Two generations of insulinotropic imidazoline compounds

The imidazoline RX871024 increased basal- and glucose-stimulated insulin release in vitro and in vivo. The compound inhibited activity of ATP-sensitive K(+) channels as well as voltage-gated K(+) channels, which led to membrane depolarization, an increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)), and insulin release. Importantly, RX871024 also enhanced the insulinotropic effect of glucose in cells with clamped [Ca(2+)](i) but in the presence of high ATP and Ca(2+)concentration inside the cell. We believe that the latter effect on insulin exocytosis was at least in part mediated by a rise in diacylglycerol, which then activated protein kinase C (PKC) and increased the generation of arachidonic acid (AA) metabolites. Activation of both the PKC and AA pathways resulted in potentiation of glucose effects on insulin secretion. Unlike RX871024, the novel imidazoline BL11282 did not block ATP-dependent K(+) channels, but similarly to RX871024, it stimulated insulin secretion in depolarized or permeabilized islets. Accordingly, BL11282 did not influence glucose and insulin levels under basal conditions either in vitro or in vivo, but it markedly enhanced the insulinotropic effects of glucose. BL11282 restored the impaired insulin response to glucose in islets from spontaneously diabetic GK rats. We conclude that BL11282 belongs to a new class of insulinotropic compounds that demonstrate a strong glucose-dependent effect on insulin exocytosis.     

Recovery from spinal cord injury: a new transection model in the C57Bl/6 mouse

Spinal cord transections in mammalian animal models lead to loss of motor function. In this study, we show that functional recovery from complete transection of the adult mouse spinal cord can in fact occur without any intervention if dural injury along with displacement of the ends of the cut cord and fibroblastic infiltration is minimized. Underlying this function is the expression of GAP-43 in axonal growth cones, axonal extension and bridging of the injury site indicated by biocytin retrograde tracing and neuronal remodeling of both the white matter and the gray matter. Such studies suggest a new murine model for the study of spinal cord regeneration.     

Childhood cerebellar hemangioblastoma does not predict germline or somatic mutations in the von Hippel-Lindau tumor suppressor gene

Tumor suppressor gene "knockout" models would predict that children who present with hemangioblastoma are likely to harbor germline mutation of the von Hippel-Lindau gene. We screened 6 pediatric patients with cerebellar hemangioblastoma for germline or somatic mutations of the von Hippel-Lindau gene. Two had prior clinical manifestations of von Hippel-Lindau disease and, as expected, had germline von Hippel-Lindau gene mutations. Four children with solitary hemangioblastoma did not have a detectable germline deletion, rearrangement, or point mutation in their von Hippel-Lindau gene, and tumor specimens in 3 of these 4 showed no somatic von Hippel-Lindau allelic loss. Solitary cerebellar hemangioblastoma in children does not predict a germline or somatic mutation in the von Hippel-Lindau tumor suppressor gene. The tumorigenesis of hemangioblastoma in younger patients may differ from that in adults, and may involve a molecular process unrelated to the von Hippel-Lindau tumor suppressor pathway.     

Using the Nordic–Baltic perinatal death classification to assess perinatal care in Ukraine

Objective: To identify health care issues important to reduce the perinatal mortality rate (PMR) in Ukraine. Study Design: Perinatal deaths in the Donetsk region (Ukraine) in 1997–1998 were compared with those in Denmark in 1996 by using the Nordic–Baltic classification for perinatal deaths. Clinical guidelines, use of technology and rates of interventions in the two regions were described. Results: A two-fold increase in PMR was found in Ukraine compared to Denmark, mainly explained by higher rates of antenatal deaths of growth restricted fetuses, intrapartum deaths, and neonatal deaths due to asphyxia. Vacuum extraction is rarely used in Ukraine. The clinical guidelines for care differ significantly between the two regions. Conclusion: Appropriate use of technology and implementation of evidence-based guidelines should be a matter of high priority in the Donetsk region, Ukraine.     

A population-based study of patterns of care for ovarian cancer: who is seen by a gynecologic oncologist and who is not?

OBJECTIVES: To determine the fraction of patients diagnosed with ovarian cancer and seen by a gynecologic oncologist and to compare outcomes with those patients and others who are not seen by a gynecologic oncologist. METHODS: The statewide, population-based Utah Cancer Registry was used to identify 848 patients diagnosed with epithelial ovarian cancer between 1992 and 1998. Differences between selected characteristics of cases seen/not seen by gynecologic oncologists were assessed with chi2 tests, and survival data were analyzed using Kaplan-Meier curves and log-rank testing. RESULTS: Of 848 incident epithelial ovarian cancer cases diagnosed in Utah residents during the period 1992-1998, 333 (39.3%) were seen by a gynecologic oncologist at some time during their cancer diagnosis and/or treatment. The percentage of ovarian cancer cases seen by a gynecologic oncologist varied with age: 35.6% of cases under 40 years of age at diagnosis were seen by a gynecologic oncologist, as were 54.5% of cases 40-59 years of age, 42.6% of cases 60-69 years, and 23.7% of women 70+ years of age (chi2 test, P < 0.01). The percentage of ovarian cancer cases seen by a gynecologic oncologists increased during the study period, from 33.0% in 1992-1993 to 47.5% in 1997-1998 (chi2 test for trend, P < 0.01). The vast majority of the state's population resides within a contiguous, four-county area near the only major city where gynecologic oncology care is available. Ovarian cancer cases that resided within that geographic area were generally more likely to have been seen by a gynecologic oncologist than those who lived in more rural regions of the state (42.7 and 27.1%, respectively; chi2 test, P < 0.01). For ovarian cancer cases diagnosed with local or regional stages of disease, there were no significant differences in survivorship between those treated or not treated by gynecologic oncologists. Among cases diagnosed with advanced disease, those cases seen by gynecologic oncologists had a significant survival advantage when compared to those that were not (median survival 26 and 15 months, respectively, P < 0.01). CONCLUSIONS: Gynecologic oncologists see less than half of ovarian cancer patients. Patients under 40 years of age, over 70 years of age, and in rural areas were significantly less likely to be seen by a gynecologic oncologist in their course of treatment. Patients with advanced disease experienced a significant survival advantage when a gynecologic oncologist was involved in their care.     

Permanent low-activity iodine-125 implants for cerebral metastases

Beginning in 1987, selected patients with metastatic braintumors were treated with permanent implants of low-activityradioactive iodine-125 (¹²⁵I) seeds. These patients underwent craniotomy,gross total resection of the metastatic lesion, andplacement of the seeds. In general, criteria fortreatment included the presence of a recurrent tumorwith a volume too large to permit radiosurgery,and a Karnofsky Performance Score of 70 orhigher. Thirteen patients underwent 14 implant procedures; allreceived external whole-brain radiotherapy. Implant dose ranged from43 Gy to 132 Gy, with a meanof 83 Gy. Survival after implantation ranged from2 weeks to almost 9 years, with amedian of 9 months. Clinical and radiographic localcontrol was obtained in 9 patients. Two patientsdied of acute, postoperative complications within a monthof implantation, so no information regarding tumor controlis available for them. Late complications included abone flap infection in one patient and aCSF leak in another; both were treated withoutfurther sequelae.These results demonstrate that permanent ¹²⁵I implants canresult in good survival and quality of life,and occasionally can yield long-term survival. Potentially, itis a cost-effective treatment in that a separateprocedure for stereotactic implantation or radiosurgery is notneeded, as is the case with the useof temporary high-activity seeds. The permanent implantation itselfadds less than 10 minutes to the craniotomy,and the risk of symptomatic radiation necrosis islow. We recommend consideration of this procedure inpatients harboring large, recurrent metastatic tumors that requirefurther surgery.     

B‐Cell lymphoproliferative disorder not associated with Epstein‐Barr Virus in a child with relapsed acute lymphoblastic leukemia

Lymphoproliferative disorder (LPD) is described in only a few children receiving chemotherapy for cancer. In all of them, an association between LPD and EBV (Epstein‐Barr Virus) was found. We report on a patient who developed LPD not associated with EBV while receiving chemotherapy for relapsed acute lymphoblastic leukemia (ALL). Despite discontinuation of chemotherapy, administration of intravenous immunoglobulins and surgery the patient died. Growing experience with this disorder may allow better treatment options in the future and will show whether LPD not associated with EBV requires different therapeutic strategies. Med Pediatr Oncol 2003;40:13–17, © 2003 Wiley‐Liss, Inc.     

Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice

We have studied the organization and cellular differentiation of dentate granule cells and their axons, the mossy fibers, in reeler mutant mice lacking reelin and in mutants lacking the reelin receptors very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). We show that granule cells in reeler mice do not form a densely packed granular layer, but are loosely distributed throughout the hilar region. Immunolabeling for calbindin and calretinin revealed that the sharp border between dentate granule cells and hilar mossy cells is completely lost in reeler mice. ApoER2/VLDLR double-knockout mice copy the reeler phenotype. Mice deficient only in VLDLR showed minor alterations of dentate organization; migration defects were more prominent in ApoER2 knockout mice. Tracing of the mossy fibers with Phaseolus vulgaris leukoagglutinin and calbindin immunolabeling revealed an irregular broad projection in reeler mice and ApoER2/VLDLR double knockouts, likely caused by the irregular wide distribution of granule cell somata. Mutants lacking only one of the lipoprotein receptors showed only minor changes in the mossy fiber projection. In all mutants, mossy fibers respected the CA3-CA1 border. Retrograde labeling with DiI showed that malpositioned granule cells also projected as normal to the CA3 region. These results indicate that ( 1 ) reelin signaling via ApoER2 and VLDLR is required for the normal positioning of dentate granule cells and (2) the reelin signaling pathway is not involved in pathfinding and target recognition of granule cell axons.