Association of pancreatic fat on imaging with pediatric metabolic co-morbidities.

BACKGROUND: The relationship between pancreatic fat on imaging and metabolic co-morbidities has not been established in pediatrics. We sought to investigate the relationship between pancreatic fat measured by MRI and endocrine/exocrine dysfunctions along with the metabolic co-morbidities in a cohort of children. OBJECTIVE: To investigate relationships between pancreatic fat quantified by MRI and endocrine and exocrine conditions and metabolic co-morbidities in a cohort of children. MATERIALS AND METHODS: This was a retrospective review of pediatric patients (n = 187) who had a clinically indicated MRI examination between May 2018 and February 2020. After 51 patients without useable imaging data were excluded, the remaining 136 subjects comprised the study sample. Laboratory studies were assessed if collected within 6 months of MRI and patient charts were reviewed for demographic and clinical information. MRI proton density fat fraction (PDFF) sequence had been acquired according to manufacturer's specified parameters at a slice thickness of 3 mm. Two blinded radiologists independently collected PDFF data. RESULTS: The median age at MRI was 12.1 (IQR: 9.0-14.8) years and the majority of patients were Caucasian (79%), followed by African American and Hispanic at 12% and 11% respectively. There was a higher median pancreas fat fraction in patients with exocrine conditions (chronic pancreatitis or exocrine insufficiency) compared to those without (3.5% vs 2.2%, p = 0.03). There was also a higher median fat fraction in the head of pancreas in patients with endocrine insufficient conditions (insulin resistance, pre-diabetes, type 1 and type 2 diabetes) compared to those without endocrine insufficiency when excluding patients with active acute pancreatitis (3.5% vs 2.0%, p = 0.04). Patients with BMI > 85% had higher mean fat fraction compared to patients with BMI ≤ 85% (head: 3.8 vs 2.4%, p = 0.01; body: 3.8 vs 2.5%, p = 0.005; tail: 3.7 vs 2.7%, p = 0.049; overall pancreas fat fraction: 3.8 vs 2.6%, p = 0.002). CONCLUSION: Pancreas fat is elevated in patients with BMI > 85% and in those with exocrine and endocrine insufficiencies.

Imaging prediction of islet yield and post-operative insulin requirement in children undergoing total pancreatectomy with islet autotransplantation.

BACKGROUND: Predicting post-operative glycemic control in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) remains difficult. The purpose of our study was to explore preoperative imaging as a marker for islet yield and insulin need in pediatric patients undergoing TPIAT. METHODS: This was a retrospective study of children (≤18 years) who had undergone TPIAT between April 2015 and December 2018 and had 6 or more months of post-TPIAT follow-up. Patient specific factors (height, weight, body mass index [BMI], body surface area [BSA]) and pancreas volume segmented from the most recent pre-operative cross-sectional imaging were explored as predictors of islet yield (total islet counts [TIC], total islet equivalents [TIE], islet equivalents per kilogram body weight [IEQ/kg]) and glycemic control (total daily dose of insulin per kilogram body weight [TDD/kg], insulin independence) using Pearson correlation and univariate and multiple regression. RESULTS: Thirty-three patients, median age 13 years (IQR: 10-15 years), 64% female (21/33) met inclusion criteria. Nine patients (27%) achieved insulin independence at six months. Median TIE isolated was 310,000 (IQR: 200,000-460,000). Segmented pancreas volume was moderately associated with TIE (coefficient estimate = 0.34, p = 0.034). On multiple regression analysis, there was no significant predictor of insulin independence but number of attacks of pancreatitis (estimate = 0.024; p = 0.018) and segmented pancreas volume by body weight (estimate = -0.71; p < 0.001) were significant predictors of insulin TDD/kg. CONCLUSION: Pancreas volume segmented from pre-TPIAT imaging has predictive performance for post-TPIAT insulin need in children.

In-hospital and 90-day outcomes after total pancreatectomy with islet autotransplantation for pediatric chronic and acute recurrent pancreatitis.

Total pancreatectomy with islet autotransplantation (TPIAT) is used to treat debilitating chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) that has failed medical and endoscopic therapy. We performed a retrospective review of TPIAT patients at a free-standing children's hospital to evaluate perioperative outcomes. Twenty patients (median age 13, 65% female) underwent TPIAT (2015 through 2017). Of the 20 patients, 95% had CP and 1 patient (5%) had ARP alone. Seventy-five percent of the patients had a pancreatitis-associated genetic mutation; 40% had pancreas divisum. The median surgical time was 757 (IQR 657 to 835) minutes. Median islet equivalents per kg of body weight (IEQ/kg) were 6404 (IQR 5018 to 7554). At 90 days postoperatively vs preoperatively, significantly fewer patients were receiving parenteral nutrition (0% vs 25%, P = .006) and opioids (45% vs 75%, P = .01). Short Form 36-Item Health Survey (SF-36) physical health module scores and total scores improved (34.0 preoperatively vs 54.6 at 90 days, P = .008, and 47.1 vs 65.3, P = .007, respectively); SF-10 physical health scores also improved (13.4 vs 33.1, P = .02). Insulin requirement decreased from 0.5 unit/kg/day to 0.4 unit/kg/day between discharge and 90 days (P = .02). TPIAT is an effective option when debilitating disease persists despite maximal medical and endoscopic therapy. Opioid, parenteral nutrition, and exogenous insulin use can successfully be weaned within 90 days after TPIAT, with gains in health-related quality of life.

Severe fasting hypoglycemia in a child after total pancreatectomy with islet autotransplantation.

TPIAT is an increasingly utilized treatment option for select children with CP. Post-TPIAT fasting hypoglycemia, unrelated to exogenous insulin, is a complication recently reported in adults. This phenomenon has not been described in children. We review a case of severe fasting hypoglycemia in an adolescent female occurring 10 months post-TPIAT. A 12-year-old girl underwent TPIAT for CP. Ten months postoperatively she developed recurrent hypoglycemia on a total daily insulin dose of 0.03 units/kg. Consequently, insulin therapy was discontinued. Approximately 20 hours after her last rapid-acting insulin exposure, she had an episode of fasting hypoglycemia (33 mg/dL on glucometer). Her CGM documented two separate, precipitous drops in glucose overnight. The family was instructed to revise her diet, and there were no subsequent episodes of severe, fasting hypoglycemia. This is the first report of fasting hypoglycemia occurring post-TPIAT in a pediatric patient. Use of a CGM allowed for documentation of glucose trends and alarm notification of hypoglycemic events. Dietary changes appeared to help mitigate hypoglycemia recurrence. This report demonstrates that fasting hypoglycemia is a potential complication that should be recognized and safeguarded against in post-TPIAT pediatric patients.

The anti-inflammatory effect of topical tofacitinib on immediate and late-phase cutaneous allergic reactions in dogs: a placebo-controlled pilot study.

BACKGROUND: Topical Janus kinase (JAK) inhibition is a promising therapeutic target for several inflammatory skin diseases of humans. OBJECTIVES: To evaluate the anti-inflammatory effect of tofacitinib, a JAK 1/3 inhibitor, on immediate and late-phase skin reactions in dogs. ANIMALS: Five healthy laboratory beagle dogs. METHODS: Topical tofacitinib (total daily dosage: 0.5 mg/cm2 ) or its gel vehicle were applied on either the left or right lateral thorax of each dog for eight days. Three days before application and after eight days of topical treatment, intradermal injections of histamine and anticanine-IgE antibodies were performed on both sides; they were evaluated by an investigator blinded to the interventions. RESULTS: The tofacitinib gel was well-tolerated; one dog developed mild erythema at Day 5 that resolved by the next application. Treatment with tofacitinib reduced histamine and anticanine-IgE global wheal scores (one-way ANOVA, P ≤ 0.005 for both) compared to baseline; there was no significant difference for the vehicle placebo (histamine; P = 0.163; IgE, P = 0.223). Late-phase reactions (LPRs) were markedly, but not significantly reduced after tofacitinib treatment (P = 0.071). A blinded histological evaluation of 6 h-anti-IgE-associated LPRs revealed a significant reduction in the total leucocyte superficial dermal cellularity (P = 0.022), as well as eosinophil (P = 0.022) and mast cell (P = 0.022) counts at tofacitinib-treated sides compared with pretreatment values. Post-treatment complete blood counts and serum chemistry profiles did not show relevant tofacitinib-induced changes. CONCLUSIONS: Our observations suggest that topical tofacitinib exerts an inhibitory effect on activated canine skin-emigrating immune cells; this drug should be investigated further as a topical immunosuppressive drug in dogs.

Obesity is associated with an altered HDL subspecies profile among adolescents with metabolic disease.

We aimed to determine the risk factors associated with the depletion of large HDL particles and enrichment of small HDL particles observed in adolescents with T2D. Four groups of adolescents were recruited: 1) lean insulin-sensitive (L-IS), normal BMI and no insulin resistance; 2) lean insulin-resistant (L-IR), normal BMI but insulin resistance (fasting insulin levels ≥ 25 mU/ml and homeostatic model assessment of insulin resistance ≥ 6); 3) obese insulin-sensitive (O-IS), BMI ≥ 95th percentile and no insulin resistance; and 4) obese insulin-resistant (O-IR), BMI ≥ 95th percentile and insulin resistance. Plasma was separated by using gel-filtration chromatography to assess the HDL subspecies profile and compared with that of obese adolescents with T2D (O-T2D). Large HDL subspecies were significantly lower across groups from L-IS > L-IR > O-IS > O-IR > O-T2D (P < 0.0001); small HDL particles were higher from L-IS to O-T2D (P < 0.0001); and medium-sized particles did not differ across groups. The contributions of obesity, insulin resistance, and diabetes to HDL subspecies profile were between 23% and 28%, 1% and 10%, and 4% and 9%, respectively. Obesity is the major risk factor associated with the altered HDL subspecies profile previously reported in adolescents with T2D, with smaller contributions from insulin resistance and diabetes.

Continuous glucose monitoring following pancreatectomy with islet autotransplantation in children.

Aim was to determine whether CGM could accurately monitor blood glucose concentration in the immediate postoperative period following pancreatectomy with IAT in children. CGM was used in nine patients undergoing IAT at our institution between April 2015 and September 2016 (eight total pancreatectomy and one subtotal pancreatectomy). MAD and MARD of CGM values compared to time-matched serum blood glucose were calculated during the first 5 days of ICU admission. Goal range was defined as 70-140 mg/dL and out-of-range was >140 mg/dL or <70 mg/dL. Of 89 time-matched measures found, 75% of CGM values were within 15 mg/dL, and 51% were within 10 mg/dL, compared to serum glucose. MAD was 11.6 mg/dL, and MARD was 10.6%. CGM values did not differ from serum glucose (P=.74). By Clarke error grid analysis, 100% of paired values were in clinically acceptable zones. By surveillance error grid analysis, 96% of paired values were within clinically acceptable agreement. CGM is a reliable tool in monitoring glycemic control in the immediate postoperative period following pancreatectomy with IAT in children.

Nonionic surfactant structure on the drug release, formulation and physical properties of ethylcellulose microspheres.

Evaluate the effects of nonionic surfactants Brij 58 and Tween 40 with different structures but similar hydrophilic lipophilic balances (HLBs) on theophylline (TH)-loaded ethylcellulose (EC) microspheres. Microspheres were formulated using ratios of the surfactants with matching HLB values but different chemical-structures at temperatures (22/35 °C) by hydrophobic solvent-emulsion evaporation. Particle size, GMD, drug loading, encapsulation efficiency and dissolution were evaluated. Drug release was determined using the zero- and first-order, Higuchi and Hixson-Crowell models. EC microspheres prepared with surfactant Brij 58 showed discrete, free-flowing spherical particles, solid interiors and increased particle smoothness as temperature increased; those prepared with Tween 40 appeared porous with coarser surface morphology as temperature increased; both were CHLB (Combined HLB) dependent. Dissolution obeyed the Higuchi model drug release for both microspheres prepared with Tween 40 and Brij 58 except for those prepared with Brij 58 at 35 °C, which presented as zero order. The results were ascribed to the different chemical structure of Brij 58 versus Tween 40 and preparation temperature. Surfactant chemical structure is an unreported processing parameter shown here to be important in microsphere formulation. Brij 58 possesses properties unique to its chemical structure that influence pharmaceutical and molecular biopharmaceutical research.

The incretin effect in obese adolescents with and without type 2 diabetes: impaired or intact?

The incretin effect reflects the actions of enteral stimuli to promote prandial insulin secretion. Impairment of this measure has been proposed as an early marker of ß-cell dysfunction and described in T2D, IGT, and even obesity without IGT. We sought to determine the effects of obesity and diabetes on the incretin effect in young subjects with short exposures to metabolic abnormalities and a few other confounding medical conditions. Subjects with T2D (n = 10; 18.0 ± 0.4 yr) or NGT, either obese (n = 11; 17.7 ± 0.4 yr) or lean (n = 8; 26.5 ± 2.3 yr), had OGTT and iso-iv. The incretin effect was calculated as the difference in insulin secretion during these tests and was decreased ∼50% in both the NGT-Ob and T2D subjects relative to the NGT-Ln group. The T2D group had impaired glucose tolerance and insulin secretion during the OGTT, whereas the lean and obese NGT subjects had comparable glucose excursions and ß-cell function. During the iso-iv test, the NGT-Ob subjects had significantly greater insulin secretion than the NGT-Ln and T2D groups. These findings demonstrate that in young subjects with early, well-controlled T2D the incretin effect is reduced, similar to what has been described in diabetic adults. The lower incretin effect calculated for the obese subjects with NGT is driven by a disproportionately greater insulin response to iv glucose and does not affect postprandial glucose regulation. These findings confirm that the incretin effect is an early marker of impaired insulin secretion in persons with abnormal glucose tolerance but suggest that in obese subjects with NGT the incretin effect calculation can be confounded by exaggerated insulin secretion to iv glucose.

Rapid deterioration of insulin secretion in obese adolescents preceding the onset of type 2 diabetes.

OBJECTIVE: To identify pathophysiologic changes that lead to the onset of type 2 diabetes (T2DM) in adolescents. STUDY DESIGN: Obese adolescents with normal glucose tolerance (n = 41) were studied longitudinally over the course of 4 years with serial measure of the acute insulin response to glucose (AIRg) as well as proinsulin (PI) concentrations. Insulin resistance was estimated with the homeostatic model assessment of insulin resistance (HOMA-IR), the disposition index (DI) computed as AIRg × 1/HOMA-IR, and intravenous glucose tolerance estimated as the glucose disappearance constant. RESULTS: Four adolescents developed diabetes mellitus (DM) during the study, and the rest of the cohort remained nondiabetic. Baseline PI exceeded the IQR of the nondiabetic group in 3 of 4 subjects with DM, and all had >85% reduction from baseline AIRg, and DI, within 6 months of diagnosis. All the subjects with DM gained weight over the course of the study, but these changes paralleled those for the nondiabetic group. HOMA-IR increased substantially in 1 of the subjects with DM at the time of diagnosis but was comparable with baseline in the other 3. The DI and glucose disappearance constant of the subjects with DM was less than the 10th percentile of the nondiabetic group before and after diagnosis. CONCLUSION: Conversion from normal glucose tolerance to T2DM in adolescents can occur rapidly, and the onset of T2DM is heralded by a substantial decrease in AIRg and DI, as well as increased release of PI. These results support loss of ß-cell function as the proximate step in the development of T2DM in this age group.

Insulin Sensitivity and ß-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents.

OBJECTIVE: To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB). STUDY DESIGN: A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5-20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose ), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling. RESULTS: In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m(2) (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved ß-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01). CONCLUSIONS: RYGB reduced body mass index and improved both insulin sensitivity and ß-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00360373.

Formulation parameters and release mechanism of theophylline loaded ethyl cellulose microspheres: effect of different dual surfactant ratios.

Altering the combined hydrophilic-lipophilic balance (CHLB), by varying the ratio of dual surfactants, on formulation parameters and in vitro drug release of ethyl cellulose microspheres was examined. Theophylline, a xanthine bronchodilator was used to model controlled release owing to its narrow therapeutic index. Microspheres were prepared using different ratios of dual surfactant in an emulsion-solvent evaporation process. Drug loading, encapsulation efficiency, particle size distribution, and geometric mean diameters were evaluated. Drug release was evaluated using several kinetic models including zero and first order, Higuchi square root, and Hixson-Crowell. Microspheres presented as mostly spherical particles and diffusional drug release was affected by microsphere construction. For this novel, dual surfactant system the microsphere matrix is a hydrophobic polymer and the release rate may be modulated with variation in ratio of dual surfactants. Dissolution data followed the Higuchi model and supports the formation of a monolithic microsphere matrix that releases theophylline by Fickian diffusion. Dual surfactants for preparation of microspheres are an inadequately studied research area that offers another means to modulate particle size and drug release. For the current study microspheres prepared with surfactant ratios of Span 65: Tween 40 between 3:1 and 2:1 provided the best control of size and drug release.

Metabolic Outcomes in Pediatric Patients One-Year Post-Total Pancreatectomy with Islet Autotransplantation after Early Pump Initiation.

We previously published that insulin pump initiation immediately after IV insulin therapy was associated with improved post-surgical glycemic outcomes compared to multiple daily injections (MDI) in pediatric patients following a total pancreatectomy with islet autotransplantation (TPIAT). We investigated metabolic outcomes of this population at one-year post-TPIAT to assess if the improved outcomes in the early pump group were sustained over time. We retrospectively reviewed 40 patients post-TPIAT previously studied at 10-days post-surgery (15 used MDI and 25 used pump therapy immediately post-ICU, and all were discharged on pump therapy). Data analyzed included: demographics, islet equivalents per kilogram (IEQ/kg) transplanted, exogenous insulin use, and baseline vs. one-year (via mixed meal testing) HbA1c, fasting glucose, insulinogenic index, and the area under the curve (AUC) for insulin and c-peptide. More patients were off insulin at one year in the early pump group compared to the MDI group (45% vs. 13%, p = 0.07). Of all patients off insulin, 100% of the early pump users weaned off by six months post-TPIAT compared to 30% of the MDI users. Two known variables associated with favorable insulin outcomes, lower age and higher IEQ/kg, were not significantly different between groups. Fasting glucose was lower in the early pump group compared to the MDI group (median 97 vs. 122 mg/dL, p = 0.003), while AUC c-peptide was greater in early pump users at one-year post-TPIAT but did not reach significance (median 57.0 vs. 50.3 ng/mL × minutes, p = 0.14). Other metabolic outcomes did not differ between groups. Despite lower median age and higher IEQ/kg in the MDI group, the early pump group had a lower fasting glucose. Younger TPIAT age (p = 0.02) and early pump users (p = 0.04) were significantly associated with insulin independence at one year. This study was limited by sample size. Early pump use may have long-term benefits in post-TPIAT endogenous insulin secretion.

Endocrine Management and Clinical Outcomes in a Cohort of Pediatric Patients Undergoing Total Pancreatectomy with Islet Autotransplantation.

Objective: To describe management strategies that contributed to optimal outcomes in pediatric recipients of a total pancreatectomy with islet autotransplantation (TPIAT). Research Design and Methods: We provide a comprehensive report of the approach to endocrine management of the pediatric TPIAT recipient from initial evaluation through the first 4 years postsurgery. We performed a retrospective review of the endocrine outcomes of TPIAT recipients to describe the impact of this approach on post-TPIAT glycemic management. Results: Outcome data from 86 TPIAT recipients were reviewed. At 12 months post-TPIAT (n = 82), the median HbA1C was 6.0% (25-75th percentile 5.6-6.7), at 18 months (n = 56) HbA1C was 6.4% (5.6-7.5), at 2 years (n = 46) HbA1C was 6.4% (5.6-7.4), at 3 years (n = 31) HbA1C was 6.5% (5.5-8.1), and at 4 years (n = 16) HbA1C was 7.2% (6.2-8.3). Conclusions: Pediatric patients at our institution have favorable endocrine outcomes as evidenced by median HbA1C under the goal of 6.5% through the initial 3 years by following our modified management protocols.

ß-cell dysfunction in adolescents and adults with newly diagnosed type 2 diabetes mellitus.

OBJECTIVE: To compare ß-cell function in adolescents and adults with newly diagnosed type 2 diabetes (T2DM). STUDY DESIGN: Thirty-nine adolescents with T2DM, 38 age- and weight-matched control subjects, and 19 adults with T2DM were studied. The adolescent subjects with diabetes were divided on the basis of whether they needed insulin to control their initial hyperglycemia. The primary outcome variable was the disposition index, computed from the acute insulin response to glucose corrected for insulin sensitivity (1/Homeostatic model assessment of insulin resistance). RESULTS: The disposition index was significantly reduced in all 3 diabetic groups (control n=3360, adolescents with T2DM without insulin n=630, adolescents with T2DM with insulin n=120, adults with T2DM n=200; P<.001), and the adolescents with more severe hyperglycemia at diagnosis had lower disposition index than those with a more modest presentation (P<.05). CONCLUSION: At the time of diagnosis, adolescents with T2DM have significant ß-cell dysfunction, comparable with adults newly diagnosed with T2DM. Thus, severe ß-cell impairment can develop within the first two decades of life and is likely to play a central role in the pathogenesis of T2DM in adolescents.

Transdermal permeation of novel n-acetyl-glucosamine/NSAIDs mutual prodrugs.

The current investigation reports skin permeation of three novel mutual prodrugs (MP) which couple n-acetyl-glucosamine with an NSAID, either ketoprofen or ibuprofen. They were evaluated for transdermal permeation using shed snakeskin, and to our knowledge represent the first MPs synthesized for this purpose, although they also could be used for subcutaneous delivery. MPs are defined as two active drug compounds usually connected by an ester linkage. Glucosamine administration has been linked to damaged cartilage repair, and pain relief in joints afflicted with osteoarthritis. NSAIDs are commonly used orally in transdermal creams or gels for joint pain relief. Two novel compounds we report (MP1 and MP2) covalently link ibuprofen and ketoprofen directly to the amide nitrogen of n-acetyl-glucosamine (NAG); the other compound (MP3) covalently links ibuprofen to the amide nitrogen, using a short chain acetyl linker. Permeability studies show that the ketoprofen mutual prodrug (MP2) permeates shed snakeskin more than three times greater than either ibuprofen derivative, while ethanol markedly increases the permeation for all three. The ketoprofen mutual prodrug appears the most likely candidate for transdermal administration; all three mutual prodrugs may be candidates for subcutaneous injection.

Is There a Benefit From Islet Autotransplantation in Patients With Type 1 Diabetes Mellitus Undergoing Total Pancreatectomy?

ABSTRACT: Children with acute recurrent and chronic pancreatitis (CP) experience abdominal pain that leads to hospitalizations, opioid dependence, and poor quality of life. Total pancreatectomy with islet autotransplantation (TPIAT) is offered as a surgical option in management of debilitating pancreatitis that fails medical and endoscopic therapy to reduce or eliminate pain. Given that patients with type 1 diabetes mellitus (T1DM) lack insulin-producing ß cells, the outcomes from autotransplanting islet isolates back into total pancreatectomy patients with T1DM are not fully known.We performed TPIAT in 2 CP patients who also had a diagnosis of T1DM for at least 6 years before the operation and evaluated the clinical and laboratory outcomes before and after the operation. Postoperatively both patients' abdominal pain had significantly subsided, they were weaned off opioid medications, and they were able to return to full-time school attendance. In addition, total daily dose of insulin in 1 patient was able to be slightly reduced at 12 months post-TPIAT. We observed in vitro that residual α cells and ß cells in T1DM islets were able to secrete a small amount of glucagon and insulin, respectively.

Predictors of Glycemic Outcomes at 1 Year Following Pediatric Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVE: Total pancreatectomy with islet autotransplantation (TPIAT) is indicated to alleviate debilitating pancreas-related pain and mitigate diabetes in patients with acute recurrent and chronic pancreatitis when medical/endoscopic therapies fail. Our aim was to evaluate predictors of insulin requirement at 1 year following TPIAT in a cohort of children. RESEARCH DESIGN AND METHODS: This was a review of 43 pediatric patients followed after TPIAT for 1 year or longer. Primary outcome was insulin use at 1 year, categorized as follows: insulin independent, low insulin requirement (<0.5 units/kg/day), or high insulin requirement (≥0.5 units/kg/day). RESULTS: At 1 year after TPIAT, 12 of 41 (29%) patients were insulin independent and 21 of 41 (51%) had low and 8 of 41 (20%) had high insulin requirement. Insulin-independent patients were younger than those with low and high insulin requirement (median age 8.2 vs. 14.6 vs. 13.1 years, respectively; P = 0.03). Patients with insulin independence had a higher number of transplanted islet equivalents (IEQ) per kilogram body weight (P = 0.03) and smaller body surface area (P = 0.02), compared with those with insulin dependence. Preoperative exocrine insufficiency was associated with high insulin requirement (P = 0.03). Higher peak C-peptide measured by stimulated mixed-meal tolerance testing (MMTT) at 3 and 6 months post-TPIAT was predictive of lower insulin requirement at 1 year (P = 0.006 and 0.03, respectively). CONCLUSIONS: We conclude that insulin independence following pediatric TPIAT is multifactorial and associated with younger age, higher IEQ per kilogram body weight transplanted, and smaller body surface area at time of operation. Higher peak C-peptide measured by MMTT following TPIAT confers a higher likelihood of low insulin requirement.

Investigating Flubendazole as an Anthelmintic Treatment for Guinea Worm (Dracunculus medinensis): Clinical Trials in Laboratory-Reared Ferrets and Domestic Dogs in Chad.

Dracunculus medinensis (Guinea worm [GW]), a zoonotic nematode targeted for eradication, has been managed using interventions aimed at humans; however, increases in domestic dog GW infections highlight the need for novel approaches. We conducted two clinical trials evaluating the efficacy of subcutaneously injected flubendazole (FBZ) as a treatment of GW infection. The first trial was conducted administering FBZ to experimentally infected ferrets; the second trial involved administering FBZ or a placebo to domestic dogs in the Republic of Tchad (Chad). We found contrasting results between the two trials. When adult gravid female GW were recovered from ferrets treated with FBZ, larvae presented in poor condition, with low to no motility, and an inability to infect copepods. Histopathology results indicated a disruption to morulae development within uteri of worms from treated animals. Results from the trial in Chadian dogs failed to indicate significant treatment of or prevention against GW infection. However, the difference in treatment intervals (1 month for ferrets and 6 months for dogs) or the timing of treatment (ferrets were treated later in the GW life-cycle than dogs) could explain different responses to the subcutaneous FBZ injections. Both trials provided valuable data guiding the use of FBZ in future trials (such as decreasing treatment intervals or increasing the dose of FBZ in dogs to increase exposure), and highlighted important lessons learned during the implementation of a field-based, double-blinded randomized control trial in Chadian dogs.