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S C Williams

Publications and source records attributed to S C Williams.

At least 73 records · Page 4Linked to original sources

Towards a functional neuroanatomy of self processing: effects of faces and words.

We studied the neural correlates of self vs. non-self judgements using functional magnetic resonance imaging (fMRI). Individually tailored faces and personality trait words were used as stimuli in three experiments (exp.). In the first two experiments, brain activation was measured while subjects viewed morphed versions of either their own (self face exp.) or their partner's face (partner's face exp.), alternating in blocks with presentation of an unknown face. In the self face exp. right limbic areas (hippocampal formation, insula, anterior cingulate), the right middle temporal lobe, left inferior parietal and left prefrontal regions showed signal changes. In the partner's face exp., only the right insula was activated. In the third exp., subjects made decisions about psychological trait adjectives previously categorized as describing their own attributes. Activation was present in the precuneus, the left parietal lobe, left insula/inferior frontal gyrus and the left anterior cingulate. A reaction time advantage was present when subjects responded to self-relevant words. The main area with signal changes during self-reference processing, regardless of the type of stimulus, was the left fusiform gyrus. The self-relevant stimuli engaged to a differential extent long term and working memory, semantic and emotional processes. We suggest that regions activated by these stimuli are engaged in self-processing.

Adult↗

Corpus callosum may be similar in children with ADHD and siblings of children with ADHD.

No previous studies have used morphological neuroimaging to compare children with ADHD with siblings of children with ADHD. To test the hypothesis that the total size of the corpus callosum is altered in children with hyperkinetic disorder, the corpus callosum was outlined from a single midline protondensity weighted slice (containing the septum pellucidum). Fifteen boys with a refined phenotype of ADHD (mean age 10.2 years) and 15 healthy male siblings of children with ADHD (mean age 10.6 years) were enrolled in the study. The two groups were compared for global brain size and the callosal areas of Witelson. No significant differences were found between the study and comparison groups for any of the corpus callosum areas, even after age, global brain size, and handedness were covaried (using MANOVA). In addition, corpus callosum sizes do not seem to differ between children with ADHD and unaffected siblings of children with ADHD. Clinicians should not base their pathophysiological diagnosis of this disorder on an abnormality of callosal development.

Adolescent↗

A differential neural response in obsessive-compulsive disorder patients with washing compared with checking symptoms to disgust.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) have symptoms that predominantly concern washing (washers) or checking (checkers), or both. Functional neuroimaging has been used to identify the neural correlates of the urge to ritualize but has not distinguished between washing and checking symptoms in OCD. We used functional magnetic resonance imaging to compare the neural response to emotive pictures in washers and checkers. METHODS: In one of two 5-minute experiments, washers (N = 7), checkers (N = 7) and age-matched normal controls (N = 14) were scanned while viewing alternating blocks of normally disgusting (rated as disgusting by all subjects) and neutral pictures. In the other experiment, all patients and a normal subgroup (N = 8) viewed alternating blocks of washer-relevant (rated as more disgusting by washers than normal controls or checkers) and neutral pictures. RESULTS: In all subjects, normally disgusting pictures activated visual regions implicated in perception of aversive stimuli and the insula, important in disgust perception. Only in washers were similar regions activated by washer-relevant pictures. In checkers, these pictures activated fronto-striatal regions associated with the urge to ritualize in OCD. Normal controls were more similar in neural response to checkers than washers to these pictures. Both normal controls and checkers had frontal regions activated significantly more by washer-relevant than normally disgusting pictures, and had these regions activated significantly more than washers by washer-relevant pictures. CONCLUSIONS: We demonstrate a differential neural response to washer-relevant disgust in washers and checkers: only washers demonstrate a neural response to washer-relevant disgust associated with emotion perception rather than attention to non-emotive visual detail.

Adolescent↗

Quantitative proton magnetic resonance spectroscopy of the subcortical white matter in motor neuron disease.

BACKGROUND: Using proton magnetic resonance spectroscopy, the authors have previously demonstrated a reduction in the N-acetyl aspartate/(creatine and phosphocreatine) (NAA/(Cr + PCr)) ratio in the motor region in bulbar-onset MND patients, attributed to neuronal loss or dysfunction leading to a reduction in NAA. We have expanded this analysis to evaluate absolute concentrations of NAA, (Cr + PCr) and choline-containing compounds (Cho) in the subcortical white matter in the motor region in 16 MND patients (8 with bulbar onset and 8 with limb onset) and 8 healthy, age-matched controls. METHODS: Single voxel 1H-MRS was performed using a PRESS localization sequence. Metabolite concentrations were determined using the water signal as an internal standard. RESULTS: We found no differences in the concentrations of NAA ([NAA]), (Cr + PCr) ([Cr + PCr]) or Cho ([Cho]) in the motor region on comparing the total MND group and controls (P > 0.3). No difference was found in [NAA] in the bulbar-onset group compared with the limb-onset group (P = 0.70), but [Cr + PCr] was significantly higher in the bulbar-onset group (P = 0.04). CONCLUSIONS: Our results suggest that [Cr + PCr] may be affected by the pathological process in MND, and this should be considered in the interpretation of metabolite peak area ratios. The elevated (Cr + PCr) may represent gliosis in the subcortical white matter in the motor cortex region.

Adult↗

The functional neuroanatomy of social behaviour: changes in cerebral blood flow when people with autistic disorder process facial expressions.

Although high-functioning individuals with autistic disorder (i.e. autism and Asperger syndrome) are of normal intelligence, they have life-long abnormalities in social communication and emotional behaviour. However, the biological basis of social difficulties in autism is poorly understood. Facial expressions help shape behaviour, and we investigated if high-functioning people with autistic disorder show neurobiological differences from controls when processing emotional facial expressions. We used functional MRI to investigate brain activity in nine adults with autistic disorder (mean age +/- standard deviation 37 +/- 7 years; IQ 102 +/- 15) and nine controls (27 +/- 7 years; IQ 116 +/- 10) when explicitly (consciously) and implicitly (unconsciously) processing emotional facial expressions. Subjects with autistic disorder differed significantly from controls in the activity of cerebellar, mesolimbic and temporal lobe cortical regions of the brain when processing facial expressions. Notably, they did not activate a cortical 'face area' when explicitly appraising expressions, or the left amygdala region and left cerebellum when implicitly processing emotional facial expressions. High-functioning people with autistic disorder have biological differences from controls when consciously and unconsciously processing facial emotions, and these differences are most likely to be neurodevelopmental in origin. This may account for some of the abnormalities in social behaviour associated with autism.

Adult↗

A temporal MRI assessment of neuropathology after transient middle cerebral artery occlusion in the rat: correlations with behavior.

The purpose of this study was to evaluate the temporal and spatial pathological alterations within ischemic tissue using serial magnetic resonance imaging (MRI) and to determine the extent and duration of functional impairment using objective behavioral tests after transient middle cerebral artery occlusion (tMCAO) in the rat. MRI signatures derived from specific anatomical regions of interest (ROI) were then appropriately correlated to the behavioral measures over the time course of the study (up to 28 days post-tMCAO). Sprague-Dawley rats (n = 12) were initially trained on the following behavioral tasks before surgery: bilateral sticky label test (for contralateral neglect); beam walking (for hindlimb coordination); staircase test (for skilled forelimb paw-reaching). Rats were then randomly assigned to receive either tMCAO (90 minutes, n = 6), by means of the intraluminal thread technique, or sham-control surgery (n = 6). Proton density, T2- and T2-diffusion-weighted MR images were acquired at 1, 7, 14, and 28 days post-tMCAO that were then smoothed into respective proton density, T2 relaxation, and apparent diffusion coefficient (ADC) maps. Apparent percent total lesion volume was assessed using T2W imaging. MR signatures were evaluated using the tissue maps by defining ROI for MCAO and sham-control groups, which corresponded to the caudate-putamen, forelimb, hindlimb, and lower parietal cortices both ipsilateral and contralateral to the occlusion site. Behavioral tests were undertaken daily from 1 to 28 days post-tMCAO. Results demonstrate that apparent percent lesion volume reduced from 1 to 7 days (P < 0.05) but then remained constant up to 28 days for the MCAO group. Pathological changes in the temporal profile of T2 and ADC tissue signatures were significantly altered in specific ROI across the time course of the study (P < 0.05 to <0.001), reflecting the progression of edema to necrosis and cavitation. Both T2 and ADC measures of ischemic pathology correlated with parameters defined by each of the functional tests (r > or =0.5, P < 0.05) across the time course. The staircase test revealed bilateral impairments for the MCAO group (P <0.001), which were best predicted by damage to the ipsilateral lower parietal cortex by means of hierarchical multiple regression analyses (R2 changes > or =0.21, P < or =0.03). Behavioral recovery was apparent on the beam walking test at 14 to 28 days post-MCAO, which was mirrored by MRI signatures within the hindlimb cortex returning to sham-control levels. This long-term study is the first of its kind in tracing the dynamic pathologic and functional consequences of tMCAO in the rat. Both serial MRI and objective behavioral assessment provide highly suitable outcome measures that can be effectively used to evaluate promising new antiischemic agents targeted for the clinic.

Animals↗

Reduced cerebral blood flow in white matter in ischaemic leukoaraiosis demonstrated using quantitative exogenous contrast based perfusion MRI.

OBJECTIVE: White matter hypoperfusion may play a part in the pathogenesis of ischaemic leukoaraiosis, but demonstration of this requires a high resolution quantitative method of cerebral blood flow (CBF) measurement. Initial exogenous contrast based MRI methods only allowed measurement of relative cerebral blood volume (CBV) values, but more recently a mathematical approach has been developed which enables absolute regional CBF and CBV to be determined. This technique was applied to patients with ischaemic leukoaraiosis to determine whether reduced white matter CBF in this patient group could be demonstrated. METHODS: Eight patients with ischaemic leukoaraiosis (radiological leukoaraiosis and clinical lacunar stroke), and nine age matched controls were studied. A spin echo echoplanar image sequence was used on a 1.5 Tesla MR system. An arterial input function was obtained from voxels placed over the middle cerebral arteries. Cerebral blood flow, CBV, and mean transit (MTT) maps were derived. Regions of interest were placed at standard positions in the white and grey matter and mean values of CBF, CBV, and MTT were compared between the two groups. RESULTS: Mean (SD) white matter CBF was significantly reduced in patients by 38% (13.40 (4.87) v 21.74 (3.53) ml/min/ 100 g, p=0.002). Significant reductions in CBF were seen in all white matter regions. By contrast there was no reduction in CBF in any grey matter region. There was no significant difference in white matter CBV between cases and controls; mean values were lower in all white matter regions for patients but this did not reach significance for any region. By contrast mean grey matter CBV was significantly higher in patients than in controls. Mean MTT values were higher in all regions of grey and white matter in the patient group, but this only achieved significance for the superior white matter. CONCLUSION: A quantitative MR perfusion method showed reduced white matter CBF in patients with ischaemic leukoaraiosis, but normal grey matter CBF. This is consistent with hypoperfusion playing a part in the pathogenesis of ischaemic leukoaraiosis. The absolute values of white matter and grey matter CBF obtained in the patient groups were very similar to those in previous PET studies, providing further evidence for the validity of the regional CBF measurements obtained using this quantitative MR perfusion technique. The high spatial resolution and lack of radioactive administration makes such techniques ideal for longitudinal studies in this condition.

Aged↗

Common and distinct neural substrates for pragmatic, semantic, and syntactic processing of spoken sentences: an fMRI study.

Extracting meaning from speech requires the use of pragmatic, semantic, and syntactic information. A central question is: Does the processing of these different types of linguistic information have common or distinct neuroanatomical substrates? We addressed this issue using functional magnetic resonance imaging (fMRI) to measure neural activity when subjects listened to spoken normal sentences contrasted with sentences that had either (A) pragmatical, (B) semantic (selection restriction), or (C) syntactic (subcategorical) violations sentences. All three contrasts revealed robust activation of the left-inferior-temporal/fusiform gyrus. Activity in this area was also observed in a combined analysis of all three experiments, suggesting that it was modulated by all three types of linguistic violation. Planned statistical comparisons between the three experiments revealed (1) a greater difference between conditions in activation of the left-superior-temporal gyrus for the pragmatic experiment than the semantic/syntactic experiments; (2) a greater difference between conditions in activation of the right-superior and middle-temporal gyrus in the semantic experiment than in the syntactic experiment; and (3) no regions activated to a greater degree in the syntactic experiment than in the semantic experiment. These data show that, while left- and right-superior-temporal regions may be differentially involved in processing pragmatic and lexico-semantic information within sentences, the left-inferior-temporal/fusiform gyrus is involved in processing all three types of linguistic information. We suggest that this region may play a key role in using pragmatic, semantic (selection restriction), and subcategorical information to construct a higher representation of meaning of sentences.

Brain↗

Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development.

Endothelin-converting enzyme-1 and -2 (ECE-1 and -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects in specific subsets of neural crest-derived tissues, including branchial arch-derived craniofacial structures, aortic arch arteries, and the cardiac outflow tract in ECE-1 knockout mice. To examine the role of ECE-2 in cardiovascular development, we have now generated a null mutation in ECE-2 by homologous recombination. ECE-2 null mice develop normally, are healthy into adulthood, are fertile in both sexes, and live a normal life span. However, when they are bred into an ECE-1-null background, defects in cardiac outflow structures become more severe than those in ECE-1 single knockout embryos. In addition, ECE-1(-/-); ECE-2(-/-) double null embryos exhibited abnormal atrioventricular valve formation, a phenotype never seen in ECE-1 single knockout embryos. In the developing mouse heart, ECE-2 mRNA is expressed in the endocardial cushion mesenchyme from embyronic day (E) 12.5, in contrast to the endocardial expression of ECE-1. Levels of mature ET-1 and ET-2 in whole ECE-1(-/-); ECE-2(-/-) embryos at E12.5 do not differ appreciably from those of ECE-1(-/-) embryos. The significant residual ET-1/ET-2 in the ECE-1(-/-); ECE-2(-/-) embryos indicates that proteases distinct from ECE-1 and ECE-2 can carry out ET-1 activation in vivo.

Animals↗

Salt-sensitive hypertension in endothelin-B receptor-deficient rats.

The role of the endothelin-B receptor (ET(B)) in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. Spotting lethal (sl) rats carry a naturally occurring deletion in the ET(B) gene that completely abrogates functional receptor expression. Rats homozygous for this mutation die shortly after birth due to congenital distal intestinal aganglionosis. Genetic rescue of ET(B)(sl/sl) rats from this developmental defect using a dopamine--hydroxylase (DBH)-ET(B) transgene results in ET(B)-deficient adult rats. On a sodium-deficient diet, DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats both exhibit a normal arterial blood pressure, but on a high-sodium diet, the former are severely hypertensive. We find no difference in plasma renin activity or plasma aldosterone concentration between salt-fed wild-type, DBH-ET(B);ET(B)(+/+) or DBH-ET(B);ET(B)(sl/sl) rats, and acute responses to intravenous L-NAME and indomethacin are similar between DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats. Irrespective of diet, DBH-ET(B);ET(B)(sl/sl) rats exhibit increased circulating ET-1, and, on a high-sodium diet, they show increased but incomplete hypotensive responses to acute treatment an ET(A)-antagonist. Normal pressure is restored in salt-fed DBH-ET(B);ET(B)(sl/sl) rats when the epithelial sodium channel is blocked with amiloride. We conclude that DBH-ET(B);ET(B)(sl/sl) rats are a novel single-locus genetic model of severe salt-sensitive hypertension. Our results suggest that DBH-ET(B);ET(B)(sl/sl) rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.

Animals↗

Exploring the social brain in schizophrenia: left prefrontal underactivation during mental state attribution.

OBJECTIVE: Evidence suggests that patients with schizophrenia have a deficit in "theory of mind," i.e., interpretation of the mental state of others. The authors used functional magnetic resonance imaging (MRI) to investigate the hypothesis that patients with schizophrenia have a dysfunction in brain regions responsible for mental state attribution. METHOD: Mean brain activation in five male patients with schizophrenia was compared to that in seven comparison subjects during performance of a task involving attribution of mental state. RESULTS: During performance of the mental state attribution task, the patients made more errors and showed less blood-oxygen-level-dependent signal in the left inferior frontal gyrus. CONCLUSIONS: To the authors' knowledge, this is the first functional MRI study to show a deficit in the left prefrontal cortex in schizophrenia during a socioemotional task.

Adult↗

Effects of three different doses of a bolus injection of gadodiamide: assessment of regional cerebral blood volume maps in a blinded reader study.

BACKGROUND AND PURPOSE: Reconstruction of first-pass bolus information to derive regional cerebral blood volume (rCBV) maps is commonly performed in many centers; however, various protocols with different doses of paramagnetic contrast injections have been reported. We evaluated the dose dependency of rCBV maps in a brain tumor population by using three different doses of gadodiamide injection to evaluate their diagnostic accuracy in blinded reader sessions. METHODS: Eighty-three patients with intraaxial brain tumors (72 gliomas) were studied at three centers and randomized to receive a bolus injection of 0.1, 0.2, or 0.3 mmol/kg per body weight of gadodiamide. rCBV maps were generated from T2*-weighted gradient-echo echoplanar sequences at 1.5 T. Data processing was performed according to the indicator dilution theory. RESULTS: The mean contrast-to-noise ratio (CNR) was significantly different between gadodiamide doses of 0.1 and 0.2 mmol/kg (CNR = 8.7 and 15.7) and between 0.1 and 0.3 mmol/kg (CNR = 17.7). No significant difference was found between doses of 0.2 and 0.3 mmol/kg. Sensitivity for the differentiation of benign and malignant brain tumors was 80%, 95%, and 91%, and specificity was 45%, 54%, and 43% by blinded readings at 0.1, 0.2, and 0.3 mmol/ kg, respectively, as compared with histologic findings. Nonblinded readings had a sensitivity of 83%, 100%, and 90% and a specificity of 82%, 100%, and 73% at 0.1, 0.2, and 0.3 mmol/kg, respectively. CONCLUSION: A dose of 0.2 mmol/kg of gadodiamide is recommended for reconstruction of rCBV maps if data are acquired with the T2*-weighted protocol described.

Blood Volume↗

Conflicting MRI signals from gliosis and neuronal vacuolation in prion diseases.

Magnetic resonance imaging (MRI) has given inconsistent results when used as a non-invasive diagnostic tool for Creutzfeldt-Jakob disease (CJD). In order to understand this finding, we studied a hamster model of scrapie by in vivo MRI and histopathology. Vacuolation of neurones/neuropil and gliosis were found to correlate with hypo-intense and hyper-intense changes in the conventional T2-weighted MR images, respectively. These opposing effects were shown to give rise to normal images of a scrapie-affected brain undergoing severe neurodegeneration, and may underlie the variability of previous CJD MRI data.

Animals↗

Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia.

Antipsychotic drug treatment of schizophrenia may be complicated by side effects of widespread dopaminergic antagonism, including exacerbation of negative and cognitive symptoms due to frontal cortical hypodopaminergia. Atypical antipsychotics have been shown to enhance frontal dopaminergic activity in animal models. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of schizophrenia would be associated with enhanced functional activation of frontal cortex. We measured cerebral blood oxygenation changes during periodic performance of a verbal working memory task, using functional MRI, on two occasions (baseline and 6 weeks later) in two cohorts of schizophrenic patients. One cohort (n = 10) was treated with typical antipsychotic drugs throughout the study. Risperidone was substituted for typical antipsychotics after baseline assessment in the second cohort (n = 10). A matched group of healthy volunteers (n = 10) was also studied on a single occasion. A network comprising bilateral dorsolateral prefrontal and lateral premotor cortex, the supplementary motor area, and posterior parietal cortex was activated by working memory task performance in both the patients and comparison subjects. A two-way analysis of covariance was used to estimate the effect of substituting risperidone for typical antipsychotics on power of functional response in the patient group. Substitution of risperidone increased functional activation in right prefrontal cortex, supplementary motor area, and posterior parietal cortex at both voxel and regional levels of analysis. This study provides direct evidence for significantly enhanced frontal function in schizophrenic patients after substitution of risperidone for typical antipsychotic drugs, and it indicates the potential value of functional MRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.

Adult↗

A differential neural response to threatening and non-threatening negative facial expressions in paranoid and non-paranoid schizophrenics.

Several studies have demonstrated impaired facial expression recognition in schizophrenia. Few have examined the neural basis for this; none have compared the neural correlates of facial expression perception in different schizophrenic patient subgroups. We compared neural responses to facial expressions in 10 right-handed schizophrenic patients (five paranoid and five non-paranoid) and five normal volunteers using functional Magnetic Resonance Imaging (fMRI). In three 5-min experiments, subjects viewed alternating 30-s blocks of black-and-white facial expressions of either fear, anger or disgust contrasted with expressions of mild happiness. After scanning, subjects categorised each expression. All patients were less accurate in identifying expressions, and showed less activation to these stimuli than normals. Non-paranoids performed poorly in the identification task and failed to activate neural regions that are normally linked with perception of these stimuli. They categorised disgust as either anger or fear more frequently than paranoids, and demonstrated in response to disgust expressions activation in the amygdala, a region associated with perception of fearful faces. Paranoids were more accurate in recognising expressions, and demonstrated greater activation than non-paranoids to most stimuli. We provide the first evidence for a distinction between two schizophrenic patient subgroups on the basis of recognition of and neural response to different negative facial expressions.

Adult↗

Diffusion tensor MRI assesses corticospinal tract damage in ALS.

BACKGROUND: A number of neurophysiologic and neuroimaging techniques have been evaluated in the research setting to assess upper motor neuron (UMN) damage in ALS. Changes in tissue structure in the CNS modify the diffusional behavior of water molecules, which can be detected by diffusion tensor MRI. OBJECTIVES: To explore the hypothesis that degeneration of the motor fibers in ALS would be reflected by changes in the diffusion characteristics of the white matter fibers in the posterior limb of the internal capsule and that these changes could be detected by diffusion tensor MRI. METHODS: We studied 22 patients with El Escorial definite, probable, or possible ALS-11 with limb onset (mean age 54.5 +/- 10.7 years) and 11 with bulbar onset (mean age 49.6 +/- 11.7 years)-and compared them with 20 healthy, age-matched controls (mean age 46.0 +/- 12.6 years). We assessed central motor conduction time (CMCT), threshold to stimulation, and silent period using transcranial magnetic stimulation. Diffusion tensor MRI was performed using a 1.5-T GE Signa system (Milwaukee, WI) fitted with Advanced NMR hardware and software capable of producing echo planar MR images. Data were acquired from seven coronal slices centered to include the posterior limb of the internal capsule. Maps of the mean diffusivity, fractional anisotropy, and T2-weighted signal intensity were generated. RESULTS: There were no differences between the subject groups on measures of CMCT, threshold to stimulation, and silent period. However, the CMCT correlated with clinical measures of UMN involvement. We found a significant increase in the mean diffusivity and reduction in fractional anisotropy along the corticospinal tracts between the three subject groups, most marked in the bulbar-onset group. The fractional anisotropy correlated with measures of disease severity and UMN involvement, whereas the mean diffusivity correlated with disease duration. CONCLUSION: The results support the use of diffusion tensor MRI in detecting pathology of the corticospinal tracts in ALS.

Adult↗

Production and functional activity of a recombinant von Willebrand factor-A domain from human complement factor B.

Factor B is a five-domain 90 kDa serine protease proenzyme which is part of the human serum complement system. It binds to other complement proteins C3b and properdin, and is activated by the protease factor D. The fourth domain of factor B is homologous to the type A domain of von Willebrand Factor (vWF-A). A full-length human factor B cDNA clone was used to amplify the region encoding the vWF-A domain (amino acids 229-444 of factor B). A fusion protein expression system was then used to generate it in high yield in Escherichia coli, where thrombin cleavage was used to separate the vWF-A domain from its fusion protein partner. A second vWF-A domain with improved stability and solubility was created using a Cys(267)-->Ser mutation and a four-residue C-terminal extension of the first vWF-A domain. The recombinant domains were investigated by analytical gel filtration, sucrose density centrifugation and analytical ultracentrifugation, in order to show that both domains were monomeric and possessed compact structures that were consistent with known vWF-A crystal structures. This expression system and its characterization permitted the first investigation of the function of the isolated vWF-A domain. It was able to inhibit substantially the binding of (125)I-labelled factor B to immobilized C3b. This demonstrated both the presence of a C3b binding site in this portion of factor B and a ligand-binding property of the vWF-A domain. The site at which factor D cleaves factor B is close to the N-terminus of both recombinant vWF-A domains. Factor D was shown to cleave the vWF-A domain in the presence or absence of C3b, whereas the cleavage of intact factor B under the same conditions occurs only in the presence of C3b.

Amino Acid Sequence↗

Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.

Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation. Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons. We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.

Age of Onset↗