Objective: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. Methods: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. Results: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein Nglycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months.

Background-Insights gained from noncontact mapping of ventricular tachycardia (VT) have not been systematically applied to contact maps. This study sought to unify both techniques for an individualized approach to the patient with multiple ischemic VTs irrespective of cycle length. Methods and Results-For 12 consecutive patients with chronic myocardial infarction and recurrent VT, bipolar contact maps were acquired during sinus or paced rhythm. Additional noncontact maps were obtained during 48 induced VTs (cycle length 192 to 579 ms). Endocardial exit sites were superimposed on contact maps and verified by pace-mapping. Radiofrequency lesions were extended for critical borders defined by multiple neighboring exits and followed the isovoltage contour line of contact maps. Nine critical borders were identified in 8 patients and constituted the substrate for 31 VTs. The voltage at exit sites was 0.8 mV (range 0.1 to 2.3). Noncontact maps revealed 23Ϯ18% of isthmus conduction. Thirty-seven (77%) of all and 83% of clinically documented VTs were rendered noninducible irrespective of cycle length by application of 27 radiofrequency lesions (range 18 to 56). Spontaneous transitions between distinct VTs along critical borders were demonstrated in 4 patients. Pace-mapping reproduced the QRS morphology of 81% of VTs and was associated with successful ablation (PϽ0.01). Noninducibility of any sustained VT was reached for 8 (67%) patients. During 15 months (range 5 to 28) of follow-up, 8 patients remained without recurrence, and VT episodes were reduced in the other 4 patients (PϽ0.01). VT cycle length was not predictive for acute or long-term success. Conclusion-The combined approach of contact and noncontact mapping effectively defines critical borders as the substrate of multiple VTs without limitation for unstable VTs.

The quinoline-3-carboxamide, linomide, protects non-obese diabetic mice from diabetes. The effects of linomide on insulin needs and beta cell function were studied in recent juvenile Type I diabetes in a double-blind trial. Patients with recent onset diabetes were randomly assigned to treatment with a fixed dose of 2.5 mg linomide (42 patients) or placebo (21 patients) for 1 year, in addition to insulin and diet. Glycated haemoglobin was 10-15% lower at 9 months (p = 0.003) and 12 months (p < 0.05) in the linomide group. The insulin dose was 32-40% smaller in the linomide group at 3 (p < 0.03), 6 (p < 0.02), 9 (p < 0.001) and 12 months (p = 0.01). Insulin doses correlated negatively with C peptide values (p = 0.001-0.002). The trend for higher C peptide values in the linomide group did not reach significance. In a post hoc subgroup analysis performed in 40 patients (25 from the linomide group and 15 from the placebo group) who still had detectable residual beta cell function at entry, linomide was associated with 45-59% higher C peptide value at 6 months (p < 0.05), 9 months (p < 0.05) and 12 months (p < 0.05). The main adverse effects of linomide were mild transitory anaemia (45 vs 10% in the linomide and placebo groups), thrombocytopenia (24 vs 10%), and mild joint discomfort (45 vs 5%) with no clinical signs. In conclusion, low-dose linomide reduced the insulin needs in patients with juvenile Type I diabetes of recent onset and improved beta cell function in patients who still had detectable beta cell function at entry. These results support further clinical and experimental studies to define the effects of linomide in Type I diabetes provided the safety of linomide is reliably established.

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Dyssynchronous segments of an ischemic myocardium show unimpaired local activation but slow wall motion, thereby limiting the benefit of ventricular preexcitation via CRT.

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A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study’s conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients’ lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.

The RCA affects CTI ablation as higher power settings are required at closer distances to the ablation site. Late conduction recurrences were observed in patients with a variation of the RCA, leaving the atrioventricular groove towards the atrial aspect.