Hepatocellular cancers (HCC) are highly resistant to chemotherapy. TGFβ has been associated with ... more Hepatocellular cancers (HCC) are highly resistant to chemotherapy. TGFβ has been associated with chemoresistance in some human cancers but the mechanisms involved are unknown. We explored how TGFβ might contribute to altered responses to therapy by assessing the involvement and mechanistic contribution of extracellular vesicle long non-coding RNA (lncRNA) in mediating TGFβ-dependent chemoresistance. TGFβ reduced the sensitivity of HCC cells to sorafenib or doxorubicin and altered the release of both extracellular vesicles and of selected lncRNA within these vesicles. Amongst these, lincRNA-ROR (linc-ROR), a stress-responsive lncRNA was highly expressed in HCC cells and enriched within extracellular vesicles derived from tumor cells. Incubation with HCC-derived extracellular vesicles increased linc-ROR expression and reduced chemotherapy-induced cell death in recipient cells. Sorafenib increased linc-ROR expression in both tumor cells and extracellular vesicles, whereas siRNA to linc-ROR increased chemotherapy-induced apoptosis and cytotoxicity. Tumor-initiating cells that express CD133 have an increased resistance to therapy. TGFβ increased expression of CD133+ cells and colony growth in limiting dilution assays, both of which were attenuated by linc-ROR knockdown. These data provide mechanistic insights into primary chemoresistance in HCC by showing that: (a) TGFβ selectively enriches linc-RoR within extracellular vesicles, which has a potential role in intercellular signaling in response to TGFβ; (b) expression and enrichment of linc-ROR during chemotherapeutic stress plays a functional role in chemoresistance; and (c) the effects of TGFβ on chemoresistance in HCC may involve linc-RoR-dependent effects on tumor-initiating cells. These findings implicate extracellular vesicle lncRNA as mediators of the chemotherapeutic response, and support targeting linc-ROR to enhance chemosensitivity in HCC.
Scheuermann&a... more Scheuermann's disease is a kyphotic deformity of the spine that develops in early adolescence. This condition has been reported to occur in 0.4% to 8% of the general population, with an equal distribution between sexes. Diagnosis of Scheuermann's disease is suggested on clinical examination; however, parents of children affected often confuse it with poor posture. Radiographs are the standard imaging modality used to confirm the diagnosis of Scheuermann's disease. Classic signs include vertebral end plate irregularity, disk space narrowing, and anterior wedging of involved vertebral bodies. Other diagnostic tools such as CT scans or magnetic resonance imaging may also be of value in the evaluation of Scheuermann's disease. The mode of treatment for this condition depends upon the severity of the deformity, remaining growth, and presence or absence of symptoms. Early treatment may be limited to observation and exercises, whereas patients who have kyphosis of up to 75 degrees and how have growth remaining may benefit from bracing. Surgical correction is reserved for severe cases that are symptomatic and refractory to conservative management.
Recent studies have suggested that noncoding RNAs (ncRNAs) contribute to the pathogenesis and pro... more Recent studies have suggested that noncoding RNAs (ncRNAs) contribute to the pathogenesis and progression of hepatocellular carcinoma (HCC). These RNA genes may be involved in various pathobiological processes such as cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Aberrant expression of ncRNA resulting from deregulated epigenetic, transcriptional, or posttranscriptional activity has been described in several studies. ncRNAs are comprised of a highly diverse group of transcripts that include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) as well as several other types of RNA genes. Understanding the molecular mechanisms by which ncRNA contribute to hepatocarcinogenesis may enable the design of ncRNA-based therapeutics for HCC. In this review, the authors provide a perspective on therapeutic applications based on the emerging evidence of a contributory role of miRNAs and lncRNAs to the pathogenesis and progression of HCC. In addition, ncRNAs that are deregulated in expression in HCC may have utility as potential prognostic or diagnostic markers.
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options... more Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options.
Over-expression of IL-6 has been implicated in cholangiocarcinoma growth but the cellular mechani... more Over-expression of IL-6 has been implicated in cholangiocarcinoma growth but the cellular mechanisms involved are unknown. Our aims were to assess the mechanisms by which over-expression of IL-6 promotes transformed cell growth in malignant cholangiocytes.Stably transfected cell lines over-expressing IL-6 were derived from malignant human cholangiocytes. Transformed cell growth was assessed by anchorage independent growth in vitro and by xenograft growth in nude mice. Expression of the anti-apoptotic protein Mcl-1 was quantitated by immunoblot analysis and by real-time PCR. Gene silencing was performed using siRNA. Dominant negative upstream kinase activators and isoform-specific constructs were used to evaluate the involvement of p38 MAP kinase signaling pathways.Over-expression of IL-6 increased xenograft growth, anchorage independent growth and cell survival but did not significantly alter cell proliferation. The basal expression of Mcl-1 was increased in IL-6 over-expressing cells. Selective knockdown of Mcl-1 by siRNA increased gemcitabine-induced cytotoxicity. Moreover, IL-6 increased Mcl-1 mRNA and protein expression via a p38 MAPK dependent mechanism.These data demonstrate a major role of survival signaling pathways in mediating the effects of IL-6 over-expression in cholangiocarcinoma growth. Mcl-1 is identified as a mediator of IL-6-induced tumor cell survival and shown to be transcriptionally regulated by IL-6 via a p38 MAPK dependent pathway. We conclude that modulation of IL-6 mediated survival signaling pathways involving the p38 MAPK or downstream targets such as Mcl-1 may prove useful therapeutic strategies for human cholangiocarcinoma.
This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonan... more This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonance imaging and quantitative discomanometry. To determine if a correlation exists between magnetic resonance imaging and quantitative discomanometry in determining disc degeneration of the lumbar spine. Several studies analyzing disc degeneration of the lumbar spine have compared magnetic resonance imaging with discography and discomanometry. The reported results are conflicting. No studies exist that compare magnetic resonance imaging and quantitative discomanometry in assessing the disc degeneration of the lumbar spine. Three fresh human cadaveric thoracolumbar spine specimens (two T11-S1 and one L1-S1) that included a total of 19 discs were used. Spines were scanned with magnetic resonance imaging, and the scans were read by a neuroradiologist. Using the quantitative discomanometry technique, discs were injected with normal saline, and pressure-volume curves were collected and quantified with six parameters: intrinsic pressure, leakage pressure, initial slope, slope from 0.0 to 0.1 mL, maximum pressure, and volume at maximum pressure. Data analysis was performed using Spearman's Rank Correlation (Rho) statistic. Based on the results from 19 discs, an overall good correlation between magnetic resonance imaging scores and the six quantitative discomanometry parameters was demonstrated. With exception of the volume at maximum pressure, correlation coefficients ranged between 0.61 to 0.78 with a P < 0.05. Magnetic resonance imaging scores and quantitative discomanometry parameters correlated well in the assessment of disc degeneration of the lumbar spine. Quantitative discomanometry may be an important technique for evaluating early disc degeneration, especially tears of the anular fibers, which may be missed on magnetic resonance imaging.
Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primar... more Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC), but some patients show an incomplete response. Silymarin is a potent antioxidant with immunomodulatory and antifibrotic properties. The aim of this study was to evaluate the safety and assess the efficacy of silymarin in patients with PBC who had shown a suboptimal response to UDCA. Twenty-seven patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 7 to 221 months and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal for more than 6 months were enrolled. Oral silymarin, 140 mg 3 times daily was given for 1 year, and patients continued on the same dosage of UDCA. No significant changes in serum alkaline phosphatase activity (897 ± 84 vs. 876 ± 95, P = .5), total bilirubin (0.9 ± 0.1 vs. 1 ± 0.1, P = .07), aspartate transaminase (AST) (58 ± 5 vs. 56 ± 6,P = .4), albumin (4.0 ± .06 vs. 4.1 ± .06,P = .4), or Mayo risk score (3.82 ± 0.2 vs. 3.88 ± 0.2, P = .4) were noted after 1 year of treatment with combination therapy. Transitory gastrointestinal adverse events occurred in 2 patients. In conclusion, although silymarin was well tolerated, this medication did not provide benefit to patients with PBC responding suboptimally to UDCA. The results of this pilot study would seem to discourage further controlled trials of silymarin in patients with PBC.(Hepatology 2000;32:897-900.)
The importance of proteases during apoptosis is becoming increasingly apparent. Because apoptosis... more The importance of proteases during apoptosis is becoming increasingly apparent. Because apoptosis contributes to a diverse variety of disease processes, understanding the roles played by proteases and their inhibitors might provide insight into the pathogenesis of these conditions and suggest novel therapeutic strategies. In this review, we discuss the involvement and role of specific proteases, substrates, and protease inhibitors that appear to participate in the apoptotic process.
This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonan... more This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonance imaging and quantitative discomanometry. To determine if a correlation exists between magnetic resonance imaging and quantitative discomanometry in determining disc degeneration of the lumbar spine. Several studies analyzing disc degeneration of the lumbar spine have compared magnetic resonance imaging with discography and discomanometry. The reported results are conflicting. No studies exist that compare magnetic resonance imaging and quantitative discomanometry in assessing the disc degeneration of the lumbar spine. Three fresh human cadaveric thoracolumbar spine specimens (two T11-S1 and one L1-S1) that included a total of 19 discs were used. Spines were scanned with magnetic resonance imaging, and the scans were read by a neuroradiologist. Using the quantitative discomanometry technique, discs were injected with normal saline, and pressure-volume curves were collected and quantified with six parameters: intrinsic pressure, leakage pressure, initial slope, slope from 0.0 to 0.1 mL, maximum pressure, and volume at maximum pressure. Data analysis was performed using Spearman's Rank Correlation (Rho) statistic. Based on the results from 19 discs, an overall good correlation between magnetic resonance imaging scores and the six quantitative discomanometry parameters was demonstrated. With exception of the volume at maximum pressure, correlation coefficients ranged between 0.61 to 0.78 with a P < 0.05. Magnetic resonance imaging scores and quantitative discomanometry parameters correlated well in the assessment of disc degeneration of the lumbar spine. Quantitative discomanometry may be an important technique for evaluating early disc degeneration, especially tears of the anular fibers, which may be missed on magnetic resonance imaging.
Prospective cohort. To determine whether preoperative radiographic parameters (translation, angul... more Prospective cohort. To determine whether preoperative radiographic parameters (translation, angular motion, and lateral disc height) can predict fusion status in patients with degenerative spondylolisthesis who underwent a single-level decompression and non-instrumented posterolateral fusion using autogenous iliac crest bone graft. Non-instrumented posterolateral fusion is sometimes considered in patients with degenerative spondylolisthesis who do not have radiographic evidence of instability. No previous study has attempted to determine whether preoperative radiographic parameters can be used to predict successful fusion. A prospective, randomized, controlled, multicenter clinical study was previously conducted to compare the outcomes of osteogenic protein 1 (BMP-7) putty to autogenous iliac crest bone graft for single-level non-instrumented posterolateral fusion for the treatment of symptomatic degenerative spondylolisthesis with spinal stenosis. A total of 90 patients who were randomized to the autograft group formed the basis of this study, 67 of whom had data on the 3 radiographic parameters. Preoperative and postoperative radiographs were evaluated by 2 independent observers. The spine was determined to be fused if there was presence of continuous bone bridging between the transverse processes, an angulation of ≤5°, and a translational movement of ≤3 mm on flexion/extension radiographs of the affected level. Forty-two (63%) of the 67 patients had a radiographic fusion. The mean preoperative translation in this group was 1.87 mm (range, 0.3-7.35 mm), the angular motion was 4.44° (range, 0.1°-12.1°), and the lateral disc height was 8.74 mm (range, 0.2-15.34 mm). Twenty-five (37%) of the 67 patients had a radiographic pseudarthrosis. The mean preoperative translation in the pseudarthrosis group was 1.20 mm (range, 0-3.55 mm), the angular motion was 4.66° (range, 1.1°-12.95°), and the lateral disc space height was 8.10 mm (range, 1.98-13.315 mm). There was no significant difference in these 3 parameters between the fusion and the pseudarthrosis group. These results indicate that preoperative radiographic parameters that may indicate the absence of gross instability in degenerative spondylolisthesis are not reliable in predicting radiographic fusion in a single-level non-instrumented fusion.
A quick-release method in four directions of isometric trunk exertions was used to study the musc... more A quick-release method in four directions of isometric trunk exertions was used to study the muscle response patterns in 17 patients with chronic low back pain and 17 matched control subjects. It was hypothesized that patients with low back pain would react to sudden load release with a delayed muscle response and would exhibit altered muscle recruitment patterns. A delay in erector spinae reaction time after sudden loading has been observed in patients with low back pain. Muscle recruitment and timing pattern play an important role in maintaining lumbar spine stability. Subjects were placed in a semiseated position in an apparatus that provided stable fixation of the pelvis. They exerted isometric contractions in trunk flexion, extension, and lateral bending. Each subject performed three trials at two constant force levels. The resisted force was suddenly released with an electromagnet and electromyogram signals from 12 trunk muscles were recorded. The time delay between the magnet release and the shut-off or switch-on of muscle activity (reaction time) was compared between two groups of subjects using two-factor analysis of variance. The number of reacting muscles and reaction times averaged over all trials and directions showed the following results: For healthy control subjects a shut-off of agonistic muscles (with a reaction time of 53 msec) occurred before the switch-on of antagonistic muscles (with a reaction time of 70 msec). Patients exhibited a pattern of co-contraction, with agonists remaining active (3.4 out of 6 muscles switched off) while antagonists switched on (5.3 out of 6 muscles). Patients also had longer muscle reaction times for muscles shutting off (70 msec) and switching on (83 msec) and furthermore, their individual muscle reaction times showed greater variability. Patients with low back pain, in contrast to healthy control subjects, demonstrated a significantly different muscle response pattern in response to sudden load release. These differences may either constitute a predisposing factor to low back injuries or a compensation mechanism to stabilize the lumbar spine.
Hepatocellular cancers (HCC) are highly resistant to chemotherapy. TGFβ has been associated with ... more Hepatocellular cancers (HCC) are highly resistant to chemotherapy. TGFβ has been associated with chemoresistance in some human cancers but the mechanisms involved are unknown. We explored how TGFβ might contribute to altered responses to therapy by assessing the involvement and mechanistic contribution of extracellular vesicle long non-coding RNA (lncRNA) in mediating TGFβ-dependent chemoresistance. TGFβ reduced the sensitivity of HCC cells to sorafenib or doxorubicin and altered the release of both extracellular vesicles and of selected lncRNA within these vesicles. Amongst these, lincRNA-ROR (linc-ROR), a stress-responsive lncRNA was highly expressed in HCC cells and enriched within extracellular vesicles derived from tumor cells. Incubation with HCC-derived extracellular vesicles increased linc-ROR expression and reduced chemotherapy-induced cell death in recipient cells. Sorafenib increased linc-ROR expression in both tumor cells and extracellular vesicles, whereas siRNA to linc-ROR increased chemotherapy-induced apoptosis and cytotoxicity. Tumor-initiating cells that express CD133 have an increased resistance to therapy. TGFβ increased expression of CD133+ cells and colony growth in limiting dilution assays, both of which were attenuated by linc-ROR knockdown. These data provide mechanistic insights into primary chemoresistance in HCC by showing that: (a) TGFβ selectively enriches linc-RoR within extracellular vesicles, which has a potential role in intercellular signaling in response to TGFβ; (b) expression and enrichment of linc-ROR during chemotherapeutic stress plays a functional role in chemoresistance; and (c) the effects of TGFβ on chemoresistance in HCC may involve linc-RoR-dependent effects on tumor-initiating cells. These findings implicate extracellular vesicle lncRNA as mediators of the chemotherapeutic response, and support targeting linc-ROR to enhance chemosensitivity in HCC.
Scheuermann&a... more Scheuermann's disease is a kyphotic deformity of the spine that develops in early adolescence. This condition has been reported to occur in 0.4% to 8% of the general population, with an equal distribution between sexes. Diagnosis of Scheuermann's disease is suggested on clinical examination; however, parents of children affected often confuse it with poor posture. Radiographs are the standard imaging modality used to confirm the diagnosis of Scheuermann's disease. Classic signs include vertebral end plate irregularity, disk space narrowing, and anterior wedging of involved vertebral bodies. Other diagnostic tools such as CT scans or magnetic resonance imaging may also be of value in the evaluation of Scheuermann's disease. The mode of treatment for this condition depends upon the severity of the deformity, remaining growth, and presence or absence of symptoms. Early treatment may be limited to observation and exercises, whereas patients who have kyphosis of up to 75 degrees and how have growth remaining may benefit from bracing. Surgical correction is reserved for severe cases that are symptomatic and refractory to conservative management.
Recent studies have suggested that noncoding RNAs (ncRNAs) contribute to the pathogenesis and pro... more Recent studies have suggested that noncoding RNAs (ncRNAs) contribute to the pathogenesis and progression of hepatocellular carcinoma (HCC). These RNA genes may be involved in various pathobiological processes such as cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Aberrant expression of ncRNA resulting from deregulated epigenetic, transcriptional, or posttranscriptional activity has been described in several studies. ncRNAs are comprised of a highly diverse group of transcripts that include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) as well as several other types of RNA genes. Understanding the molecular mechanisms by which ncRNA contribute to hepatocarcinogenesis may enable the design of ncRNA-based therapeutics for HCC. In this review, the authors provide a perspective on therapeutic applications based on the emerging evidence of a contributory role of miRNAs and lncRNAs to the pathogenesis and progression of HCC. In addition, ncRNAs that are deregulated in expression in HCC may have utility as potential prognostic or diagnostic markers.
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options... more Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with limited treatment options and low survival rates. Currently, there are no curative medical therapies for CCA. Recent advances have enhanced our understanding of the genetic basis of this disease, and elucidated therapeutically relevant targets. Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways, mutant IDH enzymes, the PI3K-AKT-mTOR pathway, and chromatin remodeling networks. A highly desmoplastic, hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion. Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma. As the mutational landscape of CCA is being illuminated, molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed, personalized treatment options.
Over-expression of IL-6 has been implicated in cholangiocarcinoma growth but the cellular mechani... more Over-expression of IL-6 has been implicated in cholangiocarcinoma growth but the cellular mechanisms involved are unknown. Our aims were to assess the mechanisms by which over-expression of IL-6 promotes transformed cell growth in malignant cholangiocytes.Stably transfected cell lines over-expressing IL-6 were derived from malignant human cholangiocytes. Transformed cell growth was assessed by anchorage independent growth in vitro and by xenograft growth in nude mice. Expression of the anti-apoptotic protein Mcl-1 was quantitated by immunoblot analysis and by real-time PCR. Gene silencing was performed using siRNA. Dominant negative upstream kinase activators and isoform-specific constructs were used to evaluate the involvement of p38 MAP kinase signaling pathways.Over-expression of IL-6 increased xenograft growth, anchorage independent growth and cell survival but did not significantly alter cell proliferation. The basal expression of Mcl-1 was increased in IL-6 over-expressing cells. Selective knockdown of Mcl-1 by siRNA increased gemcitabine-induced cytotoxicity. Moreover, IL-6 increased Mcl-1 mRNA and protein expression via a p38 MAPK dependent mechanism.These data demonstrate a major role of survival signaling pathways in mediating the effects of IL-6 over-expression in cholangiocarcinoma growth. Mcl-1 is identified as a mediator of IL-6-induced tumor cell survival and shown to be transcriptionally regulated by IL-6 via a p38 MAPK dependent pathway. We conclude that modulation of IL-6 mediated survival signaling pathways involving the p38 MAPK or downstream targets such as Mcl-1 may prove useful therapeutic strategies for human cholangiocarcinoma.
This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonan... more This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonance imaging and quantitative discomanometry. To determine if a correlation exists between magnetic resonance imaging and quantitative discomanometry in determining disc degeneration of the lumbar spine. Several studies analyzing disc degeneration of the lumbar spine have compared magnetic resonance imaging with discography and discomanometry. The reported results are conflicting. No studies exist that compare magnetic resonance imaging and quantitative discomanometry in assessing the disc degeneration of the lumbar spine. Three fresh human cadaveric thoracolumbar spine specimens (two T11-S1 and one L1-S1) that included a total of 19 discs were used. Spines were scanned with magnetic resonance imaging, and the scans were read by a neuroradiologist. Using the quantitative discomanometry technique, discs were injected with normal saline, and pressure-volume curves were collected and quantified with six parameters: intrinsic pressure, leakage pressure, initial slope, slope from 0.0 to 0.1 mL, maximum pressure, and volume at maximum pressure. Data analysis was performed using Spearman's Rank Correlation (Rho) statistic. Based on the results from 19 discs, an overall good correlation between magnetic resonance imaging scores and the six quantitative discomanometry parameters was demonstrated. With exception of the volume at maximum pressure, correlation coefficients ranged between 0.61 to 0.78 with a P < 0.05. Magnetic resonance imaging scores and quantitative discomanometry parameters correlated well in the assessment of disc degeneration of the lumbar spine. Quantitative discomanometry may be an important technique for evaluating early disc degeneration, especially tears of the anular fibers, which may be missed on magnetic resonance imaging.
Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primar... more Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC), but some patients show an incomplete response. Silymarin is a potent antioxidant with immunomodulatory and antifibrotic properties. The aim of this study was to evaluate the safety and assess the efficacy of silymarin in patients with PBC who had shown a suboptimal response to UDCA. Twenty-seven patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 7 to 221 months and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal for more than 6 months were enrolled. Oral silymarin, 140 mg 3 times daily was given for 1 year, and patients continued on the same dosage of UDCA. No significant changes in serum alkaline phosphatase activity (897 ± 84 vs. 876 ± 95, P = .5), total bilirubin (0.9 ± 0.1 vs. 1 ± 0.1, P = .07), aspartate transaminase (AST) (58 ± 5 vs. 56 ± 6,P = .4), albumin (4.0 ± .06 vs. 4.1 ± .06,P = .4), or Mayo risk score (3.82 ± 0.2 vs. 3.88 ± 0.2, P = .4) were noted after 1 year of treatment with combination therapy. Transitory gastrointestinal adverse events occurred in 2 patients. In conclusion, although silymarin was well tolerated, this medication did not provide benefit to patients with PBC responding suboptimally to UDCA. The results of this pilot study would seem to discourage further controlled trials of silymarin in patients with PBC.(Hepatology 2000;32:897-900.)
The importance of proteases during apoptosis is becoming increasingly apparent. Because apoptosis... more The importance of proteases during apoptosis is becoming increasingly apparent. Because apoptosis contributes to a diverse variety of disease processes, understanding the roles played by proteases and their inhibitors might provide insight into the pathogenesis of these conditions and suggest novel therapeutic strategies. In this review, we discuss the involvement and role of specific proteases, substrates, and protease inhibitors that appear to participate in the apoptotic process.
This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonan... more This human cadaveric study evaluated disc degeneration of the lumbar spine using magnetic resonance imaging and quantitative discomanometry. To determine if a correlation exists between magnetic resonance imaging and quantitative discomanometry in determining disc degeneration of the lumbar spine. Several studies analyzing disc degeneration of the lumbar spine have compared magnetic resonance imaging with discography and discomanometry. The reported results are conflicting. No studies exist that compare magnetic resonance imaging and quantitative discomanometry in assessing the disc degeneration of the lumbar spine. Three fresh human cadaveric thoracolumbar spine specimens (two T11-S1 and one L1-S1) that included a total of 19 discs were used. Spines were scanned with magnetic resonance imaging, and the scans were read by a neuroradiologist. Using the quantitative discomanometry technique, discs were injected with normal saline, and pressure-volume curves were collected and quantified with six parameters: intrinsic pressure, leakage pressure, initial slope, slope from 0.0 to 0.1 mL, maximum pressure, and volume at maximum pressure. Data analysis was performed using Spearman's Rank Correlation (Rho) statistic. Based on the results from 19 discs, an overall good correlation between magnetic resonance imaging scores and the six quantitative discomanometry parameters was demonstrated. With exception of the volume at maximum pressure, correlation coefficients ranged between 0.61 to 0.78 with a P < 0.05. Magnetic resonance imaging scores and quantitative discomanometry parameters correlated well in the assessment of disc degeneration of the lumbar spine. Quantitative discomanometry may be an important technique for evaluating early disc degeneration, especially tears of the anular fibers, which may be missed on magnetic resonance imaging.
Prospective cohort. To determine whether preoperative radiographic parameters (translation, angul... more Prospective cohort. To determine whether preoperative radiographic parameters (translation, angular motion, and lateral disc height) can predict fusion status in patients with degenerative spondylolisthesis who underwent a single-level decompression and non-instrumented posterolateral fusion using autogenous iliac crest bone graft. Non-instrumented posterolateral fusion is sometimes considered in patients with degenerative spondylolisthesis who do not have radiographic evidence of instability. No previous study has attempted to determine whether preoperative radiographic parameters can be used to predict successful fusion. A prospective, randomized, controlled, multicenter clinical study was previously conducted to compare the outcomes of osteogenic protein 1 (BMP-7) putty to autogenous iliac crest bone graft for single-level non-instrumented posterolateral fusion for the treatment of symptomatic degenerative spondylolisthesis with spinal stenosis. A total of 90 patients who were randomized to the autograft group formed the basis of this study, 67 of whom had data on the 3 radiographic parameters. Preoperative and postoperative radiographs were evaluated by 2 independent observers. The spine was determined to be fused if there was presence of continuous bone bridging between the transverse processes, an angulation of ≤5°, and a translational movement of ≤3 mm on flexion/extension radiographs of the affected level. Forty-two (63%) of the 67 patients had a radiographic fusion. The mean preoperative translation in this group was 1.87 mm (range, 0.3-7.35 mm), the angular motion was 4.44° (range, 0.1°-12.1°), and the lateral disc height was 8.74 mm (range, 0.2-15.34 mm). Twenty-five (37%) of the 67 patients had a radiographic pseudarthrosis. The mean preoperative translation in the pseudarthrosis group was 1.20 mm (range, 0-3.55 mm), the angular motion was 4.66° (range, 1.1°-12.95°), and the lateral disc space height was 8.10 mm (range, 1.98-13.315 mm). There was no significant difference in these 3 parameters between the fusion and the pseudarthrosis group. These results indicate that preoperative radiographic parameters that may indicate the absence of gross instability in degenerative spondylolisthesis are not reliable in predicting radiographic fusion in a single-level non-instrumented fusion.
A quick-release method in four directions of isometric trunk exertions was used to study the musc... more A quick-release method in four directions of isometric trunk exertions was used to study the muscle response patterns in 17 patients with chronic low back pain and 17 matched control subjects. It was hypothesized that patients with low back pain would react to sudden load release with a delayed muscle response and would exhibit altered muscle recruitment patterns. A delay in erector spinae reaction time after sudden loading has been observed in patients with low back pain. Muscle recruitment and timing pattern play an important role in maintaining lumbar spine stability. Subjects were placed in a semiseated position in an apparatus that provided stable fixation of the pelvis. They exerted isometric contractions in trunk flexion, extension, and lateral bending. Each subject performed three trials at two constant force levels. The resisted force was suddenly released with an electromagnet and electromyogram signals from 12 trunk muscles were recorded. The time delay between the magnet release and the shut-off or switch-on of muscle activity (reaction time) was compared between two groups of subjects using two-factor analysis of variance. The number of reacting muscles and reaction times averaged over all trials and directions showed the following results: For healthy control subjects a shut-off of agonistic muscles (with a reaction time of 53 msec) occurred before the switch-on of antagonistic muscles (with a reaction time of 70 msec). Patients exhibited a pattern of co-contraction, with agonists remaining active (3.4 out of 6 muscles switched off) while antagonists switched on (5.3 out of 6 muscles). Patients also had longer muscle reaction times for muscles shutting off (70 msec) and switching on (83 msec) and furthermore, their individual muscle reaction times showed greater variability. Patients with low back pain, in contrast to healthy control subjects, demonstrated a significantly different muscle response pattern in response to sudden load release. These differences may either constitute a predisposing factor to low back injuries or a compensation mechanism to stabilize the lumbar spine.
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