Ductal plate malformations (DPM) are developmental anomalies considered to result from lack of ductal plate remodeling during bile duct morphogenesis. In mice, bile duct development is initiated by the formation of primitive ductal structures lined by two cell types, namely ductal plate cells and hepatoblasts. During ductal plate remodeling the primitive ductal structures mature to ducts as a result from differentiation of the ductal plate cells and hepatoblasts to cholangiocytes. We here report that this process is conserved in human fetal liver. These findings prompted us to evaluate how DPM develop in three mouse models, namely mice with livers deficient in Hepatocyte Nuclear Factor (HNF)6, HNF1β or cystin-1 (cpk mice). Human liver from a patient with a HNF1B/TCF2 mutation, and from fetuses affected with Autosomal Recessive Polycystic Kidney Disease (ARPKD) were also analysed. Despite the epistatic relationship between HNF6, HNF1β and cystin-1, the three mouse models displayed distinct morphogenic mechanisms of DPM. They all developed biliary cysts lined by cells with abnormal apico-basal polarity. However, the absence of HNF6 led to an early defect in ductal plate cell differentiation. In HNF1β-deficient liver, maturation of the primitive ductal structures was impaired. Cpk mouse livers and human fetal ARPKD showed normal differentiation and maturation but abnormal duct expansion. Conclusion DPM is the common end-point of distinct defects initiated at distinct stages of bile duct morphogenesis. Our observations provide a new pathogenic classification of DPM.
Aims-Low Carbohydrate Diets (LCD) are a popular intervention for weight loss, but the effect of such diets on myocardial ischemia is not known. Myocardial energy substrates and insulin signaling pathways may be affected by these diets, and both may play a role in protection of ischemic myocardium. We investigated whether LCD increases susceptibility to cardiac injury during ischemia and reperfusion in the isolated rat heart.Main Methods-Rats were fed LCD (60% kcal from fat / 30% protein / 10% carbohydrate) or a control diet (CONT; 16% / 19% / 65%) for 2 weeks. Hearts from rats fed with LCD or CONT were isolated and subjected to normal perfusion in Langendorff mode, with 30 min global low flow ischemia (LFI; 0.3 ml/min) followed by 60 min reperfusion, or 60 min LFI followed by 120 min reperfusion.Key Findings-LCD diet led to an increase in 3-hydroxybutyrate and lower circulating insulin. LCD diet also resulted in impaired left ventricular performance during LFI, reduced recovery of function following LFI and reperfusion, and 10-to 20-fold increased injury as measured by lactate dehydrogenase release and histologic infarct area. LCD diet also led to lower myocardial glycogen stores and glycogen utilization during LFI, and lower insulin signaling as assessed by Akt phosphorylation at the end of LFI and reperfusion, but no differences in ERK 1/2 phosphorylation.Significance-These results demonstrate that LCD affects myocardial energy substrates, affects insulin signaling, and increases myocardial injury following ischemia-reperfusion in the isolated heart.
Background: American Diabetes Association (ADA) recommends psychosocial assessment for people with diabetes, including diabetes-related distress. Elevated diabetes-related distress is associated with poor selfmanagement, lower medication adherence, and poorer quality of life. Insulin delivery methods are multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Because people with type 1 diabetes mellitus (T1DM) require comprehensive insulin therapy to manage blood glucose, we explored the association of insulin delivery methods and diabetes distress in this group. Methods: The U.S. Air Force Diabetes Center of Excellence (DCOE), a specialty clinic for adults who are Military Health System beneficiaries, administers the validated 17-item Diabetes-related Distress Scale (DDS-17) as part of standard care. Patient data were analyzed from June 2015 to August 2016 using SPSS version 22.Patients were free to choose the method of insulin delivery with minimal or no additional cost. Results: There were 203 patients with T1DM who completed the DDS-17 as part of standard care during the time period. Patients were categorized as CSII (57.6%) or MDI (42.4%). Women were significantly more likely to choose MDI over CSII than men (P = 0.003). DDS-17 scores were low in both groups, and there were no significant differences in DDS-17 by insulin delivery method. Furthermore, no significant differences were found in hemoglobin A1c (HbA1c) between CSII (7.9% or 63 mmol/mol) and MDI (8.1% or 65 mmol/mol) users (P = 0.22) and no significant differences in body mass index (BMI) between patients using CSII (M = 28.33 kg/m 2 ) and MDI (28.49 kg/m 2 ) users (P = 0.15). Conclusions: Our study demonstrated that if patients are relatively free to choose the insulin delivery method (minimal or no financial constraints), there were no differences in diabetes distress scores, HbA1c, or BMI between CSII and MDI. Therefore, people with T1DM may benefit from choosing the method of insulin delivery that will enable them to achieve individual goals and manage diabetes-related distress.
Losartan is an angiotensin II receptor blocker (ARB) which may cause severe sprue‐like enteropathy (SLE) with skin manifestation. Clinicians should be informed of this side effect and its reversibility after cessation of the drug.
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