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1.  Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes 
Despite the use of intensive therapies, declining renal function is often observed during the overt nephropathy stage of type 2 diabetes. We aimed at investigating the role of serum uric acid (SUA) levels at the onset of overt nephropathy in the risk of renal function decline in type 2 diabetes patients.
Materials and Methods
The present cohort study included 290 type 2 diabetes patients who were followed from the onset of overt nephropathy. The relationship between SUA and declining renal function was assessed using Cox regression models after adjusting for known risk factors.
Over a median 4.8-year follow-up period, 85 patients (4.9/100 person-years) showed serum creatinine (Cr) doubling with a total cumulative incidence of 71.9% at 20 years of follow up. The highest SUA tertile resulted in significantly a higher incidence (7.7/100 person-years) and cumulative incidence at 20 years (85.7%) than the middle (3.9/100 person-years, 54.2%) and lowest (3.0/100 person-years, 55.5%) tertiles. The univariate Cox hazard model resulted in significant risks for Cr doubling related to female sex, short diabetes duration, smoking and elevated levels of low-density lipoprotein cholesterol (LDL-c), glycated hemoglobin and SUA tertiles. SUA tertiles remained statistically significant in the multivariate model (highest vs lowest hazard ratio 2.68, 95% confidence interval 1.48−5.00, P = 0.0009).
Elevated SUA levels within the normal range (men >6.3 mg/dL, women >5.1) at the onset of overt nephropathy resulted in an increased risk for declining renal function in type 2 diabetes patients.
PMCID: PMC4296709  PMID: 25621139
Risk factors; Type 2 diabetic nephropathy; Uric acid
2.  Laparoscopic Surgery for the Ascending Colon Cancer Associated with Malrotation of the Midgut 
The Indian Journal of Surgery  2011;75(Suppl 1):71-73.
Malrotation of the midgut is a congenital anomaly of the gastrointestinal tract that usually presents in neonates. Moreover, synchronous colon cancer has rarely been reported. In the present article, we report a preliminary experience with laparoscopic approach for intestinal malrotation with early colon cancer in a 68-year-old woman who presented with bloody stools. Colonoscopy revealed a lateral spreading tumor of the ascending colon. An air-barium contrast enema showed that the entire colon lay within the left hemiabdomen. A computed tomography revealed the superior mesenteric vein rotation sign. At surgery, a condition of malrotation of the midgut was observed: the third and the fourth part of the duodenum descended vertically without Treitz’s ligament, and the small bowel and colon were located in the right and left side of the abdominal cavity, respectively. We mobilized the terminal ileum and the right colon with laparoscopic approach. A 3-cm abdominal incision was made via the umbilicus. Right colectomy with lymph node dissection was achieved following extracorporealization. Pathological examination revealed well-differentiated tubular adenocarcinoma without nodal involvement. The patient had an uneventful postoperative course. Laparoscopic surgery for colon cancer associated with malrotation of the midgut is feasible and a promising method because of its less invasiveness and its adaptability to the malrotation without extending the skin incision.
PMCID: PMC3693239  PMID: 24426518
Malrotation of the midgut; Intestinal malrotation; Laparoscopic colectomy
3.  Concurrent Single-Incision Laparoscopic Right Hemicolectomy and Sigmoidectomy for Synchronous Carcinoma: Report of a Case 
The Indian Journal of Surgery  2012;75(Suppl 1):293-295.
Synchronous colorectal tumors that require surgical treatments are rare. Preliminary experience with concurrent single-incision laparoscopic right hemicolectomy and sigmoidectomy for synchronous carcinoma is reported. A 61-year-old woman presented to our department for the close examination of a bloody stool. Colonoscopy revealed two masses in the right-sided transverse colon and sigmoid colon and another slightly elevated lesion in the transverse colon, and all biopsies from these three lesions demonstrated adenocarcinoma. Under the diagnosis of transverse colon cancers and sigmoid colon cancer, we performed simultaneous single-incision laparoscopic sigmoidectomy and right hemicolectomy. First, a lap protector was inserted through a 2.5 cm transumbilical incision. Three 5 mm ports were placed in the lap protector. We successfully performed sigmoidectomy and right hemicolectomy with lymph node dissection. The patient was discharged on the thirteenth postoperative day. Postoperative follow-up did not reveal any umbilical wound complications. SILS should be the treatment of choice for concurrent laparoscopic surgery for also the other diseases.
PMCID: PMC3693301  PMID: 24426595
Single-incision laparoscopic surgery; Concurrent laparoscopic surgery; Laparoscopic colectomy
4.  Single-Incision Laparoscopic Ileo-Cecal Resection for Appendiceal Mucocele 
The Indian Journal of Surgery  2012;75(Suppl 1):250-252.
Mucocele of the appendix is a rare lesion which denotes a distension of the lumen due to accumulation of mucoid substance, and a possible rupture of the mucocele may result in the clinical condition of pseudomyxoma peritonei. Therefore, the laparoscopic approach for this disease is still controversial because improper handling may cause inadvertent rupture. We present a successfully treated case with the single-incision laparoscopic approach. An 88-year-old man was diagnosed with the mucocele of the appendix, and we decided to perform the single incision laparoscopic ileocecal resection. First, a lap protector was inserted through a 3.0 cm transumbilical incision. Three 5 mm ports were placed in EZ access mounted on the lap protector. On the observation of laparoscopy, a retrocecal appendix was found. We successfully mobilized the right colon and transected the ileum using an endoscopic linear stapler. The right colon with appendix was carefully extracted through the umbilical incision. Resection and anastomosis were achieved following extracorporealization. The appendix was measured 7 cm in length and 3 cm in diameter; a final histopathological diagnosis was mucocele caused by mucinous cystadenoma. This is, to our knowledge, the first case of a single-incision laparoscopic ileocecal resection for mucocele of the appendix described in the indexed literature.
PMCID: PMC3693343  PMID: 24426581
Single-incision laparoscopic surgery; Ileo-cecal resection; Single-incision laparoscopic surgery; Appendiceal mucinous cystadenoma
5.  The Transverse Colon Cancer with the Reversed Rotation of the Midgut Treated with Single Incision Laparoscopic Colectomy 
The Indian Journal of Surgery  2012;75(Suppl 1):195-198.
Reversed rotation of the midgut is a rare type of intestinal malrotation. Moreover, synchronous colon cancer has rarely been reported. Preliminary experience with single-incision laparoscopic colectomy (SILC) for colon cancer with reversed rotation of the midgut is reported.
An 82-year-old woman was admitted because of a fecal occult blood. A colonoscopy revealed transverse colon cancer. An air-barium contrast enema showed the right-sided sigmoid colon and the left-sided cecum. A computed tomography revealed that the duodenum and the transverse colon were situated at the ventral side of the superior mesenteric artery, and a preoperative diagnosis of suspicion of reversed rotation of the midgut was made.
Surgical Procedures
First, a lap protector was inserted through a 4.0 cm transumbilical incision. Four 5 mm ports were placed in the lap protector. On the observation of laparoscopy, the cecum and the ascending colon were not fixed with the retroperitoneum and situated on the left, and the sigmoid colon was situated on the right. We successfully mobilized the transverse colon using a single-incision laparoscopic approach. Resection was achieved following extracorporealization, and the anastomosis was performed extracorporeally using staplers. The patient was discharged on the thirteenth postoperative day. Postoperative follow-up did not reveal any umbilical wound complications.
SILC for colon cancer associated with malrotation of the midgut is feasible and a promising alternative method because of its less invasiveness and its adaptability to the malrotation without extending the skin incision.
PMCID: PMC3693364  PMID: 24426562
Reversed rotation; Malrotation of the midgut; Single incision laparoscopic colectomy; Laparoscopic colectomy
6.  Single Incision Laparoscopic Right Colectomy Using the Techniques of Open Surgery Through the Small Incision 
The Indian Journal of Surgery  2012;75(Suppl 1):277-279.
To perform single-incision laparoscopic colectomy (SILC) safely while maintaining the minimal invasiveness of SILC and the quality of the lymph node dissection, we have used hybrid single-incision laparoscopic colectomy (H-SILC). Preliminary experience with H-SILC in advanced colon cancer is reported. First, a multi-flap gate was inserted through a 4.0 cm transumbilical incision, and three 5 mm ports were placed in the converter sheet. The procedures were much the same as in usual laparoscopic colectomy excluding a lateral to medial approach. The initial identification or exposure of the ileocolic vessels was performed through a small incision, and lymphadenectomy was mainly achieved using laparoscopic technique. In the course of laparoscopic procedures, whenever we felt stress, we used the techniques of open surgery through the small incision. The procedure was completed successfully without any perioperative complication and no need to extend the skin incision. The operative time was 191 min. Postoperative follow-up did not reveal any umbilical wound complication or any recurrence. Our experience indicates H-SILC is safe and feasible for selected patients with colon cancer with improved cosmesis.
PMCID: PMC3693387  PMID: 24426590
Single incision laparoscopic colectomy; Single incision laparoscopic surgery; Laparoscopic colectomy
7.  Pediatric ileoileal intussusception with a lipoma lead point: a case report 
Gastroenterology Report  2013;2(1):70-72.
Intussusception is a common cause of mechanical bowel obstruction among children, with older children being more likely to have a pathological lead point. Intestinal neoplasms are rare and small intestinal lipomas are even less common. Herein we describe a case of a 7-year-old boy with ileoileal intussusception, with an ileal lipoma as the pathological lead point. Computed tomography was useful pre-operatively for revealing intussusception due to lipoma as the pathologic lead point.
PMCID: PMC3920992  PMID: 24760240
Lipoma; Intussusception; Child
8.  Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect 
International Immunology  2010;22(3):191-203.
Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic β cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD4+ and CD8+ T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2Kwm7, which exerts a diabetes-protective effect in NOD mice. We have found that H-2Kwm7 molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2Kwm7 to support T1D development could be due, at least in part, to the failure of peptides from critical β-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD8+ T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.
PMCID: PMC2829095  PMID: 20093428
autoimmunity; diabetes; MHC
9.  Use of a Population-Based Cancer Registry to Calculate Twenty-Year Trends in Cancer Incidence and Mortality in Fukui Prefecture 
Journal of Epidemiology  2010;20(3):244-252.
There have been only a limited number of trend analyses of incidence and mortality using population-based cancer registry data in Japan, and the national statistics regarding incidence are estimated data. In the present study, data from the Fukui Prefecture cancer registry, which is the most accurate in Japan, were used to observe trends in incidence and mortality rates.
Cancer incidence and mortality rates from 1984 through 2004 were obtained from the Fukui Prefecture cancer registry. Joinpoint analysis developed for the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program was used to compute and graphically present annual percentage changes in age-adjusted incidence and mortality in Fukui Prefecture.
On joinpoint analysis, there were slight increases in incidence at all cancer sites combined for both sexes from 1986, but the trend was not significant in Fukui. Mortality in women appeared to significantly decrease, while mortality in men, which had been increasing until 1999, began to significantly decrease thereafter. In an analysis by anatomical site, both the incidence and mortality of stomach cancer significantly decreased in both sexes. However, the incidence and mortality of breast and prostate cancers significantly increased. The mortality of liver and lung cancers also increased in both sexes.
Cancer mortality has been declining in recent years, and the reduction in mortality from stomach cancer has significantly affected the trends in Fukui. Urgent cancer control planning by the Fukui local government is necessary, especially for cancers of the liver, lung, prostate, and breast.
PMCID: PMC3900848  PMID: 20431235
incidence; mortality; population-based cancer registry
10.  Hes1 Directly Controls Cell Proliferation through the Transcriptional Repression of p27Kip1 
Molecular and Cellular Biology  2005;25(10):4262-4271.
A transcriptional regulator, Hes1, plays crucial roles in the control of differentiation and proliferation of neuronal, endocrine, and T-lymphocyte progenitors during development. Mechanisms for the regulation of cell proliferation by Hes1, however, remain to be verified. In embryonic carcinoma cells, endogenous Hes1 expression was repressed by retinoic acid in concord with enhanced p27Kip1 expression and cell cycle arrest. Conversely, conditional expression of a moderate but not maximal level of Hes1 in HeLa cells by a tetracycline-inducible system resulted in reduced p27Kip1 expression, which was attributed to decreased basal transcript rather than enhanced proteasomal degradation, with concomitant increases in the growth rate and saturation density. Hes1 induction repressed the promoter activity of a 5′ flanking basal enhancer region of p27Kip1 gene in a manner dependent on Hes1 expression levels, and this was mediated by its binding to class C sites in the promoter region. Finally, hypoplastic fetal thymi, as well as livers and brains of Hes1-deficient mice, showed significantly increased p27Kip1 transcripts compared with those of control littermates. These results have suggested that Hes1 directly contributes to the promotion of progenitor cell proliferation through transcriptional repression of a cyclin-dependent kinase inhibitor, p27Kip1.
PMCID: PMC1087711  PMID: 15870295
11.  Bromodomain Protein Brd4 Binds to GTPase-Activating SPA-1, Modulating Its Activity and Subcellular Localization 
Molecular and Cellular Biology  2004;24(20):9059-9069.
Brd4 is a mammalian protein that contains a double bromodomain. It binds to chromatin and regulates cell cycle progression at multiple stages. By immunopurification and mass spectrometry, we identified a Rap GTPase-activating protein (GAP), signal-induced proliferation-associated protein 1 (SPA-1), as a factor that interacts with Brd4. SPA-1 localizes to the cytoplasm and to a lesser degree in the nucleus, while Brd4 resides in the nucleus. Bifluorescence complementation revealed that Brd4 and SPA-1 interact with each other in the nucleus of living cells. Supporting the functional importance of the interaction, Brd4 enhanced Rap GAP activity of SPA-1. Furthermore ectopic expression of SPA-1 and Brd4 redirected subcellular localization of the partner and disrupted normal cell cycle progression. These effects were, however, reversed by coexpression of the two proteins, indicating that a proper balance between Brd4 and SPA-1 in G2 is required for cell division. This work reveals a novel link between Brd4 and a GTPase-dependent mitogenic signaling pathway.
PMCID: PMC517877  PMID: 15456879
12.  Physiological β Cell Death Triggers Priming of Self-reactive T Cells by Dendritic Cells in a Type-1 Diabetes Model 
The Journal of Experimental Medicine  2003;198(10):1527-1537.
The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis. This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet β cells encounter antigen-presenting cells (APCs) displaying peptides derived from β cell proteins. We show here that a ripple of physiological β cell death, which occurs at 2 wk of age in all mouse strains, precipitates the arrival of such APCs, and that the relevant APC is a dendritic cell of CD11c+CD11b+CD8α− phenotype. These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.
PMCID: PMC2194112  PMID: 14623908
autoimmune response; pancreas; PLN; antigen transport; apoptosis
13.  Rap1 Functions as a Key Regulator of T-Cell and Antigen-Presenting Cell Interactions and Modulates T-Cell Responses 
Molecular and Cellular Biology  2002;22(4):1001-1015.
Activation of T cells by antigen requires adhesive interactions with antigen-presenting cells (APC) in which leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecules (ICAMs) are important. However, it is not well understood what signaling molecules regulate this process and how the modulation of adhesive events influences T-cell activation. Here we show that Rap1 is activated in T cells in an antigen-dependent manner and accumulated at the contact site of T-cell and antigen-loaded APC. Inhibition of Rap1 activation by a dominant-negative Rap1 or SPA-1, a Rap1 GTPase-activating protein, abrogates LFA-1-ICAM-1-mediated adhesive interactions with antigen-pulsed APC and the subsequent T-cell-receptor triggering and interleukin-2 production. Conversely, augmented antigen-dependent Rap1 activation by the expression of wild-type Rap1 enhances these responses but culminates in apoptosis by Fas and FasL. Thus, Rap1 functions as a key regulator of T-cell and APC interactions and modulates T-cell responses from productive activation to activation-induced cell death by regulating the strength of adhesive interactions. Moreover, constitutive Rap1 activation rendered T cells unresponsive with accumulation of p27Kip1. Our study indicates that the activation state of Rap1 has a decisive effect on the T-cell response to antigen.
PMCID: PMC134636  PMID: 11809793
14.  Rap1 Is a Potent Activation Signal for Leukocyte Function-Associated Antigen 1 Distinct from Protein Kinase C and Phosphatidylinositol-3-OH Kinase 
Molecular and Cellular Biology  2000;20(6):1956-1969.
To identify the intracellular signals which increase the adhesiveness of leukocyte function-associated antigen 1 (LFA-1), we established an assay system for activation-dependent adhesion through LFA-1/intercellular adhesion molecule 1 ICAM-1 using mouse lymphoid cells reconstituted with human LFA-1 and then introduced constitutively active forms of signaling molecules. We found that the phorbol myristate acetate (PMA)-responsive protein kinase C (PKC) isotypes (α, βI, βII, and δ) or phosphatidylinositol-3-OH kinase (PI 3-kinase) itself activated LFA-1 to bind ICAM-1. H-Ras and Rac activated LFA-1 in a PI 3-kinase-dependent manner, whereas Rho and R-Ras had little effect. Unexpectedly, Rap1 was demonstrated to function as the most potent activator of LFA-1. Distinct from H-Ras and Rac, Rap1 increased the adhesiveness independently of PI 3-kinase, indicating that Rap1 is a novel activation signal for the integrins. Rap1 induced changes in the conformation and affinity of LFA-1 and, interestingly, caused marked LFA-1/ICAM-1-mediated cell aggregation. Furthermore, a dominant negative form of Rap1 (Rap1N17) inhibited T-cell receptor-mediated LFA-1 activation in Jurkat T cells and LFA-1/ICAM-1-dependent cell aggregation upon differentiation of HL-60 cells into macrophages, suggesting that Rap1 is critically involved in physiological processes. These unique functions of Rap1 in controlling cellular adhesion through LFA-1 suggest a pivotal role as an immunological regulator.
PMCID: PMC110813  PMID: 10688643

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