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The molecular and evolutionary processes underlying fungal domestication remain largely unknown despite the importance of fungi to bioindustry and for comparative adaptation genomics in eukaryotes. Wine fermentation and biological ageing are performed by strains of S. cerevisiae with, respectively, pelagic fermentative growth on glucose and biofilm aerobic growth utilizing ethanol. Here, we use environmental samples of wine and flor yeasts to investigate the genomic basis of yeast adaptation to contrasted anthropogenic environments. Phylogenetic inference and population structure analysis based on single nucleotide polymorphisms revealed a group of flor yeasts separated from wine yeasts. A combination of methods revealed several highly differentiated regions between wine and flor yeasts, and analyses using codon-substitution models for detecting molecular adaptation identified sites under positive selection in the high-affinity transporter gene ZRT1. The cross-population composite likelihood ratio revealed selective sweeps at three regions, including in the hexose transporter gene HXT7, the yapsin gene YPS6 and the membrane protein coding gene MTS27. Our analyses also revealed that the biological ageing environment has led to the accumulation of numerous mutations in proteins from several networks, including Flo11 regulation and divalent metal transport. Together, our findings suggest that the tuning of FLO11 expression and zinc transport networks are a distinctive feature of the genetic changes underlying the domestication of flor yeasts. Our study highlights the multiplicity of genomic changes underlying yeast adaptation to man-made habitats and reveals that flor/wine yeast lineage can serve as a useful model for studying the genomics of adaptive divergence. [ABSTRACT FROM AUTHOR]

Background and Purpose Solid lipid nanoparticles containing cholesteryl butyrate (cholbut SLN) can be a delivery system for the anti-cancer drug butyrate. These nanoparticles inhibit adhesion of polymorphonuclear and tumour cells to endothelial cells and migration of tumour cells, suggesting that they may act as anti-inflammatory and anti-tumour agents. Here we have evaluated the effects of cholbut SLN on tumour cell growth using in vitro and in vivo models. Experimental Approach Cholbut SLNs were incubated with cultures of four tumour cell lines, and cell growth was analysed by assessing viability, clonogenic capacity and cell cycle. Effects on intracellular signalling was assessed by Western blot analysis of Akt expression. The in vivo anti-tumour activity was measured in two models of PC-3 cell xenografts in SCID/Beige mice. Key Results Cholbut SLN inhibited tumour cell line viability, clonogenic activity, Akt phosphorylation and cell cycle progression. In mice injected i.v. with PC3- Luc cells and treated with cholbut SLN, . in vivo optical imaging and histological analysis showed no metastases in the lungs of the treated mice. In another set of mice injected s.c. with PC-3 cells and treated with cholbut SLN when the tumour diameter reached 2 mm, analysis of the tumour dimensions showed that treatment with cholbut SLN substantially delayed tumour growth. Conclusion and Implications Cholbut SLN were effective in inhibiting tumour growth in vitro and in vivo. These effects may involve, in part, inhibition of Akt phosphorylation, which adds another mechanism to the activity of this multipotent drug. [ABSTRACT FROM AUTHOR]

Background Thiopurines are increasingly used in the treatment of inflammatory bowel disease (IBD), being the most common immunosuppressive therapy; however, potentially harmful interactions between thiopurines and other drugs (especially 5-aminosalicylic acid, 5-ASA) were described. Aim To explore potential interactions between thiopurines and concomitant medications. Methods A total of 183 consecutive IBD patients were enrolled. Clinical characteristics and concomitant medications were recorded. Thiopurine metabolism was analysed with thiopurine S-methyl transferase (TPMT) genetic variants and enzyme activity assays. Comparisons were carried out with stratification of patients according to clinical characteristics and active treatments. Results Based on TPMT genetics, 95% IBD patients were wild-type homozygous, the remaining being heterozygous. Median TPMT activity was 24.9 U/Hgb g (IQR 20.7–29.5). No difference in TPMT activity was noted according to 5-ASA exposure. IBD patients on thiopurines had higher TPMT activity levels, but no dose-effect was evident. No difference in TPMT activity was observed in 41 (63%) patients co-treated with 5-ASA. In patients on active thiopurines also, 6-TGN and 6-MMP levels were evaluated and no significant difference was observed based on co-medication. TPMT activity was independently associated only with thiopurines dose ( P = 0.016). Conclusions Our data suggest the absence of significant interactions between thiopurines and 5-ASA. [ABSTRACT FROM AUTHOR]

Antibodies to gangliosides and Purkinje cells have been reported in patients with celiac disease (CD) with neuropathy and ataxia, respectively. Whether these antibodies are pathogenic is not clear. The response of neurological symptoms and antibody titers to a gluten-free diet is still controversial. The objective of our study was to assess whether neurological manifestations in CD patients correlate with antibody titers and a gluten-free diet.Thirty-five CD patients (9 males, 26 females, mean age 37.1 ± 12.6 yrs) were followed prospectively. At initial evaluation, 23 were on a gluten-free diet, 12 were not. At recruitment and during follow-up, patients underwent neurological and electrophysiological evaluation. IgG, IgM, and IgA anti-ganglioside antibodies were assayed by ELISA; anti-neuronal antibodies were assessed by immunohistochemistry and Western blot. Four patients, all males, had electrophysiological evidence of neuropathy; three had been on a gluten-free diet for several months, and one was newly diagnosed. One had reduced tendon reflexes; another complained of distal paresthesias. With regard to anti-ganglioside antibodies, three patients had a moderate increase in antibodies without symptoms or signs of neuropathy. No patients had ataxia or cerebellar dysfunction, although in four patients reactivity to neuronal antigens was found. In 17 patients, an electrophysiological follow-up (mean duration of follow-up, 9 months) showed no changes. In conclusion, the preliminary results of this prospective study indicate that neuropathy, usually subclinical, may accompany CD. Antibody titers do not seem to correlate with neurological symptoms/signs or diet. Ongoing follow-up will help confirm these data and clarify the role, if any, of antibodies in neurological involvement in CD. [ABSTRACT FROM AUTHOR]

Summary: Glutaric aciduria type I is an inborn error of metabolism due to the deficiency of glutaryl-CoA dehydrogenase, an enzyme responsible for the catabolism of lysine, hydroxylysine and tryptophan. The most important neurological symptoms include dyskinesia and dystonia, which can be focal, segmental or generalized. Treatment of the extrapyramidal syndrome is often unsatisfactory. We report our experience in the treatment of generalized and focal dystonia with anticholinergic drugs and botulinum toxin type A, respectively. Both therapies proved beneficial. [ABSTRACT FROM AUTHOR]

: Emerging evidence points to humoural mechanisms in neurological complications of coeliac disease. Immunoglobulin G anti-ganglioside antibodies have been reported in coeliac disease patients with neuropathy, suggesting an immune response to peripheral nerve antigens. No data are so far available on anti-ganglioside antibodies in coeliac disease children or on antibody modifications after gluten-free diet. : To evaluate the presence of antibodies to ganglioside antigens in children with coeliac disease, their modification after gluten-free diet, and possible correlations with neurological manifestations. : Sera from 42 coeliac disease children, before and after gluten-free diet, were tested by enzyme-linked immunosorbent assay for the presence of antibodies (immunoglobulin M, immunoglobulin A, immunoglobulin G) to gangliosides. Thirty-five sera of age-matched children with dyspepsia were used as control. : High anti-ganglioside antibodies titres were present in two patients. In one patient, antibody titre reversed after gluten-free diet, whereas in the other one the titre increased after diet. Neither one complained of neurological symptoms. : Anti-ganglioside antibodies do not seem to correlate with gluten ingestion or with neurological manifestations in children with coeliac disease. Mechanisms different from gluten exposure may be implicated in the antibody production. An ongoing prospective study will help clarify the role, if any, of these antibodies in coeliac disease. [ABSTRACT FROM AUTHOR]

Objective: To assess whether pegylated interferons (PEG-IFNs) treatment is associated with occurrence, worsening or improvement of peripheral neuropathy in HCV patients. Background: Alpha-IFN is associated with central nervous system side effects. There are reports of both improvement and worsening of neuropathy during alpha-IFN treatment, but the possible alpha-IFN peripheral neurotoxicity has never been consistently investigated. Patients and Methods: Twenty-six HCV patients (19 male, 7 females, median age 41.5 ± 9.6 years) have been treated with PEG-IFNs (alpha-2a 180 mcg weekly or alpha-2b 1.5 mcg, weekly) and ribavirin for 6–12 months. Eleven patients had neuropathy at recruitment (two diabetic, nine HCV-related neuropathy, one with cryoglobulins). Before therapy (T0) all patients underwent quantitative viral RNA determination, HCV genotype analysis, liver biopsy, neurological and electrophysiological evaluation. Response amplitude and conduction velocities of median, ulnar, sural, and peroneal nerves were recorded. During therapy (T1)(mean follow-up 7,8 ± 4.0 months), patients were neurologically and electrophysiologically re-evaluated. Eighteen HCV patients (11 males, 7 females, median age 47.4 ± 9.6) with comparable viral load, not in IFN treatment, were studied as controls. Results: During PEG-IFNs therapy, no significant differences of all electrophysiological parameters were detected between T0 and T1 evaluations (repeated measures ANOVA) in all 44 treated and non-treated patients, also in those with neuropathy at recruitment. No correlations were found between electrophysiological parameters and length of therapy (Spearman's Rho). Conclusions: Peripheral neuropathy seems not to complicate PEG-IFNs therapy in HCV patients. An ongoing follow-up study on a larger group of patients will help confirm these results. [ABSTRACT FROM AUTHOR]

Chemotherapy has been used for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with incosistent results. Chemotheraphy has been used for treating with inconsistent results. Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen, used to treat B-cell lymphoma and reported to be effective in some neuropathies with IgM autoreactivity. We saw a 72-year-old man with CIDP refractory to steroids, plasma exchange, IV Ig, and cyclosporin. He was unable to walk; severe impairment was present also at the upper limbs. Electrodiagnostic studies revealed slowing of motor and sensory conduction velocities, and prolonged distal motor latencies. Immunoelectrophoresis evidence an IgM/k monoclonal gammopathy. Antibodies to Myelin Associated Glycoprotein (MAG) and other peripheral nerve antigens were negative. Bone marrow biopsy documented a small lymphocytic B-cell lymphoma (CD20+). Treated with Rituximab (375 mg/m2 for 4 weeks), the patient presented at follow-up evaluations (3, 6 and 8 months later) a progressive improvement. Eventually, he was able to walk, and regained full strength at upper limbs. Consistently, electrophysiological studies improved. We suggest considering treatment with Rituximab in CIDP resistant to conventional therapy, at least in cases associated with IgM lymphoproliferative diseases. [ABSTRACT FROM AUTHOR]

Despite long-lasting use, several features of thalidomide neurotoxicity have yet to be resolved. A more detailed knowledge of thalidomide-induced sensory neurotoxicity is desirable, particularly in view of the future use of thalidomide derivatives which are currently under investigation. Our study demonstrates that thalidomide sensory neurotoxicity is cumulative dose-dependent, but this effect is evident only when the dose is relatively high (in our study >20 g). In fact, the risk of developing sensory neuropathy is low (around 10%) below this threshold, while it steadily increases with increasing cumulative doses. In our series, a discrepancy between clinical and neurophysiological results was frequent when a low cumulative dose of thalidomide was administered. Regarding the need for thalidomide withdrawal at the onset of any evidence of peripheral neuropathy, we followed up the course of seven patients who were clinically and neurophysiologically normal at baseline, but had treatment-induced neurotoxicity and a very severe change in their SAPs. In all these cases the thalidomide dose was reduced and no clinically-relevant worsening was observed despite a further marked reduction in their SAPs. This finding suggests that thalidomide withdrawal is not mandatory even in the presence of marked abnormalities in sensory neurophysiological parameters, provided that an accurate clinical follow-up is guaranteed and the dose is adjusted. [ABSTRACT FROM AUTHOR]

Aims: Platinum chemotherapy has been shown to have potent antineoplastic activity against various tumours, especially testicular, bladder, ovarian, head and neck cancers. This activity is accompanied by side-effects of nephrotoxicity and cumulative myelosuppression, the latter frequently presenting as severe anaemia. Cisplatin and carboplatin nephrotoxicity might lower erythropoietin (Epo) secretion and, by this mechanism, contribute to the anaemia that follows therapy with this chemotherapeutic agent. The aim of the present work is to study the plasma immunoerythropoietin and haemoglobin levels of cancer patients treated with platinum or 5-fluorouracil-based chemotherapy., Methods: Plasma was obtained from 25 patients who were about to receive chemotherapy for advanced malignancy: 15 treated with cisplatin or carboplatin and 10 with nonplatinum drugs. Blood was collected on the first day (before drug administration) and around day 15 of every chemotherapy course. Complete blood count, creatinine and immunoreactive Epo levels were also measured in 22 healthy volunteers., Results: An increase in Epo levels occurred following every course of 5-FU or platinum based chemotherapy in patients with steady concentrations of creatinine and decreased levels of haemoglobin (Hb). In particular, we observed an increase after about 15 days of the chemotherapy treatment and the Epo levels declined toward normal just before the following course. This phenomenon was evident in every course., Conclusions: Our results suggest that chemotherapy administration, using the current standards of hydration and forced diuresis, slightly lowered Hb levels but did not depress Epo production, both in 5-FU and in platinum treated subjects.