Highly Hydrophilic and Lipophilic Derivatives of Bile Salts.

Lipophilicity of 15 derivatives of sodium cholate, defined by the octan-1-ol/water partition coefficient (log P), has been theoretically determined by the Virtual log P method. These derivatives bear highly hydrophobic or highly hydrophilic substituents at the C3 position of the steroid nucleus, being linked to it through an amide bond. The difference between the maximum value of log P and the minimum one is enlarged to 3.5. The partition coefficient and the critical micelle concentration (cmc) are tightly related by a double-logarithm relationship (VirtuallogP=-(1.00±0.09)log(cmcmM)+(2.79±0.09)), meaning that the Gibbs free energies for the transfer of a bile anion from water to either a micelle or to octan-1-ol differ by a constant. The equation also means that cmc can be used as a measurement of lipophilicity. The demicellization of the aggregates formed by three derivatives of sodium cholate bearing bulky hydrophobic substituents has been studied by surface tension and isothermal titration calorimetry. Aggregation numbers, enthalpies, free energies, entropies, and heat capacities, ΔCP,demic, were obtained. ΔCP,demic, being positive, means that the interior of the aggregates is hydrophobic.

Asian Hornet, Vespa velutina Lepeletier 1836 (Hym.: Vespidae), Venom Obtention Based on an Electric Stimulation Protocol.

The yellow-legged Asian hornet (Vespa velutina Lepeletier 1836 (Hymenoptera: Vespidae)) is naturally distributed in China, Southeast Asia, and India; however, recently it has been detected outside of its native area, confirmed as being established in South Korea, Europe, and Japan. Health risks and deaths caused by the invasive Vespa velutina stings have become a public health concern, being the most common cause of anaphylaxis due to hymenopterans in some European regions. This in turn has led to increased demand from medical practitioners and researchers for Vespa velutina venom for diagnostic and therapeutic purposes. In this study, a straightforward, quick, and inexpensive method for obtaining Vespa velutina venom by electric stimulation is described. The venom extracts were analyzed by nuclear magnetic resonance spectroscopy (1H-NMR). The availability of Vespa velutina venom will lead to improved diagnostic and therapeutic methods, mainly by venom immunotherapy (VIT), in patients allergic to this invasive species.

Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer's disease.

PURPOSE: To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. METHODS: Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer's disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. RESULTS: In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The 'alcoholic beverages' PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. CONCLUSION: In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.

Comparative activity of ozenoxacin and other quinolones in Staphylococcus aureus strains overexpressing the efflux pump-encoding genes mepA and norA.

BACKGROUND: To evaluate the activity of ozenoxacin (OZN) in Staphylococcus aureus strains overexpressing the efflux pump-encoding genes mepA and norA. METHODS: S. aureus NCTC-8325-1, S. aureus NCTC 8225-2 (overexpressing mepA), S. aureus SA 1199 and S. aureus SA 1199B (overexpressing norA) were used. The minimum inhibitory concentrations (MICs) of OZN, moxifloxacin (MOX), levofloxacin (LVX), ciprofloxacin (CIP) and norfloxacin (NOR) in the presence and absence of reserpine (20 mg/L) were determined using the microdilution method. RESULTS: The MIC of OZN was lower in all evaluated strains compared with the other studied quinolones and was independent of the pump being overexpressed. MIC values of OZN ranged from 0.005 to 0.007 mg/L. Similar results were observed with MOX, with MIC values between 0.021 and 0.031 mg/L, without variations in the presence of reserpine. MIC values for LVX were between 0.167 and 1 mg/L with a slight increase in MIC observed in strains overexpressing the mepA or norA genes (from 0.250 to 0.833 mg/L and 0.167 to 1 mg/L, respectively). Overproduction of the efflux pump MepA did not affect CIP whereas it increased 8-fold the MIC of NOR. Overproduction of NorA increased ~5-fold and ~40-fold the MICs of CIP and NOR, respectively, resulting in a high-level of resistance to these antibiotics compared with OZN (0.007 mg/L). CONCLUSION: OZN does not seem to be a substrate for the efflux pumps MepA and NorA, which are commonly found in Gram-positive bacteria and that affect other quinolones.

Extraction and Physicochemical Characterization of Chitin Derived from the Asian Hornet, Vespa velutina Lepeletier 1836 (Hym.: Vespidae).

Fifteen years ago, at least one multimated female yellow-legged Asian hornet (Vespa velutina Lepeletier 1836) arrived in France, which gave rise to a pan-European invasion. In this study, the isolation and characterization of chitin (CHI) that was obtained from Vespa velutina (CHIVV) is described. In addition, an easy procedure is carried out to capture the raw insect, selectively and with high rates of success. The chitin contents of dry VV was observed to be 11.7%. Fourier transform infrared spectroscopy (FTIR), solid-state NMR (ssNMR), elemental analysis (EA), scanning electron microscopy (SEM), and thermogravimetric analysis (TG) characterized the physicochemical properties of CHIVV. The obtained CHIVV is close to pure (43.47% C, 6.94% H, and 6.85% N), and full acetylated with a value of 95.44%. Additionally, lifetime and kinetic parameters such as activation E and the frequency factor A using model-free and model-fitting methods, were determined. For CHIVV the solid state mechanism that follows the thermodegradation is of type F2 (random nucleation around two nuclei). The invasive Asian hornet is a promising alternative source of CHI, based on certain factors, such as the current and probable continued abundance of the quantity and quality of the product obtained.

Epidemiology of Non-Tuberculous Mycobacteria isolated from clinical specimens in Madrid, Spain, from 2013 to 2017.

The epidemiology of non-tuberculous mycobacteria (NTM) in Spain is largely unknown because systematic reporting is not compulsory. The aim of our study was to describe the frequency and diversity of NTM species in our region and their distribution according to the source sample, gender, and age of the patients. We performed a multicenter study of all NTM isolated in 24 public hospitals in Madrid from 2013 to 2017. A total of 6.923 mycobacteria were isolated: 4535 (65.5%) NTM, and 2.388 (34.5%) Mycobacterium tuberculosis complex (MTB). Overall, 61 different NTM species were identified. The most frequently isolated species were Mycobacterium avium complex (47.7%), M. lentiflavum (12.2%), M. gordonae (9.2%), M. fortuitum (8.9%), and M. abscessus (3.9%). Whereas MTB cases were stable during the study period, the number of NTM isolates increased considerably from 930 isolates in 2013 to 1012 in 2017; a sharp increase occurred in the last year. The rise in NTM isolates was mostly due to M. lentiflavum, M. kansasii, and M. abscessus mainly isolated from respiratory specimens in patients older than 60. The increase in isolation rate of NTM in our region is consistent with the increasing rates reported worldwide in the last decades. The rise in NTM isolates was mainly attributed to M. lentiflavum but it also should be noted the increasing of species with high pathogenic potential such as M. kansasii and M. abscessus.

Mutant prevention concentration of ozenoxacin for quinolone-susceptible or -resistant Staphylococcus aureus and Staphylococcus epidermidis.

Ozenoxacin (OZN) belongs to a new generation of non-fluorinated quinolones for the topical treatment of skin infections which has shown to be effective in the treatment of susceptible and resistant Gram-positive cocci. The mutant prevention concentration (MPC) of ozenoxacin, levofloxacin and ciprofloxacin was determined in quinolone-susceptible and -resistant strains including methicillin-susceptible S. aureus, methicillin-resistant S. aureus, methicillin-susceptible S. epidermidis and methicillin-resistant S. epidermidis with different profile of mutation in the quinolone resistance determining regions (QRDR). The MPC value of OZN for the methicillin-susceptible S. aureus strain susceptible to quinolones, without mutations in QRDR, was 0.05 mg/L, being 280-fold lower than that observed with ciprofloxacin and levofloxacin. In methicillin-susceptible and-resistant S. aureus strains with mutations in the gyrA or/and grlA genes the MPC of OZN went from 0.1 to 6 mg/L, whereas the MPC of levofloxacin and ciprofloxacin was > 50 mg/L for the same strains. For methicillin-susceptible and-resistant S. epidermidis the results were similar to those abovementioned for S. aureus. According to our results, the MPC of OZN was far below the quantity of ozenoxacin achieved in the epidermal layer, suggesting that the in vivo selection of mutants, if it occurs, will take place at low frequency. Ozenoxacin is an excellent candidate for the treatment of bacterial infections caused by susceptible and quinolone-resistant staphylococci isolated usually from skin infections.

Analysis of an old controversy: The compensation temperature for micellization of surfactants.

The actual significance of the so-called compensation temperature Tc for micellization of surfactants is reviewed. It is demonstrated that it is possible to obtain as many Tc values as the number of temperature intervals in which the dependencies of enthalpy and entropy changes with temperature are analyzed. The value of each Tc will be the central value To of each temperature interval. These two facts suggest that Tc is simply such experimental To. Thus any physical interpretation derived from Tc is unfounded.

Microwave-Assisted Facile Synthesis, Anticancer Evaluation and Docking Study of N-((5-(Substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl) Benzamide Derivatives.

In the present work, 12 novel Schiff's bases containing a thiadiazole scaffold and benzamide groups coupled through appropriate pharmacophore were synthesized. These moieties are associated with important biological properties. A facile, solvent-free synthesis of a series of novel 7(a-l) N-((5-(substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl) benzamide was carried out under microwave irradiation. Structures of the synthesized compounds were confirmed by IR, NMR, mass spectral study and elemental analysis. All the synthesized hybrids were evaluated for their in vitro anticancer activity against a panel of four human cancer cell lines, viz. SK-MEL-2 (melanoma), HL-60 (leukemia), HeLa (cervical cancer), MCF-7 (breast cancer) and normal breast epithelial cell (MCF-10A) using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. Most of the synthesized compounds exhibited promising anticancer activity, showed comparable GI50 values comparable to that of the standard drug Adriamycin. The compounds 7k, 7l, 7b, and 7a were found to be the most promising anticancer agents in this study. A molecular docking study was performed to predict the probable mechanism of action and computational study of the synthesized compounds 7(a-l) was performed to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, by using QikProp v3.5 (Schrödinger LLC). The results showed the good oral drug-like behavior of the synthesized compounds 7(a-l).

Ultrasound Mediated One-Pot, Three Component Synthesis, Docking and ADME Prediction of Novel 5-Amino-2-(4-chlorophenyl)-7-Substituted Phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile Derivatives as Anticancer Agents.

Herein, we report an environmentally friendly, rapid, and convenient one-pot ultrasound-promoted synthesis of 5-amino-2-(4-chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile derivatives. The in-vitro anticancer activities of these compounds were evaluated against four human tumor cell lines. Among all the synthesized derivatives, compound 4i, which has substituent 3-hydroxy-4-methoxyphenyl is found to have the highest GI50 value of 32.7 µM, 55.3 µM, 34.3 µM, 28.9 µM for MCF-7, K562, HeLa and PC-3 cancer cell lines respectively. A docking study of the newly synthesized compounds were performed, and the results showed good binding mode in the active site of thymidylate synthase enzyme. ADME properties of synthesized compounds were also studied and showed good drug like properties.

Multisite Evaluation of Cepheid Xpert Carba-R Assay for Detection of Carbapenemase-Producing Organisms in Rectal Swabs.

Rapid identification of patients who are colonized with carbapenemase-producing organisms (CPO) is included in multiple national guidelines for containment of these organisms. In a multisite study, we evaluated the performance of the Cepheid Xpert Carba-R assay, a qualitative diagnostic test that was designed for the rapid detection and differentiation of the blaKPC, blaNDM, blaVIM, blaOXA-48, and blaIMP-1 genes from rectal swab specimens. A double rectal swab set was collected from 383 patients admitted at four institutions (2 in the United States, 1 in the United Kingdom, 1 in Spain). One swab was used for reference culture (MacConkey broth containing 1 mg/liter of meropenem and subcultured to a MacConkey agar plate with a 10-µg meropenem disk) and for sequencing of DNA obtained from carbapenem-nonsusceptible isolates for carbapenemase identification. The other swab was used for the Xpert Carba-R assay. In addition to the clinical rectal swabs, 250 contrived specimens (108 well-characterized CPO and 142 negative controls spiked onto negative rectal swabs) were tested. Overall, 149/633 (23.5%) samples were positive by the Xpert Carba-R assay. In 6 samples, multiple targets were detected (4 VIM/OXA-48, 1 IMP-1/NDM, and 1 NDM/KPC). The Xpert Carba-R assay detected 155 targets (26 IMP-1, 30 VIM, 27 NDM, 33 KPC, 39 OXA-48) within a time range of 32 to 48 min. The sensitivity, specificity, and positive and negative predictive values of the Xpert Carba-R assay compared to those of the reference culture and sequencing results were 96.6% (95% confidence interval [CI], 92.2% to 98.9%), 98.6% (95% CI, 97.1% to 99.4%), 95.3%, and 99.0%, respectively. The Cepheid Xpert Carba-R assay is an accurate and rapid test to identify rectal colonization with CPO, which can guide infection control programs to limit the spread of these organisms.

In vitro selection of mutants resistant to ozenoxacin compared with levofloxacin and ciprofloxacin in Gram-positive cocci.

OBJECTIVES: To determine the frequency of selecting mutants resistant to ozenoxacin, a des-fluoro-(6)-quinolone active against pathogens involved in skin and skin structure infections, compared with levofloxacin and ciprofloxacin in quinolone-susceptible and -resistant Gram-positive cocci. METHODS: Forty-nine quinolone-susceptible and -resistant Gram-positive cocci strains with different profiles of mutations in the quinolone resistance-determining region (QRDR) were examined to determine the frequency of selecting mutants resistant to ozenoxacin compared with levofloxacin and ciprofloxacin. MICs and mutations in the QRDR were determined by standard broth microdilution and PCR amplification and sequencing, respectively. RESULTS: The mean resistance rates were 3.8 × 10(-9) (range <9 × 10(-11)-1 × 10(-8)) for ozenoxacin, 9.7 × 10(-9) (range <1.1 × 10(-11)-4.2 × 10(-8)) for levofloxacin and 1.2 × 10(-8) (range <1.6 × 10(-10)-2.6 × 10(-7)) for ciprofloxacin. Spontaneous mutants resistant to ozenoxacin showed lower MICs (≤ 16 mg/L) than mutants resistant to levofloxacin and ciprofloxacin (≤ 512 mg/L). Additional mutations were observed only in ParC at Ser-80 in Staphylococcus spp., Ser-79 in Streptococcus agalactiae and Asp-83 and Ser-89 in Streptococcus pyogenes. CONCLUSIONS: The probability of ozenoxacin selecting spontaneous resistant mutants in quinolone-susceptible and -resistant strains with pre-existing mutations in the QRDR is low, supporting the potential utility of ozenoxacin as a therapeutic alternative in the treatment of skin infections caused by strains highly resistant to quinolones.

Novel microwave-assisted synthesis of the immunomodulator organotellurium compound ammonium trichloro(dioxoethylene-O,O')tellurate (AS101).

Ammonium trichloro[1,2-ethanediolato-O,O']-tellurate (AS101) is the most important synthetic Te compound from the standpoint of its biological activity. It is a potent immunomodulator with a variety of potential therapeutic applications and antitumoral action in several preclinical and clinical studies. An experimental design has been used to develop and optimize a novel microwave-assisted synthesis (MAOS) of the AS101. In comparison to the results observed in the literature, refluxing Te(IV) chloride and ethylene glycol in acetonitrile (Method A), or by refluxing Te(IV) chloride and ammonium chloride in ethylene glycol (Method B), it was found that the developed methods in the present work are an effective alternative, because although performance slightly decreases compared to conventional procedures (75% vs. 79% by Method A, and 45% vs. 51% by Method B), reaction times decreased from 4 h to 30 min and from 4 h to 10 min, by Methods A and B respectively. MAOS is proving to be of value in the rapid synthesis of compounds with new and improved biological activities, specially based on the benefit of its shorter reaction times.

In vitro activity of Ozenoxacin against quinolone-susceptible and quinolone-resistant gram-positive bacteria.

In vitro activity of ozenoxacin, a novel nonfluorinated topical (L. D. Saravolatz and J. Leggett, Clin. Infect. Dis. 37:1210-1215, 2003) quinolone, was compared with the activities of other quinolones against well-characterized quinolone-susceptible and quinolone-resistant Gram-positive bacteria. Ozenoxacin was 3-fold to 321-fold more active than other quinolones. Ozenoxacin could represent a first-in-class nonfluorinated quinolone for the topical treatment of a broad range of dermatological infections.

Comprehensive study of honey with protected denomination of origin and contribution to the enhancement of legal specifications.

In this study the characterization of a total of 60 honey samples with Protected Denomination of Origin (PDO) collected over three harvests (2009-2011, inclusive), from the Northeast of Portugal was carried out based on the presence of pollen, physicochemical and microbiological characteristics. All samples were found to meet the European Legislation, but some didn't meet the requirements of the PDO specifications. Concerning the floral origin of honey, our results showed the prevalence of rosemary (Lavandula pedunculata) pollen. The microbiological quality of all the analyzed samples was satisfactory, since fecal coliforms, sulfite-reducing clostridia and Salmonella were absent, and molds and yeasts were detected in low counts. Significant differences between the results were studied using one-way analysis of variance (ANOVA), followed by Tukey's HSD test. The samples were submitted to discriminant function analysis, in order to determine which variables differentiate between two or more naturally occurring groups (Forward Stepwise Analysis). The variables selected were in this order: diastase activity, pH, reducing sugars, free acidity and HMF. The pollen spectrum has perfect discriminatory power. This is the first study in which a honey with PDO was tested, in order to assess its compliance with the PDO book of specifications.

Organic bee pollen: botanical origin, nutritional value, bioactive compounds, antioxidant activity and microbiological quality.

Organic bee pollen (BP, n = 22) harvested from the Douro International Natural Park (DINP, Portugal) was studied. Nine botanical families were found in the mixture of the samples. The water activity and pH ranged 0.21-0.37 and 4.3-5.2, respectively. The BP analyses averaged 67.7% carbohydrates, 21.8% crude protein, 5.2% crude fat and 2.9% ash. The energy ranged from 396.4 to 411.1 kcal/100 g. The principal fatty acid found was linolenic, followed by linoleic acid, palmitic acid and oleic acid. The phenolic and flavonoid contents varied from 12.9 to 19.8 mg of gallic acid equivalents/g of extract and from 4.5 to 7.1 mg of catechin equivalents/g of extract, respectively. The scavenger activity and ß-carotene bleaching assays values (EC50) were 3.0 ± 0.7 mg/mL and 4.6 mg/mL ± 0.9 mg/mL, respectively. E. coli, sulphite-reducing Clostridia, Salmonella and S. aureus were not found. Since there are studies indicating appreciable differences among BPs from different regions, the full characterization of BP from diverse origins still appears to be a sound research priority in order to obtain reliable data about this beehive product.

¹H-nuclear magnetic resonance analysis of the triacylglyceride composition of cold-pressed oil from Camellia japonica.

Camellia japonica (CJ) has oil-rich seeds, but the study of these oils has received little attention and has mainly focused only on their health properties. In the present work the relative composition of the fatty acid (FA) components of the triglycerides in cold-pressed oil from CJ is studied by ¹H-NMR. The results obtained were: 75.75%, 6.0%, 0.17% and 18.67%, for oleic, linoleic, linolenic and saturated FA respectively. Levels of C18 unsaturated FA found in CJ oil were similar to those reported for olive oils. We also checked the possibility of using ¹³C-NMR spectroscopy; however, the results confirmed the drawback of ¹³C over ¹H-NMR for the study of FA components of CJ triglycerides due to its low gyromagnetic ratio and its very low natural abundance.

Organic honey from Trás-Os-Montes region (Portugal): chemical, palynological, microbiological and bioactive compounds characterization.

At the present time, the quality, integrity, sanitation and nutritional value of honeys receive attention on an international level due to the increasing content of chemicals in the aforementioned matrix. This work was conducted to evaluate the quality of 75 organic honey samples from the Trás-Os-Montes region (Portugal). Mean values obtained for physico-chemical parameters were: pH 3.7; 15.6% moisture; 0.26mS/cm electrical conductivity; 0.25% ash; 1.1mg/kg HMF; 15.3 Gothe diastase activity; 40.3meq/kg free acidity; 67.8% invert sugars and 2.7% apparent sucrose. All honey samples can be classified as monofloral Erica sp., as showed by pollen features. The amounts of phenols and flavonoids in the samples were also determined. In respect to sanitary quality (fecal coliforms) and safety (sulfite-reducing clostridia and Salmonella), all organic honey samples were negative. Furthermore, yeast and molds were detected in low counts, with mean values obtained of 5.5cfu/g and the value of total aerobic mesophiles obtained from honeys was established in 1.3×10(2)cfu/g±7.5×10(1)cfu/g. The levels of flavonoids had a stronger impact on both mesophiles (p=0.0004) and molds (p=0.0138) than the sucrose concentration (p=0.001 and 0.0278; respectively). The results reported in this study should be introduced in the organic honey label, and may help beekeepers, the industry, researchers and consumers better understand honey properties.

Carbapenem Heteroresistance in VIM-1-producing Klebsiella pneumoniae isolates belonging to the same clone: consequences for routine susceptibility testing.

Susceptibility results with low reproducibility by the same or different methods have been observed for metallo-beta-lactamase (MBL)-producing Enterobacteriaceae. Eighteen VIM-1-producing Klebsiella pneumoniae isolates (one per patient) belonging to a single epidemic clone in our hospital (2005 to 2008) but with different susceptibilities to carbapenems were studied. Imipenem MICs ranged from 8 to >128 mg/liter by standard CLSI microdilution, from ≤1 to >8 mg/liter by the semiautomatic Wider system, and from 0.75 to >32 mg/liter by Etest. Meropenem MICs ranged from 0.5 to 128, ≤1 to >8, and 0.38 to >32 mg/liter, respectively. Ertapenem MICs by CLSI microdilution and Etest ranged from 1 to 64 and 0.75 to >32 mg/liter, respectively. The rates of essential agreement (±1 log(2) dilution) for imipenem and meropenem MICs between the Wider system and the reference microdilution method were 45% and 49%, respectively. Those between Etest and the reference microdilution method for imipenem, meropenem, and ertapenem MICs were 33%, 67%, and 84%. The rates of very major errors for the Wider system and Etest were 33% and 28% for imipenem and 25% and 75% for meropenem, respectively. Low MIC reproducibility was observed even when the same inoculum was used (differences up to 4-fold dilutions). Heteroresistance was suspected due to the presence of colonies in the Etest inhibition zone. It was confirmed by population analysis profiles of 4 isolates displaying different imipenem MICs, with the exception of an OmpK36-porin-deficient isolate that homogeneously expressed carbapenem resistance (MIC, >128 mg/liter). Low carbapenem MIC reproducibility could be due to the presence of resistant subpopulations and variable expression of the resistance mechanisms. Since carbapenem MICs are not good markers of MBL production, reliable and reproducible phenotypic methods are needed to detect the presence of this mechanism.

Genetic association of CASP8 polymorphisms with primary progressive multiple sclerosis.

We investigated caspase 8 (CASP8) as a candidate gene for multiple sclerosis (MS) susceptibility. Three SNPs (rs2037815, rs12990906 and rs1035140) were genotyped in 546 MS patients and 547 controls. For SNP rs2037815, GG homozygosity was associated with primary progressive multiple sclerosis (PPMS) when compared with relapse-onset MS and controls. We identified risk (GCA) and protective (ACT) haplotypes associated with PPMS when compared with relapse-onset MS and controls. GG homozygosity for SNP rs2037815 in PPMS patients was associated with a trend towards faster disease progression. These findings point to a role of CASP8 polymorphisms in the MS genetic risk in PPMS patients.