Effect of hypertriglyceridemia in dyslipidemia‐induced impaired glucose tolerance and sex differences in dietary features associated with hypertriglyceridemia among the Japanese population: The Gifu Diabetes Study

Aims/IntroductionThe mechanisms underlying hypertriglyceridemia‐induced impaired glucose tolerance in Japanese individuals remain unclear. We aimed to evaluate the effect of hypertriglyceridemia on glucose metabolism in comparison with that of increased low‐density lipoprotein or decreased high‐density lipoprotein levels and to elucidate the sex differences in hypertriglyceridemia‐related dietary intake among Japanese individuals.Materials and MethodsWe randomly selected 898 (384 men and 514 women) participants aged 40–78 years in the Gifu Diabetes Study; those taking medication for dyslipidemia or diabetes mellitus were excluded. Serum levels of glucose metabolism parameters and the food frequency were measured cross‐sectionally. The glycated hemoglobin was measured again after 5 years.ResultsGlucose metabolism parameters and the percentage of individuals with impaired glucose tolerance were significantly higher in the high triglyceride group in men and women. Similar trends were observed in the low high‐density lipoprotein group, but only in men. Meanwhile, only the homeostasis model assessment of insulin resistance was higher in the high low‐density lipoprotein group. In non‐obese men, the percentage of energy intake from alcohol per total daily energy intake was significantly greater in the high triglyceride group. In obese women, the total energy intake was significantly greater in the high triglyceride group. At the 5‐year follow up, the risk of elevated glycated hemoglobin levels with hypertriglyceridemia was increased in men.ConclusionsHypertriglyceridemia is a stronger risk factor for impaired glucose tolerance than increased low‐density lipoprotein or decreased high‐density lipoprotein. For dietary habits, increased daily alcohol energy intake in non‐obese men and increased total energy intake in obese women were associated with hypertriglyceridemia.     

Comparative sequencing of human and chimpanzee MHC class I regions unveils insertions/deletions as the major path to genomic divergence

Despite their high degree of genomic similarity, reminiscent of their relatively recent separation from each other ( approximately 6 million years ago), the molecular basis of traits unique to humans vs. their closest relative, the chimpanzee, is largely unknown. This report describes a large-scale single-contig comparison between human and chimpanzee genomes via the sequence analysis of almost one-half of the immunologically critical MHC. This 1,750,601-bp stretch of DNA, which encompasses the entire class I along with the telomeric part of the MHC class III regions, corresponds to an orthologous 1,870,955 bp of the human HLA region. Sequence analysis confirms the existence of a high degree of sequence similarity between the two species. However, and importantly, this 98.6% sequence identity drops to only 86.7% taking into account the multiple insertions/deletions (indels) dispersed throughout the region. This is functionally exemplified by a large deletion of 95 kb between the virtual locations of human MICA and MICB genes, which results in a single hybrid chimpanzee MIC gene, in a segment of the MHC genetically linked to species-specific handling of several viral infections (HIV/SIV, hepatitis B and C) as well as susceptibility to various autoimmune diseases. Finally, if generalized, these data suggest that evolution may have used the mechanistically more drastic indels instead of the more subtle single-nucleotide substitutions for shaping the recently emerged primate species.     

Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ–TIF2 fusion

Chromosomal translocations that involve the monocytic leukemia zinc finger (MOZ) gene are typically associated with human acute myeloid leukemia (AML) and often predict a poor prognosis. Overexpression of HOXA9, HOXA10, and MEIS1 was observed in AML patients with MOZ fusions. To assess the functional role of HOX upregulation in leukemogenesis by MOZ–TIF2, we focused on bromodomain-PHD finger protein 1 (BRPF1), a component of the MOZ complex that carries out histone acetylation for generating and maintaining proper epigenetic programs in hematopoietic cells. Immunoprecipitation analysis showed that MOZ–TIF2 forms a stable complex with BRPF1, and chromatin immunoprecipitation analysis showed that MOZ–TIF2 and BRPF1 interact with HOX genes in MOZ–TIF2-induced AML cells. Depletion of BRPF1 decreased the MOZ localization on HOX genes, resulting in loss of transformation ability induced by MOZ–TIF2. Furthermore, mutant MOZ–TIF2 engineered to lack histone acetyltransferase activity was incapable of deregulating HOX genes as well as initiating leukemia. These data indicate that MOZ–TIF2/BRPF1 complex upregulates HOX genes mediated by MOZ-dependent histone acetylation, leading to the development of leukemia. We suggest that activation of BRPF1/HOX pathway through MOZ HAT activity is critical for MOZ–TIF2 to induce AML.     

Effects of mosapride on esophageal motor activity and esophagogastric junction compliance in healthy volunteers

Background

The effects of the prokinetic drug mosapride on esophageal motor activity vary at standard doses. In addition to esophageal motor activities, compliance of the esophagogastric junction (EGJ) is important for prevention of gastroesophageal reflux. However, the effects of mosapride on EGJ compliance have not been reported. Here, we investigated the effects of high-dose mosapride on esophageal motor activities and EGJ compliance.

Methods

Nine healthy volunteers were enrolled in the study. Peristaltic esophageal contraction and lower esophageal sphincter pressures before and after administration of 40 mg mosapride were examined by high resolution esophageal manometry. Esophageal compliance was also investigated by intra-esophageal impedance planimetry (EndoFLIP^®).

Results

High-dose mosapride augmented peristaltic contractions, especially in the distal esophageal segments (P < 0.05). The mean resting lower esophageal sphincter pressure was elevated from 25.0 mmHg before administration to 28.9 mmHg after (P < 0.05). In addition, mosapride significantly reduced EGJ compliance (P < 0.05).

Conclusions

Mosapride at 40 mg augmented esophageal motor activities and reduced EGJ compliance in healthy volunteers.     

Helicase proteins DHX29 and RIG-I cosense cytosolic nucleic acids in the human airway system

The recognition of cytoplasmic nucleic acid is critical for innate immune responses against microbial infection and is responsible for autoimmunity induced by dead cells. Here, we report the identification of a unique cytosolic nucleic acid cosensor in human airway epithelial cells and fibroblasts: DEAH (Asp-Glu-Ala-His) box polypeptide 29 (DHX29), a member of the DExD/H (Asp-Glu-x-Asp/His)-box helicase family. Knocking down DHX29 by siRNA attenuated the ability of cells to mount type I IFN and IL-6 in response to cytosolic nucleic acids and various viruses by blocking the activation of interferon regulatory factor 3 and NF-κB-p65. The cytosolic nucleic acid sensing by DHX29 in human epithelial cells and fibroblasts is independent of stimulator of interferon genes but is dependent on retinoic acid-inducible gene 1 (RIG-I) and mitochondrial antiviral signaling protein (MAVS). DHX29 binds directly to nucleic acids and interacts with RIG-I and MAVS through its helicase 1 domain, activating the RIG-I–MAVS-dependent cytosolic nucleic acid response. These results suggest that DHX29 is a cytosolic nucleic acid cosensor that triggers RIG-I/MAVS-dependent signaling pathways. This study will have important implications in drug and vaccine design for control of viral infections and viral-induced pathology in the airway.Human airway epithelia interface with the outside air environment. Viruses, bacteria, and other airborne microorganisms frequently cause mild to serious infections in humans, which may cause or exacerbate many human diseases, including pneumonia, asthma, and chronic obstructive pulmonary disease (1). Recent studies demonstrated that in addition to providing a physical barrier, epithelia can sense viral infection. This ability is critical to subsequent activation of antiviral innate and adaptive immunity (2–8).In the past decade, various cytosolic nucleic acid sensors and their mechanisms of action have been uncovered. Cytosolic double-stranded RNA (dsRNA) polyinosinic:polycytidylic acid (poly I:C) and 5′-ppp-dsRNA, mimicking the virus-derived RNA, are sensed by RIG-I–like receptors (9–11), which signal through the adaptor protein mitochondrial antiviral signaling protein (MAVS) (also known as CARDIF, IPS-1, or VISA) (12–15). For double-stranded DNA (dsDNA), many sensors have been reported, including DAI, AIM2, RNA pol III, IFI16, DDX41, Mre11, DNA-PKcs/Ku70/Ku80, cGAS, LRRFIP1, HMGB1, LSm14A, and NLRP3 (16, 17). Some of these molecules depend on stimulator of interferon genes (STING) (also known as ERIS, MITA, or MYPS) as the signaling adaptor (18–22). Furthermore, in addition to RIG-I–like receptors, many other DExD/H helicase family members, such as DHX9, DHX36, DDX1, DDX21, DHX33, DDX3, and DDX60, have been reported to function in nucleic acid sensing (23–29). These reports suggest that, depending on the virus species, cell type, types of ligands, types of responses, and the response phase, cytosolic nucleic acids are sensed by various sensing molecules that lead to different downstream signaling (16, 17). Different cytosolic nucleic acid sensors also have been implicated in the sensing of viral infection in human airway epithelial and subepithelial cells (2–7).In this study, we systemically analyzed the function of 59 members of the DExD/H (Asp-Glu-x-Asp/His) helicase family in sensing nucleic acids in human airway-derived epithelial cells and fibroblasts. We report that in the human airway system, DHX29 is engaged in cytosolic nucleic acid and virus sensing as a cosensor of the RIG-I/MAVS pathway, independently of STING.     

Mohs Surgery in Patients Immunobullous Diseases: Should Prednisone be Increased Prior to Surgery?

Background: Mohs surgery is one of the most effective treatment options for skin cancers as it offers one of the highest chances for cure. Mohs surgery is a precise technique that removes a layer at a time. Although this may be advantageous, this treatment method is difficult in patients with immunobullous diseases. Currently the guidelines for Mohs surgery do not discuss the premanagement of immunobullous patients about to undergo Mohs surgery. Objective: To advocate for increasing prednisone dose in patients with immunobullous disease prior to undergoing Mohs surgery. Case Report: The authors present a case of an excision of a squamous cell carcinoma from a 94-year-old woman with a history of pemphigus vulgaris using Mohs micrographic surgery. Conclusion: Current preoperative guidelines for Mohs surgery do not address the issue of altering steroid medications for patients with immunobullous disease prior to the procedure. The authors suggest that patients with a history of immunobullous disease undergoing Mohs micrographic surgery should have an increase in steroid dose prior to surgery.A 94 year-old Caucasian woman with no prior history of A skin cancer presented for evaluation of a crusting Plaque on her mid-back that had been present for six months. The patient’s past medical history was significant for pemphigus vulgaris for the last 20 years for which she was on prednisone 2.5mg daily. The patient reported no allergies. She denied smoking and denied alcohol use. Review of systems was unremarkable and physical examination revealed a well-developed, well-nourished woman. Upon complete skin examination, the mid-back presented with a 5x4cm erythematous, waxy, and crusty plaque (Figure 1). The surrounding areas of skin were examined and no other suspicious lesions were noted. The lesion was biopsied and a diagnosis of squamous cell carcinoma (SCC) was established. Open in a separate windowFigure 1Left upper back—preoperativeOn the scheduled day of surgery, the patient did have a new oral ulcer on her left buccal mucosa. The patient did not exhibit any other active lesions. However, during curettage and the incision, her skin became positive for Nikolsky’s sign and the epidermis sloughed off immediately (Figure 2). The squamous cell carcinoma was then excised with wider margins using Mohs micrographic surgery (MMS) in one stage. Open in a separate windowFigure 2Left upper back—intraoperativeFurthermore, closing the lesion was very difficult (Figure 3). The defect was repaired utilizing 3-0 Vicryl and 4-0 Nylon, which were placed from opposite edges of the defect spanning the width of the opening to minimize tension at the wound edges. During microscopic examination of the frozen section, it was difficult to assess if the margins were still positive for cancer because the epidermis was not present anymore. A compression dressing consisting of xeroform was used to avoid the use of adhesive tape on surrounding tissue that had become prone to blistering. The authors’ goal was to avoid adhesives altogether, since they further traumatize the fragile skin. The patient returned for her two-week follow up for suture removal and was diagnosed with methicillin-resistant Staphylococcus aureus (MRSA) infection. This was subsequently cultured and treated with doxycycline. The patient returned one week thereafter for suture removal and healed well with no other complications. Open in a separate windowFigure 3Left upper back—postoperative     

Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011

Background

IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells. Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established. Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists.

Methods

Two IgG4-RD study groups, the Umehara and Okazaki teams, were organized by the Ministry of Health, Labor and Welfare Japan. As IgG4-RD comprises a wide variety of diseases, these groups consist of physicians and researchers in various disciplines, including rheumatology, hematology, gastroenterology, nephrology, pulmonology, ophthalmology, odontology, pathology, statistics, and basic and molecular immunology throughout Japan, with 66 and 56 members of the Umehara and Okazaki teams, respectively. Collaborations of the two study groups involved detailed analyses of clinical symptoms, laboratory results, and biopsy specimens of patients with IgG4-RD, resulting in the establishment of comprehensive diagnostic criteria for IgG4-RD.

Results

Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, and the pathological features of each organ differ, consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135?mg/dl, and (2) >40% of IgG+ plasma cells being IgG4+ and >10?cells/high powered field of biopsy sample. Although the comprehensive diagnostic criteria are not sufficiently sensitive for the diagnosis of type 1 IgG4-related autoimmune pancreatitis (IgG4-related AIP), they are adequately sensitive for IgG4-related Mikulicz??s disease (MD) and kidney disease (KD). In addition, the comprehensive diagnostic criteria, combined with organ-specific diagnostic criteria, have increased the sensitivity of diagnosis to 100% for IgG4-related MD, KD, and AIP.

Conclusion

Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists.     

Interactive effects of exercise and sleep on frailty severity in community-dwelling older adults: a cross-sectional study

Objectives: This study examined the effects of the interaction between exercise and sleep on frailty severity in community-dwelling older adults.Materials and Methods: This was a cross-sectional study. Data were collected in July 2019. In total, 2021 adults participated who responded to a questionnaire. Among them, 672 participants (317 men and 355 women) with valid responses were included in the analysis. Ordinal logistic regression analysis was performed to examine the association between frailty severity and the interaction between exercise and sleep. The dependent variable represents three different levels of frailty. The independent variables included basic information and interaction between exercise and sleep.Results: The results of ordinal logistic regression analysis (odds ratio [OR]) showed that the period from the start of exercise (OR=0.96), age (OR=1.00 for participants in their 60 s, OR=1.65 for those in their 70s, and OR=3.13 for those aged >80 years), poor subjective health perception (OR=2.12), poor quality of sleep (OR=1.88), stress (OR=1.62), and exercise–sleep interaction (OR=1.00 based on good-exercise–good-sleep interaction, OR=3.09 poor-exercise–good-sleep interaction, and OR=3.50 poor-exercise–poor-sleep interaction) significantly contributed to the model. The Nagelkerke coefficient of determination adjusted for degrees-of-freedom (R²), which represents the contribution rate of the regression equation, was 0.334.Conclusions: Our results suggest that a combination of good exercise and good sleep is needed to prevent frailty progression in community-dwelling older adults.