The effect of elevated glucose levels on myo-inositol metabolism in cultured bovine aortic endothelial cells

Bovine aorta endothelial cells were used to determine the effect of high ambient glucose concentrations on myo-inositol metabolism. Culturing the cells for a minimum of 1 week in elevated glucose concentrations caused an increase in the intracellular sorbitol content and a decrease in myo-inositol levels. The accumulation of myo-inositol from the medium and incorporation into phospholipids was reduced 25% to 50% in cells grown in the presence of 30 to 50 mmol/L glucose. This effect was not observed following a short-term exposure of the cells to elevated glucose levels. Kinetic analysis of high-affinity myo-inositol uptake showed that the K'm was significantly increased in cells grown in 30 mmol/L glucose compared to those cultured in 5.6 mmol/L glucose. This would suggest that exposing endothelial cells to high ambient glucose levels for a minimum of 1 week leads to a competitive type of inhibition of high-affinity myo-inositol uptake. The changes in myo-inositol metabolism and content and sorbitol levels mediated by glucose exposure were blocked by addition of the aldose reductase inhibitor, sorbinil, to the media, suggesting that these changes are caused by the accumulation of sorbitol by the cells. Exposure of bovine aorta endothelial cells to high ambient levels of glucose leads to accumulation of sorbitol in the cells, which is responsible for alterations in myo-inositol metabolism. These changes could result in alteration of endothelial cell membrane function and contribute to the pathology of diabetes mellitus.     

Cervical lesions of branchial origin

A brief review of the developmental background of the lateral cervical sinuses, fistulas, cysts and auricles has been presented. In all likelihood they are of branchial cleft origin. Surgical excision is the recommended treatment as shown in the cases described.     

Consistent stress profiles in mothers of children with autism

The present study extends the area of research on stress in parents of autistic children. In this study we used the Questionnaire on Resources and Stress (Holroyd, 1987) to compare the stress profiles across mothers (a) who lived in different cultural and geographic environments; (b) who had children of different ages; and (c) who had children with different functioning levels. Results showed a characteristic profile that was highly consistent across each of these subgroups. Major differences from the normative data occurred on scales measuring stress associated with dependency and management, cognitive impairment, limits on family opportunity, and life-span care. Results suggest the importance of developing treatment programs aimed at reducing stress in specific areas in families with autistic children.Orchard Mental Health CenterThis research was supported by U.S. Department of Education, NIDRR Cooperative Agreement No. G0087C0234 (Koegel and Dunlap), by U.S. Public Health Service Research Grants MH28210 (Koegel) and MH39434 (Schreibman) from the National Institute of Mental Health, by Grant No. G008530082 from the U.S. Department of Education, Handicapped Children's Early Education Program (Dunlap), and by Fogarty Senior International Fellowship 1 FOB TWO 1374-01 (Schreibman) from the Fogarty International Center of the National Institutes of Health. The authors acknowledge the contributions of Prof. Dr. med. Hedwig Amorosa, and Dorle Staniczek, Soz. Pad. of the Max Planck Institute for Psychiatry, Munich, West Germany, and express particular appreciation to Prof. Dr. med. D. Ploog, Director of the Institute.     

Keratoameloblastoma: a tumor sui generis or a chimera?

The term keratoameloblastoma has been used to describe a histologically heterogeneous group of ameloblastoma variants which have in common the formation of keratin by the ameloblastomatous epithelium. The English language literature contains reports of only 12 cases of keratoameloblastoma, of which 4 cases exhibited a papilliferous component. We report a unique tumor that we believe falls within the broad histopathologic spectrum of keratoameloblastoma. We review the key clinical and histopathologic features of the previously reported cases of keratoameloblastoma and present an additional case that presented as an expansile, radiolucent lesion with internal opacification between the roots of teeth in the left anterior maxillary alveolar ridge of a 45-year-old white male. There is wide variation in the histopathologic appearance of cases reported under the appellation keratoameloblastoma. Our case exhibited a histopathologic feature shared by only 2 of the previously reported cases, notably islands and anastomosing cords of epithelium forming lamellated, pacinian-like stacks of parakeratin that extruded into the collagenous tumor stroma without eliciting a foreign body response. Due to the small number of reported cases, we are unable to accurately assess whether the biologic behavior of keratoameloblastoma differs from other histologic types of ameloblastoma.     

An animal model of human-type memory loss based on aging, lesion, forebrain ischemia, and drug studies with the rat

The goals of this research were to develop a within-subject test of spatial working memory and performance for the rat in a T-maze, based on a delayed alternation, or "win-shift" foraging strategy. Using this model, specific aims were to compare the effects of: (1) age, (2) basal forebrain, medial septal, and amygdala lesions, (3) four vessel occlusion (4-VO), forebrain ischemia, and (4) physostigmine, scopolamine, arecoline, piracetam, and clonidine on memory and performance of young middle-aged, and old rats. Aging significantly impaired working memory and performance of Long-Evans rats. Memory of septal and basal forebrain, but not of amygdala lesioned rats was significantly impaired without effects on performance. Transient, 4-VO forebrain ischemia produced significant memory impairment, without effects on performance, and highly selective CA1 cell loss in the hippocampus. Physostigmine enhanced working memory in middle-aged and old rats. Scopolamine impaired memory in young, middle-aged, and old rats. Physostigmine reversed the scopolamine impairments of working memory. Arecoline enhanced memory in old rats without effects on performance. Piracetam and clonidine had no direct effects on memory, but piracetam increased and clonidine decreased speed of performance. From the aging, lesion, ischemia, and drug studies it was concluded that there was a convergence of evidence from 4 different approaches for a critical role for the hippocampus, particularly the CA1 fields, in spatial working memory.     

Dihydropyridine inhibition of neuronal calcium current and substance P release

Dihydropyridine (DHP) calcium channel antagonists, which inhibit the slowly inactivating or L-type cardiac calcium (Ca) current, have been shown to be ineffective in blocking⁴⁵Ca influx and Ca-dependent secretion in a number of neuronal preparations. In the studies reported here, however, the antagonist DHP nifedipine inhibited both the L-type Ca current and potassium-evoked substance P (SP) release from embryonic chick dorsal root ganglion (DRG) neurons. These results suggest that, in DRG neurons. Ca entry through L-type channels is critical to the control of secretion. The inhibition of Ca current by nifedipine was both voltage and time-dependent, significant effects being observed only on currents evoked from relatively positive holding potentials maintained for several seconds. As expected from these results, nifedipine failed to inhibit L-type Ca current underlying the brief plateau phase of the action potential generated from the cell's normal resting potential; likewise, no significant effect of the drug was observed on action potential-stimulated SP release evoked by electrical field stimulation. The results of this work are discussed in terms of an assessment of the role of L-type Ca channels in neurosecretion.This work was supported by United States Public Health Service Grant NS16483 (KD) and by a USPHS Postdoctoral Fellowship (SGR)     

A National Cost Analysis of Community Interventions to Prevent Underage Drinking and Prescription Drug Misuse

Prevention Science - This prospective cost analysis addresses a gap in the prevention literature by providing estimates of the typical real-world costs to implement community interventions focused...     

FAK+ and PYK2/CAKbeta, two related tyrosine kinases highly expressed in the central nervous system: similarities and differences in the expression pattern

Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2/cell adhesion kinase beta (PYK2/CAKbeta) are related, non-receptor, cytoplasmic tyrosine kinases, highly expressed in the central nervous system (CNS). In addition, FAK+ is a splice isoform of FAK containing a 3-amino acid insertion in the carboxy-terminal region. In rat hippocampal slices, FAK+ and PYK2/CAKbeta are differentially regulated by neurotransmitters and depolarization. We have studied the regional and cellular distribution of these kinases in adult rat brain and during development. Whereas PYK2/CAKbeta expression increased with postnatal age and was maximal in the adult, FAK+ levels were stable. PYK2/CAKbeta mRNAs, detected by in situ hybridization, were expressed at low levels in the embryonic brain, and became very abundant in the adult forebrain. Immunocytochemistry of the adult brain showed a widespread neuronal distribution of FAK+ and PYK2/CAKbeta immunoreactivities (ir). PYK2/CAKbeta appeared to be particularly abundant in the hippocampus. In hippocampal neurons in culture at early stages of development, FAK+ and PYK2/CAKbeta were enriched in the perikarya and growth cones. FAK+ extended to the periphery of the growth cones tips, whereas PYK2/CAKbeta appeared to be excluded from the lamellipodia. During the establishment of polarity, a proximal-distal gradient of increasing PYK2/CAKbeta-ir could be observed in the growing axon. In most older neurons, FAK+-ir was confined to the cell bodies, whereas PYK2/CAKbeta-ir was also present in the processes. In vitro and in vivo, a subpopulation of neurons displayed neurites with intense FAK+-ir. Thus, FAK+ and PYK2/CAKbeta are differentially regulated during development yet they are both abundantly expressed in the adult brain, with distinctive but overlapping distributions.     

Graft-versus-host disease after liver transplantation is associated with bone marrow failure,hemophagocytosis, and DNMT3A mutations

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.