Secondary effects of catalytic diesel particulate filters: copper-induced formation of PCDD/Fs.

Potential risks of a secondary formation of polychlorinated dibenzodioxins/furans (PCDD/Fs) were assessed for two cordierite-based, wall-through diesel particulate filters (DPFs) for which soot combustion was either catalyzed with an iron- or a copper-based fuel additive. A heavy duty diesel engine was used as test platform, applying the eight-stage ISO 8178/4 C1 cycle. DPF applications neither affected the engine performance, nor did they increase NO, NO2, CO, and CO2 emissions. The latter is a metric for fuel consumption. THC emissions decreased by about 40% when deploying DPFs. PCDD/F emissions, with a focus on tetra- to octachlorinated congeners, were compared under standard and worst case conditions (enhanced chlorine uptake). The iron-catalyzed DPF neither increased PCDD/F emissions, nor did it change the congener pattern, even when traces of chlorine became available. In case of copper, PCDD/F emissions increased by up to 3 orders of magnitude from 22 to 200 to 12 700 pg I-TEQ/L with fuels of < 2, 14, and 110 microg/g chlorine, respectively. Mainly lower chlorinated DD/Fs were formed. Based on these substantial effects on PCDD/F emissions, the copper-catalyzed DPF system was not approved for workplace applications, whereas the iron system fulfilled all the specifications of the Swiss procedures for DPF approval (VERT).

D-amphetamine fails to increase extracellular dopamine levels in mice lacking alpha 1b-adrenergic receptors: relationship between functional and nonfunctional dopamine release.

It was found recently that locomotor and rewarding effects of psychostimulants and opiates were dramatically decreased or suppressed in mice lacking alpha1b-adrenergic receptors [alpha1b-adrenergic receptor knock-outs (alpha1bAR-KOs)] (Drouin et al., 2002). Here we show that blunted locomotor responses induced by 3 and 6 mg/kg d-amphetamine in alpha1bAR-KO mice [-84 and -74%, respectively, when compared with wild-type (WT) mice] are correlated with an absence of d-amphetamine-induced increase in extracellular dopamine (DA) levels in the nucleus accumbens of alpha1bAR-KO mice. Moreover, basal extracellular DA levels in the nucleus accumbens are lower in alpha1bAR-KO than in WT littermates (-28%; p < 0.001). In rats however, prazosin, an alpha1-adrenergic antagonist, decreases d-amphetamine-induced locomotor hyperactivity without affecting extracellular DA levels in the nucleus accumbens, a finding related to the presence of an important nonfunctional release of DA (Darracq et al., 1998). We show here that local d-amphetamine releases nonfunctional DA with the same affinity but a more than threefold lower amplitude in C57BL6/J mice than in Sprague Dawley rats. Altogether, this suggests that a trans-synaptic mechanism amplifies functional DA into nonfunctional DA release. Our data confirm the presence of a powerful coupling between noradrenergic and dopaminergic neurons through the stimulation of alpha1b-adrenergic receptors and indicate that nonfunctional DA release is critical in the interpretation of changes in extracellular DA levels. These results suggest that alpha1b-adrenergic receptors may be important therapeutic pharmacological targets not only in addiction but also in psychosis because most neuroleptics possess anti-alpha1-adrenergic properties.

Elevated blood pressure prevalence in children did not follow the increase in overweight: results from a school-based study in a rapidly developing country, 1998-2006

Background: Blood pressure (BP) is strongly associated with body weight and there is concern that the pediatric overweight epidemic could lead to an increase in children's mean BP. Objectives: We analyzed BP trends from 1998 to 2006 among children of the Seychelles, a rapidly developing middle-income country in Africa. Methods: Serial school-based surveys of weight, height and BP were conducted yearly between 1998-2006 among all students of the country in four school grades (kindergarten, 4th, 7th and 10th years of compulsory school). We used the CDC criteria to define "overweight" (BMI _95th sex-, and age-specific percentile) and the NHBPEP criteria for "elevated BP" (BP _95th sex-, age-, and height specific percentile). Methods for height, weight, and BP measurements were identical over the study period. The trends in mean BMI and mean systolic/diastolic BP were assessed with linear regression. Results: 27,703 children aged 4-18 years (participation rate: 79%) contributed 43,927 observations on weight, height, and BP. The prevalence of overweight increased from 5.1% in 1998-2000 to 8.1% in 2004-2006 among boys, and from 6.1% to 9.1% among girls, respectively. The prevalence of elevated BP was 8.4% in 1998-2000 and 6.9% in 2004-2006 among boys; 9.8% and 7.8% among girls, respectively. Over the 9-years study period, age-adjusted body mass index (BMI) increased by 0.078 kg/m2/year in boys and by 0.083 kg/m2/year in girls (both sexes, P_0.001). Age- and height-adjusted systolic BP decreased by -0.37 mmHg/year in boys and by -0.34 mmHg/year in girls (both sexes, P_0.001). Diastolic BP did not change in boys (-0.02 mmHg/year, P: 0.40) and slightly increased in girls (0.07 mmHg/year, P: 0.003). These trend estimates were altered modestly upon further adjustment for BMI or if analyses were based on median rather than mean values. Conclusion: Although body weight increased markedly between 1998 and 2006 in this population, systolic BP decreased and diastolic BP changed only marginally. This suggests that population increases in body weight are not necessarily associated with corresponding rises in BP in children.

NEUROPATHOPHYSIOLOGICAL MECHANISMS IN GLUTARIC ACIDURIA TYPE I: 3-HYDROXYGLUTARIC ACID LEADS TO AMMONIA INCREASE AND NON-APOPTOTIC CELL DEATH

A 3D in vitro model of rat organotypic brain cell cultures in aggregates was used to investigate neurotoxicity mechanisms in glutaric aciduria type I (GA-I). 1 mM glutarate (GA) or 3-hydroxyglutarate (3OHGA) were repeatedly added to the culture media at two different time points. In cultures treated with 3OHGA, we observed an increase in lactate in the medium, pointing to a possible inhibition of Krebs cycle and respiratory chain. We further observed that 3OHGA and to a lesser extend GA induced an increase in ammonia production with concomitant decrease of glutamine concentrations, which may suggest an inhibition of the astrocytic enzyme glutamine synthetase. These previously unreported findings may uncover a pathogenic mechanism in this disease which has deleterious effects on early stages of brain development. By immunohistochemistry we showed that 3OHGA increased non-apoptotic cell death. On the cellular level, 3OHGA and to a lesser extend GA led to cell swelling and loss of astrocytic fibers whereas a loss of oligodendrocytes was only observed for 3OHGA. We conclude that 3OHGAwas the most toxic metabolite in our model for GA-I. 3OHGA induced deleterious effects on glial cells, an increase of ammonia production, and resulted in accentuated cell death of non-apoptotic origin.

Use of a renal-specific oral supplement by haemodialysis patients with low protein intake does not increase the need for phosphate binders and may prevent a decline in nutritional status and quality of life.

BACKGROUND: Protein-energy wasting is a frequent and debilitating condition in maintenance dialysis. We randomly tested if an energy-dense, phosphate-restricted, renal-specific oral supplement could maintain adequate nutritional intake and prevent malnutrition in maintenance haemodialysis patients with insufficient intake. METHODS: Eighty-six patients were assigned to a standard care (CTRL) group or were prescribed two 125-ml packs of Renilon 7.5(R) daily for 3 months (SUPP). Dietary intake, serum (S) albumin, prealbumin, protein nitrogen appearance (nPNA), C-reactive protein, subjective global assessment (SGA) and quality of life (QOL) were recorded at baseline and after 3 months. RESULTS: While intention to treat analysis (ITT) did not reveal strong statistically significant changes in dietary intake between groups, per protocol (PP) analysis showed that the SUPP group increased protein (P < 0.01) and energy (P < 0.01) intakes. In contrast, protein and energy intakes further deteriorated in the CTRL group (PP). Although there was no difference in serum albumin and prealbumin changes between groups, in the total population serum albumin and prealbumin changes were positively associated with the increment in protein intake (r = 0.29, P = 0.01 and r = 0.27, P = 0.02, respectively). The SUPP group did not increase phosphate intake, phosphataemia remained unaffected, and the use of phosphate binders remained stable or decreased. The SUPP group exhibited improved SGA and QOL (P < 0.05). CONCLUSION: This study shows that providing maintenance haemodialysis patients with insufficient intake with a renal-specific oral supplement may prevent deterioration in nutritional indices and QOL without increasing the need for phosphate binders.

Cellular immune responses to HCV core increase and HCV RNA levels decrease during successful antiretroviral therapy.

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected individuals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels. AIMS: To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication. METHODS: T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected individuals by ex vivo interferon-gamma-ELISpot responses to HCV core peptides, that predominantly stimulate CD4(+) T cells. HCV RNA levels were assessed by real-time PCR in 114 individuals. RESULTS: The proportion of individuals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in individuals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log(10) IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (-0.3 log10 IU/ml, p=0.02). CONCLUSIONS: Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected individuals.

Authors' response to 'Limitless longevity': the contribution of rectangularization to the secular increase in life expectancy: an empirical study.

Related article : Letter to the Editor: Karin Modig, Sven Drefahl, and Anders Ahlbon.Limitless longevity: Comment on the Contribution of rectangularization to the secular increase of life expectancy

Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations?

OBJECTIVE: To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk. METHODS: Population-based case-control study with malformed controls based on EUROCAT congenital anomaly registers. The study population covered 3.9 million births from 19 registries 1995-2005. Registrations included congenital anomaly among livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. Cases were 5,511 nonsyndromic OC registrations, of whom 4,571 were isolated, 1,969 were cleft palate (CP), and 1,532 were isolated CP. Controls were 80,052 nonchromosomal, non-OC registrations. We compared first trimester LTG and antiepileptic drug (AED) use vs nonepileptic non-AED use, for mono and polytherapy, adjusting for maternal age. An additional exploratory analysis compared the observed and expected distribution of malformation types associated with LTG use. RESULTS: There were 72 LTG exposed (40 mono- and 32 polytherapy) registrations. The ORs for LTG monotherapy vs no AED use were 0.67 (95% CI 0.10-2.34) for OC relative to other malformations, 0.80 (95% CI 0.11-2.85) for isolated OC, 0.79 (95% CI 0.03-4.35) for CP, and 1.01 (95% CI 0.03-5.57) for isolated CP. ORs for any AED use vs no AED use were 1.43 (95% CI 1.03-1.93) for OC, 1.21 (95% CI 0.82-1.72) for isolated OC, 2.37 (95% CI 1.54-3.43) for CP, and 1.86 (95% CI 1.07-2.94) for isolated CP. The distribution of other nonchromosomal malformation types with LTG exposure was similar to non-AED exposed. CONCLUSION: We find no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine (LTG) monotherapy. Our study is not designed to assess whether there is a generalized increased risk of malformations with LTG exposure.

Cerebral extracellular lactate increase is predominantly nonischemic in patients with severe traumatic brain injury.

Growing evidence suggests that endogenous lactate is an important substrate for neurons. This study aimed to examine cerebral lactate metabolism and its relationship with brain perfusion in patients with severe traumatic brain injury (TBI). A prospective cohort of 24 patients with severe TBI monitored with cerebral microdialysis (CMD) and brain tissue oxygen tension (PbtO2) was studied. Brain lactate metabolism was assessed by quantification of elevated CMD lactate samples (>4 mmol/L); these were matched to CMD pyruvate and PbtO2 values and dichotomized as glycolytic (CMD pyruvate >119 μmol/L vs. low pyruvate) and hypoxic (PbtO2 <20 mm Hg vs. nonhypoxic). Using perfusion computed tomography (CT), brain perfusion was categorized as oligemic, normal, or hyperemic, and was compared with CMD and PbtO2 data. Samples with elevated CMD lactate were frequently observed (41±8%), and we found that brain lactate elevations were predominantly associated with glycolysis and normal PbtO2 (73±8%) rather than brain hypoxia (14±6%). Furthermore, glycolytic lactate was always associated with normal or hyperemic brain perfusion, whereas all episodes with hypoxic lactate were associated with diffuse oligemia. Our findings suggest predominant nonischemic cerebral extracellular lactate release after TBI and support the concept that lactate may be used as an energy substrate by the injured human brain.

Unstable shoes increase energy expenditure of obese patients.

BACKGROUND: Ergonomic unstable shoes, which are widely available to the general population, could increase daily non-exercise activity thermogenesis as the result of increased muscular involvement. We compared the energy expenditure of obese patients during standing and walking with conventional flat-bottomed shoes versus unstable shoes.¦METHODS: Twenty-nine obese patients were asked to stand quietly and to walk at their preferred walking speed while wearing unstable or conventional shoes. The main outcome measures were metabolic rate of standing and gross and net energy cost of walking, as assessed with indirect calorimetry.¦RESULTS: Metabolic rate of standing was higher while wearing unstable shoes compared with conventional shoes (1.11±0.20 W/kg(-1)vs 1.06±0.23 W/kg(-1), P=.0098). Gross and net energy cost of walking were higher while wearing unstable shoes compared with conventional shoes (gross: 4.20±0.42 J/kg(-1)/m(-1)vs 4.01±0.39 J/kg(-1)/m(-1), P=.0035; net: 3.37±0.41 J/kg(-1)/m(-1)vs 3.21±0.37 J/kg(-1)/m(-1); P=.032).¦CONCLUSION: In obese patients, it is possible to increase energy expenditure of standing and walking by means of ergonomic unstable footwear. Long-term use of unstable shoes may eventually prevent a positive energy balance.

Depression with atypical features and increase in obesity, body mass index, waist circumference, and fat mass: a prospective, population-based study.

IMPORTANCE: Depression and obesity are 2 prevalent disorders that have been repeatedly shown to be associated. However, the mechanisms and temporal sequence underlying this association are poorly understood. OBJECTIVE: To determine whether the subtypes of major depressive disorder (MDD; melancholic, atypical, combined, or unspecified) are predictive of adiposity in terms of the incidence of obesity and changes in body mass index (calculated as weight in kilograms divided by height in meters squared), waist circumference, and fat mass. DESIGN, SETTING, AND PARTICIPANTS: This prospective population-based cohort study, CoLaus (Cohorte Lausannoise)/PsyCoLaus (Psychiatric arm of the CoLaus Study), with 5.5 years of follow-up included 3054 randomly selected residents (mean age, 49.7 years; 53.1% were women) of the city of Lausanne, Switzerland (according to the civil register), aged 35 to 66 years in 2003, who accepted the physical and psychiatric baseline and physical follow-up evaluations. EXPOSURES: Depression subtypes according to the DSM-IV. Diagnostic criteria at baseline and follow-up, as well as sociodemographic characteristics, lifestyle (alcohol and tobacco use and physical activity), and medication, were elicited using the semistructured Diagnostic Interview for Genetic Studies. MAIN OUTCOMES AND MEASURES: Changes in body mass index, waist circumference, and fat mass during the follow-up period, in percentage of the baseline value, and the incidence of obesity during the follow-up period among nonobese participants at baseline. Weight, height, waist circumference, and body fat (bioimpedance) were measured at baseline and follow-up by trained field interviewers. RESULTS: Only participants with the atypical subtype of MDD at baseline revealed a higher increase in adiposity during follow-up than participants without MDD. The associations between this MDD subtype and body mass index (β = 3.19; 95% CI, 1.50-4.88), incidence of obesity (odds ratio, 3.75; 95% CI, 1.24-11.35), waist circumference in both sexes (β = 2.44; 95% CI, 0.21-4.66), and fat mass in men (β = 16.36; 95% CI, 4.81-27.92) remained significant after adjustments for a wide range of possible cofounding. CONCLUSIONS AND RELEVANCE: The atypical subtype of MDD is a strong predictor of obesity. This emphasizes the need to identify individuals with this subtype of MDD in both clinical and research settings. Therapeutic measures to diminish the consequences of increased appetite during depressive episodes with atypical features are advocated.

Does Interviewer-Respondent Socio-Demographic Matching Increase Cooperation in Centralized CATI Household Panels?

Overall it seems that age and gender interviewer characteristics are relevant in achieving higher cooperation rates by telephone panel members. This appears to be the case especially for older male interviewers, who perform the best on gaining cooperation across different types of respondents. This holds if important interviewer covariates like experience are controlled for. There is no evidence that special sex age or sex matches yield a higher cooperation. It may be that not only the perceived authority of the institution that sponsors the survey plays a role when it comes to cooperation (Groves et al., 1992) but also of the interviewer who asks for this cooperation. Presumably older men have more authority to convince sample members to participate. A simple recommendation is to use as many older male interviewers as possible for the recruitment phase. It is likely that this strategy would also be successful in other western cultures than Switzerland.