Inflammation and the acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of non-cardiogenic pulmonary oedema associated with bilateral pulmonary infiltrates, stiff lungs and refractory hypoxaemia. ARDS is characterized by an explosive acute inflammatory response in the lung parenchyma, leading to alveolar oedema, decreased lung compliance and, ultimately, hypoxaemia. Although our understanding of the causes and pathophysiology of ARDS has increased, the mortality rate remains in the range of 30-50%. No major advances in pharmacological therapy have been achieved. Mechanical ventilation is the main therapeutic intervention in the management of ARDS. The only approach that has been shown to reduce the inflammatory response and mortality is the use of lung-protective ventilatory strategy with a low tidal volume and high positive-end expiratory pressure. This chapter will review the current state of the literature on the pathogenesis of ARDS and ventilatory and pharmacotherapy approaches to its management.     

Antitumor agents. 3. Design, synthesis, and biological evaluation of new pyridoisoquinolindione and dihydrothienoquinolindione derivatives with potent cytotoxic activity

New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1-7), were designed on the basis of a molecular model obtained by aligning the common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and some known anticancer agents. A Diels-Alder reaction between quinolin-5,8-dione (QD) and a 2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), was used to produce 1-7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8-14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione (16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of T compounds, were recovered from the reaction mixture. The antiproliferative activity of 1-16 was evaluated against representative human liquid and solid neoplastic cell lines. The IC(50) of these compounds had median values in the range 2.00-0.01 microM, with 2-4 and 15 exhibiting significantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones (KB(MDR), KB(7D), and KB(V20C)), was shown to be scarcely subject to the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDs were examined using UV-vis and (1)H NMR spectroscopy experiments. Accordingly, these compounds were confirmed to have an ability to intercalate into double-stranded DNA by topoisomerase I superhelix unwinding assay. Interesting structure-activity relationships were found. Three important features seem to contribute to the cytotoxic activity of these anticancer ligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical of this class of compounds, (ii) the position of the pendant phenyl ring that, according to the superimposition model, must occupy the same area of the corresponding benzo-fused ring A of PPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which can contribute improving the pi-pi stacking interactions between ligand and DNA base pairs. Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized to interpret the antiproliferative activity of the thienoquinolindione 15, which can be regarded as a cyclic cysteine derivative.     

Retinol, carotenoids and the risk of prostate cancer: a case-control study from Italy

Several studies have evaluated the possible association between intakes of retinoids and carotenoids and the risk of prostate cancer, but the evidence is still inconsistent. Further, only a few studies have investigated the role of specific carotenoids other than beta-carotene. We have thus considered the association between retinol and various carotenoids using data from a multicentric case-control study conducted in Italy between 1991 and 2002. This included 1,294 incident, histologically confirmed prostate cancer cases below age 75 years admitted to major teaching and general hospitals in the areas under study, and 1,451 controls below age 75 years selected among patients admitted to the same hospitals as cases for a wide spectrum of acute nonneoplastic conditions not related to long-term modifications of diet. Subjects' usual diet was investigated by means of a validated food-frequency questionnaire. Multivariate odds ratios and the corresponding 95% confidence intervals were estimated using unconditional logistic regression models. The risk of prostate cancer tended to decrease with increasing intake of retinol (OR=0.79 for the highest versus the lowest quintile of intake), carotene (OR=0.70), alpha-carotene (OR=0.85) and beta-carotene (OR=0.72), although the estimates were significant for carotene and beta-carotene only. No meaningful associations emerged for nonprovitamin A carotenoids, such as lycopene (OR=0.94) and lutein/zeaxanthin (OR=0.91). No systematic heterogeneity was observed across strata of age, education and body mass index. Thus, our study supports the hypothesis of a weak protective effect of carotene, particularly beta-carotene, on the risk of prostate cancer, while it indicates that other carotenoids, including lycopene, and retinol are not appreciably related to the risk of this neoplasm.     

Antidepressants activate CaMKII in neuron cell body by Thr286 phosphorylation

CaM kinase II, a regulator of synaptic plasticity, is implicated in pathophysiology and pharmacology of psychiatric disorders. Chronic treatment with antidepressants desipramine and reboxetine up-regulated CaM kinase II in neuronal cell bodies of hippocampus. mRNA/protein expression for alphaCaM kinase II was unchanged, whereas Thr phosphorylation was increased in pyramidal/granular cell bodies, suggesting that increased phosphorylation is responsible for kinase activation. Short-term treatment of neuronal cultures with reboxetine reduced kinase activation in a concentration-dependent manner. The short-term inhibitory effect of reboxetine suggests that kinase up-regulation during antidepressant drug treatment is an adaptive response compensating for initial functional down-regulation.     

Primary prevention of epilepsy in patients with different epileptogenic conditions

Epileptic seizures are a common complication of several clinical conditions affecting the CNS. In these cases, the occurrence of seizures and epilepsy may increase the functional damage provoked by the underlying epileptogenic condition and affect the patient's quality of life to a significant extent. Therefore, the search of effective means for primary prevention of seizures and epilepsy is necessary in these cases. However, the use of antiepileptic drugs for the primary prevention of seizures and epilepsy can be considered only if the ratio between efficacy, safety and tolerability of treatment is favorable, in that the advantages, in terms of seizure prevention, outweigh the disadvantages in terms of adverse effects and overall costs of treatment. In this article, the efficacy, safety and tolerability of antiepileptic drugs for the primary prevention of seizures and epilepsy are reviewed. The areas covered include: the definition of early (provoked) and late (unprovoked) seizures; knowledge of the overall risk of seizures and epilepsy in CNS disorders for which primary prevention of seizures can be attempted; rationale for the use of antiepileptic drugs for the primary prevention of epilepsy; experimental data on the antiepileptogenic properties of antiepileptic drugs; available literature findings on the prevention of early and late seizures, with specific emphasis on randomized clinical trials; and the main problems with experimental trials for the primary prevention of epileptic seizures. On this basis, practice recommendations for the primary prevention of epilepsy will be offered where indicated. Suggestions for future research are also made as concluding remarks, by indicating the areas of investigation and the design of future studies.     

Incidence and clinical features of acute inflammatory polyradiculoneuropathy in Lombardy, Italy, 1996

OBJECTIVE: To assess the annual incidence of typical Guillain-Barré syndrome (GBS) and its main variants (atypical GBS) in a well-defined population from a large area. MATERIAL AND METHODS: A population-based prospective survey of GBS was undertaken during the calendar year 1996 in Lombardy, Italy (population 8,891,652). Typical and atypical GBS was diagnosed using the National Institutes of Neurological and Communicative Disorders and Stroke (NINCDS) and Ropper criteria. Eligible cases were hospital inpatients traced through a regional registry, the hospital discharge diagnoses, and an ongoing case-control study. Diagnostic and demographic findings were collected for each case. Complete clinical and laboratory features were available for 80% of cases. RESULTS: A total of 138 patients (males 74; females 64) aged 2-91 years fulfilled the diagnostic criteria for typical GBS (128) or atypical GBS (10). GBS variants included Miller-Fisher syndrome (four cases), cranial polyneuritis (three cases), pure motor GBS (two cases), and sensory loss with areflexia (one case). The crude annual incidence of GBS was 1.55 per 100,000 (typical GBS 1.43; atypical GBS 0.11; male 1.67; female 1.43; age <35 years, 0.79; 35-54 years, 1.33; 55-74 years, 3.22; 75+ years, 4.67). The overall rate was 1.58 when age- and sex-adjusted to the 1996 Italian population. Previous infections were reported for 37% of patients. The electrophysiological findings indicated demyelination in 51%, primary axonopathy in 14%, and mixed myelin and axon involvement in 27%. CONCLUSIONS: The incidence of typical GBS is comparable with that in other reports using the NINCDS diagnostic criteria. Atypical GBS accounts for a limited number of cases.     

Morbidity in patients with epilepsy: type and complications: a European cohort study

PURPOSE: To investigate the risk of illnesses in a cohort of patients with epilepsy and in matched nonepilepsy controls, by type and complications. METHODS: A total of 951 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 904 matched controls seen in secondary and tertiary centers in eight European countries (England, Estonia, Germany, Italy, the Netherlands, Portugal, Russia, Slovenia) were followed prospectively for 17,484 and 17,206 person-months and asked to report any spontaneous complaint requiring medical attention (illness), its type and complications (hospitalization, absence from work or school, medical action). Risk assessment was done by actuarial methods, relative risks (RR), and 95% confidence intervals (CIs). RESULTS: During the study period 644 patients (68%) and 504 controls (56%) reported an illness (p < 0.0001); 30% were seizure related. The cumulative probability of illness at 12 and 24 months was 49 and 86% in the cases and 39 and 75% in the controls (p < 0.0001). The largest differences regarded disorders affecting the nervous system (NS) (RR, 3.3; 95% CI, 2.3-4.2) and ear, nose, and throat (ENT) (RR, 1.3; 95% CI, 1.0-1.6). In patients with epilepsy, an NS illness was more likely to be followed by hospital admission, work absence, or medical intervention. All risks were significantly reduced after excluding seizure-related events. CONCLUSIONS: Patients with epilepsy are at higher risk of NS and ENT illnesses and complications than the general population. However, the risk of illness is significantly reduced when seizure-related events are excluded.