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Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease. CD68-positive bone marrow (BM)-derived cells (BMDCs) accumulate in the pathological lesion in the SOD1(G93A) ALS mouse model after BM transplantation (BMT). Therefore, we investigated whether BMDCs can be applied as gene carriers for cell-based gene therapy by employing the accumulation of BMDCs. In ALS mice, YFP reporter signals were observed in 12–14% of white blood cells (WBCs) and in the spinal cord via transplantation of BM after lentiviral vector (LV) infection. After confirmation of gene transduction by LV with the CD68 promoter in 4–7% of WBCs and in the spinal cord of ALS mice, BM cells were infected with LVs expressing glutamate transporter (GLT) 1 that protects neurons from glutamate toxicity, driven by the CD68 promoter, which were transplanted into ALS mice. The treated mice showed improvement of motor behaviors and prolonged survival. Additionally, interleukin (IL)-1β was significantly suppressed, and IL-4, arginase 1, and FIZZ were significantly increased in the mice. These results suggested that GLT1 expression by BMDCs improved the spinal cord environment. Therefore, our gene therapy strategy may be applied to treat neurodegenerative diseases such as ALS in which BMDCs accumulate in the pathological lesion by BMT.

Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy., Katagi et al. show that abnormal bone marrow-derived cells originated from hematopoietic stem cells (CD106-positive short-term HSCs) aberrantly fuse with neurons to develop diabetic neuropathy. This study suggests that the pathological abnormality is memorized in the bone marrow and that it cannot be erased by conventional therapy.

Summary Several treatments have been attempted in amyotrophic lateral sclerosis (ALS) animal models and patients. Recently, transplantation of bone marrow-derived mononuclear cells (MNCs) was investigated as a regenerative therapy for ALS, but satisfactory treatments remain to be established. To develop an effective treatment, we focused on mesenchymal stem cells (MSCs) expressing hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor using human artificial chromosome vector (HAC-MSCs). Here, we demonstrated the transplantation of MNCs with HAC-MSCs in ALS mice. As per our results, the progression of motor dysfunction was significantly delayed, and their survival was prolonged dramatically. Additional analysis revealed preservation of motor neurons, suppression of gliosis, engraftment of numerous MNCs, and elevated chemotaxis-related cytokines in the spinal cord of treated mice. Therefore, growth factor-expressing MSCs enhance the therapeutic effects of bone marrow-derived MNCs for ALS and have a high potential as a novel cell therapy for patients with ALS., Graphical Abstract, Highlights • MNCs with growth factor-expressing MSCs is an effective cell therapy for ALS mice • The MSCs enhance therapeutic effects by migration of MNCs into ALS mice spinal cord • This cell therapy suppresses neuronal loss and gliosis in ALS mice spinal cord • This cell therapy induces several cytokines expression in ALS mice spinal cord, Molecular Neuroscience; Cellular Neuroscience; Stem Cells Research

Objective: SGLT2 inhibitors reduce body weight (BW) due to negative energy balance. Although previous reports suggested that SGLT2 inhibitor improved liver dysfunction and steatosis, the efficacy of SGLT2 inhibitor on intrahepatic triglyceride (IHTG) were merely quantified. Methods: The study was an open label randomized controlled trial. Fifty-two overweight patients (BMI > 23) who had inadequate glycemic control with oral antidiabetic agents were randomly assigned to dapagliflozin (Dapa) or standard treatment (Con) and followed for 24 weeks. The Primary endpoint was the change in BW from baseline to week 24 between the two groups. The secondary endpoint was IHTG which was assessed by magnetic resonance spectroscopy (MRS). Results: The change in BW was significantly larger in Dapa group compared to Con. The mean difference in changes between two groups was -1.72 kg (95% CI: -2.85, -0.59, p = 0.004) which was comparable with the previous studies of Caucasians. IHTG measured with MRS was significantly reduced in Dapa group (p = 0.033). Conclusion: Dapagliflozin treatment for 24 weeks resulted in reduction of BW and IHTG. These findings suggest the therapeutic potential of dapagliflozin for patients with NAFLD. Clinical study registration number: UMIN000020239. Disclosure K. Morino: Research Support; Self; Astellas Pharma Inc., AstraZeneca, CMIC Pharma Science, Miki Corp., Ono Pharmaceutical Co., Ltd., Sunstar Inc. K. Kondo: None. S. Tanaka: None. I. Miyazawa: None. K. Fuse: None. S. Ida: None. H. Arima: Consultant; Self; Kyowa Hakko Kirin Co., Ltd. Speaker's Bureau; Self; Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. K. Miura: None. N. Ohashi: None. S. Ugi: None. H. Maegawa: Research Support; Self; Antares Pharma, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Funding AstraZeneca; Ono Pharmaceutical Co., Ltd.

Objective: Weight gain is a common problem in the insulin treatment. SGLT2 inhibitors are expected to reduce body weight (BW) due to negative energy balance. Previous reports suggested that BW reduction is achieved mainly by loss of body fat, and ∼20% of reduction is by lean mass. However, the efficacy of SGLT2 inhibitor on BW and body composition remains unclear. We examined these in the Japanese T2DM treated with insulin. Methods: The study was an open label randomized controlled trial. Primary endpoint was the change in BW from baseline to week 24 between the two groups. Fifty overweight patients (BMI > 23) who had inadequate glycemic control with insulin treatment were randomly assigned to ipragliflozin (Ipra) or standard treatment (Con) and followed for 24 weeks. Body composition was assessed by DEXA and impedance method. Results: The change in BW was significantly larger in Ipra compared to Con. Ipra showed significant larger reduction of HbA1c. Total fat mass was reduced in the Ipra compared to Con mainly due to lower limb fat and trunk fat. Total muscle mass was maintained at lower limbs and trunk but tended to be reduced at arm in Ipra. Conclusion: Ipragliflozin treatment for 24 weeks resulted in reduction of BW mainly due to fat mass at lower limb and trunk. Reduction of the muscle mass at lower limb may be protected by anti-gravity effect. Disclosure K. Morino: Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Sunstar Inc., CMIC Pharmascience, Kowa Pharmaceutical. H. Inoue: None. K. Fuse: None. S. Tanaka: None. K. Kondo: None. H. Arima: Advisory Panel; Self; Kyowa Kirin. Speaker's Bureau; Self; Takeda Japan, Daiichi Sankyo Company, Limited. K. Miura: None. D. Sato: None. N. Ohashi: None. S. Ida: None. I. Miyazawa: None. O. Sekine: None. S. Ugi: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K. H. Maegawa: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company. Speaker's Bureau; Self; Takeda Pharmaceutical Company, Novo Nordisk A/S, Eli Lilly and Company.

Background: Mitochondria play an essential role in the heat generation in beige adipocytes. Their number and function are regulated in response to external stimuli such as cold exposure and beta-3 adrenergic receptor (β3-AR) agonist. Previously, we have reported that miR-494 regulates mitochondrial biogenesis in the skeletal muscle. However, this remains unknown in beige adipocytes. Aim: We investigated the role of miR-494 on mitochondrial biogenesis during adipogenesis and browning. Result: C57BL/6J mice were subjected to intermittent mild cold exposure. The expression levels of peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC1-α) and mitochondrial proteins including mitochondrial transcription factor A (TFAM), pyruvate dehydrogenase (PDH), mitochondrially encoded cytochrome c oxidase (MTCO1) and uncoupling protein 1 (Ucp1) were strongly increased in inguinal white adipose tissue (iWAT). On the contrary, that of miR-494 resulted in 27% reduction (p < 0.05) in iWAT following 12°C cold exposure for 6 hours. Furthermore, β3-AR stimulation potently reduced miR-494 expression in 3T3-L1 beige cells. Overexpression of miR-494 substantially reduced the protein expression of PGC1-α and its downstream targets such asTFAM and MTCO1 (p < 0.05). In contrast, antisense of miR-494 significantly increased the expression of TFAM, MTCO1 and PDH (p < 0.05). Overexpression of miR-494 strongly decreased the oxygen consumption rate in 3T3-L1 beige cells and protein expression of PGC1-α and Ucp1 (p < 0.05) in primary beige adipocytes. Finally, we explored the direct target of miR-494 and found that 3`UTR region of PGC1-α is a direct target of miR-494 by luciferase assay. Conclusion: These findings demonstrate that miR-494 directly inhibits the expression of PGC1-α in adipose tissue. The decreased miR-494 expression during adipocyte differentiation removes its inhibitory effect, leading to stimulation of Ucp1 expression and mitochondrial biogenesis. Disclosure M. Lemecha: None. K. Morino: Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Sunstar Inc., CMIC Pharmascience, Kowa Pharmaceutical. T. Imamura: None. H. Iwasaki: None. N. Ohashi: None. H. Yamamoto: None. S. Ugi: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K. H. Maegawa: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company. Speaker's Bureau; Self; Takeda Pharmaceutical Company, Novo Nordisk A/S, Eli Lilly and Company.

Dumping syndrome, or rapid gastric emptying, is a frequent complication after gastric surgery. In this case, the patient was a 47-year-old woman who 10 years previously had undergone distal gastrectomy with Billroth I reconstruction for early-stage gastric cancer. She presented with symptoms of weakness, headache, palpitation, sweating, dizziness and significant fatigue between one and two hours after a meal. Because a 75 g oral glucose tolerance test (75 g-OGTT) induced both acute postprandial tachycardia (within 1 hour) and postprandial hypoglycemia, we diagnosed this patient with early and late dumping syndrome. Dietary measures and acarbose improved symptoms of late dumping syndrome but did not prevent the symptoms of early dumping syndrome such as postprandial tachycardia, weakness, headache, palpitation, and dizziness. We therefore used the somatostatin analogue octreotide, which has been reported as an effective therapy for early dumping syndrome. Octreotide prevented the symptoms of early dumping syndrome, especially postprandial tachycardia, but caused postprandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were completely suppressed during the 75 g-OGTT following subcutaneous injection of octreotide. No change was observed in vasoactive intestinal polypeptide (VIP), which is the gastrointestinal peptide hormone generally responsible for early dumping syndrome, suggesting possible contribution of incretins in early dumping syndrome of this patient.

A foot ulcer due to diabetes and/or arteriosclerosis obliterans (ASO) frequently results in an intractable condition that resists treatment. To cope with this condition, we have developed a combination therapy that includes conventional conservative therapy plus surgical therapy. This aggressive conservative therapy using aggressive debridement, trafermin (Fiblast Spray, Kaken, Japan) treatment and vacuum-assisted closure (VAC) therapy was adopted to treat seven patients suffering from diabetes and ASO-related refractory foot ulcer accompanied by bone exposure. With the exception of one patient who died during the treatment, the remaining six patients obtained limb salvage. The mean time to cure was 8.3 months. This approach should be considered before amputation. Some patients may refuse amputation or cannot tolerate highly invasive surgical treatment including tissue transplantation. In such cases, this aggressive conservative therapy can be employed as a highly useful and reproducible technique requiring simple techniques.

With our method, general improvement is obtained as compared with traditional split-thickness skin grafting of the radial forearm flap donor site. As our method is simple and easy, the same results can be obtained wherever and by whomever it is performed.The radial forearm flap is associated with complications of graft take and a poor aesthetic appearance despite its usefulness in reconstructing the oral cavity and oropharynx. We describe a simple technique for improvement of the radial forearm donor site.We studied 12 patients who underwent reconstruction with radial forearm free flaps following resection of oral or oropharyngeal tumors. We covered the donor site defect using traditional split-thickness skin grafts and performed aftercare with a hydrocolloid dressing and an adhesive sponge to retain moisture and apply compression. After the treatment series, color matching, texture matching, depressive deformity, and hypertrophic scar were evaluated.The results of comprehensive evaluation of the two patients with premature discontinuation of compression were good. One patient was assigned only 1 point for hypertrophic scar, and another only 1 point for color match. The evaluation of the other 10 patients was excellent.

Background To treat pincer nail, both conservative therapy and surgical therapy have been reported. However, there is no consensus about the best method of treatment. Objective The use of a splint prepared from an aspiration tube after pincer nail surgery is introduced. Methods Pincer nail was treated by surgery with splinting in seven patients (nine toes). Results Nine toes from seven patients were evaluated. The postoperative follow-up period ranged from 6 to 37 months (mean 17.7 months). An excellent result was obtained in eight toes, but ingrowth of the nail occurred in one toe. The cosmetic improvement was marked and satisfactory. Conclusion This splint is cheap and easy to make, can prevent contracture of the nail matrix and nail bed, can reduce pain, and allows direct observation of the nail bed because it is transparent. Thus, this technique seems to be convenient and useful. TOSHIYUKI OZAWA, MD, TETSUJI YABE, MD, NATSUKO OHASHI, MD, TERUICHI HARADA, MD, MICHINARI MURAOKA, MD, AND MASAMITSU ISHII, MD, HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS.