Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency

X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a severe inherited neurodegenerative disease, associated with the accumulation of very long-chain fatty acids (VLCFA). The recent unexpected observation that the accumulation of VLCFA in tissues of the Abcd1-deficient mouse model for X-ALD is not due to a deficiency in VLCFA degradation, led to the hypothesis that mitochondrial abnormalities might contribute to X-ALD pathology. Here, we report that in spite of substantial accumulation of VLCFA in whole muscle homogenates, normal VLCFA levels were detected in mitochondria obtained by organellar fractionation. Polarographic analyses of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between X-ALD and control mice. Moreover, analysis by electron microscopy, revealed normal size, structure and localization of mitochondria in muscle of both groups. Similar to the results obtained in skeletal muscle, the mitochondrial enzyme activities in brain homogenates of Abcd1-deficient and wild-type animals also did not differ. Finally, studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls revealed no abnormalities. Thus, we conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa-mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice.     

THE EFFECTS OF CHANGES IN AROUSAL LEVEL ON CRITICAL FLICKER FUSION FREQUENCY AND FIGURAL REVERSAL TASKS

The present study was designed to investigate the relationship between intra-and inter-individual differences in arousal level and performance on both critical flicker fusion frequency and figural reversal tasks. Forty male undergraduate Ss were used. Electrical skin conductance was used as the indicant of arousal level. For the intra-individual comparisons white noise was used to increase the Ss’arousal levels. Significant inverted U-shaped relationships were found between both flicker fusion thresholds and rates of figural reversal and skin conductance between individuals. A significant curvilinear relationship was found between rates of figural reversal and level of conductance within individuals. No significant curvilinear relationship was found between flicker fusion thresholds and level of conductance within individuals.     

Surface properties of lymphocyte subpopulations in autoimmune NZB/NZW F1 hybrid mice: alterations correlated with the immunodeficiency of aging

Partitioning in a two-polymer aqueous phase system was used to probe the surface properties of lymphoid cell subpopulations in aged male NZB/NZW F1 hybrid (B/W) mice, an important model of autoimmunity, immunodeficiency, and lymphoid malignancy. Spleen cells were fractionated by countercurrent distribution (CCD, a multiple-step extraction procedure) in a charged dextran-polyethylene glycol system. CCD of spleen cells from young, clinically normal male B/W mice yielded several broad distribution patterns which frequently had two or more peaks. Analysis of differentiation antigens and functional properties of cells from different parts of the distribution revealed a subfractionation of the three major lymphocyte subpopulations. B lymphocytes had a low partition coefficient (K); T cells had an intermediate K and null cells had the highest K. To examine the partitioning behavior of T lymphocytes, spleen cells which were nonadherent to nylon wool columns were subjected to CCD. Nonadherent cells from young B/W mice consistently gave a single peak with high K. Aged mice (18 months) usually had nonadherent cells with a predominantly low K. In some experiments a systematic increase in the number of these cells could be demonstrated with increasing mouse age. An analysis of the adherence and partitioning behavior of lymphocyte subpopulations revealed no change in the adherence properties or proportions of B lymphocytes in aged mice. The large proportion of cells having a low partition coefficient in the nonadherent spleen cell population of old mice appears to be due to an increase in the number of null cells and in a decrease in the K of some T lymphocytes.     

Autistic-spectrum disorders in Down syndrome: further delineation and distinction from other behavioral abnormalities.

The present study extends our previous work characterizing the behavioral features of autistic-spectrum disorder (ASD) in Down syndrome (DS) using the Aberrant Behavior Checklist (ABC) and Autism Behavior Checklist (AutBehav). We examined which specific behaviors distinguished the behavioral phenotype of DS + ASD from other aberrant behavior disorders in DS, by determining the relative contribution of ABC and AutBehav subscales and items to the diagnosis of ASD. A total of 127 subjects (aged 2-24 years; mean age: 8.4 years; approximately 70% male), comprising: a cohort of 64 children and adolescents with DS and co-morbid ASD (DS + ASD), 19 with DS and stereotypic movement disorder (DS + SMD), 18 with DS and disruptive behaviors (DS + DB), and 26 with DS and no co-morbid behavior disorders (DS + none) were examined using the aforementioned measures of aberrant behavior. We found that subjects with DS + ASD showed the most severe aberrant behavior, especially stereotypy compared to DS + none and lethargy/social withdrawal and relating problems compared to DS + SMD. Specifically, relatively simple stereotypic behavior differentiated DS + ASD from DS + DB, whereas odd/bizarre stereotypic and anxious behavior characterized DS + ASD relative to DS + SMD and DS + none. Additionally, in a subset of subjects with DS + ASD and anxiety, social withdrawal was particularly pronounced. Overall, our findings indicate that a diagnosis of DS + ASD represents a distinctive set of aberrant behaviors marked by characteristic odd/bizarre stereotypic behavior, anxiety, and social withdrawal.     

Left ventricular outflow tract obstruction associated with chronic ventricular assist device support

Favorable long-term patient outcome after insertion of a left ventricular assist device (LVAD) as a bridge to recovery or destination therapy for the treatment of end-stage cardiomyopathy is adversely affected by pathophysiologic changes affecting the heart. Alterations in the native aortic valve apparatus, specifically aortic valve cusp fusion, is an example of such a phenomenon and may especially affect patients in cases of bridge to recovery, a rare but reported event. A retrospective review of the last 33 LVAD placements at our institution was conducted, including reviews of operative reports and pathologic examinations of the native hearts. Seven hearts were found to have varying degrees of aortic valve cusp fusion after chronic LVAD support (63-1, 339 days). Five of these patients had native aortic valves, and two had bioprosthetic valves. The left ventricular outflow tracts in two patients were surgically occluded at the time of LVAD insertion. Aortic valve cusp fusion occurs in roughly 25% of patients on chronic LVAD support. This phenomenon may prove to be clinically significant by creating a potential source of emboli and infection. In addition, in the case of myocardial recovery, left ventricular outflow tract obstruction could limit parallel flow and produce suprasystemic ventricular pressures that in turn would elevate left ventricular end diastolic pressures. The latter may contribute to further myocardial injury, ultimately limiting the ability of an otherwise recovered heart to be weaned from LVAD support.     

Rapid identification of dysregulated genes in cutaneous malignant melanoma metastases using cDNA technology

One important application of DNA microarray technology is the simultaneous analysis of gene expression of different mRNAs. Comparison of mRNA patterns of diseased and healthy tissue may help to understand the pathogenesis of a given disorder. In cancer tissue, identified dysregulated genes may serve as new molecular markers for diagnosis or prognosis or may ideally serve as new targets for therapy. Using membrane cDNA array technology, we analyzed gene expression in human melanomas, one of the most aggressive types of cancer with a high metastatic potential and with markedly increased incidence worldwide. To account for the heterogeneity of tumors, we compared total RNA from cutaneous melanoma metastases of 10 different patients with primary human melanocytes. An abundance of genes was dysregulated (up-/downregulated), which involved for example the apoptosis gene growth factor receptor-bound protein 10, Bcl2-associated X membrane protein, Bcl2 antagonist of cell death, glutathione S-transferase theta(1) and glutathione reductase. Ultimately, the identification of melanoma-associated genes may provide a potential therapeutic strategy for identifying and targeting malignant melanoma.