Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial.

BACKGROUND: Evidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125-200 pM/l is lacking. We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo. METHODS: This multicentre (13 general practices, two nursing homes, and one primary care center in western Switzerland), parallel, randomised, controlled, closed-label, observer-blind trial included 50 patients with serum vitamin B12 levels between 125-200 pM/l who were randomized to receive either oral vitamin B12 (1000 μg daily, N = 26) or placebo (N = 24) for four weeks. The institution's pharmacist used simple randomisation to generate a table and allocate treatments. The primary outcome was the change in serum methylmalonic acid (MMA) levels after one month of treatment. Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels. Blood samples were centralised for analysis and adherence to treatment was verified by an electronic device (MEMS; Aardex Europe, Switzerland). Trial registration: ISRCTN 22063938. RESULTS: Baseline characteristics and adherence to treatment were similar in both groups. After one month, one patient in the placebo group was lost to follow-up. Data were evaluated by intention-to-treat analysis. One month of vitamin B12 treatment (N = 26) lowered serum MMA levels by 0.13 μmol/l (95%CI 0.06-0.19) more than the change observed in the placebo group (N = 23). The number of patients needed to treat to detect a metabolic response in MMA after one month was 2.6 (95% CI 1.7-6.4). A significant change was observed for the B12 serum level, but not for the homocysteine level, hematocrit, or mean corpuscular volume. After three months without active treatment (at four months), significant differences in MMA levels were no longer detected. CONCLUSIONS: Oral vitamin B12 treatment normalised the metabolic markers of vitamin B12 deficiency. However, a one-month daily treatment with 1000 μg oral vitamin B12 was not sufficient to normalise the deficiency markers for four months, and treatment had no effect on haematological signs of B12 deficiency.

C19orf12 mutation leads to a pallido-pyramidal syndrome.

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study.

OBJECTIVE(S): To investigate the relationship between detection of HIV drug resistance by 2 years from starting antiretroviral therapy and the subsequent risk of progression to AIDS and death. DESIGN: Virological failure was defined as experiencing two consecutive viral loads of more than 400 copies/ml in the time window between 0.5 and 2 years from starting antiretroviral therapy (baseline). Patients were grouped according to evidence of virological failure and whether there was detection of the International AIDS Society resistance mutations to one, two or three drug classes in the time window. METHODS: Standard survival analysis using Kaplan-Meier curves and Cox proportional hazards regression model with time-fixed covariates defined at baseline was employed. RESULTS: We studied 8229 patients in EuroSIDA who started antiretroviral therapy and who had at least 2 years of clinical follow-up. We observed 829 AIDS events and 571 deaths during 38,814 person-years of follow-up resulting in an overall incidence of new AIDS and death of 3.6 per 100 person-years of follow-up [95% confidence interval (CI):3.4-3.8]. By 96 months from baseline, the proportion of patients with a new AIDS diagnosis or death was 20.3% (95% CI:17.7-22.9) in patients with no evidence of virological failure and 53% (39.3-66.7) in those with virological failure and mutations to three drug classes (P = 0.0001). An almost two-fold difference in risk was confirmed in the multivariable analysis (adjusted relative hazard = 1.8, 95% CI:1.2-2.7, P = 0.005). CONCLUSION: Although this study shows an association between the detection of resistance at failure and risk of clinical progression, further research is needed to clarify whether resistance reflects poor adherence or directly increases the risk of clinical events via exhaustion of drug options.

Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection.

BACKGROUND: Visceral leishmaniasis is a parasitic disease associated with high mortality. The most important foci of visceral leishmaniasis in Ethiopia are in the Northwest and are predominantly associated with high rates of HIV co-infection. Co-infection of visceral leishmaniasis patients with HIV results in higher mortality, treatment failure and relapse. We have previously shown that arginase, an enzyme associated with immunosuppression, was increased in patients with visceral leishmaniasis and in HIV seropositive patients; further our results showed that high arginase activity is a marker of disease severity. Here, we tested the hypothesis that increased arginase activities associated with visceral leishmaniasis and HIV infections synergize in patients co-infected with both pathogens. METHODOLOGY/PRINCIPAL FINDINGS: We recruited a cohort of patients with visceral leishmaniasis and a cohort of patients with visceral leishmaniasis and HIV infection from Gondar, Northwest Ethiopia, and recorded and compared their clinical data. Further, we measured the levels of arginase activity in the blood of these patients and identified the phenotype of arginase-expressing cells. Our results show that CD4(+) T cell counts were significantly lower and the parasite load in the spleen was significantly higher in co-infected patients. Moreover, our results demonstrate that arginase activity was significantly higher in peripheral blood mononuclear cells and plasma of co-infected patients. Finally, we identified the cells-expressing arginase in the PBMCs as low-density granulocytes. CONCLUSION: Our results suggest that increased arginase might contribute to the poor disease outcome characteristic of patients with visceral leishmaniasis and HIV co-infection.

Disordered eating behaviors: what about boys?

PURPOSE: To determine the characteristics specific to boys with disordered eating behaviors (DEB) and the general context in which these DEB occur. METHOD: Data were drawn from the SMASH02 database, a survey carried out among post-mandatory school students in Switzerland aged 16-20 years in 2002. Only males (N=3890) were included, and were classified into into one of four groups based on their level of concern about weight/food and on their eating behaviors, as follows: group 1: one concern without behavior (N=862); group 2: more than one concern without behavior (N=361); group 3: at least one behavior (N=798); and a control group (N=1869), according to previously validated items. Groups were compared for personal, family, school, experience of violence, and health-compromising behaviors variables on the bivariate level. All significant variables were included in a multinomial logistic regression using Stata 9 software. RESULTS: About one-half of the boys reported either a concern or unhealthy eating behavior. Compared with the control group, boys from the three groups were more likely to be students and to report a history of sexual abuse, delinquency, depression, and feeling fat. In addition, boys from group 3 were more likely to report a history of dieting, early puberty, peer teasing, having experienced violence, frequent inebriation, and being overweight. CONCLUSION: DEB concern adolescent males more frequently than thought and seem to be integrated in a general dysfunctional context, in which violence is predominant. Adolescent males also need to be screened for DEB. Moreover, prevention programs should target the increasing social and media pressure regarding boys ideal body shape and raise public consciousness about this phenomenon.

Resistance to extreme strategies, rather than prosocial preferences, can explain human cooperation in public goods games.

The results of numerous economic games suggest that humans behave more cooperatively than would be expected if they were maximizing selfish interests. It has been argued that this is because individuals gain satisfaction from the success of others, and that such prosocial preferences require a novel evolutionary explanation. However, in previous games, imperfect behavior would automatically lead to an increase in cooperation, making it impossible to decouple any form of mistake or error from prosocial cooperative decisions. Here we empirically test between these alternatives by decoupling imperfect behavior from prosocial preferences in modified versions of the public goods game, in which individuals would maximize their selfish gain by completely (100%) cooperating. We found that, although this led to higher levels of cooperation, it did not lead to full cooperation, and individuals still perceived their group mates as competitors. This is inconsistent with either selfish or prosocial preferences, suggesting that the most parsimonious explanation is imperfect behavior triggered by psychological drives that can prevent both complete defection and complete cooperation. More generally, our results illustrate the caution that must be exercised when interpreting the evolutionary implications of economic experiments, especially the absolute level of cooperation in a particular treatment.

Management of hepatitis C virus (HCV) infection in drug substitution programs.

BACKGROUND: In Switzerland, intravenous drug use (IDU) accounts for 80% of newly acquired hepatitis C virus (HCV) infections. Early HCV treatment has the potential to interrupt the transmission chain and reduce morbidity/mortality due to decompensated liver cirrhosis and hepatocellular carcinoma. Nevertheless, patients in drug substitution programs are often insufficiently screened and treated. OBJECTIVE/METHODS: With the aim to improve HCV management in IDUs, we conducted a cross sectional chart review in three opioid substitution programs in St. Gallen (125 methadone and 71 heroin recipients). Results were compared with another heroin substitution program in Bern (202 patients) and SCCS/SHCS data. RESULTS: Among the methadone/heroin recipients in St. Gallen, diagnostic workup of HCV was better than expected: HCV/HIV-status was unknown in only 1% (2/196), HCV RNA was not performed in 9% (13/146) of anti-HCV-positives and the genotype missing in 15% (12/78) of HCV RNA-positives. In those without spontaneous clearance (two thirds), HCV treatment uptake was 23% (21/91) (HIV-: 29% (20/68), HIV+: 4% (1/23)), which was lower than in methadone/heroin recipients and particularly non-IDUs within the SCCS/SHCS, but higher than in the, mainly psychiatrically focussed, heroin substitution program in Bern (8%). Sustained virological response (SVR) rates were comparable in all settings (overall: 50%, genotype 1: 35-40%, genotype 3: two thirds). In St. Gallen, the median delay from the estimated date of infection (IDU start) to first diagnosis was 10 years and to treatment was another 7.5 years. CONCLUSIONS: Future efforts need to focus on earlier HCV diagnosis and improvement of treatment uptake among patients in drug substitution programs, particularly if patients are HIV-co-infected. New potent drugs might facilitate the decision to initiate treatment.

Helicopter rescue operations involving winching of an emergency physician.

OBJECTIVE: We sought to study the epidemiologic and medical aspects of alpine helicopter rescue operations involving the winching of an emergency physician to the victim. METHODS: We retrospectively reviewed the medical and operational reports of a single helicopter-based emergency medical service. Data from 1 January 2003 to 31 December 2008 were analysed. RESULTS: A total of 921 patients were identified, with a male:female ratio of 2:1. There were 56 (6%) patients aged 15 or under. The median time from emergency call to helicopter take-off was 7 min (IQR = 5-10 min). 840 (91%) patients suffered from trauma-related injuries, with falls from heights during sports activities the most frequent event. The most common injuries involved the legs (246 or 27%), head (175 or 19%), upper limbs (117 or 13%), spine (108 or 12%), and femur (66 or 7%). Only 81 (9%) victims suffered from a medical emergency, but these cases were, when compared to the trauma victims, significantly more severe according to the NACA index (p<0.001). Overall, 246 (27%) patients had a severe injury or illness, namely, a potential or overt vital threat (NACA score between 4 and 6). A total of 478 (52%) patients required administration of major analgesics: fentanyl (443 patients or 48%), ketamine (42 patients or 5%) or morphine (7 patients or 1%). The mean dose of fentanyl was 188 micrograms (range 25-750, SD 127). Major medical interventions such as administration of vasoactive drugs, intravenous perfusions of more than 1000 ml of fluids, ventilation or intubation were performed on 39 (4%) patients. CONCLUSIONS: The severity of the patients' injuries or illnesses along with the high proportion of medical procedures performed directly on-site validates emergency physician winching for advanced life support procedures and analgesia.

A favor dels clàssics d'aventures de la literatura juvenil

No entengueu aquest article com un clam nostalgic als herois i hero'ines de tots els temps. No el vegeu tampoc com una manca de reconeixement al gran esforç realitzat per escriptors i escriptores, món educatiu i editorial per ampliar l'oferta de literatura infantil i juvenil i posar a l'abast deis adolescents un ventall de títols i col-leccions que els motivin per a la lectura. Aquestes pagines ni tan sois pretenen entrar en la polemica sobre la funció literaria i pedagógica del corrent anomenat "realisme crític", amb reflexió psicológica, on s'hi tracten temes que permeten als adolescents identificar-se, de manera explícita, amb els infortunis que succeeixen als joves protagonistes. Adhuc, en aquest escrit es vol deixar al marge la qüestió deis límits entre literatura per a nens i joves i literatura per a adults.

La literatura infantil i juvenil: presentació

Temps d'Educació ha volgut dedicar un monogràfic a la literatura infantil i juvenil. Aquesta excel·lent iniciativa arriba en un moment extraordinariament oportú. Precisem ara les línies que justifiquen aquesta oportunitat. D'una banda, assistim a una estabilització del boom editorial deis anys 80. Efectivament, des de mitjan anys 70 la producció de Ilibres per a infants i joves ha experimentat, aquí i arreu, un creixement espectacular. A més de permetre'ns disposar d'una oferta numericament extraordinària i d'una possibilitat de tria molt interessant, ha representat la familiarització amb llibres, corrents literaris, autors i estils molt diversos. Això, especialment a casa nostra, suposa un bon pas cap a la normalització del sector i l'abandó d'un cert pionerisme. I també la consolidació d'una literatura que ja ningú no pot anomenar residual o minoritaria, aïllada deis habituals sistemes de producció o imposició en el mercat. Ha arribat el moment de reflexionar-hi, de destriar, de crear les eines crítiques sobre tot aquest fenomen.

Jane Eyre: una lectura para el verano y la película que nos espera a la vuelta del otoño.

Siguiendo con la costumbre de hablar del cine de literatura, hoy proponemos la novela Jane Eyre1, escrita por Charlotte Brönte en 1847, recomendada para jóvenes a partir de los catorce años, con madurez y formación lectora previa, y con una versión cinematográfica que se estrenará en España a finales del mes de septiembre. En tiempo vacacional es un privilegio contar con historias que nos ocupen las siestas de las calurosas y largas tardes de verano con tiempo para todo, nos metan en relatos que nos absorban, nos lleven a mundos distantes y nos permitan acercarnos a vidas muy atractivas, con historias de valentía y de superación que nos impulsen a ser mejores. Es el momento de disfrutar con novela que pueden quedar a medias en otros momentos del año con más obligaciones.

La literatura infantil i juvenil, una especulació

Sovint trobem articles de revistes o capítols de llibres especialitzats que argumenten a favor o en contra de l'existencia d'una literatura específica per als nens i els joves. Els estudiosos que argumenten a favor, coherentment amb la hipótesi feta, presenten com a prova autors, generes, edats, de vegades fins i tot el sexe dels destinataris. També hi ha una defensa del contrari: Juan Ramón Jiménez, Walter Benjamin, Benedetto Croce o J. M. Carandell, per exemple, han intentat mostrar, de forma diversa, que la veritable literatura no pot tenir adjectius limitadors, que históricament adults i nens eren oients, més que lectors, deis mateixos contes, llegendes, poesies, i que és a partir del pensament de la i1-lustració quan es comenga a fer una literatura pedagógica específicament dirigida als infants amb finalitat moralitzadora. És una questió que constantment troba veus que opinen en un sentit o en un altre, arreu del mon i també a casa nostra. El resultat, en general, és consemblant en ambdues posicions donat que, malgrat les declaracions de principis d'intentar no classificar, és ben cert que hi ha una preocupació generalitzada per fer arribar als més petits i als joves les millors lectures o les més convenients, sobretot des d'un punt de vista formatiu i, tant en el segle passat com en el que vivim, aquest objectiu ha mogut a estudiosos, crítics, bibliotecaris, docents i editorials. Triar per oferir un text i no un altre comporta, si més no, inclusions i exclusions, és a dir, un cert tipus de classificació.

A la recerca del lloc de la literatura infantil i juvenil en el curriculum escolar

La Reforma del sistema educatiu, innovadora en alguns aspectes, ha assignat algun espai a la Literatura Infantil i Juvenil (d'ara endavant, LIJ) en els dissenys curriculars. Pero ho ha fet d'una manera implícita, tacita, gairebé en complicitat amb el professor que vulgui recórrerhi en les seves activitats d'aula. Com que no es tracta d'un contingut, ni d'un objectiu d'aprenentatge en ella mateixa, la seva presencia esta diluida en les previsions curriculars. Pero hi éso. En aquestes pagines intentaré de presentar un conjunt de raons i referencies que avalin l'efectivitat de la utilització de la LIJ en l'ambit escolar, que supera la del seu ús com a mer recurs didactic.

Dosage optimization of treatments using population pharmacokinetic modeling and simulation.

Pharmacokinetic variability in drug levels represent for some drugs a major determinant of treatment success, since sub-therapeutic concentrations might lead to toxic reactions, treatment discontinuation or inefficacy. This is true for most antiretroviral drugs, which exhibit high inter-patient variability in their pharmacokinetics that has been partially explained by some genetic and non-genetic factors. The population pharmacokinetic approach represents a very useful tool for the description of the dose-concentration relationship, the quantification of variability in the target population of patients and the identification of influencing factors. It can thus be used to make predictions and dosage adjustment optimization based on Bayesian therapeutic drug monitoring (TDM). This approach has been used to characterize the pharmacokinetics of nevirapine (NVP) in 137 HIV-positive patients followed within the frame of a TDM program. Among tested covariates, body weight, co-administration of a cytochrome (CYP) 3A4 inducer or boosted atazanavir as well as elevated aspartate transaminases showed an effect on NVP elimination. In addition, genetic polymorphism in the CYP2B6 was associated with reduced NVP clearance. Altogether, these factors could explain 26% in NVP variability. Model-based simulations were used to compare the adequacy of different dosage regimens in relation to the therapeutic target associated with treatment efficacy. In conclusion, the population approach is very useful to characterize the pharmacokinetic profile of drugs in a population of interest. The quantification and the identification of the sources of variability is a rational approach to making optimal dosage decision for certain drugs administered chronically.