Publications by authors named "Akihiko Inokuchi"

14 Publications

  • Page 1 of 1

Factors Affecting Postoperative Spinal Epidural Hematoma and the Optimal Order of Vertebral Body Decompression in Multivertebral Microendoscopic Laminectomy.

Cureus 2022 May 27;14(5):e25404. Epub 2022 May 27.

Department of Orthopedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, JPN.

Purpose Symptomatic postoperative spinal epidural hematoma (POSEH) is a complication of spine surgery that occurs infrequently but may cause ongoing serious neurological damage. Due to the narrow entry portal, the risk of hematoma is increased after microendoscopic laminectomy (MEL) compared with conventional open surgery, and the risk might be even higher for multivertebral MEL (m-MEL). The purpose of this study was to clarify the factors affecting the development of POSEH after m-MEL and identify the optimal order for the decompression of vertebral bodies. Methods A total of 313 patients who underwent m-MEL from 2016 to 2020 were retrospectively assessed. The cohort comprised 238 patients who underwent two-level MEL, 67 who underwent three-level MEL, and eight who underwent four-level MEL. Symptomatic POSEH was defined as the presence of an epidural hematoma at the surgical site on MRI with symptoms such as lower extremity pain or muscle weakness. We elucidated the incidence of POSEH at each vertebral level and investigated the relationship between POSEH and possible risk factors such as clinical and operative variables. Results There were 41 patients in the POSEH group and 272 patients in the non-POSEH group. Seven patients in the POSEH group underwent reoperation. The occurrence of POSEH was related to the number of decompressed vertebral bodies. Patients who underwent L2/3 and L3/4 decompression at the end of the procedure also showed a higher incidence of POSEH at the surgical level. Conclusion In patients undergoing m-MEL, treatment of the upper lumbar vertebrae at the end of decompression surgery might be a risk factor for symptomatic POSEH. The incidence of POSEH was particularly increased at L2/3, suggesting that L2/3 decompression should not be performed at last and that careful hemostasis should be applied.
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http://dx.doi.org/10.7759/cureus.25404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239321PMC
May 2022

A Case of Delayed Airway Stenosis Due to Retropharyngeal Hematoma Caused by Low Energy Trauma.

Cureus 2022 Jun 19;14(6):e26087. Epub 2022 Jun 19.

Orthopaedics, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, JPN.

Airway narrowing due to trauma-induced retropharyngeal hematoma is rare. However, it is dangerous to overlook this lesion because it can lead to airway obstruction and even death. In this article, we report a case of a patient who developed pharyngeal pain and dysphagia two days after bruising on the forehead due to a fall and required intubation management. A 52-year-old man fell while walking and bruised his forehead two days before visiting our hospital. He had a sore throat and dysphagia two days after the injury and came to our hospital three days after the injury. The swelling was observed in the anterior neck, and stenotic sounds were heard in the upper airway. Cervical CT and MRI of the cervical spine showed extensive hyperabsorption areas in the ventral side of the cervical spine that appeared to be hematomas. No fracture of the cervical spine was observed. The patient has been placed on emergency tracheal intubation due to concerns about airway stenosis caused by the hematoma. Although pneumonia was observed during treatment, it resolved with antimicrobial therapy, and the hematoma tended to shrink, so the patient was extubated on the 15th day of admission. However, the patient was intubated again on the 17th day of hospitalization due to poor oxygenation. A tracheostomy was performed on the 26th day of hospitalization due to suspected narrowing of the upper airway caused by hematoma or sputum. On day 59 of hospitalization, the cannula was removed, and the patient was discharged home on the 68th day after hospitalization. Low-energy trauma tends to be underrecognized as producing anterior cervical hematomas that can lead to fatal airway narrowing. Care should be taken because fatal anterior cervical hematomas are not often part of the differential diagnosis due to their often delayed onset. More caution is needed if an underlying disease may cause coagulation abnormalities.
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http://dx.doi.org/10.7759/cureus.26087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206850PMC
June 2022

Efficacy of Nerve Root Block for the Treatment of Lumbar Spinal Canal Stenosis in Adults Older Than 80 Years of Age.

Cureus 2022 May 9;14(5):e24863. Epub 2022 May 9.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, JPN.

Background: Patients with advanced lumbar spinal canal stenosis (LCS) often prefer non-operative treatment owing to decreased physiological function and comorbidities. Although the therapeutic value of selective nerve root block (SNRB) for LCS is confirmed, there are few reports of its effectiveness in the elderly. We investigated the efficacy of SNRB for LCS in patients over 80 years of age.

Methods:  The subjects were 112 patients aged over 80 years (mean age: 84 years; 45 men and 67 women ) with medication-resistant LCS without cauda equina syndrome who underwent SNRB. Cases with acute-onset lumbar disc herniation were excluded. We retrospectively investigated and compared the presence or absence of surgery, effect of SNRB, number of procedures, duration of disease, and magnetic resonance imaging findings. Patients who could avoid the surgery by SNRB were defined as the effective group. Patients whose symptoms were not relieved by SNRB and who underwent surgery and those whose symptoms were not relieved but who continued conservative treatment were defined as the ineffective group. A total of one to seven SNRBs were performed in both groups, and the same spine surgeon performed the entire procedure from SNRB to surgery.

Results:  There were 86 nonoperative patients (69 effective cases) and 26 operative patients; the overall rate of effectiveness was 61% (69/112 patients). The area of the spinal canal at the responsible level was 108.63 mm in the effective group compared with 77.06 mm in the ineffective group. This was significantly narrower in the ineffective group (p=0.0094). There was no significant difference in the duration of illness, number of blocks, or hernia complication rate between the groups. No patient experienced severe neuralgia that may have been caused by neuropathy during SNRB.

Discussion: Our outcome showed that more than 60% of older patients with LCS showed symptomatic improvement with SNRB. SNRB can be performed relatively safely in the elderly and appears to be a favorable treatment option for older patients with various risks, such as poor general condition.

Conclusions: Multiple sessions of SNRB may provide older patients with symptomatic improvement and may be an option for treatment.
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http://dx.doi.org/10.7759/cureus.24863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177313PMC
May 2022

Comparison of Microendoscopic Laminotomy (MEL) Versus Spinous Process-Splitting Laminotomy (SPSL) for Multi Segmental Lumbar Spinal Stenosis.

Cureus 2022 Feb 9;14(2):e22067. Epub 2022 Feb 9.

Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, JPN.

Aims  This study was aimed to compare the perioperative and postoperative outcomes of patients who underwent posterior decompression for multi-segmental lumbar spinal stenosis by microendoscopic laminotomy (MEL) versus spinous process-splitting laminotomy (SPSL) retrospectively. Methods We retrospectively reviewed 73 consecutive patients who underwent two or three levels MEL (n=51) or SPSL (n=22) for lumbar spinal stenosis between 2012 and 2018. The perioperative outcomes were operative time, intraoperative blood loss, length of postoperative hospital stay, complications, and reoperation rate. The postoperative outcomes were evaluated using a visual analog scale (VAS) and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) scores at one year postoperatively. Results The mean follow-up time was 26.6 months in MEL and 35.6 months in SPSL. The mean operative time was significantly longer in MEL than SPSL (two levels, 183.6 ± 43.2 versus 134.8 ± 26.7 min, respectively; three levels: 241.6 ± 47.8 versus 179.9 ± 28.8 min, respectively). MEL's mean postoperative hospital stay was significantly shorter than SPSL (12.3 ± 5.9 versus 15.5 ± 7.2 days, respectively). There was no significant difference in the mean intraoperative blood loss, complication rate, reoperation rate, and postoperative outcomes between the two groups. Conclusions This study suggests that both techniques are effective in treating multi-segmental lumbar spinal stenosis. There was no significant difference between the two procedures in intraoperative blood loss (IBL), complications rate, reoperation rate, or improvement in VAS and Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) scores. MEL had an advantage in the postoperative hospital stay.
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http://dx.doi.org/10.7759/cureus.22067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8916905PMC
February 2022

Risk Factors for Incidence of Postoperative Spinal Epidural Hematoma Following Multilevel Microendoscopic Laminectomy.

Spine Surg Relat Res 2022 11;6(1):45-50. Epub 2021 Jun 11.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.

Introduction: Due to the narrow portal of entry, microendoscopic laminectomy (MEL) is associated with a risk of postoperative spinal epidural hematoma (POSEH). This risk might be higher when performing multiple-level (m-) MEL. The purpose of this study is to clarify the incidence rate of POSEH following single-level (s-) and m-MEL by each interlaminar level and identify the risk factors for POSEH following m-MEL.

Methods: A total of 379 patients underwent MEL of the lumbar spine (s-MEL, n=141; m-MEL, n=238). We determined the incidence of POSEH following s-MEL and m-MEL by each interlaminar level. For m-MEL, we clarified the correlation between POSEH and possible risk factors, such as operative findings, the sequence of operated interlaminar levels, and the preoperative cross-sectional dural area (CSA) on magnetic resonance imaging.

Results: The incidence rate at L2/3 was significantly higher than that at L3/4 and L4/5. Patients who underwent L2/3 decompression at the end of the procedure showed a higher incidence of POSEH at the L2/3 level. Preoperative spinal stenosis was associated with POSEH at the L2/3 level, and CSA of 56 mm was a predictive factor for POSEH. Logistic regression analysis revealed that both were significant risk factors.

Conclusions: In patients undergoing m-MEL, the incidence of POSEH is highest at the L2/3 level, and treatment of the L2/3 level at the end of the procedure and the presence of spinal stenosis are risk factors for POSEH.
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http://dx.doi.org/10.22603/ssrr.2021-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842358PMC
June 2021

Massive Lumbar Disc Herniation Causing Cauda Equina Syndrome That Presents As Bladder and Bowel Dysfunction in the Absence of Lower Extremity Weakness.

Cureus 2021 Sep 14;13(9):e17952. Epub 2021 Sep 14.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, JPN.

The purpose of this report is to examine the features of cauda equina syndrome (CES) presenting as bladder and bowel dysfunction in the absence of lower extremity weakness. Between July 2015 and July 2016, we experienced four cases of massive LDH causing CES that presented as bladder and bowel dysfunction in the absence of lower extremity weakness. Herein, we describe the clinical features of these four patients (two males and two females) who were followed for a minimum of two years postoperatively. The mean age at the time of surgery was 46.8 years (range, 37-71 years). The disc herniation lesion was at the L4/5 level in one patient, and the L5/S1 level in three. The mean interval between the onset of CES and complete surgical decompression was 10.5 days (range, 1-18 days). Postoperative outcomes were better than poor in three of four cases, while one case had residual sphincter dysfunction. LDH causing CES is considered an indication for immediate surgical decompression; however, diagnosis of CES is likely to be delayed in atypical cases of CES that present as bladder and bowel dysfunction in the absence of lower extremity weakness. Diagnosis of CES tended to be delayed in cases without lower extremity weakness. Clinicians should recognize even sensory impairment alone of the dominant area supplied by S2-4 is an important diagnostic sign of CES in the early stage.
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http://dx.doi.org/10.7759/cureus.17952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515206PMC
September 2021

Association of Postoperative Neutrophil Lymphocyte Ratio (NLR) and Monocyte Lymphocyte Ratio (MLR) with the Presence of Osteoporosis in Japanese Patients after Hip Fracture Surgery: A Retrospective Cohort Study.

J Osteoporos 2021 15;2021:5524069. Epub 2021 Sep 15.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.

Background: The diagnosis of osteoporosis is based on bone mineral density measurements expressed as a percentage of the young adult mean (YAM) in Japan. Osteoporosis is defined as YAM <70%, and intervention is recommended at this cutoff. Because osteoporosis has a strong association with systemic metabolic disorders, we postulated that patients with YAM <70% had higher inflammatory biomarker concentrations owing to the higher systemic stress compared with YAM >70%.

Method: We retrospectively reviewed 94 patients with low-trauma hip fractures. Blood examinations were performed on postoperative day (POD) 1 and POD 7. We used neutrophil lymphocyte ratio (NLR) and monocyte lymphocyte ratio (MLR) to evaluate postoperative recovery. After dividing the 94 patients into two groups according to a YAM cutoff of 70%, we compared the differences in NLR and MLR.

Results: On POD 1, patients with YAM >70% had a median NLR of 5.7 and a median MLR of 0.66, which were significantly lower than for patients with YAM <70% (8.8 and 0.9, respectively). Similarly, on POD 7, patients with YAM >70% had a median NLR of 2.0 and a median MLR of 0.31, which were significantly lower than for patients with YAM <70% (3.5 and 0.43, respectively).

Conclusion: A YAM cutoff of 70% is an appropriate intervention threshold regarding postoperative recovery after hip fracture surgery. . Patients with YAM >70% showed lower NLR and MLR on POD 1 and POD 7. A YAM cuffoff of 70% is an appropriate intervention threshold regarding postoperative recovery after hip fracture surgery.
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http://dx.doi.org/10.1155/2021/5524069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457983PMC
September 2021

Ascending Aortic Calcification as a Potential Predictor for Low Bone Mineral Density: A Pilot Study.

J Osteoporos 2021 26;2021:5526359. Epub 2021 May 26.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.

Background: Identifying the factors related to low bone mineral density (BMD) can have significant implications for preventing hip fractures. The correlation between ascending aortic calcification and BMD has never been reported. Therefore, the purpose of the current study is to confirm the hypothesis that ascending aortic calcification can be used as a predictive factor for low BMD and to find a radiographic sign to show it.

Method: Plain film and computed tomography (CT) images of the thorax were obtained from 91 patients with hip fractures. Using the images, the calcification line of the ascending aorta adjacent to the aortic arch was evaluated. A prominent calcification line confirmed by both plain film and CT was classified as +2. A line which was ambiguous on plain film but confirmed by CT was classified as +1. Cases with no calcification were categorized as 0 (control). We compared the classified score with the BMD and calculated the kappa coefficient to measure intraobserver reliabilities for this radiographic finding.

Results: Twenty-eight patients showed a +2 line, twenty-four patients showed a +1 line, and thirty-nine patients showed 0 lines. The median BMD of each group was 0.37 for the +2 line, 0.45 for the +1 line, and 0.51 for the 0 line. The BMD for the +2 group was significantly lower than the others. The kappa coefficient was approximately 0.6 ( < 0.01).

Conclusion: The imaging finding of calcification of the ascending aorta might be considered as a potential surrogate marker of low BMD. In such subjects, BMD might be ordered for the confirmation of diagnosis of osteoporosis. . The Aortic Arch Tail Sign, a calcification line on the ascending aorta, was relevant to low BMD in the current study. BMD can be ordered for the confirmation of diagnosis of osteoporosis in a subject incidentally found to have ascending aorta calcification on X-ray or CT.
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http://dx.doi.org/10.1155/2021/5526359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177974PMC
May 2021

Changes in a Single Institution's Orthopedic Hospitalization Service in Japan Owing to COVID-19 in 2020.

Cureus 2021 Apr 10;13(4):e14410. Epub 2021 Apr 10.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, JPN.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has had immense impact on people and institutions, including the number of admissions to hospitals for surgery. Our aim in this study was to determine the impact of the pandemic on surgeries in a single institution located in Fukuoka, Japan, between 2019 and 2020. Methods We quantified the numbers of surgeries in both years according to three sites of injury (indoor, outdoor, and unknown), 14 disease categories, and 9 primary diseases using patients' medical records. We also compared the hospital cost per day in each month from March to November in both 2019 and 2020 and compared the change in these costs between the two years. Results The number of admissions in 2020 was 1,187 cases vs 1,282 cases in 2019. The average patients' age was higher in 2020 vs 2019 (69.7 ± 0.5 vs 67.5 ± 0.5 years, respectively; p = 0.004), with no gender differences (2020: 705 women and 482 men; 2019: 716 women and 566 men). We found no significant differences in the number of admissions by month between 2019 and 2020. The percentages of outdoor injuries were significantly lower in 2020 vs 2019 (29.8% vs 37.9%, respectively; p = 0.004), and we found significantly different rates when comparing 2020 and 2019 for degenerative disease (42.6% vs 37.4%; p = 0.007), trauma related to falls (34.4% vs 30.2%; p = 0.02), chronic disease (1.9% vs 3.7%; p = 0.005), and sports injuries (0.8% vs 3.7%; p < 0.0001). The rate of sports-related injury was significantly lower in 2020 (1.6%) than in 2019 (7.7%) (p < 0.0001). The daily hospital charge was $10,517.09 (US dollars) in 2020 vs $11,225.32 in 2019, and the charges in the months of April and June were significantly higher in 2020 vs 2019 (p = 0.003 and p = 0.001, for April and June, respectively). Both the number and rate of upper limb fractures were higher in 2020. Conclusions The COVID-19 pandemic is affecting some hospitals' revenue. Although the charges per day were sufficient in our institution in 2020, compared with 2019, some hospital beds were unused during this phase of the pandemic. Hospitals may increase the revenue by mixing both short-term and long-term patients' hospital stays effectively.
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http://dx.doi.org/10.7759/cureus.14410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110318PMC
April 2021

Anatomical Evaluation of Lumbar Arteries for Lateral Lumbar Interbody Fusion with Magnetic Resonance Imaging.

Spine Surg Relat Res 2020 20;4(1):69-73. Epub 2019 Sep 20.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.

Introduction: Lateral lumbar interbody fusion (LLIF) is becoming a more common surgical treatment option for adult degenerative lumbar conditions. LLIF is a mini-open access technique with wound retractors, and postoperative hematoma due to segmental vessels injury is reported. Thus, it is considered that there is a need to conduct detailed preoperative examinations to identify where the lumbar vessels are. As far as we know, there are only a few studies investigating the location of the lumbar arteries. This study evaluates the anatomical position of lumbar arteries using magnetic resonance imaging (MRI).

Methods: We studied 101 MRIs of patients with lumbar disease. The length from the upper and lower end plates of the vertebra to the lumbar arteries was measured. The measurement was conducted with coronal MRI images of every quarter slice of L1 to L4 vertebrae. We also investigated sagittal MRI images to determine whether the lumbar vessels are located on intervertebral disc in each level from L1/2 to L5/S1.

Results: The lumbar vessels are not always located at the center of the vertebrae. Some lumbar vessels are located within 8 mm from the end plates. Especially in L4, the lumbar vessels tended to go down from the anterior cranial side to the posterior caudal side (P < 0.01). 8, 24, and 54 lumbar vessels are located at the anterior quarter, the center, and the posterior quarter slice of the vertebrae, respectively, in L4. There were seven lumbar vessels in total located on the vertebral disc level.

Conclusions: It is necessary to investigate where the lumbar arteries are located to prevent its injury in LLIF, because the lumbar artery is not always located at the center of a vertebra. MRIs may provide a valuable information to avoid vascular injury during LLIF.
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http://dx.doi.org/10.22603/ssrr.2019-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002069PMC
September 2019

Primary extradural malignant melanoma of the spine: A case report.

J Orthop Sci 2019 07 4;24(4):757-760. Epub 2017 Feb 4.

Department of Orthopaedic Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, 3-23-1 Shiobaru, Minami-ku, Fukuoka 815-8588, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jos.2017.01.007DOI Listing
July 2019

A Case of Spontaneous Regression of Recurrent Desmoid Tumor Originating From the Internal Obturator Muscle After Delivery.

World J Oncol 2016 Aug 3;7(4):75-80. Epub 2016 Sep 3.

Department of Orthopedic Surgery, Kyushu-Central Hospital, 23-1 Shiobaru 3-chome, Minami-ku, Fukuoka 815-8588, Japan.

Desmoid-type fibromatoses are pathologically benign but locally aggressive tumors. We report the case of a desmoid tumor that disappeared spontaneously after recurrence. A 21-year-old woman was referred to our hospital because of left lower limb weakness during menstruation. The following day this weakness had disappeared but menstrual colic remained; consequently, the patient underwent an internal examination that revealed an intrapelvic tumor. Magnetic resonance imaging demonstrated an enhanced mass (diameter, 8 cm) arising from the internal obturator muscle and attached to the urinary bladder. The tumor was diagnosed as a desmoid-type fibromatosis after histologic evaluation of a transvaginal biopsy; marginal resection was carried out at < 1 month after the first hospital admission. The patient experienced recurrence at 2 years after surgery, which was confirmed as two enhanced masses (diameter, 1 cm) using magnetic resonance imaging. Eleven months later, the diameters of these masses had increased to 1.8 cm; however, there was no further increase in size beyond this point. The patient delivered successfully at 5 and 7 years after surgery; at 8 years, the recurrent tumors had disappeared completely as confirmed by magnetic resonance imaging. This case involving recurrence is rare for two reasons. The first was that no change in the size of the tumors occurred during pregnancy and after delivery, and the second was that the patient experienced complete remission of the recurrent tumors after only simple observation. Thus, it is important to recognize that even a recurrent desmoid tumor can sometimes exhibit spontaneous regression.
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http://dx.doi.org/10.14740/wjon963wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624703PMC
August 2016

Subchondral insufficiency fracture of the femoral head in a patient with alkaptonuria.

Skeletal Radiol 2014 Jun 20;43(6):827-30. Epub 2013 Dec 20.

Department of Orthopaedic Surgery, Kyushu Central Hospital, 3-23-1 Shiobaru, Minami-ku, Fukuoka-city, 815-8588, Japan,

We report a patient with alkaptonuria accompanied by bilateral rapidly destructive arthrosis of the hip. The destruction of the left hip joint with its severe functional impairment necessitated total hip arthroplasty (THA). The outcome was satisfactory. Both magnetic resonance imaging (MRI) and pathologic findings were compatible with a subchondral insufficiency fracture. A year and half later, during a follow-up visit, the patient complained of right coxalgia. Radiography showed that the right femoral head had already disappeared, requiring THA of the right hip. Although there have been a few reports of rapid destructive hip osteoarthritis associated with ochronotic arthropathy, the pathogenesis of the destructive change is not clear. Subchondral insufficiency fracture was diagnosed on MR imaging and pathologically confirmed in our patient with alkaptonuria, suggesting that subchondral insufficiency fracture is one of the causes of ochronotic hip destruction.
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http://dx.doi.org/10.1007/s00256-013-1796-zDOI Listing
June 2014

Interleukin-1beta represses MRP2 gene expression through inactivation of interferon regulatory factor 3 in HepG2 cells.

Hepatology 2004 Jun;39(6):1574-82

Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

The human multidrug resistance protein 2 (MRP2/ABCC2), expressed on the bile canalicular membrane, mediates the multispecific efflux of several organic anions, including conjugates of glucuronate, sulfate, and glutathione. Expression of MRP2 can be altered in response to environmental stimuli such as cholestasis and jaundice. We previously reported that MRP2 mRNA expression levels are decreased in the nontumorous part of hepatitis C virus-infected human liver tissues, and that inflammatory cytokines inhibit MRP2 expression in human hepatic (HepG2) cells. We investigated the molecular mechanisms by which inflammatory cytokines modulate MRP2 gene expression in hepatic cells. Treatment of human hepatic cells with interleukin-1beta (IL-1beta) or tumor necrosis factor alpha resulted in a decrease in the protein and mRNA levels of MRP2. IL-1beta inhibited the transcriptional activity of MRP2 promoter constructs by 40%, and this inhibition of MRP2 promoter activity was mediated through the interferon stimulatory response element (ISRE). Electrophoretic mobility shift assays with IL-1beta-treated nuclear extracts showed a decrease in the formation of DNA protein complexes, specifically those including interferon regulatory factor 3 (IRF3). Expression of recombinant human IRF3 increased MRP2 promoter activity. Treatment with a specific extracellular signal-regulated kinase inhibitor relieved IL-1beta-induced MRP2 mRNA downregulation and abrogated the binding of IRF3 to the ISRE element. In conclusion, IL-1beta induces downregulation of the MRP2 gene by inactivating IRF3 binding to ISRE on the MRP2 promoter in human hepatic cells; this inactivation is accomplished via interference with the extracellular signal-regulated kinase pathway.
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http://dx.doi.org/10.1002/hep.20216DOI Listing
June 2004
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