Phoretic behavior of the pseudoscorpion Megachernes ryugadensis on the Japanese wood mouse Apodemus speciosus.

Phoresy is a passive transportation behavior where one organism (phoront) disperses to a new location by attaching to another organism. Pseudoscorpions are arthropod predators that mainly live in soil, subterranean habitats, and under tree bark. Some species also live in animal nests and engage in phoresy on small mammals, suggesting close associations with these animals. However, the relationship between phoretic pseudoscorpions and hosts as well as the ecological significance of phoresy remain largely unexplored. Here, to understand the function of phoresy of Megachernes ryugadensis, phoretic on small mammals, their phoretic behavior was investigated in a deciduous forest in northern Japan; individual-level dynamics of phoresy were examined by over 3-year mark-recapture surveys that concurrently marked the host and phoront; and host characteristics, such as sex and age class, were analyzed based on a 2-year small mammal trapping survey. The primary host species was the abundant Japanese wood mouse Apodemus speciosus. Out of 132 pseudoscorpions marked, 5 were recaptured approximately 1 month later. No pseudoscorpions were recaptured within the same census period (3-4 days) when they were marked, indicating that phoresy events last less than one night, and pseudoscorpions are unlikely to engage in phoresy again within a few weeks of their initial engagement. Furthermore, analysis of host characteristics revealed a tendency for female mice and adult individuals to have a higher probability of being hosts compared with males and subadults, respectively. Based on the findings in this and previous studies, the function of phoresy in this species is discussed.

7-Ketocholesterol induces ROS-mediated mRNA expression of 12-lipoxygenase, cyclooxygenase-2 and pro-inflammatory cytokines in human mesangial cells: Potential role in diabetic nephropathy.

7-Ketocholesterol (7-KCHO) is a highly proinflammatory oxysterol and plays an important role in the pathophysiology of diabetic nephropathy (DN). Lipoxygenases (LOXs) and cyclooxygenases (COXs) are also involved in the development of DN. The aim of this study was to clarify the effects of 7-KCHO on mRNA expression of LOXs and COXs as well as pro-inflammatory cytokines in human mesangial cells (HMC). We evaluated cell viability by WST-8 assay and measured mRNA expression by reverse transcription-polymerase chain reaction. Intracellular reactive oxygen species (ROS) production was evaluated by flow cytometry. Although 7-KCHO did not affect cell viability of HMC, 7-KCHO stimulated significant increases in mRNA expression of 12-LOX, COX-2 and pro-inflammatory cytokines. 7-KCHO also induced an increase in ROS production, while N-acetylcysteine partially suppressed the increase. The 12-LOX and COX-2 inhibitors also suppressed mRNA expression of cytokines. These findings may contribute to the elucidation of the molecular mechanism of the pathophysiology of DN.

Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication.

UNLABELLED: Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection. We demonstrated that the expression of GALNT3 mRNA is upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells. IMPORTANCE: Viral infections that affect the upper or lower respiratory tracts, such as IAV, rapidly induce mucin production on the epithelial surfaces of respiratory cells. However, the details of how mucin-type O-linked glycosylation is initiated by IAV infection and how mucin production affects viral replication have not yet been elucidated. In this study, we show that levels of two miRNAs that target the UDP-GalNAc transferase GALNT3 are markedly decreased during the early stage of IAV infection, resulting in the upregulation of GALNT3 mRNA. We also demonstrate that the expression of GALNT3 initiates mucin production and affects IAV replication in infected cells. This is the first report demonstrating the mechanism underlying the miRNA-mediated initiation of mucin-type O-glycosylation in IAV-infected cells and its role in viral replication. Our results have broad implications for understanding IAV replication and suggest a strategy for the development of novel anti-influenza approaches.

Prognostic Index for Survival in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Third-Generation Agents.

We retrospectively evaluated clinical data from patients with advanced non-small-cell lung cancer (NSCLC) treated with third-generation chemotherapy agents prior to treatment, to determine a reliable method for predicting prognosis in such patients. We analyzed 100 patients who received third-generation agents (paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine) for the treatment of advanced NSCLC. Factors significantly related to prognosis were evaluated using the Cox regression model, and the prognostic index (PI) was determined by combining these factors. The mean follow-up duration was 12.6 months (0.2-67.0 months). Multivariate analysis identified pleural effusion, absolute neutrophil count (ANC), and C-reactive protein (CRP) level as significant factors that independently contribute to prognosis in patients with advanced NSCLC treated with third-generation agents (p < 0.05). The PI was calculated using these 3 factors, according to the following formula: PI = 0.581 × pleural effusion + 0.125 × ANC + 0.105 × CRP. The death rate in the group with the highest PI scores was significantly higher than in the group with the lowest scores (p < 0.001). Pleural effusion, ANC, and CRP level were the most important factors that contributed to prognosis following chemotherapy with third-generation agents in patients with advanced NSCLC. The PI is suggested to be an appropriate index to predict the prognosis of patients with NSCLC.

The Association between Fever and Prognosis in Lung Cancer Patients with Bone Metastases Receiving Zoledronic Acid.

Zoledronic acid is an established agent used in the management of metastatic bone disease. The administration of zoledronic acid improves overall survival (OS) of lung cancer patients with bone metastases receiving chemotherapy. However, it is currently unknown whether zoledronic acid-induced fever is associated with OS. The purpose of this study was to examine the association between zoledronic acid-induced fever and prognosis in lung cancer patients with bone metastases. We retrospectively analyzed 98 lung cancer patients with bone metastases who had received zoledronic acid. The end point outcome measure was OS. Multivariate analyses were used to estimate the hazard ratio (HR) for OS due to fever after adjusting for covariates. In multivariate analysis, white blood cell (WBC) count, lactate dehydrogenase (LDH) level, fever, chemotherapy, and hypercalcemia were independent prognostic factors, with HRs of 2.834 for WBC count (<10 × 103/µL vs. ≥10 × 103/µL, p < 0.001), 3.044 for LDH level (<250 vs. ≥250 IU/L, p < 0.001), 0.603 for fever (<37.0 vs. ≥37.0°C, p = 0.039), 0.481 for chemotherapy (chemotherapy not administered vs. administered, p = 0.006), and 2.453 for hypercalcemia (<11.0 vs. ≥11.0 mg/dL, p = 0.001). Zoledronic acid-induced fever was the most important prognostic factor in this cohort of lung cancer patients with bone metastases.

[Comparison of Response to Chemotherapy between Ovarian and Extraovarian Metastasis of Gastric Cancer].

BACKGROUND: Ovarian metastasis of gastric cancer is thought to be less sensitive to chemotherapy. METHODS: The subjects of this retrospective study were 15 gastric cancer patients with ovarian metastasis treated with first-line chemotherapy between January 1998 and April 2015. Response to chemotherapy was compared between ovarian metastasis and other measurable lesions; progression free survival(PFS), post progression survival(PPS), and overall survival(OS)were compared among the patients showing disease progression only at the ovary(group A), only at lesions other than the ovary(group B), and at both sites(group C). RESULTS: The patient characteristics were as follows: median age 58 years(range 34-79); performance status 0/1, 4/11; histology of diffuse/intestinal type, 15/0; unilateral/bilateral ovarian metastasis, 5/10; metastasis to the perito- neum/lymph node/bone/pleura, 15/5/2/1; and chemotherapy regimen with S-1+cisplatin/S-1/methotrexate+5-fluorour- acil(5-FU)/5-FU, 9/3/2/1. Partial response/stable disease/progressive disease were obtained in 1/11/3 patients, respectively. In 5 patients having measurable lesions in the ovary and lymph nodes, the median of the largest decrease in size after chemotherapy was 2.8%(range -8.2 to 31.7)at the ovary and 39.4%(range 5.4 to 75.4)at the lymph nodes(p=0.018). The number of patients in the groups A/B/C who experienced disease progression were 6/5/4, respectively; there were no differences in PFS(median 8.6/6.3/7.3months, respectively). Group A showed the longest PPS and OS compared to group B and C(median OS 19.0/9.1/13.8 months and PPS 11.4/4.3/2.5 months, respectively). CONCLUSION: Compared with other metastatic sites, our findings suggest that ovarian metastasis of gastric cancer may show less chemo-response; however, its progression may have a smaller impact on survival.

Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH.

Distinct classes of SOX10 mutations result in peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, collectively known as PCWH. Meanwhile, SOX10 haploinsufficiency caused by allelic loss-of-function mutations leads to a milder non-neurological disorder, Waardenburg-Hirschsprung disease. The cellular pathogenesis of more complex PCWH phenotypes in vivo has not been thoroughly understood. To determine the pathogenesis of PCWH, we have established a transgenic mouse model. A known PCWH-causing SOX10 mutation, c.1400del12, was introduced into mouse Sox10-expressing cells by means of bacterial artificial chromosome (BAC) transgenesis. By crossing the multiple transgenic lines, we examined the effects produced by various copy numbers of the mutant transgene. Within the nervous systems, transgenic mice revealed a delay in the incorporation of Schwann cells in the sciatic nerve and the terminal differentiation of oligodendrocytes in the spinal cord. Transgenic mice also showed defects in melanocytes presenting as neurosensory deafness and abnormal skin pigmentation, and a loss of the enteric nervous system. Phenotypes in each lineage were more severe in mice carrying higher copy numbers, suggesting a gene dosage effect for mutant SOX10. By uncoupling the effects of gain-of-function and haploinsufficiency in vivo, we have demonstrated that the effect of a PCWH-causing SOX10 mutation is solely pathogenic in each SOX10-expressing cellular lineage in a dosage-dependent manner. In both the peripheral and central nervous systems, the primary consequence of SOX10 mutations is hypomyelination. The complex neurological phenotypes in PCWH patients likely result from a combination of haploinsufficiency and additive dominant effect.

Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease.

Missense mutations in the proteolipid protein 1 (PLP1) gene cause a wide spectrum of hypomyelinating disorders, from mild spastic paraplegia type 2 to severe Pelizaeus-Merzbacher disease (PMD). Mutant PLP1 accumulates in the endoplasmic reticulum (ER) and induces ER stress. However, the link between the clinical severity of PMD and the cellular response induced by mutant PLP1 remains largely unknown. Accumulation of misfolded proteins in the ER generally leads to up-regulation of ER chaperones to alleviate ER stress. Here, we found that expression of the PLP1-A243V mutant, which causes severe disease, depletes some ER chaperones with a KDEL (Lys-Asp-Glu-Leu) motif, in HeLa cells, MO3.13 oligodendrocytic cells, and primary oligodendrocytes. The same PLP1 mutant also induces fragmentation of the Golgi apparatus (GA). These organelle changes are less prominent in cells with milder disease-associated PLP1 mutants. Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and GA fragmentation by inhibiting GA to ER trafficking. We also found that mutant PLP1 disturbs localization of the KDEL receptor, which transports the chaperones with the KDEL motif from the GA to the ER. These data show that PLP1 mutants inhibit GA to ER trafficking, which reduces the supply of ER chaperones and induces GA fragmentation. We propose that depletion of ER chaperones and GA fragmentation induced by mutant misfolded proteins contribute to the pathogenesis of inherited ER stress-related diseases and affect the disease severity.

Relationship between Lipoprotein Lipase Derived from Subcutaneous Adipose Tissue and Cardio-Ankle Vascular Index in Japanese Patients with Severe Obesity.

INTRODUCTION: Cardio-ankle vascular index (CAVI) is an arterial stiffness index that correlates inversely with body mass index (BMI) and subcutaneous fat area. Lipoprotein lipase (LPL) that catalyzes the hydrolysis of serum triglycerides is produced mainly in adipocytes. Serum LPL mass reflects LPL expression in adipose tissue, and its changes correlate inversely with changes in CAVI. We hypothesized that LPL derived from subcutaneous adipose tissue (SAT) suppresses the progression of arteriosclerosis and examined the relationship of LPL gene expression in different adipose tissues and serum LPL mass with CAVI in Japanese patients with severe obesity undergoing laparoscopic sleeve gastrectomy (LSG). METHODS: This study was a single-center retrospective database analysis. Fifty Japanese patients who underwent LSG and had 1-year postoperative follow-up data were enrolled (mean age 47.5 years, baseline BMI 46.6 kg/m2, baseline HbA1c 6.7%). SAT and visceral adipose tissue (VAT) samples were obtained during LSG surgery. LPL gene expression was analyzed by real-time PCR. Serum LPL mass was measured by ELISA using a specific monoclonal antibody against LPL. RESULTS: At baseline, LPL mRNA expression in SAT correlated positively with serum LPL mass, but LPL mRNA expression in VAT did not. LPL mRNA expression in SAT was correlated, and serum LPL mass tended to correlate inversely with the number of metabolic syndrome symptoms, but LPL mRNA expression in VAT did not. LPL mRNA expression in SAT and CAVI tended to correlate inversely in the group with visceral-to-subcutaneous fat ratio of 0.4 or higher, which is considered metabolically severe. Serum LPL mass increased 1 year after LSG. Change in serum LPL mass at 1 year after LSG tended to be an independent factor inversely associated with change in CAVI. CONCLUSIONS: Serum LPL mass reflected LPL mRNA expression in SAT in Japanese patients with severe obesity, and LPL mRNA expression in SAT was associated with CAVI in patients with visceral obesity. The change in serum LPL mass after LSG tended to independently contribute inversely to the change in CAVI. This study suggests that LPL derived from SAT may suppress the progression of arteriosclerosis.

Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells.

BACKGROUND: Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer. METHODS: Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry. RESULTS: Six out of the 7 gastric cancer cell lines overexpressed Mcl-1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44-positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44-positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations. CONCLUSION: These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells.

Changes in lifestyle-related behaviour during the COVID-19 pandemic in Japan: a questionnaire survey for examinees who underwent an annual health check-up.

OBJECTIVE: To investigate the effect of the coronavirus disease (COVID-19) pandemic on lifestyle behaviour and clinical data in a population who underwent an annual health check-up in Tokyo, Japan. METHODS: A self-report questionnaire was completed regarding changes in their physical activities, diet, alcohol intake, smoking and mental stress. For those recommended to undergo further examination or treatment, their intention to do so was also questioned. The clinical results of the check-ups across three different periods (before and during the pandemic and survey period) were statistically compared. RESULTS: During the survey period, 838 examinees responded. While physical activities decreased due to teleworking, changes in food intake and dietary patterns were varied. Furthermore, changes in mental stress were also diverse. As for the intention to undergo further clinical examination or treatment, 23.5% answered that they thought they would wait until the government lifted the state of emergency or the pandemic subsided. Compared with before the pandemic, diastolic blood pressure, liver function, kidney function and bone density tended to deteriorate. CONCLUSIONS: The COVID-19 pandemic affected the lifestyle of the current study population. To prepare for future outbreaks, real-world information should be collected and shared so that effective measures for health promotion can be developed.

Effects of beta-hydroxy beta-methyl butyrate calcium combined with exercise therapy in patients with cardiac disease: a study protocol for clinical trial.

INTRODUCTION: The current treatment for heart disease consists of exercise therapy in addition to pharmacotherapy, nutritional support and lifestyle guidance. In general, nutritional support focuses on protein, salt and energy restrictions, with no active protein or amino acid intake in cases involving moderate or higher renal failure. From this perspective, patients with cardiac disease are at high risk of frailty.Beta-hydroxy beta-methyl butyrate (HMB) is a metabolite of leucine. HMB is widely used for muscle strengthening and can be safely ingested even by patients with renal failure. The proposed study protocol will investigate the effects of HMB-calcium (HMB-Ca) administered in combination with comprehensive cardiac rehabilitation for muscle strength, muscle mass and cardiac function in patients with cardiac disease during the convalescent period. The primary outcome will be knee extensor strength. Secondary outcomes will be gross isometric limb strength and skeletal muscle mass. METHODS AND ANALYSIS: This study will be a single-blinded, randomised, controlled trial with parallel comparisons between two groups. The study period will be 60 days from the start of outpatient cardiac rehabilitation. Participants will be randomly divided into two groups: an HMB group consuming HMB-Ca one time per day for 60 days; and a Placebo group consuming reduced maltose once one time per day for 60 days. Exercise therapy will be performed by both groups. ETHICS AND DISSEMINATION: The study protocol will be published in a peer-reviewed journal. Ethics approval was provided by the Showa University Clinical Research Review Board. TRIAL REGISTRATION NUMBER: jRCTs031220139; Japan Registry of Clinical Trails.

Soluble (Pro)Renin Receptor Level in Patients with Severe Obesity Is Associated with Visceral Adiposity and Is Involved with Insulin Resistance and Renal Injury.

INTRODUCTION: High soluble (pro)renin receptor (s[P]RR) level in circulation is reported in obese patients; however, it is unclear which body composition components are responsible for it. In this study, the authors examined blood s(P)RR levels and ATP6AP2 gene expression levels in visceral and subcutaneous adipose tissue (VAT, SAT) in severely obese patients who underwent laparoscopic sleeve gastrectomy (LSG), with the aim of clarifying the relationship with body composition and metabolic factors. METHODS: Seventy five cases who underwent LSG between 2011 and 2015 and were postoperatively followed-up for 12 months at the Toho University Sakura Medical Center were included in the analysis of the cross-sectional survey at baseline, and 33 cases were included in the analysis of the longitudinal survey during the 12 months after LSG. We evaluated body composition, glycolipid parameters, liver/renal function, as well as serum s(P)RR level and ATP6AP2 mRNA expression level in VAT and SAT. RESULTS: The mean serum s(P)RR level at baseline was 26.1 ng/mL, this value was considered higher than values in healthy subjects. There was no significant difference in the expression level of ATP6AP2 mRNA between VAT and SAT. At baseline, multiple regression analysis for the association between s(P)RR and variables identified that visceral fat area, HOMA2-IR, and UACR showed the independent relationships with s(P)RR. During the 12 months after LSG, body weight, serum s(P)RR level showed a significant decrease (from 30.0 ± 7.0 to 21.9 ± 4.3). Multiple regression analysis for the association between the change in s(P)RR and variables showed that changes in visceral fat area, and alanine transaminase were independently related to the change in s(P)RR. CONCLUSION: This study showed that blood s(P)RR level was high in severely obese patients, decreased with weight loss by LSG, and was associated with visceral fat area in both pre- and postoperative changes. The results suggest that blood s(P)RR levels in obese patients may reflect the involvement of visceral adipose (P)RR in insulin resistance and renal damage mechanisms associated with obesity.

Diversity and composition of flower-visiting insects and related factors in three fruit tree species.

Animal-mediated pollination is an essential ecosystem service for the production of many fruit trees. To reveal the community composition of flower-visiting wild insects which potentially contribute to fruit production and to examine the effects of geographic location, local meteorological conditions and locally introduced domesticated pollinators on them, we investigated the community composition of insects visiting the flowers (hereafter, "visitors") of apple, Japanese pear and Oriental persimmon for 1‒3 years at 20 sites around Japan. While most of the variation (82%) of the community composition was explained by tree species with a slight contribution by geographic distance (2%), maximum temperature and tree species contributed 62% and 41% of the variation in total abundance of the visitors, respectively. Though the dominant families of the visitors varied spatiotemporally, the community composition of the visitors of apple and Japanese pear clearly differed from that of Oriental persimmon. While Andrenidae and Syrphidae together accounted for 46%‒64% of the visitors of apple and Japanese pear, Apidae represented 57% of the visitors of Oriental persimmon. The taxonomic richness, diversity and evenness of the visitors were best predicted by locally introduced domesticated pollinators and local meteorological conditions of wind speed and maximum temperature. Amongst these selected factors, locally introduced domesticated pollinators could have the largest impact. It seemed to be strongly related to the reduction of taxonomic richness, diversity and evenness of the visitors, accounting for 41‒89% of the variation. Results suggested that the community composition and total abundance of potential pollinators were predominantly determined by tree species and temperature, but locally introduced domesticated pollinators could have a determinantal pressure on the taxonomic diversity of the community.

A new species of Hyperlasion Schmitz (Diptera: Sciaridae), causing periodic outbreaks in Japan.

A sciarid species, Hyperlasion breviantenna sp. n., is described from Japan. This is the first record of Hyperlasion Schmitz, 1918, from Asia. We compared the molecular sequence data of the mitochondrial cytochrome c oxidase subunit I (COI) region and external morphological characters among congeners and related genera. Morphological features are described and illustrated, and genetic relatedness to selected species with a one-segmented maxillary palpus is shown as a maximum likelihood tree. The DNA barcoding approach revealed that the genetic sequences of Japanese specimens are identical with those of Australian specimens, which have been assigned to the genus Hyperlasion. The new species occurs in outbreaks during the rainy season, June to July, in Japan and is recognized as a nuisance pest. Newly emerged adults appear in the early morning and enter houses, facilities, and public buildings. The biology of the new species is compared with those of H. wasmanni Schmitz, 1918, and Moehnia erema Pritchard, 1960, which have been recorded as occurring in large aggregations with thousands of individuals abroad, based on published biological notes and reports on these species.

Preoperative Plasma Aldosterone Predicts Complete Remission of Type 2 Diabetes after Bariatric Surgery.

INTRODUCTION: Bariatric surgery (BS) has beneficial effects on body weight and type 2 diabetes. However, 44-52%, 20-40%, and 19-25% of patients with type 2 diabetes who undergo sleeve gastrectomy, sleeve gastrectomy with duodenal-jejunal bypass, and Roux-en-Y gastric bypass, respectively, show insufficient improvement 1 year after BS. It is thus important to predict the improvement in type 2 diabetes before BS. Many hormones are related to hyperglycemia. However, the relationship between hormones and improvement in type 2 diabetes after BS has not been studied. We aimed to evaluate the relationship between the improvement in type 2 diabetes and hormones in patients with obesity and type 2 diabetes who underwent BS. METHODS: We retrospectively reviewed 79 patients with obesity and type 2 diabetes who underwent BS, with a follow-up period of 12 months. We analyzed the relationship between some clinical parameters and complete remission (CR) of type 2 diabetes after BS. Patients were divided into two groups (type 2 diabetes CR and non-CR). Multiple regression analysis was performed to determine the parameters associated with type 2 diabetes resolution after BS. RESULTS: BS significantly improved body weight and glucose metabolism. Preoperative liver function, glycated hemoglobin (HbA1c), insulin secretion (homeostatic model assessment [HOMA]2-%B), renin activity, plasma aldosterone level, and duration of type 2 diabetes were significantly different between the CR and non-CR groups. Multiple regression analysis showed that preoperative HbA1c, HOMA2-%B, aldosterone concentration, and duration of type 2 diabetes were predictors of CR of type 2 diabetes after BS. Plasma aldosterone was the strongest predictor. DISCUSSION/CONCLUSION: Preoperative plasma aldosterone levels were related to the CR of type 2 diabetes after BS. Measuring plasma aldosterone levels preoperatively is useful for predicting the CR of type 2 diabetes after BS.

Association of Plasma Xanthine Oxidoreductase with Arterial Stiffness in Type 2 Diabetes with Liver Dysfunction.

BACKGROUND: Type 2 diabetes is a risk factor for atherosclerosis. Oxidative stress, which is a causative factor in insulin resistance, leads to atherosclerosis in patients with diabetes. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is related to oxidative stress. We aimed to examine the influence of plasma XOR activity on arterial stiffness in patients with type 2 diabetes. METHODS: In total, 458 patients with type 2 diabetes not receiving antihyperuricemic agents were enrolled and their clinical parameters including plasma XOR activity and the cardio-ankle vascular index (CAVI) were measured. Patients were divided into the liver dysfunction and absence of liver dysfunction groups. Multiple regression analysis was performed. RESULTS: The median plasma XOR activity level was 64.3 pmol/h/mL (33.3-147.3 pmol/h/mL). Plasma XOR activity was correlated significantly and positively with aspartate transaminase and alanine transaminase (ρ > 0.5). The level of plasma XOR activity in the liver dysfunction group was eight-fold higher than that in the absence of liver dysfunction group. A significant positive correlation was observed between plasma XOR activity and the CAVI only in the liver dysfunction group (ρ = 0.3968, P < 0.0043). Multiple regression models demonstrated that plasma XOR activity was an independent predictor of the CAVI in the liver dysfunction group (P = 0.0055). CONCLUSIONS: Our results suggest that plasma XOR activity is associated with arterial stiffness and may have a role in atherosclerosis development in patients with type 2 diabetes and liver dysfunction.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy increases carotid intima-media thickness and plaque score with von Willebrand factor activity elevation in patients with malignant lymphoma.

An increased risk for atherosclerosis has been noted in cancer survivors; however, studies that focus on the risk of atherosclerosis in patients treated with chemotherapy are scarce. Therefore, we evaluated 32 patients who received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy for B-cell malignant lymphoma by analysing the changes in atherosclerosis. Just before each treatment course, plasma levels of von Willebrand Factor (vWF) activity were evaluated, and carotid ultrasonography was performed at baseline and after the final treatment. Throughout the follow-up period, plasma vWF levels showed significantly transient increased by approximately 20%-40%. Both mean carotid intima-media thickness (IMT) and plaque score (PS) significantly increased during the 36.6 ± 26.0 weeks of observation (mean IMT: 0.724 ± 0.118 to 0.767 ± 0.129 mm; PS: 4.31 ± 3.53 to 4.87 ± 3.88, P < 0.001). Our study suggests that R-CHOP therapy promotes atherosclerosis.

Determinants of type 2 diabetes remission after bariatric surgery in obese Japanese patients: a retrospective cohort study.

OBJECTIVE: Bariatric surgery (BS) improves glycemic control in type 2 diabetes; however, some patients show insufficient improvement. Understanding the pathophysiology of type 2 diabetes in obese patients can facilitate appropriate treatment for type 2 diabetes after BS. The homeostatic model assessment (HOMA) 2 enables the calculation of the values from C-peptide data and evaluation of insulin users. We aimed to evaluate the pathophysiology of type 2 diabetes using pre- and postoperative parameters and HOMA2 in obese patients who underwent BS. METHODS: We retrospectively reviewed data from 45 obese patients with type 2 diabetes who underwent BS. They were followed-up for 12 months. The relationship between the HOMA2 score and complete remission (CR) of type 2 diabetes after BS was analyzed. Patients with and without CR were assigned to the CR and non-CR groups, respectively. Multiple regression analysis was used to identify factors associated with improvement in type 2 diabetes after BS. RESULTS: BS significantly improved body weight and glucose metabolism. The preoperative glycosylated hemoglobin A1c level and insulin secretion (HOMA2-%B) significantly differed between the CR and non-CR groups. Postoperative weight reduction and improved insulin sensitivity correlated significantly with CR; multiple regression showed that the preoperative HOMA 2-%B independently predicted CR of type 2 diabetes after BS. CONCLUSION: Preoperative insulin secretion, improvement in insulin sensitivity, and weight reduction after BS are related to CR of type 2 diabetes after BS. The results better reveal the pathophysiology of and treatment for type 2 diabetes in obese patients who undergo BS.

Characterisation of antithrombin-dependent anticoagulants through clot waveform analysis to potentially distinguish them from antithrombin-independent inhibitors targeting activated coagulation factors.

AIMS: While antithrombin (AT)-independent inhibitors targeting thrombin or activated factor X have been assessed through clot waveform (CWA), there are no reports on assessment with respect to AT-dependent anticoagulants. The present study aims to characterise AT-dependent anticoagulants through CWA to distinguish them from AT-independent inhibitors. METHODS: CWA was applied to the activated partial thromboplastin time (APTT) assay of plasma samples spiked with each of AT-dependent drugs (unfractionated heparin, enoxaparin and fondaparinux) and AT-independent drugs (rivaroxaban, apixaban, edoxaban, dabigatran, argatroban, hirudin and bivalirudin), which was performed using the CS-5100 or CN-6000 (Sysmex). The APTT-CWA data were automatically gained by the analyser program. The positive mode of clotting reaction curves was defined as the direction towards fibrin generation. RESULTS: Regarding dose-response curves in AT-dependent anticoagulants, the maximum positive values of the first and secondary derivatives (Max1 and Maxp2, respectively) and the maximum negative values of the secondary derivative (Maxn2) seemed to drop to zero without making an asymptotic line, consistent with the irreversibility. Such a feature was observed also in hirudin, as reported previously. Notably, the symmetric property of Max1 peaks in the waveforms was distorted dose dependently in AT independent but not AT-dependent drugs. A plot of Maxp2 logarithm versus Maxn2 logarithm was linear. The slope was about 1 in AT-dependent drugs while that was more than 1 in AT-independent drugs. These features made it possible to distinguish AT-dependent and AT-independent drugs. CONCLUSIONS: The results aid in further understanding of the pharmacological aspects of anticoagulation and in screening of candidates for novel anticoagulants.