Differential contribution of three mitogen-activated protein kinases to PDGF-BB-induced mesangial cell proliferation and gene expression

This study examined the role of mitogen-activated protein (MAP) kinase in PDGF-BB-induced proliferation and gene expression of human mesangial cells (MC). PDGF-BB stimulation of MC increased mRNA for transforming growth factor-beta1 (TGF-beta1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) and increased the cell numbers. To inhibit activation of extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38, MC were infected with recombinant adenovirus containing dominant-negative mutants of ERK, JNK, and p38 (Ad-DN-ERK, Ad-DN-JNK, Ad-DN-p38, respectively), respectively. Infection of MC with Ad-DN-ERK or Ad-DN-JNK inhibited PDGF-BB-induced increase in [(3)H]thymidine incorporation and cell numbers, whereas Ad-DN-p38 did not. Ad-DN-ERK inhibited MCP-1 and PAI-1 mRNA expression in MC, but not TGF-beta1. Ad-DN-JNK and Ad-DN-p38 inhibited TGF-beta1 and MCP-1 mRNA expression, but not PAI-1. The inhibition of activator protein-1 (AP-1) in MC, by adenovirus containing dominant-negative mutant of c-Jun (Ad-DN-c-Jun), inhibited PDGF-BB-induced cell proliferation and TGF-beta1, MCP-1, and PAI-1 expressions. Furthermore, Ad-DN-JNK or Ad-DN-p38, but not Ad-DN-ERK, attenuated PDGF-BB-induced AP-1 activation in MC, indicating the involvement of JNK and p38 in AP-1 activation. Our results indicated that ERK and JNK, but not p38, participated in PDGF-BB-induced MC proliferation. PDGF-BB-induced expression of TGF-beta1 was mediated by JNK and p38, MCP-1 expression was through ERK, JNK, and p38, whereas PAI-1 expression was due to only ERK. AP-1 activation, which was partially due to JNK and p38 activations, was involved in MC proliferation and these three gene expressions. Thus, three MAP kinases seem to contribute to progression of glomerular disease via different molecular mechanisms.     

Surgical outcome of radial osteotomy for Kienböck's disease-minimum 10 years of follow-up

PURPOSE: Long-term results of radial osteotomy for Kienb?ck's disease seldom are seen in the literature. The purpose of this study was to report the minimum 10-year results and to compare them with the 5-year results to determine whether the favorable intermediate-term results were maintained. METHODS: Twenty-five patients who underwent radial osteotomy were followed-up for a mean period of 14.5 years. They were examined for pain, grip strength, and wrist range of motion (ROM). Through a review of clinical records, 5-year postoperative results were collected. The carpal height ratio and St?hl's index were measured and the x-rays were inspected for osteoarthritic changes. We devised an original lunate grade to evaluate radiologic improvement of the ischemic lunate. Overall results were evaluated using Cooney's wrist function score and Nakamura's scoring system for Kienb?ck's disease. The long-term results were compared with both the preoperative status and the 5-year results. RESULTS: Pain, ROM, and grip strength were improved significantly after surgery, and the results were maintained for a long period. Carpal height ratio and St?hl's index did not show significant improvements but ischemic lunate showed certain radiologic improvements with time by the lunate grade system. Osteoarthritic changes were observed in 54% of patients at 5 years and in 73% of patients at the final follow-up evaluation, but the arthrosis generally was mild and did not affect the clinical results. Cooney's wrist function score was excellent or good in 96% of the patients, and the results with Nakamura's scoring system for Kienb?ck's disease were excellent or good in 68% of the patients at the final follow-up evaluation. The percentages were the same 5 years after surgery. CONCLUSIONS: Radial osteotomy for Kienb?ck's disease is a reasonable treatment option and clinical improvement lasts for a long period of time. Although radiologic improvement was not drastic, the inner structure such as sclerotic change or bone cysts of the lunate improved with time, indicating healing of the ischemic lunate. Severe osteoarthritic change or proximal migration of the capitate can be avoided.     

Intracaval endovascular ultrasonography for large adrenal and retroperitoneal tumors

BACKGROUND: An accurate diagnosis of inferior vena cava (IVC) invasion is important in deciding the surgical strategy for a large adrenal tumor. We investigated the diagnostic value of intracaval endovascular ultrasonography (ICEUS) for invasion of the IVC by a large adrenal tumor. METHODS: Nine of 163 patients with adrenal and retroperitoneal tumors underwent ICEUS between 1993 and 2002. Intravascular ultrasonography was performed through the right femoral vein with the use of an 8Fr, 20-MHz transducer. The diagnostic criterion for detecting IVC invasion with ICEUS was identification of destruction of a single echogenic layer of the IVC wall or identification of an intracaval tumor mass. The ICEUS finding was confirmed by pathologic examination. RESULTS: The mean diameter of the tumors in 9 patients undergoing ICEUS and resection was 12.6 cm (range, 8.6-16 cm). Pathologic diagnosis varied: adrenocortical carcinoma, 4; malignant pheochromocytoma, 1; leiomyosarcoma, 1; metastatic lung cancer, 1; paraganglioma, 1; and neurilemmoma, 1. Vascular invasion was identified in 2 patients by ICEUS and confirmed by examination of resected specimens. The sensitivity, specificity, and positive predictive values of ICEUS for the diagnosis of the IVC invasion were 100%, 100%, and 100%, respectively. However, these values for computed tomography were 100%, 14%, and 25%, respectively; and for cavography, 100%, 57%, and 40%, respectively. CONCLUSIONS: ICEUS provides confirmatory information regarding tumor invasion of the IVC. This modality also can assist in formulating an operative strategy for large adrenal or retroperitoneal tumors.     

Protective effect of carbon monoxide inhalation for cold-preserved small intestinal grafts

BACKGROUND: Heme oxygenase (HO)-1 system has been shown to provide protection against oxidative stress through the degradation of heme to biliverdin, free iron, and carbon monoxide (CO). This study investigated cytoprotective efficacy of CO at a low concentration on cold ischemia/reperfusion (I/R) injury of transplanted intestine. METHODS: Lewis rat recipients of syngenic orthotopic small intestinal transplantation with 6 hours UW cold preservation were either kept in room air (air-treated control) or exposed to CO (250 ppm) for 1 hour before and 24 hours after surgery. RESULTS: In air-treated grafts, mRNA levels for interleukin-6, intracellular adhesion molecule-1, cyclooxygenase-2, and inducible nitric oxide synthase promptly increased. Sequential histopathologic analysis of untreated grafts revealed initial rapid epithelial loss, subsequent recruitment of inflammatory infiltrates, and local hemorrhage in the lamina propria, which extended downward to the epithelial crypt and muscle layer with time. CO effectively blocked proinflammatory cascade during I/R injury, inhibited upregulation of inflammatory molecules and ameliorated intestinal tissue injuries. Beneficial effects of CO were associated with improved graft blood flow without inhibiting endogenous HO-1 activity. Recipient animal survival was significantly improved with CO to 100% versus 58% in air-treated controls. CONCLUSIONS: These results indicate a significant role for CO in protecting the intestine from cold I/R injury associating with small intestinal transplantation.     

Preservation of residual renal function and factors affecting its decline in patients on peritoneal dialysis

SUMMARY:     The decline of residual renal function (RRF) in peritoneal dialysis (PD) patients was analysed and assessed, and risk factors affecting its decline were identified. Residual glomerular filtration rate (GFR) was calculated from averaging the urea and creatinine clearance by 24-h urine collection, and peritoneal solute removal was evaluated by creatinine clearance calculated from 24-h effluent collection. Both GFR and peritoneal solute removal were chronologically examined in 34 PD patients from the time of initiation, and risk factors associated with rapid GFR decline were investigated. The RRF contributed to 43.1 ± 17.6% of total (peritoneal and renal) weekly creatinine clearance at 1 month after initiation of PD. Residual GFR, however, declined continuously with time (−0.19 ± 0.14 mL/min per month), and the reduction rate was high with a higher GFR, higher normalized dietary protein intake, higher urine volume and higher urine protein excretion at the initiation of PD. Other factors related to the rapid decline of GFR were: being older than 60 years of age, automated peritoneal dialysis (APD) rather than continuous ambulatory peritoneal dialysis, mean blood pressure higher than 110 mmHg, and serum human atrial natriuretic peptide level higher being than 60 pg/dL. These data suggest that while RRF plays an important role in the removal of uraemic solute in PD patients, they show a significant decrease over 2 years. The factors related to the rapid decline of GFR corresponded to older age, modality of PD (APD), higher GFR and higher amount of urine protein at initiation, higher dietary protein intake, and inadequate control of hypertension and body fluid volume.     

Cystic Lymphangioma of the Gallbladder: Report of a Case

Abdominal lymphangioma is usually diagnosed within the first 2 years of life and is extremely rare in adults. The most common location of abdominal lymphangioma is the mesentery, but there are sporadic reports of its development in the gallbladder. A 66-year-old woman was found to have a cystic lesion near the gallbladder. Preoperative studies, including endoscopic ultrasonography, computed tomography, and magnetic resonance imaging, showed a tumor with multilocular cystic structure, originating in the gallbladder fossa. The patient underwent exploratory laparotomy, and the mass was resected en bloc with the gallbladder, as there was no evidence of malignancy on intraoperative ultrasonography. Macroscopically, the tumor was a multilocular cystic mass, 6 × 3 × 2 cm in size, with a rough, sponge-like appearance. Histologically, the cystic tumor was diagnosed as a lymphangioma, originating in the gallbladder. To our knowledge, only three other cases of a cystic lymphangioma originating in the gallbladder have been reported in the medical literature of the world.     

Thyroid carcinoma with extensive tumor thrombus in the atrium

To our knowledge, only a few cases of thyroid carcinoma with an extensive tumor thrombus in the atrium have been reported in literature. We describe a unique case of papillary carcinoma of the thyroid with extensive tumor thrombus in the atrium. A 74-year-old man consulted our hospital because of thyroid carcinoma with an extensive tumor thrombus in the atrium. Computed tomography (CT) revealed a 2-cm tumor with extensive continuous tumor thrombus in the left jugular vein, innominate vein, superior vena cava, and atrium. The tumor was resected to reduce the risk of sudden death from tumor embolism into the pulmonary arteries. Histologically, the diagnosis was papillary carcinoma of the thyroid. Thyroid carcinoma, especially papillary carcinoma, rarely develops a macroscopic tumor thrombus. Patients with an extensive tumor thrombus generally have poor prognoses and high mortality. This patient has been followed for 7 months after successful operation without recurrence.     

Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice

Connective tissue growth factor (CTGF) is a potent inducer of extracellular matrix accumulation. In diabetic nephropathy, CTGF expression is markedly upregulated both in podocytes and mesangial cells, and this may play an important role in its pathogenesis. We established podocyte-specific CTGF-transgenic mice, which were indistinguishable at baseline from their wild-type littermates. Twelve weeks after streptozotocin-induced diabetes, these transgenic mice showed a more severe proteinuria, mesangial expansion, and a decrease in matrix metalloproteinase-2 activity compared to diabetic wild-type mice. Furthermore, diabetic transgenic mice exhibited less podocin expression and a decreased number of diffusely vacuolated podocytes compared to diabetic wild-type mice. Importantly, induction of diabetes in CTGF-transgenic mice resulted in a further elevation of endogenous CTGF mRNA expression and protein in the glomerular mesangium. Our findings suggest that overexpression of CTGF in podocytes is sufficient to exacerbate proteinuria and mesangial expansion through a functional impairment and loss of podocytes.     

Intracisternal infusion of magnesium sulfate solution improved reduced cerebral blood flow induced by experimental subarachnoid hemorrhage in the rat

Magnesium has neuroprotective and antivasospastic properties in the presence of subarachnoid hemorrhage (SAH). The present study investigated the effect of intracisternal administration of magnesium on cerebral vasospasm in the experimental SAH rat model. The rat double-SAH model (0.2 mL autologous blood injected twice into the cisterna magna) was used. Normal saline (SAH group, N = 8) or 10 mmol/L magnesium sulfate in normal saline (SAH + MG group, N = 8) was infused into the cisterna magna at 1.5 μL/min for 30 min on day 5. Control rats without SAH also received intracisternal infusion of normal saline (control group, N = 6). Local cerebral blood flow (CBF) at 24 locations and the weighted average were quantitatively measured by the autoradiographic technique using [¹⁴C]iodoantipyrine during infusion. The weighted average CBF was significantly reduced (P < 0.01, Student’s t-test) in the SAH group (0.78 ± 0.16 mL g⁻¹ min⁻¹) compared to the control group (1.0 ± 0.15 mL g⁻¹ min⁻¹) and was significantly improved (P < 0.01, Student’s t-test) in the SAH + MG group (0.98 ± 0.18 mL g⁻¹ min⁻¹). Local CBF was significantly reduced (P < 0.05, unpaired t test) in 16 locations in the SAH group and significantly improved (P < 0.05, unpaired t test) in 12 locations in the SAH + MG group. Intracisternal infusion of magnesium sulfate significantly improved reduced CBF induced by experimental SAH in the rat.     

The Number of Metastatic Lymph Nodes is a Significant Risk Factor for Bone Metastasis and Poor Outcome After Surgery for Linitis Plastica-type Gastric Carcinoma

BACKGROUND: Linitis plastica-type gastric carcinoma remains a disease with poor prognosis despite an aggressive surgical approach. Although a prominent pattern of disease failure is peritoneal carcinomatosis, some patients experience rapid disease progression without signs of the peritoneal disease. METHODS: Clinicopathologic data from 178 patients with linitis plastica-type gastric cancer operated on between 1991 and 2000 were analyzed. Survival stratified by curability of surgery, pN stage, and patterns of failure were evaluated by using the Kaplan-Meier method, and chi(2) test was used to evaluate correlation between the number of metastatic lymph nodes in terms of pN categories and the incidence of various patterns of metastasis and recurrence. Cox regression hazard model was used to identify independent prognostic factors. RESULTS: R0 resection was performed only among 82 patients (46% of those who underwent laparotomy). Node metastasis was frequent with only 22 patients classified as pN0. Peritoneal carcinomatosis was observed in 131 patients and was the commonest pattern of recurrence. Bone metastasis, found in 13 patients, was associated with poor outcome, and its incidence was significantly correlated with the number of metastatic nodes. pT4 status and pN3 status were identified as significant independent prognostic determinants. CONCLUSION: Treatment strategy for the linitis plastica should in general combine surgery with aggressive treatment directed toward peritoneal disease. However, patients with >16 metastatic nodes more often are associated with bone metastasis than those with modest nodal involvement and suffer from poor prognosis.