[Nutritional status predicts clinical outcomes in patients with gastric cancer undergoing radical gastrectomy].

Objective: To evaluate the effect of nutritional status on clinical and pathological data for stage Ⅰ-Ⅳ gastric cancer patients from the cancer survival investigation information. Methods: A database of 302 consecutive gastric cancer patients underwent radical gastrectomy was enrolled in this study. The clinical and pathological information of them were corrected and the relationship between the nutritional index and the patients survival time were analyzed by a Cox regression model. Results: The clinical data analysis of 302 patients with gastric cancer who received total gastric resection indicated that the nutritional status was related to the stage of tumor patients, suggesting that the later the stage was, the more necessary the nutritional therapy intervention was. Univariate analysis showed that Ⅲ+Ⅳ of TNM staging (HR=4.417, 95%CI:2.483-6.351; P =0.029), patient age of 65 and above (HR=2.217, 95%CI:0.522-3.912; P =0.038), lymph node metastasis positive (HR=2.517, 95%CI:0.516-4.518; P=0.036), poor tumor differentiation (HR=3.626, 95%CI:0.721-6.531; P =0.021) and low PNI (HR=2.612, 95%CI: 0.712-4.512; P =0.029) is an important risk factor for poor prognosis. In the multivariate analysis, Ⅲ+Ⅳ of TNM staging (HR=3.821, 95%CI:1.923-5.719; P =0.014), patient age of 65 and above (HR=1.168, 95%CI:0.321-2.015; P =0.036) and low PNI (HR=2.435, 95%CI:1.024-3.846; P =0.039) was independently correlated with poor survival time; When age was used as a stratification factor, the correlation between CONUT recurrence and survival in patients with gastric cancer ≥65 years old after total gastric resection was analyzed and compared. For disease-free survival, the CONUT high group (>3) was 25.2 months, while the CONUT low group (≤3) was 30.9 months, (χ2=3.763,P=0.029), showing a significant difference. For the overall survival, the CONUT high(>3) group was 30.3 months, compared with the CONUT low(≤3) group at 34.5 months, (χ2=4.924,P=0.042), and the difference was also statistically significant. Conclusions: High controlling nutritional status is an independent risk factor associated with poor gastric cancer survival and it is an independent risk factor in predicting overall survival (OS) in elderly (≥65) gastric cancer after radical gastrectomy.

Aldosterone induces kidney fibroblast proliferation via activation of growth factor receptors and PI3K/MAPK signalling.

BACKGROUND/AIMS: The mineralocorticoid hormone, aldosterone, has pro-fibrotic properties which can cause kidney damage. The severity of kidney interstitial fibrosis is dependent on the accumulation of fibroblasts, which result largely from local proliferation; however, it is unknown whether aldosterone stimulates kidney fibroblast proliferation. Therefore, we examined the effects of aldosterone on the proliferation of cultured kidney fibroblasts. METHODS: Uptake of (3)H-thymidine and cell number quantitation were used to determine the proliferative effects of aldosterone on a rat kidney fibroblast cell line (NRK49F cells) and interstitial fibroblasts extracted from mouse kidneys after unilateral ureter obstruction. The role of different mitogenic signalling pathways in aldosterone-induced proliferation was assessed using specific inhibitors of receptors and kinases. RESULTS: Physiological levels of aldosterone induced a doubling of proliferation of kidney fibroblasts (p < 0.0001), which was inhibited by pre-treatment with the mineralocorticoid receptor antagonist, eplerenone. Aldosterone-induced fibroblast proliferation was dependent upon the kinase activity of growth factor receptors [platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor]. Notably, PDGF ligands were not involved in aldosterone-induced PDGFR activation, indicating receptor transactivation. Aldosterone-induced fibroblast proliferation also required signalling via PI3K, JNK and ERK pathways, but not via the transforming growth factor-ß1 receptor. CONCLUSION: Aldosterone ligation of the mineralocorticoid receptor in kidney fibroblasts results in rapid activation of growth factor receptors and induction of PI3K/MAPK signalling, which stimulates proliferation. This suggests that increased levels of aldosterone during disease may promote the severity of kidney fibrosis by inducing fibroblast proliferation.

Lymphocytes promote albuminuria, but not renal dysfunction or histological damage in a mouse model of diabetic renal injury.

AIMS/HYPOTHESIS: Diabetic nephropathy is an inflammatory disease with prominent leucocyte infiltration of the kidneys. While the importance of macrophages in diabetic renal injury has been clearly demonstrated, the role of lymphocytes is still unknown. We therefore examined the development of diabetic renal injury in lymphocyte-deficient mice. METHODS: Streptozotocin was used to induce diabetes in Rag1(-/-) mice, which lack mature T and B lymphocytes, and in wild-type (Rag1(+/+) ) controls. The development of renal injury was examined over 20 weeks of diabetes. RESULTS: Both groups developed equivalent diabetes, however only Rag1(+/+) mice had kidney infiltration with CD4, CD8, CD22 and forkhead box P3-positive cells, as well as glomerular immunoglobulin deposition. At 20 weeks, Rag1(+/+) mice exhibited renal hypertrophy, increased mesangial and interstitial matrix, kidney macrophage accumulation, tubular injury, progressive albuminuria and a decline in renal function. In comparison, diabetic Rag1(-/-) mice showed similar histological damage, matrix expansion, macrophage accrual and loss of renal function, but were protected from increasing albuminuria. This protection was associated with protection against loss of podocytes and glomerular podocin production, and with reduced glomerular macrophage activation. CONCLUSIONS/INTERPRETATION: These results show that lymphocytes contribute to the development of diabetic albuminuria, which may partly arise from increasing glomerular macrophage activation and podocyte damage. In contrast, lymphocytes do not appear to promote tubular injury, increased matrix deposition or decline in renal function in a mouse model of type 1 diabetes. Our findings suggest that innate immunity rather than adaptive immune responses are the major inflammatory contributor to the progression of diabetic renal injury.

Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice.

AIMS/HYPOTHESIS: Macrophage-mediated renal injury plays an important role in the development of diabetic nephropathy. Colony-stimulating factor (CSF)-1 is a cytokine that is produced in diabetic kidneys and promotes macrophage accumulation, activation and survival. CSF-1 acts exclusively through the c-fms receptor, which is only expressed on cells of the monocyte-macrophage lineage. Therefore, we used c-fms blockade as a strategy to selectively target macrophage-mediated injury during the progression of diabetic nephropathy. METHODS: Obese, type 2 diabetic db/db BL/KS mice with established albuminuria were treated with a neutralising anti-c-fms monoclonal antibody (AFS98) or isotype matched control IgG from 12 to 18 weeks of age and examined for renal injury. RESULTS: Treatment with AFS98 did not affect obesity, hyperglycaemia, circulating monocyte levels or established albuminuria in db/db mice. However, AFS98 did prevent glomerular hyperfiltration and suppressed variables of inflammation in the diabetic kidney, including kidney macrophages (accumulation, activation and proliferation), chemokine CC motif ligand 2 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (c-Jun amino-terminal kinase and activating transcription factor 2) and Tnf-alpha (also known as Tnf) mRNA levels. In addition, AFS98 decreased the tissue damage caused by macrophages including tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (Tgf-beta1 [also known as Tgfb1] and Col4a1 mRNA). CONCLUSIONS/INTERPRETATION: Blockade of c-fms can suppress the progression of established diabetic nephropathy in db/db mice by targeting macrophage-mediated injury.

The role of stress-activated protein kinase signaling in renal pathophysiology

Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.

The role of stress-activated protein kinase signaling in renal pathophysiology.

Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.

Role of MKK3-p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice.

AIMS/HYPOTHESIS: Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. METHODS: Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. RESULTS: Mkk3 (+/+) db/db and Mkk3 (-/-) db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 (+/+) db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 ( -/- ) db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 ( -/- ) db/db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 ( -/- ) db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. CONCLUSIONS/INTERPRETATION: MKK3-p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.

Neointimal coverage of bare-metal and sirolimus-eluting stents evaluated with optical coherence tomography.

OBJECTIVE: To analyse the neointimal coverage of sirolimus-eluting stent (SES) and bare-metal stent (BMS) visualised in vivo by optical coherence tomography (OCT). METHODS: OCT images were obtained in 26 coronary vessels of 24 patients at 5-93 months after SES or BMS deployment. The short-term BMS group (BMS1) consisted of eight BMS in seven patients at 5-10 months of follow-up, the long-term BMS group (BMS2) consisted of six BMS in six patients at 23-93 months of follow-up, and the SES group (SES) consisted of 13 SES in 10 patients at 6-12 months of follow-up. The strut apposition, strut coverage and mean maximal and minimal neointimal thicknesses (NIT) for both BMS groups and SES were compared. RESULTS: OCT images were acquired successfully. Significant differences between completely apposed and malapposed stent struts (p<0.0001) and between covered and uncovered stent struts (p<0.0001) were found among the three groups. The mean maximal and minimal NIT in the SES group were all significantly less than those of the BMS1 or BMS2 group, the minimal NIT in the BMS1 group was significantly less than that of the BMS2 but the mean maximal NIT was no significant difference between the BMS1 and BMS2 groups. In an open bifurcation artery, 19 struts visualised by OCT had no discernible coverage or were surrounded by either thrombus or a thick tissue layer. CONCLUSIONS: OCT imaging can clearly visualise stent apposition and neointimal coverage of stent struts. Incomplete strut apposition and lack of strut coverage occurred with a significantly higher frequency in SES than in BMS. These findings may explain the occurrence of late thrombosis in SES. Optical coherence tomography (OCT) is the optical analogue to ultrasound, measuring the back-reflection of infrared light instead of sound waves. The greatest advantage of OCT is its high resolution, which exceeds that of any currently available in vivo imaging technology. The resolution of catheter-based systems is in the range of 10-20 microm. Furthermore, resolutions as high as 4 microm have been achieved ex vivo with more sophisticated techniques that may be applicable to future catheter-based approaches. The main components of various atheromatous plaques can be identified in OCT images, and have been validated in a histology-controlled study. Several studies have demonstrated the feasibility of OCT imaging in patients undergoing percutaneous coronary intervention (PCI). The aim of the present study was to use OCT to analyse the neointimal coverage of sirolimus-eluting stents (SES), compared with that of bare-metal stents (BMS).

A pathogenic role for JNK signaling in experimental anti-GBM glomerulonephritis.

Activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in the immune response; however, little is known of its role in immune-induced renal injury. In this study, we examine JNK signaling in the rat anti-glomerular basement membrane (GBM) disease model using CC-401, a specific JNK inhibitor. Animals were given CC-401, vehicle alone or no treatment starting before anti-GBM serum injection and continued treatment until killing. In acute disease, CC-401 blocked JNK signaling and reduced proteinuria in the first 24 h. The transient neutrophil influx seen at 3 h of disease was not affected, however. Continued CC-401 treatment suppressed glomerular and tubulointerstitial damage usually seen at 14 days. The protective effect may be due to modulation of macrophage activation, as CC-401 had no effect upon glomerular macrophage infiltration at day 14 despite the suppression of glomerular lesions and a marked reduction in renal tumor necrosis factor-alpha and inducible nitric oxide synthase messenger RNA levels. Treatment with CC-401 had no apparent effect on T cell or humoral immune responses. These studies suggest that JNK signaling promotes renal injury in acute and progressive rat anti-GBM disease. JNK inhibitors may be a novel therapeutic approach for the treatment of human glomerulonephritis.

Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice.

AIMS/HYPOTHESIS: Tissue macrophage accumulation is thought to induce insulin resistance during obesity and stimulate the progression of diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) is a potent stimulator of macrophage recruitment. It is increased in adipose tissue during obesity and in diabetic kidneys, suggesting that inflammation of these tissues may be MCP-1-dependent. Based on these findings, the aim of this study was to examine whether a deficiency in MCP-1 would alter the development of type 2 diabetes and its renal complications. MATERIALS AND METHODS: The role of MCP-1 in the progression of type 2 diabetes and its associated renal injury was assessed in obese db/db mice that were deficient in the gene encoding MCP-1 (Ccl2). RESULTS: The incidence and development of type 2 diabetes were similar in Ccl2(+/+) and Ccl2(-/-) db/db mice between 8 and 32 weeks of age. Body mass, hyperglycaemia, hyperinsulinaemia, glucose and insulin tolerance, plasma triacylglycerol and serum NEFA were not different between these strains. Pathological changes in epididymal adipose tissue, including increases in macrophage accumulation and Tnfa mRNA and reductions in Adipoq mRNA, were unaffected by the absence of MCP-1. In contrast, kidney macrophage accumulation and the progression of diabetic renal injury (albuminuria, histopathology, renal fibrosis) were substantially reduced in Ccl2(-/-) compared with Ccl2(+/+) db/db mice with equivalent diabetes. CONCLUSIONS/INTERPRETATION: Our study demonstrates that MCP-1 promotes type 2 diabetic renal injury but does not influence the development of obesity, insulin resistance or type 2 diabetes in db/db mice. MCP-1 plays a critical role in inflammation of the kidney, but not adipose tissue, during the progression of type 2 diabetes.

Lengthening and transfer of hamstrings for a flexion deformity of the knee in children with bilateral cerebral palsy: technique and preliminary results.

Between July 2000 and April 2004, 19 patients with bilateral spastic cerebral palsy who required an assistive device to walk had combined lengthening-transfer of the medial hamstrings as part of multilevel surgery. A standardised physical examination, measurement of the Functional Mobility Scale score and video or instrumented gait analysis were performed pre- and post-operatively. Static parameters (popliteal angle, flexion deformity of the knee) and sagittal knee kinematic parameters (knee flexion at initial contact, minimum knee flexion during stance, mean knee flexion during stance) were recorded. The mean length of follow-up was 25 months (14 to 45). Statistically significant improvements in static and dynamic outcome parameters were found, corresponding to improvements in gait and functional mobility as determined by the Functional Mobility Scale. Mild hyperextension of the knee during gait developed in two patients and was controlled by adjustment of their ankle-foot orthosis. Residual flexion deformity > 10 degrees occurred in both knees of one patient and was treated by anterior distal femoral physeal stapling. Two children also showed an improvement of one level in the Gross Motor Function Classification System.

Digital reconstruction using the toe flap-- report of 10 cases.

The vascular-pedicle "wrap-around" free flap was used in five patients for reconstruction in amputations distal to the metacarpophalangeal joint. In five other patients who had normal thumbs but had lost all fingers, the technique was expanded to include the second toe with great toe wrap-around flap. All patients did well, but significant bone peg resorption occurred in six patients and in three others the bone peg fractured.