Suzuki Atsushi

Recently, chronic hyponatremia, even mild, has shown to be associated with poor quality of life and high mortality. The mechanism by which hyponatremia contributes to those symptoms, however, remains to be elucidated. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a primary cause of hyponatremia. Appropriate animal models are crucial for investigating the pathophysiology of SIADH. A rat model of SIADH has been generally used and mouse models have been rarely used. In this study, we developed a mouse model of chronic SIADH in which stable and sustained hyponatremia occurred after 3-week continuous infusion of the vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) and liquid diet feeding to produce chronic water loading. Weight gain in chronic SIADH mice at week 2 and 3 after starting dDAVP injection was similar to that of control mice, suggesting that the animals adapted to chronic hyponatremia and grew up normally. AQP2 expression in the kidney, which reflects the renal action of vasopressin, was decreased in dDAVP-infused water-loaded mice as compared with control mice that received the same dDAVP infusion but were fed pelleted chow. These results suggest that "vasopressin escape" occurred, which is an important process for limiting potentially fatal severe hyponatremia. Behavioral analyses using the contextual and cued fear conditioning test and T-maze test demonstrated cognitive impairment, especially working memory impairment, in chronic SIADH mice, which was partially restored after correcting hyponatremia. Our results suggest that vasopressin escape occurred in chronic SIADH mice and that chronic hyponatremia contributed to their memory impairment.

OBJECTIVES: It is common to treat type 2 diabetes by regular injections of insulin. We compared the efficacy and safety of twice-daily administration of short-acting, premixed, and long-acting insulins. METHODS: This was a multi-center, randomized, open-label, 52-week study. Patients were randomized to administer twice daily short-acting analog insulin (Aspart) plus a sulfonylurea (SU), premixed 70/30 analog insulin (Mix), or long-acting insulin (Detemir) plus a glinide derivative. RESULTS: Twelve (mean baseline HbA1c 9.86±1.71%), eight (9.24±1.14%), and eight (11.26±1.81%) patients were treated with Aspart, Mix, or Detemir, respectively, for 52 weeks. After 12 weeks, the reductions in HbA1c were similar in the groups. A further significant reduction in HbA1c occurred between weeks 12 and 52 in the Detemir, but not the Aspart or Mix groups. After 52 weeks, the target of an HbA1c <7.4% was achieved in 16.7% of the Aspart group, 37.5% of the Mix group, and 12.5% of the Detemir group (no significant differences among the three groups by χ2 analysis). The mean changes from baseline in blood glucose concentration measured after breakfast, and before and after dinner, were also similar in each group. CONCLUSIONS: Early and meaningful reductions in HbA1c were achieved by twice-daily administration of a premix, aspart plus an SU, and detemir plus a glinide, without severe hypoglycemia or an increase in body mass. However, the target HbA1c was achieved in relatively few participants, perhaps due to an insufficient dose of insulin or the small study size.

Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.

＜Key Points＞◎慢性疾患は「イベントが起きない」状態で服薬の動機づけと維持が必要である。◎一般的にはサロゲートマーカーが用いられるが、骨粗鬆症ではサロゲートマーカーが不十分である。◎医療経済的な面や社会生活活動などについても配慮して薬剤選択を行うことが重要である。◎内服開始時に目的・目標と薬剤効果評価期間を患者と話し合うことがアドヒアランスを高める。◎本人だけではなく、家族を含めた服薬指導・注意喚起が効果的である。(著者抄録)

In this paper, we propose feature extraction method for prediction model for at the early stage of diabetic kidney disease (DKD) progression. DKD needs continuous treatment; however, a hospital visit interval of a patient at the early stage of DKD is normally from one month to three months, and this is not a short time period. Therefore it makes difficult to apply sophisticated approaches such as using convolutional neural networks because of the data limitation. The propose method uses with hierarchical clustering that can estimate a suitable interval for grouping inputted sequences. We evaluate the proposed method with a real-EMR dataset that consists of 30,810 patient records and conclude that the proposed method outperforms the baseline methods derived from related work.

We propose mini-batch top-n k-medoids to sequential pattern mining to improve CGM interpretation. Mecical workers can treat specific patient groups better by understanding the time series variation of blood glucose results. For 10 years, continuous glucose monitoring (CGM) has provided time-series data of blood glucose thanks to the invention of devices with low measurement errors. We conducted two experiments. In the first experiment, we evaluated the proposed method with a manually created dataset and confirmed that the method provides more accurate patterns than other clustering methods. In the second experiment, we applied the proposed method to a CGM dataset consisting of real data from 163 patients. We created two labels based on blood glucose (BG) statistics and found patterns that correlated with a specific label in each case.

OBJECTIVE: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ. We investigated the association between IgG4-RD and the main characteristics of Graves' disease (GD) at the time of diagnosis. Additionally, we evaluated whether serum IgG4 levels change during treatment. DESIGN AND PATIENTS: Twenty-eight patients with newly diagnosed GD were enrolled into this longitudinal follow-up study. Serum IgG4 levels and thyroid function were measured in all the participants at the time of diagnosis. Further, the serum IgG4 levels of nine of 28 patients with untreated GD were measured after the achievement of euthyroid state (through the use of methimazole). RESULTS: Two (7.1%) of 28 patients with untreated GD had elevated serum IgG4 levels of >135 mg/dL. There was no significant difference in the average IgG4 levels before and after the achievement of euthyroid state (66.2±74.0 mg/dL vs. 50.5±47.3 mg/dL). In two patients, the elevated serum IgG4 levels returned to normal after treatment. However, one patient had an elevated serum IgG4 level of 136.6 mg/dL after treatment. CONCLUSIONS: This study showed that serum IgG4 levels varied with treatment in patients with GD, independent of thyroid function, suggesting that IgG4 might be indirectly related to GD.

Artificial intelligence (AI) is expected to support clinical judgement in medicine. We constructed a new predictive model for diabetic kidney diseases (DKD) using AI, processing natural language and longitudinal data with big data machine learning, based on the electronic medical records (EMR) of 64,059 diabetes patients. AI extracted raw features from the previous 6 months as the reference period and selected 24 factors to find time series patterns relating to 6-month DKD aggravation, using a convolutional autoencoder. AI constructed the predictive model with 3,073 features, including time series data using logistic regression analysis. AI could predict DKD aggravation with 71% accuracy. Furthermore, the group with DKD aggravation had a significantly higher incidence of hemodialysis than the non-aggravation group, over 10 years (N = 2,900). The new predictive model by AI could detect progression of DKD and may contribute to more effective and accurate intervention to reduce hemodialysis.

TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

49歳男性。高血糖を主訴とした。甲状腺中毒症、TRAb陽性、超音波上の両側甲状腺の腫大と内部血流の亢進を認めた。HLAタイピングはDRB1 0405、DQA1 0303、DQB1 0401であった。自己免疫性多内分泌症候群(APS)3型のバセドウ病と診断し、チアマゾールとヨウ化カリウムの内服で甲状腺機能が改善した。内因性インスリン分泌能は保たれ、緩徐進行1型糖尿病と診断した。強化インスリン療法で血糖コントロールが改善した。APS3型9例の検討では、平均年齢39歳で、全例がバセドウ病であった。1型糖尿病9例、悪性貧血1例、白斑症1例、チアマゾール内服による無顆粒球症2例を認めた。HLA Class IIタイピングで、全例がDR4、DR9のいずれかを有した。HLA DRB1 0405を5例、HLA DRB1 0901を4例、HLA DQB1 0401を6例、HLA DQB1 0303を5例、HLA DRB1 0405/DQB1 0401を5例、HLA DRB1 0901/DQB1 0303を4例が有していた。

Long-term exposure to a high starch, low-protein diet (HSTD) induces body weight gain and hyperinsulinemia concomitantly with an increase in β-cell mass (BCM) and pancreatic islets number in mice; however, the effect of short-term exposure to HSTD on BCM and islet number has not been elucidated. In the present study, we investigated changes in body weight, plasma insulin levels, BCM and islet number in mice fed HSTD for 5 weeks followed by normal chow (NC) for 2 weeks. BCM and islet number were increased in mice fed HSTD for 5 weeks compared with those in mice fed NC. On the other hand, mice fed HSTD for 5 weeks followed by NC for 2 weeks (SN) showed decreased BCM and insulin levels, compared to mice fed HSTD for 7 weeks, and no significant differences in these parameters were observed between SN and the control NC at 7 weeks. No significant difference in body weight was observed among HSTD, NC and SN fed groups. These results suggest that a high-starch diet induces an increase in BCM in a manner independent of body weight gain, and that 2 weeks of NC feeding is sufficient for the reversal of the morphological changes induced in islets by HSTD feeding.

OBJECTIVES: Current evidence regarding metabolic surgery suggests that different types of digestive tract reconstruction can result in differences in postoperative glucose tolerance. This study evaluated the impact of Billroth I (B-I), Billroth II (B-II), and Roux-en-Y (R-Y) procedures on peri-operative glucose tolerance in patients with gastric carcinoma who had diabetes mellitus. METHODS: A single-institution, retrospective cohort study was conducted using data from patients who underwent totally laparoscopic distal gastrectomy. These patients were grouped according to the type of reconstruction (B-I, B-II, or R-Y). After the operation, we addressed the changes in glucose tolerance-including changes in HbA1c levels, remission of diabetes, and overall effects of the treatment. RESULTS: We studied 57 patients (B-I, n=32; B-II, n=17; R-Y, n=8). B-II and R-Y reconstruction improved HbA1c levels more than B-I. Notably, R-Y improved tolerance the most (B-I vs. B-II, p<0.001; B-I vs. R-Y, p<0.001; B-II vs. R-Y, p<0.001). The type of reconstruction (B-II and R-Y vs. B-I) and a pre-operative HbA1c ≥7% were the two significant independent contributing factors determining postoperative improvement in HbA1c, with odds ratio (OR) 8.437, 95% confidence interval (CI) 1.635-43.527, p=0.011; OR 16.5, 95% CI 3.361-81.011, p=0.001, respectively. CONCLUSIONS: Either R-Y or B-II should be considered the primary option for patients with gastric carcinoma and diabetes when glycemic control is insufficient.

リンパ球性漏斗下垂体後葉炎(lymphocytic infundibulo-neurohypophysitis:LINH)は自己免疫学的機序で中枢性尿崩症を呈する稀な疾患であり、腫瘍性疾患との鑑別が重要となる。症例は多飲多尿を主訴に受診した6歳男児で、精査を行い中枢性尿崩症の所見を認めた。下垂体MRIで下垂体茎の腫大とガドリウムで均一な造影効果を認めLINHが疑われた。頭痛などのmass effectは認めなかったので、ステロイドは使用せずDDAVPで治療を開始した。LINHの確定診断に必要な下垂体生検は侵襲が大きく施行しなかった。MRIをフォローし下垂体茎腫大は改善し、臨床的にLINHと診断した。また、近年、LINHの診断マーカーとして報告された血清抗ラブフィリン3A抗体は陽性であり、診断が支持された。(著者抄録)