Role of mitogen-activated protein kinases in influenza virus induction of prostaglandin E2 from arachidonic acid in bronchial epithelial cells

BACKGROUND: Influenza virus (IV) infection causes airway inflammation; however, it has not been determined whether IV infection could catabolize arachidonic acid cascade in airway epithelial cells. In addition, the responsible intracellular signalling molecules that catabolize arachidonic acid cascade have not been determined. OBJECTIVE: In the present study, to clarify these issues, we examined the cyclooxygenase (COX) expression, cytosolic phospholipase A2 (cPLA2) phosphorylation and prostaglandin E2 (PGE2) release in human bronchial epithelial cells (BEC) upon IV infection, and the role of mitogen-activated protein kinase (MAPK) including extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun-NH2-terminal kinase (JNK) in catabolizing arachidonic acid cascade in BEC. METHODS: COX-2 expression, phosphorylation of cPLA2 and phosphorylation of ERK, JNK and p38 MAPK were determined by Western blot. The concentrations of PGE2 were determined by ELISA. PD 98059 as a specific inhibitor of MAPK kinase-1 (MEK-1), an up-stream kinase of ERK, SB 203580 as a specific inhibitor of p38 MAPK and CEP-11004 as a specific inhibitor of JNK cascade were used to investigate the role of ERK, p38 MAPK and JNK in catabolizing arachidonic acid cascade in BEC. RESULTS: The results showed that (1) IV infection increases COX-2 expression, cPLA2 phosphorylation and PGE2 release, (2) ERK, p38 MAPK and JNK were phosphorylated, (3) CEP-11004 and PD 98059 predominantly attenuated COX-2 expression and cPLA2 phosphorylation, respectively, (4) SB 203580 did not remarkably affect COX-2 expression and cPLA2 phosphorylation, and (5) each inhibitor dose-dependently attenuated PGE2 release by various extents. CONCLUSION: These results indicate that IV infection activates three distinct MAPKs, ERK, p38 MAPK and JNK, to participate to various extents in the induction of PGE2 synthesis from arachidonic acid in BEC.     

Melanocytic schwannoma in the spinal canal.

A case of melanocytic schwannoma, a rare form of schwannian neoplasm, in the thoracolumbar spinal canal of a 52-year-old man is presented. Histopathologically, the tumor was composed of irregularly interlacing spindle-shaped cells showing cystic degeneration, with occasional pigmented tumor cells. The tumor cells showed a low degree of nuclear pleomorphism without any mitotic figures. These histological features were considered to be consistent with a benign schwannian tumor showing pigmentation. Most of the pigments were considered to be melanin histochemically and immunohistochemically. According to the pathological features of the present tumor and those described previously in the literature, the neoplastic Schwann cells were assumed to have melanogenetic capacity, and the concept of the common neural crest origin of Schwann cells and melanocytes appeared to be demonstrated in the present tumor.     

Malignant lymphoma of the parotid gland with monoclonal cytoplasmic immunoglobulin

A 56-year-old Japanese man with a malignant lymphoma of the parotid gland was reported. The tumor was located in the superficial lobe of the parotid gland, and somewhat invaded the surrounding soft tissues, but the regional lymph nodes were not involved. Histologically, the tumor was composed of round cells with plasmacytoid configurations and small lymphocytes. The plasmacytoid cells showed eccentric nuclei with fairly marked irregularities and perinuclearr halos. In a large number of tumor cells, a monoclonal cytoplasmic immunoglobulin (CIg), IgG-Kappa type, was demonstrated by the PAP method. Ultrastructurally, some of the tumor cells showed well-developed endoplasmic reticulum. From these findings, this tumor was diagnosed as a diffuse B-cell lymphoma, mainly composed of lymphoplasmacytoid cells. And this tumor may bear a similar nature to an extramedullary plasmacytoma of the classical terminology. Malignant lymphoma of the parotid gland is rare but a case with the demonstration of monoclonal CIg is considered very rare.     

Analysis of recombinant human tumour necrosis factor-alpha-induced CD4 expression on human eosinophils.

We examined the hypothesis that one of the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha), could induce expression of the adhesion molecule CD4 on human eosinophils. We further examined the effector function of CD4 and the mechanisms regulating CD4 expression. Human eosinophils were cultured with various concentrations of recombinant human TNF-alpha (rhTNF-alpha) with or without various drugs for 24 hr. After culture, eosinophils were stained for CD4 using a monoclonal antibody and then analysed by flow cytometry. Eosinophil-derived neurotoxin (EDN) release as eosinophil degranulation was examined by cross-linking of CD4 on eosinophils. The rhTNF-alpha induced CD4 expression on human eosinophils in a dose- and time-dependent fashion; rhTNF-alpha-induced CD4 expression was significantly inhibited by 10(-6) M cycloheximide, 10(-8) M dexamethasone, or 10(-6) M herbimycin A. Recombinant human interferon-gamma inhibited rhTNF-alpha-induced CD4 expression in a dose-dependent manner. However, cross-linking of CD4 on eosinophils did not evoke EDN release, suggesting that newly expressed CD4 molecules on human eosinophils do not play any role in triggering degranulation. Our data indicate that TNF-alpha-induced CD4 expression on human eosinophils is dependent on protein synthesis and may be dependent on tyrosine kinase activity.     

Functional transition: Inconsistently parallel to the increase in future liver remnant volume after preoperative portal vein embolization

BACKGROUNDPreoperative portal vein embolization (PVE) is a widely used strategy to enable major hepatectomy in patients with insufficient liver remnant. PVE induces hypertrophy of the future liver remnant (FLR) and a shift of the functional reserve to the FLR. However, whether the increase of the FLR volume (FLRV) corresponds to the functional transition after PVE remains unclear.AIMTo investigate the sequential relationship between the increase in FLRV and functional transition after preoperative PVE using 3-dimensional (3D) computed tomography (CT) and ^99mTc-galactosyl-human serum albumin (^99mTc-GSA) single-photon emission computed tomography (SPECT) fusion images. METHODSThirty-three patients who underwent major hepatectomy following PVE at the Department of Gastroenterological Surgery I, Hokkaido University Hospital between October 2013 and March 2018 were enrolled. Three-phase dynamic multidetector CT and ^99mTc-GSA SPECT scintigraphy were performed at pre-PVE, and at 1 and 2 wk after PVE; 3D ^99mTc-GSA SPECT CT-fused images were constructed from the Digital Imaging and Communications in Medicine data using 3D image analysis system. Functional FLRV (FFLRV) was defined as the total liver volume × (FLR volume counts/total liver volume counts) on the 3D ^99mTc-GSA SPECT CT-fused images. The calculated FFLRV was compared with FLRV.RESULTSFFLRV increased by a significantly larger extent than FLRV at 1 and 2 wk after PVE (P < 0.01). The increase in FFLRV and FLRV was 55.1% ± 41.6% and 26.7% ± 17.8% (P < 0.001), respectively, at 1 wk after PVE, and 64.2% ± 33.3% and 36.8% ± 18.9% (P < 0.001), respectively, at 2 wk after PVE. In 3 of the 33 patients, FFLRV levels decreased below FLRV at 2 wk. One of the three patients showed rapidly progressive fatty changes in FLR. The biopsy at 4 wk after PVE showed macro- and micro-vesicular steatosis of more than 40%, which improved to 10%. Radical resection was performed at 13 wk after PVE. The patient recovered uneventfully without any symptoms of pos-toperative liver failure.CONCLUSIONThe functional transition lagged behind the increase in FLRV after PVE in some cases. Evaluating both volume and function is needed to determine the optimal timing of hepatectomy after PVE.     

Changes of hepatic vitronectin levels in patients with chronic hepatitis C treated with interferon alpha

Hepatic vitronectin expression was assessed in 27 patients with chronic hepatitis C before and after interferon alpha treatment and in 7 control patients. Before interferon therapy, vitronectin was localized in the hepatocytes and in the portal and central venous regions. A high correlation was found for the vitronectin expression level with the histological grading and staging scores in the hepatocytes as well as in the portal region. After interferon therapy, the hepatic vitronectin was significantly decreased in the sustained and transient responders, but it was not as markedly decreased in the nonresponders and the non-treated group. A good correlation was found for the vitronectin expression with the staging scores but not with the grading scores in the portal region. These findings suggest that hepatic vitronectin is influenced by interferon therapy and that it may play an important role as a hepatic adhesion molecule through the improvement of inflammation, necrosis and fibrogenesis.     

Nasal continuous positive airway pressure changes blood pressure "non-dippers" to "dippers" in patients with obstructive sleep apnea

To evaluate the circadian pattern of blood pressure (BP) and the effects of nasal continuous positive airway pressure (CPAP) on patients with obstructive sleep apnea (OSA), we examined 24-hour BP in 38 male OSA patients with and without nasal CPAP. We measured the BP at 30-min intervals during daytime (800 to 2200) and nighttime (2200 to 800) hours. A "dipper" was defined as a patient who showed an average reduction of at least 10 mm Hg systolic and 5 mm Hg diastolic between daytime and nighttime values. The subjects were predominantly "non-dipper" (22 of 38 patients, 58%). Daytime hypertension (>160/95 mm Hg) was present in 11 of 38 patients (4 "dippers" and 7 "non-dippers"). After nasal CPAP treatment for 3 days, the average BP decreased significantly during the day and night in all subjects (p<0.05). Fifteen of 22 subjects who were "non-dippers" before treatment reversed to become "dippers." And daytime hypertension was detected in only 5 of these patients during nasal CPAP treatment (4 "dippers" and 1 "non-dipper"). These results showed that the "non-dipper" status was common in patients with OSA, and that nasal CPAP restored the normal circadian "dipper" pattern. We suggest that nasal CPAP may contribute to an improved prognosis in patients with OSA because of a reduction in cardiovascular risk factors in "non-dipper" with severe OSA.     

Urinary incontinence after non-nerve-sparing radical prostatectomy with neoadjuvant androgen deprivation

OBJECTIVES: The impact of non-nerve-sparing retropubic radical prostatectomy (RRP) for prostate cancer combined with neoadjuvant androgen deprivation on urinary control is not well documented. We examined the incidence and severity of urinary incontinence after such therapy and determined the etiologic factors causing this complication. METHODS: We examined the postoperative continence status of 104 consecutive patients admitted to the National Cancer Center Hospital who underwent RRP with wide resection of the pelvic nerves after neoadjuvant androgen deprivation. Incontinence was scored according to the number of pads used daily by the patient for urinary leakage. The severity of incontinence was analyzed according to patient age, weight of resected specimen, status of cancer stage, duration of neoadjuvant androgen blockade therapy, preoperative length of membranous urethra, and duration of urethral catheterization after surgery. We also measured the configuration and diameter of the reconstructed bladder neck by retrograde cystourethrography. RESULTS: In 104 patients examined, the percentage of patients who became dry postoperatively was 22% at 1 month, 47% at 3 months, 69% at 6 months, and 78% at 1 year. Of 81 patients who became dry postoperatively at any interval, 22 (27%) became continent within 1 month of RRP, 49 (61 %) were continent within 3 months, 71 (88%) became continent by 6 months, and another 10 (12%) became continent between 6 and 12 months postoperatively. Of 48 patients who were followed up for more than 1 year and for whom continence status at 1 month after surgery was available, all patients who used 1 to 2 pads per day (13 of 13) at 1 month after surgery regained continence by 1 year after surgery. However, only 62% of patients (16 of 26) who required more than 3 pads per day at 1 month after surgery became dry by 1 year after surgery. Only age (older than 70 years) and large prostate size (weight of surgical specimen more than 40 g) temporarily influenced the recovery of urinary continence after surgery. Dilation of the bladder neck evaluated by retrograde cystourethrography was prominent in severely incontinent patients in the immediate postoperative period. CONCLUSIONS: Our experience in patients who undergo non-nerve-sparing RRP after neoadjuvant androgen deprivation closely matches published surveys of patient-reported complications. Postoperative incontinence is not a major contraindication for non-nerve-sparing RRP after neoadjuvant endocrine therapy. Dilation of the bladder neck affected the recovery from incontinence, highlighting the importance of adequate reconstruction of the bladder neck.     

Measurement of local blood flow of the intestine by hydrogen clearance method; Experimental study

Local blood flow of the bowel wall was measured by hydrogen clearance method both in the muscular and submucosal layers in the mongrel dog, separately and concurrently. A platinum wire electrode with a bare tip of 0.5 mm in length and 0.2 mm in diameter was inserted into each layer. About 10 per cent hydrogen gas was inhalated directly through the side hole attached to the endotracheal tube for 1–2 minutes and the obtained clearance curves were plotted on the semi-logarithmic scale, which was almost monoexponential. The results obtained were as follows:

1. Mean basal perfusion rate of the muscular layer of the intestine was 0.81–0.92 ml/min/gm, whereas that of the submucosal layer was 1.29–1.31 ml/min/gm, respectively. There was little difference of perfusion rates between the small and the large intestine. The results showed good correlationship with those reported by other authors.
2. The effect of vasoactive substances such as vasoconstrictor and vasodilator on the local blood flow in the bowel wall was confirmed.
3. This method is repeatedly applicable for measurement and also renders the information on the distribution of blood flow in the splanchnic area.