Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue.

BACKGROUND: Fatigue is one of the most frequent and disabling symptoms in multiple sclerosis, but its pathophysiological mechanisms are poorly understood. It is in particular unclear whether and how fatigue relates to structural and functional brain changes. OBJECTIVE: We aimed to analyse the association of fatigue severity with basal ganglia functional connectivity, basal ganglia volumes, white matter integrity and grey matter density. METHODS: In 44 patients with relapsing-remitting multiple sclerosis and 20 age- and gender-matched healthy controls, resting-state fMRI, diffusion tensor imaging and voxel-based morphometry was performed. RESULTS: In comparison with healthy controls, patients showed alteration of grey matter density, white matter integrity, basal ganglia volumes and basal ganglia functional connectivity. No association of fatigue severity with grey matter density, white matter integrity and basal ganglia volumes was observed within patients. In contrast, fatigue severity was negatively correlated with functional connectivity of basal ganglia nuclei with medial prefrontal cortex, precuneus and posterior cingulate cortex in patients. Furthermore, fatigue severity was positively correlated with functional connectivity between caudate nucleus and motor cortex. CONCLUSION: Fatigue is associated with distinct alterations of basal ganglia functional connectivity independent of overall disability. The pattern of connectivity changes suggests that disruption of motor and non-motor basal ganglia functions, including motivation and reward processing, contributes to fatigue pathophysiology in multiple sclerosis.

Contribution of the innate immune system to autoimmune myocarditis: a role for complement.

Myocarditis is a principal cause of heart disease among young adults and is often a precursor of heart failure due to dilated cardiomyopathy. We show here that complement is critical for the induction of experimental autoimmune myocarditis and that it acts through complement receptor type 1 (CR1) and type 2 (CR2). We also found a subset of CD44(hi)CD62L(lo) T cells that expresses CR1 and CR2 and propose that both receptors are involved in the expression of B and T cell activation markers, T cell proliferation and cytokine production. These findings provide a mechanism by which activated complement, a key product of the innate immune response, modulates the induction of an autoimmune disease.

Lack of association between carotid artery volume blood flow and cardiac output.

OBJECTIVE: The correlation of cardiac output and cerebral perfusion is unclear. We tested this potential association by correlating cardiac output data obtained by echocardiography and cerebral blood flow data as determined by color M-mode measurements of carotid artery blood flow. METHODS: We studied 43 patients with a broad spectrum of cardiac performance by means of transthoracic echocardiography. In these patients, different cardiac indices such as stroke volume, ejection fraction, and heart minute volume were determined. The data were correlated with volumetric flow measurements (color M-mode duplex system) of the common carotid arteries bilaterally. RESULTS: Heart minute volume ranged from 1.632 to 9.836 mL/min (mean +/- SD, 4.652 +/- 1.621 mL/min); ejection fraction ranged from 18% to 76% (mean, 48% +/- 16%). The relative fraction of carotid volume flow compared with heart minute volume was 15% +/- 6%. There was no correlation between ejection fraction, stroke volume, or heart minute volume and absolute volume flow in the carotid arteries when being adjusted for age. There was a highly significant inverse correlation (r = -0.8; P < .0001) of the relative fraction of the carotid volume flow (carotid volume flow/heart minute volume [percent]) and the heart minute volume. CONCLUSION: Our data support the concept that cerebral blood flow is independent of cardiac output.

Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is used for treatment of primary biliary cirrhosis. Previous studies showed that, compared with UDCA monotherapy, bile salts plus prednisolone had no further effect on laboratory data but improved liver histology. Thirty percent of these patients had prednisolone-related side effects. Budesonide is a glucocorticoid with a high receptor affinity and a high first-pass metabolism. In this study we investigated whether budesonide and UDCA are superior to UDCA monotherapy. METHODS: A 2-year prospective, controlled double-blind trial was performed. Twenty patients (mainly with early-stage disease) were treated with UDCA at a dose of 10-15 mg/kg daily in addition to 3 mg budesonide 3 times daily (group A), and 19 patients (1 dropped out for personal reasons) were treated with UDCA plus placebo (group B). Liver biopsy specimens were taken before, after 12 months, and at the end of study. Glucose tolerance tests, serum cortisol levels, and adrenocorticotropin-stimulated cortisol secretion were assessed at regular intervals. Bone mass density was measured by dual-energy photon absorptiometry. RESULTS: Compared with pretreatment values, liver enzyme and immunoglobulin M and G levels decreased significantly in both groups. Improvement in group A was significantly more pronounced (P < 0.05) than in group B. Titers of antimitochondrial antibodies did not change. In group A, the point score of liver histology improved by 30.3%; in group B, it deteriorated by 3.5% (P < 0.001). Changes in bone mineral density after 2 years were -1.747% in group A and -0.983% in group B (P = 0.43). Budesonide had little influence on the hypothalamic-pituitary-adrenal axis. One patient in group A had budesonide-related side effects; in 3 patients in group B, complications of liver disease developed. CONCLUSIONS: Combination therapy with UDCA and budesonide is superior to UDCA and placebo.

Postoperative epidural analgesia and oral anticoagulant therapy.

The relative safety of epidural catheter placement with subsequent heparinization has been well documented. However, what is the risk of neurologic sequelae in such patients who receive warfarin perioperatively? This study retrospectively evaluates the risk of spinal hematoma in patients receiving postoperative epidural analgesia while receiving low-dose warfarin after total knee replacement. All patients received low-dose warfarin to prolong the prothrombin time (PT) to 15.0-17.3 s (normal 10.9-12.8 s). There were 192 epidural catheters placed in 188 patients. All catheters were advanced through an 18-gauge needle. In 13 instances, blood was noted during needle and/or catheter placement. In addition to warfarin, 36 patients with indwelling catheters received nonsteroidal antiinflammatory drugs (NSAIDs). Epidural catheters were left indwelling 37.5 +/- 15 h (range 13-96 h). The mean PT was not increased beyond the normal range until the third postoperative day and did not reach 15 s until the seventh postoperative day. Cumulative warfarin dose at that time was 20.0 +/- 7.6 mg. Mean PT at the time of epidural catheter removal was 13.4 +/- 2 s. There were no signs of spinal hematoma. Although epidural catheter placement and subsequent anticoagulation with warfarin appears relatively safe, there is a large variability in patient response to warfarin; therefore, coagulation status should be monitored to avoid excessive prolongation of the PT, and the patient should be watched closely for evidence of spinal hematoma.

gamma-Aminobutyric acidA receptor heterogeneity in rat central nervous system: studies with clonazepam and other benzodiazepine ligands.

The properties of [3H]clonazepam, [3H]diazepam and [3H]zolpidem (N,N,6[trimethyl-2-(4-methyl-phenyl)imidazo[1,2-a]pyridine-3-acetamide hemitratrate) binding to synaptic membranes of cerebellum, cortex, olfactory bulb, striatum and spinal cord of rat were compared to the binding properties of [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. In the cerebellar, cortical and olfactory bulb membranes, the density of high-affinity binding sites of all these tritiated benzodiazepine (BZ) ligands is almost identical. In contrast, in the striatum, the density of [3H]clonazepam and [3H]zolpidem binding sites is approximately 60 and 30%, respectively, of the density of [3H]diazepam, [3H]flunitrazepam or [3H]flumazenil sites. In spinal cord membranes, the number of high-affinity binding sites of [3H]clonazepam and [3H]zolpidem is less than 20% of the number of binding sites for [3H]diazepam, [3H]flunitrazepam, [3H]flumazenil and [3H]midazolam. Moreover, the displacement of [3H]flunitrazepam from spinal cord membranes by clonazepam and zolpidem was characterized by high IC50 values and Hill slopes significantly less than 1. Because [3H]BZ ligand binding in the spinal cord is enhanced by gamma-aminobutyric acid (GABA), these data suggest that different regions of the rat central nervous system may contain different GABA-BZ receptor subtypes. The different pharmacological properties of clonazepam, diazepam and zolpidem (i.e., regarding their ability to enhance bicuculline seizure threshold, to decrease locomotor activity, to induce ataxia or to elicit anticonflict action) further support the concept that in the rat central nervous system preferential occupancy of heterogeneous GABAA receptors by these drugs can be related to their effects on behavior.

Distribution and characterization of diazepam binding inhibitor (DBI) in peripheral tissues of rat.

We studied the expression and distribution of the polypeptide diazepam binding inhibitor (DBI) in rat peripheral organs by immunocytochemistry, radioimmunoassay, Northern blot analysis and binding assay. Variable amounts of the DBI peptide and DBI mRNA were found in all the tissues examined (liver, duodenum, testis, kidney, adrenal gland, heart, ovary, lung, skeletal muscle and spleen), with the highest level of expression in liver (220 pmol of DBI/mg protein) and the lowest in spleen (11 pmol of DBI/mg protein). A good correlation between DBI-like immunoreactivity (DBI-LI) and mRNA content was found in all tissues except the heart. The immunohistochemical analysis revealed discrete localization of DBI-LI in cell types with specialized functions: for example, the highest DBI-LI content was found in steroid-producing cells (glomerulosa and fasciculata cells of adrenal cortex, Leydig cells of testis); lower DBI-LI immunostaining was found in epithelial cells specialized for water and electrolyte transport (intestinal mucosa, distal convoluted tubules of kidney). Hepatic cells contained moderate immunoreactivity however the total content of DBI in liver is relatively high and is due to the diffuse presence of DBI in every hepatocyte. Cells with high expression of DBI have been shown to contain a high density of mitochondrial benzodiazepine (BZ) binding sites. This observation led us to perform a competitive binding assay between DBI and [3H]PK11195 (a ligand for the mitochondrial BZ binding sites) on mitochondrial membranes of adrenal cortical cells. In this experiment, DBI yielded an apparent competitive inhibition of the binding of PK11195 to the BZ binding sites. Our data support a possible role for DBI as endogenous regulator of intracellular metabolic functions, such as steroidogenesis, via the mitochondrial BZ receptors.

Facilitated blind intubation using a transtracheal guide wire.

A method of tracheal intubation facilitated by using a transtracheal guide-wire is illustrated by three selected case stories. In two cases, the patients were blindly intubated and in the third case, with epiglottitis, the aditus layngis could be identified only by use of the guidewire. Using a laryngoscope and Magill's forceps, intubation was in this case performed without complications. It is suggested that the method applied in cases of difficult intubation may reduce the rate of acute tracheostomies.

Obstructive sleep apnea syndrome caused by oral cyst: a case report.

A 47-year-old man with a typical obstructive sleep apnea syndrome (OSAS) secondary to a large oral cyst is reported. Although the patient also had a nasal septum deviation with narrowed air passage, removal of the cyst resulted in complete and lasting relief from clinical symptoms despite persisting sleep apnea and unchanged arousal reaction in the EEG. The concurrent mechanisms of OSAS in the present case are discussed, and the importance of searching for a curable underlying disorder in clinical overt OSAS is emphasized.

Relationship between histologic grading of head and neck tumours and regression after chemotherapy.

A series of 43 patients with 44 primary head and neck tumours were treated by combined BMV-chemotherapy (bleomycin, methotrexate and vincristine) given before irradiation. The tumour shrinkages were evaluated and related to the histologic grading of the primary biopsy material. No relationship was found between the tumour response and degree of malignancy as evaluated by the histologic grading. The clinical relevance and possible modification of the histologic grading system are discussed.