Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia

Resveratrol, a naturally occurring polyphenol, has been shown to protect the heart and brain against ischemic injury. The current study investigated the effects of administration with either a 1 or 10-mg/kg dose of resveratrol on CA1 neuronal injury and behavioral/cognitive impairments after 10-min global ischemia in rats. The open-field, eight-arm radial maze and object recognition tests served to evaluate effects of resveratrol treatment on ischemia-induced locomotor activity, and spatial and recognition memory impairments, respectively. CA1 and CA3 neuronal injury was assessed upon completion of behavioral testing, 85 days postischemia. A separate series of groups served to assess neuronal injury at 7 days postischemia. Global ischemia (10 min) led to approximately 50% CA1 cell injury, which was prevented at both short (7 days) and long (85 days) postischemic intervals by resveratrol treatment. Importantly, despite comparable neuronal protection, the two resveratrol doses showed distinct behavioral effects. Thus, the 10-mg/kg resveratrol dose led to an enhanced locomotor activity in the open-field 4-days postischemia and an impaired spatial memory in the delayed nonmatching to sample and delayed matching to sample radial-maze tasks initiated on day 13 postischemia. These findings suggest independent actions of resveratrol on distinct physiological systems mediating cellular survival and functional recovery and dose-related actions of the polyphenol on behavioral and memory processes.     

NOTCH, a new signaling pathway implicated in holoprosencephaly

Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization redundant 6qter deletions, DELTA Like 1 (DLL1), which is a ligand of NOTCH. We show that DLL1 is co-expressed in the developing chick forebrain with Fgf8. By treating chick embryos with a pharmacological inhibitor, we demonstrate that DLL1 interacts with FGF signaling pathway. Moreover, a mutation analysis of DLL1 in HPE patients revealed a three-nucleotide deletion. These various findings implicate DLL1 in early patterning of the forebrain and identify NOTCH as a new signaling pathway involved in HPE.     

Neuropsychological and activity of daily living script performance in patients with positive or negative schizophrenia

Cognitive and psychiatric determinants of impairment of complex activities of daily living (ADLs) were investigated in 33 schizophrenic patients and 16 normal comparison subjects. The schizophrenic patients were cognitively impaired and were deficient in the ADL. However, the impairment of ADL could not be explained specifically by impairment of higher-order executive function or by negative symptoms: memory functions were more related to impairment of ADL and positive symptoms as much as the negative ones. Positive symptoms were significantly related to commissive errors in the ADL, whereas negative symptoms were nonsignificantly related to omissive errors. Negative symptoms were significantly more related to memory impairment than to impairment on measures of higher-order executive function (working memory). This investigation demonstrates that an ecologically oriented approach to test development and measurement of ADL is fruitful in understanding schizophrenia-especially if it is constrained by cognitive constructs compatible with the phenomenology of the disease.     

Dystrophin-dependent muscle degeneration requires a fully functional contractile machinery to occur in C. elegans

In mammals, the lack of dystrophin leads to a degeneration of skeletal muscles. It has been known for many years that this pathology can be blocked by denervation or immobilization of muscles. It is not yet clear, however, whether this suppressing effect is due to the absence of fiber contraction per se, or to other mechanisms which may be induced by such treatments. We took advantage of the genetic tools available in the animal model Caenorhabditis elegans to address this question. Using RNA interference and existing mutants, we genetically impaired the excitation-contraction cascade at specific points in a dystrophin-deficient C. elegans strain which normally undergoes extensive muscle degeneration. Our data show that reducing sarcomere contraction by slightly impairing the contraction machinery is sufficient to dramatically suppress muscle degeneration. Thus, it is the physical tension exerted on the muscle fibers which is the key deleterious event in the absence of dystrophin.     

Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors

N-Methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors endowed with unique pharmacological and functional properties. In particular, their high permeability to calcium ions confers on NMDARs a central role in triggering long term changes in synaptic strength. Under excitotoxic pathological conditions, such as those occurring during brain trauma, stroke, or Parkinson's or Huntington's diseases, calcium influx through NMDAR channels can also lead to neuronal injury. This argues for the use of NMDAR antagonists as potential therapeutic agents. To date, the most promising NMDAR antagonists are ifenprodil and derivatives, compounds that act as noncompetitive inhibitors selective for NMDARs containing the NR2B subunit. Recent studies have identified the large N-terminal domain (NTD) of NR2B as the region controlling ifenprodil sensitivity of NMDARs. We present here a detailed characterization of the ifenprodil binding site using both experimental and computational approaches. 3D homology modeling reveals that ifenprodil fits well in a closed cleft conformation of the NRB NTD; however, ifenprodil can adopt either of two possible binding orientations of opposite direction. By studying the effects of cleft mutations, we show that only the orientation in which the phenyl moiety points deep toward the NTD hinge is functionally relevant. Moreover, based on our model, we identify novel NTD NR2B residues that are crucial for conferring ifenprodil sensitivity and provide functional evidence that these residues directly interact with the ifenprodil molecule. This work provides a general insight into the origin of the subunit-selectivity of NMDAR noncompetitive antagonists and offer clues for the discovery of novel NR2B-selective antagonists.     

Abdominal pain: coronal reformations from isotropic voxels with 16-section CT--reader lesion detection and interpretation time

PURPOSE: To retrospectively assess if reader detection of intraabdominal pathologic findings on coronal reformations from isotropic voxels at 16-section computed tomography (CT) was similar to reader detection on transverse scans. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study, and a waiver of informed consent was obtained. Twenty-nine consecutive patients (12 men, 17 women; mean age, 48 years; age range, 21-93 years) with abdominal pain underwent 16-section CT with coronal reformations. Eight independent readers reviewed randomized scans (transverse and coronal) and identified pathologic findings in multiple organ systems. Timing for each interpretation was recorded. One month later, readers reviewed the scan reformatted in the other imaging plane. Agreement between transverse and coronal scans was measured by using Cohen kappa coefficients. RESULTS: Agreement was moderate to near perfect between transverse and coronal interpretations for intraabdominal anatomic and pathologic findings (kappa=0.59-1.00). For transverse interpretations, more thoracic pathologic findings were noted than for coronal interpretations; for coronal interpretations, more lymph nodes were noted than for transverse interpretations. Mean transverse interpretation time was 4.9 minutes+/-1.1 (standard deviation) (range, 2.9-6.5 minutes); mean coronal interpretation time was 5.1 minutes+/-0.8 (range, 3.3-6.7 minutes). For each reader, there was no statistically significant difference in interpretation time between transverse and coronal scans (P=.06). CONCLUSION: With regard to the presence of intraabdominal pathologic findings, coronal reformations from isotropic voxels are similar to transverse scans in terms of interpretation time and reader agreement.     

Incidence and Risk Factors of Insomnia in a Population-Based Sample

Introduction:

Despite the high prevalence of insomnia, there is little information about its incidence and risk factors. This study estimated the incidence of insomnia and examined potential risk factors in a cohort of good sleepers followed over a one-year period.

Methods.

Participants were 464 good sleepers who completed 3 postal evaluations over a one-year period (i.e., baseline, 6 months, and 12 months). Questionnaires assessed sleep, psychological and personality variables, stressful life events and coping skills, and health-related quality of life. Participants were categorized into 3 subgroups: (a) good sleepers (i.e., participants who remained good sleepers at the 3 assessments), (b) insomnia symptoms incident cases (i.e., developed insomnia symptoms either at 6- or 12-month follow-up), and (c) insomnia syndrome incident cases (i.e., developed an insomnia syndrome either at 6- or 12- month follow-up).

Results:

One-year incidence rates were 30.7% for insomnia symptoms and 7.4% for insomnia syndrome. These rates decreased to 28.8% and 3.9% for those without prior lifetime episode of insomnia. Compared to good sleepers and insomnia symptoms incident cases, insomnia syndrome incident cases presented a premorbid psychological vulnerability to insomnia, characterized by higher depressive and anxiety symptoms, lower extraversion, higher arousability, and poorer self-rated mental health at baseline. They also presented a higher level of bodily pain and a poorer general health. Five variables were associated with a new onset of an insomnia syndrome: previous episode of insomnia, positive family history of insomnia, higher arousability predisposition, poorer self-rated general health, and higher bodily pain.

Conclusion:

The one-year insomnia incidence rate was very high and several psychological and health factors were associated with new onset insomnia. Improved knowledge about the nature of these predisposing factors would be helpful to guide the development of effective public health prevention and intervention programs to promote better sleep quality.

Citation:

LeBlanc M; Mérette C; Savard J; Ivers H; Baillargeon L; Morin CM. Incidence and risk factors of insomnia in a population-based sample. SLEEP 2009;32(8):1027-1037.