Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks

Autologous haematopoietic stem-cell transplantation has been evaluated over the last years as a possible new therapeutic strategy in severe forms of multiple sclerosis unresponsive to the approved therapies. Up to now, more than 400 patients have been treated and numerous are the phase I and phase II studies which addressed the feasibility of this treatment, the efficacy, side effects and transplant-related mortality. The clinical response is strongly related to the intensity of the conditioning regimen utilized as well as to the phase of the disease course in which the therapy is carried out. Rapidly evolving multiple sclerosis with a relapsing–remitting clinical course and MRI signs of activity are the cases that can take more advantage. The risk of mortality, which dropped in the last years to 2–3%, is still the main problem of this powerful therapy.     

Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections.

BACKGROUND AND METHODS: The endogenous inhibitor of nitric oxide synthase (NOs) asymmetrical dimethyl-arginine (ADMA) has been implicated as a possible modulator of inducible NOs during acute inflammation. We examined the evolution in the plasma concentration of ADMA measured at the clinical outset of acute inflammation and after its resolution in a series of 17 patients with acute bacterial infections. RESULTS: During the acute phase of inflammation/infection, patients displayed very high levels of C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin and nitrotyrosine. Simultaneous plasma ADMA concentration was similar to that in healthy subjects while symmetric dimethyl-arginine (SDMA) levels were substantially increased and directly related with creatinine. When infection resolved, ADMA rose from 0.62 +/- 0.23 to 0.80 +/- 0.18 micromol/l (+29%, P = 0.01) while SDMA remained unmodified. ADMA changes were independent on concomitant risk factor changes and inversely related with baseline systolic and diastolic pressure. Changes in the ADMA/SDMA ratio were compatible with the hypothesis that inflammatory cytokines activate ADMA degradation. CONCLUSIONS: Resolution of acute inflammation is characterized by an increase in the plasma concentration of ADMA. The results imply that ADMA suppression may actually serve to stimulate NO synthesis or that in this situation plasma ADMA levels may not reflect the inhibitory potential of this methylarginine at the cellular level.     

Functional characterization of human natural killer cells responding to Mycobacterium bovis bacille Calmette-Guérin

The kinetics of activation and induction of several effector functions of human natural killer (NK) cells in response to Mycobacterium bovis bacille Calmette-Guérin (BCG) were investigated. Owing to the central role of monocytes/macrophages (MM) in the initiation and maintenance of the immune response to pathogens, two different experimental culture conditions were analysed. In the first, monocyte-depleted nylon wool non-adherent (NW) cells from healthy donors were stimulated with autologous MM preinfected with BCG (intracellular BCG). In the second, the NW cells were directly incubated with BCG, which was therefore extracellular. In the presence of MM, CD4+ T lymphocytes were the cell subset mainly expressing the activation marker, CD25, and proliferating with a peak after 7 days of culture. In contrast, in response to extracellular BCG, the peak of the proliferative response was observed after 6 days of stimulation, and CD56+ CD3- cells (NK cells) were the cell subset preferentially involved. Such proliferation of NK cells did not require a prior sensitization to mycobacterial antigens, and appeared to be dependent upon contact between cell populations and bacteria. Following stimulation with extracellular BCG, the majority of interferon-gamma (IFN-gamma)-producing cells were NK cells, with a peak IFN-gamma production at 24-30 hr. Interleukin (IL)-2 and IL-4 were not detectable in NK cells or in CD3+ T lymphocytes at any time tested. IL-12 was not detectable in the culture supernatant of NW cells stimulated with extracellular BCG. Compared to the non-stimulated NW cells, the NW cells incubated for 16-20 hr with BCG induced the highest levels of expression of apoptotic/death marker on the NK-sensitive K562 cell line. BCG also induced expression of the activation marker, CD25, and proliferation, IFN-gamma production and cytotoxic activity, on negatively selected CD56+ CD3- cells. Altogether, the results of this study demonstrate that extracellular mycobacteria activate several NK-cell functions and suggest a possible alternative mechanism of NK-cell activation as the first line of defence against mycobacterial infections.     

Interpersonal callousness, hyperactivity/impulsivity, inattention, and conduct problems as precursors to delinquency persistence in boys: a comparison of three grade-based cohorts.

Boys who exhibit interpersonal callousness (IC), hyperactivity/impulsivity (HI), inattention (IN), and conduct problems (CP) may be at risk for exhibiting persistent delinquent behavior. However, few studies have established the distinctiveness of these constructs or examined their relative contributions to the prediction of delinquent behavior across different developmental periods. This study explores these issues using boys from the youngest (1st grade, N = 849), middle (4th grade, N = 868), and oldest (7th grade, N = 856) cohorts of the Pittsburgh Youth Study. Confirmatory factor analysis indicates that the 4 constructs are related, yet independent, from childhood to adolescence. After controlling for the overlap among the constructs, CP significantly predicted delinquency persistence in the youngest cohort, whereas CP and IN predicted delinquency persistence in the middle cohort. IC uniquely predicted delinquency persistence for the oldest cohort. The results suggest that the saliency of specific predictors of delinquent behavior may change from childhood to adolescence.     

Toxicology of various pesticides and their decomposition products on mitochondrial electron transport

The effect of various pesticides and derivatives on mitochondrial electron transport systems was assessed. DDT, DDE, TDE, Kelthane, chlorobenzilate, chloropropylate and Acarol were found to be inhibitory towards both heavy beef heart mitochondrial (HBHM) NADH-oxidase and succinoxidase enzyme systems. Dichlorobenzophenone andp-chlorophenol were less inhibitory towards the HBHM NADH-oxidase and did not inhibit the succinoxidase enzyme system. DDA did not inhibit either of the electron transport systems. Carbaryl was not inhibitory towards both HBHM oxidase systems, whereas its degradative product dihydroxynaphthalene was inhibitory at the same concentration. Furadan, Matacil, Baygon and Dimetilan were only slightly inhibitory towards the mitochondrial NADH-oxidase system and did not inhibit the succinoxidase system. Zectran was inhibitory towards the NADH-oxidase system and was not inhibitory towards the succinoxidase system. DDT, DDE and TDE, dihydroxynaphthalene and 1-naphthol inhibited the NADH-oxidase enzyme system on the substrate side of cytochrome c, whereas Kelthane inhibited on the oxygen side.Contribution to Regional Project W-45, Residues of Pesticides and Related Chemicals in the Agricultural Environment-Their Nature, Distribution, Persistence, and Texicological Implications. University of Nevada Agricultural Experiment Station No. 432.     

Lower levels of oxidative DNA damage and apoptosis in lymphocytes from patients undergoing surgery with propofol anesthesia

Propofol, which is widely used as an intravenous anesthetic, has a phenolic structure similar to that of α‐tocopherol with antioxidant properties that could prevent genotoxicity and cytotoxicity in lymphocytes of anesthetized patients. The aims of this study were to evaluate oxidative DNA damage and apoptosis in lymphocytes and the expression of DNA repair genes in blood cells from patients undergoing elective surgery under anesthesia with propofol. Twenty healthy adults of both genders (18–50 years old) who were scheduled for otorhinological surgery were enrolled in this study. Blood samples were collected before anesthesia induction (T₁‐baseline), 120 min after anesthesia induction (T₂), and on the first postoperative day (T₃). Oxidative DNA damage in peripheral lymphocytes was assessed using the comet assay. Lymphocytes were phenotyped as T helper or cytotoxic T cells, and apoptosis was evaluated using flow cytometry. The expression of DNA repair genes (hOGG1 and XRCC1) was assessed by quantitative polymerase chain reaction. A reduction in the level of oxidized purines in DNA (P < 0.01) was observed 120 min after anesthesia induction, and reduced apoptosis of T helper cells was observed 120 min after anesthesia induction and on the first postoperative day. Down‐regulation of hOGG1 and XRCC1 gene expression was observed on the first postoperative day. In conclusion, patients undergoing non‐invasive surgery under propofol anesthesia presented lower levels of oxidized purines and apoptosis of T helper lymphocytes. Furthermore, anesthesia with propofol did not directly influence the expression of the DNA repair genes hOGG1 and XRCC1 in blood cells. © Environ. Mol. Mutagen. 2012. Published 2011 Wiley Periodicals, Inc.     

Quantification of the Parameters of the Acoustic Reflex in Normal Ears

Measurement of the acoustic stapedial reflex parameters has proved to be a useful tool for evaluating the function of the acoustic-facial reflex. However, there is no agreement about the definitions of the parameters; moreover, most of the data have been obtained by manual measurement methods. The authors describe a computerized analytical method which permits the parameters to be measured according to the definitions and methods suggested by others and according to the new analytical method described, which is performed on the basis of the derivative of the stapedial reflex curve. The two methods are compared in 40 normal subjects.

La mesure des paramètres de la courbe de réponse du réflexe stapédien donne des renseignements pour l'évaluation de la fonction du réflexe acoustico-facial. II n'existe pourtant pas d'accord sur la définition des paramètres et la plupart des données ont été relevées manuellement. Dans ce travail les auteurs présentent un systeme d'analyse à l'aide d'un ordinateur qui permet de mesurer les paramètres du réflexe stapédien avec les méthodes généralement employées, d'après les définitions données par d'autres auteurs, et par une nouvelle méthode d'analyse, fondée sur l'étude de la dérivée de la courbe de réponse du réflexe. On décrit la nouvelle méthode d'analyse et on compare les résultats obtenus à l'aide des deux méthodes chez 40 sujets normaux.