Axonal protection using flecainide in experimental autoimmune encephalomyelitis

Axonal degeneration is a major cause of permanent neurological deficit in multiple sclerosis (MS), but no current therapies for the disease are known to be effective at axonal protection. Here, we examine the ability of a sodium channel-blocking agent, flecainide, to reduce axonal degeneration in an experimental model of MS, chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE). Rats with CR-EAE were treated with flecainide or vehicle from either 3 days before or 7 days after inoculation (dpi) until termination of the experiment at 28 to 30 dpi. Morphometric examination of neurofilament-labeled axons in the spinal cord of CR-EAE animals showed that both flecainide treatment regimens resulted in significantly higher numbers of axons surviving the disease (83 and 98% of normal) compared with controls (62% of normal). These findings indicate that flecainide and similar agents may provide a novel therapy aimed at axonal protection in MS and other neuroinflammatory disorders.     

Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration

Axonal degeneration can be an important cause of permanent disability in neurological disorders in which inflammation is prominent, including multiple sclerosis and Guillain-Barré syndrome. The mechanisms responsible for the degeneration remain unclear, but it is likely that axons succumb to factors produced at the site of inflammation, such as nitric oxide (NO). We previously have shown that axons exposed to NO in vivo can undergo degeneration, especially if the axons are electrically active during NO exposure. The axons may degenerate because NO can inhibit mitochondrial respiration, leading to intraaxonal accumulation of Na(+) and Ca(2+) ions. Here, we show that axons can be protected from NO-mediated damage using low concentrations of Na(+) channel blockers, or an inhibitor of Na(+)/Ca(2+) exchange. Our findings suggest a new strategy for axonal protection in an inflammatory environment, which may be effective in preventing the accumulation of permanent disability in patients with neuroinflammatory disorders.     

Radicular pain avoidance during needle placement in lumbar diskography

OBJECTIVE: The objective of our study was to determine whether a method could be found to reduce iatrogenic radicular pain during needle placement in lumbar diskography. MATERIALS AND METHODS: After obtaining permission from the institutional review board at the University of Pittsburgh Medical Center, we conducted a study using medical records and existing data that were recorded for quality control during lumbar diskography. A coaxial technique was being used for lumbar diskography. We evaluated data for 71 intervertebral disks in 26 patients in which the needle placement was randomly high (superior) or low (inferior), and the associated pain response during needle placement was recorded. In an attempt to minimize iatrogenic pain during needle placement, we identified a potentially "safe window" for needle placement on MRI of the lumbar spine. On oblique fluoroscopy of the lumbar spine, the safe window is a triangle formed by the superior articular facet medially, the superior endplate of the lower vertebra inferiorly, and an imaginary line joining the tip of the superior articular facet and the superolateral tip of the vertebral body. This safe window was then used for needle placement in another 73 intervertebral disks in 27 patients. Pain response to needle placement was recorded for quality control, and the medical records were retrospectively compared with the initial 71 intervertebral disks in which needle placement was random. RESULTS: In the initial group with random needle placement, lower extremity radicular pain occurred in 13 (18.3%) of 71 intervertebral disks with superior needle placement and in 23 (32.4%) of 71 intervertebral disks with inferior needle placement (total, 50.7%). The pain responses of the superior and inferior groups were not significantly different (p = 0.27). On MRI, the average distances between the nerve ganglion-fascicle-rami and the superior articular facets at the superior disk level were 1.1, 1.4, and 2.5 mm at L3-L4, L4-L5, and L5-S1, respectively. The average distances between the nerve ganglion-fascicle-rami and the superior articular facets at the inferior disk level were 3.0, 3.6, and 6.6 mm at L3-L4, L4-L5, and L5-S1, respectively. When the safe window was used, only five (6.8%) of 73 patients reported radicular pain. The decrease in radicular pain between the two groups was significant (p < 0.001). CONCLUSION: Iatrogenic lower extremity radicular pain is common during random needle placement at lumbar diskography. High or low needle placement in the intervertebral disk could not predict whether radicular pain would be averted. We identified a safe window that can be used for needle placement during lumbar diskography to minimize iatrogenic lower extremity radicular pain and thereby improve the reliability of the test.     

Is a 2-week duration sufficient for stenting in endopyelotomy?

PURPOSE: Internal stenting is an integral part of endopyelotomy. Studies in animals show good healing after 1 to 2 weeks of ureterotomy. Inherent stent related problems warrant a minimum possible duration of stenting without compromising the results of endopyelotomy. We performed a prospective randomized trial to evaluate the optimum duration of stenting after endopyelotomy. MATERIALS AND METHODS: A total of 57 consecutive patients with primary ureteropelvic junction obstruction were randomized to undergo 7/14Fr internal endopyelotomy stent placement for 2 (group 1) and 4 (group 2) weeks. A symptom based questionnaire was administered to all patients at stent removal. Followup was done with diuretic scanning at 3, 6, 9 and 12 months and then yearly, and thereafter with diuretic renography. RESULTS: In each group 26 patients were available for evaluation. The 2 groups were comparable in terms of age, sex, symptoms and ipsilateral glomerular filtration rate. Mean followup was 22.3 (range 12 to 36) and 21.3 months (range 12 to 35) in groups 1 and 2, respectively. At the end of 1 year 24 group 1 (92.3%) and 23 group 2 (90.3%) patients had an improved drainage pattern. This difference was not significant. Stent related symptoms were present in a good proportion of patients in groups 1 and 2 but there was a significant difference in the incidence of urinary tract infections (11.5% versus 38.1%, p = 0.04). Of the group 2 patients 64% preferred 2 weeks of stenting. CONCLUSIONS: Two weeks seems to be a sufficient duration to allow functional restoration across the ureteropelvic junction after endopyelotomy and decrease stent related complications.     

Glomerulopathy in Kuwait: the spectrum over the past 7 years

There are few studies that examine, prospectively, the epidemiological profile of glomerulopathy (GP) and its clinicopathological correlation. All patients referred to Al-Amiri renal center in Kuwait from January 1st, 1995 to December 31st, 2001 were screened for GP. Detailed clinical data were collected and serological markers were done. Renal biopsy was performed whenever indicated. During those 7 years, a total of 584 patients were diagnosed, on histological basis, to have GP, 315 of whom were Kuwaiti nationals. During the same period of the study, 26 patients presented with bilateral small kidneys, history of proteinuria > 2 g/day and lacked systemic manifestations of autoimmune disease. Furthermore, 164 patients with clinical manifestations of diabetic glomerulosclerosis were not subjected to kidney biopsy. Hence, the calculated annual incidence rate of GP in Kuwaiti nationals was 34.5 per 100,000 population (PTP). The calculated rate of diabetic glomerulosclerosis was 13.4 PTP and that of nondiabetic 21.1 PTP. The calculated incidence rates of GP increased with age and were twice as high in males compared to females. Vasculitis was more common in elderly males while SLE nephritis was a disease of adults, 88.7% of whom were females. In the subgroup of primary GP, focal segmental glomerulosclerosis was the most common histological lesion accounting for 18.0% of the total biopsies in Kuwaiti patients, yet only 36.8% of those who fulfilled the criteria of primary type. Minimal change disease was the second primary GP (13.0%), followed by immunoglobulin A deposition disease (7.9%) and membranous glomerulonephritis (5%). Autoimmune diseases such as systemic lupus erythematosus (SLE) and vasculitis were common. Interestingly, only 44 of 72 (61.1%) of patients with SLE and 11 of the 62 (17.7%) of patients with vasculitis presented with rapidly progressive glomerulonephritis. On the other hand, 10 of 58 (17.2%) patients with nephroangiosclerosis presented with renal failure and protein excretion > 2 g/day simulating primary GP. Furthermore, only 21 of 40 (52.5%) patients with IgA nephropathy presented with "benign disease". Prospective studies are essential to ascertain the actual incidence and etiology of GP. The loose clinicopathological correlation in GP dictates an aggressive diagnostic approach in its study and management.     

Spinal epidermoid tumors: novel approach to aseptic meningitis

Intraoperative hydrocortisone irrigation of the cerebrospinal fluid pathways may reduce symptoms attributed to aseptic meningitis, which often follow the resection of epidermoid spinal tumors. Here, 20 patients undergoing surgical resection of epidermoid tumors were randomly assigned to two groups: Group I received intraoperative hydrocortisone irrigation, whereas Group II served as a control. No patient receiving hydrocortisone experienced fevers or meningismus, but nontreated patients experienced fevers (100%) and meningismus (78%). Nausea and vomiting were reduced (9%) in the treated versus untreated groups (22% vs. 11%, respectively), whereas none in the treated group noted dizziness, vertigo, or diabetes insipidus. As steroid irrigation significantly decreased the perioperative morbidity of epidermoid tumor resection, indications for intravenous steroids may become more limited, thereby reducing cost.     

Effects of BIBN4096BS on cardiac output distribution and on CGRP-induced carotid haemodynamic responses in the pig

Calcitonin gene related peptide (CGRP) seems to be involved in the pathogenesis of migraine, since plasma CGRP levels increase during the headache phase. In the present study, we investigated the effects of a novel CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl] pentyl] amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [R-(R*,S*)]-), on the regional cardiac output distribution and on the carotid haemodynamic changes induced by alpha-CGRP in anaesthetised pigs. Treatment with BIBN4096BS (100, 300 and 1000 microg kg(-1), i.v.) did not affect the heart rate, mean arterial blood pressure or systemic vascular conductance, but a small decrease in cardiac output was noticed; the latter was, however, not significantly different from that in vehicle-treated animals. The highest dose of BIBN4096BS moderately decreased vascular conductance in the lungs, kidneys, spleen and adrenals. Vascular conductance in other tissues including the brain, heart, gastrointestinal system, skin and skeletal muscles remained unchanged. Intracarotid artery infusions of alpha-CGRP (10, 30 and 100 pmol kg(-1) min(-1) during 3 min) increased the total carotid blood flow and conductance, but decreased the arterial blood pressure. These responses were dose-dependently blocked by BIBN4096BS. The above results show that BIBN4096BS is a CGRP receptor antagonist in the porcine carotid and systemic circulations, but the endogenous CGRP does not seem to play an important physiological role in regulating basal vascular tone. These findings suggest that BIBN4096BS may have therapeutic usefulness in migraine.