AKAP150-anchored PKA regulation of synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the lateral habenula.

Numerous studies of hippocampal synaptic function in learning and memory have established the functional significance of the scaffolding A-kinase anchoring protein 150 (AKAP150) in kinase and phosphatase regulation of synaptic receptor and ion channel trafficking/function and hence synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a critical role in brain's processing of rewarding/aversive experiences. Here we focused on an unexplored role of AKAP150 in the lateral habenula (LHb), a diencephalic brain region that integrates and relays negative reward signals from forebrain striatal and limbic structures to midbrain monoaminergic centers. LHb aberrant activity (specifically hyperactivity) is also linked to depression. Using whole cell patch clamp recordings in LHb of male wildtype (WT) and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), we found that the genetic disruption of PKA anchoring to AKAP150 significantly reduced AMPA receptor (AMPAR)-mediated glutamatergic transmission and prevented the induction of presynaptic endocannabinoid (eCB)-mediated long-term depression (LTD) in LHb neurons. Moreover, ΔPKA mutation potentiated GABAA receptor (GABAAR)-mediated inhibitory transmission postsynaptically while increasing LHb intrinsic neuronal excitability through suppression of medium afterhyperpolarizations (mAHPs). Given that LHb is a highly stress-responsive brain region, we further tested the effects of corticotropin releasing factor (CRF) stress neuromodulator on synaptic transmission and intrinsic excitability of LHb neurons in WT and ΔPKA mice. As in our earlier study in rat LHb, CRF significantly suppressed GABAergic transmission onto LHb neurons and increased intrinsic excitability by diminishing small-conductance potassium (SK) channel-mediated mAHPs. ΔPKA mutation-induced suppression of mAHPs also blunted the synaptic and neuroexcitatory actions of CRF in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPAR and GABAAR synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPAR and potassium channel trafficking and eCB signaling within the LHb.

Occupational Health and Well-being Questionnaire (OHWQ): an instrument to assess psychosocial risk and protective factors in the workplace.

OBJECTIVES: Psychosocial stressors at work have been identified as significant risk factors for several mental and physical health problems. These stressors must be compensated by psychosocial resources to prevent or reduce adverse effects on health. Questionnaires measuring these stressors and resources already exist, but none integrate digital stress, ethical culture, and psychosocial safety climate; factors that are increasingly linked to workers' health. This study aims to develop and establish the psychometric properties of one of the most comprehensive instruments measuring the psychosocial work environment to date: the Occupational Health and Well-being Questionnaire (OHWQ). STUDY DESIGN: A cross-sectional validation study is proposed to develop the OHWQ and document its psychometric properties. METHODS: The OHWQ was developed from validated instruments to which new items were added. The questionnaire includes psychosocial dimensions, along with indicators of psychological distress, musculoskeletal disorders, and well-being. It was administered to a sample of 2770 participants from a population working in the academic field. Exploratory and confirmatory factor analyses and the calculation of Cronbach's α coefficient were used to identify the variables, items, and, dimensions of the OHWQ and to document its main psychometric properties. RESULTS: The acceptability of the measurement model was evaluated by the reliability of the items, internal consistency between the items, and the convergent and discriminant validity. Construct validity was assessed using exploratory and confirmatory factor analyses. Using factor analyses and cut-off rules, the new instrument has 124 items grouped into 22 dimensions. The OHWQ demonstrated satisfactory reliability and validity, as well as reasonable fit indices. The internal consistency of the scales was also good (Cronbach's α = 0.68-0.96, median = 0.85). CONCLUSION: The OHWQ demonstrated good psychometric properties. It could be useful for both research purposes and for workplaces interested in developing concrete action plans aimed at improving the balance between psychosocial work stressors and resources.

Acute sacral nerve stimulation reduces visceral mechanosensitivity in a cross-organ sensitization model.

BACKGROUND: Sacral nerve stimulation (SNS) is a surgical treatment of fecal and urinary incontinence that consists of inserting a stimulating electrode into one of the s3 or s4 sacral holes. In addition to the benefit of SNS in the treatment of incontinence, recent studies showed that SNS is effective in the treatment of irritable bowel syndrome as well as bladder pain syndrome. The aim of this study was to evaluate the effect of SNS on visceral mechanosensitivity in a cross-organ sensitization rat model. METHODS: Hypersensitive model was obtained by instillation of acetic acid into the bladder of rats during 5 minutes, 30 minutes before the start of the experiments. Visceral sensitivity was assessed by monitoring the change in mean arterial pressure in response to graded isobaric colorectal distension series. To decipher the mechanisms underlying SNS effect, rats were administered intravenously either a nonselective opioid receptor antagonist (naloxone) or a nitric oxide synthesis antagonist (L-NAME). Neuronal activation in the dorsal horn of the sacral spinal cord was measured by counting c-fos immunoreactive cells in response to colorectal distension and NMS. KEY RESULTS: Intravesical acetic acid instillation increased mean arterial pressure variation in response to colorectal distension when compared to saline group. SNS reduced the variation in arterial pressure. Colorectal distension induced a rise in c-fos immunoreactive cells in the dorsal horn of the spinal cord. This effect was reduced by SNS. CONCLUSIONS & INFERENCES: SNS reduces visceral mechanosensitivity in a cross-organ sensitization model.

Acute sacral nerve stimulation reduces visceral mechanosensitivity in Rat through spinal opioid pathway.

BACKGROUND: Sacral nerve stimulation (SNS) is an alternative surgical treatment of refractory urge incontinence and/or fecal incontinence. Despite its clinical efficacy, the mechanisms of action of SNS remain poorly understood. The aim of this experimental study was to evaluate the effect of SNS on visceral mechanosensitivity in rats. METHODS: Anesthetized Sprague-Dawley rats were treated with SNS or sham stimulation. SNS was performed by implanting an electrode close to the sacral nerve root S1. Rats were administered either a non-selective opioid receptor antagonist (naloxone) or a nitric oxide synthase inhibitor (L-NAME). Colonic mechanosensitivity was evaluated using the variation of arterial blood pressure as a spino-bulbar reflex in response to graded isobaric colorectal distension (CRD). C-fos immunoreactive neurons were quantified in spinal and supraspinal sites. µ-opioid receptor (MOR) internalization was counted in the sacral spinal cord with sham or effective SNS in response to CRD. KEY RESULTS: SNS reduced visceral mechanosensitivity in response to CRD. This effect was reversed by intrathecal and intraveinous naloxone administration. In both models, CRD induced increased c-fos immunoreactivity in the dorsal horn neurons of the sacral spinal cord and supraspinal areas. This increase was prevented by SNS. MOR internalization was significantly higher in stimulated group. CONCLUSIONS & INFERENCES: SNS impacts on visceral mechanosensitivity by decreasing the spino-bulbar reflex in response to CRD. Spinal opioid receptors are likely involved in this effect.

Relationship between diagnostic criteria, depressive equivalents and diagnosis of depression among older adults with intellectual disability.

BACKGROUND: Depression is more common among persons with an intellectual disability (ID) than the general population, and may be expected to increase with age just as in the general population. However, little is known about depression among older adults with ID. The literature has questioned the use of standard diagnostic criteria for depression among both older adults and persons with ID, and behavioural depressive equivalents have been suggested. This study uses the interRAI ID assessment instrument to investigate the relationship between standard diagnostic criteria for depression, depressive equivalents and a diagnosis of depression among older and younger adults with ID in community and institutional settings in Ontario, Canada. METHOD: Items in the interRAI ID assessment instrument that were representative of The Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria and depressive equivalents were examined among persons with ID in institutional (census-level data) and in community-based (sample) residential settings. Bivariate logistic regression was used to examine the relationship between depressive symptoms and a diagnosis of depression. Descriptive statistics were used to examine the prevalence of depressive symptoms among those who did not have a diagnosis of depression. RESULTS: The results indicate that DSM-IV diagnostic criteria and depressive equivalents were significantly related to a diagnosis of depression among older and younger adults with ID, and that both types of symptoms were exhibited by a non-trivial proportion of individuals without a diagnosis of depression. CONCLUSIONS: The depression rating scale embedded in the interRAI ID is helpful in identifying older adults at risk of depression. Contrary to other studies, few significant differences were found in depressive symptoms by age.

Rehabilitative management of polyarteritis: a case report.

A 75-year-old woman with polyarteritis who developed polyneuropathy and quadriplegia underwent intensive rehabilitation that resulted in significant improvement. This report discusses various therapeutic strategies for the successful management of patients with severe polyarteritis. Strategies include orthotics for both upper and lower extremities, sensory reeducation, edema management, and the use of adaptive devices in retraining the patient with activities of daily living. The associated neurological, orthopedic, renal, and cardiac complications in the context of rehabilitation for this complex condition are discussed.

Pharmacokinetic, pharmacodynamic, and pharmacotoxic profiles of recombinant-methionyl human interleukin-2[alanine-125] (r-metHuIL-2[ala-125]) following intravenous and subcutaneous administration in rats.

Comparative pharmacotoxicity studies in rats were performed to evaluate the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or subcutaneous administration, as well as to evaluate pharmacokinetic and pharmacodynamic responses. Pharmacokinetic analysis indicated that r-metHuIL-2[ala-125] showed high bioavailability and nonlinear concentration profiles. Pharmacodynamic responses to intravenous or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by white blood cell counts, were comparable. Preclinical safety studies (6, 30, and 150 micrograms kg-1 day-1) indicated that r-metHuIL-2[ala-125], whether given intravenously or subcutaneously, was associated with increased circulating and infiltrating levels of lymphocytes and eosinophils. Bone marrow lymphoid hyperplasia and splenic extramedullary hematopoiesis were similarly observed in each study. This pattern of effects was considered an exaggerated pharmacodynamic response to r-metHuIL-2[ala-125]. Of further note was a histopathologic finding described as hepatocyte single cell necrosis which was observed following both intravenous and subcutaneous administration and was considered to be a toxic response to high doses of r-metHuIL-2[ala-125]. The no observable adverse effect level (NOAEL) for r-metHuIL-2[ala-125] via intravenous administration was 6 micrograms kg-1 day-1, while that for subcutaneous administration was 30 micrograms kg-1 day-1. Data herein present a form of rHuIL-2 with pharmacokinetic and pharmacodynamic profiles that are similar when given by these two systemic routes. Pharmacotoxic data, based on NOAELs, suggest that subcutaneous administration may be a preferred clinical route of administration.

Similar chemotactic factor for monocytes predominates in different animal models of uveitis.

Anterior uveitis or iritis occurs in a variety of systemic diseases including sarcoid, Behcet's, and spondyloarthritis. Iritis is, therefore, presumed to result from a variety of pathogenetic mechanisms. We hypothesized that unique chemotactic factors should be associated with different etiologies for inflammation. We have tested this hypothesis using rabbit models of anterior uveitis. We have found that aqueous humor generally contained chemotactic activity for monocytes 24 h after an intravitreal injection of endotoxin, killed mycobacteria, or human serum albumin (in a rabbit previously immunized against human serum albumin). Anterior chamber paracentesis resulted in aqueous humor with a high protein content. However, in contrast to the other models of inflammation, paracentesis did not result in a cellular infiltrate in the anterior chamber, and aqueous humor after paracentesis was not chemotactic. For either immunologically mediated inflammation or for inflammation resulting from injection of a killed bacterial product, chemotactic activity could be digested by papain or trypsin and tended to coelute with albumin on either gel filtration or ion-exchange chromatography. These observations suggest that a similar chemotactic factor for monocytes appears to be associated with ocular inflammation that follows either an immune response or injection of a killed bacterial product.

Chemotactic activity of lens proteins and the pathogenesis of phacolytic glaucoma.

Leakage of lens proteins from a hypermature cataract can result in a characteristic glaucoma that is associated with the invasion of the anterior chamber by monocytes. We hypothesized that the lens proteins themselves might account for the monocyte response. A sonicated lens induced concentration-dependent migration of monocytes in a Boyden chamber assay system. Checkerboard analysis indicated that the movement was directed rather than merely random. Relative to a control chemoattractant, N-formyl-methionyl-leucyl-phenylalanine, the lens induced monocyte migration more potently than neutrophil migration. The ability to induce migration was markedly reduced by incubating the lens with either trypsin or papain. Chemotactic activity was readily demonstrable in lenses from young donors without cataracts. Separation of lens proteins by gel filtration with high-performance liquid chromatography indicated that the chemotactic activity was most consistently associated with the gamma crystallin fraction. The chemotactic activity of lens proteins may contribute to the pathogenesis of phacolytic glaucoma or the uveitis resulting from retained cortical material after cataract extraction.

Chemotactic activity in aqueous humor from patients with anterior uveitis.

Anterior uveitis, inflammation of the iris or ciliary body of the eye, may be associated with a variety of systemic diseases. Although a leukocytic infiltrate is characteristic of anterior uveitis, few studies have sought to detect factors in aqueous humor that could attract neutrophils or monocytes into the anterior chamber. Using modified Boyden chambers, we found that a 5% concentration of aqueous humor from patients with anterior uveal inflammation induced monocyte movement comparable to optimal or near-optimal concentrations of C (complement)5a or platelet-derived growth factor. Aqueous humor from patients with anterior uveitis induced significantly more monocyte migration than did aqueous humor from two sets of controls (either patients undergoing cataract extraction or patients with posterior uveitis). "Checkerboard" or gradient analysis indicated that a majority of inflammatory disease samples induced monocyte chemotaxis (directed migration) while the control aqueous humor consistently induced chemokinesis (stimulated random migration) (P less than 0.02). Despite their ability to induce monocyte migration, samples tended to induce minimal neutrophil migration with the exception of aqueous humor that was obtained from one patient with acute anterior disease. This sample induced marked chemokinesis. Identification of chemotactic activity may clarify the pathogenesis of uveitis and the characterization of leukocyte migration factors in aqueous humor may help define subsets of anterior uveal inflammation.

Endotoxin-induced selective dysfunction of rabbit polymorphonuclear leukocytes in response to endogenous chemotactic factors.

To assess the mechanism and specificity of polymorphonuclear leukocyte (PMN) dysfunction induced by endotoxin, rabbits were injected intravenously with 100 micrograms of Escherichia coli endotoxin, and PMN function was studied 18 to 24 h later. Compared to PMN from normal rabbits, peripheral blood PMN from rabbits injected with endotoxin showed diminished chemotactic responsiveness to two endogenous peptides, C5a (complement) and platelet-derived growth factor, and to two endogenous lipids, leukotriene B4 and platelet-activating factor. The chemotactic response to the synthetic chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), was unimpaired. In contrast to migration, endotoxin injection resulted in inhibition of the secretory response to the two endogenous peptides but not to the lipids or to FMLP. At a 1:4 (vol/vol) dilution, the plasma either 1 or 24 h after the endotoxin injection inhibited normal PMN chemotactic responses to C5a but not to FMLP. Similarly, at a 1:10 dilution, this plasma inhibited normal PMN chemotactic responses to leukotriene B4. The factor responsible for inhibiting responses to leukotriene B4 was anionic, specific for leukotriene B4 responses, and greater than 12,000 daltons. These data may be relevant to understanding PMN dysfunction during gram-negative sepsis.

Modification of lipid A reduces endotoxin-induced eye effects.

Intravenous endotoxin produces an acute toxic ocular reaction in rabbits. The core component of endotoxin, lipid A, can be modified by acid hydrolysis. This results in a detoxified ET that is relatively ineffective in inducing fever or lethal effects but which retains activity as a mitogen or as a cofactor in inducing tumor necrosis. We report that detoxified endotoxin was relatively ineffective in inducing iris hyperemia, increased ocular vascular permeability, a rise in aqueous humor prostaglandin E2, or the generation of aqueous humor neutrophil chemotactic activity. Chemotactic activity was not increased in aqueous humor even though detoxified endotoxin effectively generated chemotactic activity from serum in vitro. These observations indicate the critical role of lipid A structure in producing ET-induced ocular effects and show that the ability of ET to act as a mitogen, induce tumor necrosis, or generate serum chemotactic activity can be dissociated from its ocular toxicity.

[Characteristics of ex-psychiatric patients.]. / Caractéristiques d'ex-patients psychiatriques.

In this article the author takes account of a study on the characteristics of (former psychiatric patients. The group in question consists of 44 former patients with a length of hospital stay varying from 5 to 31 years and more. The author hypothesizes that the longer his or her period of institutionalization, the less chance the individual has to remain in society after discharge. The following sub-hypothesis is also formulated: the diagnosis at the point of discharge will indicate a cure of the patient's condition. These hypotheses are studied in the light of the following Information: age at admission and at discharge, place of birth, social and/ or family isolation, actual mental state, diagnosis at admission and at discharge. It appears quite difficult to determine what enables former psychiatric patients to succeed in finding a socially-acceptable modus vivendi. The hypotheses are not confirmed by study and the author wonders: who is the former psychiatric patient ?

[General attitude towards the mentally ill and the ex-mentally ill.]. / Attitudes en général devant les malades et les ex-malades mentaux.

After demonstrating the failure of the 18th century mental health pionne era in their attempt to change public prejudice toward the mentally ill, the author enumerates various common public attitudes such as the rejection of the mentally ill. The author then goes on to underline that,' despite current negative attitudes of the population, it is nevertheless possible to change these attitudes. The two principal methods she advances to achieve this end are concentration on the positive affective elements in attitudes toward the mentally ill and research into the negative positions.

[Prejudices against the mentally ill.]. / Les préjugés contre les malades mentaux.

This study examines attitudes of the local population towards a group of 44 former psychiatric female patients out of the hospital X and living in a village but who return to the hospital to work (maintenance departments, etc.) and on the interaction of the reaction of these former patients towards the attitudes of this population. The main question of this study is the following : What is the reaction of the local population towards the fact that this group of 44 mentally ill women live in this village ? And by interaction, what is the reaction of the mentally-ill women towards the attitudes of this local population ?