Protective effects of melatonin on changes occurring in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

BACKGROUND: Melatonin has been related to the pathophysiology of multiple sclerosis (MS), and its anti-inflammatory and immunomodulatory properties have been proved in numerous neurodegenerative diseases. This study aimed to find out whether a melatonin supplement in MS is able to act as a benefit to its clinical status, i.e. oxidative stress, inflammation and indirect biomarkers of bacterial dysbiosis, lipopolysaccharide (LPS) and LPS-binding protein (LBP), verifying its therapeutic potential and its possible clinical use in patients with MS. METHODS: The animal MS model, experimental autoimmune encephalomyelitis (EAE), was employed whereby 25 male Dark Agouti rats (5 animals per group) were divided into: a control group (not manipulated); a control+vehicle group; a control+melatonin group; an EAE group; an EAE+melatonin group. Melatonin was administered daily for 51 days, at a dose of 1 mg/kg body weight/i.p., once a day, five days a week. RESULTS: The results from the administration of melatonin demonstrated an improvement in clinical status, a diminution in oxidative stress and inflammation, as well as in bacterial dysbiosis. CONCLUSION: Melatonin could play an effective role against MS, either alone or as a therapy combined with traditional agents.

NFL during acute spinal cord lesions in MS: a hurdle for the detection of inflammatory activity.

INTRODUCTION: Levels of neuro-filament light chain (NFL) correlate with clinical and radiological activity in multiple sclerosis (MS) and have been used as a surrogate biomarker of axonal destruction related to inflammatory activity. The main objective of this work is to explore the specific contribution of acute inflammation within the spinal cord to the elevation of NFL levels. PATIENTS AND METHODS: MS patients with a baseline study of NFL at diagnosis of the disease and a brain and spinal cord MRI scan were selected. Patients were classified according to the presence, number and location of gadolinium enhancing lesion (GEL) and the relationship between NFL levels and both brain and spinal cord GEL were explored. RESULTS: Seventy-seven patients were selected. NFL levels were significantly higher in patients with only one GEL restricted to the brain than those without GEL (1702 pg/ml vs 722.7 pg/mL, p = 0.03) and correlated with number. However, no differences were seen among patients with GEL limited to the spinal cord and those without GEL (735.2 pg/ml vs 722.7 pg/mL). CONCLUSION: Our study reaffirms the value of NFL levels in monitoring asymptomatic inflammatory activity in the brain measured by GEL. However, NFL concentration is not as useful when only inflammatory activity occurs in the spinal cord.

Straightforward estimation of the elastic constants of an isotropic cube excited by a single percussion.

Ritz's method is applied to calculate accurate values of the lowest non-dimensional natural frequencies of a freely vibrating isotropic cube. The dependence of such frequencies and their quotients on Poisson's ratio is established. Vibration of a cube caused by percussion is detected at a point by a laser interferometer. With the help of the tables and graphs provided and with the values of the first lowest frequencies obtained experimentally in a single test, Poisson's ratio and the shear modulus are calculated by means of elementary arithmetical operations.

Optimization of the magnetic field homogeneity of circular and conical coil pairs.

The magnetic field generated by a pair of coaxial circular loops is analyzed in order to find the optimum separation between the loops for each value of a prescribed homogeneity. For the maximum heterogeneities considered here, 0.1%, 1%, and 10%, the optimum loop spacing is obtained following a graphical procedure so that the length of the homogeneous field region along the axis is the longest possible. This study is extended to regions near the axis and to the entire region surrounding the center, calculating the loop separation that produces the largest homogeneous volume. The field homogeneity of a pair of "Helmholtz" coaxial conical coils is also investigated to obtain the optimum spacing between the conical coils; the volumes calculated with the desired homogeneity are compared with those obtained with a single pair of optimum coaxial loops. A new arrangement is hereby proposed based on double conical coils with optimum separation between the coils and optimum aperture of the cones. Some of the proposed arrangements are carried out in the laboratory where the experimental results are in good agreement with the theoretical predictions.

Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing-remitting multiple sclerosis is effective and safe.

BACKGROUND: It has been described that treating relapsing-remitting multiple sclerosis (RRMS) patients with alemtuzumab following fingolimod could be less effective due to the different dynamics of lymphocyte repopulation. Effectiveness and safety of alemtuzumab compared to rituximab after fingolimod withdrawal were analyzed. PATIENTS AND METHODS: A follow-up of a cohort of RRMS patients treated with alemtuzumab or rituximab after fingolimod withdrawal was accomplished. Effectiveness, measured by the percentage of patients with no evidence of disease activity (NEDA), and the presence of side effects (SE) were registered. RESULTS: Fifty-five patients, 28 with alemtuzumab and 27 with rituximab, were analyzed. No differences in the washout period or in the baseline lymphocytes counts were observed. After a mean follow-up period of 28.8 months, the annualized relapsing rate was significantly reduced in the alemtuzumab group from 1.29 to 0.004 (p < 0.001) and in the rituximab group from 1.24 to 0.02 (p < 0.001), without differences. A significant reduction of the median EDSS from 2.8 to 2.0 in the alemtuzumab group and from 3.5 to 2.5 (p < 0.01) in the rituximab group was observed, without differences. Eighty-two per cent (n = 28) of patients in alemtuzumab group and 69.2% (n = 26) in rituximab group achieved NEDA criteria, without differences (p = 0.3). Symptoms related to the infusion were the most frequent SE in both groups. No serious SE were registered. CONCLUSION: Treating RRMS patients with alemtuzumab or rituximab after fingolimod withdrawal is effective and safe, without significant differences between both groups in our series.

Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study.

INTRODUCTION: Rituximab is considered as a potential therapeutic option in relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in MS. PATIENTS AND METHODS: Observational study of effectiveness (clinical and radiological) and safety of rituximab in RRMS and PMS. RESULTS: A total of 90 rituximab-treated patients were collected: 31 RRMS and 59 PMS All patients had an active disease despite standard treatment. The annualized relapse rate (ARR) the year before rituximab was 0.86, 53.3% of patients had gadolinium enhanced lesion, and mean Expanded Disability Status Scale (EDSS) had increased from 4.2 to 4.9. During treatment, the ARR was reduced an 88.4% (p < 0.001). A significant decrease of EDSS to 4.6 was observed (p = 0.01) after 1 year of treatment, which remained stable during the second year in both groups. There was no evidence of disease activity in 70% of total sample, 74.2% of RRMS, and 67% of the PMS patients. Infusion-related symptoms were the most prevalent side effect (18.8%) and most were mild. Three thrombotic events were detected. CONCLUSION: Rituximab could be an effective and safe treatment in aggressive RRMS. Some selected PMS patients could also benefit from this treatment.

Magnetic field homogeneity of a conical coaxial coil pair.

An analytical study of the magnetic field created by a double-conical conducting sheet is presented. The analysis is based on the expansion of the magnetic field in terms of Legendre polynomials. It is demonstrated analytically that the angle of the conical surface that produces a nearly homogeneous magnetic field coincides with that of a pair of loops that fulfills the Helmholtz condition. From the results obtained, we propose an electric circuit formed by pairs of isolated conducting loops tightly wound around a pair of conical surfaces, calculating numerically the magnetic field produced by this system and its heterogeneity. An experimental setup of the proposed circuit was constructed and its magnetic field was measured. The results were compared with those obtained by numerical calculation, finding a good agreement. The numerical results demonstrate a significant improvement in homogeneity in the field of the proposed pair of conical coils compared with that achieved with a simple pair of Helmholtz loops or with a double solenoid. Moreover, a new design of a double pair of conical coils based on Braunbek's four loops is also proposed to achieve greater homogeneity. Regarding homogeneity, the rating of the analyzed configurations from best to worst is as follows: (1) double pair of conical coils, (2) pair of conical coils, (3) Braunbek's four loops, (4) Helmholtz pair, and (5) solenoid pair.

Pomegranate juice supplementation in chronic obstructive pulmonary disease: a 5-week randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The aim of the present study is to investigate the effect of antioxidant polyphenol-rich pomegranate juice (PJ) supplementation for 5 weeks on patients with stable chronic obstructive pulmonary disease (COPD), since the oxidative stress plays a major role in the evolution and pathophysiology of COPD. DESIGN: A randomized, double-blind, placebo-controlled trial was conducted. SUBJECTS: A total of 30 patients with stable COPD were randomly distributed in two groups (15 patients each). INTERVENTIONS: Both groups consumed either 400 ml PJ daily or matched placebo (synthetic orange-flavoured drink) for 5 weeks. Trolox Equivalent Antioxidant Capacity (TEAC) of PJ, blood parameters (14 haematological and 18 serobiochemical), respiratory function variables, bioavailability of PJ polyphenols (plasma and urine) and urinary isoprostane (8-iso-PGF(2alpha)) were evaluated. RESULTS: The daily dose of PJ (containing 2.66 g polyphenols) provided 4 mmol/l TEAC. None of the polyphenols present in PJ were detected in plasma or in urine of volunteers. The most abundant PJ polyphenols, ellagitannins, were metabolized by the colonic microflora of COPD patients to yield two major metabolites in both plasma and urine (dibenzopyranone derivatives) with no TEAC. No differences were found (P > 0.05) between PJ and placebo groups for any of the parameters evaluated (serobiochemical and haematological), urinary 8-iso-PGF(2alpha), respiratory function variables and clinical symptoms of COPD patients. CONCLUSIONS: Our results suggest that PJ supplementation adds no benefit to the current standard therapy in patients with stable COPD. The high TEAC of PJ cannot be extrapolated in vivo probably due to the metabolism of its polyphenols by the colonic microflora. The understanding of the different bioavailability of dietary polyphenols is critical before claiming any antioxidant-related health benefit. SPONSORSHIP: 'Fundación Séneca' (Murcia, Spain), Project PB/18/FS/02 and Spanish CICYT, Project AGL2003-02195.

[Tuberculosis in the area of Lorca: to adapt or resist]. / Tuberculosis en la comarca de Lorca: adaptarse o resistir.

OBJECTIVE: We studied the epidemiological characteristic of tuberculosis in Lorca area, drug resistant and the effect of the immigration population (Ecuador) in this area. PATIENTS AND METHODS: A retrospective study for six years ago (1999, January to 2004, December) was realized. Epidemiological data, initial diagnostic probability, mycobacteria stain and cultive, drug resistance, treatment response, and epidemiological differences between immigrants and spain population were compared. RESULTS: Within 158 cases registered, 41.7 percent were immigrants with less than one year in Spain, the most part Ecuador population. We observed that extrapulmonar tuberculosis was lower initial diagnostic probability than pleural disease as well too haemoptisis, pleural pain and weight loss. It was identified positive micobacterial stain in 35.4 percent of respiratory samples. It was successfully results in 74 percent of cases and 13.9 percent of patients were lost, this result was frequently registered in immigrants, The isoniazide resistant in patients with not previous treatment was 5.3 percent and it was 9.5 percent in immigrants and 10.8 percent in Ecuador population. CONCLUSION: It is necessary improve: the diagnostic of extrapulmonar tuberculosis and avoid loss patient by programs of capture and then the successfully treatments raise. The isoniazide resistant in this area suggest that we must use initial four drug than tree and this manner not raise the drug resistant in the area.

Low-grade systemic inflammation, hypoadiponectinemia and a high concentration of leptin are present in very young obese children, and correlate with metabolic syndrome.

OBJECTIVE: To determine the concentration levels of C-reactive protein (CRP), leptin and adiponectin in obese pre-pubertal children, and their possible relation with metabolic syndrome, fibrinogen and plasminogen activator inhibitor-1. METHODS: A study was carried out in 51 obese children (aged 6 to 9 years) and the same number of non-obese children (control group), matched by age and sex. (Cross-sectional study of obese children). Body mass index (BMI), waist/hip ratio (WHR) and blood pressure were determined for each child. Serum CRP, leptin, adiponectin, glucose, insulin, lipid profile, plasminogen activator inhibitor-1 (PAI-1) and fibrinogen were all measured. RESULTS: The levels of CRP serum (1.67+/-0.222 vs 0.92+/-0.16 mg/l) and leptin (15.56+/-1.27 vs 4.68+/-0.62 ng/ml) were significantly higher in obese children. The adiponectin level was significantly higher in non-obese children (11.58+/-0.63 vs 9.64+/-0.49 microg/dl). In the obese group, log. CRP showed a positive correlation with BMI, insulin, homeostasis model assessment (HOMA), triglycerides, alanine aminotransferase (ALT), uric acid, PAI-1, fibrinogen and interleukin 6 (IL-6), and correlated negatively with apolipoprotein A-I and high-density lipoprotein cholesterol (HDL-C). The leptin was positively correlated with BMI, insulin, HOMA, triglycerides and PAI-1 and negatively with Apo A-I and HDL-C. Adiponectin correlated negatively with BMI, insulin, HOMA, and triglycerides. CONCLUSIONS: Low-grade systemic inflammation, elevated leptin concentration and low adiponectin level are described in very young obese children, correlating with a range of variables of metabolic syndrome. Inflammation and adipocytokines can play an important role in the etiopathogeny of metabolic syndrome.

[Scintigraphic study of gastric emptying of rehydration drinks in athletes]. / Estudio gammagráfico del ritmo de vaciado gástrico de bebidas de reposición en deportistas.

UNLABELLED: This study aims to evaluate how rehydration beverage ingestion influences gastric emptying rate (in cycle ergometer) at rest and during exercise at 70 % of maximal oxygen consumption (VO2max). MATERIAL AND METHOD: 26 well-trained cyclists performed a preliminary maximal test until exhaustion to evaluate their VO2max, and two submaximal exercise tests at 70 % of their mode-specific VO2max. Each test was separated by one week. During the two submaximal tests, cyclists consumed 200 ml of a 99mTc-DTPA labeled rehydration beverage (A or B) and scintigraphy determinations were performed at rest. After, exercise was initiated for 60 minutes with an intake rate of 200 ml every 15 minutes, making gastric serial scintigraphy determinations. The difference regarding chemical composition between A and B drinks resides in the fact that drink A contains a smaller load in carbohydrates (10.3 g/100 ml versus 15.2 g/100 ml of B), proteins in form of serum milk and antioxidants in form of fruit juice. Both contain ions and vitamins. RESULTS: at rest, gastric count number was significantly reduced (p > 0.000) from 0 to 25 minutes for both A and B beverage. At the end of exercise (60 min), there was greater gastric retention for B beverage than for A, this difference being statistically significant (p < 0.031). CONCLUSIONS: The A beverage, a rehydration drink on the market with protein and antioxidants with fruit juice content, has a faster gastric emptying rate than the B sport beverage.

Quantification of profilins by a monoclonal antibody-based sandwich ELISA.

Profilins are plant allergens responsible for cross-reactivities in pollen and fruit-allergic patients. A two-site enzyme-linked immunosorbent assay has been developed for the quantification of profilins and its suitability for quantifying profilin in different plant extracts has been evaluated. The assay is based on two profilin-specific monoclonal antibodies (mAbs) with different epitope specificities. These antibodies were immobilized on ELISA plates and incubated with samples containing profilin. Bound profilin was detected by a combination of biotinylated profilin-specific antiserum and peroxidase-streptavidin conjugate. The optimized ELISA measured profilin concentrations ranging from 4 to 250 ng/ml and could quantify profilins from plant species of a variety of different botanical families. No reactivity to mites, molds, or crustaceans was detected, suggesting that the immunoassay is plant-specific. The results indicate that this sensitive profilin-assay will be helpful both for quantifying the profilin content of allergenic extracts intended for clinical use and for studying cross-reactivities between pollen extracts.

Sex hormone-binding globulin as a marker for hyperinsulinemia and/or insulin resistance in obese children.

OBJECTIVE: A relationship between hyperinsulinemia and decreased serum sex hormone-binding globulin (SHBG) has been described in adults. We evaluated the usefulness of SHBG as an index of hyperinsulinemia and/or insulin resistance in obese children (aged 6-9 years) of both sexes and its possible influence on the androgenic status. DESIGN: We carried out a cross-sectional study of cases and controls. We studied 61 obese children (22 males, 39 females) with body mass index (BMI) superior to the 90(th) percentile and a control group of age- and sex-matched non-obese children. We measured serum glucose, insulin, TSH, free thyroxine, 17beta-estradiol, testosterone and SHBG. Also, we correlated these parameters with anthropometric measures. RESULTS: The obese group presented significantly elevated levels of insulin (P=0.001) and insulin/glucose ratio (P=0.0012) compared with the control group. SHBG (P=0.0001) and testosterone (P=0.0169) levels were significantly lower than those in the non-obese group. We did not find any difference in the free androgen index (FAI). Fasting insulin (r=-0.4512; P<0.001), BMI (r=-0.3185; P<0.05) and testosterone (r=-0.3705; P<0.01) were inversely correlated with SHBG concentration. According to multivariate analyses, insulin was the only independent predictor factor for serum SHBG concentration in the obese group (r partial=0.1280; P=0.0171). CONCLUSIONS: In summary, at this age there is a strong relationship between insulin and SHBG. The changes in SHBG levels of the obese group did not affect FAI and, therefore, they did not cause changes in the androgenic status. Our data support the role of insulin in the regulation of serum SHBG levels.

Infantile obesity: a situation of atherothrombotic risk?

Obesity is a major risk factor for cardiovascular disease frequently associated with hypertension, dyslipidemia, and diabetes. In recent years, alterations in the hemostatic system have been added to these dysfunctions. We analyzed some of these alterations in coagulation and fibrinolysis in obese children (6 to 9 years old) of both sexes. We studied 61 obese children (mean body mass index [BMI], 22.35 kg/m2; 95% confidence interval [CI], 21.82 to 22.87) and 70 non-obese children (mean BMI, 16.58 kg/m2; 95% CI, 16.24 to 16.93) as a control group. The obese subjects presented significantly elevated values for insulin (P < .001), tissue-plasminogen activator ([t-PA] P < .001), plasminogen activator inhibitor-1 ([PAI-1] P < .001), and fibrinogen (P < .001) with respect to the control group. We found no significant differences in the concentration of glucose and fragment 1 + 2 of prothrombin (F1 + 2). In the obese subjects, insulin, PAI-1, and F1 + 2 were positively correlated with the BMI. On the other hand, t-PA was correlated with insulin and PAI-1 but not with the BMI. Therefore, in the obese children, there was an increment of the risk factors for cardiovascular disease.

A new case of trisomy 5 as sole cytogenetic anomaly in acute myeloid leukemia.

We present a case of acute myeloid leukemia (AML-M2) with trisomy 5 (+5) as the sole cytogenetic abnormality in a woman previously diagnosed with schizophrenia. To date, only two cases of AML (other than M2) with +5 as the only change have been reported. Moreover, an association between schizophrenia and partial trisomy of chromosome 5p has been described recently. To our knowledge, this is the first report of AML (subtype-M2) with +5. Noteworthy is the association with schizophrenia.

Childhood obesity and hormonal abnormalities associated with cancer risk.

There is growing evidence that overweight and obesity increase the risk of certain cancers. Studies in adults support the role of insulin-like growth factors (IGFs) and oestrogens in the pathogeneses of several cancers. We propose that hormone alterations described as risk factors for cancer in obese adults are present in prepubertal obese children. A group of obese children aged 6-9 years (n=40), and control group paired for age and sex, were used for the study. The obese children presented a significantly high level of IGF-I (P=0.0173) and insulin (P=0.0250), with a drop in sex hormone-binding globulin (SHBG) (P=0.0282). The 17 beta-oestradiol (E2)/SHBG ratio increase in obese subjects was marginally significant (P=0.0635). Grouping together all the children in quartiles for insulin and body mass index, the upper quartiles showed a rise in IGF-I and E2/SHBG. In a multivariant correlation analysis, only height (partial r=0.2464) and insulin (partial r=0.3002) were independent prediction variables for IGF-I concentration. The only variables statistically correlated with the E2/SHBG ratio were insulin (r=0.2879) and IGF-I (r=0.4140). The obese children in our study showed hormone changes described as risk factors for cancer in obese adults. These changes were significantly associated with the hyperinsulinaemia. We hypothesize that this potential risk should be taken into account given the long period of exposure involved in the presence of hormone alterations at such early ages.

Occupational rhinitis and bronchial asthma due to TBTU and HBTU sensitization.

Exposure to an increasing amount of products in the work environment is leading to new cases of occupational asthma among workers. We report the case of a worker at a pharmaceutical plant who developed occupational rhinitis and bronchial asthma due to HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate sensitization, two chemical products widely used in peptide synthesis and coupling. Skin tests (prick test) with HBTU and TBTU solutions in PBS were positive at a concentration of 1 mg/ml. Skin tests with the same solutions in 10 atopic controls yielded a negative result. Nasal challenge tests with these products were positive with HBTU at a concentration of 0.01 mg/ml and TBTU at a concentration of 1 mg/ml. In both cases PNIF (peak nasal inspiratory flow) decreased by more than 60% and severe sneezing and rhinorrhea were induced. Nasal challenge tests performed on 10 atopic controls with TBTU and HBTU at a concentration of 1 mg/ml were negative. We conclude that the patient presents occupational rhinitis and bronchial asthma due to TBTU and HBTU; the operational mechanism is probably immunological IgE-mediated given the positive prick tests and nasal challenge with these products.

Lactating females Syrian hamster (Mesocricetus auratus) show protection against experimental Leishmania infantum infection.

The Syrian hamster (Mesocricetus auratus) is the best animal model for human leishmaniosis, an emergent disease that causes 400,000 new cases every year. The main objective of this assay was to prove the relationship between female lactation, which implies hyperprolactinaemia (IFN-gamma, IL-12, IL-2 and TNF-alpha elevated), and leishmaniosis (IFN-gamma, IL-12, IL-2 and TNF-alpha diminished). The results demonstrate the clear implication of lactation in immune response. The infected lactating females did not show any symptoms of sickness, a 24 g mean increase was noticed, throughout the assay they were negative in the indirect diagnosis test (Direct Agglutination Test (DAT)), and in the direct diagnosis tests (N-N-N isolation, tissue impressions).

[Pharmacoeconomic analysis of community-acquired pneumonia treatment with telithromycin or clarithromycin]. / Analisis farmacoeconomico del tratamiento de la neumonia adquirida en la comunidad con telitromicina o claritromicina.

A pharmacoeconomic analysis was carried out comparing the efficacy of two treatment options for community-acquired pneumonia (CAP): telithromycin and clarithromycin. It was a retrospective analysis using a decision tree model. The efficacy of the two treatment options was estimated from a randomized, double-blind clinical trial, in which 800 mg/day oral telithromycin for 10 days was compared to 1000 mg/day oral clarithromycin for 10 days in patients with CAP (162 and 156 respectively). The use of resources was estimated based on the clinical trial and Spanish sources, and the unit costs from a Spanish health costs database. Costs were evaluated for the acquisition of antibiotic treatments, change of antibiotic due to therapeutic failure, hospital admissions, adverse reactions to treatment, primary care visits, tests and indirect costs (working days lost). The model was validated by a panel of Spanish clinical experts. As the clinical trial was designed to show equivalence, there were no significant differences in efficacy between the treatment options (clinical cure rate 88.3% and 88.5%, respectively), and a cost minimization analysis was performed. In the base case, the average cost of the disease per patient was 308.29 euros with telithromycin and 331.5 euros with clarithromycin (a difference of 23.21 euros). The results were stable in the susceptibility analysis, with differences favorable to telithromycin ranging between 5.50 and 45.45 euros. Telithromycin results in a cost savings of up to 45.45 euros per CAP patient compared to clarithromycin.

Measurement of the longitudinal and transverse vibration frequencies of a rod by speckle interferometry.

A heterodyne interferometric system was used to detect the normal and tangential components of the displacement at one point of a sample when it is vibrating freely in its natural modes, arising from transient excitation. A cylindrical aluminium rod was the test sample. An analysis of the spectrum associated with the in-plane and out-of-plane displacements made it possible to determine the values of the longitudinal and transverse natural frequencies.