Cardiorenal outcomes and mortality after sodium-glucose cotransporter-2 inhibitor initiation in type 2 diabetes patients with percutaneous coronary intervention history.

AIMS: To evaluate the effects of initiating sodium-glucose cotransporter-2 (SGLT2) inhibitors on cardiorenal outcomes and mortality compared to dipeptidyl peptidase-4 (DPP-4) inhibitors as active comparators in patients diagnosed with type 2 diabetes with a history of percutaneous coronary intervention (PCI). MATERIALS AND METHODS: We used an active-comparator, new-user design and nationwide data from the National Health Insurance Service in South Korea from 2014 to 2019. Of the 56 392 patients who underwent PCI, 4610 new SGLT2 inhibitor users were paired 1:1 with DPP-4 inhibitor users for analysis using propensity-score matching. RESULTS: During 13 708.59 person-years of follow-up, the initiation of SGLT2 inhibitors, compared with the initiation of DPP-4 inhibitors, was associated with a significantly lower risk of composite repeat revascularization, myocardial infarction, stroke, heart failure (HF), all-cause death and end-stage renal disease (ESRD). The beneficial effects of SGLT2 inhibitor use were consistent with the components of stroke, HF, all-cause death and ESRD. In the cohort that included health examination data, including anthropometric and metabolic factors, new use of SGLT2 inhibitors was associated with a significantly lower risk of HF (hazard ratio [HR] 0.574, 95% confidence interval [CI] 0.36-0.915), all-cause death (HR 0.731, 95% CI 0.567-0.942), and ESRD (HR 0.076, 95% CI 0.018-0.319). The effects of SGLT2 inhibitor use were consistent regardless of the timing of the previous PCI. CONCLUSIONS: The initiation of SGLT2 inhibitors in patients with type 2 diabetes and a history of PCI was significantly associated with a reduced risk of cardiorenal consequences and mortality, irrespective of time since the last PCI.

Association of Dynamic Changes in Metabolic Syndrome Status with the Risk of Parkinson's Disease: A Nationwide Cohort Study.

BACKGROUND: The longitudinal association between dynamic changes in the metabolic syndrome (MS) status and Parkinson's disease (PD) has been poorly studied. OBJECTIVE: We examined whether dynamic changes in MS status are associated with altered risk for PD. METHODS: This study was a nationwide retrospective cohort study. We enrolled 5,522,813 individuals aged≥40 years who had undergone health examinations under the National Health Insurance Service between 2009 and 2010 (two health examinations with a 2-year interval). Participants were followed up until the end of 2017. The participants were categorized into four groups according to MS status changes over 2 years: non-MS, improved MS, incident MS, and persistent MS groups. Multivariable Cox hazard regression was performed. RESULTS: During the 7-year median follow-up, there were 20,524 cases of newly developed PD. Compared with non-MS group, improved, incident, and persistent MS groups for 2 years were significantly associated with higher risks of PD (model 3; hazard ratio: 1.12, 95%confidence interval: 1.06-1.19 [improved MS]; 1.15, 1.09-1.22 [incident MS]; and 1.25, 1.20-1.30 [persistent MS]). Individuals with incident and persistent abdominal obesity, low levels of high-density lipoprotein cholesterol, hypertriglyceridemia, and hyperglycemia had a significantly increased risks of PD compared with those without either condition over 2 years. CONCLUSION: Persistent and incident MS and its components may be risk factors for incident PD. Ever exposure to MS may also be associated with PD risk. Appropriate intervention for preventing and improving MS may be crucial in decreasing the PD incidence.

Best Achievements in Clinical Medicine in Diabetes and Dyslipidemia in 2020.

Over the last two decades, our understanding of diabetes and treatment strategies have evolved tremendously, from scientific, mechanistic, and human perspectives. The categories of anti-diabetic medications expanded from a few to numerous, enabling clinicians to personalize diabetes care and treatment. Thanks to rapid growth in the field of science and medical engineering, newer treatment options are coming to the market with various advantages and disadvantages to be aware of. Therefore, clinicians should rapidly adopt new trends based on guidelines and data from many clinical trials in the field of diabetes. In the treatment of dyslipidemia, trends and guidelines are changing every year, and novel therapies are being developed. In this review, we would like to summarize the major achievements in clinical medicine in 2020 in the field of diabetes mellitus and dyslipidemia.

The Association between Pancreatic Steatosis and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients.

BACKGROUND: Whether pancreatic steatosis has a local or systemic effect, like ectopic fat of other major organs, remains unknown. Data on the influence of pancreatic steatosis on microvascular complication are rare. Therefore, we investigated the relationship between pancreatic steatosis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). METHODS: The attenuation of three pancreatic regions (head, body, and tail) and the spleen (S) in 186 patients with T2DM was measured using non-enhanced computed tomography imaging. We used three parameters for the assessment of pancreatic steatosis ('P' mean: mean attenuation of three pancreatic regions; P-S: difference between 'P' mean and 'S'; P/S: the 'P' mean to 'S' ratio). The presence of DR was assessed by an expert ophthalmologist using dilated fundoscopy. RESULTS: The average P mean was 29.02 Hounsfield units (HU), P-S was -18.20 HU, and P/S was 0.61. The three pancreatic steatosis parameters were significantly associated with the prevalence of DR in non-obese T2DM patients. In the non-obese group, the odds ratios of P mean, P-S, and P/S for the prevalence of DR, after adjustment for age, sex, and glycosylated hemoglobin level, were 2.449 (P=0.07), 2.639 (P=0.04), and 2.043 (P=0.02), respectively. CONCLUSION: In this study, pancreatic steatosis was significantly associated with DR in non-obese patients with T2DM. Further studies are necessary to clarify the causal relationship between pancreatic steatosis and the development of DR.

Sequential Sonographic Features of Primary Invasive Aspergillosis Involving Only the Thyroid Gland: A Case Report and Literature Review.

A 29-year-old woman with systemic lupus erythematosus (SLE) presented with palpitation and neck swelling. Initial sonography showed an ill-defined hypoechoic lesion in the right thyroid gland, mentioning subacute thyroiditis. The patient received conservative care for one week. However, her neck swelling worsened and she complained of dyspnea. Follow up sonography showed marked enlargement of both thyroid glands. Irregular infiltration of hypoechoic lesions was detected along the subcapsular region of both thyroid glands. She underwent immediate intubation to secure the airway and total thyroidectomy. Histopathological staining revealed features of fungal thyroiditis with fungal hyphae characteristic of Aspergillus. There was no abnormality in the lung or paranasal sinuses. In this report, we describe the sequential sonographic findings of invasive aspergillosis in the thyroid gland presenting as progressive enlargement without other organ involvement.

Differentiation of benign and malignant thyroid nodules based on the proportion of sponge-like areas on ultrasonography: imaging-pathologic correlation.

PURPOSE: The purpose of this study was to determine whether it is possible to differentiate benign from malignant thyroid nodules according to the proportion of sponge-like appearance within the nodules. METHODS: A total of 201 thyroid nodules containing sponge-like appearance from 195 patients (157 women and 38 men) were included this study. Each thyroid nodule was classified into one of three grades by real-time ultrasonography (US) based on the areas with a sponge-like appearance within nodule: grade I had sponge-like areas occupying <50%; grade II, between 50% and 75%; and grade III, >75%. We evaluated whether a correlation existed between these grades and cytopathologic diagnoses. RESULTS: Of the 201 nodules, 196 were benign and five were malignant, and according to the US classification, 101 nodules were grade I, 45 were grade II, and 55 were grade III. Of the five malignant nodules, four were grade I, and one was grade II. No statistically significant difference was found in the rate of malignancy between grade III and grades I and II, due to insufficient statistical power. A sponge-like appearance was correlated with follicles filled with colloid and cholesterol granules in benign nodules and with papillary fronds around the dilated cystic spaces in malignant nodules. CONCLUSION: No malignancies were found in thyroid nodules with >75% sponge-like appearance. Due to the overall low incidence of malignancy and the limited number of patients, a statistically significant difference could not be found in the prevalence of malignancy depending on the proportion of sponge-like areas within the nodule.

Involvement of lipid rafts in the budding-like exit of Orientia tsutsugamushi.

Orientia tsutsugamushi is an intracellular parasite that causes scrub typhus. After entering the cytoplasm by induced phagocytosis, O. tsutsugamushi escapes from the primary phagosome into the host cytosol, where it replicates slowly. Subsequently, it is released from the host cells by a process resembling viral budding with a remaining bacterial aggregate near the nucleus. Lipid rafts have been implicated in the life cycle of a wide variety of pathogenic microorganisms. We have observed that proteins of O. tsutsugamushi were co-fractionated with the lipid rafts over a sucrose density gradient, suggesting the possible involvement of lipid rafts during the intracellular life cycle of O. tsutsugamushi. The entry of O. tsutsugamushi into the host cells was shown to be independent on lipid rafts as judged by the inability of lipid raft-disrupting agents to inhibit bacterial entry and no co-localization of bacterial proteins with caveolin. To our interest, a 47-kDa protein (HtrA) was observed to be co-localized with caveolin at the cell membrane at 72 h after infection, when bacterial particles move to the cell membrane and initiate the exit into the extracellular environment. Our results suggest that O. tsutsugamushi involves lipid rafts of the host cells in the budding-like process to exit from host cells.

Novel polysaccharide antigen of Orientia tsutsugamushi revealed by a monoclonal antibody.

Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium that replicates in the cytosol of host cells. Although several protein antigens have been characterized and cloned, little information exists regarding the polysaccharide antigen of this bacterium. In this study, we identified and characterized a novel antigen defined by a monoclonal antibody (MAb), NT19, against O. tsutsugamushi. Immunofluorescence microscopic studies showed that the NT19 antigen is released from the bacteria in the cytosol of host cells forming aggregates with bacteria. Immunoblot analysis showed that MAb NT19 recognized a strong band with a molecular mass of 20 kDa that was resistant to proteinase K digestion and sensitive to periodate oxidation, suggesting that the NT19 antigen is a polysaccharide. The function of this polysaccharide is not known, but considering its distribution within a bacterial microcolony, it is suspected to be involved in forming a biofilm-like structure within host cells.

Chemopreventive effect of chitosan oligosaccharide against colon carcinogenesis.

Chitosan oligosaccharide (COS, 3 kDa

Improved antibiotic susceptibility test of Orientia tsutsugamushi by flow cytometry using monoclonal antibody.

Orientia tsutsugamushi causes scrub typhus, which is endemic in many countries in the Asia-Pacific region including Korea. Recent emergence of doxycycline-resistant strains from Thailand has underlined the importance of the susceptibility tests of O. tsutsugamushi to antibiotics. To improve the flow cytometric technique for the susceptibility test, we applied a monoclonal antibody (MAb) in the quantification of O. tsutsugamushi. With using MAb FS15, we determined the doxycycline susceptibility of two strains, Boryong and AFSC-4 strain which is reported to be doxycycline-sensitive and resistant, respectively. The growth of both strains was inhibited to below 10% of the control in the presence of 0.1 microg/mL or higher concentrations of doxycycline. We suggest that our approach is more quantitative and reproducible than the conventional microscopic methods.

Inhibition of proinflammatory cytokine-induced invasiveness of HT-29 cells by chitosan oligosaccharide.

The effect of chitosan oligosaccharide (COS, 1 kDa

AT1 antagonist modulates activin-like kinase 5 and TGF-beta receptor II in the developing kidney.

Previous studies by our group have demonstrated that angiotensin-converting enzyme (ACE) inhibition in the developing kidney modulates transforming growth factor-beta receptors. Blocking of angiotensin II (ANG II) mainly through angiotensin II type 1 receptor (AT1) has been implicated in mediating this ACE inhibition. The present study was designed to investigate the effects of an AT1 antagonist, losartan, on transforming growth factor-beta1 (TGF-beta1), TGF-beta receptor I [TbetaRI, activin-like kinase (ALK)-1, ALK-5], TGF-beta receptor II (TbetaRII), and alpha-smooth muscle actin (alpha-SMA) expression in the developing kidney. Newborn rat pups were treated with losartan (30 mg/kg per day) or normal saline for 7 days. Kidneys were removed for immunohistochemistry, reverse transcription polymerase chain reaction (PCR), and Western blotting of TGF-beta1, ALK-1, ALK-5, TbetaRII, and alpha-SMA. Renal ALK-5 and TbetaRII protein expressions in the losartan-treated group were found to be significantly increased (P<0.05), whereas TGF-beta1, ALK-1, and alpha-SMA protein expressions were not changed by losartan treatment. The losartan-treated group also showed significantly increased mean tubular diameter and interstitial area of the kidney (P<0.05). These results suggest that AT1 inhibition in the developing kidney impairs renal growth and development and modulates the expression of ALK-5 and TbetaRII.

An epitope shared by cellular cytokeratin and Orientia tsutsugamushi.

Many microbial pathogens have epitopes shared with host cell components and these epitopes may induce transient or longer-term tissue-damaging autoantibody responses. We observed that several mouse monoclonal antibodies (MAbs) raised against Orientia tsutsugamushi were also reactive with host cells. One such antibody, MAb Rb105, cross-reacted with the cytoskeleton, as shown by immunofluorescent staining. Biochemical studies identified the cross-reacting component as a cytokeratin protein. These results identify an epitope shared by O. tsutsugamushi and the cytokeratins of host cells. In addition, antibodies cross-reactive with the cytoskeleton were detected in the sera of scrub typhus patients, suggesting that an epitope similar to that detected by MAb Rb105 may be recognized by human antibodies.

Japanese spotted fever, South Korea.

We describe the first case of Japanese spotted fever and the first isolate of spotted fever group rickettsia from a patient in South Korea. The isolated rickettsia from the patient was identified as Rickettsia japonica by analysis of the nucleotide sequences of 16S rRNA, gltA, ompA, ompB, and sca4 genes.

Orientia tsutsugamushi inhibits tumor necrosis factor alpha production by inducing interleukin 10 secretion in murine macrophages.

Orientia tsutsugamushi (OT) is the causative agent of scrub typhus or Tsutsugamushi disease. We have previously reported that OT suppresses the production of inflammatory cytokines in murine macrophages. In this study, we examined the mechanism of OT to suppress the tumor necrosis factor alpha (TNF-alpha) production. J774 macrophages were preinfected with OT for various times and then treated with lipopolysaccharide (LPS) for 24 h. Preinfection by OT inhibited LPS-induced production of TNF-alpha, but did not affect the activation of NF-kappaB. This suppression was also induced by the conditioned medium (CM) from OT-infected macrophages. Interestingly, the CM contained a potent interleukin-10 (IL-10)-inducing factor that is active on activated macrophages. Therefore, the IL-10-inducing factor might enhance the negative-feedback mechanism ascribed to IL-10, to allow bacterial survival in the hostile environment of macrophages.

Narrow-bore high performance liquid chromatographic method for the determination of cetirizine in human plasma using column switching.

An improved column switching high performance liquid chromatographic (HPLC) method was developed for determination of cetirizine in human plasma. Plasma samples were prepared by liquid-liquid extraction using methylene chloride. The samples extracted were initially injected into a clean-up Capcell Pak MF C8 column and the peaks of cetirizine and internal standard were separated to an analytical C18 micro-column via column switching device. This analysis showed highly sensitive and selective results. Also, it was successfully applied to evaluate the pharmacokinetics of cetirizine in human volunteers after single oral administration.

Application of monoclonal antibody, specific for intracellular Orientia tsutsugamushi, to immunofluorescent antibody test for determining antibiotic susceptibility.

The simple quantification of viable intracellular bacteria is important for the study of an obligate intracellular bacterium, Orientia tsutsugamushi. We applied a novel monoclonal antibody (M686-13)--specific for intracellular Orientia--to an immunofluorescent antibody (IFA) test for determining antibiotic susceptibility of O. tsutsugamushi. M686-13 did not react with Orientia that was inhibited by doxycycline, although bacterial particles still remained in the cells. This preferential staining of proliferating bacteria made the IFA test rapid and precise. Using this method, we could successfully measure the minimal inhibitory concentration (MIC) of a Korean strain of O. tsutsugamushi to doxycycline and clindamycin. This method may be used in other procedures to evaluate the growth of Orientia.

Aurintricarboxylic acid translocates across the plasma membrane, inhibits protein tyrosine phosphatase and prevents apoptosis in PC12 cells.

Aurintricarboxylic acid (ATA) prevents apoptosis in a diverse range of cell types including PC12 cells. It is known to stimulate tyrosine phosphorylation of signaling proteins including Shc proteins, phosphatidylinositol 3-kinase, phospholipase C-g and mitogen-activated protein kinases (MAPKs). However, it has been unclear how ATA increases the phosphorylation of these proteins as it was believed to be membrane impermeable. We found that ATA translocates across the plasma membrane of PC12 cells and have confirmed that it is a potent inhibitor of protein tyrosine phosphatases (PTP ases). Other PTPase inhibitors also prevented apoptosis independent of ATA. These observations indicate that ATA exerts its anti-apoptotic effect on PC12 cells at least in part by inhibiting certain PTPase(s).

Orientia tsutsugamushi inhibits apoptosis of macrophages by retarding intracellular calcium release.

Orientia tsutsugamushi shows both pro- and antiapoptotic activities in infected vertebrate cells. Apoptosis of THP-1 cells induced by beauvericin was inhibited by O. tsutsugamushi infection. Beauvericin-induced calcium redistribution was significantly reduced and retarded in cells infected with O. tsutsugamushi. Antiapoptotic activities of O. tsutsugamushi in infected cells are most probably due to inhibition of the increase in the cytosolic calcium concentration.

Characterization of monoclonal antibody reacting exclusively against intracellular Orientia tsutsugamushi.

Intracellular bacteria often change the expression of their genes in order to adapt to new environmental conditions. Here we describe a monoclonal antibody (MAb) that reacts exclusively against intracellular Orientia tsutsugamushi. Although MAb applied to the 56-kDa protein, a major outer membrane protein, reacted against a large number of bacteria that had attached to host cells at the early stage of infection, M686-13 reacted against only a minor portion of the attached bacteria. In the later stage of the intracellular growth cycle, both antibodies showed identical staining patterns by double immunofluorescent staining. These results suggest that M686-13 reacted to an epitope or a protein that had probably been expressed during the intracellular growth cycle and rapidly diluted or degraded upon release into the extracellular environment. Although its molecular characteristics remain unknown, the reactive antigen may prove to be a novel developmental antigen and this MAb could be used as reagent for the staining of viable O. tsutsugamushi.