3-(Fur-2-yl)-10-(2-phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a Novel Adenosine Receptor Antagonist with A(2A)-Mediated Neuroprotective Effects

In this study, compound FTBI (3-(2-furyl)-10-(2-phenylethyl)[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one) was selected from a small library of triazinobenzimidazole derivatives as a potent A(2A) adenosine receptor (AR) antagonist and tested for its neuroprotective effects against two different kinds of dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and methamphetamine (METH), in rat PC12 and in human neuroblastoma SH-SY5Y cell lines. FTBI, in a concentration range corresponding to its affinity for A(2A) AR subtype, significantly increased the number of viable PC12 cells after their exposure to METH and, to a similar extent, to MPP+, as demonstrated in both trypan blue exclusion assay and in cytological staining. These neuroprotective effects were also observed with a classical A(2A) AR antagonist, ZM241385, and appeared to be completely counteracted by the AR agonist, NECA, supporting A(2A) ARs are directly involved in FTBI-mediated effects. Similarly, in human SH-SY5Y cells, FTBI was able to prevent cell toxicity induced by MPP+ and METH, showing that this A(2A) AR antagonist has a neuroprotective effect independently by the specific cell model. Altogether these results demonstrate that the A(2A) AR blockade mediates cell protection against neurotoxicity induced by dopaminergic neurotoxins in dopamine containing cells, supporting the potential use of A(2A) AR antagonists in dopaminergic degenerative diseases including Parkinson's disease.     

Preoperative assessment of nonfunctioning pancreatic endocrine tumours: role of MDCT and MRI

Purpose

This study was done to compare the diagnostic accuracy of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) in the preoperative assessment of nonfunctioning pancreatic endocrine tumours (NFPET).

Materials and methods

Fifty-one patients (25 men, 26 women; mean age, 52 years), preoperatively investigated by both MDCT and MRI and subsequently operated on with a histological diagnosis of NFPET, were included in this study. MDCT and MRI accuracy in evaluating location, size, margins, baseline density/signal intensity, structure, pattern of enhancement, peak enhancement phase, involvement of main pancreatic duct, involvement of adjacent organs, infiltration of peritumoural vessels, involvement of locoregional lymph nodes, and liver metastases was compared using Pearson correlation, Mann-Whitney and chi-square tests. A value of p<0.05 was considered statistically significant.

Results

MDCT and MRI had similar accuracy in assessing size, margins, baseline density/signal intensity, structure, pattern of enhancement, peak enhancement phase, involvement of main pancreatic duct, involvement of adjacent organs, involvement of locoregional lymph nodes, and liver metastases (p>0.05). MDCT was superior to MRI in evaluating the infiltration of peritumoural vessels (p=0.025).

Conclusions

MDCT performed better than MRI in assessing vascular involvement and should be considered the best imaging tool for preoperative evaluation of NFPET.     

Selective lesions of rabbit extraocular muscles injected with the anti-AChR immunotoxin saporin-mAb 73

PURPOSE: To evaluate the effects on extraocular muscles of a skeletal muscle-specific immunotoxin, saporin-mAb 73, as an alternative to botulinum toxin to induce a permanent correction of oculo-facial dystonias or some forms of ocular motility disorders. METHODS: An immunotoxin was prepared with a monoclonal antibody (mAb 73) against acetylcholine receptors of skeletal muscle, linked to saporin, a type 1 ribosome-inactivating protein (RIP) from Saponaria officinalis. Sixteen New Zealand white rabbits were treated with a single injection of immunotoxin directly into the medial rectus muscle of one eye. Four different dosages of 2, 5, 20, or 50 ng saporin-mAb 73 were used. The rabbits were sacrificed at two, 7 and 14 days post-injection. The medial rectus muscle and the retractor bulbi muscle of both the injected and the fellow eyes were taken and serial sections were examined by light microscopy in a blinded manner. RESULTS: Saporin-mAb 73, even at the dosage of 2 ng, brought about focal damage in the extraocular muscles of rabbits without histological changes in adjacent muscles. The histological examination revealed necrotic/apoptotic lesions restricted to the sites of inoculation and largely infiltrated by macrophages. No evident inflammatory reaction was detected at any time and neutrophils were substantially absent. At 14 days after injection, necrosis/apoptosis was still evident and the sclerotic reaction was minimal. CONCLUSIONS: The immunotoxin saporin-mAb 73 injections into the extraocular muscles of rabbits caused focal damage to the muscles. There was no significant inflammatory reaction and muscle fiber loss was present even at the lower doses. Although the lesions were followed for only 14 days, our results suggest that saporin-mAb 73 has potential to cause safe focal muscle damage but longer-term follow-up are needed to investigate the persistence of muscle weakness.     

A randomised cross-over study on the haemodynamic effects of oral dofetilide compared with oral sotalol in patients with ischaemic heart disease and sustained ventricular tachycardia

OBJECTIVE: To assess the haemodynamic effects of short-term treatment with dofetilide in comparison with sotalol in patients with ischaemic heart disease. METHODS: Twelve patients with ischaemic heart disease and sustained ventricular tachycardia were treated with dofetilide [500 microg twice daily (b.i.d.)] or sotalol (160 mg b.i.d., randomised sequence separated by wash-out period) for 3-5 days. Right-heart catheterisation was performed at baseline and at the end of each short-term treatment phase. RESULTS: The main findings were a significant reduction in heart rate, mean systemic pressure and cardiac index (-13%) during treatment with sotalol. Conversely, cardiac index increased significantly during dofetilide (mean percentage change 11%) with no effect on heart rate and systemic blood pressure. CONCLUSIONS: Oral dofetilide exerts favourable haemodynamic effects in comparison with D,L-sotalol following short-term oral treatment. In view of these observations, the use of dofetilide may be proposed also in patients with ventricular tachyarrhythmias associated with impaired left-ventricular function. Whether the haemodynamic differences between dofetilide and D,L-sotalol are the basis for differences in tolerability remains to be evaluated.     

Taurine: evidence of physiological function in the retina

Taurine is a free amino acid found in high millimolar concentrations in mammalian tissue and is particularly abundant in the retina. Mammals synthesize taurine endogenously with varying abilities, with some species more dependent on dietary sources of taurine than others. Human children appear to be more dependent on dietary taurine than adults. Specifically, it has been established that visual dysfunction in both human and animal subjects results from taurine deficiency. Moreover, the deficiency is reversed with simple nutritional supplementation with taurine. The data suggest that taurine is an important neurochemical factor in the visual system. However, the exact function or functions of taurine in the retina are still unresolved despite continuing scientific study. Nevertheless, the importance of taurine in the retina is implied in the following experimental findings: (1) Taurine exhibits significant effects on biochemical systems in vitro. (2) The distribution of taurine is tightly regulated in the different retinal cell types through the development of the retina. (3) Taurine depletion results in significant retinal lesions. (4) Taurine release and uptake has been found to employ distinct regulatory mechanisms in the retina.     

Temperament in adolescents with anxiety and depressive disorders and in their families

Aim of this study was to investigate whether specific temperamental features were associated with anxiety and depressive disorders in adolescents, in their siblings and in their parents. Thirty adolescents with Anxiety disorders and 25 with both Anxiety and Depressive disorders were compared to 25 adolescents with learning disorders and to 28 normal subjects. Temperament in subjects and relatives was assessed by their parents with the EAS questionnaire. Subjects with Anxiety and Anxiety-Depression and their siblings showed higher scores on Emotionality and Shyness than Learning Disability and Normal subjects. Mothers and fathers of subjects from the Anxiety-Depression group had the highest Emotionality score. These findings suggest that both Emotionality and Shyness are prominent temperamental features in adolescents with anxiety with or without depression, and in their parents and siblings.     

alpha-Melanocyte-stimulating hormone protects the allograft in experimental heart transplantation

BACKGROUND: With the increasing need for organ transplantation and the use of "marginal" organs, novel approaches are sought to increase the efficiency and survival of transplanted tissue. We tested the idea that treatment with the anti-inflammatory peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous hormone that does not cause marked immunosuppression but does reduce reperfusion injury, may protect allografts and prolong their survival. METHODS: Donor cardiac grafts (Brown Norway) were transplanted heterotopically into the abdomen of recipient (Lewis) rats. Treatments consisted of intraperitoneal injections of Nle DPhe -alpha-MSH (NDP-alpha-MSH) or saline from the time of transplantation until sacrifice or spontaneous rejection. Allografts were removed on day 1, day 4, or at the time of rejection and examined for histopathology and expression of molecules prominent in reperfusion injury, transplant rejection, and apoptosis. RESULTS: NDP-alpha-MSH treatment caused a significant increase in allograft survival and a marked decrease in leukocyte infiltration. Expression of molecules such as endothelin 1, chemokines, and adhesion molecules, which are involved in allograft rejection, was significantly inhibited in NDP-alpha-MSH-treated rats. CONCLUSIONS: The results indicate that protection of the allograft from early injury with alpha-MSH can postpone rejection. Addition of this early protection with the peptide to usual treatment with immunosuppressive agents may, therefore, improve success of organ transplants.     

New 1,2,3-triazolo[1,5-a]quinoxalines: synthesis and binding to benzodiazepine and adenosine receptors. II

On pursuing research about 1,2,3-triazolo[1,5-a]quinoxalines, in this paper we report synthesis and binding assays toward the benzodiazepine and A(1) and A(2A) adenosine receptors, of a new series of derivatives, bearing some structural changes (introduction of fluorine and trifluoromethyl in the seventh position, amino substituents in the fourth position, benzyl group in the fifth position and aroyl substituents in the third position). The biological tests have shown that only the 7-fluorosubstituted compounds 3a and 4a and the N-benzyl derivative 7 have a good affinity toward the benzodiazepine receptors, while only the 7-trifluoromethyl substituted compound 3b presents a moderate affinity with low selectivity toward the A(1) adenosine receptors. The other structural modifications strongly decreased biological activity.     

Assessment of Anxiety and Depression in Adolescents with Mental Retardation

This report examines the concurrent validity of different informant and self-report assessment instruments of psychopathology, both general and specific for anxiety and/or depression, in referred mentally retarded adolescents with a depressive and anxiety disorders, according to DSM IV criteria. A consecutive, unselected sample of 50 mildly and moderate mentally retarded adolescents (29 males and 21 females, aged 11.8 to 18 years, mean age 15.1) were assessed using standardized assessment techniques: Psychopathology Instrument for Mentally Retarded Adults (PIMRA) (informant version) (total score, affective and anxiety subscales), Child Behavior Checklist (CBCL) (informant version) (total score, internalizing and externalizing scores, anxiety-depression scale), Zung Self-Rating Depression Scale and Zung Self-Rating Anxiety Scale. Patterns of correlation among measures were calculated. PIMRA and CBCL total scores were closely intercorrelated. Internalizing and externalizing scores of CBCL were not intercorrelated, but they both correlated with CBCL and PIMRA total scores. Anxiety measures were positively correlated; they correlated with PIMRA and CBCL total scores, as well as with the internalizing score of CBCL. Depression measures were not correlated; their correlation with more general measures of psychopathology was weak. Clinical implications of these findings are discussed.