Oxidative stress and mitochondrial dynamics malfunction are linked in Pelizaeus‐Merzbacher disease

Pelizaeus‐Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP‐tg^66/66) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient‐derived fibroblasts and spinal cords of the PLP‐tg^66/66 mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient''s fibroblasts, which was prevented by the antioxidant N‐acetyl‐cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient''s fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP‐tg^66/66 mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention.     

Reproducibility of fetal lung volume measurements with 3-dimensional ultrasonography.

OBJECTIVE: To build a nomogram of normal fetal lung volumes and to assess the reproducibility of measurements using 3-dimensional ultrasonography. METHODS: Inclusion criteria were healthy women, singleton normal pregnancies, reliable dating, and 20 to 30 weeks' gestation. Exclusion criteria were discordance between clinical and ultrasonographic dating, patients lost to follow-up, and birth weight disorders. Patients were scanned at intervals longer than 2 weeks. Three volumes were acquired for each patient; only data from the volume with the best image quality was used for analysis. Volumes were rated and measured by the manual tracing method. We recorded whether the clavicle was visualized. Only good-quality volumes were included in analysis. The best volume was chosen, and each lung was measured. RESULTS: A total of 75 patients were studied over a 9-month period, from which 182 volumes were analyzed. Of the 182 volumes, 15 (8.2%) were excluded for poor quality. The remaining 167 volumes were included in the final analysis. In 83 volumes (50%), the clavicle was not visualized. The best fit for total lung volume was a second-degree polynomial regression curve. Lung volume was 10.28 mL at 20 weeks and 51.49 mL at 30 weeks. Assessment of agreement was studied by selection of 40 volumes. Intraobserver variability was 5.48 mL (10.6%) and 3.07 mL (5.96%). Interobserver variability was 7 mL. CONCLUSIONS: Our findings suggest that 3-dimensional ultrasonographically derived measurements are reliable and reproducible up to 30 weeks if a standard measurement technique is used.     

Influência da dose de propofol e dos componentes sanguíneos na duração das convulsões elétricas em eletroconvulsoterapia

Background and objectives

Propofol is commonly employed as a hypnotic agent to perform electroconvulsive therapy, but it exhibits also anticonvulsant properties. The main objective was to study the effect of the weight‐adjusted dose of propofol on duration of the electrical seizure. Secondary objectives were to study the effect of absolute dose of propofol on duration of electrical seizure, the effect of both absolute and weight‐adjusted doses on values of bispectral index, and the influence of blood chemistry on anticonvulsant effect.

Thymidylate synthase germline polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy based on 5-fluorouracil

Purpose

Chemoradiotherapy using 5-fluorouracil has shown to be effective treatment for rectal cancer. Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. However, the predictive role of TS levels in early stage rectal cancer is not yet well understood. We analyzed the value of TS gene polymorphisms as a predictive marker in patients with stage II and III rectal cancer treated with preoperative concomitant radiotherapy and fluoropyrimidine-based chemotherapy.

Methods and materials

Between 1998 and 2007, blood samples were obtained from 51 patients with stage II/III rectal cancer. Forty patients were T2–3 (78%), 11 were T4 (22%), and 59% were N+. DNA was extracted from peripheral blood, and the genotypes were analyzed using PCR-restriction fragment length polymorphism and automated sequencing techniques.

Results

The *3/*3 thymidylate synthase genotype was associated with a higher response rate (pathological complete remission and microfoci residual tumor; 61 vs. 22% in *2/*2 and *2/*3; P = 0.013). In the multivariate analysis, the *3/*3 thymidylate synthase genotype was also an independent prognostic factor for better survival (P < 0.05).

Conclusions

The thymidylate synthase genotype might help to identify patients with stage II/III rectal cancer who could benefit from pre- and postoperative fluorouracil-based chemotherapy.     

MRI and cognitive impairment in Parkinson's disease

Patients with Parkinson's disease (PD) may present impairment in cognitive functions even at early stages of the disease. When compared with the general population, their risk of dementia is five to six times higher. Recent investigations using structural MRI have shown that dementia in PD is related to cortical structural changes and that specific cognitive dysfunctions can be attributed to atrophy in specific structures. We review the structural MRI studies carried out in PD using either a manual region of interest (ROI) approach or voxel‐based morphometry (VBM). ROI studies have shown that hippocampal volume is decreased in patients with PD with and without dementia; in addition, hippocampal atrophy correlated with deficits in verbal memory. VBM studies have demonstrated that dementia in PD involves structural changes in limbic areas and widespread cortical atrophy. Findings in nondemented patients with PD are less conclusive, possibly because cognitively heterogeneous groups of patients have been studied. Patients with PD with cognitive impairment and/or visual hallucinations present greater brain atrophy than patients without these characteristics. These findings suggest that cortical atrophy is related to cognitive dysfunction in PD and precedes the development of dementia. Structural MRI might therefore provide an early marker for dementia in PD. © 2009 Movement Disorder Society     

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

Lysinuric protein intolerance (LPI) is a rare autosomal inherited disease caused by defective cationic aminoacid transport 4F2hc/y(+)LAT-1 at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is a multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. The SLC7A7 gene, which encodes the y(+)LAT-1 protein, is mutated in LPI patients. Mutation analysis of the promoter localized in intron 1 and all exons of the SLC7A7 gene was performed in 11 patients from 9 unrelated LPI families. Point mutation screening was performed by exon direct sequencing and a new multiplex ligation probe amplification (MLPA) assay was set up for large rearrangement analysis. Eleven SLC7A7-specific mutations were identified, seven of them were novel: p.L124P, p.C425R, p.R468X, p.Y274fsX21, c.625+1G>C, DelE4-E11 and DelE6-E11. The novel large deletions originated by the recombination of Alu repeats at introns 3 and 5, respectively, with the same AluY sequence localized at the SLC7A7 3' region. The novel MLPA assay is robust and valuable for LPI molecular diagnosis. Our results suggest that genomic rearrangements of SLC7A7 play a more important role in LPI than has been reported, increasing the detection rate from 5.1 to 21.4%. Moreover, the 3' region AluY repeat could be a recombination hot spot as it is involved in 38% of all SLC7A7 rearranged chromosomes described so far.