Changes in classic and alternative pathways of bile acid synthesis in chronic liver disease

BACKGROUND: Cholesterol elimination occurs through bile acid synthesis that starts within the liver from 7alpha-hydroxylation or in extrahepatic tissues from 27-hydroxylation. This study was aimed at investigating in vivo these two pathways in patients with chronic liver disease. METHODS: Serum concentrations of 7alpha- and 27-hydroxycholesterol were measured in 54 patients (29 with primary biliary cirrhosis and 25 with chronic hepatitis C) and 18 controls. The rate of oxysterol plasma appearance was calculated after intravenous infusions of deuterated 7alpha- and 27-hydroxycholesterol in patients (n=8) and control subjects (n=8) who gave consent. The expression of sterol 27-hydroxylase was evaluated in macrophages isolated from 20 subjects. RESULTS: In patients with liver disease, the rate of plasma appearance of 7alpha-hydroxycholesterol was significantly reduced (1.44+/-0.96 vs. 2.75+/-1.43 mg/hour, p=0.03), the degree of reduction being related with the severity of the disease (p=0.01) whereas that of 27-hydroxycholesterol was unaffected. The rate of plasma appearance of 27-hydroxycholesterol was significantly related to its serum concentrations (r=0.54, p=0.03) and to its release from cultured macrophages ( r=0.85, p=0.03). CONCLUSIONS: In liver disease 7alpha-hydroxylation of cholesterol seems to be impaired while 27-hydroxylation is unaffected. Serum concentrations of 27-hydroxycholesterol are useful to obtain information on the activity of this alternative pathway.     

The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents

OBJECTIVE: Individuals with schizophrenia show severe deficits in their ability to decode emotions based upon vocal inflection (affective prosody). This study examined neural substrates of prosodic dysfunction in schizophrenia with voxelwise analysis of diffusion tensor magnetic resonance imaging (MRI). METHOD: Affective prosodic performance was assessed in 19 patients with schizophrenia and 19 comparison subjects with the Voice Emotion Identification Task (VOICEID), along with measures of basic pitch perception and executive processing (Wisconsin Card Sorting Test). Diffusion tensor MRI fractional anisotropy valves were used for voxelwise correlation analyses. In a follow-up experiment, performance on a nonaffective prosodic perception task was assessed in an additional cohort of 24 patients and 17 comparison subjects. RESULTS: Patients showed significant deficits in VOICEID and Distorted Tunes Task performance. Impaired VOICEID performance correlated significantly with lower fractional anisotropy values within primary and secondary auditory pathways, orbitofrontal cortex, corpus callosum, and peri-amygdala white matter. Impaired Distorted Tunes Task performance also correlated with lower fractional anisotropy in auditory and amygdalar pathways but not prefrontal cortex. Wisconsin Card Sorting Test performance in schizophrenia correlated primarily with prefrontal fractional anisotropy. In the follow-up study, significant deficits were observed as well in nonaffective prosodic performance, along with significant intercorrelations among sensory, affective prosodic, and nonaffective measures. CONCLUSIONS: Schizophrenia is associated with both structural and functional disturbances at the level of primary auditory cortex. Such deficits contribute significantly to patients' inability to decode both emotional and semantic aspects of speech, highlighting the importance of sensorial abnormalities in social communicatory dysfunction in schizophrenia.     

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.     

Hemispheric asymmetry and callosal integration of visuospatial attention in schizophrenia: a tachistoscopic line bisection study

BACKGROUND: A hallmark of visuospatial neglect syndrome is that patients with lesions to right parietal cortex misbisect horizontal lines far rightward of veridical center. Neurologically normal subjects misbisect lines with a systematic leftward bias (pseudoneglect). Both phenomena, as well as neuroimaging studies, disclose a predominant right-hemisphere control of spatial attention. Numerous studies of patients with schizophrenia have implicated global deficits of either right or left hemisphere function, as well as compromised integrity of the corpus callosum. METHODS: To better understand the functional implications of schizophrenia we utilized a forced-choice tachistoscopic line bisection task to probe the status of right-hemisphere control of spatial attention, and compared left- versus right-hand unimanual responses to index the degree of callosal transfer of visuospatial information in both patient and control groups. RESULTS: In contrast to the significant leftward bisection errors of control subjects, patients exhibit no significant leftward error. Whereas control subjects evince a significant correlation between left- and right-hand bisection errors, patients lack a significant intermanual correlation. CONCLUSIONS: The lack of significant leftward bisection error of patients implies a deficit of right-hemisphere function. The lack of a significant correlation between left- and right-hand bisection errors in patients implies a loss of callosal integrity.     

The physics of FeldenkraisPart 3: stability

In the last article in this series, we briefly examined the Principle of Least Effort and the five forms of strain. Strain, you may recall, in physics, describes a change in the volume of a material when a force is applied. Our treatments are a blend of rotation and translation movements of our hands with a changing mix of strains being applied onto the client's tissues. Harnessing and interweaving the various forms of strain with dexterity may aid us in improving our treatment efficacy.In this tissue, we will consider the importance of anchorage and stability in treatment, We will consider a set of ‘House Rules' for improving treatment. In addition, we will explore Bernstein's concept of degrees of freedom.