In this prematurely stopped and therefore underpowered study, there was a lack of clinical benefit of intensive insulin therapy (target 4.4-6.1 mmol/L), associated with an increased incidence of hypoglycaemia, as compared to a 7.8-10.0 mmol/L target. (ClinicalTrials.gov # NCT00107601, EUDRA-CT Number: 200400391440).

Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

As a consequence of its large volume, a microencapsulated islet graft can be implanted only into the peritoneal cavity. The graft volume can be reduced by using small capsules. However, reduction of the diameter of the capsules holds a certain risk, because with smaller capsules, more islets may be found to protrude from the capsules. We have developed a lectin binding assay which, after encapsulation, specifically labels islets or parts of islets that are insufficiently immunoprotected as a consequence of inadequate, and particularly incomplete, encapsulation. With this assay, we found that a reduction of the capsule diameter from 800 micrometers to 500 micrometers was associated with an increase in the percentage of inadequately encapsulated islets from 6.3+/-1.2% to 24.2+/-1.5%. The in vivo significance of this finding was investigated by performing allotransplantations with large diameter (700-800 micrometers) and small diameter (400-500 micrometers) capsules. With large-capsule islet grafts, all recipients (n=5) became normoglycemic for 7-16 weeks, whereas with small-capsule islet grafts, only one of seven recipients became normoglycemic. The in vivo significance of inadequate encapsulation was further substantiated by our finding that most large capsules were floating freely in the peritoneal cavity without any cell adhesion, whereas the vast majority of small capsules was found to be adherent to the surface of intra-abdominal organs and infiltrated by immune cell elements characteristic of both an allograft reaction and a foreign body reaction. We conclude that successful use of capsules with small diameters requires further study to determine which factors in the encapsulation procedure should be modified to reduce the number of inadequate small capsules.

Recommendations regarding the practical aspects of tight glucose control by intensive insulin therapy cannot be presently issued. An intermediate target level for blood glucose of 140-180 mg/dL seems to be associated with the lowest risk-to-benefit ratio.

Several factors stand in the way of successful clinical transplantation of alginate-polylysine-alginate microencapsulated pancreatic islets. These obstacles can be classified into three categories. The first regards the technical aspects of the production process. Limiting factors are the insufficient ability to produce small capsules with an adequate production rate, and insufficient insight into the factors determining the optimal chemical and mechanical properties of the capsules. The second category regards the functional aspects of the microencapsulated islets, such as the limitations of the transplantation site and the absence of a physiologic insulin response of the encapsulated islets to elevated blood glucose levels. The third category regards the fact that survival times of encapsulated islet grafts are still limited to several weeks or months, which is mainly explained by a pericapsular fibrotic overgrowth reaction as a consequence of the bioincom-patibility of the capsule membrane. This study describes these obstacles, and thereby summarizes the requirements needed for successful clinical application of encapsulated islet transplantation.

Practical recommendations for the implementation of tight glucose control using intensive insulin therapy cannot be disseminated until questions relating to optimal blood glucose level and the corresponding categories of patients have been resolved. The issues of glucose variability and the most efficient method of preventing hypoglycaemia will probably represent important parameters for comparing the safety and quality of protocols used for tight glucose control.

Extracorporeal shock wave lithotripsy (ESWL) was performed for the treatment of urinary tract calculi in 28 children. All treatments were done with the standard Siemens Lithostar device in situ: no special adaptations for adequate positioning of children are required to target the stone precisely. A total of 42 calculi in 30 renal units was treated, requiring 50 ESWL sessions. The mean energy used was 16.4 kv. and the number of shock waves averaged 3,188. Mean fluoroscopy time per session was 1.5 minutes. In 26 of 50 sessions (52%) general anesthesia was needed for the child to remain perfectly still. A complete stone-free rate was achieved in 38 of 42 calculi (90.5%): after 1 session in 30 (71.4%), after 2 sessions in 6 (13.7%) and after 3 sessions in 2 (4.8%). Five staghorn calculi were treated with ESWL monotherapy. A complete stone-free result was obtained after 3 treatments in 2 patients, while 2 had residual fragments in the lower pole (5 mm. after 6 sessions and 11 months of followup in 1, and 7 mm. after 3 sessions and 3 months of followup in 1). A cystine staghorn stone necessitated open nephrolithotomy after 3 sessions without any fragmentation. One impacted sacroiliac ureteral stone required endoscopic laser lithotripsy. Except for these 2 failures no adjuvant procedures were needed. There were no intraoperative or postoperative complications and minor skin bruising at the coupling site after 3 treatments did not require any therapy. We conclude that electromagnetic ESWL with the standard Lithostar unit is a safe and effective method to treat calculi throughout the urinary tract in children.

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