The Tohoku Journal of Experimental Medicine
Online ISSN : 1349-3329
Print ISSN : 0040-8727
ISSN-L : 0040-8727
Volume 260, Issue 4
August
Displaying 1-9 of 9 articles from this issue
Invited Review
  • Takayoshi Ohkubo, Michihiro Satoh
    2023 Volume 260 Issue 4 Pages 273-282
    Published: 2023
    Released on J-STAGE: August 09, 2023
    Advance online publication: June 08, 2023
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    The Ohasama Study is a long-term prospective cohort study of the general population in the town of Ohasama (currently, Hanamaki city) in Iwate Prefecture, Japan, that was started in 1986. Ohasama is a typical farming village in the Tohoku region that consists of part-time farming households that cultivate mainly fruit trees. At the start of the study, the prevention of hypertension, a main cause of strokes, was taken to be an important issue in public health activities because of the many people who died or needed care as a result of strokes in Ohasama. A home blood pressure measurement program was then begun with the aim of preventing hypertension while increasing a sense of solidarity among community residents and the awareness that “one must protect one’s own health.” As a result, this project became the world’s first community-based epidemiological study using home blood pressure, as well as 24-hour ambulatory blood pressure, for which measurements were also initiated. In the 1990s, the Ohasama Study reported a linear “the lower, the better” relationship between out-of-office blood pressure and cardiovascular risk. To date, we have accumulated advanced evidence regarding the clinical significance of out-of-office blood pressure. Those have contributed to hypertension management guidelines around the world. This article summarizes the results of representative long-term follow-up studies of the Ohasama Study.

Regular Contribution
  • Hong Wang, Jinglin Xu, Guoming Ding, Shouhao Zheng, Yingmin Han, Xinho ...
    2023 Volume 260 Issue 4 Pages 283-291
    Published: 2023
    Released on J-STAGE: August 09, 2023
    Advance online publication: April 20, 2023
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    Supplementary material

    Omentin-1 regulates inflammation, lipid accumulation, endothelial dysfunction, and atherosclerosis; the latter factors contribute to the occurrence of major adverse cardiac and cerebrovascular events (MACCE). This study aimed to explore the predictive implication of serum omentin-1 for MACCE risk in patients receiving hemodialysis. A total of 319 patients receiving hemodialysis and 160 healthy controls were prospectively enrolled in this study. Omentin-1 from serum was detected by enzyme-linked immunosorbent assay. MACCE was recorded during follow-up (median 18.9 months; range 1.9-62.9 months) in patients receiving hemodialysis. Omentin-1 was reduced in patients receiving hemodialysis versus healthy controls (P < 0.001). In patients receiving hemodialysis, omentin-1 was negatively related to C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol (all P < 0.05); whereas omentin-1 was not related to other clinical characteristics. Notably, the 1-year, 2-year, 3-year, 4-year, and 5-year accumulating MACCE rates in patients receiving hemodialysis were 7.9%, 18.3%, 25.9%, 36.1%, and 41.4%, respectively. Interestingly, high omentin-1 related to decreased accumulating MACCE rate (P = 0.003), which was further validated by multivariate Cox regression analysis (hazard ratio = 0.458, P = 0.006). Additionally, by direct comparison, omentin-1 was reduced in hemodialysis patients who experienced MACCE compared to those who did not (P < 0.001); meanwhile, the receiver operator characteristic curve displayed that omentin-1 had an acceptable ability to estimate MACCE risk with an area under the curve (95% confidence interval) of 0.703 (0.628-0.777). Serum omentin-1 reflects reduced inflammation and lipid accumulation, as well as predicts decreased MACCE risk in patients receiving hemodialysis.

  • Chao Liu, Juxian Gu, Yan Yao
    2023 Volume 260 Issue 4 Pages 293-300
    Published: 2023
    Released on J-STAGE: August 11, 2023
    Advance online publication: April 27, 2023
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    Supplementary material

    Retinol-binding protein 4 (RBP4) promotes dyslipidemia, insulin resistance, inflammation, and atherosclerosis, etc. which may participate in the progression of acute ischemia stroke (AIS). This study aimed to evaluate the longitudinal change of RBP4 after disease onset and its correlation with prognosis in AIS patients. Plasma RBP4 was measured by enzyme-linked immunosorbent assays in 402 AIS patients at admission, one day (D1), 3 days (D3), 7 days (D7), and 30 days (D30) after admission; and in 100 healthy controls after enrollment. The neurological-function recovery was evaluated by the modified Rankin Scale (mRS) at 3 months (M3); disease relapse and death were also recorded during a median 20-month follow-up in AIS patients. Our study revealed that RBP4 was elevated in AIS patients compared with healthy controls. RBP4 was related to a history of diabetes mellitus, a history of cardiovascular disease, and elevated National Institutes of Health Stroke Scale score in AIS patients. Longitudinally, RBP4 was increased from admission to D1/D3, then reduced gradually to D30 in AIS patients. Notably, RBP4 at admission and D1 was elevated in AIS patients with mRS > 2 compared to those with mRS ≤ 2. Meanwhile, RBP4 at admission, D1, D3, D7, and D30 were all higher in AIS patients occurred relapse than those without; RBP4 at D3, D7, and D30 were also higher in AIS patients who died later than those who survived. In conclusion, plasma RBP4 originally elevates and continuously decreases during disease, which forecasts neurological-function recovery status, relapse, and death risk of AIS.

Case
  • Hirona Ichimura, Satoshi Ichikawa, Koya Ono, Kyoko Inokura, Yosuke Hos ...
    2023 Volume 260 Issue 4 Pages 301-304
    Published: 2023
    Released on J-STAGE: August 11, 2023
    Advance online publication: May 11, 2023
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    Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases, characterized by activated macrophages with hemophagocytosis and multiple organ damage. We report a case of MAS associated with systemic lupus erythematosus that initially presented with severe liver dysfunction. Although it was improved with steroids and plasmapheresis, severe pancytopenia was subsequently experienced, and the bone marrow showed severe aplasia similar to aplastic anemia. Nevertheless, the administration of immunosuppressants resulted in the recovery of blood counts within two weeks. When severe MAS results in cytokine overproduction, bone marrow aplasia may occur, for which immunosuppressive therapy may be highly effective.

Regular Contribution
  • Bo Huang, Zhuo He
    2023 Volume 260 Issue 4 Pages 305-314
    Published: 2023
    Released on J-STAGE: August 11, 2023
    Advance online publication: May 25, 2023
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    Protein kinase D1 (PKD1) controls tumor growth and invasion of gastrointestinal tract-related cancers, but its prognostic role in colorectal cancer (CRC) is not clear yet. Therefore, this research intended to assess the potential of PKD1 as a marker for CRC patients’ management, also to evaluate its effect on 5-fluorouracil (5-FU) chemosensitivity in CRC cell lines. PKD1 protein and mRNA expressions were measured by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction assays in 214 CRC patients, respectively. The PKD1 overexpression plasmids and negative control (NC) plasmids were transfected into the HCT-116 and LoVo cell lines followed by 0-16 μM 5-FU treatment. PKD1 protein (P < 0.001) and mRNA expressions (P < 0.001) were both descended in tumor tissues compared to tumor-adjacent tissues. Meanwhile, tumor PKD1 protein and mRNA expressions were both negatively related to lymph node metastasis, N stage, and tumor-node-metastasis (TNM) stage (all P < 0.05). Prognostically, high expressions of PKD1 protein and mRNA were linked with prolonged disease-free survival (DFS) and overall survival (OS) (all P < 0.05). After adjustment by multivariate Cox analyses, PKD1 mRNA high expression independently forecasted longer DFS [hazard ratio (HR) = 0.199, P = 0.002] and OS (HR = 0.212, P = 0.022). In vitro experiments revealed that PKD1 overexpression decreased the half maximal inhibitory concentration value of 5-FU in the HCT-116 (P = 0.016) and LoVo (P = 0.007) cell lines. PKD1 expression links with less lymph node metastasis risk and satisfied prognosis in CRC patients, which promotes CRC cell chemosensitivity to 5-FU chemosensitivity as well.

  • Lan Liu, Sijia Sun, Zhengkai Yang, Shasha Zhu, Cao Zou
    2023 Volume 260 Issue 4 Pages 315-327
    Published: 2023
    Released on J-STAGE: August 23, 2023
    Advance online publication: June 01, 2023
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    Supplementary material

    The incidence, prevalence, and economic burden of heart failure have continued to increase worldwide. It remains unclear whether LCZ696 can ameliorate calcium reuptake in the sarcoplasmic reticulum via the sarcoplasmic endoplasmic reticulum calcium ion-ATPase 2α (SERCA2α)-dependent pathway during cardiac diastole. We investigated whether LCZ696 could ameliorate tachycardia-induced myocardial injury by modulating cardiac SERCA2α levels. A tachycardia-induced myocardial injury model was established by daily intraperitoneal administration of 60 mg/kg isoprenaline (ISO) for 2 weeks. LCZ696 was orally administered for the following 4 weeks. SERCA2α and calcium ion (Ca2+)-related protein expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. For additional in vitro studies, HL-1 cardiomyocytes were used. A SERCA2α overexpression vector was constructed and transfected into HL-1 cells. The expression of SERCA2α and Ca2+-related proteins were also measured using qRT-PCR and western blotting. Our in vivo results demonstrated that myocardial injury was successfully induced by intraperitoneal administration of ISO. The expression of both SERCA2α- and Ca2+-related proteins was impaired. Oral administration of LCZ696 increased the expression of SERCA2α, alleviated Ca2+-related protein impairment and cardiac Ca2+ dyshomeostasis, and ameliorated myocardial injury. These results were compared with our in vitro findings. Ca2+-related proteins are affected by the overexpression of SERCA2α. LCZ696 improved tachycardia-induced myocardial injury by increasing SERCA2α expression, which reversed the development of heart failure in ISO-induced mice. These results provide new insights into how sustained LCZ696 treatment in heart failure improves cardiac function through intracellular Ca2+-regulatory mechanisms.

  • Wei Qin, Wenping Xue, Jinxin Nie, Yanan Tian, Lili Zhu, Jiamei Liu, Ha ...
    2023 Volume 260 Issue 4 Pages 329-336
    Published: 2023
    Released on J-STAGE: August 23, 2023
    Advance online publication: June 01, 2023
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    Soluble low-density lipoprotein receptor-related protein-1 (sLRP-1) plays a crucial role in facilitating inflammation, lipid accumulation, and atherosclerosis, and the latter factors are involved in the pathology of cardiovascular diseases. This study aimed to explore the ability of plasma sLRP-1 for reflecting stenosis degree in acute coronary syndrome (ACS) patients. sLRP-1 was detected from plasma by enzyme-linked immunosorbent assay in 169 ACS patients and 77 non-ACS subjects (as controls) after admission. Our study illustrated that sLRP-1 was increased in ACS patients versus controls (P < 0.001). Meanwhile, sLRP-1 was positively correlated with body mass index (P = 0.021), white blood cells (P = 0.009), neutrophils (P = 0.002), cardiac troponin I (P = 0.009), and brain natriuretic peptide (P = 0.008) in ACS patients. Notably, sLRP-1 was positively associated with the Gensini score (P = 0.002) and Gensini score stratified stenosis severity (P = 0.004) in ACS patients. After adjustment, sLRP-1 [odds ratio (OR) = 1.333, P = 0.045] independently estimated a higher risk of moderate-severe stenosis, so did numbers of coronary artery lesions (OR = 2.869, P = 0.001), but ejection fraction forecasted a lower risk (OR = 0.880, P = 0.012). Interestingly, a combination of sLRP-1, ejection fraction, and numbers of coronary artery lesions exhibited a good ability to estimate moderate-severe stenosis risk with an area under the curve (95% confidence interval) of 0.845 (0.783-0.906). In summary, increased plasma sLRP-1 represents an aggravated inflammation, impaired cardiac function, and especially a higher stenosis severity in ACS patients.

Case
  • Hiroki Kudo, Ryota Suzuki, Atsushi Kondo, Kandai Nozu, Yuki Nakamura, ...
    2023 Volume 260 Issue 4 Pages 337-340
    Published: 2023
    Released on J-STAGE: August 23, 2023
    Advance online publication: June 08, 2023
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    Fanconi syndrome is a disorder of the proximal renal tubule. Recently, advanced genetic analysis technology has revealed that several genes cause familial Fanconi syndrome. We identified a family with autosomal dominant Fanconi syndrome and chronic kidney disease with a novel glycine amidinotransferase (GATM) variant. Case 1 was a 57-year-old Japanese woman. Her father and two siblings had Fanconi syndrome or chronic kidney disease. She presented to our hospital at the age of 34 years with recurrent glucosuria. Her height and weight were 151 cm and 46.6 kg, respectively. Laboratory tests showed glucosuria, hypophosphatemia, hypouricemia, and normal renal function. Her serum creatinine level gradually increased over the following next two decades, and she developed end-stage renal disease. Case 2, the daughter of Case 1, was a 26-year-old woman. Her height and weight were 151 cm and 37.5 kg, respectively. Glucosuria was detected at the age of 13 years, which led to a referral to our hospital. Urinalysis showed low-molecular-weight proteinuria. She was diagnosed with Fanconi syndrome. At the age of 26 years, she had glucosuria, low-molecular-weight proteinuria, hypouricemia, and normal renal function. Genetic testing of both cases revealed a novel missense variant in GATM. The heterozygous missense variants in GATM have been reported to cause familial Fanconi syndrome, which manifests early in life and progresses to renal glomerular failure by mid-adulthood. The novel GATM variant detected in our cases was suspected to be associated with the development of Fanconi syndrome. GATM variants should be tested in patients with idiopathic Fanconi syndrome.

  • Manabu Suzuki, Kohei Takahashi, Mika Watanabe, Ko Hashimoto, Takahiro ...
    2023 Volume 260 Issue 4 Pages 341-346
    Published: 2023
    Released on J-STAGE: August 23, 2023
    Advance online publication: June 08, 2023
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    Primary malignant lymphoma confinement to the cauda equina is rare. Only 14 cases of primary malignant lymphoma in the cauda equina have been reported. In these cases, the clinical features were similar to those of lumbar spinal canal stenosis (LSCS). This report describes a case of diffuse large B-cell lymphoma of the cauda equina that was diagnosed after decompression surgery for LSCS. An 80-year-old man presented with gait disturbance due to progressive muscle weakness in the lower extremities over the previous two months. He was diagnosed with LSCS, and decompression surgery was performed. However, the muscle weakness worsened after surgery; therefore, he was referred to our department. Plain magnetic resonance imaging (MRI) revealed swelling of the cauda equina. It demonstrated marked homogenous enhancement by gadolinium-diethylenetriamine pentaacetic acid. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) revealed diffuse accumulation of 18F-FDG in the cauda equina. These imaging findings were consistent with those of cauda equina lymphomas. To confirm the diagnosis, we performed an open biopsy of the cauda equina. Histological examination indicated diffuse large B-cell lymphoma. Considering the patient’s age and activities of daily living, further treatment was not performed. The patient died four months after the first surgery. Rapid progression of muscle weakness, which cannot be prevented by decompression surgery, and swollen cauda equina on MRI may be signs of this disorder. Gadolinium-enhanced MRI, 18F-FDG PET, and histological investigation of the cauda equina should be performed for diagnosing primary malignant lymphoma of the cauda equina.

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