bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortisol Synthesis Enzyme CYP11B1 as Tissue Biomarker for Diabetic Foot Ulcers
Authors: VILEIKYTE LORETTA , SHEN BIING-JIUN , PASTAR IRENA , BOULTON ANDREW J. , KIRSNER ROBERT , TOMIC-CANIC MARJANA , HARDMAN MATTHEW 
Published: June 2018

An urgent need exists to identify predictive biomarkers to guide management of diabetic foot ulcers (DFUs). The steroid hormone, cortisol, is elevated in chronic inflammatory states and its pathogenic role and/or prognostic role for poor outcomes across a range of diseases has been suggested. However, the role of cortisol in DFUs is not well understood and the significance of local, tissue-specific cortisol regulation in DFUs remains unclear. We performed a multi-center study of 63 well vascularized, superficial neuropathic, non-infected DFU subjects receiving standard care and used wound biopsy obtained at baseline study to quantify expression levels (via immunohistochemistry) of the major cortisol synthesis enzymes CYP11B1 and 11BHSD1, and other inflammatory cytokines. Subjects were predominantly men in their late-fifties (58±10 years) with poor glycemic control (HbA1C 8.9±2.3%); while hemoglobin (12.6±1.8g/dl), creatinine (1.27±0.5mg/dl) and albumin (4.1±0.42g/dl) were within the normal range. We found high cutaneous levels of CYP11B1 strongly linked to failure to heal DFUs at 6 weeks (p≤0.016), while 11BHSD1 did not correlate with healing (p=0.351). In the logistic regression analyses controlling for demographics and disease characteristics, higher levels of CYP11B1 (10-based log-transformed) were predictive of non-healing of DFU at 6 weeks (OR = 6.83, p =.010). High local tissue levels of the pro-inflammatory TNFalpha were also significantly associated with lack of ulcer healing (p≤0.019). This observation is consistent with reports that TNFalpha is essential for local induction of CYP11B1. In turn, local induction of CYP11B1 and subsequent induced tissue cortisol levels activate membranous glucocorticoid receptor triggering PLC/PKC/GSK-3beta/beta-catenin pathway that inhibits healing. Taken together, these data suggest CYP11B1 is a potential predictive biomarker for DFU outcomes, and may serve as a future target for therapeutic interventions.

Disclosure
L. Vileikyte: None. B. Shen: None. I. Pastar: None. A.J. Boulton: None. R. Kirsner: None. M. Tomic-Canic: None. M. Hardman: None.
Diabetes Foot Wound Healing—A Collaborative Approach
Authors: MCNULTY JACQUELINE N. , LEWIS BRANDON J. , LA FONTAINE JAVIER , ROSE APRIL , GOMEZ MIRIAM , MENEGHINI LUIGI , GUNASEKARAN UMA , RUIZ MARIA S. 
Published: June 2018

There exists limited data demonstrating that glycemic control can improve healing of diabetic foot wounds. From March through December 2017, patients followed in the Foot Wound Clinic of a large urban safety net health system were concurrently seen by diabetes specialists to determine whether improving glycemic control via an integrated treatment approach impacted wound healing. This pilot study is the first to examine the effect of diabetes specialty co-management with podiatric care of diabetic foot wounds.
Sixty patients were included in the analysis of this pilot program and were followed for an average of 220 days. Patients were classified as having either improved glycemic control (IGC) or non-improved glycemic control (NIGC) defined as &lt; 1% HbA1c change at study end. Cohort characteristics and outcomes are summarized in Table 1. All patients had aggressive diabetic foot care including wound debridement and appropriate antibiotic therapy as determined by their podiatrist.
Ulcers worsened in 47% of NIGC patients compared to 13% of IGC patients with IGC patients having an average HbA1c reduction of 2%. With both NIGC and IGC groups receiving similar wound management, 63% of NIGC patients had decreased ulcer volume compared to 87% of IGC patients, suggesting that improving glycemic control, in collaboration with diabetes specialist co-management, contributes to improved wound healing and a trend for decreased resource utilization.Table 1. Cohort characteristics and study outcomesIGCNIGCp-valueTotal No. of patients3030Total No. of ulcers3641Median ulcer size (mm3)BaselineStudy End170010040Patients with improved ulcer healing, n (%)26 (87)19 (63)0.04HbA1c, mg/dLBaselineStudy End10.68.210.211.10.47&lt;0.005Hypertension, n (%)Pre-existingControlled at baselineControlled at study end25 (83)19 (63)19 (63)24 (80)16 (53)21 (70)ED visitsTotal visitsAverage No. of visits per patientFoot relatedDiabetes related351.9104502.32620.190.020.38Average number of podiatric appointments570.92No. of patients seen by Diabetes specialistAverage No. of specialist visits per patientNo. of patients seen in co-management visitNo. seen in sporadic visitNo visits252.32505242.81686Lost to follow-up with diabetes specialist, n (%)13 (43)15 (50)

Disclosure
J.N. McNulty: None. B.J. Lewis: None. J. La Fontaine: None. A. Rose: None. M. Gomez: None. L. Meneghini: Advisory Panel; Self; Novo Nordisk Inc., Sanofi US. Consultant; Self; Sanofi US, Novo Nordisk Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; American Diabetes Association. U. Gunasekaran: None. M.S. Ruiz: None.
Osteomyelitis and Neuropathic Ulcers in Forefoot—Amputation Is the Only Surgical Intervention Resolving?
Authors: SKOUTAS DIMITRIOS , SAYEGH FARES , METALLIDIS SYMEON , SGOUTZAKOS SOKRATIS , KATSANOS IOANNIS , GEORGA STAMATA , NIKOLAIDIS ATHANASIOS , DOUKAS LOUKAS , MATOPOULOU ELENA , TESFAYE SOLOMON , MANES CHRISTOS , TZATZAGOU GLYKERIA 
Published: June 2018

Background and Aim: The aim of this study is to show a simple therapeutic method in cases of neuropathic ulcer complicated by osteomyelitis in the forefoot to resolve this complication avoiding amputation.
Patients-Methods: Our material consists of 28 patients (19 males, 9 females) with “diabetic foot” aged 57,31±10,25 years, mean HbA1c: 8,65±1,7%, of duration of diabetes 13,84±9,2 years and 32% of them are active smokers. NDS, VPT, ABI are measured. All of them had neuropathic ulcers located in the forefoot and 10 of them had previous amputations. The average duration of the ulcer was 1 year complicated with osteomyelitis in admission time. The diagnosis of osteomyelitis was made with MRI, RX, probe-to-bone test and verification of elevated ESR and CRP. We start with the collection of the cultures (bone sample in 6 of 28 patients) and antibiotic treatment according the cultures. After the diagnosis of osteomyelitis we proceeded to prepare a surgical field and through the ulcer we removed the infected bone-phalanx taking a bone sample for microbiological study. After we scraped and cleaned the cavity well, a 48-hour drain was placed and becomes transdermal wound suture if is a necessary. The duration of the antibiotic treatment depends from the lesion area, the results of microbiological culture and varies from 4-6 weeks to 4-6 months.
Results: After practicing this technique all cases were healed at an average 40 days with an effective offload and an appropriate topical care to keep the ulcer clean and with an optional moisture. The duration of hospitalization 2-8 days depending on the severity of the infection.
Conclusion: It is essential to raise other less invasive and conservative methods than amputation. Specially in those with good distal arterial perfusion that in many cases are young, the avoidance of a amputation has many benefits in their quality of life. Finally, the applied method is rapid inexpensive without disturbing the biomechanical balance of the foot to a large extent.

Disclosure
D. Skoutas: None. F. Sayegh: None. S. Metallidis: None. S. Sgoutzakos: None. I. Katsanos: None. S. Georga: None. A. Nikolaidis: None. L. Doukas: None. E. Matopoulou: 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. C. Manes: None. G. Tzatzagou: None.
Single Cell RNA-Seq Analyses of Healthy Lower Extremity Skin and Diabetic Foot Ulcers Uncover Distinct Immune Landscape of Diabetic Wound Healing
Authors: THEOCHARIDIS GEORGIOS , BHASIN SWATI S. , KOUNAS KONSTANTINOS , BHASIN MANOJ K. , VEVES ARISTIDIS 
Published: June 2018

Fifteen percent of diabetes mellitus (DM) patients are expected to develop a diabetic foot ulcer (DFU) within their lifetime. DFUs represent an ever increasing burden for the healthcare system. Chronic wounds, lack the linear progression from one classical phase of healing to the next and are mainly characterized by the persistence of the inflammatory phase. To define the transcriptome landscape of healthy uninjured skin, DM and DFU skin, we performed transcriptome profiling on skin specimens from foot surgeries obtained from 4 controls, 4 DM patients without DFU and on samples from 2 DM patients after DFU debridement . We generated the single cell transcriptome profiles of 3,766 and 3,469 cells from non-DM and DM patients and of 660 cells from patients with active DFUs. Further, bioinformatics analysis identified clusters of cells with similar transcriptome states. The most abundant cell type was fibroblast. Other clusters included adipocytes and endothelial cells. T-cells, monocytes, and macrophages were the main immune cell types identified. As macrophages are critical for healing of DFUs, we estimated the abundance of total macrophages and their polarization. Approximately 10% of cells were macrophages in each group while DFU group had significantly more M1 polarized as compared to M2 (M1/M2=2.4 times). Supervised analysis identified a set of 66 and 1genes that are significantly differentially expressed in macrophages of DFU and DM patients respectively as compared to controls. A master regulator (MR) analysis in DFU patients identified activation of inflammatory and angiogenesis related MRs (e.g., STAT3, IL15). while in DM patients it identified activation of distinct inflammatory MRs (e.g., SMAD3, CD44).
In summary, we present for the first time sc-RNAseq data on lower extremity skin samples that could help delineate the molecular mechanisms of dysregulated wound healing and identify novel therapeutic targets.

Disclosure
G. Theocharidis: None. S.S. Bhasin: None. K. Kounas: None. M.K. Bhasin: None. A. Veves: Advisory Panel; Self; HyperMed Imaging, Inc., AOBiome.
Barriers and Facilitators to Perceived Diabetes Self-Management in Arab Americans with Diabetes
Authors: MASRI DANA EL , PIATT GRETCHEN , KOSCIELNIAK NIKOLAS J. , JABER LINDA 
Published: June 2018

Arab Americans (AAs) are at increased risk of type 2 diabetes, with a reported prevalence of 18%. Despite the increasing prevalence, there remains a lack of data on diabetes self-management (DSM) practices and barriers to care in this population. The purpose of this study was to assess patient perceptions of DSM behaviors in order to facilitate individualized care plans by providers. A 39-item survey was created based on focus group discussions designed to understand the impact of AA culture on DSM. The survey assessed diet, adherence to medications, exercise, healthy lifestyle, and family support. Two hundred AAs with diabetes completed the survey via face-to-face interviews. Most participants were above fifty years of age (79%), females (59%), and originated from Lebanon (73%). Individuals receiving Arabic instructions perceived that good portion control (p=0.07), food selection (p=0.01), and maintaining a healthy lifestyle (p=0.003) were important DSM behaviors, compared to those who did not receive Arabic instructions. Unemployed individuals were less likely to perceive regular exercise (p=0.05), portion control (p=0.06), and maintaining a healthy lifestyle (p=0.08) as important DSM behaviors compared to employed individuals. Individuals who had family support and encouragement were more likely to perceive that discussions with their clinicians were important (p=0.003) compared to those without family support. Individuals with family who understood their food choices were more likely to perceive regular exercise (p=0.03) as important compared to those with families who did not understand food choices.
In conclusion, this survey may serve as a valuable tool for providers to assess perceptions surrounding DSM behaviors in order to provide patient-centered care that will help to improve patient outcomes. This study supports the importance of integrating cultural influences into DSM education and support when providing care to a population with a strong cultural identity.

Disclosure
D. El Masri: None. G. Piatt: None. N.J. Koscielniak: None. L. Jaber: None.
Insomnia Is Associated with an Increased Risk of Type 2 Diabetes in the Clinical Setting
Authors: LEBLANC ERIN , SMITH NING , ALLISON MICHAEL , NICHOLS GREGORY , CLARKE GREG 
Published: June 2018

Aims: Determine association between insomnia and risk of type 2 diabetes (T2DM).
Methods: We conducted a retrospective panel cohort study to examine risk of developing T2DM among prediabetes patients with and without insomnia (physician identified or insomnia medication dispense). Participants with prediabetes (physician identified or by 2 laboratory tests) between 1/1/2007 and 12/31/2015 were followed until 12/31/2016. Patients were determined to have T2DM when two of the following occurred within 2 years: physician-entered outpatient T2DM diagnosis, dispensing of an anti-hyperglycemia agent, A1C ≥6.5%, or fasting plasma glucose &gt;125 mg/dl. One hospital inpatient stay with an associated T2DM diagnosis was also sufficient for T2DM classification.
Results: Our cohort comprised 79,608 persons with prediabetes. Almost 30% (23,370) were classified as having insomnia during the observation period. After adjustment for traditional risk factors, those with insomnia were 28% more likely to develop T2DM than those without. This estimate was essentially unchanged after adjusting for baseline A1C level (Table).
Conclusions: The association of insomnia with increased T2DM risk is similar to that of traditional risk factors such as overweight and nonwhite race. This finding has the potential to be of great value as a modifiable factor in diabetes prevention efforts.

Disclosure
E. LeBlanc: None. N. Smith: None. M. Allison: None. G. Nichols: Research Support; Self; Boehringer Ingelheim GmbH, Amarin Corporation, Janssen Pharmaceuticals, Inc., Sanofi. G. Clarke: None.
Exercise Regulates the Concentration of Novel Circulating Factors in Humans
Authors: MIDDELBEEK ROELAND , RICHARD JEFFREY J. , PRINCE NOAH B. , ROWLAND LESLIE , DREYFUSS JONATHAN , PAN HUI , GOODYEAR LAURIE J. 
Published: June 2018

Exercise can improve metabolic health for all people and patients with diabetes; however, the molecular mechanisms that mediate the exercise response are not well understood. We and others have hypothesized that exercise causes factors to be released from skeletal muscles, adipose tissue, and possibly other tissues into the circulation, and that these factors may contribute to the beneficial effects of exercise on health. To identify novel exercise-stimulated factors, healthy subjects (n=6 males and 6 females; age=29.2±0.6 years; BMI=22.5±0.7; VO2peak=40.6±1.3ml/kg/min) performed 45min of treadmill exercise at 75% VO2peak. Blood was collected at baseline, 15min, 45min during acute exercise, and 1 hour post-exercise and 1,310 circulating factors were measured using an aptamer-based proteomic method. Remarkably, this single bout of moderate intensity exercise significantly altered 247 or 19% of the measured circulating factors. In total, 171 unique proteins were increased and 76 proteins were decreased. Importantly, based on our literature review, ∼85% of these proteins have not been previously identified as exercise-stimulated circulating factors. Cardiorespiratory fitness (VO2peak) significantly correlated with the concentration of 112 factors at rest, suggesting that some of these proteins may be biomarkers of cardiorespiratory fitness. Of these factors, baseline concentrations of 40S ribosomal protein S3, a multi-functional protein that has been reported to be present in exosomes, correlated most strongly with VO2peak (p&lt;0.0007). This data set will provide the basis for ongoing studies to unravel the mechanisms by which exercise mediates its beneficial effects on diabetes and overall health.
In summary, we have identified &gt;200 novel exercise-stimulated proteins and &gt;100 circulating proteins that correlate with cardiorespiratory fitness level in healthy human subjects.

Disclosure
R. Middelbeek: None. J.J. Richard: None. N.B. Prince: None. L. Rowland: None. J. Dreyfuss: None. H. Pan: None. L.J. Goodyear: None.
Feasibility of Mother–Daughter Dyadic Gestational Diabetes (GDM) Risk Reduction Intervention for American Indian and Alaska Native (AIAN) Teens
Authors: MOORE KELLY R. , STOTZ SARAH A. , NADEAU KRISTEN J. , SEREIKA SUSAN M. , REYES YESENIA GARCIA , STEIN HOWARD R. , CHARRON-PROCHOWNIK DENISE 
Published: June 2018

AIAN women have twice the risk compared to the general U.S. population of adolescent obesity, pregnancy, and GDM. Stopping GDM (SGDM), a GDM risk reduction intervention tailored for at-risk AIAN teens, is based on a validated preconception-counseling program, READY-Girls. Prior to starting a multi-tribal randomized controlled trial (RCT) to test SGDM’s effectiveness, a feasibility study was conducted in Denver, CO with AIAN participants (4 mothers, 5 daughters). Mother-daughter (M-D) dyads were recruited through an Urban Indian Health program. Daughters were at risk for GDM as assessed by BMI &gt;85th percentile and did not have diabetes based on finger-stick HbA1c &lt; 6.5%. Mother’s (M) mean age was 44.4±8.8 years and 100% had some college education; daughter’s (D) mean age was 15.9±2.7 years and 80% were &lt;12th grade. A pre-post online questionnaire evaluated the 2-hour online intervention which included viewing the electronic SGDM book and video. Outcomes included knowledge about GDM, reproductive health and healthy lifestyle, self-efficacy, and satisfaction with the eBook and video. Post open-ended questions revealed that participants had concerns about the font size and length of the materials and enjoyed the video; could relate to the stories, images, and actors; and appreciated learning about GDM specific to AIAN women. Mean pre- to post-knowledge increased for both mothers and daughters on diabetes prevention (M 70% to 80%; D 42% to 60%) and reproductive health and GDM knowledge (M 65% to 92%; D 34% to 71%). Daughters also demonstrated increased self-efficacy for healthy living and pregnancy planning. The eBook, video, and website were scored moderately high to very high on satisfaction.
In conclusion, we determined that the SGDM intervention is feasible and acceptable in AIAN M-D dyads. These findings will be used to finalize the SGDM education materials and data collection protocol for the upcoming full-scale RCT.

Disclosure
K.R. Moore: Advisory Panel; Self; Merck Foundation. S.A. Stotz: None. K.J. Nadeau: None. S.M. Sereika: None. Y. Garcia Reyes: None. H.R. Stein: None. D. Charron-Prochownik: None.
GDF15 Is a Contraction-Induced Myokine That Regulates Pancreatic ß-Cell Function
Authors: ZHANG HUI , MULYA ANNY , NIEUWOUDT STEPHAN , MCDOWELL RUTH , KIRWAN JOHN P. 
Published: June 2018

β-cell dysfunction plays a major role in the onset of type 2 diabetes (T2D). Exercise improves or restores β-cell function in both humans and rodents with T2D. The specific mechanism is unclear. We hypothesized that exercise-induced myokines engage in cross-talk with the pancreas to help regulate β-cell function and mass. To test our hypothesis, differentiated C2C12 myotubes were subjected to electrical pulse stimulation (EPS) to simulate in vivo exercise. EPS-conditioned media from the contracting myotubes significantly elevated glucose-stimulated insulin secretion (GSIS) in β-cells vs. non-EPS control conditions (P&lt;0.05). RNA-sequencing and bioinformatic analysis enabled us to identify Growth Differentiation Factor 15 (GDF15) as a novel contraction-induced myokine that potentially communicates with β-cells. At the cellular level, recombinant GDF15 protein treatment upregulated the GSIS response in β-cells by 55% (P&lt;0.05), with no effect on cellular apoptosis, cytotoxicity or proliferation. Furthermore, qRT-PCR analysis, ELISA, immunoblots, and intracellular assays demonstrated that GDF15 may regulate first-phase insulin secretion by increasing the intracellular ATP/ADP ratio, inhibiting K+ channels and increasing the intracellular Ca2+ without affecting insulin synthesis. Using translational approaches, we found a positive correlation between fasting plasma GDF15 and insulin secretion in prediabetic subjects (R=0.64, P&lt;0.01, n=22). A 6 week supervised functional high-intensity exercise intervention increased fasting plasma GDF15 by 35% in adults with T2D (P&lt;0.01, n=12) and, interestingly, the increase in GDF15 was positively correlated with an increase in the β-cell disposition index (R=0.72, P&lt;0.01, n=12), providing further support that GDF15 may be involved in improving β-cell function.
In summary, these findings expand our understanding of skeletal muscle as an endocrine organ and identify GDF15 as a potential myokine for T2D therapy.

Disclosure
H. Zhang: None. A. Mulya: None. S. Nieuwoudt: None. R. McDowell: None. J.P. Kirwan: None.
The Impact of Lifestyle Intervention on Stage of Change toward Healthy Eating and Development of Diabetes in Prediabetic Individuals in Precontemplation Stage
Authors: SAKANE NAOKI , NIRENGI SHINSUKE , TAKAHASHI KAORU , SUGANUMA AKIKO , OKAZAKI KENTARO , IZUMI KAZUO , NODA MITSUHIKO , KUZUYA HIDESHI 
Published: June 2018

Objective: The aim of this study was to evaluate the stages of change toward healthier behavior by telephone-delivery intervention in prediabetic individuals.
Research Design and Methods: A total of 2607 participants aged 20-65 years with impaired fasting glucose were randomized to a one-year telephone-intervention intervention arm (n=1240) or a self-directed control arm with weighing scale and pedometer (n=1367). Stages of change were assessed using a self-administered questionnaire.
Results: At the baseline, 5.9% were in the precontemplation stage, 50.6% were in the contemplation stage, and 25.5% were in the preparation stage in the change to healthy eating. At the baseline, 9.4% were in the precontemplation stage, 50.2% were in the contemplation stage, and 12.0% were in the preparation stage in the change toward adopting exercise habits. For participants who were in the precontemplation stage, the proportions of those progressing to the action/maintenance stage for a healthy eating after 1-year intervention and at the end of the trial were increased (17.5 and 16.1-percentage-point increase, respectively), but there was small increase for exercise habits (5.4 and 2.7-percentage-point increase, respectively). For participants who were in the precontenplation stage, the odds of progressing to the action/maintenance stage for the intervention vs. control arm for healthy eating after 1-year intervention and at the end of the trial were 3.07 (95% CI=1.23, 8.13) and 2.21 (95% CI=1.04, 4.67), respectively. The corresponding odds for excise habits were 1.59 (95% CI=0.70, 3.61) and 1.27 (95% CI=0.55, 2.91). The hazard ratio for the development of diabetes on receiving the intervention in the precontenplation stage of healthy eating at the baseline was 0.51.
Conclusions: The intervention advanced the stages of changes toward healthy eating and might be effective for preventing diabetes even in the precontemplation stage.

Disclosure
N. Sakane: Research Support; Spouse/Partner; Pwc. S. Nirengi: None. K. Takahashi: None. A. Suganuma: None. K. Okazaki: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Taisho Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Astellas Pharma US, Inc., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation, MSD K.K., Sanwa Kagaku Kenkyusho Co., Ltd.. Other Relationship; Self; Aichi prefecture government and Nagoya city government. K. Izumi: None. M. Noda: None. H. Kuzuya: None.