Chronic treatment with the mGlu5R antagonist MPEP reduces the functional effects of the mGlu5R agonist CHPG in the striatum of 6-hydroxydopamine-lesioned rats: possible relevance to the effects of mGlu5R blockade in Parkinson's disease

This study was designed to test whether chronic treatment with the metabotropic glutamate receptor 5 (mGlu5R) antagonist MPEP showed antiparkinsonian effects in rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA) (a "classic" model of Parkinson's disease, PD), and to evaluate whether chronic MPEP influenced the functional properties and/or the expression of striatal mGlu5Rs. Wistar rats were lesioned with 6-OHDA and then treated with MPEP (3 mg/kg/day, i.p.) or its vehicle over 2 weeks. Chronic MPEP did not induce measurable antiparkinsonian effects, since no differences were found between MPEP- and vehicle-treated animals in the pattern of L-DOPA-induced contralateral rotations. In corticostriatal slices taken from animals chronically treated with MPEP, the functional effects of the mGlu5R agonist CHPG were significantly reduced in the lesioned vs. the intact side, while no changes were found in slices taken from vehicle-treated rats. The binding of [3H]MPEP to striatal membranes showed that neither the maximal number of binding sites (Bmax) nor the dissociation constant (Kd) were changed by the lesion and/or by chronic MPEP. While chronic MPEP did not potentiate L-DOPA-induced turning in a classical model of PD, its ability to reduce mGlu5R-associated signal could help to explain the neuroprotective/antiparkinsonian effects observed in other models of PD.     

Comparative analysis of the neuronal activation and cardiovascular effects of nitroglycerin, sodium nitroprusside and L-arginine

In this study, we compare the biological effects, Fos expression and cardiovascular responses induced in the rat, of different nitric oxide modulators (nitroglycerin, sodium nitroprusside and L-arginine). Nitroglycerin and sodium nitroprusside induced a similar pattern of neuronal activation in several areas, which include the paraventricular and supraoptic nuclei of the hypothalamus, central nucleus of the amygdala, parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius. However, only nitroglycerin activated the periaqueductal grey and nucleus trigeminalis caudalis. L-arginine-induced neuronal activation was restricted to the paraventricular and supraoptic nuclei of the hypothalamus. As regards cardiovascular effect, both nitroglycerin and sodium nitroprusside induced moderate hypotension (nitroglycerin: -23.3%, sodium nitroprusside: -24.3%) that lasted 40 min in the case of sodium nitroprusside and 80 min in the case of nitroglycerin. L-arginine did not significantly influence blood pressure. These data suggest that nitroglycerin, sodium nitroprusside and L-arginine are associated with different biological effects on both the central nervous system and the cardiovascular system. Of the NO-related drugs tested in this study, only nitroglycerin confirmed its ability to activate brainstem areas implicated in nociception.     

Analysis of the human locus coeruleus in perinatal and infant sudden unexplained deaths. Possible role of the cigarette smoking in the development of this nucleus

We investigated the immunohistochemical expression of the tyrosine hydroxylase (TH) enzyme and the morphometric parameters of the human locus coeruleus (LC) in the brainstems of 32 subjects aged from 17 gestational weeks to 12 postnatal month, died of unknown (sudden unexplained perinatal and infant deaths) and known causes. The goals of this study were: (1) to obtain basic information about the structure and physiology of the LC during the first phases of human nervous system development; (2) to evaluate whether there is altered expression of TH and/or structural alterations of the LC in cases of sudden perinatal and infant death; and (3) to verify if morphological and/or physiological abnormalities of the LC could be related to maternal cigarette smoking. Morphometric analysis showed homogeneous data in cases of sudden perinatal and infant death and in age-matched controls who had died of known aetiology. However, immunohistochemistry demonstrated in a wide subset of sudden and unexplained deaths a negativity or low positivity of TH. High distribution of TH protein were instead detectable in the LC neurons of foetuses aged 17-18 gestational weeks who had died of known causes. Therefore, we postulate the functional importance of the LC in the early phases of central nervous system development. Besides, the observation of a significant correlation between sudden unexplained death, negativity of TH staining and maternal smoking, prompted us to suppose a close relation between smoking in utero and a decrease of the noradrenergic activity of the LC, leading to sudden death in the last part of pregnancy and in the first year of life.     

Reliability of panoramic radiography in evaluating the topographic relationship between the mandibular canal and impacted third molars

BACKGROUND: The authors conducted a study to evaluate the predictive value of five radiographic markers on the panoramic radiograph, or PR, to point out the relationship between the mandibular canal and the impacted third molar. METHODS: The authors evaluated the accuracy of the radiographic markers by comparing the PR with an axial computed tomographic, or CT, scan. They identified a sample of 73 third molars that showed a close relationship between the tooth roots and the mandibular canal on the PR, and then classified them on the basis of five radiographic markers. They also detected contact between the third molar and the mandibular canal on the CT scan. RESULTS: The distribution of the five radiographic markers was as follows: 37 teeth exhibited increased radiolucency, 13 exhibited superimposition, 14 exhibited interruption of the radiopaque border, 14 exhibited narrowing of the canal and seven exhibited diversion of the canal. In 11 cases, two or more markers were recognizable. The predictive values of a positive test result were as follows: increased radiolucency, 73 percent; superimposition, 38.5 percent; interruption of the radiopaque border, 71.4 percent; narrowing, 78.6 percent; and diversion, 100 percent. The authors detected contact in all of the cases that exhibited two or more markers. CONCLUSION: Increased radiolucency, narrowing and interruption of the radiopaque border, as well as the concomitant presence of two or more radiographic markers, on the PR were highly predictive of contact between the third molar and the mandibular canal. An axial CT scan probably is indicated in such cases. CLINICAL IMPLICATIONS: The results of this study may lead to some guidelines for oral surgeons evaluating whether to obtain an axial CT scan for further investigation after examining an impacted mandibular third molar via PR.     

Evaluation of rapid assay for detection of Streptococcus pneumoniae urinary antigen among infants and young children with possible invasive pneumococcal disease

The usefulness of the rapid assay for detection of Streptococcus pneumoniae urinary antigen was evaluated in 155 children ages 1 to 60 months with suspected invasive pneumococcal disease and 200 healthy controls. Although the assay was highly sensitive in the children with invasive pneumococcal disease, it should be interpreted with caution in young patients because a positive urine test result may simply be the result of nasopharyngeal colonization.     

Design, synthesis, and 3D QSAR of novel potent and selective aromatase inhibitors

The design, synthesis, and biological evaluation of a series of new aromatase inhibitors bearing an imidazole or triazole ring linked to a fluorene (A), indenodiazine (B), or coumarin scaffold (C) are reported. Properly substituted coumarin derivatives displayed the highest aromatase inhibitory potency and selectivity over 17-alpha-hydroxylase/17-20 lyase. The modeling of the aromatase inhibition data by Comparative Molecular Field Analysis (CoMFA/GOLPE 3D QSAR approach) led to the development of a PLS model with good fitting and predictive powers (n = 22, ONC = 3, r(2) = 0.949, s = 0.216, and q(2) = 0.715). The relationship between aromatase inhibition and the steric and electrostatic fields generated by the examined azole inhibitors enables a clear understanding of the nature and spatial location of the main interactions modulating the aromatase inhibitory potency.     

Toward the pharmacogenomics of cystic fibrosis--an update

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasians, with a frequency of approximately 1 in 3000 live births. The mutated gene is a defective chloride channel in epithelial cells, named cystic fibrosis transmembrane conductance regulator (CFTR). Several different protocols for the scanning of the entire gene have aided molecular diagnosis and improved our understanding of the disorder's pathophysiology, but also showed the disease's complexity. Therefore, CF phenotype remains difficult to predict from CFTR mutation data alone: several studies have suggested that additional genes could modulate its clinical outcome. Gene replacement therapy is still far from being used in patients with CF, mostly due to the difficulties with targeting the appropriate cells. In this review, we summarize recent advances, both in the pharmacological and gene therapy field, aimed for the treatment of the disease.