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- Personalized metabolic profile estimation with the oral glucose tolerance test. [JOURNAL ARTICLE]
- Prog Biophys Mol Biol 2014 Aug 22.
Oral glucose tolerance test (OGTT) has been used to diagnose the diabetes mellitus (DM). However, the data of blood glucose and insulin change produced from OGTT contains information about the intestinal absorption, glucose control of glucose and insulin, pancreatic insulin secretion, and peripheral tissue glucose and insulin control. Therefore, proper dynamic model should reveal those data from OGTT. We made an OGTT model and could generate the each organic function to control glucose and insulin.We developed an OGTT model of five compartments for insulin dynamics and two compartments for glucose dynamics based on the previous reports. Anthropometric data of each individuals were used for assuming the cardiac output. Using simplex and Levenberg-Marquardt algorithm, we fit the data obtained from 42 normal subjects (24 men and 20 women) and 8 subjects of DM.We found clear sexual differences in intestinal glucose absorption kinetics, glucose sensitivity of pancreas, the maximal insulin production capacity, and the endogenous glucose production. We also found differences in normal vs. DM. Especially in case of DM, including pancreas dysfunction, liver dysfunction was evident. The differences of glucose and insulin dynamics in pancreas, liver and peripheral tissue between normal vs. DM subjects, such as the insulin resistance, the insulin secretion, and the relative roles of glucose disposal of each organ were clearly and quantitatively shown in a the time-dependent way during OGTT.From the above study, for the first time, we could generate the quantitative dynamic interaction of the glucose and the insulin from OGTT data and show the organ function during OGTT. Using this approach, we could find which organ is problematic in controlling glucose and insulin. Based on the model produced data, the personalized and targeted approach is possible in glucose and insulin related problems.
- Proinsulin specific, HLA-DQ8 and HLA-DQ8 transdimer restricted, CD4+ T cells infiltrate the islets in type 1 diabetes. [JOURNAL ARTICLE]
- Diabetes 2014 Aug 25.
Type 1 diabetes develops when the insulin-secreting beta cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize beta-cell derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These long-standing observations implicate CD4(+) T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human beta cells we isolated and characterized 53 CD4(+) T cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of these encoded proinsulin specific TCRs. On an individual clone basis, 14 of 53 (26%) CD4(+) T-cell clones recognized six distinct, but overlapping, epitopes in the C-peptide of proinsulin These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/DQ8 heterozygous individuals. Responses to these epitopes were detected in the PBMC of some people with recent onset T1D, but not in HLA-matched control subjects. Hence, proinsulin specific, HLA-DQ8 and DQ8 transdimer restricted, CD4(+) T cells are strongly implicated in the autoimmune pathogenesis of human T1D.
- Depleting antibody induction in simultaneous pancreas-kidney transplantation: a prospective single-center comparison of alemtuzumab versus rabbit anti-thymocyte globulin. [JOURNAL ARTICLE]
- Expert Opin Biol Ther 2014 Aug 25.:1-8.
Background: The study purpose was to analyze midterm outcomes in a prospective trial of alemtuzumab (Alem) versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous pancreas-kidney transplantation (SPKT). Methods: From February 2005 to October 2008, 46 SPKTs (45 portal-enteric drainage) were prospectively randomized as part of a larger kidney transplant study to receive either single-dose Alem (30 mg intraoperatively) or multiple-dose rATG antibody induction (starting intraoperatively, minimum three doses administered) with tacrolimus/mycophenolate ± steroids. Results: Of 222 kidney transplant patients enrolled in the study, 46 received SPKTs; 28 (61%) received Alem and 18 (39%) rATG induction. Follow-up ranged from 67 to 111 months (mean 80 months). There were no significant differences between the two groups in 5 years actual patient (86% Alem vs 89% rATG), kidney (82% Alem vs 61% rATG, p = 0.17) or pancreas (68% Alem vs 56% rATG) graft survival rates. Five years death-censored kidney (92% Alem vs 69% rATG, p = 0.09) and pancreas (76% Alem vs 56% rATG, p = 0.198) graft survival rates were slightly higher in patients receiving Alem. Acute rejection (21% Alem vs 44% rATG, p = 0.12) and major infection (39% Alem vs 67% rATG, p = 0.13) rates were slightly lower in the Alem group; cytomegalovirus infections were significantly lower (0 Alem vs 17% rATG, p = 0.05). The incidence of late acute rejection was low in both groups. There were no differences in early pancreas thrombosis (3.6% Alem vs 11% rATG), postoperative bleeding (11% Alem vs 0 rATG), other surgical complications, readmissions or freedom from steroids between groups. In patients with functioning grafts, 5 years mean serum creatinine (1.4 Alem vs 1.6 mg/dl rATG), calculated abbreviated modification of diet in renal disease glomerular filtration rate (55 Alem vs 52 ml/min/1.73 m(2) rATG), hemoglobin A1c (both 5.4%) and C-peptide (2.6 Alem vs 2.3 ng/ml rATG) levels were similar. Conclusions: Single-dose Alem and multiple-dose rATG induction provide similar midterm patient survival and graft functional outcomes with no major differences in morbidity or resource utilization.
- The clinical significance of somatostatin in pancreatic diseases. [JOURNAL ARTICLE]
- Ann Endocrinol (Paris) 2014 Aug 22.
The aim of the study was to provide knowledge on somatostatin and its action on the body, particularly the pancreas - in physiological and pathological conditions. In order to get to know the properties of somatostatin, a hormone discovered over forty years ago, many studies that define its structure and the mechanisms by which it operates have been conducted. The properties of somatostatin receptors and the effect of somatostatin on the body - both a healthy one and in various disease stages - were determined. It was proven that the somatostatin had an inhibitive effect on the endo- and exocrine secretion of this organ, which allowed a hypothesis that it might play an important role in the pathophysiology of diabetes. In patients with severe acute pancreatitis, both somatostatin and octreotide appear to reduce the mortality rate significantly, without any effect on the incidence of complications. Nevertheless, somatostatin analogues may be the cause of acute pancreatitis. With regard to severe chronic pancreatitis, refractory to other forms of therapy, it was demonstrated that octreotide significantly alleviated pain in many patients. A similar risk of death, and generally a lower risk of complications were found in the group of somatostatin-treated patients with chronic pancreatitis when compared to those receiving placebo or untreated. The occurrence of hyperglycemia after the application of somatostatin analogues, and in particular after pasireotide, is disturbing. Somatostatin analogues have found application in the treatment of cancers. They may improve symptoms in patients with gastroenteropancreatic neuroendocrine tumors (NETs) and stabilize the tumor growth (PROMID study). However, the optimal hormone dose sizes and frequencies necessary to ensure a full therapeutic effect in selected diseases of the pancreas have not been completely determined.
- Radiation dosimetry and biodistribution of the translocator protein radiotracer [(11)C]DAA1106 determined with PET/CT in healthy human volunteers. [JOURNAL ARTICLE]
- Nucl Med Biol 2014 Aug 1.
When microglia become activated (an integral part of neuroinflammation), cellular morphology changes and expression of translocator protein (TSPO) 18kDa is increased. Over the past several years, [(11)C]DAA1106 has emerged as a reliable radiotracer for labeling TSPO with high affinity during positron emission tomography (PET) scanning. While [(11)C]DAA1106 PET scanning has been used in several research studies, a radiation dosimetry study of this radiotracer in humans has not yet been published.Twelve healthy participants underwent full body dynamic [(11)C]DAA1106 PET scanning, with 8 sequential whole body scans (approximately 12 bed positions each), following a single injection. Regions of interest were drawn manually, and time activity curves (TACs) were obtained for 15 organs. OLINDA/EXM 1.1 was used to compute radiation absorbed doses to the target organs, as well as effective dose (ED) and effective dose equivalent (EDE).The ED and EDE were 4.06 ± 0.58μSv/MBq and 5.89 ± 0.83μSv/MBq, respectively. The highest absorbed doses were to the heart wall, kidney, liver, pancreas, and spleen. TACs revealed that peak dose rates are during the first scan (at 6min) for all organs other than the urinary bladder wall, which had its peak dose rate during the fourth scan (at 30min).The recently developed radiotracer [(11)C]DAA1106 has its EDE and target-organ absorbed dose such that, for a single administration, its radiation dosimetry is well within the U.S. FDA guidelines for basic research studies in adults. This dose level implies that the dosimetry for multiple [(11)C]DAA1106 scans within a given year also falls within FDA guidelines, and this favorable property makes this radiotracer suitable for examining microglial activation repeatedly over time, which may in the future be useful for longitudinal tracking of disease progression and monitoring of therapy response in conditions marked by neuroinflammation (e.g., head trauma and multiple sclerosis).
- Serous neoplasms of the pancreas share many, but not all aspects of their microvascular and angiogenic profile with low-grade clear cell renal cell carcinomas. [JOURNAL ARTICLE]
- Pathol Res Pract 2014 Aug 1.
Similarly to clear cell renal cell carcinomas (CCRCC), serous neoplasms (SN) of the pancreas frequently show inactivation of VHL gene, clear cell histology and abundant microvasculature. Data on the microvascular and angiogenic profile of SN are scarce. Aiming to examine further the striking resemblance of clear cell epithelial neoplasia in pancreas and kidney, we compared the microvascular profile and expression of pro-angiogenic factors in SN and in CCRCC using immunohistochemical stains. SN and CCRCC shared a predominance of differentiated blood vessels, scarcity of lymphatic vessels, presence of CD105 and claudin-5 in tumoral vessels, expression of vascular endothelial growth factor (VEGF)-A, cyclooxygenase-2 (COX-2), carbonic anhydrase IX in tumoral cells, and lack of VEGF-C in tumoral cells. In contrast to CCRCC, SN showed lower pericyte coverage of vessels, lower blood vessel endothelial cell proliferaction fraction, more pronounced VEGF receptor (VEGFR)-2 and glucose transporter-1 expression, higher inducible (iNOS) but lower endothelial nitric oxide synthase (eNOS) expression, as well as presence of VEGFR-3 and D2-40 expression in epithelial cells. In conclusion, we found a significant similarity but not equality of microvascular biology of SN and CCRCC. We recognized VEGFR-2, VEGFR-3, COX-2, iNOS, eNOS and D2-40 as new markers of epithelial cells of SN of the pancreas.
- The Kidney Donor Profile Index (KDPI) of Marginal Donors Allocated by Standardized Pretransplant Donor Biopsy Assessment: Distribution and Association With Graft Outcomes. [JOURNAL ARTICLE]
- Am J Transplant 2014 Aug 25.
Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score <4 [median KDPI: 87; interquartile range (IQR): 78-94] and 62 with a score = 4 [median KDPI: 87; IQR: 76-93]; 102 dual transplants [median KDPI: 93; IQR: 86-96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18-51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80-90 and of 37% for kidneys with a KDPI of 91-100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (-9.3, -17.9 and -18.8 mL/min, for dual transplants, single kidneys with PTDB score <4 and =4, respectively; p < 0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80-1.79; p = 0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.
- Type 1 Autoimmune Pancreatitis and IgG4-Related Sclerosing Cholangitis Is Associated With Extrapancreatic Organ Failure, Malignancy, and Mortality in a Prospective UK Cohort. [JOURNAL ARTICLE]
- Am J Gastroenterol 2014 Aug 26.
OBJECTIVES:Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-related SC) are now recognized as components of a multisystem IgG4-related disease (IgG4-RD). We aimed to define the clinical course and long-term outcomes in patients with AIP/IgG4-SC recruited from two large UK tertiary referral centers.METHODS:Data were collected from 115 patients identified between 2004 and 2013, and all were followed up prospectively from diagnosis for a median of 33 months (range 1-107), and evaluated for response to therapy, the development of multiorgan involvement, and malignancy. Comparisons were made with national UK statistics.RESULTS:Although there was an initial response to steroids in 97%, relapse occurred in 50% of patients. IgG4-SC was an important predictor of relapse (P<0.01). Malignancy occurred in 11% shortly before or after the diagnosis of IgG4-RD, including three hepatopancreaticobiliary cancers. The risk of any cancer at diagnosis or during follow-up when compared with matched national statistics was increased (odds ratio=2.25, CI=1.12-3.94, P=0.02). Organ dysfunction occurred within the pancreas, liver, kidney, lung, and brain. Mortality occurred in 10% of patients during follow-up. The risk of death was increased compared with matched national statistics (odds ratio=2.07, CI=1.07-3.55, P=0.02).CONCLUSIONS:Our findings suggest that AIP and IgG4-SC are associated with significant morbidity and mortality owing to extrapancreatic organ failure and malignancy. Detailed clinical evaluation for evidence of organ dysfunction and associated malignancy is required both at first presentation and during long-term follow-up.Am J Gastroenterol advance online publication, 26 August 2014; doi:10.1038/ajg.2014.223.
- Minimally invasive central pancreatectomy: current status and future directions. [JOURNAL ARTICLE]
- J Hepatobiliary Pancreat Sci 2014 Aug 25.
There is controversy regarding the recommended surgical approach for pancreatic tumors near the neck or proximal body of the pancreas. Unlike pancreatic cancer patients, those with benign and borderline (low-grade) malignant tumors of the pancreas are expected to have long-term survival after successful pancreatic resection. Therefore, surgeons need to consider not only oncologic safety, but also quality of life in their choice of surgical treatment. Laparoscopic central pancreatectomy (CP) is an ideal approach for pancreatic tumors near the neck or proximal body of the pancreas because it preserves endocrine and exocrine pancreatic function and conserves spleen function. Consequentially, CP can improve quality of life. However, there are no standardized studies supporting the use of laparoscopic CP. In this manuscript, we review the current status of minimally invasive CP in the advanced laparoscopic era and assess the quality of the evidence supporting the use of CP. We also propose future directions for scientific efforts to assess the utility of this surgical approach for benign and borderline malignant tumors near the neck of the pancreas.
- DNA glycosylase activity and cell proliferation are key factors in modulating homologous recombination in vivo. [JOURNAL ARTICLE]
- Carcinogenesis 2014 Aug 25.
Cancer susceptibility varies between people, affected by genotoxic exposures, genetic makeup and physiological state. Yet, how these factors interact among each other to define cancer risk is largely unknown. Here, we uncover the interactive effects of genetic, environmental and physiological factors on genome rearrangements driven by homologous recombination (HR). Using FYDR mice to quantify HR-driven rearrangements in pancreas tissue, we show that DNA methylation damage (induced by methylnitrosourea) and cell proliferation (induced by thyroid hormone) each induce HR and together act synergistically to induce HR-driven rearrangements in vivo. These results imply that developmental or regenerative proliferation as well as mitogenic exposures may sensitize tissues to DNA damaging exposures. We exploited mice genetically deficient in alkyl-adenine DNA glycosylase (Aag) to analyze the relative contributions of unrepaired DNA base lesions versus intermediates formed during base excision repair (BER). Remarkably, results show that, in the pancreas, Aag is a major driver of spontaneous HR, indicating that BER intermediates (including abasic sites and single strand breaks) are more recombinogenic than the spontaneous base lesions removed by Aag. Given that mammals have about a dozen DNA glycosylases, these results point to BER as a major source of pressure on the HR pathway in vivo. Taken together, methylation damage, cell proliferation and Aag interact to define the risk of HR-driven sequence rearrangements in vivo. These data identify important sources of sequence changes in a cancer-relevant organ, and advance the effort to identify populations at high risk for cancer.