one month. Moreover, dose intensity of the chemotherapy for the small cell lung cancer was limited by expectancy of augmented myelosuppression, due to the effect of prior chemotherapy for malignant lymphoma. However, a strong neutropenia-induced postoperative abdominal infection necessitated discontinuation of chemotherapy and treatment with radiotherapy alone. In addition, the therapies for the newly developed squamous cell lung cancer, the sixth malignancy, were also limited because of reduced lung function and myelopoiesis. In treatment or follow-up of patients with multiple primary malignancies, as opposed to those with a single malignant disease, the characteristics of other malignancies and the morbidities by preceding therapies must be considered.

[Relationship between chronic obstructive pulmonary disease and gastroesophageal reflux disease defined by the Frequency Scale for the Symptoms of gastroesophageal reflux disease].

Little is known about gastroesophageal reflux disease (GERD) in chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to investigate the prevalence, clinical characteristics and risk factors for GERD in COPD patients, based on the Frequency Scale for the Symptoms of GERD (FSSG). In 228 COPD patients, the prevalence of GERD was 26.7%, independent of COPD stage. Logistic regression multivariate analysis revealed significant risk factors for accompanying GERD were age (p = 0.009; odds ratio (OR), 0.933; 95% confidence interval (CI) 0.885 to 0.983) and number of COPD exacerbation within one year (p = 0.043; OR, 1.675; 95% CI, 1.075 to 2.764). The risk factors of COPD exacerbation were total FSSG score (p = 0.031; OR, 1.079; 95% CI, 1.007 to 1.156) and inhaled corticosteroid use (p = 0.003; OR, 3.238; 95% CI, 1.482 to 7.076). Moreover, the Spearman rank correlation test showed that FSSG score was weakly but significantly correlated with the number of COPD exacerbations (rs = 0.317, p < 0.001). In conclusion, the incidence of GERD in COPD patients is high, and the incidence of GERD is closely related to COPD exacerbation.

Mechanical stretch enhances IL-8 production in pulmonary microvascular endothelial cells.

In patients with acute respiratory distress syndrome, mechanical over-distension of the lung by a large tidal volume causes further damage and inflammation, called ventilator-induced lung injury (VILI), however, it is unclear how mechanical stretch affects the cellular functions or morphology in human pulmonary microvascular endothelial cells (HPMVECs). IL-8 has been proposed to play an important role in the progression of VILI by activating neutrophils. We demonstrated that HPMVECs exposed to cyclic uni-axial stretch produce IL-8 protein with p38 activation in strain- and time-dependent manners. The IL-8 synthesis was not regulated by other signal transduction pathways such as ERK1/2, JNK, or stretch-activated Ca(2+) channels. Moreover, cyclic stretch enhanced IL-6 and monocyte chemoattractant protein-1 production and reoriented cell perpendicularly to the stretch axis accompanied by actin polymerization. Taken together, IL-8 production by HPMVECs due to excessive mechanical stretch may activate neutrophilic inflammation, which leads to VILI.

Regulation of endothelin-1-induced interleukin-6 production by Ca2+ influx in human airway smooth muscle cells.

Endothelin-1 is considered to be an important mediator in the pathophysiology of asthma because it induces contraction, hypertrophy, and proliferation in airway smooth muscle cells as well as inflammatory responses in the airway. Airway smooth muscle cells have been suggested to contribute to airway inflammation in asthma by producing cytokines. Nevertheless, the role of intracellular Ca(2+) signal in cytokine production in human airway smooth muscle cells is still unclear. We investigated the mechanisms by which endothelin-1 induces production of interleukin (IL)-6, a pleiotropic cytokine, in primary cultured human airway smooth muscle cells. Levels of IL-6 protein and mRNA were significantly increased by endothelin-1 in dose- and time-dependent manners. Endothelin-1-induced IL-6 production was markedly attenuated by EGTA and various Ca(2+) channel inhibitors such as 3,5-bis(trifluoromethyl)-1H-pyrazole derivative (BTP-2), 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride (SKF96365), and nifedipine. Endothelin-1-induced increases in intracellular Ca(2+) concentrations were significantly inhibited in Ca(2+)-free solution and by BTP-2, SKF96365, and nifedipine. The IL-6 synthesis was also inhibited by the extracellular signal-regulated kinase (ERK)1/2 inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)-butadiene ethanolate (U0126) and the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), but not by the c-Jun NH2-terminal kinase inhibitor anthra[1,9-cd]-pyrazol-6-(2H)-one (SP600125). Endothelin-1 significantly upregulated phosphorylation of ERK1/2 and p38 but blocking Ca(2+) influx pathways did not inhibit either upregulation. These findings demonstrate that endothelin-1-induced IL-6 synthesis in airway smooth muscle cells occurs via two parallel but independent events that include Ca(2+) influx and activation of ERK1/2 and p38.

Licochalcone A is a potent inhibitor of TEL-Jak2-mediated transformation through the specific inhibition of Stat3 activation.

Aberrant activation of Jak/Stat signaling causes a number of hematopoietic disorders and oncogenesis, and therefore the effective inhibitors of the Jak/Stat signaling pathway may be therapeutically useful. TEL-Jak2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. Expression of TEL-Jak2 protects Ba/F3 cells from IL-3 withdrawal-induced apoptotic cell death and leads to IL-3-independent growth. However, its mechanisms remain to be only partially understood. Here, we first found that Licochalcone A, one of the flavonoids isolated from the root of Glycyrrhiza inflate, inhibited TEL-Jak2-mediated cell proliferation and survival in the absence of IL-3. Licochalcone A failed to inhibit the activity of TEL-Jak2, however, this induced apoptosis of TEL-Jak2-transformed cells with a much lower concentration in the absence of IL-3 than in the presence of IL-3. Interestingly, Licochalcone A significantly inhibited the phosphorylation and nuclear localization of Stat3, which is essential for TEL-Jak2-induced cell transformation. These data suggest that Licochalcone A is a specific inhibitor for Stat3 and would be employed for the treatment of various diseases caused by disorders of the Jak/Stat pathway.

A novel Ca2+ influx pathway activated by mechanical stretch in human airway smooth muscle cells.

In response to mechanical stretch, airway smooth muscle exhibits various cellular functions such as contraction, proliferation, and cytoskeletal remodeling, all of which are implicated in the pathophysiology of asthma. We tested the hypothesis that mechanical stretch of airway smooth muscle cells increases intracellular Ca(2+) concentration ([Ca(2+)](i)) by activating stretch-activated (SA) nonselective cation channels. A single uniaxial stretch (3 s) was given to human bronchial smooth muscle cells cultured on an elastic silicone membrane. After the mechanical stretch, a transient increase in [Ca(2+)](i) was observed. The [Ca(2+)](i) increase was significantly dependent on stretch amplitude. The augmented [Ca(2+)](i) due to stretch was completely abolished by removal of extracellular Ca(2+) and was markedly attenuated by an application of Gd(3+), an inhibitor of SA channels, or ruthenium red, a transient receptor potential vanilloid (TRPV) inhibitor. In contrast, the stretch-induced rises of [Ca(2+)](i) were not altered by other Ca(2+) channel inhibitors such as nifedipine, BTP-2, and SKF-96365. Moreover, the [Ca(2+)](i) increases were not affected by indomethacin, a cyclooxygenase inhibitor, U-73122, a phospholipase C inhibitor, or xestospongin C, an inhibitor of the inositol-trisphosphate receptor. These findings demonstrate that a novel Ca(2+) influx pathway activated by mechanical stretch, possibly through the Ca(2+)-permeable SA channel activated directly by stretch rather than by indirect mechanisms via intracellular messenger production, is involved in human airway smooth muscle cells. A molecular candidate for the putative SA channel may be one of the members of the TRPV channel family. Thus, abnormal Ca(2+) homeostasis in response to excessive mechanical strain would contribute to the pathogenesis of asthma.

Inhibition by licochalcone A, a novel flavonoid isolated from liquorice root, of IL-1beta-induced PGE2 production in human skin fibroblasts.

Licochalcone A, a novel flavonoid isolated from the root of Glycyrrhiza inflata, has been reported to exhibit anti-inflammatory activity in animal models. In this study, we examined the effect of licochalcone A on the production of chemical mediators such as prostaglandin (PG)E2 and cytokines by interleukin (IL)-1beta in human skin fibroblasts. Licochalcone A (IC50 15.0 nM) inhibited PGE2 production, but not IL-6 and IL-8 production, in response to IL-1beta. NS-398 (IC50 1.6 nM), a COX-2 selective inhibitor, also suppressed the PGE2 production. Furthermore, licochalcone A and NS-398 suppressed PGF(2alpha) production by IL-1beta. However, licochalcone A (1 microM) had no effect on increased levels of cyclooxygenase (COX)-2 mRNA and protein in cells. Dexamethasone (100 nM) not only inhibited PGE2, PGF(2alpha), IL-6 and IL-8 production but also strongly suppressed the expression of COX-2 mRNA and protein. Licochalcone A had no effect on COX-1-dependent PGE2 production, whereas indometacin (100 nM), a dual inhibitor of COX-1 and COX-2, was very effective. These results suggest that licochalcone A induces an anti-inflammatory effect through the inhibition of COX-2-dependent PGE2 production. Furthermore, it appears that the inhibitory effect of licochalcone A on PGE2 production in response to IL-1beta is quite different from that of the steroid.

Parasite mitochondria as a target of chemotherapy: inhibitory effect of licochalcone A on the Plasmodium falciparum respiratory chain.

Parasites have exploited unique energy metabolic pathways as adaptations to the natural host habitat. In fact, the respiratory systems of parasites typically show greater diversity in electron transfer pathways than do those of host animals. These unique aspects of parasite mitochondria and related enzymes may represent promising targets for chemotherapy. Natural products have been recognized as a source of the candidates of the specific inhibitors for such parasite respiratory chains. Chalcones was recently evaluated for its antimalarial activity in vitro and in vivo. However, its target is still unclear in malaria parasites. In this study, we investigated that licochalcone A inhibited the bc1 complex (ubiquinol-cytochrome c reductase) as well as complex II (succinate ubiquinone reductase, SQR) of Plasmodium falciparum mitochondria. In particular, licochalcone A inhibits bc1 complex activity at very low concentrations. Because the property of the P. falciparum bc1 complex is different from that of the mammalian host, chalcones would be a promising candidate for a new antimalarial drug.