Shay Porat

Control of pancreatic β cell regeneration by glucose metabolism.

Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.

Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells.

β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.

Fetal intracranial hemorrhage (fetal stroke): does grade matter?

To determine if the severity of antenatally diagnosed hemorrhagic fetal brain insults and fetal stroke detected by ultrasound and magnetic resonance imaging (MRI) predicts postnatal neurodevelopmental prognosis.

Glucose regulates cyclin D2 expression in quiescent and replicating pancreatic β-cells through glycolysis and calcium channels.

Understanding the molecular triggers of pancreatic β-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in β-cell proliferation and mass homeostasis, but its specific function in β-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent β-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the β-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G(2)-M phases of each β-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent β-cells and modulates the down-regulation of cyclin D2 in replicating β-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and β-cell replication.

The Role of Magnetic Resonance Imaging in the Evaluation of Isolated Mild Ventriculomegaly

Objective. Isolated mild ventriculomegaly is defined as dilatation of the lateral ventricle from 10 to 15 mm, with no other structural abnormalities observed at the time of diagnosis. Its reported frequency is between 1 per 50 and 1 per 700 deliveries. There are no universal recommendations for evaluation of isolated mild ventriculomegaly. Targeted sonography, karyotype analysis, and viral antigen testing, particularly for cytomegalovirus, are most often used for further investigation of this finding. We studied the role of magnetic resonance imaging as part of the prenatal evaluation of isolated mild ventriculomegaly. Methods. Thirty‐six pregnant women were referred to 2 Hadassah hospitals between 1999 and 2002 for evaluation of isolated mild ventriculomegaly. They underwent targeted sonography to exclude other anomalies, genetic amniocentesis for fetal karyotype, and serologic cytomegalovirus tests. Mild ventriculomegaly was the only pathologic finding diagnosed. Fetal brain magnetic resonance imaging was performed to evaluate the correlation between sonographic and magnetic resonance imaging findings and the additional contribution of magnetic resonance imaging in evaluating isolated mild ventriculomegaly. Results. Thirty‐six magnetic resonance imaging studies were performed. All tests were adequate for evaluation. In 3 (8.3%) of 36 cases, magnetic resonance imaging showed additional findings: in a severely obese woman, ventricular dilatation up to 18 mm and periventricular cystic lesions with abnormal sulcation suggestive of diffuse parenchymal abnormality were diagnosed, and in 2 cases, bleeding in germinal centers was found. On subsequent sonographic examination, no other finding but isolated mild ventriculomegaly was diagnosed. In the remaining 33 women (91.7%), magnetic resonance imaging studies correlated well with sonographic findings. Further sonographic follow‐up in this subgroup failed to reveal any other pathologic findings. Conclusions. Our study supports the view that magnetic resonance imaging should be considered as part of the evaluation of isolated mild ventriculomegaly, especially when objective difficulties preclude detailed sonographic examination.

Glucose metabolism: key endogenous regulator of β-cell replication and survival.

Recent studies in mice have shown that pancreatic β‐cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that β‐cell regeneration is based on the replication of fully differentiated, insulin‐positive β‐cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control β‐cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for β‐cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within β‐cells, and through a signalling cascade that resembles the pathway for glucose‐stimulated insulin secretion. We introduce the concept that the individual β‐cell workload, defined as the amount of insulin that an individual β‐cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell‐autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on β‐cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on β‐cells may allow for the development of effective regenerative therapies for diabetes.

Emergency Cerclage: Literature Review

Abstract This article reviews the use and effectiveness of emergency cerclage for women who present with a dilated cervix in the second trimester of pregnancy and seeks to identify predictors of favorable emergency cerclage outcomes. We searched PubMed and the Cochrane Library for the period January 1995 to April 2012 and used the terms “emergency cerclage,” “emergency stitch,” “rescue cerclage,” and “rescue stitch.” Thirty-four studies in which transvaginal emergency cervical cerclage was performed in women with a dilated cervix were identified and included. Predictors of poor outcome were prolapsed membranes, evidence of intra-amniotic or systemic infection, symptomatic presentation, cervical dilatation greater than 3 cm, or cerclage after 22 weeks. According to observational and limited randomized controlled trials, the cerclage group did significantly better than the bed-rest group in mean randomization-to-delivery interval, preterm delivery before 34 weeks, and compound neonatal morbidity. The current data suggest that emergency cerclage is associated with a longer latency period and, most often, with better pregnancy outcomes when compared with bed rest. Many of the predictors of adverse outcomes appear to be associated with evidence of inflammation or infection. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to review the use and evaluate the effectiveness of emergency cerclage for women who present with a dilated cervix in the second trimester, to identify predictors of favorable emergency cerclage outcomes, and to compare emergency cerclage versus bed rest.

Mild tricuspid regurgitation: a benign fetal finding at various stages of pregnancy

Objective Tricuspid regurgitation (TR) may accompany various anatomical malformations and/or dysfunction of the fetal right heart. It may also appear in an anatomically healthy heart. With improved ultrasound modalities, more cases than the previously estimated prevalence of fetal TR in the low-risk population are being diagnosed. The objective of this study was to determine the prevalence of mild fetal TR in a low-risk obstetric population. Methods In 157 low-risk pregnant women (age range, 18–42 years) undergoing both early second-trimester and mid-trimester targeted organ scanning, including complete fetal echocardiography according to the five transverse planes technique, the apical four-chamber view was visualized using gray-scale, color Doppler and spatiotemporal image correlation (STIC) ultrasound modalities, with optimal acquisition parameters. Results Mild-to-moderate TR was discovered in the early second-trimester scan in 131/157 (83.4%) fetuses. No cases of cardiac malformation were found. All fetuses showed normal flow in the ductus venosus, including in one case diagnosed with moderate TR. Only in 39 (24.8%) cases was mild TR still evident at the second, mid-trimester scan. Neonatal echocardiography revealed mild TR in eight (5.1%) cases. No cases of chromosomal anomalies were detected. Conclusion Mild TR is a benign finding of a temporal nature in early pregnancy. Copyright

Intrauterine balloon tamponade as a treatment for immune thrombocytopenic purpura-induced severe uterine bleeding

OBJECTIVE To report our experience of applying balloon tamponade in the treatment of intrauterine bleeding in two patients with immune thrombocytopenic purpura (ITP). Immune thrombocytopenic purpura is a well-known hematologic autoimmune disease. The uterus may be a major site of bleeding in patients with ITP. Halting bleeding is imperative to reduce blood loss and platelet consumption and to allow medical treatment to increase platelet count. Balloon tamponade has been described as an effective method to control bleeding in a variety of clinical situations; it is an effective and accessible modality, requiring no analgesia or anesthesia, and helps facilitate continuous monitoring of uterine bleeding. DESIGN Report of two cases. SETTING Obstetrics and gynecology department in a tertiary care center in Jerusalem, Israel. PATIENT(S) Two patients with ITP with severe uterine bleeding refractory to treatment with estrogen and IV IgG. INTERVENTION(S) Intrauterine balloon tamponade. MAIN OUTCOME MEASURE(S) Cessation of uterine bleeding, appearance of complications. RESULT(S) Insertion of balloon tamponade successfully controlled bleeding in both cases. The patient in case 1 subsequently had persistent hypomenorrhea. The patient in case 2 had abdominal pain and suspected pelvic inflammation. CONCLUSION(S) Our presented cases demonstrate that uterine bleeding can be controlled successfully in patients with ITP with an intrauterine balloon. This novel application raises many technical issues, such as the appropriate filling pressures and duration of treatment. Possible risks, such as endometrial injury, still remain to be resolved and mandate future clinical research.

Determinants of pancreatic β-cell regeneration

Recent studies have revealed a surprising plasticity of pancreatic β‐cell mass. β‐cell mass is now recognized to increase and decrease in response to physiological demand, for example during pregnancy and in insulin‐resistant states. Moreover, we and others have shown that mice recover spontaneously from diabetes induced by killing of 70–80% of β‐cells, by β‐cell regeneration. The major cellular source for new β‐cells following specific ablation, as well as during normal homeostatic maintenance of adult β‐cells, is proliferation of differentiated β‐cells. More recently, it was shown that one form of severe pancreatic injury, ligation of the main pancreatic duct, activates a population of embryonic‐type endocrine progenitor cells, which can differentiate into new β‐cells. The molecular triggers for enhanced β‐cell proliferation during recovery from diabetes and for activation of embryonic‐type endocrine progenitors remain unknown and represent key challenges for future research. Taken together, recent data suggest that regenerative therapy for diabetes may be a realistic goal.