Enhanced brain delivery with lower hepatic exposure of lazaroid loaded nanostructured lipid carriers developed using a design of experiment approach.

The current study was designed to develop and optimize lazaroid loaded nano-structured lipid carriers (LAZ-NLCs) using design of experiment approach for enhancing lazaroid brain exposure. Response surface plots were used to determine the effects of independent variables (amount of PEGylating agent and liquid lipid) on dependent variables (particle size, zeta potential and encapsulation efficiency), while numerical optimization was used for optimizing LAZ-NLCs composition. The optimal LAZ-NLCs were spherical in shape with measured size of 172.3 ±â€¯3.54 nm, surface charge of -4.54 ±â€¯0.87 mV and encapsulation efficiency of 85.01 ±â€¯2.60%. The optimal LAZ-NLCs were also evaluated for hemolytic potential, storage stability and solid-state properties. The plasma pharmacokinetics along with brain and hepatic distributions of control lazaroid citrate solution and optimal LAZ-NLCs formulation were evaluated in Sprague-Dawley rats after the single bolus intravenous administration. The optimized LAZ-NLCs and the control lazaroid citrate solution had similar plasma pharmacokinetic profiles; however, differential organ bio-distributions were observed. The lazaroid exposure in brain was enhanced by two times with a decreased liver exposure by half for the NLCs group compared to the solution group.

Effects of U-74389G (21-Lazaroid) and Ascorbic Acid on Liver Recovery After Acute Ischemia and Reperfusion in Rats.

BACKGROUND/AIM: The free radical-scavenging effects of the lazaroid U-74389G have been shown in several experimental models to protect the liver from ischemia/reperfusion (I/R), however, the mechanism of cytoprotection is not fully understood. Similar findings were observed when ascorbic acid was administered. This study investigates the effects of infusion of lazaroid U-74389G and ascorbic acid on cytokines and liver structure in a liver I/R rat model. MATERIALS AND METHODS: Sixty male Wistars rats, weighting 220-290 g, were used in the study. Six experimental groups were formed: Group 1 (control group): ischemia for 30 min and reperfusion for 60 min; group 2 (control group): ischemia for 30 min and reperfusion for 120 min; group 3: ischemia for 30 min, intraportal injection of ascorbic acid, and reperfusion for 60 min; group 4: ischemia for 30 min, ascorbic acid administration, and reperfusion for 120 min; group 5: ischemia for 30 min, U-74389G administration, and reperfusion for 60 min; and group 6: ischemia for 30 min, U-74389G administration, and reperfusion for 120 min. Tissue and blood sampling took place upon completion of each model's reperfusion. U-74389G was administered at 10 mg/kg animal body weight and ascorbic acid at 100 mg/kg. Anesthesia was induced with ketamine and xylazine. Surgery was performed through a midline laparotomy. The portal vein and the common hepatic artery were isolated and prepared for occlusion. Blood samples and wedge liver biopsies were taken to measure levels of liver enzymes, cytokines and for microscopic analysis upon completion of reperfusion once for each model. RESULTS: Histopathological evaluation revealed a statistically significant reduction in the degree of necrosis of liver tissue in the treated groups compared to the control groups 1 and 2 [groups 3, 5 (p=0.010) and 4, 6 (p<0.0005)]. On the other hand, tissue malondialdehyde levels (MDA) were statistically significantly increased only between control group 2 and groups 4, 6 (p<0.0005). There was no statistically significant difference in tumor necrosis factor-α between groups. As for liver enzymes, only alkaline phosphatase (ALP) and gamma-glutamyl transferase (gGT) were statistically significantly reduced in treated groups 3 and 5 (ALP: p=0.027, and gGT: p=0.002) and 4 and 6 (ALP: p=0.004, and gGT: p=0.015) compared to control groups 1 and 2. CONCLUSION: Based on histological data and the reduction of some of the liver enzymes, in spite of a rise of malondialdehyde, in this rat model, administration of U-74389G in liver ischemia/reperfusion (I/R) injury has potential in attenuating liver damage.

Neuronal tumour necrosis factor-α and interleukin-1ß expression in a porcine model of intracerebral haemorrhage: Modulation by U-74389G.

Tumour necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) are important mediators of intracerebral haemorrhage (ICH) inflammatory response. Lazaroids, established antioxidants and neuroprotectants, have been studied in several brain pathologies. The present study was designed to investigate: a) TNF-α and IL-1ß changes, in neurons and b) U-74389G effects, 4 and 24h after haematoma induction in a porcine model of intracerebral haemorrhage. In twenty male landrace pigs (swines) aged 135-150 days old, autologous whole blood was injected around the right basal ganglia territory; in ten of the pigs the lazaroid compound U-74389G was administered. Brain TNF-α and IL-1ß immunopositive neurons were determined by immunoarray techniques at 4 and 24h timepoints. After the haematoma induction the number of TNF-α immunopositive neurons ipsilateral to the haematoma was significantly higher compared to the contralateral site at 4h (p<0.0005), while U-74389G significantly reduced the number of TNF-α immunopositive neurons, ipsilateral to the haematoma, at 4h (p=0.002); at 24h, TNF-α immunopositive neurons were found significantly lower in the control group ipsilateral to the haematoma in comparison to 4h timepoint(p<0.0005). The number of IL-1ß immunopositive neurons at 4h after the hematoma induction was significantly higher ipsilateral to the haematoma site (p<0.0005). U-74389G had no statistical significant effect. TNF-α and IL-1ß, increase in neurons, 4h after the haematoma induction, ipsilateral to the haematoma site. The administration of the antioxidant compound U-74389G, results in early (at 4h) decrease of TNF-α immunopositive neurons but shows no statistical significant effect to IL-1ß immunopossitive neurons.

Pharmacologic Management of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.

Antioxidant 21-aminosteroid "U-74389G" ameliorates the short-time effect of hypoxia-reoxygenation on the platelet count in rats.

AIM: The aim of this experimental study was to examine the effect of the antioxidant drug "U-74389G", on rat model and particularly in a hypoxia-reoxygenation protocol. The beneficial effect or non-effectiveness of that molecule were studied hematologically using blood mean platelet count. Results were that U-74389G administration interacted or not with reoxygenation time decreased the platelet count by 6.12% ± 3.58% (p = 0.0857) and 12.83% ± 5.79% (p = 0.0303) respectively. CONCLUSIONS: U-74389G administration interacted or not with reoxygenation time decreases the platelet count within short-term time of 2 hours by different significance levels.

Symptomatic lumbar facet joint cysts treated by CT-guided intracystic and intra-articular steroid injections.

OBJECTIVE: To evaluate percutaneous computed tomography (CT)-guided intracystic and intra-articular steroid injections for the treatment of lumbar facet joint cyst causing radicular pain. METHODS: A single-centre prospective study involving 120 consecutive patients with symptomatic lumbar facet joint cyst-induced radicular pain was done (72 women, 48 men). The average age was 68.2 years (52-84). Patients were treated by percutaneous CT-guided intracystic and intra-articular steroid injections. The clinical course of nerve root pain was evaluated after 1 day, and 1, 3 and 6 months, with long-term follow-up after 12 months. RESULTS: Patient follow-ups in our series show supportive results: within 120 patients, 54% of patients were satisfied with a long-lasting result from the first intra-cystic and intra-articular steroid injections (n = 65), while 20.8% were satisfied with a long-lasting result from a second intervention. Combining these two results shows that 75% of patients were satisfied with a long-lasting result. CONCLUSIONS: Our results showed that percutaneous treatment of vertebral lumbar facet joint cysts by double injections is an effective and economic therapeutic technical management among 75% of our patients. Thus we recommend that it should be considered as a first choice of treatment. KEY POINTS: Lumbar facet joint cysts are a common feature of back and radicular pain. They may be treated effectively by interventional radiologists using CT guidance. Percutaneous treatment using double injections can save surgery in 75% of patients.

An animal model to study the molecular basis of tardive dyskinesia.

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects. This limitation presents a marked therapeutic challenge. The present method (21 days administration of haloperidol, 5 mg/kg, i.p.) has been established to gain deeper insight into the molecular etiology (inflammation and apoptosis) of haloperidol-induced cellular death. In the present model, besides the corresponding increase in the vacuous chewing movements (VCMs), enhanced oxidative stress, there was a significant increase in cellular markers of inflammation and apoptotic protein (caspase-3), leading to cellular death. We also suggest that this model will be effective in preclinical testing of new chemical entities for the treatment of haloperidol induced tardive dyskinesia and related symptoms.

CT-guided percutaneous infiltration for the treatment of Alcock's neuralgia.

The pudendal nerve may be strained either between the sacrospinous and sacrotuberous ligaments at the ischial spine level or within Alcock's canal. Alcock's neuralgia is a rare, painful condition caused by compression of the pudendal nerve within Alcock's canal (pudendal canal) which is an aponeurotic tunnel that cannot be stretched. Patients usually present with intense, unilateral pain involving anatomic areas along the pudendal nerve's root, genital, anal, and pelvic regions causing mobility impairment. A computed tomography (CT)--guided percutaneous infiltration of the pudendal nerve with a mixture of a local anesthetic and a long-acting corticosteroid is a safe and efficient method that reduces the pain caused by the neuralgia. Corticosteroids and local anesthetics interfere with the neurons, the encoding, and the processing of noxious stimuli; interrupt the pain-spasm cycle; and reduce inflammation. The injected glucocorticosteroid may take 3-5 days to reach its anti-inflammatory effect; therefore, the initial pain relief from the local anesthetic is followed by a baseline pain return and then secondary pain relief at 3-5 days. The procedure is performed under minimal or no anesthesia. In general, at discharge, a responsible person must accompany the patient and ensure a safe return home. Clinical evaluation is performed after 7-10 days. There are 2 types of potential complications that are associated with percutaneous steroid infiltrations: intra-operative (associated with needle placement) and post-operative (infection, bleeding and those associated with the injectate administration). In all cases that steroids were administered within therapeutic doses, no complications were noted. In conclusion, CT-guided percutaneous infiltration with a mixture of long-acting corticosteroid and local anesthetic seems to be a safe and efficient method for the treatment of Alcock's neuralgia.

[The contribution of capsular distension to the treatment of primary adhesive capsulitis of the shoulder: a comparative study versus rehabilitation]. / Apport de l'arthrodistension dans la prise en charge de la capsulite rétractile primitive de l'épaule : étude comparative versus rééducation.

OBJECTIVES: To describe the epidemiological and clinical features of patients with primitive adhesive capsulitis of the shoulder treated by capsular distension and then rehabilitation; to evaluate the short-, mid- and long-term efficiency of this therapeutic protocol and compare it with rehabilitation alone. MATERIALS AND METHODS: This was a two-year prospective study. Sixty patients were included and divided into populations P1 (capsular distension and rehabilitation) and P2 (rehabilitation only). Assessment of the treatments' efficacy was based on the following parameters: pain on a visual analogue scale (VAS), joint motion in several axes, a simplified Constant score (functional ability) and the SF-36 quality of life score. RESULTS: Thirty patients (mean age: 56) underwent capsular distension. The Constant score was judged to be poor in over half of the patients. All the quality of life parameters were modified. When compared with P2, the P1 group showed a statistically significant improvement in terms of the pain score (p=0.005), anterior elevation (p=0.001), lateral elevation (p=0.005), external rotation (p=0.006) and the Constant score (p<0.001) one week after capsular distension. One year after capsular distension, this gain persisted in a statistically significant manner for all functional parameters and all SF-36 dimensions (p<0.001 for PF, RP, BP, SF and RE; p=0.01 for GH and VT and p=0.002 for MH). CONCLUSION: Our results show that capsular distension and subsequent intensive rehabilitation have a beneficial effect. This combination enables rapid, significant improvement from the first week onwards. The improvement phase lasts for one month and may hold steady for up to 12 months.

[Evaluation of the efficacy of CT-guided epidural and transforaminal steroid injections in patients with diskogenic radiculopathy]. / Evaluation de l'efficacité des infiltrations canalaires et foraminales de corticoïdes guidées par TDM dans le traitement des radiculalgies par conflit disco radiculaire.

PURPOSE: To evaluate the efficacy of CT-guided epidural and transforaminal steroid injections in patients with diskogenic radiculopathy. MATERIALS AND METHODS: Seventy patients underwent CT guided injections after failure of medical management. Only patients with minimal degenerative changes and diskogenic monoradicular symptoms were treated. Only two patients with fibrosis were included. RESULTS: 78.6% of patients experienced persistent symptomatic improvement. No difference was noted between lumbar segments and there was no more failures with epidural injections compared to transforaminal injections. Cervical disk herniations responded better than lumbar disk herniations. Good results were obtained in younger patients (M=46.25 years), symptomatic for 3-4 months or less, and with clear radicular symptoms and clinical neurological deficits (hypoesthesia, absent DTR) without motor deficit. No patient with severe spinal stenosis (S-) was included and the disk herniations were small (b1, b2, c1, c2 or d1, d2). Only a single injection was needed. Cortivazol provided superior results compared to dexamethasone. CONCLUSION: CT-guided injections should be included in the therapeutic armamentarium after standard medical management, with cure as the goal.

Systemic effects of epidural and intra-articular glucocorticoid injections in diabetic and non-diabetic patients.

INTRODUCTION: Whereas the systemic effects of glucocorticoid therapy have been extensively reported, little is known about those of local glucocorticoid injections. The objective of this study was to look for systemic effects of local glucocorticoid injections at two sites in diabetic and non-diabetic patients. METHODS: We studied 29 patients (18 women and 11 men with an age range of 18-86 years). The injection site was the epidural space in 18 patients (4 with and 14 without diabetes) with disk-related sciatica and the shoulder in 11 patients (8 with and 3 without diabetes) with frozen shoulder. Each patient was given three injections of 1.5 ml cortivazol (5.625 mg of cortivazol or about 85 mg prednisone-equivalent per injection and about 250 mg prednisone-equivalent in all), at 3-day intervals. Of the 12 patients with diabetes, 2 were on insulin therapy. At baseline and at the post-treatment visits 1, 7, and 21 days after the third injection, the following tests were done: plasma cortisol and ACTH at 8 am, urinary free cortisol excretion in 24 hours, fasting and postprandial blood glucose, serum cholesterol and triglycerides, and serum sodium and potassium. Blood pressure was measured at each visit. RESULTS: Mean systolic blood pressure increased significantly between baseline (123+/-10 mmHg) and the first two post-treatment visits (day 1, 127+/-9 mmHg; and day 7, 128+/-10 mmHg) but returned to baseline values by the third post-treatment visit (day 21). Mean postprandial blood glucose was significantly higher at the day 1 post-treatment visit (10.1+/-5.4 mmol/l) than at baseline (7.5+/-2.9 mmol/l). At the day 7 post-treatment visit, blood glucose remained significantly elevated compared to baseline in the 12 diabetic patients (13.9+/-4.8 mmol/l versus 9.4+/-3.3 mmol/l at baseline). In both the overall population and the various subgroups, plasma cortisol and ACTH and urinary free cortisol were markedly reduced at the day 1 and day 7 post-treatment visits, compared to baseline. At the day 21 visit, these variables were diminished in the group given epidural injections, whereas plasma cortisol and ACTH were normal in the group treated intra-articularly. No significant variations were noted for fasting blood glucose or for serum levels of cholesterol, triglycerides, sodium, and potassium. CONCLUSION: The administration of three local cortivazol injections was followed by suppression of the corticotropic axis that persisted beyond 21 days after epidural injection and recovered more rapidly after intra-articular injection. Systolic blood pressure increased transiently. Elevations in postprandial glucose levels lasted longer in diabetic than non-diabetic patients.

Effect of U-74389G (21-lazaroid) on intestinal recovery after acute mesenteric ischemia and reperfusion in rats.

Although it has been demonstrated that lazaroids can protect various organs from ischemia reperfusion injury, results obtained in the small intestine have been conflicting. On the other hand, it is not known whether inhibition of lipid peroxidation prevents intestinal ishemia-reperfusion injury. We investigated whether the administration of the aminolazaroid U-74389G had a beneficial effect on the repair process of the intestinal mucosa after transient mesenteric ischemia in a randomized-blind trial. Six groups of rats were subjected to a model of 60 min of intestinal ischemia that was produced by occluding the superior mesenteric artery. At the end of ischemia, U-74389G was administered intravenously and the clamp was removed to allow reperfusion. At 60 min after reperfusion animals were sacrificed and a 10-cm section of terminal ileum was resected. Its efficacy was evaluated by histopathological assessment, measurement of polymorphonuclear leukocytes and the extent of lipid peroxidation by measuring the small intestine tissue malondialdehyde. After 1 h of reperfusion, mucosal damage in both U-74389G-treated rats and control group rats was similar. However, the number of polymorphonuclear leukocytes in the intestinal mucosa was lower in the U-74389G group. Of particular interest was that U-74389G resulted in a statistically significant reduction in the concentration of small intestine tissue malondialdehyde, compared to the controls. When administered in an imitated clinical setting, U-74389G did not prevent intestinal ischemia reperfusion injury, however it protected the rat small intestine from oxidative damage by inhibiting lipid peroxidation.

Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen.

BACKGROUND AND PURPOSE: A combined therapeutic approach has been advocated repeatedly for treatment of focal cerebral ischemia. A clinical example of combined therapy is administration of nimodipine, mannitol, dexamethasone, and barbiturates during temporary occlusion of a cerebral artery in neurovascular surgery. We have recently demonstrated outstanding neuroprotective properties of a combination therapy with magnesium (calcium antagonist and glutamate antagonist), tirilazad (antioxidant), and mild hypothermia (MTH). In this study we compared this treatment strategy with the customary treatment options in a rat model of transient focal cerebral ischemia. METHODS: Sprague-Dawley rats (n=120) were subjected to 90 minutes of middle cerebral artery occlusion by an intraluminal filament (n=10 per group). In experiment 1, the customary treatment options (nimodipine, mannitol, dexamethasone, methohexital) were evaluated as monotherapy and in combination. In experiment 2, the customary and the new combination therapy (MTH) were compared. Mild hypothermia (33 degrees C) was maintained for 2 hours. Neurological examinations were performed daily. Infarct size was assessed histologically after 7 days. RESULTS: In experiment 1, infarct volume was attenuated by 34% at maximum, with mannitol and methohexital being the most effective drugs given as monotherapy. In experiment 2, combined administration of the customary treatment options had no additive effect (infarct volume -36%). Combination therapy with MTH reduced total infarction by 73% and almost completely abolished cortical infarction (-91%). None of the animals of this group had any residual neurological deficit at the end of the observation period (P<0.05 versus all other groups). CONCLUSIONS: The efficacy of drugs (monotherapy or in combination) most commonly used for neuroprotection during neurovascular surgery is limited. The newly proposed combination therapy (magnesium, tirilazad, and mild hypothermia), which is based on pathophysiological considerations, seems to be a promising alternative for neuroprotection in cerebrovascular surgery.

Effect of U-74500A, a 21-aminosteroid on renal ischemia-reperfusion injury in rats.

Renal ischemia-reperfusion injury constitutes the most common pathogenic factor for acute renal failure and is the main contributor to renal dysfunction in allograft recipients and revascularization surgeries. Many studies have demonstrated that reactive oxygen species play an important role in ischemic acute renal failure. The aim of the present study was to investigate the effects of the synthetic antioxidant U-74500A, a 21-aminosteroid in a rat model of renal ischemia-reperfusion injury. Renal ischemia-reperfusion was induced by clamping unilateral renal artery for 45 min followed by 24 h of reperfusion. Two doses of U-74500A (4.0 mg/kg, i.v.) were administered 45 min prior to renal artery occlusion and then 15 min prior to reperfusion. Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS) in kidney homogenates. Renal function was assessed by estimating serum creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological alterations were assessed by histopathological examination of hematoxylin-eosin stained sections of the kidneys. Ischemia-reperfusion produced elevated levels of TBARS and deteriorated the renal function as assessed by increased serum creatinine, BUN and decreased creatinine and urea clearance as compared to sham operated rats. The ischemic kidneys of rats showed severe hyaline casts, epithelial swelling, proteinaceous debris, tubular necrosis, medullary congestion and hemorrhage. U-74500A markedly attenuated elevated levels of TBARS as well as morphological changes, but did not improve renal dysfunction in rats subjected to renal ischemia-reperfusion. These results clearly demonstrate the in vivo antioxidant effect of U-74500A, a 21-aminosteroid in attenuating renal ischemia-reperfusion injury.

Regional differences in patient characteristics, case management, and outcomes in traumatic brain injury: experience from the tirilazad trials.

OBJECT: Regional differences have been shown in patient characteristics and case management within multiple unselected series of patients suffering from traumatic brain injury (TBI). One might expect that such regional heterogeneity would be small in a more selected population of a randomized clinical trial. The goal of this study was to examine what regional differences in patient characteristics, case management, and outcomes exist between continents and among countries within a patient population included in a randomized clinical trial. METHODS: Data were extracted from two concurrently conducted randomized clinical trials of the drug tirilazad; the designs of these studies were similar. The studies included 1701 patients with severe and 476 patients with moderate TBI. Differences were primarily investigated between studies performed in Europe and North America, but also among European regions and between Canada and the United States. Associations among regions and outcomes (6-month mortality rate and Glasgow Outcome Scale scores) were studied using multivariable logistic regression analysis. Comparisons between continents and among regions within Europe showed differences in the distribution of patient ages, causes of injury, and several clinical characteristics (motor score, pupillary reactivity, hypoxia, hypotension, intracranial pressure [ICP]). and findings on computerized tomography scans. Secondary referrals occurred 2.5 times more frequently in Europe. Within Europe secondary referral was mainly associated with an increased proportion of patients with mass lesions (46% in the European Study compared with 40% in the North American Study). Therapy for lowering ICP was more frequently applied in North America. After adjustments for case mix and management, mortality and unfavorable outcomes were significantly higher in Europe (odds ratios = 1.58 and 1.46, respectively). Significant differences in outcome between regions within Europe or within North America were not observed. CONCLUSIONS: Despite the use of a strict study protocol, considerable differences in patient characteristics and case management exist between continents and among countries, reflecting variations in social, cultural, and organizational aspects. Outcomes of TBI may be worse in Europe compared with North America, but this finding requires further study.

Reproducibility of measurements of cerebral infarct volume on CT scans.

BACKGROUND AND PURPOSE: Infarct volume is increasingly used as an outcome measure in clinical trials of therapies for acute ischemic stroke. We tested which of 5 different methods to measure infarct size or volume on CT scans has the highest reproducibility. METHODS: Infarct volume and total intracranial volume were measured with Leica Q500 MCP image analysis software, or with a caliper, on 38 CT scans of patients who participated in the Tirilazad Efficacy Stroke Study II (TESS II). The scans were performed 8 days (+/-2 days) after the onset of symptoms. The 5 methods tested were based on (1) semiautomated pixel thresholding, (2) manual tracing of the perimeter, (3) a stereological counting grid, (4) measurement of the 3 largest diameters, and (5) the single largest diameter. The measurements were performed independently by 2 observers; the first observer performed all measurements twice. RESULTS: The single largest diameter did not correlate well with infarct volume. Of the other methods, manual tracing of the perimeter of the infarct had the lowest intraobserver and interobserver variability: coefficients of variation were 8.6% and 14.1%, respectively. For total intracranial volume, manual tracing also provided the highest reproducibility: intraobserver and interobserver coefficients of variation were 3.3% and 4.9%, respectively. CONCLUSIONS: Manual tracing of the perimeter is the most reproducible method for measuring the volumes of the infarct and the total intracranial space in multicenter trials of therapies for acute ischemic stroke.

Efficacy of nerve root versus interspinous injections of glucocorticoids in the treatment of disk-related sciatica. A pilot, prospective, randomized, double-blind study.

STUDY OBJECTIVES: Pilot study comparing the short-term efficacy on pain and functional impairment of nerve root sheath versus interspinous glucocorticoid injections in patients admitted to a French rheumatology department for disk-related sciatica or femoral neuralgia. PATIENTS AND METHODS: Thirty patients with refractory nerve root pain (sciatica, n = 29; femoral neuralgia, n = 1) for a mean of four months were randomized to nerve root injection (n = 17) or interspinous injection (n = 13) of the same mixture of 0.10 g of lidocaine hydrochloride and 3.75 mg of cortivazol. Both injection methods were performed under analgesia and benzodiazepine sedation to maintain double blinding. Each patient was evaluated daily during the first seven days of bed rest in the hospital, then after discharge on postinjection day 28. RESULTS: Prompt pain relief was obtained in both groups. On day 1, the mean pain scale score (0-100) fell from 70 +/- 3.9 to 26 +/- 5.6 in the nerve root group and from 63 +/- 4 to 23 +/- 4.7 in the interspinous group. These results were sustained on D7 and D28. CONCLUSIONS: The unusually high level of efficacy of glucocorticoid injection in our study may be ascribable in part to strong placebo and Hawthorne effects and in part to the intrinsic effects of the injections. Whether nerve root injection is superior over interspinous injection remains unproven.

Efficacy of transluminal angioplasty for the management of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

OBJECT: Transluminal angioplasty has become a widely used adjunct therapy to medical management of symptomatic cerebral vasospasm following subarachnoid hemorrhage (SAH). Despite anecdotal reports of universal, angiographically confirmed reversal of vasospasm and high rates of clinical improvement, no rigorous examination of the efficacy of this procedure has been conducted. In this study the authors assess the efficacy of the aforementioned procedure. METHODS: Thirty-eight patients enrolled as part of the North American trial of tirilazad in aneurysmal SAH underwent transluminal angioplasty for symptomatic cerebral vasospasm. Fifty-three percent of these patients showed good recovery or moderate disability based on their 3-month Glasgow Outcome Scale score. Among the 38 patients who underwent angioplasty, the severity and type of vasospasm, use of papaverine in addition to balloon angioplasty, timing of treatment, and dose of study drug did not have an effect on the outcome. The results of their neurological examinations improved in only four of the 38 patients immediately after the procedure. A conditional logistic regression analysis was performed in which these patients were compared with individuals matched for age, sex, dose of study drug, admission neurological grade, and modified Glasgow Coma Scale score at the time of angioplasty. No effect on favorable outcomes was found for this procedure. CONCLUSIONS: Transluminal cerebral angioplasty is very effective in reversing angiographically confirmed vasospasm, and anecdotal reports of its clinical utility are numerous. However, in this report the authors conclude that its superiority to medical management for symptomatic cerebral vasospasm is questionable.