The Tohoku Journal of Experimental Medicine
Online ISSN : 1349-3329
Print ISSN : 0040-8727
ISSN-L : 0040-8727
Volume 235, Issue 4
April
Displaying 1-10 of 10 articles from this issue
Regular Contribution
  • Takaaki Murakami, Takuo Nambu, Tomoko Kato, Yuki Matsuda, Shin Yonemit ...
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 255-260
    Published: 2015
    Released on J-STAGE: March 25, 2015
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    The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-acting insulin analogue is widely used in clinical practice. However, some patients fail to achieve lower postprandial hyperglycemia. Mitiglinide, a short-acting insulinotropic sulfonylurea receptor ligand, is effective for postprandial hyperglycemia. Recently, it has been reported that the combination therapy of mitiglinide with a DPP-4 inhibitor could improve glycemic control. However, the efficacy of those under long-acting insulin analogue therapy remains to be investigated. Thus, we conducted a prospective single-center study of eight Japanese patients with type 2 diabetes mellitus receiving mitiglinide added to the combination therapy of sitagliptin and insulin glargine, and evaluated its efficacy and safety by continuous glucose monitoring (CGM). Participants’ (four men and four women) mean age was 70.3 ± 10.6 years. Their mean body mass index, HbA1c level, and urinary C-peptide level were 22.0 ± 2.8 kg/m2, 9.2 ± 1.2%, and 50.0 ± 31.4 μg/day, respectively. CGM showed that as compared with the combination of only sitagliptin and insulin glargine, mitiglinide in combination with sitagliptin and insulin glargine significantly reduced glycemic fluctuation indices, total area for the range of 24-h glycemic fluctuations (p = 0.04), mean amplitude of glycemic excursions (p = 0.03), and the proportion of time in hyperglycemia (p = 0.02) without significant difference in the proportion of time in hypoglycemia (p = 0.18). Hence, we have demonstrated the efficacy and safety of the add-on treatment with mitiglinide in type 2 diabetic patients, receiving the combination therapy of sitagliptin and insulin glargine.
  • Shunchang Sun, Wenwu Zhang, Xi Chen, Huiwen Song
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 261-266
    Published: 2015
    Released on J-STAGE: March 21, 2015
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    Coronary heart disease (CHD) is a disease resulting from the interaction between genetic variations and environmental factors. Zinc finger homeobox 3 (ZFHX3) is a transcription factor and contains a poly-glutamine tract in a compositionally biased region that is encoded by exon 9, containing a cluster of CAG and CAA triplets followed by the polymorphic CAA repeats: (CAG)2(CAA)2(CAG)3CAACAG(CAA)nGCA. Thus, nine successive glutamine residues precede the poly-glutamine tract, encoded by the polymorphic CAA repeats. The aim of this study was to investigate the association of the CAA repeat polymorphism in exon 9 of the ZFHX3 gene with the risk of CHD in a Chinese population. The CAA repeat polymorphism was determined by polymerase chain reaction followed by DNA sequencing in 321 CHD patients. Genotype frequencies were compared using the non-parametric mood median test. Four alleles of CAG(CAA)10GCA, CAG(CAA)8GCA, CAG(CAA)9GCA, and CAG(CAA)11GCA were found in Chinese CHD patients in exon 9 of the ZFHX3 gene. The CAG(CAA)10GCA was a major allele (95.95%), and the CAG(CAA)8GCA was a minor allele (3.58%). The CAG(CAA)9GCA and CAG(CAA)11GCA were rare alleles (0.31% and 0.16%). The CAG(CAA)10GCA allele encodes a poly-glutamine tract of 19 residues. Importantly, the CHD patients homozygous for the CAG(CAA)10GCA allele had a higher risk of CHD, compared to the heterozygous patients carrying a CAG(CAA)8GCA allele. Moreover, the CAG(CAA)10GCA allele was significantly associated with hypertension, diabetes mellitus, or dyslipidemia (P < 0.05). Thus, the CAA repeat polymorphism in exon 9 of the ZFHX3 gene contributes to the CHD susceptibility in the Chinese population.
  • Wei-De Lin, Yu-Yuan Ke, I-Ching Chou, Chung-Hsing Wang, Fuu-Jen Tsai
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 267-273
    Published: 2015
    Released on J-STAGE: March 21, 2015
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    Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB), one of the enzymes required for the degradation of dermatan sulfate (DS). Accumulation of DS in connective tissue causes growth failure, resulting in short stature. Here, we observed a 5-year-old girl who was the only one affected member of her family and who presented with an exaggerated, convex curvature of the back at the age of one year. Abnormal excretion of DS in the urine and extremely low leukocyte ARSB activity were noted. The patient was suspected to have MPS VI. Direct DNA sequencing indicated that there was no mutation in the coding region of ARSB. However, RT-PCR analysis of RNA prepared from blood samples indicated the deletion of the entire exon 4. Further analysis of the genomic DNA by quantitative PCR confirmed a homozygous deletion of exon 4, an unusual intragenic deletion in ARSB. The deletion led to a truncated protein that lacks most of the catalytic domain. The patient received recombinant human ARSB as enzyme replacement therapy (ERT) at an early stage (2 years), and responded positively in terms of skeletal development and other developmental milestones. The early identification of type VI MPS patients and subsequent treatment with ERT may be beneficial for the clinical outcome of MPS VI patients. In addition, detailed gene analysis may enhance the ability to provide genetic counseling to families of patients affected by MPS VI.
  • Yuki Inagaki, Yukio Oshiro, Naoyuki Hasegawa, Kuniaki Fukuda, Masato A ...
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 275-282
    Published: 2015
    Released on J-STAGE: March 21, 2015
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    Hepatitis E caused by hepatitis E virus (HEV) is a serious public health concern in developing countries where HEV is mainly transmitted through contaminated water. Recently, in industrialized countries, autochthonous hepatitis E, a porcine zoonosis, has been increasingly recognized. In Japan, the number of national notifications of acute hepatitis E has increased since the introduction of anti-HEV IgA antibody measurement, covered by the national health insurance program, in 2011. In the past three years, we examined five patients of acute hepatitis or acute-on-chronic liver failure caused by HEV infection who presented various clinical courses in the southern area of Ibaraki prefecture in Japan. Of these patients, 78-year-old and 63-year-old male patients presented acute hepatitis E and recovered by only bed rest. The latter patient had a history of consuming grilled or undercooked pork and shellfish prior to the onset of hepatitis E. Among the five patients examined, the infection route was detected only in this patient. Of note, a 65-year-old female patient presented severe hepatitis associated with painless thyroiditis. The patient was diagnosed with probable autoimmune hepatitis and was successfully treated with prednisolone (40 mg/day). Lastly, 58-year-old and 62-year-old male patients, both of whom had a history of diabetes mellitus and alcoholic liver disease, developed acute-on-chronic liver failure, and the latter patient with pre-existing liver cirrhosis died due to liver failure. Thus, patients with clinical HEV infection who display multiple underlying diseases can develop acute-on-chronic liver failure. In conclusion, HEV infection manifests the diverse clinical courses.
Case
  • Juan Xu, Yuan Tang, Sha Zhao, WenYan Zhang, YingJie Xiu, Ting Liu, Yu ...
    Article type: Case
    2015 Volume 235 Issue 4 Pages 283-288
    Published: 2015
    Released on J-STAGE: March 27, 2015
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    Angioimmunoblastic T-cell lymphoma (AITL) is recognized as a distinct clinicopathological subtype of peripheral T-cell lymphomas. Its clinical features include generalized lymphadenopathy, constitutional symptoms, and autoimmune-related findings, such as hemolytic anemia. Pathologically, AITL is characterized by a polymorphous infiltrate in lymph nodes with prominent proliferation of high endothelial venules and follicular dendritic cells. We present an 80-year-old Chinese man with generalized lymphadenopathy and pulmonary infection, diagnosed as AITL based on the distinctive pathological findings and T-cell receptor gamma (TCR-γ) gene rearrangement analysis of lymph nodes. Importantly, the patient suffered from a coexisting plasma cell myeloma, as judged by monoclonal immunoglobulin in the serum, immature plasma cells, and rearrangement of the immunoglobulin heavy-chain (IgH) gene in the bone marrow. The patient received two courses of the chemotherapy but died of pneumonia 6 months after diagnosis. AITL can be accompanied by polyclonal or clonal proliferation of B lymphocytes; however, AITL are rarely associated with plasma cell proliferation. In fact, 14 AITL cases with plasma cell proliferation have been reported in the literature, but none of them manifested the infiltration of monoclonal immature plasma cells in the bone marrow. To the best of our knowledge, this is the first report of newly diagnosed, concurrent AITL and plasma cell myeloma, providing the evidence for the interplay between malignant T cells and plasma cell proliferation. A review of the literature has also supported a relationship between AITL and plasma cell proliferation. Awareness of this relationship is important for correct diagnosis and appropriate treatment of AITL.
  • Ryu Watanabe, Hiroshi Fujii, Yukiko Kamogawa, Kyohei Nakamura, Tsuyosh ...
    Article type: Case
    2015 Volume 235 Issue 4 Pages 289-294
    Published: 2015
    Released on J-STAGE: March 28, 2015
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    Systemic lupus erythematosus (SLE) is an autoimmune disease and can cause multi-organ damage. Peritoneal involvement, also called lupus peritonitis, is a rare but sometimes fatal manifestation. Deposition of immune complexes consisting of immunoglobulin G and complement is considered to be involved in the pathogenesis of lupus peritonitis; however, it remains unknown whether inflammatory cytokines contribute to the pathology of this manifestation. Here we present two patients with treatment-resistant lupus peritonitis: a 37-year-old woman with a 26-year history of SLE who had been treated with prednisolone and cyclophosphamide followed by azathioprine and a 65-year-old woman with a 33-year history of SLE who had been treated with prednisolone alone. Both patients were admitted to our department because of abdominal distention. Computed tomography scans showed massive ascites. Ascitic fluid examinations of both patients showed leukocytosis with no evidence of malignancy or infection. After eliminating other causes for ascites, they were diagnosed with lupus peritonitis. Despite the intensified immunosuppressive therapy, they died of uncontrolled peritonitis several months after admission. Examinations of the ascites at admission also revealed a large content of interleukin (IL)-6, compared with other inflammatory cytokines, IL-1β and tumor necrosis factor-α. In fact, the ascitic IL-6 levels of these two patients were 12,389 pg/mL and 5,486 pg/mL, much higher than their serum IL-6 levels of 36 pg/mL and 140 pg/mL, respectively. We therefore suggest that IL-6 may contribute to the pathogenesis of lupus peritonitis and that the inhibition of IL-6 signaling may provide a novel therapeutic strategy for lupus peritonitis.
Regular Contribution
  • Hyung Ah Jo, Jung Nam An, Jung Pyo Lee, Kook-Hwan Oh, Chun Soo Lim, Yu ...
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 295-304
    Published: 2015
    Released on J-STAGE: April 02, 2015
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    Visit-to-visit systolic blood pressure variability (VTV-SBPV) is correlated with cardiovascular complications. However, it still remains unclear whether VTV-SBPV is related to cardiovascular outcomes in patients with peritoneal dialysis (PD), who often manifest hypertension. We, therefore, evaluated the association of VTV-SBPV with all-cause mortality, cardiovascular complications, or the loss of residual renal function (RRF) that is a powerful predictor of mortality and morbidity in PD patients. We retrospectively reviewed the medical records for patients undergoing maintenance PD for at least 12 months at Seoul National University Hospital. The patients were divided into quartiles of VTV-SBPV based on the standard deviation of systolic blood pressure (SBP). We checked the SBP of the patients for up to 2 years after the initiation of PD. Among 216 PD patients, 16 primary outcome events (cardiovascular complications and all-cause mortality) occurred. VTV-SBPV was not associated with primary outcomes. During the follow-up, RRF loss occurred in 46 patients. The hazard ratios (HRs) for the loss of RRF in the 4 quartiles of VTV-SBPV, based on the highest to the lowest variability, were as follows: 6.201 (95% CI: 1.982-19.401, p = 0.002), 2.542 (95% CI: 0.859-7.523, p = 0.092), and 2.133 (95% CI: 0.635-7.165, p = 0.246), respectively. The loss of RRF was more frequently detected in patients with higher VTV-SBPV. VTV-SBPV was indicated as an independent risk factor for the loss of RRF. Therefore, the degree of variations in SBP should be carefully monitored to preserve the RRF of these patients.
  • Shin Hisahara, Takashi Matsushita, Hiroyasu Furuyama, Go Tajima, Yosuk ...
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 305-310
    Published: 2015
    Released on J-STAGE: April 03, 2015
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    Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial β-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial β-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and myoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial β-oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed.
  • Yutaro Arata, Akira Horii, Hidemitsu Saito, Manabu Miyamoto, Hiroo Mat ...
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 311-325
    Published: 2015
    Released on J-STAGE: April 08, 2015
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    Students of the Tohoku University School of Medicine experienced the Great East Japan Earthquake on March 11, 2011. We conducted a series of surveys to examine the relationships among their experiences and activities on the day of the earthquake, their physical, mental, and economic problems following the disaster, and how their problems changed over time. The initial survey was performed in April 2011, with three follow-up surveys in July 2011, February 2012, and April 2013. The initial survey focused on students’ experiences and living conditions during the disaster, which contained questions on their locations and circumstances, family circumstances, lives after the earthquake, voluntary works, physical or mental health problems, and desire for counseling. The follow-up surveys included new items regarding their circumstances, changes in their health problems, and their desire for economic assistance. Students who answered the first survey to the 4th one, with response rates in the following bracket, were as follows: 472 (28.0%), 640 (29.9%), 681 (36.0%), and 678 (39.0%), respectively. Six months after the earthquake, about 20% having experienced physical and/or mental problems. Although there was a trend toward a reduction in suffering and health problems over time, some students’ conditions remained unchanged or worsened. It is notable that students who had participated in voluntary activities, despite their own suffering of harm and distress, were identified as the group that required the closest attention. Our present results can be applied to appropriate supports for students in future large-scale disasters.
  • Ki-Eun Hwang, Young-Jun Shon, Byong-Ki Cha, Mi-Jeong Park, Min-Su Chu, ...
    Article type: Regular Contribution
    2015 Volume 235 Issue 4 Pages 327-333
    Published: 2015
    Released on J-STAGE: April 08, 2015
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    Residual pleural thickening (RPT) is the most frequent complication associated with pleural tuberculosis, and may occur even after successful anti-tuberculosis medications. Matrix metalloproteinases (MMPs) are zinc-dependent proteinases capable of degrading all components of the extracellular matrix. The proteolytic action of MMPs may be involved in the pathogenesis of tuberculosis. MMP-9, secreted by monocytes and lymphocyte, may lead to long-term fibrosis. The aim of the present study was to determine whether MMP-2 and/or MMP-9 and their specific inhibitors, tissue inhibitors of metalloproteinase 1 (TIMP-1) and TIMP-2, could be used to predict RPT. This retrospective study enrolled 52 patients diagnosed with pleural tuberculosis. Levels of MMP-2, MMP-9, TIMP-1, and TIM-2 were determined in the pleural fluid by ELISA. The RPT was measured on chest X-ray at the completion of treatment and the final follow-up. The average periods of anti-tuberculosis medication and the follow-up after completion of treatment were 6.7 and 7.6 months, respectively. MMP-2 or MMP-9 levels had no significant correlation to RPT. The patients with RPT > 2 mm at the completion of anti-tuberculosis medication and the final follow-up had higher TIMP-1 levels (p = 0.00 and p = 0.001, respectively). However, patients with RPT > 2 mm at the completion of anti-tuberculosis medication had lower TIMP-2 levels (p = 0.005). In a logistic regression model, elevated TIMP-1 levels at the completion of anti-tuberculosis medications were associated with RPT. In conclusion, higher TIMP-1 levels are responsible for the development of RPT and may be helpful for predicting RPT in pleural tuberculosis.
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