Distributed cortical networks for focused auditory attention and distraction

We used behavioral measures and functional magnetic resonance imaging (fMRI) to study the effects of parametrically varied task-irrelevant pitch changes in attended sounds on loudness-discrimination performance and brain activity in cortical surface maps. Ten subjects discriminated tone loudness in sequences that also included infrequent task-irrelevant pitch changes. Consistent with results of previous studies, the task-irrelevant pitch changes impaired performance in the loudness discrimination task. Auditory stimulation, attention-enhanced processing of sounds and motor responding during the loudness discrimination task activated supratemporal (auditory cortex) and inferior parietal areas bilaterally and left-hemisphere (contralateral to the hand used for responding) motor areas. Large pitch changes were associated with right hemisphere supratemporal activations as well as widespread bilateral activations in the frontal lobe and along the intraparietal sulcus. Loudness discrimination and distracting pitch changes activated common areas in the right supratemporal gyrus, left medial frontal cortex, left precentral gyrus, and left inferior parietal cortex.     

Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B

Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether beta-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a beta-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyper-glycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located alpha-cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of beta-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.     

Two separate mechanisms underlie auditory change detection and involuntary control of attention

We used behavioral and event-related potential (ERP) measures to study the neural mechanisms of involuntary attention switching to changes in unattended sounds. Our subjects discriminated two equiprobable sounds differing in frequency (fundamental frequency 186 or 196 Hz) while task-irrelevant intensity decrements or increments (-3, -6, -9, +3, +6, or +9 dB, standard intensity 60 dB HL) infrequently occurred in the same sounds. In line with the results of previous studies, discrimination performance deteriorated with increasing magnitude of the task-irrelevant intensity change. However, these distraction effects were dissimilar for intensity increments and decrements: while there were no differences in reaction time (RT) between intensity decrements and increments, hit rates (HR) were lower for large intensity increments than for large decrements. ERPs to task-irrelevant intensity increments and decrements were also distinctly different: the response to intensity increments consisted of an N1 enhancement, mismatch negativity (MMN), and P3a, while the response to intensity decrements consisted only of MMN. These results are consistent with the assumption that two separate mechanisms (indexed by N1 and MMN) underlie auditory change detection. However, the finding that distinct distraction effects were obtained for both intensity decrements and increments but that the P3a is elicited only by the intensity increments seems to suggest that P3a may not be regarded as a general index of attentional shift but rather it is only generated in conditions in which an enhanced N1 is elicited, too.     

Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma

The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.     

Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase.

We have cloned a cDNA for a myocardial cGMP-inhibited cAMP phosphodiesterase (cGI PDE) from a human heart cDNA library in lambda Zap II. The open reading frame [3.5 kilobases (kb)] of cDNA clone n.13.2 (7.7 kb) encodes a protein of 125 kDa. In Northern blots of total human ventricle RNA, a single mRNA species (8.3 kb) hybridized with a 4-kb EcoRI restriction fragment of clone n.13.2 cDNA (containing the entire open reading frame). The carboxyl-terminal region of the deduced amino acid sequence of the cGI PDE contains the putative catalytic domain conserved among mammalian PDE families. A partial cDNA clone, n.2, encoding a truncated, 54-kDa cGI PDE containing the conserved domain was expressed as a catalytically active fusion protein in Escherichia coli. cAMP hydrolytic activity was inhibited by cGMP and OPC 3911 but not by rolipram. Thus, this report provides direct proof that the conserved domain contains the catalytic core of cGI PDEs.