bluuebunny/crossref_metadata_2025 huggingface dataset:
Subcutaneous Transplantation of MIN6 Beta Cells Embedded in mPEG-Ala Hydrogel
Authors: JUANG JYUHN-HUARNG , LIN HSIU-CHAO , CHEN CHEN-YI , KAO CHEN-WEI , WU SHU-TING , LIN SUNG-HAN , SHEN CHIA-RUI , WANG JIUN-JIE , CHU I-MING
Published: June 2018

The liver is the current site of choice for clinical islet transplantation, but many intraportal grafts were lost in the early stage of transplantation. Other disadvantages include the difficulty of monitoring the islets and procedure-associated complications. In contrast, the subcutaneous space offers the advantages of a large space, a less invasive procedure and easy graft monitoring and removal. However, islet transplantation into an unmodified subcutaneous site has poor efficacy; possibly due to poor oxygenation and inadequate vascularization of the transplanted tissue. In this study, we tested the feasibility of subcutaneous transplantation of MIN6 beta cells embedded in temperature-sensitive poly(ethylene glycol) methyl ether (mPEG)-Ala hydrogels as scaffolds. After culturing for 14 days, the viability of MIN6 beta cells in mPEG-Ala hydrogel was comparable with those in medium, either assayed by MTT or LIVE/DEAD. Static incubation showed that both had comparable insulin secretion. For in vivo experiments, we infected MIN6 beta cells with luciferase by AAV and then transplanted 5*106 cells embedded in mPEG-Ala hydrogel into the subcutaneous space of each nude mouse’s upper back. Positive In Vivo Imaging System (IVIS) images and positive insulin staining of tissue histology were observed up to 41 days after transplantation. Meanwhile, we incubated MIN6 beta cells with chitosan-coated superparamagnetic iron oxide (CSPIO) overnight and then transplanted 5*106 MIN6 beta cells into the subcutaneous tissue of each nude mouse’s left flank. The graft of CSPIO-labeled MIN6 beta cells was visualized on Magnetic Resonance (MR) scans as distinct hypointense spots on T2-weighted images located at the transplantation site at day 6 and 20. These results indicate that subcutaneous transplantation of MIN6 beta cells embedded in temperature-sensitive mPEG-Ala hydrogels is feasible. Moreover, the IVIS and MR imaging are useful tools for detecting and monitoring beta cells at the subcutaneous site.

Disclosure

J. Juang: None.H. Lin: None.C. Chen: None.C. Kao: None.S. Wu: None.S. Lin: None.C. Shen: None.J. Wang: None.I. Chu: None.
Efficacy of Metreleptin for Weight Loss in Overweight and Obese Adults with Low Leptin Levels
Authors: DEPAOLI ALEX , LONG ALISON , FINE GREGORY M. , STEWART MURRAY , O'RAHILLY STEPHEN
Published: June 2018

Leptin, an adipokine, regulates appetite, glucose and fat metabolism, and neuroendocrine function. A post-hoc pooled analysis of 4 studies (N=1064) in adults with BMI 27.0-40.0 kg/m2 showed that metreleptin (MTL), a leptin analogue, reduced weight in subgroups of adults with low baseline (BL) leptin levels (Fig. 1). A subsequent study (N=267) in adults with low BL leptin (females, ≤16 ng/mL; males, ≤5 ng/mL) and BMI 27.5-38.0 kg/m2 was conducted. Subjects (64% female; mean [SD] BL leptin, 14.2 [13.3] ng/mL) received QD subcutaneous MTL 10 mg, MTL 20 mg, or placebo. Both MTL doses decreased weight over time among subjects with low BL leptin (Fig. 2). MTL 20 mg showed statistically significant decreases by week 8. MTL was well tolerated. Thus, MTL 20 mg QD holds promise for weight loss among overweight and obese adults with low leptin levels.

Disclosure

A. DePaoli: Research Support; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. A. Long: Employee; Self; Aegerion Pharmaceuticals. G.M. Fine: Employee; Self; Aegerion Pharmaceuticals. M. Stewart: Employee; Self; Novelion. Stock/Shareholder; Self; Novelion. S. O'rahilly: Advisory Panel; Self; Aegerion Pharmaceuticals, Pfizer Inc., AstraZeneca, MedImmune, Novo Nordisk Inc., ERX Pharmaceuticals, Inc..
Influence of Diabetes Complications on the Cost-Effectiveness of A1C Treatment Goals in Older U.S. Adults
Authors: SHAO HUI , ROLKA DEBORAH B. , GREGG EDWARD W. , ZHANG PING
Published: June 2018

The American Diabetes Association (ADA) recommends glycemic management goals for older diabetes patients take into account the complexity of complications. Little information is available on how cost-effectiveness (CE) of glycemic control goals relates to a patient’s level of complications. We examined the CE of intensive glycemic control (A1c <7.5%) compared to standard treatment (A1c <8.5%) among adults aged 65 y with type 2 diabetes having various complications. 2011-2016 National Health and Nutrition Examination Survey data were used to generate nationally representative samples with various complications. The CDC-RTI diabetes simulation model was used to project the long-term health and cost consequences of intensive/standard glycemic control. The CE of the intensive glycemic control was measured in costs (2017 USD) per quality adjusted life year (QALY). Based on a $50,000/QALY threshold, intensive glycemic control was only marginally cost effective for patients with no complications or any microvascular complication (excluding renal failure) but was not cost-effective for patients with one or more macrovascular complications. Current ADA standards recommend intensive glycemic control among older adults with fewer than 3 complications. From a CE perspective, our results only support the intervention among those with no complications or only microvascular complication.

Disclosure

H. Shao: None. D.B. Rolka: None. E.W. Gregg: None. P. Zhang: None.
Postmenopausal Women with Endometrial Cancer Have Greater Metabolic Dysfunction and Higher BMI than Women with Benign Endometrium
Authors: COOKE KATHERINE M. , DUN ERICA , ANAM ANIKA K. , FLANNERY CLARE
Published: June 2018

Obesity is an independent risk factor for endometrial adenocarcinoma (EC), yet it is unknown which attributes of obesity contribute to EC pathogenesis. We hypothesize that heterogeneity in metabolic health distinguishes which obese women are at risk for EC. We previously found that more premenopausal women with pre-malignant hyperplasia had type 2 diabetes and dyslipidemia than women with benign hyperplasia (BH), despite similar BMI. BH is the ideal control condition since presenting symptoms are similar, yet malignant transformation is negligible. Thus, we sought to compare metabolic abnormalities in postmenopausal women with EC and BH. We reviewed medical records of 284 women who received a biopsy/hysterectomy at our center over 3 years. We examined non-Hispanic white women age 50-65 years with BMI 25-50 kg/m2, to limit variability in factors known to affect metabolism. 122 women had histologically confirmed EC (n=74) or BH (n=48), and 60% had lab data. Variables were analyzed by chi-squared or Student’s T test. Women with EC were older (58 ± 0.5 vs. 53 ± 0.4 years, p<0.0001) and had higher BMI (37 ± 1 vs. 32 ± 1 kg/m2, p<0.0001) than women with BH. BMI distribution was markedly different between groups, with a higher frequency and greater severity of obesity among women with EC (p<0.0001). More women with EC than BH had type 2 diabetes (19% vs. 4%, p<0.05) and hypertension (54% vs. 25%, p<0.01). Women with EC had higher triglycerides (140 ± 12 vs. 110 ± 13 mg/dL, p<0.05) and lower HDL (55 ± 2 vs. 60 ± 4 mg/dL, p=NS). However, these differences can be explained by the skewed BMI distribution. LDL and total cholesterol as well as statin use (20% vs. 25%) were similar between groups (p=NS). The striking differences in BMI among postmenopausal women with EC and BH highlights the role of obesity in EC pathogenesis. Since BMI affects metabolism, a prospective study of BMI-matched women is necessary to determine whether metabolic dysregulation independently influences cancer development.

Disclosure

K.M. Cooke: None. E. Dun: None. A.K. Anam: None. C. Flannery: None.
Glycation and Deamidation Result in HDL Dysfunction in Patients with Type 2 Diabetes
Authors: KASUMOV TAKHAR , GOLIZEH MAKAN , KASHYAP SANGEETA
Published: June 2018

Diabetes is associated with HDL dysfunction and perturbed iron metabolism. ApoAI, transferrin (Trf) and ceruloplasmin (Cp) are the key HDL proteins involved in cholesterol efflux and iron metabolism. We tested the hypothesis that hyperglycemia-induced glycation contributes to HDL dysfunction and altered iron metabolism in diet-controlled patients with T2D. HDL from patients with T2D and matched healthy controls (n=9/group) was isolated and it’s anti-oxidant and cholesterol efflux properties were quantified. HDL proteome composition and post-translational modification of proteins were quantified by proteomics aproach. Metabolic 2H2O-labeling was applied to quantify HDL proteome dynamics. Patients with T2D and controls had similar lipid (triglycerides, total cholesterol, and HDL cholesterol) profile. HDL from T2D patients had reduced anti-oxidant (PON1 activity) and macrophage-cholesterol efflux capacity (P<0.05) and was enriched with glycated apoAI and transferrin (Tf), and deamidated ceruloplasmin (Cp), the key HDL proteins involved in cholesterol and iron transport. Both ApoAI and Trf glycation were directly correlated with HbA1c and the extent of glycations were associated with their increased degradation. ApoAI glycation was inversely correlated with cholesterol efflux activity of HDL. Trf glycations at Lys-2and Lys-534 sites involved in iron coordination, were 2-3 fold higher in T2D than in the controls. The PTM search on Cp revealed five asparagine deamidation sites in T2D patients with N-943 being located on one of the oxidation-prone motifs and may result in the loss of Cp’s ferroxidase activity. In vivo HDL flux study demonstrated that glycated apoAI and Tf, and deamidated Cp species were degraded 3, 10, and 2 fold faster than the respective non-modified native proteins. HDL dysfunction and oxidative stress in T2D is related to glycation- and deamidation-induced instability of HDL proteins, including ApoAI, Tf and Cp.

Disclosure

T. Kasumov: None. M. Golizeh: None. S. Kashyap: None.
Estrogen-Responsive Neurons in the Ventrolateral VMH Regulate Glucose Balance
Authors: HE YANLIN , XU PINGWEN , XIA YAN , YANG YONGJIE , CAI XING , HYSENI ILIRJANA , XU YONG
Published: June 2018

Brain glucose-sensing neurons can detect glucose fluctuations and prevent severe hypoglycemia. We observed that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) are all glucose-sensing neurons, being either glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). In particular, hypoglycemia inhibits GE-ERαvlVMH neurons through opening the KATP channel, and activates GI-ERαvlVMH neurons via enhanced t-type voltage-gated calcium currents. GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN); selective activation of the ERαvlVMH◊mpARH circuit and inhibition of the ERαvlVMH◊DRN circuit both increase blood glucose. Importantly, loss of estrogen-ERα signals impairs glucose-sensing properties of ERαvlVMH neurons and attenuates hyperglycemic response to the central glucopenia in female mice. Depletion of estrogen impairs the AMP kinase pathway which accounts for the reduced glucose-sensing capability of these ERαvlVMH neurons; enhanced AMP kinase activity selectively in ERαvlVMH restores the glucose response in female mice depleted of estrogen. Thus, our results indicate that estrogen-ERα-AMP kinase signals in ERαvlVMH neurons are required for these neurons to detect hypoglycemia and therefore are indispensable for defending against severe hypoglycemia in female mice.

Disclosure

Y. He: None. P. Xu: None. Y. Xia: None. Y. Yang: None. X. Cai: None. I. Hyseni: None. Y. Xu: None.
The Role of Epicardial Adipose Tissue Lymphocytes in Low-Grade Inflammation and Coronary Artery Disease
Authors: MRAZ MILOS , CINKAJZLOVA ANNA , LACINOVÁ ZDENA , KLOUCKOVA JANA , KRATOCHVILOVA HELENA , LIPS MICHAL , KOPECKY PETR , PORIZKA MICHAL , LINDNER JAROSLAV , HALUZIK MARTIN
Published: June 2018

Lymphocytes play a role in the development of adipose tissue inflammation. Epicardial adipose tissue was shown to be a potential source of inflammatory mediators contributing to coronary atherosclerosis. The aim of the study was to assess lymphocyte content in peripheral blood, subcutaneous (SAT) and epicardial adipose tissue (EAT) in subjects with coronary artery disease (CAD) along with the effects of elective cardiac surgery. Twelve subjects without CAD (non-CAD group) and 24 age-, BMI- and HbA1C-matched subjects with CAD were included into the study. Blood, SAT and EAT samples were obtained before and at the end of elective cardiac surgery. Lymphocyte populations were quantified as percent of CD45+ cells using flow cytometry. Subjects with CAD had higher total lymphocyte (CD45+) amount in EAT compared to SAT (32.24±7.45 vs. 11.22±1.34%, p=0.025) with a similar trend observed in non-CAD subjects (29.68±7.61 vs. 10.13±2.01%, p=0.067). CD3+ cells were increased and CD3- cells decreased in EAT of CAD relative to non-CAD group with no difference between EAT and SAT. In both groups EAT showed reduced percentage of NK cells (CD15/56+CD3-) and elevated B cells (CD19+) relative to SAT (NK cells: 5.96±1.32 vs. 13.22±2.10%, p=0.012 for CAD and 5.32±1.97 vs. 13.81±2.72%, p=0.022 for non-CAD; B cells: 5.22±2.43 vs. 0.96±0.21%, p=0.039 for CAD and 12.49±5.83 vs. 1.16±0.19%, p=0.016 for non-CAD). CD8+ and NKT (CD16/56+CD3+) cells in EAT correlated positively with fasting glucose and HbA1C, while showing no association in SAT. Cardiac surgery decreased total lymphocytes in peripheral blood, SAT and EAT of both groups, while having only minor effects on lymphocyte subpopulations. To conclude, epicardial adipose tissue in subjects with CAD shows increased amount of total and CD3+ lymphocytes as compared with SAT or non-CAD subjects. These changes could contribute to the development of local inflammation and coronary atherosclerosis.

Disclosure

M. Mraz: None. A. Cinkajzlova: None. Z. Lacinov : None. J. Klouckova: None. H. Kratochvilova: None. M. Lips: None. P. Kopecky: None. M. Porizka: None. J. Lindner: None. M. Haluzik: None.
Long Noncoding RNA Zfas1 in Diabetic Cardiomyopathy
Authors: FENG BIAO , CHEN SHALI , CHAKRABARTI SUBRATA
Published: June 2018

Fibrosis is a significant problem in diabetic cardiomyopathy (DCM). Both long noncoding RNAs (LncRNAs) and miRNAs (miR) play important roles in cellular processes. miR-9 targets important extracellular matrix(ECM) protein, such as fibronectin(FN) and collagen(Col), which are upregulated in DCM. The role of ZNFX1-AS1 (Zfas1), a LncRNA targeting miR-9 in DCM is not clear. We investigated Zfas1 in vitro and in vivo and its regulatory mechanism on ECM protein through miR-9.

Microarrays were used to examine LncRNAs and miRNAs expression in ECs exposed to 25 mM glucose (HG) compare to 5 mM glucose and were validated by qPCR. Expression of ECM proteins targeted by miR-9 were examined. Luciferase assay was used to determine the interaction between miR-9 and its target genes. Cardiac tissues from streptozotocin-induced diabetic mice were examined similarly.

The array and qPCR analysis showed glucose-induced upregulation of LncRNA Zfas1 and downregulation of miR-9 in ECs. FN mRNA, Col1&4 mRNA and protein levels were increased in ECs treated with HG. Luciferase assay showed the binding of miR-9 to FN 3’-UTR and miR-9. Zfas1 silencing expression of its target genes expression in HG. Furthermore miR-9 mimics co-transfection with Zfas1 siRNA partially recovered these ECM protein expression. Interestingly, methylation blockade also reduced ECM protein expression. In the hearts of the diabetic animals, Zfas1 expression was increased and miR-9 was decreased and expression of transcripts regulated by miR-9 were increased.

These studies indicate a novel glucose-induced mechanism of increased ECM protein production, which is regulated by Zfas1 through miR-9 in diabetes. Identifying such mechanisms may lead to potential RNA based treatment for diabetic complications.

Disclosure

B. Feng: None. S. Chen: None. S. Chakrabarti: None.
Improving Quality of the Informed Consent Process—Developing an Easy-to-Read, Multimodal, Patient-Centered Format in Diabetes Research
Authors: LINDSLEY KAREN
Published: June 2018

Objective: To develop a patient-centered informed consent and assessment written at a 6th grade-level that is multimodal, affordable, transportable, and readily modifiable for protocol updates.

Methods: This quality improvement initiative was performed in two phases on an actively-recruiting, familial study at a pediatric diabetes multi-site clinic. In phase I, 38 subjects completed the standard paper consent, a comprehension assessment and provided process feedback. Using feedback and the structure of the Plan-Do-Study-Act cycle a multimodal consent explanation and assessment were developed. In phase II, subjects were randomized to the standard (n=25) or the multimodal consent (n=25) and all completed the same comprehension assessment via touch-screen tablet. Primary outcomes were comparison of the individual and total comprehension assessment scores.

Results: Total comprehension scores were higher in the multimodal vs. the standard consent group (p<0.001) and on the elements of benefits (p<0.001), risks (p<0.001), volunteerism (p<0.012), results (p<0.001), confidentiality (p<0.004) and privacy (p<0.001).

Conclusion: A multimodal consent explanation and assessment presented sequentially on a touch-screen tablet were patient-centered enhancements to standard consent.

Disclosure

K. Lindsley: None.
Increased Deacetylation of Proteins in Sensory Neurons by Sirtuin 1 Protein Overexpression Reverses T2D Peripheral Neuropathy
Authors: CHANDRASEKARAN KRISH , HO CHENG-YING , SALIMIAN MOHAMMAD , KUMAR PRANITH H. , REDDY KONDURU SAI SRUTHI , RUSSELL JAMES W.
Published: June 2018

Sirtuin1 (SIRT1) protein uses NAD+ as a substrate to deacetylate transcription factors, cofactors, and histones to enhance mitochondrial function. We tested the hypothesis whether increased expression of SIRT1 protein in dorsal root ganglion (DRG) neurons would rescue mice from peripheral neuropathy induced by a high fat diet (HFD). Neuron-specific, doxycycline (DOX)-inducible, SIRT1 protein over expressing C57BL6 transgenic mouse (nSIRT1OE Tg) were generated. Expression of SIRT1 protein was observed in small to medium sized DRG neurons. nSIRT1OE was shut off by feeding, weaned Tg mice, with DOX in the diet for 12 weeks. The Tg mice were divided into 3 groups. Group # 1: nSIRT1OE Tg mice fed with standard diet (STD) plus DOX for 4 months; Group # 2: nSIRT1OE Tg mice fed with HFD plus DOX for 4 months; Group # 3: nSIRT1OE Tg mice fed with HFD plus DOX for 2 months until they develop neuropathy and then switched to HFD minus DOX for additional 2 months. Neuropathy was determined by mechanical allodynia thresholds (MAT) and nerve conduction velocity (NCV) at 0, 2 and 4 months. Intraepidermal nerve fiber density (IENFD) was measured at 4 months. MAT, NCV and IENFD were decreased in HFD-fed (Group # 2) mice compared to STD-fed mice (Group # 1) at 2 and 4 months. In Group # 3 mice, 2 months after turning on nSIRT1OE, we observed a reversal of mechanical allodynia, NCV and attenuation of IENFD (Group # 3 compared to Group # 2). Western blot of protein extracts from DRG neurons showed that HFD increased acetylation of proteins and SIRT1OE abolished the HFD-induced acetylation of proteins. The mitochondrial bioenergetics profile of cultured adult DRG neurons showed that hyperglycemia induced a decrease in the spare respiratory capacity in wild type (WT) DRG neurons. This was corrected in nSIRT1OE Tg DRG neurons. In type 2 diabetic neuropathy, altered acetylation of proteins and reduced mitochondrial function via a defective SIRT1 pathway may contribute to developing distal axonopathy.

Disclosure

K. Chandrasekaran: None. C. Ho: None. M. Salimian: None. P.H. Kumar: None. S. Konduru: None. J.W. Russell: None.
Comparison of Cognitive Function, Depression, and Sleep Quality among Type 2 Diabetes Mellitus Patients With and Without Diabetic Neuropathy
Authors: RADHAKRISHNAN CHANDNI , CR RINU R. , SREEJITH K , ANJUSHA UT
Published: June 2018

Diabetic neuropathy is one of the most common complication of diabetes mellitus. Many studies had reported that type 2 diabetes mellitus increases the risk of cognitive impairement,depression and sleep impairement in patients with diabetes mellitus.

The main objective of the study is to determine whether any significant impairement in cognition function, sleep quality and depression status exist among diabetic neuropathy patients compared to patients with type 2 diabetes mellitus alone. A prospective observational study was conducted in a tertiary care teaching hospital. Patients who satisfied both inclusion and exclusion criteria were included in the study. A total of 59 type 2 diabetes mellitus patients with neuropathy and 55 patients with out neuropathy were enrolled in to the study after obtaining written informed consent. Cognitive status was assessed with the help of MOCA questionnaire. Sleep quality was assessed by using pittsburgh sleep quality index questionnare and depression, by using PHQ-9 questionnaire. The diabetic neuropathic patients showed a significant impairement in cognitive status (P value 0.003), sleep quality (P value 0.000) and depression status (p value 0.000). The study concluded that diabetic neuropathy increases the risk of cognitive impairement, impairement in sleep quality and depression in type 2 diabetes mellitus patients.

Disclosure

C. Radhakrishnan: None. R.R. Cr: None. S. K: None. A. Ut: None.
Effect of Ezetimibe Add-On Therapy on Non-HDL-C in Type 2 Diabetes Subjects—A Post-Hoc Analysis of RESEARCH Study
Authors: SAKAMOTO KENTARO , KAWAMURA MITSUNOBU , TAGAMI MOTOKI , TANAKA AKIRA , MORI YASUMICHI , HIRANO TSUTOMU , SHIBA TERUO ,   RESEARCH STUDY GROUP
Published: June 2018

Background: In RESEARCH study, we demonstrated the superiority of ezetimibe add-on therapy over statin-doubling in T2DM.Non-HDL-C is attracting attention as an index including TG rich lipoproteins reflecting insulin resistance in diabetics.

Methods: 109 T2DM adults with LDL-C >=120 mg/dL (>=100 mg/dL in secondary preventive) despite statin treatment were randomly assigned to statin doubling group (S) or adding ezetimibe (E) for 12 weeks.As a post-hoc analysis, non-HDL-C change and TG rich lipoproteins were analyzed.

Results: The rate of non-HDL-C reduction was significantly greater in E(20.9%) than in S(8.3%). Assuming the non-HDL-C target as <150 mg/dl (<130 mg/dl for secondary preventive), the achievement rate was significantly higher in E(88.7%) than in S(57.1%). The rates of apoB and apoE reduction were significantly larger in E (apoB 14.8% and apoE 7.7%) than in S (apoB 9.0% and apoE 2.9%). By regression analysis, apoE change rate showed correlation with sd-LDL change rate or RLP-C change rate, respectively, with larger correlation and regression coefficient in E. The percentage change in non-HDL-C was correlated with the percentage change in sd-LDL, with larger regression coefficient in E. Analysis was also made for 43 subjects with TG>=150 mg/dl before treatment, and 73 subjects without achievement in the non-HDL-C target before treatment. Non-HDL-C reduction rates were greater in E (21.1% and 25.1%) than in S (8.9% and 8.7%), respectively. Target achievement rates were also significantly larger in E (77.8% and 83.9%) than in S (48.0% and 42.9%). ApoB reduction was 13.2% and 11.6% in S, and 12.5% and 17.1% E, and apoE reduction was 9.4% and 5.4% in S and 13.0% and 9.4% in E, respectively. The correlation of change rates showed almost the same tendency compared to the whole population.

Conclusion: Ezetimibe combination therapy effectively reduced non-HDL-C reflecting TG rich lipoproteins, compared with statin-doubling therapy.

Disclosure

K. Sakamoto: None. M. Kawamura: None. M. Tagami: None. A. Tanaka: Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Kewpie Corporation. Y. Mori: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca. T. Shiba: Speaker's Bureau; Self; Shionogi & Co., Ltd., Pfizer Inc., Merck Sharp & Dohme Corp., Kowa Company, Ltd., Daiichi Sankyo Company, Limited.
Tu Puedes—An Exploratory Usability Pilot of a Postpartum Education "App" for Latina Women with Previous Gestational Diabetes
Authors: CASTORINO KRISTIN , ALVAREZ SILVIA , MATHERS HANNAH M. , LAREZ ARIANNA J. , AXELROD CEARA
Published: June 2018

Gestational diabetes mellitus (GDM) affects nearly 14% of Latina women—a rate significantly higher than the background population. Standard-of-care dictates that postpartum education should be provided though it is rarely done due to socioeconomic, linguistic, transportation and childcare barriers. We propose that a smartphone application (app) has the potential to serve as a cost-effective approach to delivering health education that can break through these barriers and empower postpartum Latina women with the education requisite for making positive lifestyle changes. We designed a small pilot study to test the app’s usability to inform larger studies. Tu Puedes is a culturally and linguistically appropriate diabetes prevention app we developed in Spanish. Women with previous GDM aged 18-40 years completed 4 lessons, either though the app or via an in-person classroom setting with a scripted curriculum. A pre- and post-survey was given to assess participants’ qualitative experience using the app. In addition, standard metabolic measures at baseline and post-intervention (4 weeks) were completed, and compared for both groups. Of the 22 women recruited, 17 completed all 4 lessons, with greater retention in the app group. Survey responses were overall positive, with 73% of participants deeming the app both easy to use and better than any past group education. Users had a 40% increase in self-perceived health, 67% of users wanted to continue use of the app, and all users would recommend it to a friend. Though insufficiently powered and for nominal duration, we found significant decreases in weight and BMI compared to the control group with 90% and 95% confidence respectively, but not in blood pressure or waist circumference. Our results suggest that the Tu Puedes app is a feasible and user-friendly way to disseminate postpartum diabetes prevention education to a Spanish-speaking Latina population with previous GDM, and support the need for further research.

Disclosure

K. Castorino: None. S. Alvarez: None. H.M. Mathers: None. A.J. Larez: None. C. Axelrod: None.
Effect of Dairy Consumption and Its Fat Content on Glycemic Control and Cardiovascular Risk Factors in Patients with Type 2 Diabetes—A Randomized Controlled Study
Authors: MOTTALIB ADHAM , MITRI JOANNA , SALSBERG VERONICA , ASHRAFZADEH SAHAR , ELSEAIDY TAHA , TOMAH SHAHEEN , ALSIBAI KHALED , MAHMOUD NOOR , HAMDY OSAMA
Published: June 2018

The 2015 Dietary Guidelines for Americans recommend daily consumption of 3 servings of low or non-fat dairy. However, the effects of dairy consumption and its fat content on glycemic control and cardiovascular risk factors in patients with type 2 diabetes (T2D) are unknown. This study was designed to evaluate the impact of higher consumption of full-fat and low/non-fat dairy on HbA1c, lipid profile and blood pressure (BP) in patients with T2D.

We enrolled 72 participants with uncontrolled T2D (mean age 59±8 years, 46% females) who were consuming <3 servings of dairy/day and randomized them into 3 groups. Group A was asked to incorporate ≥3 daily servings of full-fat dairy and group B to incorporate ≥3 daily servings of low/ non-fat dairy into their diet. Group C was asked to maintain the baseline dairy intake. Participants were counseled by a registered dietitian about maintaining their daily caloric intake and body weight. They were asked to maintain their usual doses of diabetes, antihypertensive and hypolipidemic medications. Participants were evaluated at baseline, 3 and 6 months.

At baseline, mean T2D duration was 14±8 years, HbA1c 8.1±1.0%, body weight 92±17 kg, daily caloric intake 1885±600 kcal (43.4±7.0% carbohydrates, 37.8±5.5% fat, 13.0±2.8% saturated fat, and 18.1±3.6% protein), LDL-C 80±26 mg/dL, HDL-C 47±16 mg/dL, triglycerides 172±178 mg/dL, systolic BP 129±16 mmHg and diastolic BP 72±8 mmHg. There were no differences between groups in any of these parameters at baseline. At 6 months, percent calories from saturated fat increased by 3.7±0.8% in group A (p<0.0001), and decreased by 4.4±1.7% in group B (p=0.014). There were no differences in HbA1c, body weight, total caloric intake or percent calories from carbohydrates, lipid parameters or BP between groups.

This study shows that increasing consumption of dairy products to ≥3 servings/day, irrespective of fat content, has no effect on HbA1c, lipid profile or BP in patients with T2D.

Disclosure

A. Mottalib: None. J. Mitri: Research Support; Self; National Dairy Council, Kowa Pharmaceuticals America, Inc.. Research Support; Spouse/Partner; AbbVie Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc., Gilead Sciences, Inc.. Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Biogen, AbbVie Inc.. V. Salsberg: None. S. Ashrafzadeh: None. T. Elseaidy: None. S. Tomah: None. K. Alsibai: None. N. Mahmoud: None. O. Hamdy: Research Support; Self; Abbott. Advisory Panel; Self; AstraZeneca. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Healthimation, LLC.. Consultant; Self; Sanofi-Aventis.
MEDI0382, a GLP/Glucagon Receptor Dual Agonist, Significantly Reduces Hepatic Fat Content in Subjects with Type 2 Diabetes Mellitus
Authors: JAIN MEENA , TSAI LAN-FENG , ROBERTSON DARREN , HIRSHBERG BOAZ , HOCKINGS PAUL , JOHANSSON LARS , AMBERY PHILIP
Published: June 2018

MEDI0382 is a balanced GLP-1/glucagon receptor dual agonist in development for type 2 diabetes mellitus (T2DM). We investigated the effects of MEDI0382 on hepatic fat content in overweight/obese subjects with T2DM and a BMI of 27-40 kg/m2. In a phase 2a study (NCT02548585), 51 subjects were randomized to receive MEDI0382 200 μg or placebo daily during a 41-day treatment period. Quantification of liver proton density fat fraction, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) was performed as an exploratory analysis in a subset of patients (MEDI0382 n = 17, placebo n = 21) who had MRI scans taken at baseline and day 41. Mean (SD) liver fat content at baseline was 15.7% (8.97) and 18.1% (8.38) in the MEDI0382 and placebo groups, respectively. Patients treated with MEDI0382 showed a highly significant relative reduction from baseline in hepatic fat content vs. placebo (Table). This was positively correlated with reductions in both body weight (r = 0.49, P = 0.002) and alanine aminotransferase (r = 0.42, P = 0.009). Treatment with MEDI0382 was also associated with reductions in both SAT and VAT vs. placebo. These data demonstrate the efficacy of MEDI0382 in reducing liver fat and its potential for the treatment of nonalcoholic fatty liver disease, including steatohepatitis.MeasurementChange from Baseline, LS Mean (90% CI)P MEDI0382 (n - 17)Placebo (n = 21)Hepatic fat content, absolute change (%)-5.98 (-7.67, -4.29)-3.17 (-4.68, -1.65)0.017Hepatic fat content, relative change (%)-39.12 (49.11, -29.14)-19.51 (-28.49, -10.53)0.006SAT (L)-0.39 (-0.48, -0.30)-0.21 (-0.30, -0.13)0.008VAT (L)-0.36 (-0.52, -0.19)-0.14 (-0.29, 0.01)0.057

Disclosure

M. Jain: Employee; Self; MedImmune. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. P. Hockings: Other Relationship; Self; MedImmune, AstraZeneca. L. Johansson: Stock/Shareholder; Self; Antaros Medical. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
Excess Nicotinamide Induces Reactive Oxygen Species Generation, Insulin Resistance, and Epigenetic Change in Rats and Humans
Authors: ZHOU YIMING , CHEN NANA , LI DA , SUN WUPING , ZHOU SHI-SHENG
Published: June 2018

The implementation of grain fortification with niacin, commonly in the form of nicotinamide, has significantly increased niacin per capita consumption in U.S. from 1930s. Nicotinamide is the precursor of NAD and NADP, which participate in many biological reactions. Therefore, nicotinamide homeostasis is vitally important for the body. This study is to investigate the effects of excess nicotinamide on ROS generation, insulin resistance, and epigenetic change, which are hallmarks of type 2 diabetes.

We found acute nicotinamide overload increased ROS generation, insulin resistance, and reduced muscle glycogen level in adult rats. Besides these effects, long-term nicotinamide overload led to oxidative stress in kidney and liver, increased their DNA damage, and decreased their global DNA methylation profile. We further demonstrated that decreasing nicotinamide degradation and excretion level was crucial for the ROS generation- and insulin resistance-inducing effects using an impaired skin detoxification rat model.

Using oral glucose tolerance test (OGTT), we observed that in healthy volunteers, nicotinamide addition induced higher levels of ROS generation and insulin resistance in the early phase, followed by hypoglycemia in the late phase. Compared to controls, diabetic patients showed a disturbed nicotinamide degradation pattern, characterized by higher plasma N1-methylnicotinamide (NMN) levels and lower urinary degraded metabolite, N1-methyl-2-pyridone-5-carboxamide (2-Py).

Mechanistically nicotinamide degradation process was associated with ROS generation; excess nicotinamide led to higher ROS generation causing kidney and liver damage. We also found that excess nicotinamide disturbed the monoamine neurotransmitters degradation and DNA methylation by competing for the biological methyl-donor, betaine in the body.

In summary, our results indicate that excess nicotinamide may play an important role in type 2 diabetes.

Disclosure

Y. Zhou: None. N. Chen: None. D. Li: None. W. Sun: None. S. Zhou: None.
Effect of Stevia on Glycemic and Insulin Responses in Obese Patients—A Randomized, Double-Blind, Placebo-Controlled Crossover Study
Authors: SAMAKKARNTHAI PARINYA , PAYANUNDANA MANAPORN , SATHAVARODOM NATTAPOL , SIRIWAN CHONPITI , BOONYAVARAKUL APUSSANEE
Published: June 2018

Background: Stevia is natural nonnutritive sweeteners (NNS) that is considered to be metabolic inert in contrast with artificial NNS, especially sucralose, which cause glucose intolerant in obese patients. However, acute effect of stevia ingestion on glycemic and insulin responses in obese patients are not clearly established.

Objectives:To assess acute effect of stevia on glycemic and insulin responses in obese patients.

Material and Methods: Obese patients underwent a 75 gram oral glucose tolerance test (OGTT) preceded by consuming pills containing either 200 mg stevia or placebo for 60 minutes before test on two separate occasions, 1 week apart, in a randomized crossover design. Blood samples were obtained for glucose and insulin at 0,30,60,90 and 120 minutes. Area under the curve (AUC) of glucose and insulin responses were calculated. Indices for insulin sensitivity (Matsuda index) and Insulin secretion (Insulinogenic index) were calculated using minimal models of glucose and insulin kinetics.

Results: Twenty obese patients (BMI 28.75±3.68 kg/m2) were recruited to the study. There were no significant differences in AUC of glucose and insulin between stevia and placebo (glucose, 15,285±4,531 vs. 15,101 ±3,955, p=0.89 and insulin 8,507 ±5,858 vs. 7,652 ± 5,020,p=0.62) Insulin sensitivity derived from OGTT using Matsuda index was not significant difference between stevia and placebo (4.74±1.86 vs. 5.84±2.96,p=0.09). Insulin secretion using Insulinogenic index was not significant difference between stevia and placebo (p=0.155).

Conclusions: Stevia does not affect in acute glycemic and insulin responses to OGTT in obese patients. This findings need to be determined in longer duration of ingestion study.

Disclosure

P. Samakkarnthai: None. M. Payanundana: None. N. Sathavarodom: None. C. Siriwan: None. A. Boonyavarakul: None.
Mir-128 Targets Thioredoxin-Interacting Protein 3’UTR and Downregulates Its Expression in Pancreatic Beta Cells
Authors: JING GU , CHEN JUNQIN , XU GUANLAN , SHALEV ANATH
Published: June 2018

Thioredoxin-interacting protein (TXNIP) expression is induced by glucose, promotes beta cell apoptosis and is essential for glucotoxicity-induced beta cell death, whereas TXNIP deficiency protects against diabetes. Carbohydrate-response element-binding protein (ChREBP/MondoA) is the major transcription factor conferring glucose-induced TXNIP expression. However, we recently discovered that glucose was still able to induce TXNIP in ChREBP knockout mouse islets suggesting the existence of other factors involved in glucose-induced TXNIP regulation. Analyses of the TXNIP 3’UTR revealed several potential miRNA binding sites including miR-93, miR-106b and miR-128. However, using INS-1 beta cells, primary mouse islets and T2D human islets, we found that only miR-128 was downregulated by glucose or diabetes. This suggested that glucose might decrease miR-128 and thereby promote TXNIP expression. In fact, we found overexpression of miR-128 significantly reduced TXNIP mRNA and protein expression whereas inhibition of miR-128 increased beta cell TXNIP expression. Furthermore, luciferase assays using reporter constructs with the wild type TXNIP 3’UTR or a mutated TXNIP 3’UTR confirmed that TXNIP is indeed a direct target of miR-128. Taken together, the results of these studies have identified a novel microRNA directly targeting TXNIP and revealed an alternative, post-transcriptional pathway by which glucose induces TXNIP expression.

Disclosure

G. Jing: None. J. Chen: None. G. Xu: None. A. Shalev: None.
Evidence for Necroptosis as a Mechanism of Islet Amyloid–Induced Beta-Cell Death
Authors: TEMPLIN ANDREW T. , HOGAN MEGHAN F. , ESSER NATHALIE , ZRAIKA SAKENEH , HULL REBECCA L. , KAHN STEVEN E.
Published: June 2018

Islet amyloid deposition occurs in the majority of individuals with type 2 diabetes (T2D) and contributes to beta-cell death by mechanisms which are not fully understood. Necroptosis is an immunogenic form of cell death dependent on tumor necrosis factor receptor 1 (TNFR1) signaling, receptor interacting protein kinase 3 (RIPK3) oligomerization, and mixed lineage kinase domain-like (MLKL) phosphorylation. We previously showed mRNA and protein levels of TNFa, a TNFR1 ligand, are increased in islets by amyloid deposition in vitro and in vivo, raising the possibility that amyloid formation induces necroptosis. Thus, we sought to determine whether the components of necroptosis are present in beta cells, and if islet amyloid-induced TNFa expression elicits beta-cell necroptosis. We observed protein expression of TNFR1, RIPK3, and MLKL in the INS-1 beta-cell line, indicating necroptosis components are present in beta cells. In human islet amyloid polypeptide (hIAPP) transgenic mouse islets cultured in 16.7 mM glucose, an in vitro model of islet amyloidosis, we found necroptosis signaling to be increased compared to amyloid-free wild type (WT) islets. This manifested as increased oligomerization of RIPK3 protein (trimers: 2.7 ± 0.2 [hIAPP] vs. 1.0 [WT], n=3, p<0.01) and phosphorylation of the RIPK3 target MLKL (1.8 ± 0.3 vs. 1.0, n=3, p=0.06), without a change in TNFR1 protein expression (1.1 ± 0.1 vs. 1.0, n=2, p=0.74). As further support that amyloid induces immunogenic cell death, immune cell mRNA abundance was increased in vivo in amyloid containing hIAPP transgenic islets vs. WT islets (macrophages: Emr1, 1.6 ± 0.2 [hIAPP] vs. 1.1 ± 0.1 [WT], n=4, p=0.04, T cells: Cd3, 2.7 ± 0.5 vs. 1.0 ± 0.2, n=4, p=0.03, and B cells: Cd20, 2.3 ± 0.2 vs. 1.2 ± 0.5, n=2, p=0.17). These data suggest that necroptosis may be a previously unrecognized mechanism of beta-cell death in response to islet amyloid formation. Further studies are needed to determine whether inhibition of necroptosis signaling may reduce beta-cell death in T2D.

Disclosure

A.T. Templin: None. M.F. Hogan: None. N. Esser: None. S. Zraika: None. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S.
Positive Impact of Integrative Medicine Approaches on Diabetes Related Care
Authors: KU JEONG-HEE , FREEBY MATTHEW , MULLUR RASHMI S.
Published: June 2018

Patients with diabetes have higher prevalence of depression and diabetes-related distress that negatively impacts care. Mindfulness-based approaches have shown to improve depression, diabetes-related distress, and in small studies also improve glycemic outcomes. We created a 90-minute, shared medical appointment; led by an endocrinologist, teaching patients integrative approaches to manage diabetes- related distress. We included patients with type 2 diabetes referred by a primary care provider or an endocrinologist, and assessed Diabetes Distress Scale (DDS), Patient Health Questionnaire-9 (PHQ-9) as well as Hemoglobin A1C (HbA1C), weight, blood pressure (BP), heart rate (HR) before the group visit.

Thirty-four patients attended group sessions, with mean age of 63.9 years, mean baseline HbA1C 7.7% and mean BMI 33.3. The mean DDS was 36.2, and mean PHQ-9 was 7.8. Twenty-four patients followed up in clinic 3 months after initial appointment and showed mean reduction in HbA1C by 0.18% (p=0.35). Subgroup analysis of patients with baseline HbA1C ≥ 7.5% (n=11) showed mean reduction in HbA1C by 0.8% (p=0.005). No statistically significant changes in BP, HR or weight were seen, while a subgroup of patients with baseline A1C ≥7.5% had non-statistically significant mean weight loss of 1.3kg. This retrospective study of a mindfulness-based approach suggests positive clinical impact and need for a larger, randomized trial.

Table 1. Baseline characteristics, change in parameters 3 months after interventionBaseline characteristicsTotal patients who attended (N=34)Patients with 3 months follow up (n=24)Subgroup with baseline HbA1C ≥7.5 (n=11)Mean age in years (SD)63.9 (10.2)65.2 (9.7)64.6 (10.9)% Women67.60%66.70%72.70%Mean body weight, kg (SD)94.3 (22.8)90.2 (16.6)91.7 (17.5)Mean BMI (SD)33.3 (7.2)31.9 (5.54)31.8 (6.0)Mean HgbA1C, % (SD)7.7 (1.3)7.5 (1.2)8.5 (0.9)Mean DDS (SD)36.2 (13.7)35.7 (14.3)35.9 (15.8)Mean PHQ-9 (SD)7.8 (5.2)7.4 (5.8)7.1 (6.7)Change in HbA1C from baseline to 3 months- 0.15 % (p=0.35)- 0.8 % (p=0.005)Change in weight from baseline to 3 months- 0.4 kg (p=0.48)- 1.3kg (p=0.17)

Disclosure

J. Ku: None. M. Freeby: None. R.S. Mullur: None.
Associations between A1C and Continuous Glucose Monitoring–Derived Glycemic Parameters
Authors: CALHOUN PETER , JOHNSON TERRI , WELSH JOHN , WALKER TOMAS C. , PRICE DAVID A.
Published: June 2018

The percentage of continuous glucose monitoring (CGM)-derived sensor glucose (SG) values in the 70-180 mg/dL range (time in range [TIR]) is an important outcome for patients and their clinicians; however, consensus TIR goals are lacking. This study aimed to characterize associations between CGM-derived glycemic metrics and A1C in 4 clinical trials: DIAMOND Phase 1 (N=104), DIAMOND Phase 2 (N=69), REPLACE-BG (N=216), and HypoDE (N=141). Each study lasted ≥24 weeks, used current-generation CGM systems (Dexcom, Inc.), and included comparisons of central-lab end-of-study A1C to CGM data during the preceding 3 mo. Data from 530 adults with diabetes (455 type 1) were analyzed. The Figure shows mean SG (MSG), TIR, time <70, <54, and >250 mg/dL for individuals in 6 A1C bins. Higher A1C bins were associated with higher MSG and lower TIR; lower A1C bins were associated with lower MSG and higher TIR. For subjects with A1C <7.0%, median TIR was 72%, with 90% of subjects having TIR >57%. Median time with SG <54 mg/dL was <20 min/day for all A1C bins, but median time with SG >250 mg/dL increased from 0.6 h/day to 6.7 h/day across bins. For subjects with A1C ≥8.0%, median TIR was 44%, with 90% of the subjects having TIR <59%. In CGM users, low A1C values can be achieved with minimal additional exposure to very low SG values. The observed associations between TIR and A1C may help clinicians and patients establish appropriate TIR goals.

Disclosure

P. Calhoun: Employee; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc.T. Johnson: Employee; Self; Dexcom, Inc.J. Welsh: Employee; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc., Medtronic. T.C. Walker: Employee; Self; Dexcom, Inc.D.A. Price: Employee; Self; Dexcom, Inc..
Evaluointi opettajan vuorovaikutustoimintana
Authors: Heinonen Pilvi
Published: June 2018

Pilvi Heinosen suomen kielen alaan kuuluva väitöskirja tarkastettiin Helsingin yliopistossa 16. joulukuuta 2017. Vastaväittäjänä toimi dosentti Mia Halonen Jyväskylän yliopistosta ja kustoksena professori Marja-Leena Sorjonen.

Pilvi Heinonen: Evaluointi opettajan vuorovaikutustoimintana: osallistujuuden ulottuvuudet luokkahuoneessa. Helsinki: Helsingin yliopisto 2017.

Väitöskirja on luettavissa osoitteessa https://helda.helsinki.fi/handle/10138/228394.
Geology Of Tanjung Medan ,Rokan IV Koto , Rokan Hulu District, Riau Province
Authors: Prayitno Budi , Susilo Susilo
Published: June 2018

The Administrative of research area has been in Tanjung Medan, Rokan IV Koto, Rokan Hulu, Riau Province and geographically located at 0 ° 37 '28.488 "- 0 ° 40' 10.3692" LU and 100 ° 24 '55.6884 "- 100 ° 27 '37.5804 "BT. Research method used approach method and laboratory analysis to get data of geology modeling and re-construction of geological history in research area. Based on surface observation, the geology of research area consists of Slate (Permian-carbon), Granite intrusion (Permian-Trias) with distribution SouthWest-SouthEast on the center of map. Arenite Sandstone unit (Easly Eocene) unconformity with slate on the bottom. Alluvial Rokan river crosses all type off rocks from north to south of map. While structure growth  in the research area have been joints structure with main stress Southwest-NorthEast, its similar with trend tectonic setting of Sumatra island, on the other hand reverse fault indicates the formation of a basin of extension stress in the early Eocene. the formation of basins in basement rocks begun at the time of the formation of the north-south trending northern form of the fault block forming horst and graben as well as accommodated the precipitation of pre-tertiary clastic materials. Whereas the Oligocene trans-tensional compression system accommodating the sedimentation system in the formed of arenite sandstone (SBPa) unconformity above the basement rocks simultaneously on the basin base decrease. The distribution of arenite sandstones based on the geological reconstruction covering all parts of the rock distribution which then undergoes the same weathering process of the formation of Bukit Barisan volcanic path that controls the development of geological structure up to the present.
New Aggregation Operator for Triangular Fuzzy Numbers based on the Geometric Means of the Slopes of the L- and R- Membership Functions
Authors: Pandey Manju , Khare Dr. Nilay
Published: June 2018

In recent work authors have proposed four new aggregation operators for triangular and trapezoidal fuzzy numbers based on means of apex angles [1][2][3][4]. Subsequently authors have proposed [5] a new aggregation operator for TFNs based on the arithmetic mean of slopes of the L- and R- membership lines. In this paper the work is extended and a new aggregation operator for TFNs is proposed in which the L- and R- membership function lines of the aggregate TFN have slopes which are the geometric means of the corresponding L- and R- slopes of the individual TFNs. Computation of the aggregate is demonstrated with a numerical example. Corresponding arithmetic and geometric aggregates as well as results from the recent work of the authors on TFN aggregates have also been computed.