Micronized palmitoylethanolamide/trans-polydatin treatment of endometriosis-related pain: a meta-analysis.

Objectives. 1. To demonstrate clinical effectiveness of micronized palmitoylethanolamide-trans-polydatin combination in reducing endometriotic chronic pelvic pain (main objective); 2. To reduce other endometriotic-associated pain; 3. To assess the effects of this treatment in patient sub-groups; 4. To demonstrate that such therapy modifies natural history of the disease. Data sources. Systematic reviews of PubMed, SCIELO, Scopus, and AJOL, without regard to time frame and other limits. Study eligibility criteria. Randomized trials and observational studies reporting a visual analogue scale for pain or similar assessments at enrollment and at least at one follow-up in endometriotic patients. Study appraisal and synthesis methods: stringent, subjective, semi-quantitative assessment of study quality in relation to data availability and results exposure; additional assessment of study availability to meet meta-analysis objectives. Quantifying of mean improvement of visual analogue scale (or visual analogue scale-like) scores at enrollment and at a three month-follow-up. Interpreting data from a clinical point of view, according to generally accepted criteria. Results. Data were collected from 4 studies of poor quality (5 effect sizes). These were unable to satisfy objectives 3 and 4, and partially answered objective 2. In a heterogeneous sample of endometriotic patients with pain, the oral administration of micronized palmitoylethanolamide/trans-polydatin (400 mg/40 mg) twice a day for three months provided a clinically relevant improvement in chronic pelvic pain and dysmenorrhea while improving deep dyspareunia to a limited degree. No clinically relevant improvement was found for dyschezia. Conclusion. The combination of micronized palmitoylethanolamide/trans-polydatin appears to be a promising treatment for chronic pelvic pain and, possibly, other acute pain in endometrioic patients. More good-quality evidence on this treatment is warranted

Individual susceptibility to hexavalent chromium of workers of shoe, hide, and leather industries. Immunological pattern of HLA-B8,DR3-positive subjects

Background. This study was designed to examine the effects of hexavalent chromium [Cr(VI)] on the immunological pattern of shoe, hide, and leather industry workers, moving from the hypothesis that some haplotypes (HLA-B8,DR3) can be important hidden risk cofactors. Methods. Workplaces of 20 firms were monitored for total and respirable dusts and for total and hexavalent chromium. Cr(VI) on materials was also measured. Assay of chromium levels in blood and urine of 44 serological human leukocytes antigen (HLA)-typed workers (20 exposed, 15 HLA-B 8,DR3-negative/5-positive and 24 non-exposed, 18 HLA-B8,DR3-negative/6-positive subjects) was performed by atomic absorption, and lymphocyte subsets (FACS-analysis), mitogen-mediate lympho-proliferation ([H-3]thymidine incorporation), cytokine levels (ELISA), natural killer (NK) cytotoxic activity (Cr-51-release assay) were determined. Results. The environmental parameter levels are lower than threshold limit value-time-weighted average (TLV-TWA); in the materials, the Cr(VI) values exceeded the levels allowed. The peripheral blood mononuclear cells (PBMC) proliferation and the T-helper1 (TH1) cytokine pattern of subjects chronically exposed were significantly raised; addition in vitro of Cr(VI) further stimulated these parameters and in general the entire TH1 system and NK activity. The TH2 system was unaltered. In the HLA-B8,DR3-positive workers, immunologically "low responders", the addition of Cr(VI) in vitro caused a further reduction of the considered parameters in the exposed subjects with a dramatic deficit of the TH1 system. Conclusions. Results indicate the unsuitability of TLV-TWA as a line of demarcation between safe and dangerous Cr(VI) concentrations and the importance of individual genetic susceptibility for occupational and preventative medicine. In particular, the presence of the HLA-138,DR3 alleles can represent an important cofactor of immunotoxic susceptibility consequent to chronic low-dose Cr(VI) exposure. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved

Immunological pattern alteration in shoe, hide, and leather industry workers exposed to exavalent chromium

The aim of this work was to assess the effects of hexavalent chromium [Cr(VI)] on shoe, leather, and hide industry workers, based on the assumption that Cr(VI) can behave as an environmental immunological "stressor." The immunological patterns of 84 male subjects were studied in relation to Cr(VI) hematic and urinary levels. Cr(VI) was measured through atomic absorption. Lymphocyte subsets, mitogen-mediated lymphocyte-proliferation, cytokine levels, and natural killer (NK) cytotoxic activity were also assayed. RESULTS: The urinary levels of the total amount of Cr(VI) were significantly higher in a subgroup of exposed subjects (group B) than in the control or in the lower exposed (group A). In group B, Cr(VI) caused a decrease in the density of glucocorticoid receptors (GR) on peripheral blood mononuclear cells (PBMC) and a increase of IL-6. Cr(VI) did not modify NK-mediated cytotoxicity, the plasmatic levels of inflammatory cytokines and related soluble receptors, and prostaglandin levels, while it tended to increase lymphocyte sensitivity to mitogens and the production of immunomodulant cytokines (IFN-gamma, IL-4, and IL-2). The experimental addition of Cr(VI) to the in vitro lymphocyte culture determined a significant inhibition of phagocytosis percentage, index, and killing percentage. These effects were neutralized by exogenous IFN-gamma. Cr(VI) could represent an environmental immunological stressor whose effects can be evaluated through laboratory surveys. The lymphocyte mitogen-induced proliferation, GR receptor on PBMC, and IL-6 plasma levels may represent a discriminating element between Cr(VI)-induced stress and other kinds of stress

The functional VNTR MNS16A of the TERT gene is associated with human longevity in a population of Central Italy.

Telomerase, encoded by TERT, is the ribonucleoprotein polymerase that maintains telomere ends and it plays a crucial role in cellular senescence. TERT single nucleotide polymorphisms (SNPs) have been associated both with various malignancies and telomere length (TL). The association of TERT SNPs with longevity remains uncertain and varies with ethnicity. The aim of this study was to investigate whether the functional variable number of tandem repeat (VNTR) MNS16A of TERT is associated with longevity. METHODS: MNS16A genotypes have been determined for 1072 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes: for men (women), the first class consists of individuals 88 years old (>91 years old). TL was assessed using genomic DNA from whole blood of 72 selected individuals by a multiplex real-time PCR assay. RESULTS: MNS16A appears associated to longevity, showing significant associations in Comparison 2 (Age Class 3 vs. Age Class 2) under both additive (odds ratio [O.R.] 0.749; p=0.019) and dominant (O.R. 0.579; p=0.011) models. The MNS16A*L allele is significantly underrepresented in Age Class 3 (O.R. 0.759; p=0.020) compared to Age Class 2. A significant telomere attrition is reported along the three age classes (p=0.0001), that remains significant only in L*/L* genotype carriers (p=0.002) when the analysis was conducted according to MNS16A genotype. CONCLUSIONS: The TERT MNS16A*L allele appears negatively associated with longevity. The concomitant significant telomere cross sectional attrition rate observed for L*/L* genotype suggests that this polymorphism could influence human longevity by affecting TL

Dopaminergic system is differently altered in hippocampus and facial nucleus of trimethyltin rat model

Trimethyltin (TMT) is an organotin compound which is considered a useful tool to obtain an animal model of neurodegeneration associated with cognitive impairment (Pompili et al., 2011; Geloso et al., 2011). In the present work, this model was used in order to investigate the animal behaviour in association with the immunohistochemical expression of dopaminergic system (D1- and D2-like receptors and dopamine transporters DAT, VMAT-1 and -2) and cells viability (NEU-N) in the rat hippocampus and facial nucleus regions. TMT-treated group showed impaired spatial reference memory in a Morris water maze task compared to control group whereas the memory consolidation tested 24h after was preserved. In the open field, TMT-treated rats showed a decreased in time spent in rearing episodes reflecting a lower interest to explore a novel environment. In the hippocampal area of TMT-treated group, cell viability was significantly reduced by 45.9% whereas the D1, D2, DAT and VMAT- 2 receptor proteins immunoreactivity was significantly decreased by 57.5, 72.8, 64.1, 72.1%. In the facial nucleus, immunoreactivity reduction was observed only for dopamine transporters (average: 60% about) while the NEU-N reduction was 40%. These data were confirmed by real time RT-PCR analysis. These results suggest a differential involvement of the D1-type and D2-type receptors in the regulation of learning and memory. Besides, alterations on the functional ratio of DAT to VMAT-2 could predispose the cells to injury even at very low doses of TMT. The data obtained in facial nucleus demonstrate a different sensibility to xenobiotic of dopamine receptors and transporters. The TMT model could contribute to elucidate the role of dopaminergic system on two different CNS regions. Supported by PRIN 2008 - prot. 20089MANHH_002 and prot. 20089MANHH_003

Dopamine receptors and transporters sensitivity to trimethyltin in rat hippocampus and facial nucleus

Trimethyltin (TMT) is considered a useful tool to obtain an experimental model of neurodegeneration. TMT is known to cause neurotoxicant effects especially marked in the hippocampus. Despite many studies are published, there are poor literature on the interaction of this xenobiotic with dopaminergic system. In the present work, we investigate in rat brain, after 21 days following TMT intraperitoneal administration, the cells viability (N-NEU) and the animal behaviour in association with the immunohystochemical expression of dopamine receptors (D1- and D2-like) and transporters membrane (DAT) and vesicular monoamine trasporters (VMAT-1 and -2) in rat hippocampus and facial nucleus. The animal behaviour shows a significant reduction of spatial reference memory in a Morris water maze task according with the reduction (70% Vs control) of hippocampus dopaminergic system expression, despite the cell viability is maintained at about 50%. In the facial nucleus, a different reduction of dopamine receptors and trasporters (30% against 60%) was observed while the N-NEU reduction was 40%. These results suggest that the toxic interaction of TMT with the dopaminergic system in rat hippocampus may be responsible for learning and memory deficits. Data obtained in facial nucleus demonstrate different sensitivity of dopamine receptors and dopamine transporters to xenobiotic. Supported by PRIN 2008 - prot. 20089MANHH_00

Autonomic innervation of immune organs and neuroimmune modulation

1. Increasing evidence indicates the occurrence of functional interconnections between immune and nervous systems, although data available on the mechanisms of this bi-directional cross-talking are frequently incomplete and not always focussed on their relevance for neuroimmune modulation. 2. Primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid organs are supplied with an autonomic (mainly sympathetic) efferent innervation and with an afferent sensory innervation. Anatomical studies have revealed origin, pattern of distribution and targets of nerve fibre populations supplying lymphoid organs. 3. Classic (catecholamines and acetylcholine) and peptide transmitters of neural and non-neural origin are released in the lymphoid microenvironment and contribute to neuroimmune modulation. Neuropeptide Y, substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide represent the neuropeptides most involved in neuroimmune modulation. 4. Immune cells and immune organs express specific receptors for (neuro)transmitters. These receptors have been shown to respond in vivo and/or in vitro to the neural substances and their manipulation can alter immune responses. Changes in immune function can also influence the distribution of nerves and the expression of neural receptors in lymphoid organs. 5. Data on different populations of nerve fibres supplying immune organs and their role in providing a link between nervous and immune systems are reviewed. Anatomical connections between nervous and immune systems represent the structural support of the complex network of immune responses. A detailed knowledge of interactions between nervous and immune systems may represent an important basis for the development of strategies for treating pathologies in which altered neuroimmune cross-talking may be involved

Synergistic action of Nikkomicin X/Z with azole antifungals on Candida albicans.

Fluconazole, ketoconazole and tioconazole were shown to act synergistically in vitro with the antibiotic nikkomycin X/Z on the pathogenic fungus Candida albicans. The phenomenon was demonstrated using a checkerboard technique and growth inhibition experiments. The azole antifungal agents, even at concentrations not affecting growth, decreased the incorporation of the 14C-label from [14C]glucose into chitin of the candidal cell wall. After 3 h incubation with tioconazole, 1 microgram ml-1, the incorporation of the radiolabelled glucose into chitin of intact cells and regenerating spheroplasts of C. albicans was inhibited by 43% and 30%, respectively. Moreover, the relative chitin content was approximately 45% lower than that of control cells. The chitin content increased after prolonged incubation with azoles, thus confirming the known phenomenon of azole-induced uncoordinated chitin synthesis and deposition. On the other hand, azole derivatives had very little effect on the rate of nikkomycin transport into C. albicans cells. A sequential blockade mechanism of synergism is proposed

Netilmicin influences siderophores production and iron receptor expression in Escherichia coli

This study investigated the effect of subinhibitory concentrations of netilmicin on the phenolate (enterochelin), hydroxamate (aerobactin) and total siderophores production and on the 81-kDa and 74-kDa receptors expression in Escherichia coli. Netilmicin at 1/40 MIC reduces total siderophores by 40%; the cathecols by 50% and the hydroxamate by 80%. Concomitant with siderophores reduction, the antibiotic induces the upregulation of the 81-kDa protein receptor. Both effects reduce the ability of the bacterium to survive in the hos