越坂 理也

BACKGROUND AND OBJECTIVES: Red yeast rice contains monacolin K, an inhibitor of cholesterol synthesis, and gamma-aminobutyric acid, a neurotransmitter. The daily dose of red yeast rice and monacolin K in previous studies was relatively high; therefore, there were safety concerns. We aimed to examine the effects of low daily dose red yeast rice on arteriosclerosis in patients with mild dyslipidemia. METHODS AND STUDY DESIGN: Eighteen patients without known cardiovascular disease and unsatisfactory low-density lipoprotein cholesterol (3.96±0.19 mmol/L) controlled only by diet therapy were randomly allocated to receive low dose red yeast rice (200 mg/day) containing 2 mg monacolin K or diet therapy alone for 8 weeks. The primary outcome was the absolute change in low-density lipoprotein cholesterol. Secondary outcomes included total cholesterol, apolipoprotein B, and blood pressure. RESULTS: Low-density lipoprotein cholesterol decreased significantly in the red yeast rice group than in the diet therapy group (median [interquartile range]: control -0.20 [-0.62, 1.19] mmol/L vs. red yeast rice -0.96 [-1.05, -0.34] mmol/L, p=0.030). The red yeast rice group also exhibited significant decreases in total cholesterol, apolipoprotein B, and blood pressure. No severe treatment-related adverse effects on muscles, liver, or renal function were observed. CONCLUSIONS: We found that patients in the red yeast rice group exhibited significant reductions in lowdensity lipoprotein cholesterol, total cholesterol, apolipoprotein B, and blood pressure without any recognised adverse effect. This suggests that low daily dose red yeast rice could reduce cardiovascular risk in patients with dyslipidemia.

Adult progeria, Werner syndrome (WS), is an autosomal recessive disorder that develops accelerated aging-associated symptoms after puberty. Refractory skin ulcer of limbs, which is one of the symptoms specific to WS, is seriously painful and sometimes results in amputation. In recent years, cell therapy using mesenchymal stem cells (MSCs) has been attracting attention; however, the effect of WS-derived MSCs on skin ulcers is still unclear. In this study, we generated iPS cells from a patient with WS and a normal subject, differentiated them into MSCs (WS- and NM-iMSC, respectively), and performed cell therapy to a refractory skin ulcer mouse model. As a result, WS-iMSC recapitulated premature senescence phenotypes in vitro. Upon subcutaneous injection around the wounds of mice, WS-iMSC was significantly inferior in wound healing effect compared to NM-iMSC. Proteome and transcriptome analysis revealed altered expression of genes related to angiogenesis, inflammation, and proliferation in WS-iMSC with remarkable downregulation of VEGF, a potent angiogenic factor. In addition, simultaneous administration of recombinant human VEGF and WS-iMSC improved the wound healing effect in vivo. These results indicate that the expression of angiogenic factors is reduced in WS-iMSC, and its supplementation restores the wound healing ability. This finding may pave the way to develop the treatment of intractable skin ulcers of WS.

INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors are widely used in the management of type 2 diabetes mellitus; they prevent cardiovascular events and reduce fat mass. However, little is known about the effects of SGLT2 inhibitors on type 1 diabetes mellitus as an adjuvant to insulin therapy. Therefore, we aimed to elucidate the effects of SGLT2 inhibitors on body composition of patients with type 1 diabetes mellitus and assess blood glucose variability. METHODS: A single-center, single-arm, prospective, interventional study was performed on Japanese patients with type 1 diabetes mellitus who were not administered SGLT2 inhibitors prior to this study. These patients were equipped with flash glucose monitoring (FGM) and administered ipragliflozin 50 mg daily. Body composition was evaluated using bioelectrical impedance analysis, and glycemic variabilities were assessed using FGM before and after SGLT2 inhibitor treatment. RESULTS: After 52 weeks of treatment, the total fat mass tended to be reduced (- 9.10% from baseline, P = 0.098). In addition, skeletal muscle mass also decreased (- 2.98% from baseline, P = 0.023). Although the basal insulin dose was reduced, SGLT2 inhibitors decreased HbA1c levels. FGM revealed that glycemic variabilities were also reduced, and time within the target glucose range increased (51.7% vs. 62.5%, P = 0.004). CONCLUSION: SGLT2 inhibitors have beneficial effects on glycemic variabilities and fat mass reductions in patients with type 1 diabetes mellitus. However, loss of skeletal muscle is a major concern; therefore, caution is required when using SGLT2 inhibitors in lean patients with type 1 diabetes mellitus. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN000042407).

Adult progeria Werner syndrome (WS), a rare autosomal recessive disorder, is characterized by accelerated aging symptoms after puberty. The causative gene, WRN, is a member of the RecQ DNA helicase family and is predominantly involved in DNA replication, repair, and telomere maintenance. Here, we report the generation of iPS cells from a patient with WS and correction of the WRN gene by the CRISPR/Cas9-mediated method. These iPSC lines would be a valuable resource for deciphering the pathogenesis of WS.

Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts in vitro. On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.

Skin ulcers in Werner's syndrome often arise from hyperkeratotic lesions and trauma to pressure points such as the plantar region, and are more difficult to treat than wound healing in healthy individuals. Multiple factors contribute to the intractable skin ulcers in Werner's syndrome, including skin thinning, sclerosis, fatty tissue loss, impaired blood flow, calcification, and excessive pressure due to osteoarticular deformity. Treatment includes topical application of a keratolytic agent for keratosis around the ulcer. Treatment of ulcers is the same as for normal ulcers, and if the ulcer is associated with infection and necrotic tissue, surgical debridement with a scalpel or scissors should be performed as much as possible after washing with saline or mildly warm water or with an antibacterial agent. Topical medications that promote softening and debridement of the necrotic tissue are used with careful control of moisture in the wound. Topical agents that promote granulation should be used in wounds where necrotic tissue has been removed without infection. Dressings to maintain a moist environment in the wound may also be useful. If the wound does not improve with conservative treatment, surgical treatment should be considered. Geriatr Gerontol Int 2021; 21: 160-162.

AIM: Sarcopenia is defined as a condition that combines decreased skeletal muscle mass with weakness or decreased physical function. It is well known that in older adults, the presence of sarcopenia is a risk of frailty, falls and physical dysfunction. Patients with Werner syndrome are characterized by visceral fat accumulation and thin limbs, but the prevalence of sarcopenia in patients with Werner syndrome has not been investigated. METHODS: A literature search was conducted using Werner syndrome and skeletal muscle as keywords. We also analyzed data from our 7 Werner syndrome patients. RESULTS: A literature search on the relationship between Werner syndrome and skeletal muscle yielded only one article reported from Japan. According to this paper, a decrease in skeletal muscle mass (appendicular skeletal muscle index) was observed in all 9 Werner syndromes investigated. On the other hand, in our 7 Werner syndrome patients, their appendicular skeletal muscle indexes were below the standard value except for one male patient who had continued resistance exercise. CONCLUSION: The decrease in skeletal muscle mass frequently occurs in patients with Werner syndrome. However, resistance exercise may prevent the appearance of sarcopenia and requires early intervention in patients with Werner syndrome. Geriatr Gerontol Int 2021; 21: 139-141.

AIMS: To evaluate the characteristics of diabetes associated with Werner syndrome. METHODS: A literature search was done with search term "Werner syndrome" and "Diabetes". RESULTS AND CONCLUSIONS: Prevalence of diabetes is extremely high in Werner syndrome. Diabetes associated with Werner syndrome is classified as "accompanied with other diseases and conditions and the one occurring mainly in association with other genetic syndromes." This type of diabetes is marked by accumulated visceral fat and high insulin resistance, despite low body mass index. Thiazolidine derivatives and metformin are effective for glycemic control. New antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, could be potentially beneficial for patients with Werner syndrome. Furthermore, the establishment of diet therapy as well as exercise therapy is warranted. Geriatr Gerontol Int 2021; 21: 142-145.

AIM: To provide guidelines on the diagnosis, treatment, and prevention of skin ulcers in Werner syndrome. METHODS: This article was based on literature from 1996, when WRN was identified as a gene responsible for Werner syndrome, and we evaluated several authentic clinical cases of genetically diagnosed patients. There were 63 patients with Werner syndrome in the Japanese reports retrieved from Medical Online between January 1996 and December 2017. There were 56 patients with Werner syndrome in English reports written by Japanese authors and retrieved from PubMed during the same period. RESULTS: Records on skin ulcers were found in 27 (43%) out of 63 patients and 22 (40%) out of 56 patients from the Japanese and English reports, respectively. The reported ulcers were often located at the distal one-third of the lower legs. There were 8 patients with callosities in the foot in the Japanese reports and 9 patients in the English reports. A skin ulcer in Werner syndrome is generally intractable. Weight-bearing ulcers or callosity should be critically assessed in surgical procedures because they have effects on patient pain and gait. By adopting a recently advanced technique to facilitate wound healing, the cases of ulcers that were difficult to treat and those requiring major operations can be closed with minimally invasive surgery. CONCLUSIONS: Skin ulcers in Werner syndrome are refractory, and they lead to reduced quality of life of patients. A callosity in Werner syndrome is an important therapeutic target for the prevention of ulcers. Geriatr Gerontol Int 2021; 21: 153-159.

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.

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 2021; 21: 163-165.

INTRODUCTION: In Japan, several sodium glucose co-transporter 2 (SGLT2) inhibitors have been used for type 1 diabetes mellitus as an adjuvant therapy to insulin therapy; however, there are no clinical reports regarding the satisfaction of its use. Therefore, we conducted a survey among patients with type 1 diabetes undergoing treatment using an SGLT2 inhibitor. METHODS: This is a single-arm open-label prospective study including 24 patients with type 1 diabetes who were to be initiated on ipragliflozin treatment between March and August 2019. All participants provided written informed consent. They completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ) for the survey and 3 months of observation after the administration of an SGLT2 inhibitor (50 mg of ipragliflozin), and changes from baseline diabetes treatment satisfaction were evaluated using modified DTSQ scores (five-step evaluation) and were analyzed. RESULTS: The average score for each question on DTSQ significantly increased [mean (standard deviation); 0.25 (0.25) vs 0.83 (0.77), P = 0.004]. Approximately 75% of the patients perceived an improvement in glycemic control over short periods of time. Finally, 54.2% of patients were highly satisfied and would recommend the SGLT2 inhibitor treatment [0.0 (0.0) vs. 0.92 (1.32), P < 0.001]. After the administration of ipragliflozin, reductions in body weight [24.0 (2.9) vs. 23.4 (2.9) kg/m2, P = 0.002], total insulin [39.1 (12.9) vs. 34.3 (12.5) units, P = 0.013], and glycated hemoglobin [7.77 (0.97) vs. 7.40 (0.86) %, P = 0.013] were observed, without any severe side effects. Improvements in glycemic variability indexes were observed through flash glucose monitoring. CONCLUSIONS: SGLT2 inhibitors may improve clinical treatment satisfaction by improving glycemic variability in patients with type 1 diabetes mellitus, while not inducing severe side effects with careful use. TRIAL REGISTRATION: This study is registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000040487).

Patients with Werner syndrome present with diverse signs of aging that begin in adolescence. A Japanese nationwide survey was conducted to establish a registry that could clarify the disease profile of patients with Werner syndrome. The questionnaires were sent to 7888 doctors. The survey identified 116 patients diagnosed with Werner syndrome based on the diagnosis criteria. Forty patients were enrolled in the registry. Data on clinical symptoms, treatment information, and laboratory examination from patients who provided informed consent were collected. The data at enrollment were analyzed. The patients' average age at enrollment was 50.1±7.5 years. The mean onset age was 26.1±9.5 years, but the mean age at diagnosis was 42.5±8.6 years. Average height and weight of the study patients were lower than those of Japanese individuals. Almost all patients experienced hair change and cataracts. More than 60% of patients presented with glycolipid abnormalities. Overall, 15% of patients had a history of foot amputation. Approximately 30% of the patients' parents had a consanguineous marriage. The average grip strength, walking speed, and skeletal muscle mass index met the diagnostic criteria for sarcopenia. The registry revealed that there are opportunities for early diagnosis and intervention; therefore, sensitization about the disease is needed.

BACKGROUND: We present here a 72-y-old Japanese woman with lipoprotein lipase (LPL) deficiency and analyzed her lipolytic enzymes in detail before and after pemafibrate treatment. METHODS: She had a serum triglycerides (TG) of 22.6 mmol/l at a medical checkup at the age of 52 y. She was referred to our hospital at the age of 61 y. Her serum lipoprotein lipase (LPL) concentration was extremely low, suggesting the clinical diagnosis of LPL deficiency. She experienced an event of acute pancreatitis at the age of 65 y. RESULTS: Next-generation sequencing analysis revealed a homozygous nonsense mutation in the LPL gene, c.1277G > A (p.Trp409Ter). Her serum TG, LPL and hepatic lipase (HL) concentrations were 15.0 mmol/l, 23 ng/ml and 66 ng/ml, respectively. Fifteen minutes after intravenous heparin injection (30 U/kg), her serum TG, LPL and HL concentrations turned to 14.1 mmol/l, 20 ng/ml and 660 ng/ml, respectively. Eight weeks of pemafibrate treatment (0.2 mg/day) caused a modest reductions in serum TG (15.02 → 13.58 mmol/l) and considerable increases in preheparin HL (66 → 76 ng/ml) and PHP-HL (660 → 1118 ng/ml) concentrations and PHP-HL activities (253 → 369U/l) despite almost no effect on LPL concentrations and activities. CONCLUSIONS: These findings suggest that HL may contribute to the reduction of plasma TG in LPL deficiency.

INTRODUCTION: To compare the effects of ipragliflozin, a sodium-glucose transporter 2 inhibitor, with those of metformin on visceral fat (as well as muscles and bones) in Japanese elderly patients with type 2 diabetes (T2D), we conducted a sub-analysis of a prospective, multicenter, blinded-endpoint randomized-controlled study. METHODS: In total, 103 patients with T2D (body mass index ≥ 22 kg/m2; glycated hemoglobin, 7-10%) and being treated with sitagliptin (a dipeptidyl peptidase-4 inhibitor) were included and randomized to receive ipragliflozin or metformin. The primary outcome was the change in visceral fat area measured using computed tomography 24 weeks following treatment. The secondary outcomes included changes in subcutaneous and total fat area, muscle volume, bone density measured using computed tomography, handgrip strength, bone markers, plasma glucose, insulin, homeostasis model assessment (HOMA)2-beta, HOMA2-R, glycated hemoglobin, lipid panel, uric acid, blood pressure, adiponectin, and high-sensitivity C-reactive protein. All patients aged 65-74 years were selected for sub-analysis. RESULTS: The sub-analysis included 15 and 14 patients in the ipragliflozin and metformin groups, respectively. The patients' backgrounds were well balanced. Visceral fat area reduction was greater in the ipragliflozin group than in the metformin group (- 10.58% vs. - 6.93%; P = 0.034). There were significant differences in the changes in bone absorption markers, uric acid, and total cholesterol levels between the groups. CONCLUSION: Ipragliflozin significantly reduced the visceral fat area compared with metformin when added to sitagliptin in elderly patients with T2D. Long-term and large-scale studies are required to elucidate whether ipragliflozin is suitable for elderly patients. TRIAL REGISTRATION: The study was registered at https://www.umin.ac.jp/ctr/ (UMIN-ID: UMIN 000015170).

Werner syndrome (WS), a type of progeria, is a hereditary condition caused by a mutation in the WRN gene. A 62-year-old Japanese woman was diagnosed with WS at the age of 32 and has been visiting the hospital for follow-up since the last 30 years. The patient developed diabetes at the age of 46, and at the age of 60, her body mass index increased from 20.1 to 22.7 kg/m2 owing to her unhealthy eating habits; her visceral fat area at the age of 61 was 233 cm2. With dietary control, her body weight, including the visceral fat and subcutaneous fat, decreased at the age of 62, and her insulin secretion, obesity, and fatty liver improved. We conducted the oral glucose challenge test four times, including at the prediabetic stage, to evaluate the insulin-secretion ability. The patient's insulin resistance gradually increased for more than 14 years, and her insulin secretion ability began to decrease 14 years after her diabetes diagnosis. Despite a remarkable decrease in body weight and fat mass with dietary management, the psoas muscle index did not decrease significantly in proportion to the body weight or fat mass. However, muscle mass monitoring is important for preventing the progression of sarcopenia. Hence, gradual reduction of visceral fat and weight by dietary management may be useful in treating diabetes in patients with WS, particularly in those whose visceral fat is significantly increased.

INTRODUCTION: Recent randomized clinical trials have suggested that sodium-glucose co-transporter-2 (SGLT2) inhibitors may reduce cardiovascular events and heart failure and have renal protective effects. Despite these remarkable benefits, the effects of SGLT2 inhibitors on bone and muscle are unclear. METHODS: A sub-analysis of a randomized controlled study was performed to evaluate the effects of the SGLT2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline BMI ≥ 22 kg/m2 and HbA1c 7-10 %) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1000-1500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase (BAP); the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. RESULTS: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength, and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared to patients treated with metformin (median 11.94 % vs. -10.30 %, P < 0.0001), indicating that ipragliflozin can promote bone resorption. CONCLUSIONS: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is needed to further understand the effects of this TRACP-5b increase caused by ipragliflozin. CLINICAL TRIAL REGISTRATION: http://www.umin.ac.jp/ctr/ (UMIN-ID: UMIN 000015170).

【症例】18歳女性。30週558kgと極低出生体重児として出生、成長ホルモン及び甲状腺ホルモン分泌低下のため、成長ホルモンとレボチロキシンが投与されていた。【現病歴】以前から空腹時採血にて400mg/dL台の高中性脂肪血症が指摘され、ベザフィブラート100mgが投与されていた。3週間前に急性膵炎を発症し、入院し、絶飲食、抗生剤、ガベキサートメシル酸塩投与により膵炎の改善を認め、静注用脂肪乳剤が投与された。中性脂肪が137mg/dLから998mg/dLへと上昇を認め、静注用脂肪乳剤中止され当科紹介となった。【入院後経過】絶食下、リポ蛋白リパーゼ126ng/mLと低下を認めた。フィブラート製剤をフェノフィブラート80mgに変更し、NSTによる介入、脂質制限(総エネルギーの15%以下/日)を行い、イコサペント酸エチルも開始した。薬物療法および通常の脂質制限のみでは効果が不十分であり、0.8%エネルギー比の厳密な脂質制限に加えて中鎖脂肪酸を使用し、最大998mg/dLであった中性脂肪が2ヵ月後には278mg/dLにまで改善し、HDLコレステロール、LDLコレステロールの改善も認めた。【結論】薬物療法、脂質制限で効果不十分な高中性脂肪血症の症例の治療において中鎖脂肪酸とオメガ3脂肪酸を用いた包括的治療と臨床的治療判断におけるNSTによる介入が有用であった。(著者抄録)

Purpose: Diabetic macular edema (DME) is a vision-threatening condition that develops in diabetic patients. The first-line therapy for DME is intravitreal injections of antivascular endothelial growth factor (anti-VEGF) agents; however, the high frequency of repeat injections, invasiveness of the procedure, and high cost are drawbacks for this treatment. The purpose of this report is to present our findings in 3 patients with chronic DME whose edema was resolved soon after oral doses of sodium-glucose cotransporter-2 (SGLT2) inhibitors were used. Case Presentation. Case 1 was a 66-year-old woman diagnosed with moderate nonproliferative diabetic retinopathy (DR) with DME that had developed a decade earlier. The DME persisted for 4 years in the left eye. The addition of oral empagliflozin, a SGLT2 inhibitor, led to a marked improvement of the DME after one month, and this improvement continued over two years. Case 2 was a 68-year-old woman who was diagnosed with preproliferative DR with bilateral DME. The addition of oral dapagliflozin led to the improvement of the DME after two months, and this improvement continued over one year. Case 3 was a 61-year-old woman who was diagnosed with moderate nonproliferative DR with DME. Oral luseogliflozin was given which led to better glycemic control, and her left central retinal thickness (CRT) was markedly reduced after only two weeks. This reduction was maintained in her left eye for six months without any additional ophthalmic procedures. Conclusions: Although this study involved only three cases, our findings indicate that SGLT2 inhibitors might have possible efficacy for chronic DME.

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 <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period. RESULTS: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events. CONCLUSION: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123.

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.

Background: There is a lack of evidence that multidrug use triggers adverse events. Therefore, the main purpose of this study was to clarify the relationship between the total number of drugs and number of high-risk prescriptions administered to Japanese elderly patients. Methods: Using hospital electronic medical records (EMR), we evaluated the prescriptions of outpatients aged 65 years or older. We defined prescriptions of potentially inappropriate medications (PIMs) and overlapping prescription of drugs with the same mechanism of action (DSAs) as high-risk prescriptions. We analyzed the relationship among total number of drugs and high-risk prescriptions. In addition, we performed a secondary research to determine whether the hospitalization rate and concomitant medication contents differ depending on the high-risk prescriptions. Results: Data for 13,630 outpatients were analyzed. A significant positive correlation between the numbers of total drugs and PIMs was found. The prescription frequency of individual PIMs rose as the total number of prescription drugs increased. The odds ratio (OR) of overlapping DSAs was significantly higher in patients using 5 or more drugs. In addition, there were significantly more prescriptions of laxatives among patients with overlapping prescriptions of anticholinergic drugs. The use of almost all PIMs was not an independent risk factor for hospitalization; instead, the number of PIMs was an independent risk factor for hospitalization [OR 1.18 (95% CI, 1.12-1.26)]. Conclusions: The number of PIMs and overlapping DSAs were high in patients receiving multidrug treatment. To avoid adverse events and hospitalization, it might be useful to review prescriptions and consider the number of PIMs and overlapping DSAs.

Podocalyxin is a cell surface sialomucin, which is expressed in not only glomerular podocytes but also vascular endothelial cells. Urinary podocalyxin is used as a marker for glomerular disease. However, there are no reports describing serum podocalyxin (s-Podxl) levels. Therefore, the association between s-Podxl levels and clinical parameters were examined with 52 patients. s-Podxl level was evaluated using enzyme-linked immunosorbent assay. The median s-Podxl level was 14.2 ng/dL (interquartile range: 10.8-22.2 ng/dL). There were significant correlations (correlation coefficient: r &gt 0.2) of s-Podxl levels with carotid intima media thickness (IMT) (r = 0.30, p = 0.0307). Multiple logistic regression analysis showed that s-Podxl levels remained significantly associated with carotid IMT &gt 1 mm (OR: 1.15 95% CI 1.02-1.31, p = 0.026) after adjustments for traditional cardiovascular risk factors such as age, sex, current smoking status, hypertension, dyslipidemias, and diabetes. In conclusion, s-Podxl is independently associated with carotid IMT and might be used as a novel biomarker for cardiovascular disease.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by systemic accelerated aging. It is caused by pathogenic variants of the WRN gene that encodes a nuclear helicase. In this report, we describe 4 newly identified WS cases among those referred to the Japanese Werner Consortium, Chiba University, Japan. All 4 cases were compound heterozygotes of the Japanese founder mutation, c.3139-1G>C, and a novel null pathogenic variant, c.1587G>A, c.2448+1G>A, or c.3233+1G>T, or an amino acid substitution variant, c.1720G>A, p.Gly574Arg. These 3 null pathogenic variants were not previously described. The p. Gly574Arg was previously reported in a European patient, and the identification of the second p. Gly574Arg case, with classical WS features, further confirmed the pathogenic nature of this variant. For the case with c.3233+1G>T, we determined the phase of 2 disease-causing mutations and demonstrated that they are on different chromosomes. This assay would be particularly important for those cases with ambiguous clinical diagnosis.

Background: Patients with type 2 diabetes are at high risk for cardiovascular disease. Although hydroxymethylglutaryl-CoA reductase inhibitors (statins) can reduce cardiovascular events, residual risk remains even after target low-density lipoprotein cholesterol (LDL-C) levels have been achieved. Lipoprotein particle size and fraction changes are thought to contribute to such risks. The purpose of this study was to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid and docosahexaenoic acid, on lipoprotein particle size, concentration, and glycemic control in Japanese patients with type 2 diabetes and hypertriglyceridemia. Methods: This was a multicenter, prospective, open-label, single arm study. We enrolled 14 patients with type 2 diabetes and hypertriglyceridemia treated with statins and dipeptidyl peptidase-4 inhibitors with glycated hemoglobin (HbA1c) &lt 8.0%, LDL-C &lt 120 mg/dL, and fasting triglyceride ≥150 mg/dL. After a 12-week observation period, they were treated with 4 g/day n-3 PUFAs for 12 weeks. Lipoprotein particle sizes, concentrations, lipoprotein insulin resistance (LPIR) scores, lipid profiles, HbA1c, and fasting plasma glucose (FPG) were measured before and after treatment. Lipoprotein profiles were measured by nuclear magnetic resonance spectroscopy. Data were analyzed using Wilcoxon signed-rank tests. Results: Concentrations of total cholesterol (P &lt 0.001), LDL-C (P = 0.003), and triglyceride (P &lt 0.001) decreased following n-3 PUFA administration. N-3 PUFAs decreased the size of very low-density lipoprotein (VLDL P &lt 0.001) particles, but did not affect LDL or high-density lipoprotein (HDL) particles. The concentration of large LDL increased, whereas small LDL decreased, causing the large to small LDL ratio to increase significantly (P = 0.042). Large VLDL and chylomicron concentrations significantly decreased, as did the large to small VLDL ratio (all P &lt 0.001). FPG levels unchanged, whereas HbA1c levels slightly increased. LPIR scores improved significantly (P = 0.001). Conclusions: N-3 PUFAs partly improved atherogenic lipoprotein particle size and concentration, and produced less atherogenic lipoprotein subclass ratios in patients that achieved target LDL-C levels and glycemic control. These results suggest that n-3 PUFAs may reduce residual cardiovascular risk factors in statin-treated patients with type 2 diabetes and hypertriglyceridemia.