Cognitive Impairment in Myotonic Dystrophy Type 1 Is Associated with White Matter Damage

Objective

To investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1).

Methods

A case-control study including 51 DM1 patients (17 jDM1 and 34 aDM1) and 34 controls was conducted at an academic medical center. Clinical, cognitive and structural MRI evaluations were obtained. Quantitative assessments of regional GM volumes, WM hyperintensities (WMHs), and microstructural WM tract damage were performed. The association between structural brain damage and clinical and cognitive findings was assessed.

Results

DM1 patients showed a high prevalence of WMHs, severe regional GM atrophy including the key nodes of the sensorimotor and main cognitive brain networks, and WM microstructural damage of the interhemispheric, corticospinal, limbic and associative pathways. WM tract damage extends well beyond the focal WMHs. While aDM1 patients had severe patterns of GM atrophy and WM tract damage, in jDM1 patients WM abnormalities exceeded GM involvement. In DM1, WMHs and microstructural damage, but not GM atrophy, correlated with cognitive deficits.

Conclusions

WM damage, through a disconnection between GM structures, is likely to be the major contributor to cognitive impairment in DM1. Our MRI findings in aDM1 and jDM1 patients support the hypothesis of a degenerative (premature aging) origin of the GM abnormalities and of developmental changes as the principal substrates of microstructural WM alterations in DM1.     

Epidemiology and Prognosis of Coagulase-Negative Staphylococcal Endocarditis: Impact of Vancomycin Minimum Inhibitory Concentration

This study describes coagulase-negative staphylococcal (CoNS) infective endocarditis (IE) epidemiology at our institution, the antibiotic susceptibility profile, and the influence of vancomycin minimum inhibitory concentration (MIC) on patient outcomes. One hundred and three adults with definite IE admitted to an 850-bed tertiary care hospital in Barcelona from 1995-2008 were prospectively included in the cohort. We observed that CoNS IE was an important cause of community-acquired and healthcare-associated IE; one-third of patients involved native valves. Staphylococcus epidermidis was the most frequent species, methicillin-resistant in 52% of patients. CoNS frozen isolates were available in 88 patients. Vancomycin MICs of 2.0 μg/mL were common; almost all cases were found among S. epidermidis isolates and did not increase over time. Eighty-five patients were treated either with cloxacillin or vancomycin: 38 patients (Group 1) were treated with cloxacillin, and 47 received vancomycin; of these 47, 27 had CoNS isolates with a vancomycin MIC <2.0 μg/mL (Group 2), 20 had isolates with a vancomycin MIC ≥2.0 μg/mL (Group 3). One-year mortality was 21%, 48%, and 65% in Groups 1, 2, and 3, respectively (P=0.003). After adjusting for confounders and taking Group 2 as a reference, methicillin-susceptibility was associated with lower 1-year mortality (OR 0.12, 95% CI 0.02-0.55), and vancomycin MIC ≥2.0 μg/mL showed a trend to higher 1-year mortality (OR 3.7, 95% CI 0.9-15.2; P=0.069). Other independent variables associated with 1-year mortality were heart failure (OR 6.2, 95% CI 1.5-25.2) and pacemaker lead IE (OR 0.1, 95%CI 0.02-0.51). In conclusion, methicillin-resistant S.epidermidis was the leading cause of CoNS IE, and patients receiving vancomycin had higher mortality rates than those receiving cloxacillin; mortality was higher among patients having isolates with vancomycin MICs ≥2.0 μg/mL.     

Sex-specific differences in chromosome-dependent regulation of vascular reactivity in female consomic rat strains from a SSxBN cross

High-throughput studies in the Medical College of Wisconsin Program for Genomic Applications (Physgen) were designed to link chromosomes with physiological function in consomic strains derived from a cross between Dahl salt-sensitive SS/JrHsdMcwi (SS) and Brown Norway normotensive BN/NHsdMcwi (BN) rats. The specific goal of the vascular protocol was to characterize the responses of aortic rings from these strains to vasoconstrictor and vasodilator stimuli (phenylephrine, acetylcholine, sodium nitroprusside, and bath hypoxia) to identify chromosomes that either increase or decrease vascular reactivity to these vasoactive stimuli. Because previous studies demonstrated sex-specific quantitative trait loci (QTLs) related to regulation of cardiovascular phenotypes in an F2 cross between the parental strains, males and females of each consomic strain were included in all experiments. As there were significant sex-specific differences in aortic sensitivity to vasoconstrictor and vasodilator stimuli compared with the parental SS strain, we report the results of the females separately from the males. There were also sex-specific differences in aortic ring sensitivity to these vasoactive stimuli in consomic strains that were fed a high-salt diet (4% NaCl) for 3 wk to evaluate salt-induced changes in vascular reactivity. Differences in genetic architecture could contribute to sex-specific differences in the development and expression of cardiovascular diseases via differential regulation and expression of genes. Our findings are the first to link physiological traits with specific chromosomes in female SS rats and support the idea that sex is an important environmental variable that plays a role in the expression and regulation of genes.     

The effects of spirotetramat on life history traits and population growth of Tetranychus urticae (Acari: Tetranychidae)

The effects of spirotetramat, a tetramic acid derivative, on gross fertility, net fertility, female longevity and the instantaneous rate of increase of two-spotted spider mite, Tetranychus urticae (Acari: Tetranychidae) were investigated after treatment of female teleiochrysalises (the first assay) and pre-ovipositional females (the second assay). Spirotetramat was applied to the leaf discs by Potter spray tower and the following series of concentrations was applied: 200, 60, 18, 5.4 and 1.62 mg/l. In both assays after 24 h of exposure, surviving females without symptoms of poisoning were used for further procedure. In the first assay, gross fertility of treated females was reduced by 2.4–64.7% and net fertility by 12.4–88.8%, compared to the control. Gross fertility of the females treated with 1.62 and 5.4 mg/l did not significantly differ from the control, whereas all concentrations, except the lowest, significantly reduced net fertility and female longevity. Treatments with 200, 60, and 18 mg/l significantly reduced the instantaneous rate of increase. In the second assay, gross fertility and net fertility were reduced by 43.7–93.3% and 73.8–98.5%, respectively. All concentrations, except the lowest, significantly reduced gross fertility, whereas net fertility and longevity in all treated females were significantly lower compared to the control. All concentrations, except the lowest, significantly reduced the instantaneous rate of increase, provided that concentrations of 200, 60 and 18 mg/l caused population decline. The effects of spirotetramat and its impact on T. urticae management are discussed.     

ARF6-mediated endosomal transport of Telencephalin affects dendritic filopodia-to-spine maturation

Dendritic filopodia are dynamic structures thought to be the precursors of spines during synapse development. Morphological maturation to spines is associated with the stabilization and strengthening of synapses, and can be altered in various neurological disorders. Telencephalin (TLN/intercellular adhesion molecule-5 (ICAM5)) localizes to dendritic filopodia, where it facilitates their formation/maintenance, thereby slowing spine morphogenesis. As spines are largely devoid of TLN, its exclusion from the filopodia surface appears to be required in this maturation process. Using HeLa cells and primary hippocampal neurons, we demonstrate that surface removal of TLN involves internalization events mediated by the small GTPase ADP-ribosylation factor 6 (ARF6), and its activator EFA6A. This endocytosis of TLN affects filopodia-to-spine transition, and requires Rac1-mediated dephosphorylation/release of actin-binding ERM proteins from TLN. At the somato-dendritic surface, TLN and EFA6A are confined to distinct, flotillin-positive membrane subdomains. The co-distribution of TLN with this lipid raft marker also persists during its endosomal targeting to CD63-positive late endosomes. This suggests a specific microenvironment facilitating ARF6-mediated mobilization of TLN that contributes to promotion of dendritic spine development.     

Aziridinyl peptides as inhibitors of cysteine proteases: effect of a free carboxylic acid function on inhibition

Peptides containing aziridine-2,3-dicarboxylate (Azi) as electrophilic building block are evaluated as inhibitors of the cysteine proteases papain, cathepsin B, cathepsin L and clostripain. The influence of a free carboxylic acid as functional group at different positions of the inhibitor molecule on inhibition is analyzed. Structure-activity relationships and binding mode hypotheses are discussed. In contrast to the bacterial enzyme clostripain, the papain like mammalian proteases (cathepsins) are irreversibly inactivated by aziridinyl peptides. N-Unsubstituted aziridines are much more potent inhibitors of papain and cathepsins if they contain the free carboxylic acid attached to the aziridine ring (HOAzi-Leu-ProOBzl). Two free carboxylic acid functions at the aziridine ring are necessary for good inhibition of these enzymes by N-acylated aziridinyl peptides (BOC-Phe-Azi(OH)2). Chimeric bispeptidyl derivatives are selective CB inhibitors if the free acid is located at the C-terminus of the peptide (BOC-Phe-(EtO)Azi-Leu-ProOH). Clostripain is only inhibited by aziridinyl peptide esters.