Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor

BACKGROUND: Zellweger syndrome (ZS) is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses. HYPOTHESIS: We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients. TESTING THE HYPOTHESIS: Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI) as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A) receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A) in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A) agonists during pregnancy. IMPLICATIONS OF THE HYPOTHESIS: We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome

Quality of life and treatment satisfaction in adults with Type 1 diabetes: A comparison between continuous subcutaneous insulin infusion and multiple daily injections

Aims: The aim of this case-control study was to compare quality of life (QoL) and treatment satisfaction in adults with Type 1 diabetes (T1DM) treated with either continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). Methods: Consecutive patients aged between 18 and 55 years, and attending diabetes clinics for a routine visit, completed the Diabetes-Specific Quality-of-Life Scale (DSQOLS), the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the SF-36 Health Survey (SF-36). Case (CSII) and control subjects (MDI) were recruited in a 1 : 2 ratio. Results: Overall, 1341 individuals were enrolled by 62 diabetes clinics; 481 were cases and 860 control subjects. Cases had a longer diabetes duration and were more likely to have eye and renal complications. Age, school education, occupation and HbA1c were similar. Of control subjects, 90% followed glargine-based MDI regimens and 10% used NPH-based MDI regimens. On multivariate analysis, after adjusting for socioeconomic and clinical characteristics, scores in the following areas of the DSQOLS were higher in cases than control subjects: diet restrictions (β = 5.96; P < 0.0001), daily hassles (β = 3.57; P = 0.01) and fears about hypoglycaemia (β = 3.88; P = 0.006). Treatment with CSII was also associated with a markedly higher DTSQ score (β = 4.13; P < 0.0001) compared with MDI. Results were similar when CSII was compared separately with glargine- or NPH-based MDI regimens. Conclusions: This large, non-randomized, case-control study suggests quality of life gains deriving from greater lifestyle flexibility, less fear of hypoglycaemia, and higher treatment satisfaction, when CSII is compared with either glargine-based or NPH-based MDI regimens. © 2008 The Authors

MODULATION OF INSULIN-SECRETION BY DIAZEPAM BINDING INHIBITOR AND ITS PROCESSING PRODUCTS

The effect of purified rat brain diazepam binding inhibitor (DBI) and that of synthetic DBI fragments DBI33-50 [octadecaneuropeptide (ODN)], DBI17-50 [triakontatetraneuropeptide (TTN)], DBI42-50 and DBI53-62 were studied on glucose-induced secretion of insulin from isolated rat pancreatic islets in both static incubation and perifusion experiments. DBI and ODN did not affect the secretion of insulin in the presence of 2.8 mM glucose (basal condition) but reduced the release of insulin induced by 16.7 mM glucose. The effects of DBI and ODN were significant at concentrations as small as 1-10 nM. In contrast, 100 nM TTN, DBI42-50 (which corresponds to the COOH-terminal region of ODN) and DBI53-62 (which corresponds to a region of DBI that is conserved among species), were without effect on both basal and 16.7 mM glucose-stimulated insulin secretion. DBI has previously been localized to the delta cells of islets of Langerhans (Ostenson, Ahren, Karlsson, Sandberg and Efendic, 1990) and the presence of DBI- and ODN-like immunoreactivity in isolated rat pancreatic islets has now been demonstrated. These results suggest that DBI and some of its processing products (ODN) may modulate glucose-stimulated secretion of insulin through a paracrine mechanism

Effects of profile interpolation in cam mechanisms

Realization of cam profiles passes through a discretization, truncation and interpolation of ideal designed motion profiles. This process affects the kinematics and the dynamics of a cam mechanism. This work aims to study and quantify this process and suggest a correct choice of the number of points that describes the profile, the number of digits adopted to represent these points and the type of interpolation adopted in working machines to reconstruct the original motion profile. The case of a single dwell rotary cam with translating follower is presented through numerical and experimental tests. The obtained results demonstrate that the linear interpolation can be an effective solution, interpolating a number of points in an optimal range avoiding excesses. Furthermore, the study highlights that the number of adopted digits may show a non-negligible effect

Expression, processing, and secretion of the neuroendocrine VGF peptides by INS-1 cells

The neurotropin-inducible gene vgf is expressed in neuronal and endocrine tissues. It encodes a secretory protein that is proteolytically processed in neuronal cells to low molecular mass polypeptides. In the present report, we show that vgf is expressed in different insulinoma cell lines and in normal rat pancreatic islets. In the insulinoma-derived beta-cell line INS-1, vgf messenger RNA was transcriptionally up-regulated by increased levels of intracellular cAMP, but not by the addition of glucose (20 mM) or phorbol 12-myristate 13-acetate (100 nM). Furthermore, nerve growth factor failed to stimulate vgf gene expression. In INS-1 cells, the VGF protein was shown to be processed in a post endoplasmic reticulum compartment to produce a peptide profile similar to that seen in neurons. The release of such VGF peptides occurred at a low rate in the absence of secretory stimuli (<2%/h). A 3-fold increase in the rate of release was seen after the addition of glucose (15 mM), a 4-fold increase was seen after (Bu)(2)cAMP (1 mM), and a 6-fold increase was seen after phorbol la-myristate 13-acetate (100 nM). These results indicated that insulin-containing cells produce VGF-derived peptides that are released via a regulated pathway in response to insulin secretagogues