RESUMEN
PURPOSE: The molecular mechanism behind pain in degenerative disc disease (DDD) and chronic low back pain (LBP) patients is largely unknown. This present study examines the association of LBP and disability to mediators of the inflammatory cascade, as indexed by mRNA gene expression of pro-inflammatory cytokine markers in the intervertebral disc (IVD). METHODS: Biopsies of the annulus fibrosus (AF) and the nucleus pulposes (NP) from patients with DDD undergoing 1-2 level fusion surgery at L4/L5 or L5/S1 were obtained from total of 34 patients [9 M, 25 F] with average age of 53 [32-63]. The mRNA expression of TNF-α, IL-1ß, and IL-6 in the AF and NP was analyzed using quantitative real-time polymerase chain reaction (RT-qPCR), and the expression level of these markers was correlated to the visual analogue scale (VAS) and Oswestry Disability Index (ODI) scores (0-100) for pain and disability. RESULTS: We report a statistically significant positive correlation between pain intensity (VAS score) and the expression of TNF-α in both the AF (r = 0.54, p = 0.001) and NP (r = 0.40, p = 0.02), similarly with IL-1ß in AF (r = 0.37, p = 0.02) and IL-6 in NP (r = 0.40, p = 0.02). In addition, we found significant positive correlation observed between disability score (ODI) and expression of IL-6 in both AF (r = 0.36, p = 0.03) and NP (r = 0.41, p = 0.01). CONCLUSION: We conclude that the intensity of LBP and disability is associated with the level of inflammation in the disc.
Asunto(s)
Dolor de la Región Lumbar , Fusión Vertebral , Adulto , Biopsia , Citocinas/genética , Humanos , Vértebras Lumbares/cirugía , Persona de Mediana Edad , ARN MensajeroRESUMEN
Rifabutin is effective in the treatment and prevention of Mycobacterium avium infection in people with HIV infection. Rifabutin is structurally related to another rifamycin, rifampin, a well-known inducer of the human P-450 isoform 3A. The rabbit isoform CYP3A6 and the human isoform CYP3A4 have similar P-450 predominance and substrate specificity and are both induced by rifampin. Our goal was to predict the CYP3A induction capacity of rifabutin and to determine if ex vivo CYP3A induction potential of rifamycins is predictive of that obtained in vivo. We determined the in vivo and ex vivo CYP3A6 induction by 4 days of treatment with rifabutin (100 mg/kg), rifampin (100 mg/kg), or vehicle (DMSO) in the rabbit. The ex vivo measures were CYP3A6 activity (N-demethylation of erythromycin and hydroxylation of triazolam) and CYP3A content in rabbit hepatic microsomes preparations. The in vivo measures were oral clearance of triazolam and its formation clearance to its hydroxylated metabolites, alpha-hydroxytriazolam and 4-hydroxytriazolam. Rifampin increased CYP3A6 activity by 2- to 3-fold in hepatic microsomes compared to vehicle. Rifabutin increased CYP3A content 1.7-fold, but did not significantly increase microsomal CYP3A6 activity. Oral triazolam clearance and formation clearances to the two hydroxylated metabolites were 2- to 3-fold greater in rabbits treated with rifampin. These clearances were unaffected by rifabutin administration. Ex vivo enzyme activities correlated with in vivo changes in clearance of triazolam and the formation clearance to its hydroxylated metabolites. Rifabutin is a weaker inducer of CYP3A6 than rifampin. These data suggest that ex vivo enzyme activity is a viable approach to predict in vivo inductive potential of CYP3A inducers.
Asunto(s)
Antibióticos Antituberculosos/farmacología , Hidrocarburo de Aril Hidroxilasas , Sistema Enzimático del Citocromo P-450/biosíntesis , Oxidorreductasas N-Desmetilantes/biosíntesis , Rifabutina/farmacología , Rifampin/farmacología , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP3A , Inducción Enzimática/efectos de los fármacos , Hipnóticos y Sedantes/farmacocinética , Inmunoquímica , Técnicas In Vitro , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Tamaño de los Órganos/efectos de los fármacos , Unión Proteica , Conejos , Triazolam/farmacocinéticaRESUMEN
We have investigated interstitial deletions of chromosome 8 in 70 colorectal carcinomas and 11 colonic adenomas using 11 microsatellite markers, including eight spanning the centromeric region of chromosome 8p (p11.2-p12). Allelic loss or imbalance was observed in 38 (54%) cancers and four (36%) adenomas. Twenty-eight (40%) of the cancers had deletions of 8p11.2-p12. Two distinct and independent regions of interstitial loss were found within this region. Fluorescent in situ hybridization, using an alpha satellite repeat probe to the centromere of 8p and two probes to the P1 region, was performed in four tumours that demonstrated allelic imbalance. Localized heterozygous deletions were confirmed in all four tumours. Eleven (16%) cancers had localized deletion in the region ANK-1 to D8S255 (P1) and a further eleven (16%) cancers had a less well localized deletion in the region defined by the markers D8S87 to D8S259 (P2). Loss of both centromeric loci was identified in a further six (9%) tumours. A functional significance for these two deletion regions was sought by correlation with primary and secondary tumour characteristics. Isolated P2 deletion was associated with 'early' T1 cancers (2p=0.0002), and were also identified in 3/11 adenomas. Conversely, interstitial deletions of the P1 locus were more frequently seen in 'locally invasive' T3/4 cancers (2p=0.015), and isolated P1 deletions were also associated with the presence of liver metastases (2p=0.016). Our data provide evidence of at least two genes within the 8p11.2-p12 region, mutations in which may confer different and independent roles in the pathogenesis of colorectal cancer.