Immunomodulator structure-activity relationships: contribution of molecular modeling

Molecular modeling used to compare 64 immunostimulant compounds with pyrrolie quinolein or purine nuclei has pointed out that a common spatial structure is found in most of the active compounds. An additional study of immunostimulants (levamisole, muramyldipeptide) or immunosuppressive molecules (rapamycin) was performed. A common pharmacophore was found on every studied compound. It was composed of three neighboring electroattractive atoms and a further fourth atom. The favorable conformation of rapamycin for immunosuppressive action, which is not the more stable conformation, could explain the loss of its activity, or those of related macrolides, when some minor chemical modifications are tested. These findings validate the proposed concept and provide a view of the mechanism of action of most of the immunomodulator compounds for preparing novel compounds     

Clinical heterogeneity in Sanfilippo disease (mucopolysaccharidosis III) type D: presentation of two new cases

Clinical, radiological and biochemical findings of two new cases of Sanfilippo disease, type D are reported. A high percentage of heparan sulfate was found in the urinary glycosaminoglycan pattern and a severe deficiency of N-acetylglucosamine-6-sulfate sulfatase was demonstrated in skin cultured fibroblasts from the patients. One of the patients presented mild intellectual impairment which differentiates him from the other cases described to date.     

Design,synthesis, and physicochemical and biological characterization of a new iron chelator of the family of hydroxychromenes

Increasing evidence suggests that iron plays an important role in tissue damage both during chronic iron overload diseases (i.e., hemochromatosis) and when, in the absence of actual tissue iron overload, iron is delocalized from specific carriers or intracellular sites (inflammation, neurodegenerative diseases, postischaemic reperfusion, xenobiotic intoxications, etc.). In the present work, we appropriately modified an iron chelator of the hydroxychromene family in order to obtain a tridentate chelator that would inactivate the iron redox cycle after its complexation, with a view to using this molecule in human therapy and/or in disease prevention. We synthesized such a chelator for the first time and show, by different physicochemical analysis, its tridentate nature and, importantly, its capacity to chelate iron with enough strength to inhibit both iron-dependent H(2)O(2) generation and lipid peroxidation in in vitro biological systems.     

Infectious diseases in Rome during the Millennium Year

During 2000, the millennium year, 26 million people visited Rome. An improved surveillance system for infectious diseases, especially for foodborne disease outbreaks (FBDO), meningitis, and legionnaires' disease was introduced in 1997. This rapid alert network links public health services with the principal sources of diagnosis and laboratory based surveillance. For travel related legionnaires' disease, international surveillance was implemented. Specific control measures for FBDOs were adopted. No increase in the overall incidence of these diseases was observed, and no atypical pathogens in FBDOs or meningitis were isolated in 2000 relating to 1998-99. Cases of legionnaires' disease and FBDOs involving foreign tourists increased (10/4 and 7/2 observed/expected respectively). Three out of six FBDOs involving pilgrims occurred in religious guesthouses. While an increase in cases of legionnaires' disease and FBDOs among foreign tourists was observed by the surveillance system, the millennium year did not influence the epidemiology of infectious diseases in the residential population of Lazio.     

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.     

The role of the locus coeruleus in the development of Parkinson's disease

In Parkinson's disease, together with the classic loss of dopamine neurons of the substantia nigra pars compacta, neuropathological studies and biochemical findings documented the occurrence of a concomitant significant cell death in the locus coeruleus. This review analyzes the latest data obtained from experimental parkinsonism indicating that, the loss of norepinephrine in Parkinson's disease might worsen the dopamine nigrostriatal damage. Within this latter context, basic research provided a new provocative hypothesis on the significance of locus coeruleus in conditioning the natural history of Parkinson's disease. In particular, the loss of a trophic influence of these neurons might be crucial in increasing the sensitivity of nigrostriatal dopamine axons to various neurotoxic insults. In line with this, recently, it has been shown that locus coeruleus activity plays a pivotal role in the expression of various immediate early genes and in inducing the phosphorilation of cyclic adenosine monophosphate response element-binding proteins, suggesting a role of the nucleus in sustaining a protective effect.     

Radiologic analysis of interval cancers in the screening program called Florence Woman Project

PURPOSE: The aim of the present study was to provide data on interval cancer incidence after the first round of the screening program in the city of Florence, and to provide and discuss the results of the review of previous screening mammograms. MATERIAL AND METHODS: The screening program "Progetto Firenze Donna" involves all women age 50 to 69 years resident in the city of Florence. In the interval from the end of the first and the start of the second screening round 51 interval cancers were identified, of which 41 were available for radiological review. Films were reviewed by expert screening radiologists, not involved in the program and blinded to the final diagnosis, according to the review criteria recommended by the UK Guidelines for radiologists (blind and informed review). RESULTS: Sensitivity (screening errors/total) was different among blind reviewers (reader A = 7.3%, reader B = 14.6%), as well as specificity which shows an inverse pattern (reader A = 98.4%, reader B = 97.6%). Informed review classified 5 cases as "screening error" (12.2%), 11 as "minimal sign" (26.8%) and 25 as "occult" (61%). Informed review classified a higher proportion of cases as "minimal sign" (minimal abnormalities are better perceived with the knowledge of the site and the pattern of subsequent cancer). DISCUSSION AND CONCLUSIONS: Analysis of interval cancers is fundamental for the quality control of a screening program. According to this experience, informed review tends to overestimate "minimal signs" in the cancer site and should not be used (or "minimal signs" should be anyhow assumed as negative). Identification of interval cases as "minimal signs" may be influenced by individual variability. Standard criteria should be adopted to identify and review/classify interval cancers to allow comparisons between different programs.     

颅内动脉瘤栓塞后并发脑缺血的原因分析

1 临床资料我们总结2004-02/2004-06在第四军医大学唐都医院神经外科住院行栓塞治疗颅内动脉瘤患者27(男12,女15)例,年龄32～72岁.