Mitochondrial dysfunction is implicated in the pathophysiology of Parkinsons disease (PD), a common age-associated neurodegenerative disease characterized by intraneuronal inclusions (Lewy bodies) and progressive degeneration of the nigrostriatal dopamine (DA) system. It has recently been demonstrated that midbrain DA neurons of PD patients and elderly humans contain high levels of somatic mtDNA mutations, which may impair respiratory chain function. However, clinical studies have not established whether the respiratory chain deficiency is a primary abnormality leading to inclusion formation and DA neuron death, or whether generalized metabolic abnormalities within the degenerating DA neurons cause secondary damage to mitochondria. We have used a reverse genetic approach to investigate this question and created conditional knockout mice (termed MitoPark mice), with disruption of the gene for mitochondrial transcription factor A (Tfam) in DA neurons. The knockout mice have reduced mtDNA expression and respiratory chain deficiency in midbrain DA neurons, which, in turn, leads to a parkinsonism phenotype with adult onset of slowly progressive impairment of motor function accompanied by formation of intraneuronal inclusions and dopamine nerve cell death. Confocal and electron microscopy show that the inclusions contain both mitochondrial protein and membrane components. These experiments demonstrate that respiratory chain dysfunction in DA neurons may be of pathophysiological importance in PD.inclusion ͉ mitochondria ͉ mtDNA ͉ neurodegeneration ͉ Parkinson

Background Endotoxin induces an inflammatory response, with secondary release of cytokines, which can progress to shock and multiple organ failure. We explored whether continuous renal replacement therapy (CRRT) using a modified membrane (oXiris) capable of adsorption could reduce endotoxin and cytokine levels in septic patients. Methods Sixteen patients requiring CRRT for septic shock-associated acute renal failure and who had endotoxin levels >0.03 EU/ml were prospectively randomized in a crossover double-blind design to receive CRRT with an oXiris filter or with a standard filter. Endotoxin and cytokine levels were measured at baseline and 1, 3, 8, 16 and 24 hours after the start of CRRT. Norepinephrine infusion rate and blood lactate levels were monitored. Results During the first filter treatment period, endotoxin levels decreased in 7 of 9 (77.8%) oXiris filter patients, but in only 1 of 6 (16.7%) standard filter patients ( P = 0.02). Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 and interferon (IFN)γ decreased more with the oXiris filter than with the standard filter. Lactate concentration decreased with oXiris (-1.3[-2.2 to -1.1] mmol/l, P = 0.02), but not with the standard filter (+0.15[-0.95 to 0.6]). The norepinephrine infusion rate was reduced during oXiris CRRT, but not during standard filter CRRT. In the second filter treatment period, there was no significant reduction in endotoxin or cytokine levels in either group. Conclusions CRRT with the oXiris filter seemed to allow effective removal of endotoxin and TNF-α, IL-6, IL-8 and IFNγ in patients with septic shock-associated acute renal failure. This may be associated with beneficial hemodynamic effects.

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Phosphate alterations in ICU patients are common and associated with worse morbidity and mortality. Many underlying pathophysiologic mechanisms may play a role. A rapidly changing phosphate level or isolated hypo or hyperphosphatemia should be urgently corrected.

objective:To examine the effect of orlistat on dietary restraint, disinhibition, hunger, and binge eating and to understand the relation between changes in eating behavior and weight maintenance. Methods and Procedures: Subjects were 306 women and men (age: 19-45 years; BMI: 37.5 ± 4.1 kg/m 2 ) included in the Scandinavian Multicenter study of Obese subjects with the Metabolic Syndrome, a 3-year clinical trial of orlistat or placebo following an 8-week very low energy diet (VLED). Outcomes were changes in weight and in the Three Factor Eating Questionnaire (TFEQ) and Binge Eating Scale (BES) between screening and 17 and 33 months after randomization. As reported previously, weight gain following VLED was lower in subjects treated with orlistat than with placebo. Results: Compared to screening results, dietary restraint was increased and disinhibition, hunger, and binge eating were decreased in both groups. These changes were similar in both groups with the exception of the hunger score at month 33 that was reduced more in the placebo than in the orlistat group (difference between groups −1.1 (95% CI (−2.0, −0.2)) P = 0.014). In multivariate analyses, scores for restraint, disinhibition and binge eating were associated with weight loss after adjustment for BMI, gender, age, and treatment (all P ≤ 0.002, model R 2 = 0.12-0.17). Discussion: Orlistat did not affect eating behavior differently in any substantial way than the placebo did in this long-term weight maintenance trial. The results indicate that increased restraint and decreased disinhibition and binge eating are important for sustained weight maintenance in obese subjects with the metabolic syndrome.