Search

For the purpose of examining the characteristics of dyslipidemia and fatty liver in patients with Werner syndrome in Japan in recent years, we searched all case reports of Japanese Werner syndrome reported on Medical Online and PubMed since 1996, and collected and examined the data and clinical features described in these reports. In addition, as there are few descriptions of treatment methods in these reports from Medical Online and PubMed, we analyzed 12 cases for which detailed data on treatment methods are available at Chiba University. Geriatr Gerontol Int 2021; 21: 133-138.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay‐linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti‐human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low‐density lipoprotein receptor–related protein–associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S‐transferase–fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis‐related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well‐known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking., Some cancers and arteriosclerosis may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma for SEREX. Serum LRPAP1 antibody is a useful marker for the early diagnosis of some cancers and atherosclerotic diseases.

Aim To clarify the diagnostic value of the calcification in the Achilles tendon for Werner syndrome. Methods Calcification of the Achilles tendon in the plain radiograph was investigated in 92 patients with Werner syndrome provided from the nationwide secondary survey in 2010. And the same investigation was performed for 2151 feet in 1853 patients without Werner syndrome, who underwent foot and ankle surgeries at the department of orthopaedic surgery in Nara Medical University from 2004 to 2015. Result and conclusion Achilles tendon calcification was observed in 70 (76.1%) out of 92 patients with Werner syndrome, whereas that was observed only in 19 feet (0.88%) without Werner syndrome, accompanied by 1 to 4 calcified masses with a maximum diameter ranging from 9.7mm to 63.2mm. The frequency of Achilles tendon calcification in patients with Werner syndrome is far higher than that of patients without Werner syndrome. Achilles tendon calcification could be included in the diagnostic criteria for Werner syndrome. Geriatr Gerontol Int 2020; ••: ••-••.

AIM An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome. METHODS A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and

A prospective, multicentre, open‐label, blinded‐endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium‐dependent glucose transporter‐2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%‐10%, and body mass index (BMI) ≥ 22 kg/m2. Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000‐1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (−12.06% vs. −3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)‐resistance, and increased HDL‐cholesterol levels. Metformin significantly reduced HbA1c and LDL‐cholesterol levels and increased HOMA‐beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase‐4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Lipodystrophy is a rare condition that is often accompanied by one or more metabolic diseases. Here, we report a case of lipoatrophic diabetes induced by juvenile dermatomyositis. Although pioglitazone was not effective for lowering blood glucose levels, our observation suggested that it improved liver function slightly. The effectiveness of metreleptin for lowering blood glucose levels could not be determined, as we administered it in a short period. Liver biopsy showed burned‐out non‐alcoholic steatohepatitis. The present results show that the successful treatment of lipoatrophic diabetes induced by juvenile dermatomyositis requires an early diagnosis and therapeutic intervention.

Aims/Introduction The incidence of type 2 diabetes is higher in elderly patients, in whom this disease is associated with dementia, falling, stroke and death. We utilized a continuous glucose monitoring device to analyze the relationship between hypoglycemia and diabetes treatments to identify risk factors for hypoglycemia (defined as a blood glucose level

Objectives To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. Design Retrospective cohort. Setting Longitudinal survey of WS and literature search for case reports. Participants Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). Measurements A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines. Since 2009, Chiba University Hospital consecutively evaluated the WRN gene in 67 individuals throughout Japan who had requested genetic testing. A literature search was also conducted for case reports on Japanese WS reported since 1997. Results A definitive diagnosis of WS was confirmed genetically in 50 of 67 participants. Through the literature search, 16 individuals diagnosed genetically with WS were identified. Of these 66 individuals with WS, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes. One novel mutant allele was identified in an individual with the compound heterozygous genotype. The proportion of compound heterozygotes (31.8%) was significantly greater than reported previously (14.2%), indicating that the incidence of consanguineous marriage of parents has decreased. Conclusion The increased frequency of individuals with WS with the compound heterozygous genotype is a recent trend in Japan. A long-term follow-up study on WRN homozygotes and compound heterozygotes will allow the relationship between WRN genotype and clinical severity of WS to be evaluated in the future.

Aim Laparoscopic sleeve gastrectomy (LSG) has proven to be the most effective strategy for the treatment of morbid obesity, however its efficacy and safety in an aging population has not yet been confirmed. In this study, we evaluated the effectiveness and safety of LSG in elderly obese Japanese patients. Methods Three obese individuals aged >60 years and 11 obese individuals aged 60 years had reduced bone mineral density in the femoral neck after LSG; one was diagnosed with osteoporosis. Conclusions Although the present results suggest that LSG could be of considerable benefit to elderly obese Japanese patients, long-term careful observation after bariatric surgery is especially important in elderly patients to prevent future osteoporosis. Geriatr Gerontol Int 2017; 17: 2068–2073.

Aims/Introduction To assess the efficacy and safety of sitagliptin compared with α-glucosidase inhibitors in Japanese patients with type 2 diabetes inadequately controlled by metformin or pioglitazone alone. Materials and Methods In the present multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority trial, 119 patients aged 20–79 years with type 2 diabetes who had glycated hemoglobin 6.9–8.8% on stable metformin (500–1,500 mg/day) or pioglitazone (15–30 mg/day) alone were randomly assigned (1:1) to receive the addition of sitagliptin (50 mg/day) or an α-glucosidase inhibitor (0.6 mg/day voglibose or 150 mg/day miglitol) for 24 weeks. The primary end-point was change in glycated hemoglobin from baseline to week 12. All data were analyzed according to the intention-to-treat principle. Results After 12 weeks, reductions in adjusted mean glycated hemoglobin from baseline were −0.70% in sitagliptin and −0.21% in the α-glucosidase inhibitor groups respectively; between-group difference was −0.49% (95% confidence interval −0.66 to −0.32, P

Aim The risk factors for ischemic heart disease (IHD) or cerebrovascular accident (CVA) in elderly diabetic individuals with type IIb dyslipidemia are not fully known. Therefore, we investigated the relationship between lipid levels and IHD and CVA in diabetic individuals with type IIb dyslipidemia. Method The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4014 type 2 diabetic patients (1936 women; age 67.4 ± 9.5 years). The primary end-points were the onset of IHD or CVA. Lipid and glucose levels, and other factors were investigated in relation to the occurrence of IHD or CVA. A total of 462 participants were included in the group of patients with type IIb dyslipidemia. Results The 462 diabetic participants with type IIb dyslipidemia were divided into those who were aged 75 years (n = 168, 190 and 104, respectively). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol/HDL-C were significantly associated with the risk of cardiovascular events in diabetic individuals with type IIb dyslipidemia who were aged

Aim: Werner syndrome (WS) is an autosomal recessive disorder of progeroid symptoms and signs. It is caused by mutations in the WRN gene, which encodes a RecQ DNA helicase. The aim of this study was to revise the diagnostic criteria for Japanese Werner syndrome. Methods: A nationwide epidemiological study was carried out from 2009 to 2011, involving 6921 surveys sent to hospitals with more than 200 beds to assess existing WS diagnostic criteria, as well as additional signs of high incidence on the basis of clinical experience with WS. Results: The existing diagnostic criteria were reviewed, and signs with >90% incidence were listed as cardinal signs. Several criteria were added, including genetic testing and calcification of the Achilles tendon, whereas criteria that are practically difficult to obtain, such as measurement of urinary hyaluronic acid, were omitted. Conclusion: The 26-year-old diagnostic criteria for WS were revised on the basis of the results of a nationwide epidemiological study. The proposed revised criteria will facilitate simpler, faster and more robust diagnosis of WS in the Japanese population. Geriatr Gerontol Int 2013; 13: 475–481.

Werner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in the WRN DNA helicase. It is characterized by the graying and loss of hair, juvenile cataracts, sclerosis and ulceration of skin, insulin-resistant diabetes mellitus, dyslipidemia, abdominal adiposity, osteoporosis, atherosclerosis, and malignant neoplasm. Patients are usually diagnosed in their 30s or 40s, but the early pathophysiology of the syndrome is still not fully understood. Here we report a 29-year-old female patient who displayed cataracts, hair graying, and tendinous calcinosis. Her parents were first cousins. Interestingly, the patient lacked the metabolic signs typical for WS, including glucose intolerance, dyslipidemia, and visceral fat accumulation. A hyperinsulinemic response at 30 min was observed in an oral glucose tolerance test. Mutational analysis for the WRN gene revealed a homozygous nucleotide substitution 3190C>T in exon 24, resulting in a protein product with replacement of an arginine residue at position 573 by termination codon (Arg987Ter). The mutated WRN protein was unable to translocate into the nucleus in an in vitro cell assay. A WS patient with an Arg987Ter mutation has been previously reported in Switzerland, the present case is the first to be identified in Asia. This case demonstrates the early clinical features of WS and suggests that metabolic abnormality, including insulin resistance, is not an essential component of WS at disease onset. Moreover, a follow-up study of such case would be useful to understand how the various clinical symptoms in WS develop and progress over the years.

A 57-year-old woman was admitted to our hospital with characteristic aging of the face and thin body. Before admission, she had been treated for diabetes mellitus type 2 and had undergone amputation of the right leg due to ischemic disease. Abdominal computed tomography revealed primary liver tumor. Biopsy of the liver mass revealed poorly differentiated adenocarcinoma, not hepatocellular carcinoma. Genetic sequencing indicated a homozygous mutation in the Werner syndrome gene (WRN) and she was diagnosed with Werner syndrome with primary liver tumor. She declined medications for the liver tumor and eventually died 6 months after diagnosis. Werner syndrome is a rare autosomal recessive disorder associated with premature aging, and most cases of Werner syndrome have been reported from Japan. The main causes of death with Werner syndrome are malignancy and atherosclerotic vascular disease. With respect to malignancy, non-epithelial tumors are more common in Werner syndrome patients than in the general population. Some cases also show complications of epithelial tumors, as in the present case. When a liver tumor of unknown etiology is accompanied by characteristic aging of the face, Werner syndrome should be suspected and a comprehensive search for other tumors and complications of metabolic disorders undertaken.

A 52-year-old man with Werner Syndrome (WS) was admitted to our hospital for the treatment of skin ulcers on his thighs. Routine chest radiography revealed an abnormal shadow in the left upper lung field. Computed tomography (CT) revealed a poorly demarcated homogeneous mass (diameter, 4 cm) in the S1 + 2 lung area; no pleural effusion was observed. CT-guided percutaneous needle biopsy revealed the presence of an adenocarcinoma. Other imaging studies did not reveal any lymph-node involvement or presence of metastatic lesions. The patient was diagnosed with stage IB adenocarcinoma (T2N0M0), and a left upper lobectomy was successfully carried out; postoperative wound healing was steady and uneventful, with no obvious ulcer formation. Primary lung cancers very rarely develop in patients with WS; non-epithelial tumors are usually observed in such patients. Patients with WS usually develop severe skin problems, such as refractory skin ulcers in the extremities; however, our patient did not develop any skin-related complications after surgery. As the expected lifespan of patients with WS is increasing, we need to pay attention not only to the rare non-epithelial malignancy, but also cancer. Further, the expected short lifespan of patients with WS, as well as the possibility of skin-related problems after surgery, should not be considered while deciding whether to take the option of surgery in the case of malignancy. Geriatr Gerontol Int 2010; 10: 319–323.

To advance our understanding of development, function and diseases in the kidney glomerulus, we have established and large-scale sequenced cDNA libraries from mouse glomeruli at different stages of development, resulting in a catalogue of 6053 different genes. The glomerular cDNA clones were arrayed and hybridized against a series of labeled targets from isolated glomeruli, non-glomerular kidney tissue, FACS-sorted podocytes and brain capillaries, which identified over 300 glomerular cell-enriched transcripts, some of which were further sublocalized to podocytes, mesangial cells and juxtaglomerular cells by in situ hybridization. For the earliest podocyte marker identified, Foxc2, knockout mice were used to analyze the role of this protein during glomerular development. We show that Foxc2 controls the expression of a distinct set of podocyte genes involved in podocyte differentiation and glomerular basement membrane maturation. The primary podocyte defects also cause abnormal differentiation and organization of the glomerular vascular cells. We surmise that studies on the other novel glomerulus-enriched transcripts identified in this study will provide new insight into glomerular development and pathomechanisms of disease.

Forsterite (Mg2SiO4) ceramics were prepared using Mg(OH)2 and SiO2 as precursors, and the effect of powder characteristics of Mg(OH)2 on calcination and sintering was investigated. The use of highly dispersed Mg(OH)2 powder (HD powder) resulted in a lower calcination temperature. Forsterite powder of high homogeneity and small particle size prepared from the HD powder enabled synthesis of high-density forsterite ceramics by ordinary sintering without applying external pressure. Moreover, transparent forsterite ceramics were successfully synthesized through addition of excess Mg to the precursors to compensate for Mg evaporated during the sintering process. Subsequent dielectric measurements revealed that the transparent forsterite ceramics had a very low dielectric loss (tan δ

BACKGROUND C-peptide has been shown to ameliorate diabetes-induced functional and structural renal changes in animal models as well as in patients with type 1 diabetes. This study aims to examine the molecular effects of C-peptide on early glomerular changes in a mouse model of type 1 diabetes. METHODS Fourteen days after induction of diabetes by streptozotocin (STZ), the animals received rat C-peptide for either 24 h or 7 days. Urinary albumin excretion was measured by ELISA. Glomerular mRNA expression of the transforming growth factor (TGF)-beta(1) and type IV collagen was quantified by real-time PCR. The effect of C-peptide on type IV collagen gene expression in cultured murine podocytes was also examined. RESULTS C-peptide decreased urinary albumin excretion from 0.29 to 0.18 microg/min (-40.7%, P < 0.01). The transcript level of (alpha3)IV collagen in glomeruli was up-regulated 2.2-fold in diabetic mice and was inhibited by 45-70% (P < 0.05) upon C-peptide treatment. C-peptide suppressed glomerular expression of TGF-beta(1) by 36.6% after 7 days (P < 0.05) but not 24 h after injection. In vitro studies using cultured podocytes revealed that C-peptide dose-dependently inhibited TGF-beta-induced up-regulation of type IV collagen. Moreover, both pertussis toxin (PTX) and a specific inhibitor for extracellular signal-regulated kinase (ERK) pathway reversed the inhibitory effect of C-peptide on TGF-beta. Finally, C-peptide was shown to up-regulate the activity of ERK in podocytes. CONCLUSIONS These findings indicate that C-peptide suppresses specific aspects of early glomerular changes in a mouse model of diabetes and that the effect is at least in part mediated via interaction with the TGF-beta signal in glomerular podocytes.

1. It has been suggested that osteopontin promotes the development of atherosclerosis, especially under diabetic conditions. 2. In the present study, we found that NK-104, a new potent synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, reduced osteopontin expression both at protein and mRNA levels in cultured rat aortic smooth muscle cells. 3. The inhibitory effect of NK-104 was almost completely reversed by mevalonate, suggesting that mevalonate or its metabolites play important roles in the regulation of osteopontin expression. 4. Furthermore, oral administration of NK-104 (3 mg kg(-1) day(-1) for 7 days) effectively suppressed abnormally upregulated expression of osteopontin mRNA in the aorta and kidney of streptozotocin-induced diabetic rats. 5. These data support a notion that NK-104 is a suitable drug for the treatment of diabetic patients with hypercholesterolaemia.