SummaryBackgroundKCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.MethodsIn this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.Findings90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol [41·0–56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2–10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5–24·0] vs 4·1 years [1·3–10·2]; p=0·0005). Initial improvement was noted following transfer to sulfo...

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A series of carbonyl derivatives of 5‐imino‐Δ3‐1,2,4‐thiadiazolines has been prepared and shown by X‐ray analysis of a selected example to have a trithiapentalene‐like structure. When diphenylketene was used as acylating reagent, the primary product (14), obtained at room temperature, rearranged on heating in a polar solvent into a Δ2‐thiazolin‐4‐one (15). The structure of 15 has been confirmed by X‐ray analysis, and shown to be a zwitterion. Rearranged products (i.e., 16 and 20‐22) were also obtained when 3 was reacted with dimethyl acetylenedicarboxylate or methanesulfonyl chloride, whereas tosyl chloride gave normal tosylated derivatives (17‐19). The latter have also a nearly linear N‐S…O arrangement, but the interaction between S and O is weak.

a six-membered ring; a 36-line spectrum would be expected for (6). The FD mass spectrum[51 also provides important evidence in favor of the four-membered ring. The peak at mje=459 corresponds to the dication of ( 4 ) , but could also be assigned to the trebly charged cation (6). The latter possibility is discounted by the appearance of the highest mass peak at m/e=917, i. e. for [K2+ -H+]+ and by the absence of ions in the range m/e= 1000-1 500. Another line at m/e = 841 arises from a cation containing one less phenyl group [Kz+ -Ph+]+. Procedure (17.4g, 41.8 mmol) in a minimal amount of CHZCIZ is slowly added dropwise PhzPCl (18.4 g, 83.6mmol) diluted with the same amount of CH2C12. After 2 h the precipitated trichlorodiphenylphosphorane is filtered off (10 g = 34 mmol = 82 %) and that remaining in solution decomposed with 1,2-epoxybutane. The solvent is distilled off in uucuo and the dry residue dissolved in CH3CN. Ether is added to the gently stirred solution until it becomes slightly turbid; precipitation is complete within 30min. The product is filtered off, washed with ether, and dried in uucuo at 40°C. Yield: 16.8g (71 %) of (2), m.p. 192°C (dec.). 'H-NMR: multiplet at 6=7.4 to 8.0ppm. 31P-NMR: two doublets at 6 = -23.63 and + 62.63 ppm; J(P,P) =42.5 Hz.( 4 ) : To a solution of (2) (8.5g, 15mmol) in CH2C12 is added solid trimorpholinophosphane (4.3 g, 15 mmol) in a single batch and the mixture is stirred at room temperature for 10 to 20min. After evaporation to dryness at 40°C the residue is taken up in benzene and the mixture filtered. The filter cake is stirred with CH2C12, whereupon (OC4HsN)3PC12 dissolves. The white residual solid is recrystallized from methanol. After washing with CHzClz it is dried at 80°C. Yield: 5.8g (79%) of (4), m.p. 385"C.-The action of bromine on the solution of ( 4 ) in CHzClz gives ( 5 ) , dec. 365"C, in quantitative yield. 31P-NMR: two triplets at 6= 14.44 and 33.64ppm; J(P,P)=7.35Hz.(2): To an ice-cooled, stirred solution of

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