TGF-β1 Promotes Lymphangiogenesis during Peritoneal Fibrosis

Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-β1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-β1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-β type I receptor (TGFβR-I) inhibitor. TGF-β1–induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFβR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-β–VEGF-C pathway.The decrease in ultrafiltration capacity that is associated with the high peritoneal solute transport that is observed after prolonged peritoneal dialysis (PD) treatment is a major reason for its discontinuation.^1–4 Several studies have shown that a higher peritoneal solute transport rate is associated with reduced survival of PD patients.^1,2,5 The characteristic features of chronic peritoneal damage in PD treatment are associated with submesothelial fibrosis and neoangiogenesis.^6,7 Analyses of the surface peritoneum showed no significant changes in vessel density with duration of PD.^6,8 In addition, the vessel density in patients with ultrafiltration failure (UFF) was significantly higher than the vessel density in normal individuals or non-PD patients, but it was not higher than the vessel density in patients undergoing PD.⁶ These findings suggest that factors other than increased vascular density may be involved in disease states associated with increased transport of peritoneal membranes. In addition, the relationship between peritoneal fibrosis and UFF remains obscure.Blood capillaries have a continuous basal lamina with tight interendothelial junctions and are supported by pericytes and smooth muscle cells. In contrast, lymphatic capillaries are thin-walled with a wide lumen and do not contain pericytes or basement membrane. The structures of lymphatic vessels are suitable for the removal of tissue fluid, cells, and macromolecules from the interstitium.^9–11 If lymphangiogenesis develops in the peritoneal membrane, absorption of the PD fluid could be increased and lead to UFF. An increase in the number of lymphatic vessels has recently been reported in several disease conditions, including tumor metastasis,^12–15 chronic respiratory inflammatory diseases,^16–18 wound healing,¹⁹ and renal transplant rejection.^20,21 We recently reported that lymphangiogenesis had developed in tubulointerstitial fibrosis of human renal biopsy specimens,²² and we also reported the mechanisms of lymphangiogenesis in rat unilateral ureteral obstruction models.²³The lymphatic absorption rate, which is measured by the rate at which intraperitoneally administered radioactive serum albumin or macromolecule dextran 70 disappears, is significantly higher in patients with UFF, and lymphatic reabsorption is considered to be one of the causes of UFF.^24–27 However, the results from these clinical approaches have been controversial.^28,29 In addition, little is known about the pathology and the process of lymphangiogenesis in patients with UFF and peritonitis.In this study, we investigated lymphangiogenesis and the expression of vascular endothelial growth factor-C (VEGF-C), which is a potentially important mediator of lymphangiogenesis, in human peritoneal tissues, PD effluent, and peritoneal mesothelial cells. We also explored VEGF-C induction by TGF-β1 in the human mesothelial cell line (Met-5A) and cultured human peritoneal mesothelial cells (HPMCs) from the spent PD effluent of patients with varying rates of peritoneal transport. Finally, we explored the relationship between peritoneal fibrosis and lymphangiogenesis in rats that were administered chlorhexidine gluconate (CG) into the abdominal cavity, which provides a model of chemically induced peritoneal inflammation/fibrosis.^30–32 This work is the first report to show that lymphangiogenesis is linked to the peritoneal fibrosis that is often associated with a high peritoneal transport rate.     

Dual diffusion model for single-cell recording data from the superior colliculus in a brightness-discrimination task

Monkeys made saccades to one of two peripheral targets based on the brightness of a central stimulus. Task difficulty was manipulated by varying the ratio of stimulus black-and-white pixels. Correct response probability for two monkeys varied directly with difficulty. Deep layer SC neurons exhibited robust presaccadic activity the magnitude of which was unaffected by task difficulty when the stimulus specified a saccade toward a target within the neuron's response field. Activity after stimuli specifying saccades to targets outside the response field was affected by task difficulty, increasing as the task became more difficult. A quantitative model derived from studies of human decision-making was fit to the behavioral data. The model assumes that information from the stimulus drives two independent diffusion processes. Simulated paths from the model were compared with neuron activity, assuming that firing rate is linearly related to position in the accumulation process. The firing rate data show delayed availability of discriminative information for fast, intermediate, and slow decisions when activity is aligned on the stimulus and very small differences in discriminative information when aligned on the saccade. The model produces exactly these patterns of results. The accumulation process is highly variable, allowing the process both to make errors, as is the case for the behavioral performance, and also to account for the firing rate results. Thus the dual diffusion model provides a quantitative account for both the behavior in a simple decision-making task as well as the patterns of activity in competing populations of neurons.     

ASO Visual Abstract: A Prospective Multicenter Interventional Study of Surgical Resection for Liver Metastasis from Gastric Cancer: R0 Resection Rate and Operative Morbidity and Mortality

Annals of Surgical Oncology -     

Enhancement of ultrasound-induced apoptosis and cell lysis by echo-contrast agents

To determine the effects of echo-contrast agents (ECAs) on ultrasound (US)-induced apoptosis and cell lysis, human myelomonocytic lymphoma U937 cells in suspension were exposed to 1 MHz continuous waves US for 1 min at an intensity of 0.5, 1.0, 2.0 or 4.0 W/cm(2) with or without non-shell type ECA, Levovist (2 mg/ml), and shell type, Optison (1 microl/ml) or YM454 (1 microl/ml). Levovist minimally enhanced the US-induced apoptosis at 1.0 W/cm(2) while Optison and YM454 did at 2.0 and 4.0 W/cm(2), as detected by flow cytometry. Cell lysis was also augmented when Levovist was combined with US at 2.0 W/cm(2), and when Optison was combined with US at 2.0 and 4.0 W/cm(2). YM454 showed the highest rate of enhanced cell lysis at 1.0, 2.0 and 4.0 W/cm(2). Therefore, this study shows that Optison and YM454 are effective in augmenting the US-induced cell killing, but not Levovist. Another result indicates that cavitation plays a role in the augmented effects and that inertial cavitation appears necessary for Optison and YM454 to effect their actions. In addition, results show that the rate of apoptosis is lower in the presence of ECAs with higher free radical scavenging activity, suggesting a possible role for free radicals in apoptosis. These findings suggest that some ECAs have potential to be adjuncts in cases wherein augmented US-induced cell killing is needed, such as in cancer therapy with US.     

Blue laser imaging identifies endoscopic findings corresponding to metachronous esophageal squamous cell carcinoma

Esophagus - This study aimed to evaluate endoscopic findings using non-magnifying blue laser imaging (BLI) to determine the risk factors for metachronous esophageal squamous cell carcinoma (ESCC)....     

Acquisition of antimicrobial-resistant variants in repeated infections caused by Pseudomonas aeruginosa revealed by whole genome sequencing

Pseudomonas aeruginosa, responsible for serious nosocomial-acquired infections, possesses intrinsic antibiotic resistance mechanisms and commonly exhibits multidrug resistance. Here, we report the evolving resistance profiles of strains isolated from the sputum of a patient being treated for repeated P. aeruginosa infections following cancer resection. Whole genome sequencing of six isolates obtained over a 2-month period revealed two key single nucleotide polymorphisms in the mexR and gyrB genes that affected efflux pump expression and antimicrobial resistance.     

Prognostic significance of multiple-detector computed tomography in conjunction with TIMI risk score for patients with non-ST elevation acute coronary syndrome

Risk stratification among patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) has been made by clinical scoring. Recently, multiple-detector computed tomography (MDCT) appeared to provide noninvasive coronary angiography (CAG). To clarify the prognostic significance of MDCT, we aimed to evaluate the clinical utility of MDCT in the early management and in predicting the long-term prognosis of NSTE-ACS with low to intermediate risk. Among 84 consecutive patients with NSTEACS, risk stratification using a TIMI risk score was done. A total of 48 patients were categorized as low to intermediate risk. Multiple-detector CT was performed in 30 patients using 16-slice MDCT. MDCT detected coronary stenoses in 18 patients. Compared to invasive CAG, MDCT successfully depicted the coronary stenosis (P < 0.005), with sensitivity of 100% and specificity of 86%. The incidence of in-hospital major adverse clinical events (death, subsequent myocardial infarction, revascularization) was significantly higher in patients with a positive MDCT than in those with a negative MDCT test (44% vs 0%, P < 0.005). Moreover, a Kaplan-Meier analysis showed a significant difference in the event — free survival between MDCT positive and negative groups (33% vs 100%, respectively, P < 0.0001) during the mean follow-up period of 9.9 ± 7.5 months. Sixteen-slice MDCT in conjunction with a TIMI risk score appeared to demonstrate prognostic significance in patients with NSTE-ACS.     

Serum insulin-like growth factor II in chronic liver disease

Insulin-like growth factor II is secreted primarily by the liver and is reported to be transcribed in many primary hepatocellular carcinoma (PHC) cell lines. We have studied diagnostic significance of serum IGF-II in chronic liver diseases using specific enzyme immunoassay. Serum IGF-II levels (mean +/- SE) were decreased in chronic hepatitis (538 +/- 51 ng/ml; N = 29), liver cirrhosis (427 +/- 45; 50) and PHC (260 +/- 41; 17) compared to controls (830 +/- 49; 57). Serum IGF-II was not different from controls in any of nonhepatic diseases such as diabetes (1032 +/- 97; 19) pancreatic cancer (1413 +/- 282; 8), chronic pancreatitis (999 +/- 126; 17), peptic ulcer (1186 +/- 43; 11), irritable bowel syndrome (1002 +/- 109; 12), gastrointestinal tract cancer (1250 +/- 216; 21) and chronic renal failure (733 +/- 135; 14). In liver diseases serum IGF-II showed a significant correlation with liver function test (negative with retention of indocyanine green and total bile acids; positive with albumin, thrombo-test, and cholinesterase). These results suggest that serum IGF-II reflects a reduced production of IGF-II in the liver and that it can be an index for the residual capacity of liver function.