Studies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems.

The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antagonists have been evaluated in normotensive volunteers on various salt diets. In the first study, the renal response to a single oral dose of losartan (100 mg) was assessed in subjects on a low (50 mmol Na/d) and on a high (200 mmol Na/d) salt intake. In a second protocol, the renal effects of 50 mg irbesartan were investigated in subjects receiving a 100 mmol Na/d diet. Both angiotensin II antagonists induced a significant increase in urinary sodium excretion. With losartan, a modest, transient increase in urinary potassium and a significant increase in uric acid excretion were found. In contrast, no change in potassium and uric acid excretions were observed with irbesartan, suggesting that the effects of losartan on potassium and uric acid are due to the intrinsic pharmacologic properties of losartan rather than to the specific blockade of renal angiotensin II receptors. Assessment of segmental sodium reabsorption using lithium as a marker of proximal tubular reabsorption demonstrated a decreased distal reabsorption of sodium with both antagonists. A direct proximal tubular natriuretic effect of the angiotensin II antagonist could be demonstrated only with irbesartan. This apparent discrepancy allowed us to reveal the importance of acute water loading as a possible confounding factor in renal studies. The results of the present analysis show that acute water loading per se may enhance renal sodium excretion and hence modify the level of activity of the renin-angiotensin system expected from a given sodium diet. Since acute water loading is a common practice in clinical renal studies, this confounding factor should be taken into account when investigating the renal effects of vasoactive systems.

Recovery of paraplegia after type B dissection due to spinal collateral recruitment.

Acute paraplegia could be a symptom of aortic dissection due to sudden compromise of arterial spinal cord blood supply. Complete spontaneous neurologic recovery is possible and was observed in the present case 3 hours after symptom onset. Spontaneous spinal cord reperfusion after acute type B dissection was probably due to two main mechanisms. Reperfusion of false lumen and collateral vascular network recruitment, recently confirmed by anatomic animal studies, serve as potential explanations. Favorable evolution of acute paraplegia after aortic dissection exists, but prognosis is uncertain, probably due to individual variable anatomic distribution of spinal cord blood supply.

The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.

Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund's adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.

Invasion of lesion territory by regenerating fibers after spinal cord injury in adult macaque monkeys.

In adult macaque monkeys subjected to an incomplete spinal cord injury (SCI), corticospinal (CS) fibers are rarely observed to grow in the lesion territory. This situation is little affected by the application of an anti-Nogo-A antibody which otherwise fosters the growth of CS fibers rostrally and caudally to the lesion. However, when using the Sternberger monoclonal-incorporated antibody 32 (SMI-32), a marker detecting a non-phosphorylated neurofilament epitope, numerous SMI-32-positive (+) fibers were observed in the spinal lesion territory of 18 adult macaque monkeys; eight of these animals had received a control antibody infusion intrathecally for 1month after the injury, five animals an anti-Nogo-A antibody, and five animals received an anti-Nogo-A antibody together with brain-derived neurotrophic factor (BDNF). These fibers occupied the whole dorso-ventral axis of the lesion site with a tendency to accumulate on the ventral side, and their trajectories were erratic. Most of these fibers (about 87%) were larger than 1.3μm and densely SMI-32 (+) stained. In the undamaged spinal tissue, motoneurons form the only large population of SMI-32 (+) neurons which are densely stained and have large diameter axons. These data therefore suggest that a sizeable proportion of the fibers seen in the lesion territory originate from motoneurons, although fibers of other origins could also contribute. Neither the presence of the antibody neutralizing Nogo-A alone, nor the presence of the antibody neutralizing Nogo-A combined with BDNF influenced the number or the length of the SMI-32 (+) fibers in the spinal lesion area. In summary, our data show that after a spinal cord lesion in adult monkeys, the lesion site is colonized by fibers, a large portion of which presumably originate from motoneurons.

Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model.

PURPOSE: The combination of embolic beads with a multitargeted tyrosine kinase inhibitor that inhibits tumor vessel growth is suggested as an alternative and improvement to the current standard doxorubicin-eluting beads for use in transarterial chemoembolization. This study demonstrates the in vitro loading and release kinetics of sunitinib using commercially available embolization microspheres and evaluates the in vitro biologic efficacy on cell cultures and the resulting in vivo pharmacokinetics profiles in an animal model. MATERIALS AND METHODS: DC Bead microspheres, 70-150 µm and 100-300 µm (Biocompatibles Ltd., Farnham, United Kingdom), were loaded by immersion in sunitinib solution. Drug release was measured in saline in a USP-approved flow-through apparatus and quantified by spectrophotometry. Activity after release was confirmed in cell culture. For pharmacokinetics and in vivo toxicity evaluation, New Zealand white rabbits received sunitinib either by intraarterial injection of 100-300 µm sized beads or per os. Plasma and liver tissue drug concentrations were assessed by liquid chromatography-tandem mass spectroscopy. RESULTS: Sunitinib loading on beads was close to complete and homogeneous. A total release of 80% in saline was measured, with similar fast-release profiles for both sphere sizes. After embolization, drug plasma levels remained below the therapeutic threshold (< 50 ng/mL), but high concentrations at 6 hours (14.9 µg/g) and 24 hours (3.4 µg/g) were found in the liver tissue. CONCLUSIONS: DC Bead microspheres of two sizes were efficiently loaded with sunitinib and displayed a fast and almost complete release in saline. High liver drug concentrations and low systemic levels indicated the potential of sunitinib-eluting beads for use in embolization.

Repeated sprinting on natural grass impairs vertical stiffness but does not alter plantar loading in soccer players.

This study aimed to determine changes in spring-mass model (SMM) characteristics, plantar pressures, and muscle activity induced by the repetition of sprints in soccer-specific conditions; i.e., on natural grass with soccer shoes. Thirteen soccer players performed 6 × 20 m sprints interspersed with 20 s of passive recovery. Plantar pressure distribution was recorded via an insole pressure recorder device divided into nine areas for analysis. Stride temporal parameters allowed to estimate SMM characteristics. Surface electromyographic activity was monitored for vastus lateralis, rectus femoris, and biceps femoris muscles. Sprint time, contact time, and total stride duration lengthened from the first to the last repetition (+6.7, +12.9, and +9.3%; all P < 0.05), while flight time, swing time, and stride length remained constant. Stride frequency decrease across repetitions approached significance (-6.8%; P = 0.07). No main effect of the sprint number or any significant interaction between sprint number and foot region was found for maximal force, mean force, peak pressure and mean pressure (all P > 0.05). Center of mass vertical displacement increased (P < 0.01) with time, together with unchanged (both P > 0.05) peak vertical force and leg compression. Vertical stiffness decreased (-15.9%; P < 0.05) across trials, whereas leg stiffness changes were not significant (-5.9%; P > 0.05). Changes in root mean square activity of the three tested muscles over sprint repetitions were not significant. Although repeated sprinting on natural grass with players wearing soccer boots impairs their leg-spring behavior (vertical stiffness), there is no substantial concomitant alterations in muscle activation levels or plantar pressure patterns.

Influence of the morphology of the dural sac on surgical decision making in lumbar spinal stenosis

Introduction: Surgical decision making in lumbar spinal stenosis (LSS) takes into account primarily clinical symptoms as well as concordant radiological findings. We hypothesized that a wide variation of operative threshold would be found in particular as far as judgment of severity of radiological stenosis is concerned. Patients and methods: The number of surgeons who would proceed to decompression was studied relative to the perceived severity of radiological stenosis based either on measurements of dural sac cross sectional area (DSCA) or on the recently described morphological grading as seen on axial T2 MRI images. A link to an electronic survey page with a set of ten axial T2 MRI images taken from ten patients with either low back pain or LSS were sent to members of three national or international spine societies. Those 10 images were randomly presented initially and re-shuffled on a second page including this time DSCA measurements in mm2, ranging from 14 to 226 mm2, giving a total of 20 images to appraise. Morphological grades were ranging from grade A to D. Surgeons were asked if they would consider decompression given the radiological appearance of stenosis and that symptoms of neurological claudication were severe in patients who were otherwise fit for surgery. Fisher's exact test was performed following dichotomization of data when appropriate. Results: A total of 142 spine surgeons (113 orthopedic spine surgeons, 29 neurosurgeons) responded from 25 countries. A substantial agreement was observed in operating patients with severe (grade C) or extreme (grade D) stenosis as defined by the morphological grade compared to lesser stenosis (A&B) grades (p<0.0001). Decision to operate was not dependent on number of years in practice, medical density in practicing country or specialty although more neurosurgeons would operate on grade C stenosis (p<0.005). Disclosing the DSCA measurement did not alter the decision to operate. Although 20 surgeons only had prior knowledge of the description of the morphological grading, their responses showed no statistically significant difference with those of the remaining 122 physicians. Conclusions: This study showed that surgeons across borders are less influenced by DSCA in their decision making than by the morphological appearance of the dural sac. Classifying LSS according to morphology rather than surface measurements appears to be consistent with current clinical practice.

Changes in leg spring behaviour, plantar loading and foot mobility magnitude induced by an exhaustive treadmill run in adolescent middle-distance runners.

OBJECTIVES: This study aimed to determine adjustments in spring-mass model characteristics, plantar loading and foot mobility induced by an exhaustive run. DESIGN: Within-participants repeated measures. METHODS: Eleven highly-trained adolescent middle-distance runners ran to exhaustion on a treadmill at a constant velocity corresponding to 95% of velocity associated with VO₂max (17.8 ± 1.4 kmh(-1), time to exhaustion=8.8 ± 3.4 min). Contact time obtained from plantar pressure sensors was used to estimate spring-mass model characteristics, which were recorded (during 30 s) 1 min after the start and prior to exhaustion using pressure insoles. Foot mobility magnitude (a composite measure of vertical and medial-lateral mobility of the midfoot) was measured before and after the run. RESULTS: Mean contact area (foot to ground), contact time, peak vertical ground reaction force, centre of mass vertical displacement and leg compression increased significantly with fatigue, while flight time, leg stiffness and mean pressure decreased. Leg stiffness decreased because leg compression increased to a larger extent than peak vertical ground reaction forces. Step length, step frequency and foot mobility magnitude did not change at exhaustion. CONCLUSIONS: The stride pattern of adolescents when running on a treadmill at high constant velocity deteriorates near exhaustion, as evidenced by impaired leg-spring behaviour (leg stiffness) and altered plantar loading.

Preoperative assessment of neurovesical function in children with anorectal malformation: association with vertebral and spinal malformations.

PURPOSE: We preoperatively assessed neurovesical function and spinal cord function in children with anorectal malformations. In cases of neurovesical dysfunction we looked for an association with vertebral malformation or myelodysplasia. MATERIALS AND METHODS: We prospectively evaluated 80 children with anorectal malformations via preoperative urodynamics and magnetic resonance imaging of the spine. Bladder compliance and volume, detrusor activity and vesicosphincteric synergy during voiding allowed urodynamic evaluation. Results were reported according to Wingspread and Krickenbeck classifications of anorectal malformations. RESULTS: Urodynamic findings were pathological in 14 children (18%). Pathological evaluations did not seem related to type of fistula or level of anorectal malformation. Vertebral anomalies were seen in 34 patients (43%) and myelodysplasia in 16 (20%). Neither vertebral anomaly nor myelodysplasia seemed associated with type of fistula or severity of anorectal malformation. Of 14 children with pathological urodynamics no vertebral anomaly or myelodysplasia was found in 7. Of 66 children with normal urodynamics 40 presented with vertebral or spinal malformation. CONCLUSIONS: Lower urinary tract dysfunction is common in patients with anorectal malformations. Normal spine or spinal cord does not exclude neurovesical dysfunction. Myelodysplasia or vertebral anomaly does not determine lower urinary tract dysfunction. Thus, we recommend preoperative urodynamic assessment of the bladder and magnetic resonance imaging of the spine in children with anorectal malformations.

Cross-cultural adaptation, reliability, internal consistency and validation of the Spinal Function Sort (SFS) for French- and German-speaking patients with back complaints.

Introduction Functional subjective evaluation through questionnaire is fundamental, but not often realized in patients with back complaints, lacking validated tools. The Spinal Function Sort (SFS) was only validated in English. We aimed to translate, adapt and validate the French (SFS-F) and German (SFS-G) versions of the SFS. Methods Three hundred and forty-four patients, experiencing various back complaints, were recruited in a French (n = 87) and a German-speaking (n = 257) center. Construct validity was estimated via correlations with SF-36 physical and mental scales, pain intensity and hospital anxiety and depression scales (HADS). Scale homogeneities were assessed by Cronbach's α. Test-retest reliability was assessed on 65 additional patients using intraclass correlation (IC). Results For the French and German translations, respectively, α were 0.98 and 0.98; IC 0.98 (95% CI: [0.97; 1.00]) and 0.94 (0.90; 0.98). Correlations with physical functioning were 0.63 (0.48; 0.74) and 0.67 (0.59; 0.73); with physical summary 0.60 (0.44; 0.72) and 0.52 (0.43; 0.61); with pain -0.33 (-0.51; -0.13) and -0.51 (-0.60; -0.42); with mental health -0.08 (-0.29; 0.14) and 0.25 (0.13; 0.36); with mental summary 0.01 (-0.21; 0.23) and 0.28 (0.16; 0.39); with depression -0.26 (-0.45; -0.05) and -0.42 (-0.52; -0.32); with anxiety -0.17 (-0.37; -0.04) and -0.45 (-0.54; -0.35). Conclusions Reliability was excellent for both languages. Convergent validity was good with SF-36 physical scales, moderate with VAS pain. Divergent validity was low with SF-36 mental scales in both translated versions and with HADS for the SFS-F (moderate in SFS-G). Both versions seem to be valid and reliable for evaluating perceived functional capacity in patients with back complaints.

Idarubicin-loaded ONCOZENE drug-eluting embolic agents for chemoembolization of hepatocellular carcinoma: in vitro loading and release and in vivo pharmacokinetics.

PURPOSE: To present in vitro loading and release characteristics of idarubicin with ONCOZENE (CeloNova BioSciences, Inc, San Antonio, Texas) drug-eluting embolic (DEE) agents and in vivo pharmacokinetics data after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in patients with hepatocellular carcinoma. MATERIALS AND METHODS: Loading efficacy of idarubicin with ONCOZENE DEE agents 100 µm and DC Bead (Biocompatibles UK Ltd, Farnham, United Kingdom) DEE agents 100-300 µm was monitored at 10, 20, and 30 minutes loading time by high-pressure liquid chromatography. A T-apparatus was used to monitor the release of idarubicin from the two types of DEE agents over 12 hours. Clinical and 24-hour pharmacokinetics data were recorded after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in four patients with unresectable hepatocellular carcinoma. RESULTS: Idarubicin loading in ONCOZENE DEE agents was > 99% at 10 minutes. Time to reach 75% of the release plateau level was 37 minutes ± 6 for DC Bead DEE agents and 170 minutes ± 19 for ONCOZENE DEE agents both loaded with idarubicin 10 mg/mL. After transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents, three partial responses and one complete response were observed with only two asymptomatic grade 3 biologic adverse events. Median time to maximum concentration for idarubicin in patients was 10 minutes, and mean maximum concentration was 4.9 µg/L ± 1.7. Mean area under the concentration-time curve from 0-24 hours was equal to 29.5 µg.h/L ± 20.5. CONCLUSIONS: ONCOZENE DEE agents show promising results with very fast loading ability, a favorable in vivo pharmacokinetics profile with a sustained release of idarubicin during the first 24 hours, and encouraging safety and responses. Histopathologic and clinical studies are needed to evaluate idarubicin release around the DEE agents in tumor tissue and to confirm safety and efficacy.

Video-assisted thoracic surgery diagnosis of thoracic spinal tuberculosis.

Tuberculous spondylitis is rare in economically well-developed countries. MRI is the most sensitive radiologic method of diagnosis. CT-guided fine needle aspiration can be an appropriate method for obtaining samples for culture, with positive cultures in 25 to 89% of cases. However, it can take >6 weeks for specimens to grow, and it is essential to have adequate culture and sensitivity studies for the diagnosis and treatment of mycobacterial diseases. We propose a minimally invasive diagnostic approach that ensures that adequate surgical specimens are obtained prior to initiating treatment.

Spinal epidural abscess from group A Streptococcus after varicella infection: a case report and review of the literature.

INTRODUCTION: Spinal epidural abscess (SEA) is a very rare condition in pediatric patients. Varicella zoster infection could be a predisposing factor, and SEA should be suspected in patients with signs of secondary bacterial infection and even mild neurological signs. CLINICAL CASE: We describe here a case of a 30-month-old girl with a history of remitting varicella infection, diagnosed for a lumbar epidural abscess and sacro-ileitis, secondary to group A Streptococcus (GAS). DISCUSSION: This is the third case of SEA from GAS reported in the literature in a pediatric population with varicella infection. We discuss here the clinical presentation and the diagnostic challenges for SEA in childhood through a review of the literature.