Indomethacin blocks the nucleus pulposus-induced effects on nerve root function

Inflammatory mechanisms have been suggested to be involved in the basic pathophysiologic events leading to nerve root injury after local application of nucleus pulposus. To assess if these nucleus pulposus-induced effects could be blocked by anti-inflammatory treatment, 41 dogs were exposed to either incision of the L6-7 disc to induce experimental disc herniation with (n=12) or without (n=14) indomethacin treatment per os (5 mg/kg per day), and no incision with (n=5) or without (n=10) indomethacin. Intraneural blood flow and nerve conduction velocity were assessed after 7 days to evaluate the degree of nerve injury. Disc incision induced a reduction in nerve root and dorsal ganglion blood flow as well as nerve function, similarly to previous studies. However, simultaneous treatment with indomethacin efficiently blocked the negative effects on both blood flow and nerve conduction but had no effects per se. The present study thus indicates that inflammatory mechanisms may be of relevance in the pathophysiology of nucleus pulposus-induced nerve root injury and thereby also for sciatica.This study was supported by grants from the Fukushima Medical Research Promotion Foundation and the Swedish Medical Research Council (9758)     

Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats

The present study was designed to compare the functional outcome of the intraspinal transplantation of CD34+ human umbilical cord blood (CB) cells with that of human bone marrow stromal (BMS) cells in adult rats with spinal cord injury. Sixty adult Wistar rats were subjected to left spinal cord hemisection, and then divided into three groups randomly. The control group received an injection of PBS without cells, while the two other groups of rats received a transplantation of 5 x 10(5) CD34+ CB or BMS cells, respectively. Functional outcome was measured using the modified Tarlov score at days 1, 7, 14, 21, and 28 after transplantation. A statistically significant improvement in functional outcome and survival rate in the experimental groups of rats was observed compared with the control group. Rats that received CD34+ CB cells achieved a better improvement in functional score than those that received BMS cells at days 7 and 14 after transplantation. Histological evaluation revealed that bromodeoxyuridine (BrdU)-labeled CD34+ CB and BMS cells survived and migrated into the injured area. Some of these cells expressed glial fibriliary acidic protein (GFAP) or neuronal nuclear antigen (NeuN). Our data demonstrate for the first time that intraspinal transplantation of human CD34+ CB cells provides benefit in function recovery after spinal cord hemisection in rats and suggest that CD34+ CB cells may be an excellent choice of cells as routine starting material of allogenic and autologous transplantations for the treatment of spinal cord injury.     

Reduction of perlecan synthesis and induction of TGF-beta1 in human peritoneal mesothelial cells due to high dialysate glucose concentration: implication in peritoneal dialysis

Prolonged exposure of the peritoneal mesothelium to high dialysate glucose concentrations reduces anionic sites that are critical to its selective permeability, thereby impairing the peritoneal transport properties in patients on long-term peritoneal dialysis (PD). Perlecan, an anionic heparan sulfate proteoglycan, is pivotal to the selective permeability of basement membranes, and high glucose concentrations modulate its synthesis in mesangial cells. The effect of glucose on perlecan expression in the peritoneal mesothelium has not been established. We investigated perlecan expression in peritoneal biopsies from patients on PD, and the effect of high glucose concentrations on perlecan synthesis in cultured human peritoneal mesothelial cells (HPMC). Peritoneal biopsies from PD patients showed reduced perlecan expression compared with controls. Exposure of HPMC to high glucose concentrations resulted in a dose-dependent reduction in the synthesis of perlecan polypeptide and its deposition into the extracellular matrix. These effects were mediated in part through the induction of TGF-beta1. Characterization studies showed that perlecan synthesized by HPMC contained solely heparan sulfate glycosaminoglycan (HS GAG) chains, and [(35)S]-incorporation studies demonstrated progressive reduction of their de novo synthesis with increasing glucose concentrations (68142 +/- 3658, 48147 +/- 2517, 31468 +/- 5781, and 25575 +/- 3621 cpm/ micro g cellular protein for 5 mM, 30 mM, 75 mM, and 120 mM D-glucose, respectively; P < 0.001 for 5 mM versus 30 mM D-glucose, and P < 0.0001 for 5 mM versus 75 mM or 120 mM D-glucose). Both the length and the charge density of the HS GAG chains remained unchanged. Reduction of peritoneal perlecan expression in long-term PD was attributed to high dialysate glucose concentrations, which induced TGF-beta1 and reduced perlecan synthesis in HPMC. Since perlecan can sequester growth factors, thereby modulating cell migration and differentiation perturbation of peritoneal perlecan expression contributes to the structural and functional changes of the peritoneum in long-term PD.     

Incidence and outcome of antiglomerular basement membrane disease in Chinese

Background: Antiglomerular basement membrane (anti‐GBM) disease is an uncommon disease, especially among Asian population. Many reports and studies on this condition in the Caucasian population are available, but little information exists on anti‐GBM disease in Asians. To study the incidence and clinical characteristics of anti‐GBM disease among Chinese patients, we reviewed our experience of anti‐GBM disease in our hospital (Queen Mary Hospital, Hong Kong) from 1992 to 2003. Methods: All patients who were admitted for acute renal impairment, which was caused by crescentic glomerulonephritis associated with linear immunoglobulin G (IgG) staining on immunofluorescence, were included in the analysis. Serum anti‐GBM antibodies were detected by either enzyme‐linked immunofluorescence or indirect immunofluorescence. Ten patients were treated for anti‐GBM disease during this 11‐year period, yielding an incidence of approximately 0.6 cases per million population per year. Results: In this cohort, anti‐GBM disease predominantly affected older patients (mean age: 58.6 ± 21.7 years). Eight patients were aged between 60 and 80 years and there was a female preponderance (M:F = 2:8). The 1‐year renal and patient survival was 15% (95% CI 0–40%) and 70% (95% CI 42–98%), respectively. Most patients presented with non‐specific symptoms as well as impaired renal function. Detection of anti‐GBM antibody provided a good screening test for the disease. Antiglomerular basement membrane antibodies were not detected in two patients. All but two patients received steroid, cyclophosphamide and intensive plasmapheresis therapy. Haemoptysis occurred in four patients (40%), and usually lagged behind the renal presentation and commencement of treatment. Six patients required long‐term dialysis after the acute disease. Three patients died from the disease, two died from pulmonary complications and one died suddenly after a partial recovery of renal function. Conclusion: Antiglomerular basement membrane disease is uncommon among the Chinese population. It predominantly affects older patients, and prognosis is poor. Long‐term preservation of renal function after the initial attack is unusual.     

Thebesian valve imaging with electron beam CT angiography: implications for resynchronization therapy

We report visualization of a prominent coronary sinus os valve (Thebesian valve), by electron beam computed tomographic angiography, which impeded an endocardial approach to left ventricular pacing. Resynchronization therapy was therefore performed with an epicardial approach to left ventricular lead placement. Electron beam computed tomographic angiography can provide detailed information for coronary sinus instrumentation, including anomalies potentially affecting the approach to resynchronization therapy.     

Environmental tobacco smoke and the risk of pancreatic cancer: findings from a Canadian population-based case-control study

BACKGROUND: Despite the fact that tobacco is a well-recognized risk factor for pancreatic cancer, no study has yet reported on the association between environmental tobacco smoke (ETS) and this malignancy. We investigated the relationship between pancreatic cancer and childhood and adult exposure to ETS using a case-control study design. METHODS: Our study population consisted of 583 pancreatic cancer cases and 4,813 population-based controls that were identified within 8 Canadian provinces between 1994 and 1997. Mail-out questionnaires were used to collect risk factor information and a lifetime residential and occupational history of exposure to ETS. RESULTS: Among never smokers, those who were exposed to ETS both as a child and as an adult had an odds ratio of 1.21 (95% CI=0.60-2.44) relative to those with no exposure. For active smoking, when the referent group consisted of never smokers who had not been regularly exposed to ETS, the risk increases were more pronounced with an increased number of years of smoking, cigarette pack-years, years since quit smoking, and average number of cigarettes smoked daily. CONCLUSIONS: Overall, our results are suggestive of a weak association between pancreatic cancer and ETS. Perhaps more importantly, they suggest that ETS smoking exposures may confound the risk of pancreatic cancer associated with active smoking measures commonly used in epidemiologic studies.     

Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel

A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.     

Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice

Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain. To investigate this possibility, we measured neurogenesis by intraperitoneal injection of bromodeoxyuridine (BrdU), which labels newborn neurons, in wild-type and CB1R-knockout (CB1R-KO) mice. CB1R-KO mice showed reductions in the number of BrdU-labeled cells to approximately 50% of wild-type (WT) levels in dentate gyrus and subventricular zone (SVZ), suggesting that CB1R activation promotes neurogenesis. To test this further, WT mice were given the CB1R antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) before measuring neurogenesis with BrdU. SR141716A paradoxically increased the number of BrdU-labeled cells by approximately 50% in SVZ; another CB1R antagonist, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251), had a similar effect. To investigate this discrepancy, SR141716A was given to CB1R-KO mice, in which it still stimulated neurogenesis, indicating involvement of a non-CB1 receptor. Action at one such non-CB1, SR141716A-sensitive site, the VR1 vanilloid receptor, was tested by administering SR141716A to VR1-KO mice, in which the ability of SR141716A to enhance neurogenesis was abolished. Thus, CB1 and VR1 receptors both seem to have roles in regulating adult neurogenesis.     

Effect of α-pinene on nuclear translocation of NF-κB in THP-1 cells

AIM: To study the effects of α-pinene on nuclear translocation of nuclear factor-κB (NF-κB) and the expression of the inhibitor of NF-κB (IκBα) in human monocyte THP-1 cell line. METHODS: THP-1 cells were incubated with α-pinene (1, 10, and 100 mg/L, for 30 min) before being stimulated with lipopolysaccharide (LPS, 1 mg/L, 30 min).The location of NF-κB p65 subunit (NF-κB/p65) in THP-1 cells was detected by immunofluorescence and laser scanning confocal microscope (LSCM). The expression of NF-κB/p65 in nuclei and that of IκBα in cytoplasm were measured by Western-blot analysis. RESULTS: The majority of FITC-labelled NF-κB/p65 was located in the nuclei being stimulated with LPS. Whereas, no such fluorescence was seen in the nuclei of the groups pretreated with α-pinene or control cells, α-Pinene pretreatment decreased the NF-κB/p65 nuclear translocation in LPS-stimulated THP-1 cells, and this effect was dose-dependent, but there was no reaction in LPS-unstimulated THP-1 cells, α-Pinene pretreatment increased IκBα protein level in cytoplasm, compared with that in LPS-stimulated THP-1 cells. CONCLUSION: In a dose-related fashion, α-pinene inhibits the nuclear translocation of NF-κB induced by LPS in THP- 1 cells, and this effect is partly due to the upregulation of IκBα expression.