White matter hyperintensities alter functional organization of the motor system

Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 ± 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits.     

Admission levels of soluble CD137 are increased in patients with acute pancreatitis and are associated with subsequent complications

The progression of acute pancreatitis to necrotizing pancreatitis which often results in high morbidity and mortality is difficult to predict. Here we report that serum concentrations of sCD137 are increased in patients with acute pancreatitis. Admission levels and 10-day median sCD137 levels positively correlate with markers of biliary pancreatitis and the 10-day sCD137 median is significantly higher in metabolic than in alcoholic pancreatitis. Serum concentrations of sCD137 at time of admission and the 10-day median of sCD137 correlate with the Ranson and APACHE II disease scores but not with the radiological Balthazar and Schroeder scores that reflect pancreatic and peripancreatic necrosis. Further, sCD137 levels correlate with the probability of complications and lethality. The association of sCD137, a product of activated T cells, with the severity of acute pancreatitis suggests that T cells contribute to the pathogenesis of acute pancreatitis.     

Adiponectin reduces connective tissue growth factor in human hepatocytes which is already induced in non-fibrotic non-alcoholic steatohepatitis

Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor β (TGFβ). Recently we have shown that the hepatoprotective adipokine adiponectin downregulates CTGF in primary human hepatocytes (PHH). In the current study, the mechanisms mediating suppression of CTGF by adiponectin and the well described downstream effector of adiponectin receptor 2 (AdipoR2), peroxisome proliferator activated receptor α (PPARα), were analyzed in more detail. Adiponectin downregulated CTGF mRNA and protein in primary human hepatocytes (PHH) and suppression was blocked by a PPARα antagonist indicating that AdipoR2 is involved. The PPARα agonists fenofibrate and WY14643 also reduced CTGF protein in these cells. Adiponectin further impaired TGFβ-mediated upregulation of CTGF. Phosphorylation of the TGFβ downstream effectors SMAD2 and –3 was reduced in PHH incubated with adiponectin or PPARα agonists suggesting that early steps in TGFβ signal transduction are impaired. CTGF and TGFβ mRNA levels were increased in human non-fibrotic non-alcoholic steatohepatitis (NASH), and here AdipoR2 expression was significantly reduced. Current data show that CTGF and TGFβ are already induced in non-fibrotic NASH and this may be partly explained by low adiponectin bioactivity which interferes with TGFβ signaling by reducing phosphorylation of SMAD2/3 and by downregulating CTGF.     

Genome-wide identification of Streptococcus pneumoniae genes essential for bacterial replication during experimental meningitis

Meningitis is the most serious of invasive infections caused by the Gram-positive bacterium Streptococcus pneumoniae. Vaccines protect only against a limited number of serotypes, and evolving bacterial resistance to antimicrobials impedes treatment. Further insight into the molecular pathogenesis of invasive pneumococcal disease is required in order to enable the development of new or adjunctive treatments and/or pneumococcal vaccines that are efficient across serotypes. We applied genomic array footprinting (GAF) in the search for S. pneumoniae genes that are essential during experimental meningitis. A total of 6,000 independent TIGR4 marinerT7 transposon mutants distributed over four libraries were injected intracisternally into rabbits, and cerebrospinal fluid (CSF) was collected after 3, 9, and 15 h. Microarray analysis of mutant-specific probes from CSF samples and inocula identified 82 and 11 genes mutants of which had become attenuated or enriched, respectively, during infection. The results point to essential roles for capsular polysaccharides, nutrient uptake, and amino acid biosynthesis in bacterial replication during experimental meningitis. The GAF phenotype of a subset of identified targets was followed up by detailed studies of directed mutants in competitive and noncompetitive infection models of experimental rat meningitis. It appeared that adenylosuccinate synthetase, flavodoxin, and LivJ, the substrate binding protein of a branched-chain amino acid ABC transporter, are relevant as targets for future therapy and prevention of pneumococcal meningitis, since their mutants were attenuated in both models of infection as well as in competitive growth in human cerebrospinal fluid in vitro.     

Sequencing and Functional Annotation of Avian Pathogenic Escherichia coli Serogroup O78 Strains Reveal the Evolution of E. coli Lineages Pathogenic for Poultry via Distinct Mechanisms

Avian pathogenic Escherichia coli (APEC) causes respiratory and systemic disease in poultry. Sequencing of a multilocus sequence type 95 (ST95) serogroup O1 strain previously indicated that APEC resembles E. coli causing extraintestinal human diseases. We sequenced the genomes of two strains of another dominant APEC lineage (ST23 serogroup O78 strains χ7122 and IMT2125) and compared them to each other and to the reannotated APEC O1 sequence. For comparison, we also sequenced a human enterotoxigenic E. coli (ETEC) strain of the same ST23 serogroup O78 lineage. Phylogenetic analysis indicated that the APEC O78 strains were more closely related to human ST23 ETEC than to APEC O1, indicating that separation of pathotypes on the basis of their extraintestinal or diarrheagenic nature is not supported by their phylogeny. The accessory genome of APEC ST23 strains exhibited limited conservation of APEC O1 genomic islands and a distinct repertoire of virulence-associated loci. In light of this diversity, we surveyed the phenotype of 2,185 signature-tagged transposon mutants of χ7122 following intra-air sac inoculation of turkeys. This procedure identified novel APEC ST23 genes that play strain- and tissue-specific roles during infection. For example, genes mediating group 4 capsule synthesis were required for the virulence of χ7122 and were conserved in IMT2125 but absent from APEC O1. Our data reveal the genetic diversity of E. coli strains adapted to cause the same avian disease and indicate that the core genome of the ST23 lineage serves as a chassis for the evolution of E. coli strains adapted to cause avian or human disease via acquisition of distinct virulence genes.     

Pupil and salivary indicators of autonomic dysfunction in autism spectrum disorder

Dysregulated tonic pupil size has been reported in autism spectrum disorder (ASD). Among the possible sources of this dysregulation are disruptions in the feedback loop between norepinephrine (NE) and hypothalamic systems. In the current study, we examined afternoon levels of salivary alpha‐amylase (sAA, a putative correlate of NE) and cortisol (used to assess stress‐based responses) in two independent samples of children with ASD. We found a larger pupil size and lower sAA levels in ASD, compared to typical and clinical age‐matched controls. This was substantiated at the individual level, as sAA levels were strongly correlated with tonic pupil size. Relatively little diurnal variation in sAA taken in the home environment in the ASD group was also observed, while typical controls showed a significant linear increase throughout the day. Results are discussed in terms of potential early biomarkers and the elucidation of underlying neural dysfunction in ASD. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 465–482, 2013     

Manganese superoxide dismutase is reduced in the liver of male but not female humans and rodents with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver diseases. Oxidative stress is one of the pathogenic mechanisms contributing to the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH). Manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidative enzyme and here its expression in rodent and human NAFLD has been analyzed. MnSOD is found reduced in the liver of male mice fed a high fat diet and male ob/ob mice. Female mice fed an atherogenic diet to induce NASH have MnSOD protein levels comparable to controls. In a cohort of 30 controls, 41 patients with fatty liver and 39 NASH patients, MnSOD mRNA is significantly lower in the steatotic and NASH liver. When analyzed in both genders separately reduction of MnSOD expression is only found in males. Here, MnSOD mRNA negatively correlates with steatosis grade but not with extent of fibrosis or inflammation. MnSOD is, however, not reduced in primary human hepatocytes (PHH) treated with palmitate or oleate to increase cellular triglycerides. Lipopolysaccharide, TNF, IL-6, TGFβ and leptin which are all raised in NAFLD do not affect MnSOD in PHH. Adiponectin which attenuates oxidative stress partly by increasing MnSOD in macrophages does not induce MnSOD in PHH. In summary, current data show that hepatic MnSOD is reduced in male but not female humans and rodents with NAFLD.     

Stability of event-related (de-) synchronization during brain–computer interface-relevant mental tasks

ObjectiveThe aim of this study was to examine the temporal stability of event-related desynchronization/synchronization (ERD/S) patterns over several sessions as a function of mental task, frequency band, brain region and time interval during the imagery period.MethodsNine volunteers participated in four sessions within 2 weeks of multi-channel EEG recordings. They performed seven mental tasks (i.e. mental rotation, word association, auditory imagery, mental subtraction, spatial navigation, imagery of familiar faces, motor imagery) during 7-s imagery periods. Cronbach’s alpha coefficients were calculated over sessions to evaluate the stability of ERD/S values.ResultsThe word association, mental subtraction and spatial navigation task showed highest stability. Cronbach’s alpha coefficients were highest in the alpha bands (7–10, 10–13 Hz), poorer in the beta bands (13–20, 20–30 Hz) and poorest in the theta band (4–7 Hz). In the majority of tasks, the first time interval and posterior left regions showed highest stability and strongest ERD in the alpha and beta bands.ConclusionStability of ERD/S is strongly dependent on the specific task and differs between time intervals of the imagery period. Furthermore, stability was related to ERD in the alpha and beta bands.SignificanceThe reliability of brain activation patterns is highly relevant for brain–computer interface developments.     

Early socio-communicative forms and functions in typical Rett syndrome

Rett syndrome (RTT) is a severe neurological disorder characterized by a developmental regression in motor and speech-language domains. There is, however, limited research on socio-communicative development of affected children before the onset of regression. We analyzed audio–video recordings made by parents of six 9- to 12-month old girls later diagnosed with typical RTT, applying the Inventory of Potential Communicative Acts (IPCA) to identify early communicative forms and functions. Each girl used at least one communicative form (e.g., body movement, eye gaze, or vocalizations) to gain attention and answer, but none were observed to make choices or request information. Varying numbers of children were observed to perform other communicative functions according to the IPCA including social convention, rejecting or requesting an object. Non-verbal forms (e.g., reaching, moving closer, eye contact, smiling) were more common than non-linguistic verbal forms (e.g., unspecified vocalizations, pleasure vocalizations, crying). (Pre-)linguistic verbal forms (e.g., canonical or variegated babbling, proto-words) were not used for communicative purposes. These data suggest that atypical developmental patterns in the socio-communicative domain are evident prior to regression in young individuals later diagnosed with RTT.