Hybrid natural orifice transluminal endoscopic surgery: endoscopic full-thickness resection of early gastric cancer and laparoscopic regional lymph node dissection--14 human cases.

BACKGROUND AND STUDY AIM: Minimally invasive treatment has become a mainstay management strategy for early gastric cancer (EGC). Full-thickness incision of the gastric wall using natural orifice transluminal endoscopic surgery (NOTES) has been reported but is not easily applicable in clinical settings at present. The aim of the current study was to assess the feasibility of hybrid NOTES, which consists of endoscopic full-thickness gastric resection and a laparoscopic lymphadenectomy. PATIENTS AND METHODS: This was a prospective, pilot study at a single tertiary care referral center. A total of 14 patients with EGC located above the lower third of the stomach underwent hybrid NOTES. Clinically, the patients had contraindications to exclusive treatment using endoscopic submucosal dissection (ESD). The main outcome measure was technical success of hybrid NOTES. RESULTS: All cases were resected en bloc with negative surgical margins. Histologically, four cases were mucosal cancers, and 10 cases were submucosal cancers. The median tumor size was 26 mm (range 12 - 90 mm). Lymphatic vessel invasion was found in four cases without lymph node metastasis (LNM). The median number of obtained lymph nodes was 18 (range 7 - 67). LNM was discovered in one case of undifferentiated submucosal cancer without lymphovascular invasion. Hybrid NOTES was conducted without intraoperative or postoperative adverse events in nine cases. The median operating time and estimated blood loss of successful cases were 143 minutes (range 110 - 253 minutes) and 16 mL (range 5 - 30 mL), respectively. The median hospital stay was 6 days (range 4 - 10 days). Five cases were converted to a subtotal gastrectomy for various reasons. CONCLUSIONS: Hybrid NOTES could be a bridge between endoscopic resection and laparoscopic surgery and may prevent extensive gastrectomy in patients with EGC.

Effects of target concentration infusion of propofol and tracheal intubation on QTc interval.

This study was designed to evaluate the effect of target controlled infusion of propofol on QTc interval and tracheal intubation. Twenty-five unpremedicated, ASA class I or II patients were selected and target concentration infusion of propofol at 5 microg x ml(-1) was used throughout the study. The QTc interval was measured before anaesthetic induction (baseline, T1), 10 min after propofol infusion (T2), immediately after tracheal intubation (T3), and 1 min after tracheal intubation (T4). The QTc interval increased significantly at 10 min after the propofol infusion started compared to baseline (p = 0.003). After tracheal intubation, the QTc interval was further increased when compared to that at T2 (p < 0.0001). The increased QTc interval was within normal limit and no patient had an arrhythmia. In conclusion, although statistically significant, the increase in QTc interval was too small to be clinically significant during propofol infusion. However, the combination of propofol and tracheal intubation must be used carefully in patients with prolonged QTc interval.

Urinary Tissue Inhibitor of Metalloproteinase and Insulin-like Growth Factor-7 as Early Biomarkers of Delayed Graft Function After Kidney Transplantation.

BACKGROUND: Recently, urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-7 (IGFBP-7), markers for G1 cell cycle arrest, have been identified and validated in predicting the development of acute kidney injury in critically ill patients. It is unknown, however, whether these two biomarkers could predict the development of delayed graft function (DGF) after kidney transplantation (KT). METHODS: This is a single-center, prospective, observational study. We enrolled 74 patients who underwent KT between August 2013 and December 2016. Urine sample were collected immediately after the operation. The primary outcome was development of DGF as defined by need for dialysis of more than 1 session within 7 days of KT. RESULTS: Twenty-three patients (31%) were diagnosed with DGF. In univariate analysis, kidneys from expanded criteria donors, higher donor serum creatinine, lower donor estimated glomerular filtration rate, antithymoglobulin exposure, neutrophil gelatinase associated lipocalin, and urinary [TIMP-2]·[IGFBP7] were significantly different between early graft function and DGF. However, in multivariate analysis adjusting other factors, deceased donor and urinary [TIMP-2]·[IGFBP7] at 0 hours post-transplantation could predict the development of DGF. The receiver operating characteristic curve for prediction of DGF showed an area under the curve of 0.867 (sensitivity 0.86, specificity 0.71) for a cutoff value of 1.39. CONCLUSIONS: Our results indicate that urine [TIMP-2]·[IGFBP7] immediately after transplantation could be an early, predictive biomarker of DGF in kidney transplantation.

Role of vascular endothelial growth factor in diabetic nephropathy.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent cytokine that is considered to be an important mediator in the pathogenesis of endothelial dysfunction in diabetes. METHODS: This study investigates the effect of high glucose on the signaling and production of VEGF in rat mesangial cells in culture and measures the urinary VEGF level in patients with different stages of diabetic nephropathy. To elucidate the role of VEGF in vivo further, expression of VEGF in control and diabetic kidneys was examined using immunohistochemistry. RESULTS: A high ambient glucose concentration in the culture medium increased VEGF mRNA expression and protein production within 3 h in a concentration-dependent manner. A protein kinase C (PKC) inhibitor and PKC down-regulation inhibited glucose-induced increases in VEGF production. Urinary excretion of VEGF significantly increased according to the degree of proteinuria in patients with diabetes. A weak but significant correlation was found between urinary VEGF excretion and the levels of serum creatinine, creatinine clearance, microalbuminuria, and proteinuria. Immunohistochemistry revealed marked differences in the extent of mesangial VEGF staining between diabetic and control kidneys. Pronounced up-regulation of VEGF was observed in the glomerular epithelial cell in the early phase of diabetic kidney disease, whereas widespread expression of VEGF was found in the tubular segments, especially the proximal segment, in advanced diabetic nephropathy. CONCLUSIONS: These results suggest that VEGF may play a role in the pathogenesis of diabetic nephropathy.

Urine neutrophil gelatinase-associated lipocalin predicts graft outcome up to 1 year after kidney transplantation.

BACKGROUND: Several recent reports demonstrated the usefulness of new biomarkers in early prediction of delayed graft function (DGF) and graft recovery after kidney transplantation (KT). It is unknown, however, whether these biomarkers would predict long-term graft outcome. In this study, we examined whether the biomarkers including neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) can predict 1-year graft outcome as well as short-term graft function especially in patients with early graft function (EGF). METHODS: This was a single-center, prospective observational study. Urine samples at 0 hours and 2 and 6 days were obtained and the level of NGAL and L-FABP were measured. RESULTS: Of the 69 KT recipients enrolled, seven developed DGF, and the remaining 62 patients were finally enrolled as EGF recipients. EGF recipients were additionally divided into immediate graft function (IGF, n = 48) and slow graft function (SGF, n = 14) groups. Urinary NGAL (u-NGAL) level on day 2, but not L-FABP nor serum creatinine, was significantly higher in SGF compared to IGF group. Higher day 2 u-NGAL level was associated with more frequent development of SGF and, in addition, with significantly lower 1-year estimated glomerular filtration rate (eGFR). In multivariate logistic regression analysis, day 2 u-NGAL was a significant, independent factor for predicting poor long-term graft function (1-year eGFR < 60 mL/min/1.73 m(2)). CONCLUSIONS: This study demonstrates the possibility that u-NGAL might be useful in predicting adverse 1-year outcome as well as short-term graft function even in EGF patients.

Prevention of uncuffed hemodialysis catheter-related bacteremia using an antibiotic lock technique: a prospective, randomized clinical trial.

As a result of the high rate of infection, the NKF-K/DOQI guidelines recommended that an uncuffed catheter (UC) should not be used for longer than three weeks. However, the findings of the Dialysis Outcomes and Practice Patterns Study recognized that 48% of new hemodialysis patients in the US and 75% in Europe used UC for temporary access during arteriovenous fistula or graft maturation. The antibiotic lock technique (ALT) has been recommended to prevent catheter-related bacteremia (CRB). Here, we prospectively evaluated the efficacy of catheter-restricted filling using an antibiotic lock solution in preventing CRB. A total of 120 new hemodialysis patients requiring a temporary catheter while waiting for placement and maturation of an arteriovenous fistula or graft were enrolled in this study. Patients with a UC were randomly assigned to receive either an antibiotic-heparin lock solution (antibiotic group: cefazolin 10 mg/ml, gentamicin 5 mg/ml, heparin 1000 U/ml) or a heparin lock solution (no-antibiotic group: heparin 1000 U/ml) as a catheter lock solution during the interdialytic period. The end point of the trial was CRB. CRB developed in seven (11.7%) patients in the no-antibiotic group (Staphylococcus aureus, two; Staphylococcus epidermidis, five) whereas only one patient in the antibiotic group had S. aureus bacteremia. CRB rates per 1000 catheter-days were 0.44 in the antibiotic group versus 3.12 in the no-antibiotic group (P=0.031). Kaplan-Meier analysis also showed that mean CRB-free catheter survival of 59 days (95% CI, 58-61 days) in the antibiotic group was greater than that in the no-antibiotic group (55 days; 95% CI, 50-59 days). The results suggest that ALT may be a beneficial means of reducing the CRB rate in hemodialysis patients with UC.

Mycobacterium fortuitum peritonitis associated with continuous ambulatory peritoneal dialysis.

Runyon group IV atypical mycobacteria, Mycobacterium fortuitum, is an environmental organism and is capable of producing a variety of clinical infections such as cutaneous infection, abscess and pulmonary and ocular infection. Rarely, it has been a documented cause of peritonitis in patients receiving continuous ambulatory peritoneal dialysis (CAPD). We report a case of M. fortuitum peritonitis in a patient undergoing CAPD and emphasize the importance of mycobacterial cultures in patients with CAPD-associated peritonitis whose routine culturing yields no organisms repeatedly.

Degradation of human immunoglobulins and cytotoxicity on HeLa cells by live Trichomonas vaginalis.

The present study was undertaken to determine whether live T. vaginalis degrades human secretory IgA, serum IgA and IgG molecules. Human immunoglobulins were exposed to live trophozoites, parasite lysate, and excretory-secretory product (ESP) of T. vaginalis. To determine the fragmentation of immunoglobulins, the reaction sample was subjected to SDS-PAGE and EITB, and peroxidase conjugated antihuman IgA and IgG were used as probes. Live trophozoites degraded secretory IgA. Serum IgA and IgG, and degradation were pressed forward by the prolongation of the incubation time and by increasing the number of trichomonads respectively. Also the lysates and ESP of trichomonads degraded IgA and IgG. The cysteine and serine proteinase inhibitors such as E-64, antipain, iodoacetic acid, iodoacetamide, TLCK reduced the ability of cleaving immunoglobulins. The proteinase activity and cytotoxicity of T. vaginalis to HeLa cells were decreased when live T. vaginalis was treated with metallo-proteinase inhibitor as well as cysteine and serine proteinase inhibitors. These results suggest that proteinase secreted from live T. vaginalis may play a part role in host pathogenesis by T. vaginalis, and the cleaving ability of host immunoglobulins by the proteinase may contribute as a one of immune evasion mechanism for parasite survival in the host.

A case of Rathke's Cleft Cyst inflammation presenting with diabetes insipidus.

Rathke's Cleft Cyst (RCC), which is located at the intrasellar region, is considered to be the distended remnants of Rathke's pouch, an invagination of the stomodeum. Lined with columnar or cuboidal epithelium of ectodermal origin, RCC usually contains mucoid material and it is found in 13-22% of normal pituitary glands. The cyst rarely leads to the development of symptoms but, when it does, the most common presenting symptoms are headache, visual impairment, hypopituitarism and hypothalamic dysfunction. However, in some cases it presents symptoms of diabetes insipidus, decreased libido and impotence. Recently we experienced a case of RCC inflammation presenting with diabetes insipidus and treated with transsphenoidal surgery. To our knowledge, this is the first report of RCC presenting with symptoms of diabetes insipidus in Korea.

ACE gene polymorphism and renal responsiveness to ACE inhibitors in IgA nephropathy patients.

We examined the renal responsiveness to ACE inhibitor in IgA nephropathy (IgAN) patients according to the grouping of ACE gene polymorphism. Sixty one patients diagnosed as IgAN by renal biopsy and prescribed with ACE inhibitors were enrolled. Genomic DNA was extracted from whole blood and PCR was performed. The I/D polymorphism was determined by the presence of the 287 bp fragment in intron 16 of chromosome 17. During the follow-up period (mean; 44.6 months, median: 44.5 months, 5 to 113 months), the blood pressure of 61 patients was controlled below 130/80 mmHg. The renal responsiveness was determined by the degree of changes of proteinuria at 12 months after initiation of ACE inhibitors and by the slope of reciprocal variation of the serum creatinine against follow-up duration ¿(1/Cr2-1/Cr1)/durations¿. The distribution of the II, ID and DD genotype among 61 patients was 21, 16 and 24 patients, respectively. There were no differences among three genotypes in age, sex, the number of patients with initial blood pressure over 140/90 mmHg, initial serum creatinine level, the number of patients with initial azotemia (> 1.4 mg/dL) and with initial 24-hr proteinuria amount over 2.0 g. Significant anti-proteinuric effect of ACE inhibitor was found in IgAN (p = 0.001), but no significant difference was found among genotypes. Significant difference (p = 0.011) was noticed between II type and DD type in the slope of reciprocal variation of the serum creatinine against follow-up duration. In conclusion, efficacy of ACE inhibitors on renal function preservation in IgAN was more pronounced in DD genotype than II genotype.

alpha-MSH decreases apoptosis in ischaemic acute renal failure in rats: possible mechanism of this beneficial effect.

BACKGROUND: Apoptosis frequently occurs in acute renal injury but the molecular mechanisms responsible for this distinct form of cell death are largely unknown. Fas belongs to the tumour necrosis factor (TNF)/nerve growth factor superfamily and engagement by Fas ligand induces apoptosis in various epithelial cells. To investigate the role of apoptosis and associated mechanisms, we examined the occurrence of apoptosis and Fas and Fas ligand expression, and the therapeutic effect of alpha-melanocyte-stimulating hormone (alpha-MSH), a potent anti-inflammatory cytokine in an ischaemic acute renal failure (ARF) rat model. We also examined neutrophil infiltration together with intercellular adhesion molecule-1 (ICAM-1) expression because of their possible involvement in apoptosis due to their ability to release various inflammatory cytokines and reactive oxygen species. METHODS: After unilateral nephrectomy in female Sprague-Dawley rats, the renal artery of the contralateral kidney was clamped for 40 min and reperfused. alpha-MSH or vehicle was injected intraperitoneally immediately after reperfusion and at 1, 6, or 24 h after reperfusion. The expression of Fas and Fas ligand was studied by western blot analysis and semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) method, and neutrophil infiltration by naphthol AS-D chloracetate staining. The degree of apoptosis, neutrophil infiltration, and Fas and Fas ligand, and ICAM-1 expression, as well as biochemical and histological data were compared between the alpha-MSH and the vehicle-treated groups. RESULTS: Intraperitoneally administered alpha-MSH significantly reduced renal injury, measured by blood urea nitrogen (BUN) and creatinine and by the degree of tubular necrosis (109.6+/-7.1/54.7+/-3.1 mg/dl for BUN, and 1.6+/-0.2/1.03+/-0.06 mg/dl for creatinine 24 h after ischaemia) (5.4+/-0.8/2.6+/-0.3 for injury score 24 h after ischaemia). Ischaemia caused an increase in Fas and Fas ligand expression and was accompanied by morphological evidence of apoptosis. alpha-MSH significantly reduced the degree of apoptosis, as well as Fas and Fas ligand expression (mean apoptotic cell number, 41.7+/-3.5/14.2+/-2.2 per x200 field at 24 h after ischaemia. Fas protein expression: sham, 1409+/-159 DI (densitometric index); vehicle/alpha-MSH, 2818+/-635/1306+/-321 DI at 24 h and 5542+/-799/2867+/-455 DI at 72 h after ischaemia. Fas ligand protein expression: sham, 1221+/-181 DI; vehicle/alpha-MSH, 2590+/-85/1279+/-169 DI at 4 h, 4376+/-268/2432+/-369 DI at 24 h and 5200+/-648/2253.7+/-1104 DI at 72 h after ischaemia). Neutrophil infiltration and ICAM-1 expression were also significantly reduced in alpha-MSH group (neutrophil infiltration: vehicle/ alpha-MSH, 5.05+/-1.8/1.59+/-0.4) (ICAM-1 expression, vehicle/alpha-MSH 0.46+/-0.21/0.29+/-0.19). CONCLUSION: These results suggest that apoptosis clearly contributes to tubular cell loss in ischaemia/reperfusion (I/R) injury possibly by neutrophil-mediated pathways or an increase in Fas-Fas ligand expression. The observed beneficial effect of alpha-MSH could be related to these mechanisms.

alpha-Melanocyte stimulating hormone (MSH) decreases cyclosporine a induced apoptosis in cultured human proximal tubular cells.

The pathogenesis of chronic cyclosporine A (CsA) nephrotoxicity has not been elucidated, but apoptosis is thought to play an important role in CsA induced tubular atrophy. Recently Fas-Fas ligand system mediated apoptosis has been frequently reported in many epithelial cells as well as in T lymphocytes. We investigated the ability of CsA to induce apoptosis in cultured human proximal tubular epithelial cells and also the effect of alpha-MSH on them. Fas, Fas ligand, and an intracellular adaptor protein, Fas-associating protein with death domain (FADD) expression, and poly-ADP ribose polymerase (PARP) cleavage were also studied. CsA induced apoptosis in cultured tubular epithelial cells demonstrated by increased number of TUNEL positive cells and it was accompanied by a significant increase in Fas mRNA and Fas ligand protein expressions. FADD and the cleavage product of PARP also increased, indicating the activation of caspase. In alpha-MSH co-treated cells, apoptosis markedly decreased with downregulation of Fas, Fas ligand and FADD expressions and also the cleavage product of PARP. In conclusion, these data suggest that tubular cell apoptosis mediated by Fas system may play a role in tubular atrophy in chronic CsA nephrotoxicity and pretreatment of alpha-MSH may have a some inhibitory effect on CsA induced tubular cell apoptosis.

Homocyst(e)ine and atherosclerosis in patients on chronic hemodialysis.

Hyperhomocyst(e)inemia is an established risk factor for atherosclerosis. We performed this study to identify the correlating variables and risk factors for atherosclerosis, as measured by the atherosclerotic score (AS), and to determine the relative risk for cardiovascular disease in relation to plasma homocyst(e)ine levels in patients on chronic hemodialysis. We evaluated and measured 61 patients on chronic hemodialysis for clinical and biochemical parameters including atherosclerotic score (AS) and plasma homocyst(e)ine. We divided patients into high and low groups, first, by the mean AS, and second, by the median value of plasma total homocyst(e)ine levels. Then we compared the variables between the two groups. Out of the 61 patients, the median plasma total homocyst(e)ine level was 24.4 micromol/L (mean+/-SD, 27.7+/-17.4; range, 9.8-127.4 micromol/L), and the median AS was 5 (mean+/-SD, 6.2+/-2.8; range, 3-13) out of a possible 20 points. AS was significantly correlated with plasma total homocyst(e)ine levels (r=0.37) and age (r=0.67). Through multivariate analysis, plasma total homocyst(e)ine level and age were determined as significant risk factors for the high-AS group (p<0.05). However, plasma total homocyst(e)ine level did not correlate with age (p>0.05). Eighteen of the 61 patients, presented with cardiovascular disease until the present study, had an AS>6. Cardiovascular disease was found more often in the high-homocyst(e)ine group (>24.4 micromol/L) than in the low-homocyst(e)ine group (odds ratio, 9.3; 95% confidence interval, 2.3-37.4). Regardless of age, hyperhomocyst(e)inemia (especially homocyst(e)ine levels >24.4 micromol/L) is a risk factor that can be modified for the development of cardiovascular disease in patients on chronic hemodialysis.