Preventing microvascular diabetic complications in children and adolescents: looking beyond glycaemic control

Type 1 diabetes mellitus is associated with the development of micro- and macrovascular disease, and diabetic angiopathy in children and adolescents. It is represented mainly by microangiopathy, characterised by structural changes in the eye, renal glomeruli and peripheral nerves. The pathogenesis of the vascular complications of diabetes is controversial, but without any doubt, endothelial dysfunction play an important role in the pathogenesis of glomerulosclerosis and atherosclerosis. Preventive strategies for these three major complications are discussed in this review. Appropriate surveillance for the earliest evidence of microvascular disease should begin at the onset of puberty, and after 3 - 5 years of diabetes. Therapeutic interventions, particularly excellent metabolic control, may be almost effective in preventing complication onset, or significantly retarding the rate of progression.     

Involvement of nitric oxide and tachykinins in the effects induced by protease-activated receptors in rat colon longitudinal muscle

(1) The aim of the present study was to verify a possible involvement of nitric oxide (NO) and of tachykinins in the contractile and relaxant effects caused by the activation of protease-activated receptor (PAR)-1 and PAR-2 in the longitudinal muscle of rat colon. (2) Mechanical responses to the PAR-1 activating peptides, SFLLRN-NH(2) (10 nM-10 micro M) and TFLLR-NH(2) (10 nM-10 micro M), and to the PAR-2-activating peptide, SLIGRL-NH(2) (10 nM-10 micro M), were examined in vitro in the absence and in the presence of different antagonists. (3) The relaxation induced by SFLLRN-NH(2), TFLLR-NH(2) and SLIGRL-NH(2) was antagonised by the inhibitor of NO synthase L-N(omega)-nitroarginine methyl ester (300 micro M), or by the inhibitor of the guanylyl cyclase, 1-H-oxodiazol-[1,2,4]-[4,3-a]quinoxaline-1-one (10 micro M). (4) The contractile responses to PAR-1 and PAR-2 activation were concentration-dependently attenuated by SR140333 (0.1-1 micro M), NK(1) receptor antagonist, or by SR48968 (0.1-1 micro M), NK(2) receptor antagonist. The combined pretreatment with SR140333 (1 micro M) and SR48968 (1 micro M) produced additive suppressive effects on the contractile responses to PAR activation. Pretreatment of the preparation with capsaicin (10 micro M) markedly reduced the contractions evoked by SFLLRN-NH(2), TFLLR-NH(2) and SLIGRL-NH(2), while omega-conotoxin GVIA (0.2 micro M) had no effect. (5) The present results suggest that in rat colonic longitudinal muscle, PAR-1 and PAR-2 activation can evoke (i) relaxation through the production of NO or (ii) contraction through the release of tachykinins, likely, from sensory nerves. These actions may contribute to motility disturbances during intestinal trauma and inflammation.     

Immunotherapy and biological modifiers for the treatment of malignant brain tumors

The relative ineffectiveness of current therapies for malignant gliomas has led to the need for novel therapeutics. Therapies based on biologic modifiers are among a variety of cancer treatments currently in use or under experimental evaluation and have shown great promise, especially since several potent stimulators of the immune system have been cloned and are now available for clinical use. Early attempts at glioma therapy based on biologic modifiers, however, have failed to demonstrate significant effectiveness. In this review, we select and summarize the results of preclinical and clinical studies published during the past two years that focus on immunotherapy and biologic modifiers for treating gliomas. Despite limited clinical success, we conclude that an increased understanding of molecular biology and immunology from recent studies may pave the way for more effective approaches.     

Protein kinase C activity,translocation, and selective isoform subcellular redistribution in the rat cerebral cortex after in vitro ischemia

Protein kinase C (PKC) involvement in ischemia-induced neuronal damage has been investigated in superfused rat cerebral cortex slices submitted to 15 min of oxygen-glucose deprivation (OGD) and in primary cultures of rat cortical neurons exposed to 100 microM glutamate (GLU) for 10 min. OGD significantly increased the total PKC activity in the slices, mostly translocated in the particulate fraction. After 1 hr of reperfusion, the total PKC activity was reduced and the translocated fraction dropped by 84% with respect to the control. Western blot analysis of OGD samples showed an increase in total beta(2) and epsilon PKC isoform levels. After reperfusion, the total levels of alpha, beta(1), beta(2) and gamma isoforms were significantly reduced, whereas the epsilon isoform remained at an increased level. Endogenous GLU release from OGD slices increased to about 15 times the basal values after 15 min of oxygen-glucose deprivation, and to 25 and 35 times the basal level in the presence of the PKC inhibitors staurosporine (0.1 microM) and bisindolylmaleimide (1 microM), respectively. Western blot analysis of GLU-treated cortical neurons showed a significant decrease only in the total level of beta(2) isoforms. Cell survival was reduced to 31% in GLU-treated neuronal cultures; PKC inhibitors were not able to modify this effect. These findings demonstrate that the cell response to OGD and GLU involves PKC in a complex way. The net role played by PKC during OGD may be to reduce GLU release and, consequently, neurotoxicity. The isoforms beta(2) and epsilon are affected the most and may play a significant role in the mechanisms underlying neurotoxicity/neuroprotection.     

Unusual early-onset Huntingtons disease

Huntington's disease is an autosomal dominant progressive neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral disorders leading to functional disability. In contrast to patients with adult onset, in which chorea is the major motor abnormality, children often present with spasticity, rigidity, and significant intellectual decline associated with a more rapidly progressive course. An unusual early-onset Huntington's disease case of an 11-year-old boy with severe hypokinetic/rigid syndrome appearing at the age of 2.5 years is presented. Clinical diagnosis was confirmed by polymerase chain reaction study of the expanded IT-15 allele with a compatible size of 102 cytosine-adenosine-guanosine repeats L-Dopa mildly ameliorated rigidity, bradykinesia, and dystonia. We conclude that Huntington's disease should be included in the differential diagnoses of regressive syndromes of early childhood.     

Reduced hemodynamic load and cardiac hypotrophy in patients with anorexia nervosa

BACKGROUND: Anorexia nervosa is associated with lower left ventricular mass (LVM) and systolic dysfunction. Whether these abnormalities reflect chronic protein-energy malnutrition or are primarily related to lower cardiac workload is unclear. OBJECTIVE: The objective of the study was to verify whether low LVM in anorexia nervosa is explained by low hemodynamic load. DESIGN: Ninety-one women with anorexia nervosa [macro x +/- SD age: 20.5 +/- 6.1 y; body mass index (in kg/m(2)): 15.6 +/- 1.9; group 1] and 62 normal-weight female control subjects (age: 22.5 +/- 5.5 y; body mass index: 20.9 +/- 1.2; group 2) underwent Doppler echocardiography. LVM was evaluated as the percentage predicted by body height, sex, and stroke work (systolic blood pressure x stroke volume). RESULTS: The left ventricular chamber dimension was smaller and the chamber walls were thinner in group 1 than in group 2, which resulted in significantly lower LVM and LVM indexes (P < 0.0001). Ejection fraction, heart rate, stroke volume, and cardiac output were significantly (P < 0.007) lower in group 1, but peripheral resistance was substantially higher (P < 0.0001). The deviation of LVM from predicted values was lower and the proportion of subjects with inadequate LVM was significantly higher in group 1 than in group 2 (P < 0.0001). This difference was attenuated after adjustment for body weight and heart rate. There were no relations between LVM and laboratory tests in group 1. CONCLUSIONS: Anorexia nervosa is a condition of low hemodynamic load that leads to low LVM. Even with adjustment for stroke work, however, LVM is lower than would be predicted by height, because of the effect of body weight reduction (ie, wasting of lean body mass).     

Characterization of 27-hydroxy-13-desmethyl spirolide C and 27-oxo-13,19-didesmethyl spirolide C. Further insights into the complex Adriatic Alexandrium ostenfeldii toxin profile

Alexandrium ostenfeldii is a widespread toxic dinoflagellate that has recently bloomed across the Adriatic Sea, seriously threatening both shellfish consumers and aquacultures. In 2007 we reported on preliminary studies carried out on field samples and cultures of A. ostenfeldii. At the time, along with three major spirolides – among which 27-hydroxy-13,19-didesmethyl spirolide C (3) proved to be a novel compound – a number of new minor spirolides were detected. Unfortunately, for all of them only Mass Spectrometry-based structural hypotheses could be ventured due to their very small amount. In the present paper we report on isolation and High Resolution Mass Spectrometry- and NMR-based structural elucidation of two of those minor spirolides detected in our previous study.     

Quantification of extracranial carotid artery stenosis by ultrafast three-dimensional ultrasound

This study was designed to evaluate the possible contribution of 3-dimensional (3D) ultrasound (US) for noninvasive detection of extracranial carotid artery stenosis. Sixty-nine stenotic lesions of extracranial carotid artery were studied by (1) B-mode (Bm) US, (2) Doppler spectral analysis, and (3) a prototype of 3D vascular system. When indicated (46 stenotic lesions), biplane carotid angiography (CA) was performed. The degree of luminal narrowing measured as percent area reduction in the 3D data set correlated well with the degree of stenosis estimated by CA (r = 0.79, P <.01, mean difference 7.8% +/- 15.5%); however, for stenosis between 40% and 70%, 3D US tended to give higher values. Compared with CA, the sensitivity, specificity, diagnostic accuracy, and positive predictive value of 3D US for significant (> or =70%) stenosis were 96.0%, 77.7%, 88.3%, and 85.7%, respectively. Thus, 3D US showed good sensitivity and diagnostic accuracy for detection of significant stenosis of extracranial carotid artery. For stenosis between 40% and 70%, 3D US indicated a higher degree than CA; this finding suggests that CA may underestimate the severity of stenosis due to known discrepancies between linear measurement and true anatomic situation.