bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alterations in Somatomotor Network Functional Connectivity in Painful Diabetic Neuropathy—A Resting State Functional Magnetic Resonance Imaging Study
Authors: SELVARAJAH DINESH , AWADH MOHAMMED , GANDHI RAJIV , WILKINSON IAIN D. , TESFAYE SOLOMON 
Published: June 2018

Aims: Painful diabetic neuropathy (Painful-DN) is a common disabling condition, with no objective biomarkers and less than optimal treatments. RS-fMRI is a quick (5 minute) functional imaging method that evaluates regional cortical interactions that occur when a subject is at rest. The aim of this study was to explore resting functional connectivity of the somotomotor network in painful DN as a possible objective biomarker for neuropathic pain.
Methods: 46 patients with diabetes (No DN, n=16; Painful DN, n=15; Painless DN, n=15) and 16 healthy volunteers underwent detailed clinical and neurophysiological assessments. RS-fMRI data were acquired at 3T (Philips Healthcare) and functional connectivity analysis was performed using FSL (www.fmrib.ox.ac.uk/fsl).
Results: There was reduced functional connectivity in the sensorimotor network (postcentral gyrus -42,-22,56; all TFCE, corrected p&lt;0.05) and default mode network (precuneus -6,-46,40; p&lt;0.05), superior frontal gyrus (34,62,60; p&lt;0.05), Heschl’s gyrus (-42,-22,12; p&lt;0.05), insular cortex (34,62,60; p&lt;0.05) and superior parietal lobule (-22,-42,68; p&lt;0.05). Somatomotor network functional connectivity significantly correlated with quantitative pain assessments (Short Form 36, r=-0.52; p=0.03 and Chronic Pain Acceptance Questionnaire r=-0.55, p=0.045).
Conclusion: These findings demonstrate that chronic pain has a widespread impact on overall brain function in diabetes, and suggests that disruptions of the resting state networks may underlie the cognitive and behavioural impairments accompanying chronic pain. Specifically within the somatomotor network, we have demonstrated abnormal functional connectivity in painful DPN which correlates with clinical measures of pain and behaviour. RS-fMRI has the potential to serve as an objective biomarker for the chronic pain condition in DPN.

Disclosure
D. Selvarajah: None. M. Awadh: None. R. Gandhi: None. I.D. Wilkinson: None. S. Tesfaye: Speaker's Bureau; Self; Pfizer Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Wörwag Pharma GmbH & Co. KG.
Lipoprotein(a) Levels Are Twice as High in Left-Handed T2DM Patients
Authors: HERMANS MICHEL P. , AHN SYLVIE A. , ROUSSEAU MICHEL F. 
Published: June 2018

Background: We previously reported that T2DM patients with elevated lipoprotein(a) [Lp(a)] were characterized by lesser insulin resistance and high frequency of left-handedness.
Objective: The aim of this work was therefore to characterize the lipids and lipoproteins in T2DM, to see if there were quantitative or qualitative differences depending on motor laterality.
Methods: The cardiometabolic phenotype of 517 Caucasian patients with type 2 diabetes (T2DM) was determined according to laterality, 444 patients being right-handed (RHs; 86%) and 73 left-handed or ambidextrous (non-RHs; 14%). Besides routine lipids, Lp(a), non-Lp(a)-LDL-C, apoB100, apoA-I, and atherogenic dyslipidemia were also measured, including pre-/post-statin levels in treated paitients.
Results: Non-RHs had a stronger family history of early-onset CVD, were more insulin- sensitive, and were less often treated with insulin. RHs and non-RHs did not differ as regards use and intensity of statins, routine lipids, apoB100, apoA-I, prevalence/severity of atherogenic dyslipidemia, and LDL size. In contrast, Lp(a) levels were significantly higher in non-RHs (median 37.0 vs. 18.7 nmol/L in RHs; p 0.0018), resulting in 32% of non-RHs having pathological Lp(a) vs. 20% in non-HRs (p 0.0467). Although pre-statin LDL-C was 15% higher in non-RHs, partly related to higher Lp(a), on-statin LDL-C did not differ between groups, suggesting better response/compliance to statins.
Conclusion: Lp(a) levels are twice as high in left-handed diabetic patients, while routine lipids and lipoproteins are unaffected by motor laterality. Elevated Lp(a) in left-handers also underlies higher LDL-C before statins, yet on-treatment LDL-C in left-handers decreased more after statins than that of right-handers, hinting to better compliance and/or greater response to statins.

Disclosure
M.P. Hermans: Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim GmbH, Mylan. Advisory Panel; Self; Novo Nordisk A/S, OmniPod. Speaker's Bureau; Self; Servier. Advisory Panel; Self; Sanofi-Aventis, Merck Sharp & Dohme Corp.. S.A. Ahn: None. M.F. Rousseau: None.
Atorvastatin Increases Fatty Acid Desaturases (FADSs) and Elongation of Very-Long-Chain Fatty Acids (ELOVLs) through Geranylgeranyl Pyrophosphate (GGPP)-Dependent Rho Kinase Pathway in HepG2 Cells
Authors: TATSUNO ICHIRO , TANAKA SHOU , ISHIHARA NORIKO 
Published: June 2018

Background: The plasma concentration of arachidonic acid, one of the omega-6 long-chain polyunsaturated fatty acids (LCPUFAs), was increased by the treatment of statin in several clinical studies indicating that statin affects the endogenous synthesis of LCPUFAs, which is regulated by the action of the fatty acid desaturases (FADSs) and elongation of very long-chain fatty acids (ELOVLs).
Aims: We investigated the roles of the intrinsic mevalonate cascade and rho-dependent pathway in the statin-induced regulation of these desaturases and elongases using human hepatocellular carcinoma cell line HepG2 cells.
Methods: Cell viability was assessed by measuring mitochondrial activity of WST-8, and the activity of caspase-3 and -7 (caspase-3/7) was measured. Gene expression was analyzed by quantitative real-time PCR. Protein expressions were detected by Western blot analysis.
Results: Although atorvastatin decreased the cell viability with increasing activity of caspase-3/7 in a dose-dependent manner, both mRNA and protein expression of FADS2 were stimulated by atorvastatin at lower dose of 12.5 and 25 uM, where mRNA expression of FADS1 and Elovl5 also increased. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), not cholesterol, fully restored the atorvastatin-induced inhibition of cell viability, and the atorvastatin-induced upregulation of mRNA and protein of FADS2. The Rho-associated protein kinase (ROCK) inhibitor Y-27632 inhibits the restoration of mevalonate and GGPP. Both EPA and DHA, but not AA, significantly suppressed the atorvastatin-induced upregulation of gene expression of FADS1, FADS2 and Elovl5.
Conclusions: These data demonstrated that statin may affect the endogenous synthesis of LCPUFAs by the regulation of these desaturases and elongases through GGPP-dependent rho kinase pathway in HepG2 cells.

Disclosure
I. Tatsuno: None. S. Tanaka: None. N. Ishihara: None.
Effects of High-Intensity Statins on Glucose Homeostasis in Patients with Type 2 Diabetes
Authors: THONGTANG NUNTAKORN , SRIUSSADAPORN SUTIN , TANGKITTIKASEM NATTHAKAN 
Published: June 2018

Statin use has been reported to increase the risk of new onset diabetes, and potentially worsen glycemic control in patients with type 2 diabetes (T2D). The risk of new onset diabetes from statin is higher with increased dose of statin administration. This study was aimed to evaluate the effects of high-intensity statins as compared to the lower intensity statins on glucose homeostasis and glycemic control in patients with T2D. T2D who were taking simvastatin up to 20 mg/day (N=100) were randomized to continue using the same dosage of simvastatin (low- to moderate-intensity statin group; LS) for 12 weeks or change to atorvastatin 40 mg/day for 6 weeks and if tolerable increased to atorvastatin 80 mg/day for 6 weeks (high-intensity statin group; HS). Fasting plasma glucose (FPG), HbA1c, fasting plasma insulin, HOMA-IR and HOMA-B were assessed at baseline, 6 weeks and 12 weeks. Oral hypoglycemic agents were unchanged throughout the study period and patients who were on human insulin were excluded from the analysis. Ninety-eight patients completed the study (73% female), mean age 58.9±9.6 years, mean BMI 27.3±4.5 kg/m2, median duration of diabetes was 102 (48-180) months. Mean baseline FPG and HbA1c were 130.4±35.3 mg/dl and 6.9±0.9%, respectively. Median baseline insulin level, HOMA-IR, and HOMA-B were 10.8 (7.5-17.7) mIU/L, 3.3 (2.2-5.5), and 65.5 (37.7-113.8), respectively. There was no significant difference in baseline characteristic and baseline glucose homeostasis parameters between the LS (n=49) and HS group (n=51). There was a slight increase in HbA1c in the HS group as compared to the LS group at 6 weeks (+0.1% vs. 0%, p=0.05), and 12 weeks (+0.1% vs. -0.1%, p=0.13) respectively. However; there were no significant changes in FPG, fasting plasma insulin, HOMA-IR and HOMA-B between the LS and HS group.
In conclusion, there was no significant deterioration in glucose homeostasis with high-intensity statins as compared to low dose statins in patients with T2D.

Disclosure
N. Thongtang: Other Relationship; Self; Pfizer Inc.. S. Sriussadaporn: None. N. Tangkittikasem: None.
Ophthalmologic Findings in Congenital Generalized Lipodystrophy—A Possible Marker of Metabolic Disorders
Authors: FERNANDES VIRGINIA O. , GOMES LORENA M.A. , MONTENEGRO ANA PAULA D.R. , PONTE CLARISSE M.M. , BATISTA LIVIA A.A. , ARAGÃO RICARDO E.M. , SILVA JAILTON V. , MONTENEGRO RENAN M. 
Published: June 2018

Background and Aims: Metabolic disorders can present ophthalmologic changes. Congenital Generalized Lipodystrophy (CGL) is characterized by severe metabolic manifestations such as insulin resistance, diabetes and hypertriglyceridemia, but there are few data published about ophthalmologic findings in this condition. The purpose of this study is to describe ocular abnormalities in patients with CGL.
Materials and Methods: It was a cross sectional study with 15 patients with CGL of both sex, aged between 2 and 29 years old. We evaluated the symptoms of surface eye disease and visual acuity. In the slit lamp, were evaluated the anterior segment of the eye, the break up time of the tear film with fluorescein and the corneal findings. Under mydriasis, the eye fundus examination was performed.
Results: All subjects had dyslipidemia: 15/15 (100%) hypertriglyceridemia; 15/15 (100%) low HDL-c; 4/15 (26,7%) and high levels of LDL-c. Diabetes was presented in 7/15 (46,7%) cases. Symptoms of surface eye disease (blurred vision, pruritus, hyperemia or dry eye sensation) were presented in 9/15 (60%) patients and 8/15 (53%) had refractive errors: 5/8 (62,5%) astigmatism, 2/8 (25%) myopia and 1/8 (13%) myopia and astigmatism. In the slit lamp, 12/15 (80%) presented anterior blepharitis (seborrheic or meibomite), 13/15 (87%) decrease in the break up time of the tear (less than 8 seconds) and 5/15 (33,3%) keratitis. In the fundoscopy, 2/15 (13,3%) presented retinopathy (one with nonproliferative diabetic retinopathy and another presented proliferative diabetic retinopathy).
Conclusion: These findings demonstrate high frequency of blepharites and its complications in patients with CGL, even in young subjects without diabetes. These data allow us to speculate that the presence of abnormalities in the anterior segment of the eye may be a marker of metabolic disorders as dyslipidemia and insulin resistance.

Disclosure
V.O. Fernandes: None. L.M.A. Gomes: None. A.D.R. Montenegro: None. C.M.M. Ponte: None. L.A.A. Batista: None. R.E.M. Aragão: None. J.V. Silva: None. R.M. Montenegro: None.
Differential Association of Inflammatory Markers and Growth Factors with Type 2 Diabetes and Polyneuropathy—A Multimarker Approach
Authors: BÖNHOF GIDON J. , STROM ALEXANDER , RATHMANN WOLFGANG , HEIER MARGIT , MEISINGER CHRISTA , PETERS ANNETTE , RODEN MICHAEL , THORAND BARBARA , HERDER CHRISTIAN , ZIEGLER DAN 
Published: June 2018

There is emerging evidence supporting a role of inflammation in the development and progression of diabetic sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes. We aimed to characterize inflammatory signatures associated with DSPN and/or type 2 diabetes using a multimarker approach. We measured 92 serum biomarkers including pro- and anti-inflammatory cytokines, chemokines, and growth factors (GF) using the Proseek Multiplex INF I assay (OLINK Proteomics) in 304 individuals with type 2 diabetes and polyneuropathy, defined by the Toronto Consensus Criteria (2011), from the PROPANE study (DSPN) as well as 158 individuals with type 2 diabetes without DSPN (T2D) and 354 individuals with normal glucose tolerance and without DSPN (CON) from the KORA F4 study (DSPN/T2D/CON [mean±SD]: age: 68±9/71±6/69±5 years; male: 76/59/41%; BMI: 30.8±5.3/30.8±4.4/26.9±3.7 kg/m²; diabetes duration: 13.5±9.6/7.6±5.8/- years; HbA1c: 7.4±1.3/6.6+1.0/5.5+0.3%). After adjustment for multiple testing and sex, age, BMI, and smoking, a biphasic pattern of serum levels (normalized protein expression values) with an increase in T2D and decrease in DSPN was observed for four GFs (e.g., transforming GF (TGF)-α: 4.51±0.51 vs. 4.63±0.56 vs. 3.91±0.51; vascular endothelial GF (VEGF): 10.9±0.5 vs. 11.0±0.5 vs. 10.8±0.6), two chemokines (e.g., C-C motif ligand 4 (CCL4): 8.18±0.57 vs. 8.4±0.6 vs. 7.93±0.68) and one cytokine (oncostatin M: 4.83±0.62 vs. 5.06±0.63 vs. 4.35±0.75). Compared to T2D, the levels of another 12 biomarkers were lower in DSPN (e.g., tumor necrosis factor (TNFSF)-14: 5.65±0.55 vs. 4.90±0.77; matrix metalloproteinase (MMP)-1: 14.4±0.7 vs. 14.1±0.9), while five were higher (e.g., CCL20: 5.2±1.1 vs. 5.79±1.23) (all P&lt;0.00024).
In conclusion, deficits in growth factors promoting nerve regeneration/angiogenesis and a complex cross-talk between innate and adaptive immunity may contribute to the development of DSPN in type 2 diabetes.

Disclosure
G.J. Bönhof: None. A. Strom: None. W. Rathmann: Advisory Panel; Self; AstraZeneca. Research Support; Self; Novo Nordisk A/S. M. Heier: None. C. Meisinger: None. A. Peters: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. B. Thorand: None. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company. D. Ziegler: None.
Renal Function as a Predictor of Reamputation after Initial Transmetatarsal Amputation in the Perioperative Period—An ACS-NSQIP Study
Authors: AHN JUNHO , RASPOVIC KATHERINE M. , LALLI TRAPPER , LIU GEORGE T. , VANPELT MICHAEL D. , WUKICH DANE 
Published: June 2018

Previous reports correlating renal function and reamputation after transmetatarsal amputation (TMA) have been mixed. This study aims to evaluate renal function as a factor for reamputation after initial TMA during the perioperative period in a large population database.
Patients who underwent TMA were identified in the American College of Surgeons-National Surgical Quality Improvement Program® database. Reamputation was defined as unplanned TMA or higher-level amputation in the 30-day perioperative period. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Of 1,775, the rate of reamputation was 6.5%. Reamputation was correlated with higher white blood cell counts (p&lt;.00001), greater serum creatinine (p=.021), higher blood urea nitrogen (p=.021), type of glycemic control (p=.002), stage of CKD (p=.003), and dialysis (p=.001). CKD stage was directly associated with reamputation rates (p=.003) and mortality (p&lt;.00001).
In the current study, CKD predicted reamputation after TMA and 30-day mortality. Our findings corroborate previous reports correlating dialysis-dependent renal failure and mortality. Whether patients in certain stages of CKD would achieve better outcomes with higher-level amputation rather than a TMA requires further study.

Disclosure
J. Ahn: None. K.M. Raspovic: None. T. Lalli: None. G.T. Liu: Consultant; Self; Gramercy Extremity Orthopedics. M.D. VanPelt: None. D. Wukich: None.
Critical Regulation of Angiogenesis by Nrf2 Signaling Is Absent in Diabetic Wound Healing
Authors: RABBANI PIUL S. , DAVID JOSHUA A. , SULTAN DARREN L. , VILLARREAL-PONCE ALVARO P. , KWONG JENNIFER , LEE JASMINE , SHEN CHEN , ABDOU SALMA A. , CERADINI DANIEL 
Published: June 2018

Diabetes-associated ulcers account for 11% of non-traumatic limb and extremity amputations. Tailoring therapies for chronic diabetic wounds is challenging, however, as specific molecular/cellular events responsible for the extreme delays or lack of wound healing mostly remain at large. We previously identified dysfunction of the cytoprotective Nrf2/Keap1 signaling pathway induced by chronic hyperglycemia and diabetes. In the diabetic wound bed, we found detrimental impact on angiogenesis which is a requisite for tissue repair. Exogenous activation of Nrf2 in the whole diabetic wound bed accelerated healing and illustrated the promise of targeting Nrf2 activity for reversing diabetes-associated impairments. Here, we explored the specific role of Nrf2 in endothelial cells of the wound tissue repair niche, and corresponding deficiencies in Nrf2 activity during diabetic wound healing. We generated Cadherin5-CreER;Nrf2fl/fl mice to deplete Nrf2 specifically in endothelial cells, upon tamoxifen administration (Nrf2KO mice). Stented excisional wounds (10mm diameter) on Nrf2KO mice, induced prior to wounding, required 33±1.23 days for closure. This delayed repair phenotype was significantly higher than that of wild type wounds requiring 14.5±0.29 days (p&lt;0.05), but very similar to the 31.5±0.65 days required by wounds on Leprdb/db diabetic mice. Successful inhibition of Nrf2 in microvasculature-derived endothelial cells in vitro demonstrated compromised proliferation (7.12±1.19 units), compared to cells transfected with non-sense siRNA (11.37±0.96 units, p&lt;0.05). Endothelial cells with silenced Nrf2 also demonstrated less angiogenic capacity in vitro, unable to branch or form nodes. Our data prove that Nrf2 activity regulates endothelial cell proliferation and angiogenesis among features that are vital during wound repair. Our results reinforce the necessity of Nrf2 activation in skin for wound repair and underscore the impact of its deficiency in diabetic skin.

Disclosure
P.S. Rabbani: None. J.A. David: None. D.L. Sultan: None. A.P. Villarreal-Ponce: None. J. Kwong: None. J. Lee: None. C. Shen: None. S.A. Abdou: None. D. Ceradini: None.
Incidence and Risk Factors for Amputation in Patients with Diabetes in Japan—Historical Cohort Study Using a Nationwide Claims Database
Authors: KANEKO MASANORI , FUJIHARA KAZUYA , YAMAMOTO MASAHIKO , KITAZAWA MASARU , ISHIZAWA MASAHIRO , OSAWA TAEKO , HARADA MAYUKO , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , SONE HIROHITO 
Published: June 2018

Since amputation of a lower extremity predisposes patients with diabetes to a lower quality of life and higher rates of cardiovascular events and mortality, identifying predictors of amputation is of clinical relevance in diabetes management. Although the incidence of amputation is known to be much lower in East Asians compared to those in Western countries, there has been no large cohort study of the accurate incidence of amputations in East Asians. Thus we analyzed data from a nationwide claims database involving 17,288 individuals with diabetes in Japan (2942 women, mean age 50.2 y, HbA1c 7.2%) from 2008-16. During a mean follow-up period of 5.3 y, 16 amputations occurred (0.17/1000 person-years), which was about one tenth of the typical rates reported by Western countries. Multivariate Cox regression analysis showed that age and HbA1c were independent predictors of amputation (hazard ratio (HR) 1.11(95% CI 1.03-1.19) and 1.43(1.13-1.81), respectively). Compared with those age &lt;58 y and with HbA1c &lt;8%, the HR for those age ≥58 y and HbA1c ≥8% was 32.0 (7.72-133.5). Kaplan-Meyer analysis confirmed the strikingly high risk in this category (Figure). Our results implied large differences in incidence and risk profiles for amputation in Japanese patients with diabetes, suggesting the need for ethnic group-specific strategies to prevent diabetic foot disease.

Disclosure
M. Kaneko: None. K. Fujihara: None. M. Yamamoto: None. M. Kitazawa: None. M. Ishizawa: None. T. Osawa: None. M. Harada: None. Y. Matsubayashi: None. T. Yamada: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..
The Leucopatch® System in the Management of Hard-to-Heal Diabetic Foot Ulcers—A Multicentre, Multinational, Observer-Blinded, Randomised Controlled Trial
Authors: GAME FRANCES , JEFFCOATE WILLIAM , TARNOW LISE , JACOBSEN JUDITH L. , WHITHAM DIANE J. , HARRISON ELEANOR F. , ELLENDER SHARON J. , LONDAHL MAGNUS 
Published: June 2018

Background: The LeucoPatch® device uses bedside centrifugation without additional reagents to generate a disc comprising autologous platelets, fibrin and leucocytes which is applied to the surface of the wound. The aim of the study was to test the effectiveness of LeucoPatch® on the healing of hard-to-heal foot ulcers in people with diabetes.
Methods: 595 people with diabetes and a foot ulcer consented to participate. After a 4 week run-in-period those with a reduction in ulcer area of &lt; 50% were randomised to either pre-specified good standard care alone or care supplemented by weekly application of LeucoPatch®. The primary outcome was percentage of ulcers healed within 20 weeks, defined as complete epithelialisation confirmed by an observer blind to randomisation group and maintained for four weeks.
Results: 269 people were randomised; mean age 62 years, 82% male, 82% type 2 diabetes. In the intervention group 34.1% (n=45/132) of ulcers healed within 20 weeks vs. 21.6% (n=29/134) of the controls (OR 1.58, 95% CI 1.06-2.35; p= 0.02) by intention-to-treat analysis. Time to healing was shorter in the intervention group (p=0.0246) (Figure). No difference in adverse events was seen between groups.
Interpretation: The use of LeucoPatch® is associated with significant enhancement of healing of hard-to heal foot ulcers in people with diabetes.

Disclosure
F. Game: Research Support; Self; Reapplix aps. W. Jeffcoate: Research Support; Self; Reapplix Aps, Urgo, France. L. Tarnow: Stock/Shareholder; Self; Novo Nordisk A/S. J.L. Jacobsen: Consultant; Self; Reapplix. D.J. Whitham: Other Relationship; Self; Reapplix. E.F. Harrison: Research Support; Self; Reapplix. S.J. Ellender: None. M. Londahl: Speaker's Bureau; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; ReApplix AS.