Physical features of pediatric patients with lumbar spondylolysis and effectiveness of rehabilitation.

The purpose of this study was to evaluate the physical features of pediatric patients with lumbar spondylolysis (LS), factors that increase the load during compensatory movements at the lumbar spine, and the outcomes of rehabilitation. Twenty patients were included. Fifteen items were used:fingertip-to-floor distance (FFD), straight leg raising (SLR), heel-to-buttock distance (HBD), tightness of the rectus femoris, the lateral and medial rotator muscles, iliopsoas, tensor fascia lata, adductor muscles, soleus muscle, and latissimus dorsi, and trunk rotation, sit-ups and endurance of the abdominal and back muscles. Initial findings were judged as positive or negative using previously reported cut-off values and were re-evaluated 2 or 3 months later. Positive tests were found for HBD and tightness of the rectus femoris in 85% of the patients, for endurance of the abdominal muscles in 75%, SLR and sit-ups in 70%, and FFD and tightness of the external rotator muscles in 60%. The physical features varied according to the type of sport played, and some patients were refractory to rehabilitation. Only 17.6%, 33.3%, and 40.0% of patients with initially positive findings for HBD, tightness of the external rotator muscles, and endurance of the abdominal muscles, respectively, achieved improvements after rehabilitation. J. Med. Invest. 65:177-183, August, 2018.

Alterations in deep tissue temperature around the knee after total knee arthroplasty: its association with knee motion recovery in the early phase.

PURPOSE: Cryotherapy has been employed to reduce postoperative inflammation for enhancement of the recovery of total knee arthroplasty (TKA). However, the clinical advantages in functional recovery after TKA remain controversial. This study was conducted to clarify the postoperative alterations in deep temperature around the knee and to evaluate the association between the temperature changes and functional recovery in the early phase after TKA. METHODS: Postoperative changes in deep temperature around the knee were evaluated with the probe that can measure subcutaneous tissue temperature at the depth of 1 cm in 28 patients with medial knee osteoarthritis undergoing unilateral TKA through medial parapatellar approach. The same rehabilitation protocol was provided without cryotherapy. Outcome assessment included knee range of motion (ROM) and 10-meter fast speed walking test. RESULTS: The operated knee showed a greater increase in deep temperature at postoperative days 1 and 2, followed by a gradual decrease by day 14 when the temperature was still higher than the baseline. When deep temperature change around the operated knee was calculated by subtracting the preoperative temperature from the highest postoperative one, significant association was found between deep temperature change and knee ROM recovery at day 14. The operated knees with more than 2°C increase in postoperative deep temperature resulted in poor ROM recovery. There was no association of deep temperature change with 10-meter fast speed walking test improvement at day 14 or ROM recovery at 1-year follow-up. CONCLUSIONS: This study has provided the first data on deep temperature alterations around the knee after TKA. More than 2°C increase in postoperative deep temperature could result in poor ROM recovery after TKA. The results may support establishment of adequate procedures of cryotherapy for early gain in knee motion after TKA.

Association between medial meniscus extrusion and spontaneous osteonecrosis of the knee.

AIM: Medial meniscus tear has been proposed as a potential etiology of spontaneous osteonecrosis of the knee (SONK). Disruption of collagen fibers within the meniscus causes meniscal extrusion, which results in alteration in load distribution in the knee. Our purpose was to determine whether the extent of medial meniscus extrusion correlates with the severity of SONK in the medial femoral condyle. METHODS: Radiological stage of SONK and femorotibial angle (FTA) were determined on knee radiographs. Ellipsoid volume of SONK lesion and meniscal pathology (degeneration, tear and extrusion) were evaluated by magnetic resonance imaging. RESULTS: All the 18 knees with SONK in the present study showed substantial extrusion (≥ 3 mm) and degeneration of the medial meniscus. The extent of meniscal extrusion and FTA were strongly associated with the stage and volume of the SONK lesion. Multiple linear regression analysis revealed that medial meniscus extrusion and FTA were useful predictors of the volume of the SONK lesion. CONCLUSION: There was high association of medial meniscus extrusion and FTA with the radiological stage and volume of the SONK lesion. Increased loading in the medial femoral condyle with greater extrusion of medial meniscus and varus alignment may contribute to expansion and secondary osteoarthritic changes of a SONK lesion.

Outcomes of Surgical Treatment for Thoracic Myelopathy: A Single-institutional Study of 73 Patients.

STUDY DESIGN: Retrospective study. OBJECTIVE: The aim was to investigate the clinical outcomes in patients with thoracic myelopathy in a single institution and to identify prognostic factors for poor outcomes. SUMMARY OF BACKGROUND DATA: Because of the rarity of thoracic myelopathy, a few studies have analyzed a large number of clinical results for patients with thoracic myelopathy treated in a single institution. METHODS: Seventy-one patients who underwent surgical treatment for thoracic myelopathy between 2000 and 2011 in a single institution were included in this analysis. We investigated the patients' characteristics, surgical outcomes, and prognostic factors for poor outcomes. RESULTS: Of the 73 patients, eight patients had disc herniation (DH) or spinal stenosis (SS), 10 patients had ossification of the posterior longitudinal ligament (OPLL), 40 patients had ossification of the ligamentum flavum (OLF), and 15 patients had OPLL + OLF. The mean patient age at the time of surgery was 61.9 years. Thoracic myelopathy was caused by OPLL and/or OLF in 65 patients (89%). Fifty-eight patients underwent laminectomy, eight patients underwent laminectomy and posterior fusion, four patients underwent OPLL extirpation and posterior fusion, and three patients underwent OPLL extirpation. The mean Japanese Orthopedic Association Scoring System scores before surgery and at the final follow-up examination were 6.0 ±â€Š1.8 and 7.7 ±â€Š2.0 points, respectively, yielding a mean recovery rate of 30% ±â€Š43%. The JOA score improved significantly postoperatively (P < 0.05). Risk factors for poor outcomes were longer preoperative symptom duration, preoperative JOA score < 7, and OPLL and/or OLF. Large blood loss volume was significantly associated with a worse postoperative JOA score. CONCLUSION: A considerable degree of neurological recovery was observed after surgical treatment in patients with thoracic myelopathy. Prognostic factors for poor outcomes were longer preoperative duration of symptoms, worse preoperative symptoms, OPLL and/or OLF, and large volume of intraoperative bleeding. LEVEL OF EVIDENCE: 4.

Familial schwannomatosis with a germline mutation of SMARCB1 in Japan.

Schwannomatosis is the third major form of neurofibromatosis (NF) and is distinct from NF1 and NF2. The disease is not well recognized in Asian countries and the role of germline SMARCB1 mutations requires investigation. A 35-year-old Japanese man complaining of headache underwent an MRI examination, which showed a cystic tumor at the left cerebellopontine angle. The tumor was surgically removed and diagnosed as vagus nerve schwannoma. He had a past medical history of multiple schwannomas of the neck, groin and intercostal nerves, which were also treated surgically. He had a family history of multiple schwannomas for his father and sister. Systemic examinations of these family members ruled out a diagnosis of NF1 or NF2, and thus schwannomatosis was suspected. Genetic analysis revealed a germline mutation (c. *82C > T) of SMARCB1, and a somatic mutation of NF2 without loss of heterozygosity at the chromosome 22 locus. This is the first report of familial schwannomatosis associated with a germline mutation of SMARCB1 in an Asian country.

Three-dimensional, but not two-dimensional, culture results in tumor growth enhancement after exposure to anticancer drugs.

Previously, we have adapted a recently developed three-dimensional chemosensitivity test, the collagen gel droplet embedded culture drug sensitivity test (CD-DST), for evaluation of chemosensitivity of 12 anticancer drugs against colorectal adenocarcinoma, and surprisingly, it was found that tumor growth enhancement was occasionally observed even after exposure to anticancer drugs. In this study, the CD-DST was applied for human cervical carcinoma cell line HeLa-Ohio (HeLa) cells and its MDR1/P-glycoprotein-overexpressing subline, Hvr100-6 cells, and 12 anticancer drugs were assessed in terms of chemosensitivity and deterioration of tumor, and the results were compared with those by two-dimensional WST-1 assay. Growth enhancement was observed in Hvr100-6 cells, not in HeLa cells, for mitomycin C with the ratio of total volume of colonies in the treated group to that in the untreated group (T/C%) of 135.0%, doxorubicin with T/C% of 162.5% and cyclophosphamide with T/C% of 122.0%, and this was not observed in WST-1 assay. Multidrug resistance was detected both for CD-DST and WST-1 assay. The values of T/C% in CD-DST were comparable with or higher than those of the survival fraction (%) in WST-1 assay, and modification of WST-1 assay procedure gave similar results, suggesting a higher resistance in three-dimensional than in two-dimensional culture. Further investigations should be addressed to the association of MDR1/P-glycoprotein with tumor growth enhancement.

VEGF T-1498C polymorphism, a predictive marker of differentiation of colorectal adenocarcinomas in Japanese.

BACKGROUND: Previously, MDR1 T-129C polymorphism, encoding multidrug resistant transporter MDR1/P-glycoprotein, was reported to be predictive of poorly-differentiated colorectal adenocarcinomas. Here, VEGF T-1498C, C-634G and C-7T polymorphisms, encoding vascular endothelial growth factor (VEGF), were investigated in terms of their association with differentiation grade. METHODS: VEGF genotypes were determined by TaqMan(R) MGB probe based polymerase chain reaction and evaluated were confirmed by direct sequencing in 36 Japanese patients. RESULTS: VEGF T-1498C, but not C-634G or C-7T, was predictive of poorly-differentiated ones, and thereby a poor prognosis (p = 0.064 for genotype, p = 0.037 for allele), and this effect can be explained by that on VEGF expression. Treatment of a colorectal adenocarcinoma cell line, HCT-15, with sodium butyrate, a typical differentiating agent, resulted in an increase of alkaline phosphatase activity and MDR1 mRNA expression, but in a decrease of VEGF mRNA expression. The transfection of VEGF small interfering RNA (siRNA) induced the expression of MDR1 mRNA to 288-332% of the control level, whereas MDR1 siRNA had no effect on VEGF mRNA expression. CONCLUSIONS: VEGF T-1498C polymorphism is also a candidate marker predictive of poorly-differentiated colorectal adenocarcinomas, but further investigations with a large number of patients should be addressed to draw a conclusion.

IL-1beta genotype-related effect of prednisolone on IL-1beta production in human peripheral blood mononuclear cells under acute inflammation.

Glucocorticoids such as prednisolone are used for their anti-inflammatory properties. But there is evidence to suggest that under certain conditions, glucocorticoids have pro-inflammatory effects, for example, enhancement of IL-1beta production. To date, it has been reported that IL-1beta production intensity was associated with single nucleotide polymorphisms at positions -1470, -511, and -31 in the promoter region and at position 3954 in exon 5 of the IL-1beta gene. In the present study, it was examined whether these IL-1beta genotypes were associated with the suppressive effect of prednisolone on IL-1beta production in human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS). A midrange concentration (10(-6) M) of prednisolone suppressed the LPS-induced increase in IL-1beta mRNA expression and protein release, while higher concentrations (10(-5) M, 10(-4) M) exhibited less suppression or had a synergistic stimulative effect on IL-1beta production in certain subjects. Under treatment with 10(-4) M prednisolone, the levels of IL-1beta protein production stimulated by LPS in PBMC extracted from the subjects with the IL-1beta TT(-31), TC(-31), and CC(-31) genotypes were suppressed to 6.0+/-3.4%, 31.4+/-57.0%, and 87.7+/-84.8%, respectively, of the level in prednisolone-untreated control cells (TT(-31) vs. CC(-31), p<0.05). Glucocorticoid-based anti-inflammatory therapy might be less effective in patients with the IL-1beta TC(-31) and CC(-31) genotypes than those with the TT(-31) genotype.

Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport.

PURPOSE: With the growing clinical usage of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), the number of reports concerning serious drug-drug interaction has been increasing. Because recent studies have shown that conversion between acid and lactone forms occurs in the body, drug-drug interaction should be considered on both acid and lactone forms. Thus, we investigated the inhibitory effects of acid and lactone forms of eight statins, including one recently withdrawn, cerivastatin, and two recently developed, pitavastatin and rosuvastatin, on cytochrome P450 (CYP) 2C8, CYP2C9, and CYP3A4/5 metabolic activities and multidrug resistance protein 1 (MDR1) transporting activity. METHODS: The inhibitory effects of statins on CYP metabolic activities and MDR1 transporting activity were investigated using human liver microsomes and MDR1-overexpressing LLC-GA5-COL150 cells, respectively. RESULTS: The acid forms had minimal inhibitory effects on all CYP activities tested, except for fluvastatin on CYP2C9-mediated tolbutamide 4-hydroxylation (IC50 = 1.7 microM) and simvastatin on CYP3A4/5-mediated paclitaxel 3-hydroxylation (12.0 microM). Lactone forms showed no or minimal inhibitory effects on CYP2C8, CYP2C9, and CYP2C19 activities, except for rosuvastatin on the CYP2C9 activity (20.5 microM), whereas they showed stronger inhibitory effects on the CYP3A4/5 activity with the rank order of atorvastatin (5.6 microM), cerivastatin (8.1 microM), fluvastatin (14.9 microM), simvastatin (15.2 microM), rosuvastatin (20.7 microM), and lovastatin (24.1 microM). Pitavastatin and pravastatin had little inhibitory effect, and a similar order was found also for testosterone 6beta-hydroxylation. MDR1-mediated transport of [3H]digoxin was inhibited only by lactone forms, and the rank order correlated with that of inhibitory effects on both CYP3A4/5 activities. Inhibitory effects on MDR1 activity, and on both CYP3A4/5 activities, could be explained by the lipophilicity; however, a significant correlation was found between the lipophilicity and inhibitory effects on CYP2C8-mediated paclitaxel 6alpha-hydroxylation. CONCLUSIONS: We showed the difference between the acid and lactone forms in terms of drug interaction. The lipophilicity could be one of the important factors for inhibitory effects. In the case of statins, it is important to examine the effects of both forms to understand the events found in clinical settings, including the pleiotropic effects.

Haloperidol is an inhibitor but not substrate for MDR1/P-glycoprotein.

The involvement of the multidrug resistant transporter MDR1/P-glycoprotein in the penetration of haloperidol into the brain and absorption in the intestine was investigated to examine its role in inter/intra-individual variability, using the porcine kidney epithelial cell line LLC-PK(1) and its MDR1-overexpressing transfectant, LLC-GA5-COL150. The inhibitory effect of haloperidol on other MDR1 substrates was also investigated in terms of the optimization of haloperidol-based pharmacotherapy. The transepithelial transport of [(3)H]haloperidol did not differ between the two cell lines, and vinblastine, a typical MDR1 substrate, had no effect on the transport, suggesting that haloperidol is not a substrate for MDR1, and it is unlikely that MDR function affects haloperidol absorption and brain distribution, and thereby the response to haloperidol. However, haloperidol was found to have an inhibitory effect on the MDR1-mediated transport of [(3)H]digoxin and [(3)H]vinblastine with an IC50 value of 7.84+/-0.76 and 3.60+/-0.64 microM, respectively, suggesting that the intestinal absorption, not distribution into the brain, of MDR1 substrate drugs could be altered by the co-administration of haloperidol in the clinical setting, although further clinical studies are needed.

Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs.

The effects of micafungin on cytochrome P450 3A4 (CYP3A4) metabolic and multidrug resistance protein 1 (MDR1) transport activities were investigated and compared with those of amphotericin B and four azole antifungal drugs (ketoconazole, itraconazole, fluconazole and miconazole). The effects on the metabolic activity of CYP3A4 were examined by measuring nifedipine oxidase activity in human liver microsomes and the effects on MDR1 transport activity were evaluated using [3H]digoxin in MDR1-overexpressing LLC-GA5-COL150 cells. An inhibitory effect on CYP3A4 activity was found for ketoconazole, itraconazole and miconazole, with 50% inhibitory concentrations of 11.7, 32.6 and 74.2 nM, respectively. Fluconazole and micafungin had only slight inhibitory effects and amphotericin B had no effect. The MDR1-mediated transport of [3H]digoxin was inhibited by ketoconazole and itraconazole, and slightly by miconazole. It is suggested that micafungin and amphotericin B would be unlikely to cause drug-drug interactions by inhibition of CYP3A4 and MDR1. A positive correlation between the inhibitory effects on CYP3A4 and MDR1 activities was observed, and the physicochemical mechanisms involved and impact on clinical treatment should be studied further.

Simvastatin and lovastatin, but not pravastatin, interact with MDR1.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, was compared with simvastatin and lovastatin from the viewpoint of susceptibility to interaction with or via the multidrug transporter, MDR1 (P-glycoprotein). This was carried out using the MDR1-overexpressing cell line LLC-GA5-COL150, established by transfection of MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells, and [3H]digoxin, which is a well-documented substrate for MDR1. Pravastatin, at 25-100 microM, had no effect on the transcellular transport of [3H]digoxin whereas simvastatin and lovastatin suppressed the basal-to-apical transport of [3H]digoxin and increased the apical-to-basal transport. It was suggested that recognition by MDR1 was due to the hydrophobicity. In conclusion, simvastatin and lovastatin are susceptible to interaction with or via MDR1, but pravastatin is not. This is important information when selecting the HMG-CoA reductase inhibitors for patients taking drugs that are MDR1 substrates.