Distinct cytokine patterns associated with different forms of chronic dysimmune neuropathy

To better understand the presumed immune system dysregulation of chronic dysimmune neuropathy (CDN) patients, we designed a study to evaluate the levels of pro- and anti-inflammatory cytokines in the most common forms of CDN: chronic inflammatory demyelinating polyneuropathy (CIDP), and anti-myelin-associated glycoprotein (MAG)-related polyneuropathy (MAGnp). Sixteen patients fulfilled diagnostic criteria for CIDP, 14 were diagnosed with MAGnp, and 36 were classified as exhibiting "chronic idiopathic polyneuropathy" (CIP). Cytokine production in mitogen-stimulated peripheral blood mononuclear cells (PBMCs) was analyzed by flow cytometry. CIDP and MAGnp patients were compared with CIP patients, those with monoclonal gammopathy without polyneuropathy (MGUS), and healthy controls (HC). We observed an increase in pro-inflammatory cytokines in the CIDP group, whereas interleukin-10 (IL-10) was augmented in the MAGnp patients. These distinctive immune alterations may represent a biological tool in differential diagnosis and future therapeutic approaches.     

Selenium supplementation prevents the increase in atherogenic electronegative LDL (LDL minus) in the postprandial phase

Evidence is accumulating that postprandial phenomena play a role in atherogenesis. Dietary lipid hydroperoxides that escape from the gastrointestinal barrier can be incorporated into plasma lipoproteins, leading to a modified form of LDL (LDL minus).The present human study was designed to investigate the effect of selenium supplementation on the formation of LDL minus in the postprandial phase. Fourteen healthy subjects ate the same test meal, high in lipid hydroperoxides, at baseline and after 10-day selenium supplementation (110 μg/day). Plasma selenium, LDL minus, LDL resistance to oxidative modification, plasma antioxidants (ascorbic acid, GSH and GPx activity) and MDA were measured in preprandial (time 0) and postprandial (3 h) phases. Supplementation did not induce changes in the concentration of selenium in fasting plasma, but, at the same time, it induced a significant decrease in preprandial plasma GPx activity and inhibited the meal-induced increase in GPx activity. Selenium supplementation fully prevented the meal-induced increase in both LDL minus level and LDL susceptibility to oxidation.This study demonstrated the efficacy of selenium in preventing postprandial oxidative stress. The results, obtained on subjects adequately supplied with selenium, suggest that a non-limiting selenium availability counteracts the postprandial formation of the atherogenic form of LDL and provide a rationale for the epidemiological evidence of the inverse correlation between selenium intake and the incidence of chronic and degenerative diseases.     

West Nile virus circulation detected in northern Italy in sentinel chickens

Ninety percent (56/62) of sentinel chickens introduced to two regions within the Italian Alps seroconverted to West Nile virus (WNV) during the summer of 2005, showing a range of antibody titres from 1/20 to 1/320 in a virus neutralization test. Neutralization specificity for WNV antibodies was confirmed on an additional 34 sera that were tested in parallel against WNV (16/34 seropositivity), Usutu virus (3/34 seropositivity) and Koutango virus. The geometric mean neutralizing titre (GMT) calculated for WN-specific antibodies was 33.68 and did not differ significantly amongst sample sites, although the overall results indicate more active circulation of WNV at the higher elevations. Such high levels of seroconversion raise the possibility that many chickens may have been exposed to virus via routes other than mosquito transmission. No chickens or any other local animals were associated with illness due to WNV implying that WNV, and to a much lower extent Usutu virus, circulate harmlessly amongst wildlife species in northern Italy from late May onwards until early autumn.     

Inhalable metal-rich air particles and histone H3K4 dimethylation and H3K9 acetylation in a cross-sectional study of steel workers

Background: Epidemiology investigations have linked exposure to ambient and occupational air particulate matter (PM) with increased risk of lung cancer. PM contains carcinogenic and toxic metals, including arsenic and nickel, which have been shown in in vitro studies to induce histone modifications that activate gene expression by inducing open-chromatin states. Whether inhalation of metal components of PM induces histone modifications in human subjects is undetermined.Objectives: We investigated whether the metal components of PM determined activating histone modifications in 63 steel workers with well-characterized exposure to metal-rich PM.Methods: We determined histone 3 lysine 4 dimethylation (H3K4me2) and histone 3 lysine 9 acetylation (H3K9ac) on histones from blood leukocytes. Exposure to inhalable metal components (aluminum, manganese, nickel, zinc, arsenic, lead, iron) and to total PM was estimated for each study subject.Results: Both H3K4me2 and H3K9ac increased in association with years of employment in the plant (p-trend = 0.04 and 0.006, respectively). H3K4me2 increased in association with air levels of nickel [β = 0.16; 95% confidence interval (CI), 0.03–0.3], arsenic (β = 0.16; 95% CI, 0.02–0.3), and iron (β = 0.14; 95% CI, 0.01–0.26). H3K9ac showed nonsignificant positive associations with air levels of nickel (β = 0.24; 95% CI, –0.02 to 0.51), arsenic (β = 0.21; 95% CI, –0.06 to 0.48), and iron (β = 0.22; 95% CI, –0.03 to 0.47). Cumulative exposures to nickel and arsenic, defined as the product of years of employment by metal air levels, were positively correlated with both H3K4me2 (nickel: β = 0.16; 95% CI, 0.01–0.3; arsenic: β = 0.16; 95% CI, 0.03–0.29) and H3K9ac (nickel: β = 0.27; 95% CI, 0.01–0.54; arsenic: β = 0.28; 95% CI, 0.04–0.51).Conclusions: Our results indicate histone modifications as a novel epigenetic mechanism induced in human subjects by long-term exposure to inhalable nickel and arsenic.     

Mitigation of tumor necrosis factor alpha cytotoxicity by aurintricarboxylic acid in human peripheral B lymphocytes

The aims of this study were to ascertain whether aurintricarboxylic acid (ATA), an endonuclease inhibitor, known to interfere, with the actions of cytokines such as interferons, is able to antagonize the toxic effects produced by tumor necrosis factor alpha (TNF-alpha) in human healthy peripheral B lymphocytes and try to elucidate the molecular machinery through which this possible antagonism takes place. Results evidenced that the balance of survival signals of human B lymphocytes in the presence of TNF-alpha was altered by the interaction of TNF-alpha with a salicylate compound, ATA. Apoptosis effected by TNF-alpha alone was suppressed in the presence of ATA, and this effect appeared essentially characterized by: (i) phosphorylation of phosphatidylinositol-3 kinase (PI-3K), influencing in turn protein kinase B/Akt (Akt) and Bad phosphorylation; (ii) nuclear translocation of the nuclear factor kappa B (NF-kappaB) and (iii) nuclear translocation of protein kinase C zed (PKCzeta). Reversal of TNF-alpha/ATA effects occurred in the presence of the PI-3K specific inhibitors wortmannin or LY294002 in the culture medium and was coincident with inhibition of the translocation of PKCzeta in the nucleus, while NF-kappaB was less affected. These results indicate, therefore, that PI-3K-mediated activation and nuclear transfer of PKCzeta might be essential steps of ATA antagonism against TNF-alpha, suggesting that possible ATA pharmacological applications might be taken into account for staving off systemic or local toxic effects produced by TNF-alpha.     

Apolipoprotein E e4 allele affects risk of hyperhomocysteinemia in the elderly

BACKGROUND: Apolipoprotein E (APOE) plays a central role in VLDL metabolism. Both APOE e4 allele (APOE4) and C-reactive protein (CRP) are associated with greater risk of dementia and vascular disease, but APOE4 carriers have lower blood concentrations of CRP than do noncarriers, possibly through a mechanism favoring the clearance of the CRP VLDL-bound fraction. Homocysteine, another risk factor for vascular disease and dementia, also binds to VLDL in blood. However, the association between APOE4 and hyperhomocysteinemia has never been thoroughly investigated. OBJECTIVE: We investigated in an elderly population whether 1) APOE4 is associated with hyperhomocysteinemia [plasma total homocysteine (tHcy) > 15 micromol/L], 2) hyperhomocysteinemia affects the association between APOE4 and high CRP (serum CRP > 3 mg/L), and 3) B vitamin status affects these associations. DESIGN: APOE4 genotypes were assessed and tHcy, CRP, and serum concentrations of folate and vitamin B-12 were measured in 671 cognitively healthy subjects (52% women; mean age: 73 y) from an Italian population-based prospective cohort study. RESULTS: APOE4 carriers without high CRP [multivariate-adjusted odds ratio (OR): 0.22; 95% CI: 0.08, 0.59] had a lower risk of hyperhomocysteinemia than did noncarriers. The risk of high CRP was lower in APOE4 carriers without hyperhomocysteinemia (multivariate-adjusted OR: 0.51; 95% CI: 0.31, 0.85) than in noncarriers. The associations were not affected by B vitamin status. CONCLUSION: Independently from B vitamin status, APOE4 carriers have a lower risk of hyperhomocysteinemia and of high CRP than do noncarriers, but the presence of one condition attenuates the association of APOE4 with the other condition.     

Antimicrobial resistance among non-fermentative Gram-negative bacilli isolated from the respiratory tracts of Italian inpatients: a 3-year surveillance study by the Italian Epidemiological Survey

The Italian Epidemiological Survey evaluated antibiotic susceptibility of non-fermentative Gram-negative bacilli isolated from inpatient respiratory-tract specimens collected throughout Italy during 1997-1999. The minimal inhibitory concentrations of 14 antibiotics for 1474 Pseudomonas aeruginosa strains, 307 Stenotrophomonas maltophilia strains and 114 Acinetobacter baumannii strains were determined in 57 clinical microbiology laboratories by means of a standardised micro-dilution method. The most active drugs against P. aeruginosa isolates were meropenem (81% susceptible) and amikacin (80% susceptible). Imipenem and meropenem proved to be the only agents active against A. baumannii isolates, although 13 and 16%, respectively, of strains were resistant to these drugs. Trimethoprim-sulphamethoxazole (TMP-SMZ) showed activity only against S. maltophilia isolates (83% susceptible). A total of 185 multidrug-resistant P. aeruginosa isolates (resistant to piperacillin, ceftazidime, gentamicin, and imipenem) were found. Resistance rates and trends showed consistent regional variations, including sharp increases from 1997 to 1999 in imipenem resistance among P. aeruginosa isolates from central and southern Italy.     

Management of hypertension in chronic kidney disease

Optimal blood pressure control (<130/80 mm Hg) in patients with chronic kidney disease (CKD), despite being the main objective of conservative therapy, is rarely achieved in clinical practice. A major area of improvement is the correction of the extracellular volume expansion. This goal can be reached by means of dietary salt restriction (≤ü100 mEq/d of NaCl). If this intervention fails, hypertension can be treated by thiazide diuretics in patients with mild CKD, whereas loop diuretics at adequate doses are indicated in patients with more advanced CKD. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are more effective than other drugs in slowing progression of proteinuric diabetic and nondiabetic CKD. However, the control rates of blood pressure are usually inadequate with antihypertensive therapy including only these drugs; therefore, addition of other classes of antihypertensive drugs is often required.     

Development of mucoadhesive patches for buccal administration of ibuprofen.

A new formulation for topical administration of drugs in the oral cavity has been developed using several film-forming and mucoadhesive polymers. The films have been evaluated in terms of swelling, mucoadhesion and organoleptic characteristics. The best film, containing polyvinylpyrrolidone (PVP) as film-forming polymer and carboxymethylcellulose sodium salt (NaCMC) as mucoadhesive polymer, was loaded with ibuprofen as a model compound and in vitro and in vivo release studies were performed. Statistical investigation of in vitro release revealed that the diffusion process was the main drug release mechanism and the Higuchi's model provided the best fit. In vivo studies showed the presence of ibuprofen in saliva (range 70-210 microg/ml) for 5 h and no irritation was observed. These mucoadhesive formulations offer many advantages in comparison to traditional treatments and can be proposed as a new therapeutic tool against dental and buccal diseases and disturbs.