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Asthma is often exacerbated by airway infection, and some patients with severe asthma may be unresponsive to conventional corticosteroid treatment. Src family kinases (SFKs) were recently implicated in the inflammatory responses of mice induced by allergen and bacterial toxin lipopolysaccharide (LPS). Therefore, we examined the effects of dasatinib (DAS), a Src inhibitor, on airway inflammation in mice induced by ovalbumin (OVA) and LPS. Male A/J mice were sensitized to OVA Day -14 and -7, challenged with intranasal OVA on Day 0, 2, 4, 6 and 8, and on Day 10, mice were also challenged with OVA via inhalation. Mice were treated intranasally with DAS or fluticasone propionate (FP), a glucocorticoid, twice daily for 3 d starting 1 d after OVA inhalation. Moreover, some mice were also administrated LPS 2 h after DAS or FP treatment to model of asthma exacerbation. One day after the last intervention, lung tissue and bronchoalveolar lavage fluid (BALF) were collected. DAS attenuated the accumulation of inflammatory cells and cytokines/chemokines in BALF induced by both OVA and OVA+LPS, while FP did not reduce accumulations induced by OVA+LPS. Therefore, targeting SFKs may be a superior therapeutic approach for asthma exacerbation by infection.

Asthma and chronic obstructive pulmonary disease (COPD) are characterised by chronic inflammation in the lung that is associated with airway obstruction. Inhaled therapy with a combination of corticosteroid and a long-acting β 2 -agonist is an effective anti-inflammatory medicine for asthma, but in patients with severe asthma and COPD fails to completely control these symptoms with current therapies. The inflammatory process in these diseases, which involves activation of the coagulation and fibrinolytic system in the lung, offers the opportunity for alternative anti-inflammatory therapies. In this study, we investigated the effects of anti-coagulants on lipopolysaccharide (LPS)-induced airway inflammation in mice. A/J mice were exposed to LPS, a bacterial endotoxin, intranasally and accumulation of inflammatory cells, TNF-α, C-X-C motif chemokine (CXCL) 1, and osteopontin in bronchoalveolar lavage fluid (BALF) was monitored by flow cytometry and an enzyme-linked immunosorbent assay. LPS exposure induced airway neutrophilia and accumulation of TNF-α, CXCL1, and osteopontin in BALF. This LPS-induced airway inflammation was not relieved using a corticosteroid, fluticasone propionate (FP), or a direct inhibitor of Factor Xa, rivaroxaban. In contrast, a direct thrombin inhibitor, dabigatran, inhibited LPS-induced airway neutrophilia and decreased inflammatory cytokine production in a dose dependent manner. Furthermore, combination of dabigatran and FP elicited stronger inhibition of LPS-induced airway inflammation. Therefore, these results suggest that dabigatran could be an effective new therapy for severe respiratory diseases.

Corticosteroid insensitive airway inflammation is one of major barrier to effective managements of chronic airway diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. The role of nonreceptor tyrosine kinase Src is important in airway inflammation in mice models of atopic asthma and COPD. Thus, in this study, we determined the effects of Src inhibitor, dasatinib, on airway inflammation induced by repeated intranasal exposure to lipopolysaccharide (LPS). Male mice (A/J strain, 5 weeks old) were intranasally exposed to LPS twice daily for 3 d, and dasatinib was intranasally treated 2 h prior to each LPS exposure. A day after the last stimulation, lungs and bronchoalveolar lavage fluid (BALF) were collected. Dasatinib attenuated the accumulation of inflammatory cells in lungs, and the increase in the numbers of inflammatory cells and the accumulation of cytokines/chemokines in BALF in a dose dependent manner. Therefore, this study suggested that targeting the Src can provide a new therapeutic approach for corticosteroid insensitive pulmonary diseases.

Reduction of corticosteroid responsiveness is one of the important clinical problems in chronic obstructive pulmonary disease (COPD). In this study, we determined the effects of neutralization of tumor necrosis factor-α (TNF-α) on corticosteroid insensitivity in mice models of airway inflammation induced by poly(I:C) and tobacco smoke (TS) exposure. Mice (male A/J strain, 5 weeks old) were exposed to TS for 10 d, or TS for 11 d and poly(I:C) for 3 d. Anti-TNF-α antibody was intranasally treated once every other day 2 h before the TS exposure, and dexamethasone 21-phosphate (DEX) was treated 30 min before the TS or poly(I:C) exposure. On the next day of the last stimulation, mice were sacrificed. The combination treatment of DEX and TNF-α neutralization was significantly attenuated the increase of the numbers of inflammatory cells in BALF and the TNF-α mRNA expression levels induced by TS and poly(I:C) exposure, even though TNF-α neutralization alone had little effect. These data indicated that neutralization of TNF-α restores corticosteroid responsiveness. Therefore, our study suggests that targeting TNF-α signaling pathway provides a new therapeutic approach to corticosteroid refractory airway diseases.

We describe a patient with thrombosis of the pampiniform plexus cured using heparin. A 40-year-old man was referred to our hospital with pain in the left scrotum. A physical examination revealed a painful, 20-mm long, beaded mass in the upper left paratesticular region. Magnetic resonance imaging and ultrasonography revealed 10-mm long thrombosis in the left pampiniform plexus, so intravenous heparin was started. The patient recovered well and was discharged on oral anticoagulation therapy after five days of hospitalization. The patient was completely asymptomatic, and ultrasonographic findings of the left testicle were normal at six months after starting treatment. We found 19 patients with thrombosis of the pampiniform plexus including the present patient, in the English and Japanese literature to date. Here, we review these 19 patients and discuss their clinical features.

IgG4-related kidney disease (IgG4-RKD) is a comprehensive term for renal lesions associated with IgG4-related disease (IgG4-RD), which is a recently recognized clinical entity characterized by a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells with fibrosis affecting several organs. A 70-year-old woman was referred to our hospital for an abnormality at the left renal hilum detected by CT scan. Urinalysis was negative, urine cytology was rated as Class IIIa, and contrast-enhanced CT revealed left renal pelvic wall thickening without an irregular lumen and swelling of bilateral obturator lymph nodes. Ureterorenoscopy and biopsy were performed, and results showed no evidence of malignancy. Then, laparoscopic pelvic lymphadenectomy was performed. Plasma cells were the predominant infiltrating inflammatory cells; immunostaining showed marked infiltration of IgG4+ plasma cells with >10 IgG4+ plasma cells per high-power field, and the IgG4+/IgG+ cell ratio was over 40%. Serum IgG4 was extremely high. We made a final diagnosis of possible IgG4-related disease according to Comprehensive diagnostic Criteria for IgG4-related disease 2011. We report a long-term (40-month) follow-up case of IgG4-related kidney disease without therapy because there are no symptoms.

We describe renal mucinous tubular and spindle cell carcinoma (MTSCC) that metastasized to the lymph nodes seven years after radical nephrectomy. An 80-year-old man was admitted for treatment of a right renal tumor. A 6.5×6.0-cm tumor in the right kidney (cT1bN0M0) revealed by abdominal computed tomography was treated by laparoscopic radical nephrectomy. The pathological findings at that time suggested papillary renal cell carcinoma type 1. Imaging findings seven years later revealed enlarged pre-caval and right external iliac lymph nodes indicative of delayed metastasis, and these were treated by laparoscopic lymphadenectomy. The pathological findings and re-evaluation of the primary tumor suggested MTSCC. The patient remains free of metastasis at 24 months of follow-up. MTSCC has been a distinct entity in the World Health Organization classification of kidney tumors since 2004. Tumors consist of tubules and cords separated by pale mucinous material in some areas, whereas others have dense cellularity without significant mucin. They are usually of low malignant potential, and metastasis has rarely been reported. To our knowledge, this is the first report of MTSCC with retroperitoneal lymph node metastasis treated by lymphadenectomy.

In the treatment of hepatocellular carcinoma, atypical, off guideline multidisciplinary approaches are sometimes effective. A 70-year-old man was diagnosed with multiple hepatocellular carcinomas, multiple bone metastases, and a right adrenal metastasis. Sunitinib was started and the primary hepatic lesions and bone metastases disappeared. However, his adrenal metastasis worsened. Sorafenib, radiotherapy, and some investigational agents were administered, but the adrenal metastasis did not respond. There were no other new lesions except the adrenal lesion 4 years after the initial treatment, so we decided to perform a resection. In the left half lateral decubitus position, the adrenal mass was removed with right thoracolaparotomy. After the surgery, his tumor markers quickly returned to normal. Seven years after the initial treatment(2 years and 4 months after the last surgery), he is alive without any recurrence. Multidisciplinary treatment with chemotherapy, radiotherapy, and surgery may result in long term survival even for patients with advanced hepatocellular carcinoma with multiple extra-hepatic lesions.

The prostate gland is the sole organ that uses not targeted but systematic biopsy in the pathological diagnosis of prostate cancer due to its anatomical location and lack of adequate imaging modality to depict cancer nodules clearly. The U.S. Preventive Services Task Force published that the harms of PSA based screening outweigh the benefits, yielding a grade D recommendation against screening. In this current situation, what we need is to optimize a biopsy template that maximizes the detection rate of clinically significant cancer and provides adequate pathological information for a treatment plan while minimizing the detection of indolent cancers and has good cost-effectiveness and safety. In this manuscript, optimal systematic biopsy templates and possible role of MRI-guided biopsy are reviewed.

Circadian rhythm of blood pressure (BP) is closely linked with sodium balance. With positive sodium balance the nocturnal BP is elevated, resulting in non-dipper pattern. Nocturnal BP elevation plays an important role in the cardio-renal association to cause the cardiovascular events. It is vey important, therefore, how to lower nocturnal hypertension especially in CKD.

We reported the experience with a case of plasmacytoid variant of urothelial carcinoma of urinary bladder. A 75-year-old woman complained of gross hematuria. She was hospitalized to be diagnosed as the bladder tumor on abdominal CT. TUR-BT was performed and pathological finding was invasive urothelial carcinoma. But she refused radical cystectomy. 2 months later, she was hospitalized again with worsening hematuria. Simple cystectomy was performed. Histological examination revealed a plasmacytoid appearance of the infiltrating tumor cells. Immunohistochemical stains for lymphoid markers were negative. Those findings lead to the diagnosis of plasmacytoid variant of urothelial carcinoma. She died due to local recurrence for 1.5 months after simple cystectomy.

Background: It has been reported that oral administration of Lactobacillus acidophilus strain L-55 (L-55) suppressed nasal symptom and antigen-specific IgE induced by antigen challenge in mice. We investigated clinical effects of L-55-contained yogurt on symptoms and IgE production in the patients with Japanese cedar pollinosis., Method: The study was performed as a randomized double blind placebo-controlled trial. L-55-contained yogurt (L-55 yogurt) or placebo yogurt was started to administer to each subject from 4 weeks prior to the onset of Japanese cedar pollen release for total 13 weeks., Result: The mean value of symptom score and symptom medication score were lower in L-55 yogurt group compared with placebo yogurt group during 5th week to 9th week from the first week of Japanese cedar pollination. Especially, in medicated subjects, total symptom score and throat symptom score were significantly lower in L-55 yogurt group compared with placebo yogurt group at 5th and 4th week from the first week of Japanese cedar pollination, respectively. Moreover, in medicated subjects, change ratio of serum total IgE was significantly lower in L-55 yogurt group compared with placebo yogurt group at 1st week from the first week of Japanese cedar pollination., Conclusion: Intake of L-55 during Japanese cedar pollinating season may be effective in alleviating the allergic symptoms related to Japanese cedar pollinosis. From these finding, it was suggested that L-55 is a possible candidate as a complementary medicine for Japanese cedar pollinosis.

Recurrence of urothelial cancer in an ileal conduit after radical cystectomy is rare. A 79-year-old man suffered bladder cancer (UC cTisN0M0 G2＞3) and underwent total cystectomy with ileal conduit. He had recurrence of the right renal pelvis carcinoma 6 years after the total cystectomy, and was treated by right radical nephroureterectomy (pT3 G2＝3). The patient had another episode of recurrence in the ileal conduit 13 years after the initial operation. The entire ileal conduit (UC, G3, ew (-)) was resected and left cutaneous ureterostomy was performed. This case suggests that long-term follow-up is necessary after radical cystectomy and ileal conduit for urinary diversion.

Background: Inhaled corticosteroid (ICS) will be effective if used properly. Inadequate intake may result in insufficiency, such as for elderly asthmatics, in particular, for use of dry powder inhalers., Methods: 312 asthmatics treated with ICS for at least 6 months in the 6 facilities belonging to the Chugoku Shikoku Adult Asthma Research Forum were subject to investigation of the peak inspiratory flow (PIF) measured using In-check® and related factors., Results: Nine (2.8%) patients were considered to have insufficient intake. By multivariate analysis, PIF (L/min) prediction formula was as follows: 79.0+0.19* peak expiratory flow (PEF: L/min)+22.9* FVC (L)-0.68* onset age (years)+34.7* gender (male, 1; female, 0)+16.1* V50/V25, [r^2=0.677, p<0.0001]. Using cluster analysis with Euclidean distance and Ward's method, the PIF without an adaptor was included in the same category as height and PEF, and the PIF with an adaptor was included in the same category as %FVC and %FEV1.0., Conclusion: The cases with insufficient PIF are few but present. Adequate device selection and inhalation guidance may be important. The meaning of PIF differs depending on whether or not an adaptor is present. Further investigation of intake is considered necessary.

When RAS inhibitors are prescribed as the first-line agent in hypertension, the combination of diuretics on them exerts several preferable effects in both blood pressure lowering and organ protection. As far as low-dose of diuretics, the unfavorable side effects such as hypokalemia and insulin resistance can be minimized by RAS inhibitors. Therefore, unless the compelling indication for Ca channel blockers exists, diuretics should be added on RAS inhibitors.

A 50-year-old man visited our hospital with a complaint of painful masses in bilateral scrotums for 2 months. Ultra sonography shows isoechoic mass in both scrotum. Antibiotic was treated for 2 weeks but had no effects on scrotal swelling and testicular neoplasm cannot ruled out, so we performed bilateral high orchiectomy. Pathological examination shows necrotizing vasculaitis surrounded by glanulomas and pathologically diagnosed as Polyarteritis Nodosa in bilateral epididymis. After orchiectomy, blood examination of immunity was revealed no specific findings, that made us diagnosed as isolated PN. 2 years after operation, he had no reccurence.

Ca channel blockers have been widely prescribed as an antihypertensive agent in Japan, because the blood pressure (BP) lowering effect of it is strong among Japanese patients whose amount of salt intake is high and patients with chronic kidney disease (CKD) whose sodium sensitivity of BP is enhanced. In addition, it can maintain the perfusion pressure into important organs including kidneys despite lowered systemic BP, and can be used efficiently in combinations with many types of antihypertensive agents. On the other hand, most of Ca channel blockers dilate mainly preglomerular afferent arterioles, resulting in elevated glomerular capillary pressure. Therefore, renal protection by Ca channel blockers remains in debate. We will discuss the renal protective action of new Ca channel blockers, which can dilate postglomerular efferent arterioles.

Among hypertensive cardiovascular complications only end-stage renal failure (ESRD) is progressively increasing, while the increases in the incidence of stroke and coronary heart disease have been suppressed. On the other hand, it is well established that CKD, especially due to diabetic nephropathy and IgA nephropathy, can be arrested into complete remission if treated in the early stages. Therefore, early detection program is highly and urgently required. To achieve this goal, we must consider what we can do now in nation-wide scale including patients, doctors and governments. There are remarkable regional differences in both the incidence of ESRD and the increasing rate within Japan. Japanese Society of Dialysis Therapy has the unique system to register the patients who reach ESRD, resulting in chronic dialysis therapy. Therefore, if we can build the patient identification system compatible to the above, then we immediately know who has reached ESRD. In this way, we can analyze the backgrounds of the ESRD patients to find out the risk factors of CKD in addition to the regional differences. I anticipate that the incidence of ESRD will be reduced in near future in Japan as seen in diabetic nephropathy in Denmark and USA. We must act now to accomplish this important issue: integrated care of CKD.

Bilateral nephron-sparing surgery was performed on a 56-year-old man with von Hippel-Lindau disease as initial therapy for renal cell carcinoma (RCC). Two years after the surgery, an abdominal computerized tomography (CT) scan revealed local recurrence of RCC. The patient was admitted to our hospital after another CT scan three years later that indicated aggravation of the cancer. On physical examination, he complained of swelling of the scrotum. The patient was diagnosed with an intra-scrotal malignant tumor and local recurrence of RCC. We performed high orchiectomy and nephrectomy. The testicular tumor was diagnosed as testicular metastasis of RCC on pathological examination.

A 54-year-old man with general fatigue and lumbago was admitted for further examination of hypercalcemia and leukocytosis. CT showed a huge renal tumor and extension of the tumor thrombus to the inferior vena cava (IVC). Moreover, the serum granulocyte colony-stimulating factor (G-CSF) and the C-terminal of parathyroid hormone-related protein (PTHrP) were elevated. Under the diagnosis of advanced renal tumor, we performed nephro-ureterectomy and throbectomy. Pathological examination revealed squamous cell carcinoma of the renal pelvis. To our knowledge, this is the first case in Japan that of the simultaneous production of G-CSF and PTHrP in squamous cell carcinoma of the renal pelvis accompanied with IVC thrombus.

Objective: To investigate in vitro antituberculous activity of ofloxacin (OFLX) and levofloxacin (LVFX) against multidrug-resistant tuberculosis and to study the clinical outcomes., Subjects and Methods: In vitro antituberculous activity of OFLX and LVFX against multidrug-resistant strains of Mycobacterium tuberculosis isolated from 46 patients with pulmonary tuberculosis and a retropective clinical analysis of 45 patients were investigated., Results: In susceptibility testing, resistance rates to OFLX or LVFX were higher in intractable cases (7/20: 35%) and in cases with prior chemotherapy using new quinolones (5/12: 42 %). Sputum culture conversion was observed in 34 patients (76%), however 9 among them later reverted to positive culture. In a single variate proportional hazards model, risk factors related to poor outcomes (treatment failure or relapse) were resistance to OFLX or LVFX, advanced disease on chest radiograph, and the number of susceptible drugs four or less. In a multiple variate proportional hazards model, a risk factor was resistance to OFLX or LVFX. Eighteen patients (40%) died, and among them, 10 died of tuberculosis. Survival time of treatment failure patients was significantly shorter than patients with sputum culture conversion., Conclusion: Resistance to OFLX or LVFX was considered to be a risk factor related to treatment failure and relapse in multidrug-resistant tuberculosis.

A 60-year-old man was admitted to our Department of Urology because of the lack of effectiveness of CHOP therapy for a retroperitoneal tumor. The tumor was finally diagnosed as poorly differentiated adenocarcinoma by CT-guided needle biopsy. He received combination chemotherapy with CDDP and 5-FU. After the end of this therapy, he noticed dyspnea and cough. He was referred to our department and a diagnosis of drug-induced pneumonitis was made because of diffuse shadows in bilateral lung fields, 67Ga citrate scintigraphy, his clinical course and histological examination of TBLB specimens. He received steroid therapy including methylprednisolone pulse therapy, after which his symptoms and abnormal chest findings improved. Although lymphocyte stimulation tests by CPA, DXR, VCR, CDDP and 5-FU were negative, it was suggested that CPA primed and 5-FU induced the pneumonitis in this patient judging from past literatures.

Pathogenesis of edema is in depth considered based on Starling's rule on capillary fluid dynamics. Edema can be divided into 4 types based on the mechanisms causing edema: increased capillary hydrostatic pressure, decreased plasma oncotic pressure, enhanced hydraulic permeability of capillary walls, and lymphatic obstruction. Each of the types can be further divided into generalized and local forms. Edema, defined as the expansion of interstitial fluid compartment, is initiated by imbalance of Starling forces across capillary walls between plasma and interstitium, but is maintained by enhanced sodium reabsorption from renal tubules.

We reported a case of pulmonary infection by Mycobacterium tuberculosis complicated by endobronchial spread. Chest roentogenography and CT for an 85-year-old male complaining of cough showed endobronchial spread in right upper lung field. His sputum culture for eight weeks showed 10-20 colonies of Mycobacterium tuberculosis. Transbronchial lung biopsy revealed granulomas with caseous necrosis. Findings in chest XP and CT after the therapy with INH, RFP and EB for six months showed much improvement.

We describe the case of a 69-year-old woman with advanced adenocarcinoma of the lung, in whom interstitial pneumonia was induced by gefitinib. The shadow was not clear on chest radiography, but diffuse ground-glass opacity was detected on high-resolution CT. Two treatments with pulse corticosteroids improved the lung injury temporarily. However, it became worse on reduction of the steroids. The improvement and deterioration of the pneumonia had been followed in detail by 8 examinations by high-resolution CT. The ground-glass opacity seen in the CT did not completely disappear or progress rapidly under steroid therapy. The patient died 46 days after the onset of the pneumonia. Autopsy disclosed marked cancerous invasion of the lung, and diffuse alveolar damage was also recognized in parts. The cause of death was considered to be respiratory failure due mainly to cancer progression and additionally to diffuse alveolar damage induced by gefitinib.