Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis

Hypothalamo-pituitary-adrenal (HPA) dysregulation has recently been demonstrated in multiple sclerosis (MS) by means of combined dexamethasone corticotropin-releasing hormone (Dex-CRH) suppression tests. Authors found a correlation with course of disease and to a lesser extent with depressive symptoms. In this study, we aimed to further evaluate whether HPA disturbances in MS are correlated with cognitive impairment, disability status, and fatigue. Dex-CRH tests were performed in a total of 40 patients and 11 healthy controls. Concomitantly, cognitive impairment was evaluated using the symbol digit modalities test and fatigue was assessed by different fatigue severity scales.When comparing patient subpopulations to healthy subjects, Dex-CRH stimulation tests indicated an HPA hyperactivity in primary and secondary progressive MS, while relapsing-remitting patients had response patterns similar to controls. However, results were only significant for one of the six analysed parameters, i.e. area under the curve calculations of ACTH stimulation. Within the patient sample, clear-cut differences emerged between groups of different cognitive impairment, being significant for all ACTH response parameters. Our results suggest an HPA hyperactivation related to increased cognitive impairment. Indicators of HPA axis activation further correlated substantially with neurologic disability, but only moderately with duration of disease and even less with depressive symptoms and fatigue. We conclude that the observed dysregulation is more likely a secondary effect of the extent of brain damage rather than primarily involved in the pathogenesis of MS.     

Down-regulation of retroviral transgene expression during differentiation of progenitor-derived dendritic cells

OBJECTIVE: Hematopoietic progenitor cells are a promising source for generation of genetically modified dendritic cells. A prerequisite for using these cells in therapeutic approaches is stable vector-mediated transgene expression during and after cell maturation. We investigated the expression of enhanced green fluorescence protein (EGFP) mediated by retroviral vectors in dendritic cells and other hematopoietic cells differentiated in vitro. MATERIAL AND METHODS: CD34(+) cells were efficiently transduced with retroviral vector constructs known to mediate different expression levels due to distinct cis-acting elements. EGFP(+) cells were purified by cell sorting and differentiated to monocytes, granulocytes, dendritic cells, and erythrocytes. Coexpression of EGFP and cell type-specific markers was analyzed by flow cytometry. RESULTS: Transgene expression from various retroviral vectors was silenced exclusively in dendritic cells, but not in other mature myeloid cells. Loss of EGFP was most pronounced in cells initially displaying low expression levels. This was confirmed by using a retroviral vector coding for a variant of EGFP with significantly reduced half-life. In contrast, a majority of dendritic cells showed stable expression when a self-inactivating retroviral construct using an internal cytomegalovirus promotor was used. CONCLUSIONS: We suggest that expression from the retroviral long terminal repeat is silenced during dendritic cell differentiation in vitro. High levels of stable transgene product in progenitor cells may mask a loss of expression. An improvement of retroviral vectors mediating stable transgenic expression is necessary for therapeutic approaches using gene-modified dendritic cells.     

Bilateral sacral spinal nerve stimulation for fecal incontinence after low anterior rectum resection

BACKGROUND AND AIMS: The somatomotor innervation pattern has been shown to differ in patients undergoing percutaneous nerve evaluation for sacral nerve stimulation. In some patients bilateral stimulation might improve clinical outcome; however, only single-channel pulse generators have until now been available. We report a patient with fecal incontinence after surgery for rectal carcinoma in whom a dual-channel, individually programmable, pulse generator permitted implantation of neurostimulation electrodes bilaterally. PATIENTS AND METHODS: Intractable fecal incontinence developed in a 48-year-old man who underwent low anterior rectum resection, owing mainly to reduced internal anal sphincter function. The morphology of the anal sphincter was without defect. Based on the findings of unilateral and bilateral temporary sacral nerve stimulation the patient underwent placement of foramen electrodes on S4 bilaterally. Both electrodes were connected to a dual-channel impulse generator for permanent low-frequency stimulation. RESULTS: The percentage of incontinent bowel movements decreased during unilateral test stimulation from 37% to 11%, during bilateral test stimulation to 4%, and with chronic bilateral stimulation to 0%. The Wexner continence score improved from 17 preoperatively to 2, and quality of life (ASCRS score) was notably enhanced. Anorectal manometry revealed improved striated anal sphincter function; the internal anal sphincter remained unaffected. CONCLUSION: Sacral nerve stimulation can effectively treat incontinence after rectal resection, and bilateral stimulation can improve the therapeutic effect.     

Nutritional abnormalities contributing to cachexia in chronic illness

Cachexia is a common consequence of chronic illness. The nutritional abnormalities contributing to the clinical picture are often a composite of reduced appetite, dietary factors including protein, energy and micronutrient intake, malabsorption and increased consumption or loss of nutrients. In this article, using chronic heart failure as an example, we have reviewed the potential influences of chronic disease on each of these and how they might lead to the relentless progression of wasting and the poor prognosis associated with it.