Anemoside B4 inhibits SARS-CoV-2 replication in vitro and in vivo / 中草药·英文版

OBJECTIVE@#Anemoside B4 (AB4), the most abundant triterpenoidal saponin isolated from Pulsatilla chinensis, inhibited influenza virus FM1 or Klebsiella pneumoniae-induced pneumonia. However, the anti-SARS-CoV-2 effect of AB4 has not been unraveled. Therefore, this study aimed to determine the antiviral activity and potential mechanism of AB4 in inhibiting human coronavirus SARS-CoV-2 in vivo and in vitro.@*METHODS@#The cytotoxicity of AB4 was evaluated using the Cell Counting Kit-8 (CCK8) assay. SARS-CoV-2 infected HEK293T, HPAEpiC, and Vero E6 cells were used for in vitro assays. The antiviral effect of AB4 in vivo was evaluated by SARS-CoV-2-infected hACE2-IRES-luc transgenic mouse model. Furthermore, label-free quantitative proteomics and bioinformatic analysis were performed to explore the potential antiviral mechanism of action of AB4. Type I IFN signaling-associated proteins were assessed using Western blotting or immumohistochemical staining.@*RESULTS@#The data showed that AB4 reduced the propagation of SARS-CoV-2 along with the decreased Nucleocapsid protein (N), Spike protein (S), and 3C-like protease (3CLpro) in HEK293T cells. In vivo antiviral activity data revealed that AB4 inhibited viral replication and relieved pneumonia in a SARS-CoV-2 infected mouse model. We further disclosed that the antiviral activity of AB4 was associated with the enhanced interferon (IFN)-β response via the activation of retinoic acid-inducible gene I (RIG-1) like receptor (RLP) pathways. Additionally, label-free quantitative proteomic analyses discovered that 17 proteins were significantly altered by AB4 in the SARS-CoV-2 coronavirus infections cells. These proteins mainly clustered in RNA metabolism.@*CONCLUSION@#Our results indicated that AB4 inhibited SARS-CoV-2 replication through the RLR pathways and moderated the RNA metabolism, suggesting that it would be a potential lead compound for the development of anti-SARS-CoV-2 drugs.

Bilateral adrenal hemorrhage caused by anticoagulant therapy after joint replacement surgery: One case report and literature review / 中华内分泌代谢杂志

Bilateral adrenal hemorrhage is a rare cause of primary adrenal insufficiency, and bilateral adrenal hemorrhage due to anticoagulant use is even rarer. We describe the case of a 62-year-old woman receiving post total knee arthroplasty anticoagulant therapy who presented fever, vomitting, stomachache, and severe fatigue on the 8th day. It was until 4 months later that the patient was finally diagnosed with adrenal insufficiency resuting from bilateral adrenal hemorrhage, her symptoms were relieved by glucocorticoid replacement therapy. In order to promote the awareness, diagnosis, and mangement of post-surgery anticoagulants induced bilateral adrenal hemorrhage, the clinical characteristics of the reported cases were summarized and analyzed.

Application of ACMMM management model in elderly patients with unsafe events / 中国实用护理杂志

Objective To explore the application of ACMMM management model in elderly patients with unsafe events. Methods A retrospective analysis of elderly patients who had been hospitalized for more than three months at the Chinese People′s Liberation Army General Hospital from May 2017 to May 2018 was performed. According to the patient′s hospitalization time, they were divided into group A and group B. Group A was hospitalized between May 2016 and May 2017 (n=1 258), and group B was hospitalized between June 2017 and May 2018 (n=1 309). Patients in group A were given routine nursing intervention, and patients in group B were combined to implement ACMMM management model intervention on the basis of routine nursing intervention. The incidence of various types of unsafe events in the two groups of patients was compared. The severity of the fall in the two groups of patients was compared. Comparison of nursing satisfaction between the two groups of patients. Results In group A, 47 patients had unsafe events, 11 patients in group B had unsafe events, and group A had higher incidence of unsafe events than group B (χ2=24.358, P<0.05). In group A, the frequency of pressure sores and burns was higher than that of group B (χ2=7.966, 4.353, 5.800, P<0.05). There was no statistically significant difference in the frequency of occurrence of falling, suffocation, self-injury, and misuse between the two groups (P>0.05). The severity of patients with falls in group A was higher than that in group B (Z=-2.124, P<0.05). The satisfaction of nursing in group B was 79.53% (1 041/1 309), the satisfaction of nursing in group A was 57.15%(719/1 258), and the satisfaction degree in group B was better than that in group A. The data were statistically significant (Z=-15.238, χ2=148.962, P <0.05). Conclusions The use of ACMMM management model for long-term hospitalized elderly patients with nursing intervention can effectively reduce the incidence of unsafe events in elderly patients, reduce the severity of falls and other related injuries, and effectively improve patient care satisfaction.

Application of ACMMM management model in elderly patients with unsafe events / 中国实用护理杂志

Objective@#To explore the application of ACMMM management model in elderly patients with unsafe events.@*Methods@#A retrospective analysis of elderly patients who had been hospitalized for more than three months at the Chinese People′s Liberation Army General Hospital from May 2017 to May 2018 was performed. According to the patient′s hospitalization time, they were divided into group A and group B. Group A was hospitalized between May 2016 and May 2017 (n=1 258), and group B was hospitalized between June 2017 and May 2018 (n=1 309). Patients in group A were given routine nursing intervention, and patients in group B were combined to implement ACMMM management model intervention on the basis of routine nursing intervention. The incidence of various types of unsafe events in the two groups of patients was compared. The severity of the fall in the two groups of patients was compared. Comparison of nursing satisfaction between the two groups of patients.@*Results@#In group A, 47 patients had unsafe events, 11 patients in group B had unsafe events, and group A had higher incidence of unsafe events than group B (χ2=24.358, P<0.05). In group A, the frequency of pressure sores and burns was higher than that of group B (χ2=7.966, 4.353, 5.800, P<0.05). There was no statistically significant difference in the frequency of occurrence of falling, suffocation, self-injury, and misuse between the two groups (P>0.05). The severity of patients with falls in group A was higher than that in group B (Z=-2.124, P<0.05). The satisfaction of nursing in group B was 79.53%(1 041/1 309), the satisfaction of nursing in group A was 57.15%(719/1 258), and the satisfaction degree in group B was better than that in group A. The data were statistically significant (Z=-15.238, χ2=148.962, P <0.05).@*Conclusions@#The use of ACMMM management model for long-term hospitalized elderly patients with nursing intervention can effectively reduce the incidence of unsafe events in elderly patients, reduce the severity of falls and other related injuries, and effectively improve patient care satisfaction.

Learning from POSTAL study: can levothyroxine improve pregnancy outcomes in women with thyroid autoimmunity? / 中华内分泌代谢杂志

Whether levothyroxine ( LT4 ) treatment improves outcomes following in vitro fertilization and embryo transfer ( IVF-ET) in euthyroid women who have tested positive for thyroid autoantibodies remains unclear. In Pregnancy Outcome Study in enthyroid women with Thyroid Autoimmunity after Levothyroxine ( POSTAL) trial, which was a randomized controlled study involving 600 euthyroid women undergoing IVF-ET who were tested positive for thyroperoxidase antibodies, the miscarriage rate, clinical pregnancy rate and live-birth rate were not significantly different between the LT4 intervention group and control group. Therefore, LT4 treatment did not appear to improve pregnancy outcomes among women with thyroid autoantibodies undergoing IVF-ET.

Clinical assessment of combination serum miR-21 and CA199 for pancreatic cancer diagnosis / 中华检验医学杂志

Objective To investigate the diagnostic value of serum miR-21 andCA199 for pancreatic cancer,and aim to provide a potential diagnostic method for the diagnosis of pancreatic cancer in clinical practice.Methods Detect the levels of CA199 and the relative expression of miR-21 in 134 pancreatic cancer patients,97 benign pancreatic disease patients and 106 healthy subjects from January 2014 to December 2015 in Clinical Laboratory of 263 Clinical Department of Army General Hospital,Evaluate the diagnostic value of single and combined detection of CA199 for pancreatic cancer.The diagnostic values were evaluated by receiver operating characteristic curve,sensitivity and specificity.The area under the receiver operating characteristic curve was compared by the z-score test.Results Compared with healthy control group,CA199 and miR-21 in benign pancreatic disease group and pancreatic cancer group showed significantly increased.Compared with benign pancreatic disease group,CA199 and miR-21 alsoshowed significantly increased in pancreatic cancer group.For discriminating the healthy control group and pancreatic cancer group,the sensitivity and specificity were 77.61％and 69.81％respectively when combination CA199 and miR-21.The AUC of combination CA199 and miR-21 was0.85,it showed significantly higher when compared with CA199 and miR-21 alone(P=0.021,P=0.036).For discriminating the benign pancreatic disease group and pancreatic cancer group,the sensitivity and specificity were 69.40％and 65.98％respectively when combination CA199 and miR-21.The AUC of combination CA199 and miR-21 was 0.78,it showed significantly higher when compared with CA199 and miR-21 alone(P=0.017,P=0.023).Conclusions miR-21 showed certain diagnostic value for pancreatic cancer.Combined with CA199,miR-21 may provide a potential assistant diagnostic method for the diagnosis of pancreatic cancer.

Preparation of a novel monoclonal antibody againstα-galactosidase from Bacteroides fragilis for detection of minimal residual enzyme in universal red blood cells / 军事医学

Objective To establish a method of quantiying trace α-galactosidase from Bacteroides fragilis in enzymatic conversion of blood group B to O red blood cells ( B-ECO RBCs) .Methods BALB/c mice were immunized with purified recombinant B.fragilisα-galactosidase ( the purity>90%) to prepare monoclonal antibodies.The ascites were prepared using hybridoma cell lines stably secreting antibody and purified by HiTrap rProtein A column.The antibody titer and spe-cificity were detected by ELISA and Western blotting, respectively.Purified monoclonal antibody and rabbit polyclonal an-tibody were applied to detect residual enzyme in B-ECO RBCs and the washing solution was analyzed by indirect ELISA. Results A high titer and purity antibody was obtained.Western blotting showed that the antibody specifically reacted with B.fragilisα-galactosidase.Moreover, indirect ELISA was sensitive enough to detect the minimal amount of residualα-gal-actosidase at the concentration of 1 ng/ml.After four repeat washing cycles with 1∶4 ( v/v) phosphate-buffered saline, the amount of residual enzyme in B-ECO RBCs was less than 10 ng/ml.Conclusion An effective method of detecting the min-imal amount of residual α-galactosidase in blood conversion is established for safety evaluation of universal RBCs prepara-tion by enzymatic treatment.

Diagnostic and prognostic value of presepsin for sepsis / 中华检验医学杂志

Objective To investigate the diagnostic and prognostic value of presepsin for sepsis.Methods Diagnostic accuracy test.The plasma presepsin levels of 57 sepsis patients,64 systemic inflammatory response syndrome (SIRS) patients and 120 healthy individuals admitted to the 263 Clinical Branch,General Hospital of Beijing Military Region between January 2012 and December 2013were detected by PATHFAST system.Receiver operating characteristic (ROC) curve analysis was used to assess and compare the diagnostic value of presepsin and procalitonin (PCT).Logistic regression model was used to estimate the association between presepsin and sepsis.In addition,the correlations between presepsin and the clinical characteristics were analyzed in sepsis patients.Results Sepsis patients [1 266 (754-2 181) pg/ml] had higher presepsin level than SIRS[517 (349-939)pg/ml] and healthy individual controls [(182 ± 56)pg/ml] (Z value was 5.94 and 10.71,respectively,P value was ＜ 0.01 for all).The areas under curve (AUCs) of presepsin and PCT were 0.81 (95％ CI:0.74-0.89) and 0.78 (95％ CI:0.71-0.86),respectively,with no statistical significance (x2 =0.60,P =0.47).After adjusted for PCT,presepsin ＞ 1 060 pg/ml was independently associated with sepsis,with odds ratio (OR) of 7.80 (95 ％ CI:3.07-20.32).Severe sepsis patients [2 723 (2 002-4 234) pg/ml] had higher presepsin than sepsis patients[1 145 (656-1 436) pg/ml] (Z =4.00,P ＜0.01).The patients with inhosptal mortality [2 365 (1 256-3 567)pg/ml] had higher presepsin than survival ones[1 146 (660-1 452) pg/ml] (Z =2.99,P =0.003).Presepsin was positively correlated with PCT (r =0.75,P ＜ 0.01).The reference for presepsin was 72 to 292 pg/ml.Conclusions Presepsin was an useful biomarker for sepsisdiagnosis.The diagnostic value of presepsin and PCT was not completely overlap,and combinational using of these two biomarkers may improve the diagnostic accuracy of sepsis.In addition,presepsin had potential value for prognosis estimation.

Enzymatic removal of α-Gal antigen in porcine skin / 军事医学

Objective To reduce immunogenicity of porcine skin by removingα-Gal epitopes expressed in cell surface and extracellular matrix using recombinant α-galactosidase produced by Bacteroides fragilis.Methods The porcine skin was harvested from healthy 2-month-old pigs without any skin disorders before being sterilized by iodine and 75%alcohol, respectively.Enzymatic removal of α-Gal antigen was followed by washing with PBS.The α-Gal antigen in the prepared porcine skin was measured with immunofluorostaining of cryosections and the residual enzyme was measured with a double-antibody sandwich ELISA method.Enzymatic removal procedures were optimized by detecting residual enzyme and the effi-cacy ofα-Gal removal under different enzymatic and washing conditions.Results Efficient enzymatic and washing methods were established to removeα-Gal antigen.Theα-Gal removal efficacy was above 90% and residual enzyme was undetect-able (αprescribed minimum ofα-galactosidase detection with indirect ELISA was 1 ng/ml) .Conclusion It is feasible to efficiently removeα-Gal antigen under these enzymatic and washing conditions, and a method of producing low-immunoge-nicity pig skin dressing for burn is established.

Application of Delphi method in modular allocation of emergency medical equipment / 医疗卫生装备

To study the equipment modular allocation in the emergency medical unit after Beijing emergency public affairs. Using an improved Delphi method, 25 experts from various fields in Beijing were involved into two rounds consultations. The questionnaire of the first round consultation was formed based on analysis of emergency rescue equipment. Based on the result of the first round consultation, the questionnaire of the second round consultation was set up. The two rounds of questionnaires had the responding rates of experts 100% respectively, and the au-thoritative coefficients of the experts were 0.81 and 0.88. An emergency medical rescue equipment solution with three de-grees modular configuration in Beijing was made based on the consultations and experts' advices. The solu-tion develops the emergency medical service ability of mobile medical units and vehicle-mounted mobile hospital. LUO Ying and GAO Hong-wei are the first authors who contributecl equally to the article.

Thinking on Construction of Ethical Review Platform of Chinese Medicine Clinical Trial / 世界科学技术-中医药现代化

In order to ensure the science and rationality of the research , ethical review has been the general principles of the international community before biomedical research . Along with the development of Chinese medicine in China , the Chinese government has paid close attention to the construction of ethical review in re-cent years . Relying on the State Clinical Research Center of Chinese Trial Program Affiliated to State Adminis-tration of Traditional Chinese Medicine of the People's Republic of China , our hospital has some experiences in the construction of ethical review platform . The academic exchanges and strengthening of personnel training can increase the ethical review level in order to provide supports and insurance for the Chinese medicine clini-cal research .

Internal fixation plus bone grafting for treatment of thoracolumbar fractures via paraspinal intermuscular approach / 中华创伤杂志

Objective To test the safety and effectiveness of transpedicular fixation combined with transpedicular bone grafting via less invasive paraspinal intermusclar approach in treatment of thoracolumbar fractures.Methods The study involved 23 cases of thoracolumbar fractures treated with paraspinal multifidus intramusclular mini-incision,transpedicular bone grafting,and short-segment pedicle screw fixation from June 2009 to June 2012.There were 16 males and 7 females at age of 19-55 years (average 38.8years).Time from injury to surgery varied from 6 hours to 7 days (average 3.2 days).Fracture level was T11 in three cases,T12 in seven,L1 in nine,and L2 in four.According to Denis fracture classification,there were altogether 10 compression fractures and 13 burst fractures.McCormack load sharing classification scored average 5.3.Before operation,anterior vertebral body height ratio was average 58.6％(range,45 ％-73％) and kyphosis angle was average 23.7° (range,15°-34°).Results Operation lasted for average 95.5 minutes (range,75-130 minutes) with intraoperative bleeding of average 160.3 ml (range,115-220 ml).Unilateral incision that was averaged 3.5 cm (range 3.2-4.0 cm) in length obtained primary healing.Average follow-up time was 12.6 months (range,7.5-18 months).Average height of the anterior border was corrected to 97.3％ and average kyphosis angle was corrected to 4.6°.There was neither instrumentation failure nor symptom of persistent postoperative back pain.Conclusions Transpedicular fixation with transpedicular bone grafting via paraspinal muscle approach provides effective recovery of vertebral morphology and correction of kyphotic deformity.Furthermore,the technique gains advantages of easy operation,small trauma,less blood loss and rapid recovery.

The clinical implication and interpretation of glycated hemoglobin A1c testing / 中华检验医学杂志

Glycated hemoglobin A1c ( HbA1c) is worldwide used as the gold standard for long term glycemic control in patients with diabetes.Recently,it has been recommended as one of the diagnostic criteria of diabetes mellitus.To improve the accuracy and comparability of HbA1c testing,expedite the standardization of HbA1c assay and make a reasonable interpretation of the HbA1c results in clinical practice are inevitably faced by clinical laboratorians together with physicians.

Study on the relationship between the metabolic factors and the quality of 18F-fluorode oxyglucose myocardial metabolic imaging in patients with type 2 diabetes / 中华老年医学杂志

Objective To evaluate the effects of metabolic factors on the quality of 18F-fluorode oxyglucose (18F-FDG) myocardial metabolic imaging in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM). Methods Seventy CAD patients aged 60 years or over with T2DM were studied with myocardial 18 F-FDG dual isotope simultaneous acquisition (DISA) single photon emission computed tomography (SPECT). Fasting plasma glucose, total triglyceride (TG),total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-eholesterol(LDL-C), insulin, C peptide and glyeosylated hemoglobia (HbAlc) were detected. Insulin resistance and islet β cell function were calculated by using the Homeostasis Model Assessment (HOMA) equation. Results Compared with the bad image quality group (36 cases), patients in the excellent image quality group (34 cases) were younger [with average age of (62.2±8.5) years vs. (67.6±8.3) years, P<0.01] and slimmer [with BMI of (24.7±2.6)kg/m2 vs. (26.1±2.5)kg/m2, P<0.05]. The levels of fasting insulin and C peptide were lower in the excellent image quality group than those in the bad image quality group [with fasting insulin level of 8.3 (5.1～12.4) mIu/L vs. 12.7,(6.1～17.9)mIu/L and C-peptide level of 0.6(0.5～0.9)nmol/L vs. 0.9(0.6～1.2)nmol/L, respectively,both P<0.05]. The HOMA insulin resistant index was reduced in the excellent image group [2.7(1.6～4.0) vs. 4.1(1.7～6.5), P<0.05]. Logistic regression analysis showed that obesity and age≥65 years were independent risk factors for image quality, with OR value of 3.73 (95% CI: 1.12～12.45,P=0.022)and 3.75 (95%CI:0.96～14.6,P=0.058)after adjustment of other metabolic factors. Conclusions Insulin resistance is the main factor that influences the quality of 18F-FDG myocardial metabolic imaging in patients with T2DM. In addition, age≥65 years and obesity are also risk factors for image quality.

Toxic effect of oral ricin on the mouse intestinal tract and immune organs / 中国兽医学报

The experiment aimed to study the toxic effect of oral ricin on gastrointestinal tract and immune organs of mice with the dose of 1/5 LD50.In early days of intoxication,there was an obviously decrease in daffy weight and relative weight of thymus and spleen,fllowing the excretion of toxin,they had a trend of recovering to the normal state.Also,results of pathological section,scanning electron microscope and transmission electron microscope showed that ricin would induce a series of pathological reaction in intestines,meanwhile,the splenocytes displayed significant symptom of apoptosis and necrosis.

The frequency and function of FoxP3~+ regulatory T cell in patients with acute hepatitis B / 细胞与分子免疫学杂志

AIM: To investigate the dynamic variety of frequency and function of FoxP3~+ regulatory T cells in patients with acute hepatitis B (AHB). METHODS: Peripheral blood mononuclear cells (PBMCs) from 15 AHB patients at acute phase (week 1 of illness), convalescent phase (primary occurrence of both ALT level normalization and HBsAg negative conversion), resolved phase (at least 8 weeks after both ALT normalization and HBsAg seroconversion, and 15 health subjects were analyzed for FoxP3 (Forkhead/winged helix transcription factor) mRNA expression in MACS magnetic beads-purified CD4~+ T cells by real-time RT-PCR assay. The effects of Treg cells on the proliferation of CD4~+CD25~- T cells were examined by a ~3[H]-thymidine incorporation assay. RESULTS: AHB patients presented a significantly higher FoxP3 mRNA expression at convalescent phase than acute phase (t=-6.04, P<0.01) and resolved phase (t=4.45, P<0.01), and healthy controls (t=3.44, P<0.01). We also observed that the suppression efficiency of Treg cells on proliferation of CD4~+CD25~- T cells was lower at acute phase than convalescent phase (t=-5.30, P<0.01) and resolved phase (t=-3.20, P<0.05), but there was no significant difference between healthy controls and any phase of AHB. CONCLUSION: AHB patients presented lower circulating Treg frequency and suppression function at acute phase, and both of them are increased at convalescent phase, and then return to normal level along with disease resolved. This follow-up study furthers our understanding of Treg' s role in immunopathogenesis of hepatitis B.

Screening of sexual differentially expressed genes in the chicken early embryonic gonads using DNA microarray / 生物工程学报

Using Affymetrix's Chicken Genome Array, we used total RNA isolated from the gonads of male and female chicks at embryonic day 9 to identify the genes differentially expressed between male and female. Statistical results show 19 493 genes expressed in male chick's embryonic gonads and 19 368 genes expressed in female. There were 145 genes specificity expressed in male and 189 genes in female. The gene ontology classification (GOC) indicated these differentially expressed genes were mainly involved in cellular component, cell process and molecular banding, a part of genes were involved in organelle component, metabolic process, biologic process, catalytic activity and signal transducer activity. Some genes had reported for sex determination and differentiation in birds, such as avian sex-specific avian sex-specific W-linked, chomodomain-helicase-DNA-binding protein 1 and sex determining region Y-box 9. In addition, we also found several genes or hypothetical proteins were unknown function for the gonad differentiation and development, focus to their biological function and expression pattern in further works would provide a beneficial reference for understand the mechanism of sex differentiation and determination in birds.

Clinical efficacy of L-carnitine in treating diabetic peripheral neuropathy / 中华内分泌代谢杂志

One hundred patients with type 2 diabetic neuropathy were divided into L-carnitine group and control group with 50 eases in each group. Data showed significant improvements in clinical symptoms scores, visual analogue scale and quantitative sense test after 16-week L-earnitine treatment (all P < 0.05). The study demonstrates that L-earnitine has affirmative effect on patients with diabetic neuropathy, especially in alleviating pain.

Cloning of PTD-NPY fusion gene and its secretory expression in Pichia pastoris / 生物工程学报

The PTD-NPY fusion gene derived from HIV-1 TAT protein transduction domain and rat neuropeptide Y was amplified by overlap extension PCR, digested and subcloned into yeast expression vector pPICZ alpha A to construct recombinant expression plasmid pPICZ alpha-PTD-NPY. The cloned PTD-NPY fusion gene was identified by PCR and restriction enzyme digestion and sequenced. The exact recombinant plasmid was linearized by Sac I and integrated by electrotransformation into the genome of Pichia pastoris GS115 cells. Then, these positive recombinant yeast cells were induced by 10 mL/L methanol to express soluble PTD-NPY fusion protein. After 120 h of methanol induction, the SDS-PAGE electrophoresis result indicated PTD-NPY fusion protein was efficiently secreted into the medium. Western blotting analysis proved that the expressed fusion protein had specific NPY binding activity. The successful expression of PTD-NPY fusion protein in Pichia pastoris provided basis for its further application study.

The target of glycemic control:more close to normal level,the better / 中国实用内科杂志

In post-trial follow-up of DCCT,UKPDS and Steno-2 studies,sustained beneficial effects on the risk reductions for microvascular and macrovascular complications has been observed in previous intensive treatment group,suggesting that patients with diabetes benefit mostly from early intensive blood glucose control.On the other hand,intensive glucose lowering therapy has been shown to increase the risk of all cause mortality in high-risk patients with type 2 diabetes in ACCORD study.Therefore,the target of blood glucose control should be individualized for each diabetic patient.Not only intensive glucose lowering therapy but also avoidance of hypoglycemia during therapy should be highly considered.