Hyperinsulinism of infancy: the regulated release of insulin by KATP channel-independent pathways

Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic beta-cells. Here we describe stimulus-secretion coupling mechanisms in beta-cells and intact islets of Langerhans isolated from three patients with a novel SUR1 gene defect. 2154+3 A to G SUR1 (GenBank accession number L78207) is the first report of familial HI among nonconsanguineous Caucasians identified in the U.K. Using patch-clamp methodologies, we have shown that this mutation is associated with both a decrease in the number of operational ATP-sensitive K+ channels (KATP channels) in beta-cells and impaired ADP-dependent regulation. There were no apparent defects in the regulation of Ca2+- and voltage-gated K+ channels or delayed rectifier K+ channels. Intact HI beta-cells were spontaneously electrically active and generating Ca2+ action currents that were largely insensitive to diazoxide and somatostatin. As a consequence, when intact HI islets were challenged with glucose and tolbutamide, there was no rise in intracellular free calcium ion concentration ([Ca2+]i) over basal values. Capacitance measurements used to monitor exocytosis in control and HI beta-cells revealed that there were no defects in Ca2+-dependent exocytotic events. Finally, insulin release studies documented that whereas tolbutamide failed to cause insulin secretion as a consequence of impaired [Ca2+]i signaling, glucose readily promoted insulin release. Glucose was also found to augment the actions of protein kinase C- and protein kinase A-dependent agonists in the absence of extracellular Ca2+. These findings document the relationship between SUR1 gene defects and insulin secretion in vivo and in vitro and describe for the first time KATP channel-independent pathways of regulated insulin secretion in diseased human beta-cells.     

Ex vivo delineation of placental angioarchitecture with the microbubble contrast agent Levovist

OBJECTIVE: The aim of this study was to delineate placental vasculature with the microbubble contrast agent Levovist (99.9% galactose and 0.1% palmitic acid; Schering AG, Berlin, Germany), with the ultimate goal of delineating placental vascular anatomy in utero. STUDY DESIGN: A placental lobule from each of 11 term human placentas was perfused on the fetal side of the circulation under physiologic conditions. Randomly assigned dose-concentration combinations of Levovist were administered through a chorionic artery into the corresponding placental lobule, and the resultant echoenhancement with power Doppler imaging was recorded for digital analysis. Interplacental variability was corrected for by averaging the results of three injections at each dose-concentration combination. RESULTS: Echoenhancement was seen at all dose-concentration combinations in the injected lobule but not in adjacent control lobules. The three dose-concentration combinations that achieved optimal maximal integrated intensity and duration of action for both chorionic vessel and villus enhancement were 100 microL/kg of 400-mg/mL Levovist, 200 microL/kg of 400-mg/mL Levovist, and 400 microL/kg of 200-mg/mL Levovist. CONCLUSION: Microbubble contrast injection into the fetal vasculature enabled power Doppler imaging echoenhancement both in chorionic vessels and within the villus tree. We speculate that fetal injection of contrast agent may be applied to the delineation of placental lesions or areas of interfetal transfusion, although its applicability will be hindered by the need for fetal blood sampling.     

Techniques to maximize mammary artery length

The available length of the internal mammary artery has limited its versatility as a bypass conduit. Several techniques for increasing usable internal mammary artery length are described.     

Determinants of 10-year survival after primary myocardial revascularization.

The first 1000 patients undergoing primary isolated myocardial revascularization each year from 1971 to 1978 were analyzed to elucidate the determinants of long-term survival. Five-year survival was 93.2%, and 10-year survival was 79.3%. Five-year survivals were 96.1%, 94.2%, 92.1%, and 90.8%, respectively, for single, double, triple, and left main disease. Ten-year survivals for the same subsets were 88.6%, 83.0%, 74.9%, and 70.9%. Five-year survivals were 95.3%, 92.4%, 88.0%, and 81.3% for patients with normal, mild, moderate, and severe impairment of the left ventricle. Ten-year survivals for the same subsets were 84.1%, 76.5%, 65.8% and 53.6%. Patients receiving internal mammary artery grafts had 95.6% and 85.8% 5- and 10-year survivals that were superior to 92.0% and 76.2% in patients with only vein grafts. Patients completely revascularized had 95.0% and 82.5% 5- and 10-year survivals, while incompletely revascularized patients had lower (90.5% and 75.2%) 5- and 10-year survivals. Advancing age was the most important factor influencing late survival. Other risk factors in descending order of significance were impaired left ventricular function, no mammary artery graft, smoking, abnormal EKG, three vessel or left main disease, left ventricular end diastolic pressure (LVEDP) greater than 24, hypertension, 1971 to 1974 surgical era, cholesterol greater than 300, incomplete revascularization, and two vessel disease.     

Direct leukocyte migration inhibition by myelin basic protein in exacerbations of multiple sclerosis.

Studies in 13 normal subjects, 9 patients with multiple sclerosis (MS) within 3 weeks of exacerbation and 16 others 1 to 6 months after onset were carried out for evidence of cell-mediated hypersensitivity to myelin basic protein. Ten patients with stroke and 10 with Guillain-Barré syndrome were studied as additional controls. Peripheral leukocytes obtained by leukapheresis were packed into capillary tubes and allowed to migrate out onto glass in the presence or absence of myelin basic protein. Cells of patients within 3 weeks of an MS episode gave a mean migration index of 68 +/- 9%, and those 1 to 6 months after onset, 93 +/- 21%. For the entire MS group the mean index was 88 +/- 20%, for those with Guillain-Barré, 103 +/- 7%; and for the stroke patients, 107 +/- 11%. Results for the acutely ill MS patients were significant (P less than 0.005). The data are similar to those obtained using the migration inhibition factor assay but show that sensitized lymphocytes also elaborate a second mediator during acute exacerbations of illness. These observations strengthen evidence that sensitization to this potent encephalitogen occurs simultaneously with exacerbations of clinical illness.     

Enhanced cardiac performance following cardiopulmonary bypass

Changes in cardiac performance during coronary revascularization surgery were followed in 22 selected patients with normal or mildly impaired left ventricles; vasoactive or inotropic drugs were generally avoided. Arterial pressure, filling pressures, and cardiac output were measured; stroke volume and work were calculated before induction of anesthesia, following sternotomy, soon after discontinuation of extracorporeal circulation, and one hour postoperatively. Induction and sternotomy were associated with a depressant effect on cardiac performance. After extracorporeal circulation, however, cardiac performance recovered, cardiac output increased to 7 +/- 0.5 l/min from a preoperative control of 4.9 +/- 0.3 L/min (p less than 0.002) without an elevation of atrial pressures. This increase in cardiac output after bypass resulted from decreased afterload and increased preload secondary to hemodilution. Cardiac performance approached control values early in the postoperative period.     

The application of cryobiology to the microbiological assay of nystatin.

Improvements in the reproducibility of nystatin agar diffusion assays have been achieved by the use of liquid nitrogen stored inocula and deep frozen standard stock solutions. The overall percentage variability of the assay has been reduced from over 5% with daily prepared standards and inocula to around 1% with a frozen inocula and to 0.6% with a combination of frozen inocula and standards. The implications of these improvements in the standardization of nystatin assays, and microbiological assays generally are discussed.     

An 11 Year Evolution of Coronary Arterial Surgery (1967-1978)

All patients who underwent isolated myocardial revascularization procedures from 1967-70 (n = 741) were compared with the first 1,000 patients who received similar elective operations each year from 1971 through 1978. Data from these eight years were processed through a computerized cardiovascular information registry. Median age increased from 50 to 56 years, multiple-vessel disease increased from 44 to 89%, and left ventricular asynergy from 41 to 54%. The number of grafts per patient increased from 1.5 to 2.5 and yet morbidity declined in every category except neurologic deficit. Operative mortality was 1.1% from 1967 through 1978 and 0.9% from 1971 through 1978. Graft patency was determined for 475 patients from 1967-70, 553 patients from 1971, 519 from 1972, and 540 from 1973. Patency rates after a mean catheterization interval of 21 months were 77, 77, 84, and 87% respectively. Higher graft patency coincides with introduction of the internal mammary artery graft. Five year follow-up was completed for the 1967-1970 series and 1971, 1972, and 1973 cohorts. Actuarial five year survival was 89.6, 91.6, 93.2, and 91.7%. Five year survival comparisons between 1967-1970 patients and 1971-1973 patients in single-, double-, and triplevessel disease categories show significant extended longevity in the later experience. Abnormal ventricular function and incomplete revascularization adversely influenced longevity (p < 0.05) in all years surveyed. In those series the percentage of asymptomatic patients at five years was 66, 65, 69, and 67%. Lower risk and higher five year survival are attributed to greater technical experience, changing technology, and improved management rather than to selection of lower risk cases.     

Neoadjuvant temozolomide followed by complete resection of a 1p- and 19q-deleted anaplastic oligoastrocytoma: case study

A 38-year-old woman presented with an infiltrative tumor of the right frontal lobe and genu of the corpus callosum that was deemed only partially resectable. A stereotactic biopsy was performed, which revealed a right frontal oligoastrocytoma that had some anaplastic features as well as allelic loss of chromosome arms 1p and 19q. The patient was treated with temozolomide for 24 months. The partial response of the tumor to chemotherapy rendered the lesion amenable to gross total resection, which was performed subsequently. The patient remains alive and well without evidence of recurrence 7 months after resection and 48 months after initial diagnosis. Thus, preoperative chemotherapy decreased tumor mass to a degree that subsequently enabled a gross total resection. This treatment strategy, although common in the treatment of other solid tumors, is rarely utilized in adult neuro-oncology and raises another potential role for chromosome testing in oligodendroglial tumor management.