Publications by authors named "Hitoshi Suzuki"

494 Publications

A 1-bp deletion in Mc1r in a Norway rat (Rattus norvegicus) from Sado Island, Japan gives rise to a yellowish color variant: an insight into mammalian MC1R variants.

Genes Genet Syst 2021 May 15. Epub 2021 May 15.

Graduate School of Environmental Science, Hokkaido University.

The melanocortin-1 receptor gene (MC1R) controls production of the pigments eumelanin and pheomelanin. Changes in MC1R lead to variation in coat color in mammals, which can range from entirely black (melanism) to yellowish. In this study, we report a case of a wild-caught Norway rat (Rattus norvegicus) from Sado Island, Japan with a yellowish coat color. Upon sequencing the whole coding region of the Mc1r gene (954 bp), we found a 1-bp deletion at site 337 (c.337del), indicative of a frameshift mutation, which was characterized as a severe loss-of-function or null mutation. A spectrophotometer was used to measure coat color, revealing that the rat had a distinctly lighter coat, based on lightness score, than mice with homozygous similar loss-of-function mutations. This implies that loss-of-function mutations can yield different phenotypes in murine rodents. The loss-of-function-mutant rat exhibited a contrasting coat pattern consisting of darker and lighter colors along its dorsal and ventral sides, respectively. Similar patterns have been observed in homozygous MC1R-deficient mutants in other mammals, implying that the countershading pattern can still be expressed despite the absence of MC1R in the melanocyte.
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http://dx.doi.org/10.1266/ggs.20-00049DOI Listing
May 2021

Utility of remission criteria for the renal prognosis of IgA nephropathy.

Clin Exp Nephrol 2021 May 11. Epub 2021 May 11.

Department of Nephrology, Juntendo University Faculty of Medicine, Hongo 2-1-1, Bunkyo-Ku, Tokyo, 113-8421, Japan.

Background: Novel criteria for the remission of Immunoglobulin A nephropathy (IgAN) based on an opinion survey of Japanese nephrologists and literature review were proposed in 2013. This single-center, longitudinal retrospective cohort study was conducted to validate this criteria.

Methods: Present study included the IgAN patients diagnosed between 2001 and 2005 in the Juntendo University Hospital. Remission of hematuria was defined as three consecutive dipstick test results of ( -) to ( ±) or a red blood cell count < 5 in urinary sediment per high-power field during at least 6 months. Remission of proteinuria was defined as three consecutive dipstick results of ( -) to ( ±) during at least 6 months. We categorized four groups according to the remission status which was assessed 2 years after the renal biopsy. The primary outcome was a 50% increase in the serum creatinine over the baseline. We evaluated the slope of eGFR decline (mL/min/1.73 m/year) and a decrease in the eGFR of 30% from baseline eGFR as the secondary outcome, respectively.

Results: A total of 74 patients (male: 47.3%, median age: 30 years) were included and were followed for a median of 86.5 months. During the period, forty-one patients achieved neither remission of proteinuria nor hematuria (NR). Twelve patients met the primary study outcome. A survival analysis revealed that the NR had the worst prognosis and the steepest slope of eGFR decline.

Conclusion: Although further validation in a large cohort is necessary, these novel remission criteria for IgAN patients appear to predict the renal prognosis.
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http://dx.doi.org/10.1007/s10157-021-02069-wDOI Listing
May 2021

Nasal-associated lymphoid tissue is the major induction site for nephritogenic IgA in murine IgA nephropathy.

Kidney Int 2021 May 5. Epub 2021 May 5.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan. Electronic address:

Dysregulation of mucosal immunity may play a role in the pathogenesis of IgA nephropathy (IgAN). However, it is unclear whether the nasal-associated lymphoid tissue (NALT) or gut-associated lymphatic tissue is the major induction site of nephritogenic IgA synthesis. To examine whether exogenous mucosal antigens exacerbate the pathogenesis of IgAN, we assessed the disease phenotypes of IgAN-onset ddY mice housed germ-free. These mice were transferred to a specific pathogen-free environment and divided into three groups: challenged with the Toll-like receptor 9 (TLR9) ligand CpG-oligodeoxynucleotide, fecal transplantation, and the untreated control group. The levels of aberrantly glycosylated IgA and IgG-IgA immune complexes were measured in the serum and supernatant of cultured cells purified from the NALT, mesenteric lymph nodes, and Peyer's patch. Although the germ-free IgAN-onset ddY mice did not develop IgAN, they showed aggravation of kidney injury with mesangial IgA deposition after transfer to the specific pathogen-free state. The NALT cells produced more aberrantly glycosylated IgA than those from the mesenteric lymph node and Peyer's patch, resulting in induction of IgG-IgA immune complexes formation. Additionally, TLR9 enhanced the production of nephritogenic IgA and IgG-IgA immune complexes by nasal-associated lymphoid but not gut-associated lymphatic cells. Furthermore, the germ-free IgAN-onset ddY mice nasally immunized with CpG-oligonucleotide showed aggravation of kidney injury with mesangial IgA deposition, whereas those that received fecal transplants did not develop IgAN. Thus, NALT is the major induction site of the production of aberrantly glycosylated IgA in murine IgAN.
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http://dx.doi.org/10.1016/j.kint.2021.04.026DOI Listing
May 2021

Development of a novel knee contracture mouse model by immobilization using external fixation.

Connect Tissue Res 2021 Mar 4:1-14. Epub 2021 Mar 4.

Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Fukuoka, Japan.

: Several studies have used animal models to examine knee joint contracture; however, few reports detail the construction process of a knee joint contracture model in a mouse. The use of mouse models is beneficial, as genetically modified mice can be used to investigate the pathogenesis of joint contracture. Compared to others, mouse models are associated with a lower cost to evaluate therapeutic effects. Here, we describe a novel knee contracture mouse model by immobilization using external fixation.: The knee joints of mice were immobilized by external fixation using a splint and tape. The passive extension range of motion (ROM), histological and immunohistochemical changes, and expression levels of fibrosis-related genes at 2 and 4 weeks were compared between the immobilized (Im group) and non-immobilized (Non-Im group) groups.: The extension ROM at 4 weeks was significantly lower in the Im group than in the Non-Im group (p < 0.01). At 2 and 4 weeks, the thickness and area of the joint capsule were significantly greater in the Im group than in the Non-Im group (p < 0.01 in all cases). At 2 weeks, the mRNA expression levels of the fibrosis-related genes, except for the , and the protein levels of cellular communication network factor 2 and vimentin in the joint capsule were significantly higher in the Im group (p < 0.01 in all cases).: This mouse model may serve as a useful tool to investigate the etiology of joint contracture and establish new treatment methods.
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http://dx.doi.org/10.1080/03008207.2021.1892088DOI Listing
March 2021

Galactose-deficient IgA1 and nephritis-associated plasmin receptors as markers for IgA-dominant infection-related glomerulonephritis: A case report.

Medicine (Baltimore) 2021 Feb;100(5):e24460

Division of Nephrology and Hypertension, Department of Internal Medicine, St Marianna University School of Medicine, Kawasaki.

Rational: Immunoglobulin A (IgA) nephropathy is a common heterogeneous kidney disease. One of the causes of secondary immunoglobulin A nephropathy is infection-related glomerulonephritis (IRGN), however, its accurate diagnosis is difficult.

Patient Concerns: We report a rare case of an 82-year-old male presenting rapidly progressive glomerulonephritis. Assessment of a kidney biopsy by light microscopy revealed endocapillary glomerulonephritis with subendothelial deposits, such as wire loop lesions and cellular crescents. Immunofluorescence demonstrated strong staining for IgA and C3 along the glomerular capillary. Additional tests included positive staining for nephritis-associated plasmin receptor and positive plasmin activity in the glomeruli. Moreover, IgA and galactose-deficient IgA1 (Gd-IgA1) staining merged using immunofluorescence, followed by confirmation of high serum levels of Gd-IgA1 (9.3 μg/mL) by ELISA was observed.

Diagnosis: The diagnosis of IgA-dominant IRGN was made.

Interventions And Outcomes: We have initiated treatment with intravenous methylprednisolone 500 mg/day for 3 days, followed by oral prednisolone 25 mg/d as rapidly progressive glomerulonephritis. However immunosuppressive therapy was halted because of a poor response, and hemodialysis was initiated.

Lessons: This is a case of IgA-dominant IRGN patient exhibiting positive glomerular staining for nephritis-associated plasmin receptor accompanied with high titers of serum Gd-IgA1. Our observations suggest that serum and kidney tissue of Gd-IgA1 may be useful for the diagnosis of IgA-dominant IRGN.
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http://dx.doi.org/10.1097/MD.0000000000024460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870202PMC
February 2021

Influence of Quaternary environmental changes on mole populations inferred from mitochondrial sequences and evolutionary rate estimation.

Zoological Lett 2021 Feb 15;7(1). Epub 2021 Feb 15.

Graduate School of Environmental Science, Hokkaido University, North 10, West 5, Sapporo, 060-0810, Japan.

Quaternary environmental changes fundamentally influenced the genetic diversity of temperate-zone terrestrial animals, including those in the Japanese Archipelago. The genetic diversity of present-day populations is taxon- and region-specific, but its determinants are poorly understood. Here, we analyzed cytochrome b gene (Cytb) sequences (1140 bp) of mitochondrial DNA (mtDNA) to elucidate the factors determining the genetic variation in three species of large moles: Mogera imaizumii and Mogera wogura, which occur in central and southern mainland Japan (Honshu, Shikoku, and Kyushu), and Mogera robusta, which occurs on the nearby Asian continent. Network construction with the Cytb sequences revealed 10 star-shaped clusters with apparent geographic affinity. Mismatch distribution analysis showed that modes of pairwise nucleotide differences (τ values) were grouped into five classes in terms of the level, implying the occurrence of five stages for rapid expansion. It is conceivable that severe cold periods and subsequent warm periods during the late Quaternary were responsible for the population expansion events. The first and third oldest events included island-derived haplotypes, indicative of the involvement of land bridge formation between remote islands, hence suggesting an association of the ends of the penultimate (PGM, ca. 130,000 years ago) and last (LGM, ca. 15,000 years ago) glacial maxima, respectively. Since the third event was followed by the fourth, it is plausible that the termination of the Younger Dryas and subsequent abrupt warming ca. 11,500 years ago facilitated the fourth expansion event. The second event most likely corresponded to early marine isotope stage (MIS) 3 (ca. 53,000 years ago) when the glaciation and subsequent warming period were predicted to have influenced biodiversity. Utilization of the critical times of 130,000, 53,000, 15,000, and 11,500 years ago as calibration points yielded evolutionary rates of 0.03, 0.045, 0.10 and 0.10 substitutions/site/million years, respectively, showing a time-dependent manner whose pattern was similar to that seen in small rodents reported in our previous studies. The age of the fifth expansion event was calculated to be 5800 years ago with a rate of 0.10 substitutions/site/million years ago during the mid-Holocene, suggestive of the influence of humans or other unspecified reasons, such as the Jomon marine transgression.
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http://dx.doi.org/10.1186/s40851-021-00169-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885446PMC
February 2021

Association between atrial fibrillation and white blood cell count after the Great East Japan Earthquake: An observational study from the Fukushima Health Management Survey.

Medicine (Baltimore) 2021 Feb;100(6):e24177

Radiation Medical Science Center for the Fukushima Health Management Survey.

Abstract: We had earlier reported about the increase in the prevalence of atrial fibrillation (AF) among residents in the evacuation zone of Fukushima Prefecture after the Great East Japan Earthquake. In the present investigation, we explored the association between the prevalence of AF and white blood cell (WBC) count after the earthquake through an observational cross-sectional study.A total of 14,800 participants (6427 men and 8373 women) were included in the Fukushima Health Management Survey. For the present study, 12-lead electrocardiogram tracings and the WBC count and its subtypes were obtained and analyzed. The odds ratios (ORs) of AF after the earthquake and the 95% confidence intervals (CIs) for one standard deviation of differential WBC count were calculated after adjustments for age and other potential confounding factors using the logistic regression model.Our results revealed a prevalence of AF of 1.8% (269 participants) after the earthquake. Monocyte count and neutrophil/lymphocyte ratio exhibited a significant association with the prevalence of AF in the multivariable-adjusted model. The adjusted ORs of monocyte count and neutrophil/lymphocyte ratio for AF were 1.21 (95% CI, 1.05-1.40, P = .01) and 1.22 (95% CI, 1.01-1.44, P < .05), respectively.The prevalence of AF was associated with increased monocyte count and neutrophil/lymphocyte ratio among residents in the evacuation zone in Fukushima Prefecture, suggesting that inflammation and psychological stress could be important factors mediating the development of AF after the earthquake.
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http://dx.doi.org/10.1097/MD.0000000000024177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886431PMC
February 2021

Identification, genetic variation, and structural analysis of 18S rRNA of Theileria orientalis and Theileria velifera-like isolates from Myanmar.

Parasitol Int 2021 Jun 2;82:102299. Epub 2021 Feb 2.

Laboratory of Parasitology, Graduate School of Infectious Diseases, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address:

Ribosomal RNA genes have been widely used for the identification and phylogenetic analysis of various organisms, including parasitic protozoa. Here, we report nine near full-length Theileria orientalis 18S rRNA gene sequences from cattle from different areas of Myanmar. Phylogenetic analysis of the 18S rRNA genes revealed a considerably close genetic relationship among T. orientalis isolates from Australia, China, Japan, Korea, Myanmar, and Pakistan. We also obtained four Theileria velifera-like (Theileria cf. velifera) 18S rRNA gene sequences from two cattle and two water buffaloes from the northernmost area of Myanmar. The phylogenetic analysis of T. cf. velifera isolates from Myanmar along with T. velifera and T. cf. velifera isolates from African countries suggested an evolutionary lineage of greater complexity in T. velifera-related parasites. DNA alignment analysis indicated the presence of 51 and 55 nucleotide variation positions within the 18S rRNA genes from 15 T. orientalis and 11 T. velifera-related isolates, respectively. Alignment entropy analysis of the 18S rRNA sequences indicated that both T. orientalis and T. velifera-related isolates had three hyper variable regions, corresponding to V2, V4, and V7 regions in eukaryotes. The degree of variation was prominent in the V2 in T. orientalis and V4 in T. velifera-related isolates. The secondary structure analysis of the 18S rRNA predicted using minimum free energy algorism revealed that the structure of V4 region differed most significantly between T. orientalis and T. velifera. These results provide novel insights into common structures, variations and functions of small subunit rRNA in Theileria species.
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http://dx.doi.org/10.1016/j.parint.2021.102299DOI Listing
June 2021

Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy.

J Autoimmun 2021 Mar 25;118:102593. Epub 2021 Jan 25.

University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Background: IgA nephropathy is thought to be an autoimmune disease wherein galactose-deficient IgA1 (Gd-IgA1) is recognized by IgG autoantibodies, resulting in formation and renal accumulation of nephritogenic immune complexes. Although this hypothesis is supported by recent findings that, in renal immunodeposits of IgA nephropathy patients, IgG is enriched for Gd-IgA1-specific autoantibodies, experimental proof is still lacking.

Methods: IgG isolated from sera of IgA nephropathy patients or produced as a recombinant IgG (rIgG) was mixed with human Gd-IgA1 to form immune complexes. IgG from healthy individuals served as a control. Nude and SCID mice were injected with human IgG and Gd-IgA1, in immune complexes or individually, and their presence in kidneys was ascertained by immunofluorescence. Pathologic changes in the glomeruli were evaluated by quantitative morphometry and exploratory transcriptomic profiling was performed by RNA-Seq.

Results: Immunodeficient mice injected with Gd-IgA1 mixed with IgG autoantibodies from patients with IgA nephropathy, but not Gd-IgA1 mixed with IgG from healthy individuals, displayed IgA, IgG, and mouse complement C3 glomerular deposits and mesangioproliferative glomerular injury with hematuria and proteinuria. Un-complexed Gd-IgA1 or IgG did not induce pathological changes. Moreover, Gd-IgA1-rIgG immune complexes injected into immunodeficient mice induced histopathological changes characteristic of human disease. Exploratory transcriptome profiling of mouse kidney tissues indicated that these immune complexes altered gene expression of multiple pathways, in concordance with the changes observed in kidney biopsies of patients with IgA nephropathy.

Conclusions: This study provides the first in vivo evidence for a pathogenic role of IgG autoantibodies specific for Gd-IgA1 in the pathogenesis of IgA nephropathy.
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http://dx.doi.org/10.1016/j.jaut.2021.102593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997636PMC
March 2021

Heat hypersensitivity is attenuated with altered expression level of spinal astrocytes after sciatic nerve injury in TRPV1 knockout mice.

Neurosci Res 2021 Jan 10. Epub 2021 Jan 10.

Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Transient receptor potential vanilloid 1 (TRPV1) modulates pain. Studies have indicated that TRPV1 is upregulated in the spinal dorsal horn in the neuropathic pain model, but its mechanism is unknown. Here, we examined the mechanism by which TRPV1 modulates neuropathic pain by employing partial sciatic nerve ligation (pSNL) in adult male C57BL/6 J (wild-type: WT) and TRPV1 knockout (Trpv1-/-) mice. We analyzed mechanical/heat sensitivities (von Frey test/hot plate test) and glial/neuronal activities (Iba-1/GFAP/FosB by immunofluorescence) in laminae I and II in the L5 ipsilateral dorsal horn of the spinal cord. Mechanical/heat sensitivities, expression levels of microglial Iba-1 and astrocytic GFAP, and the number of FosB-positive neurons were significantly increased on days 7 and 14 in the pSNL group compared with the sham-operated and non-operated groups of both WT and Trpv1-/- mice. While mechanical sensitivity was comparable between WT and Trpv1-/- mice, the threshold against heat sensitivity was markedly prolonged in Trpv1-/- than WT mice on day 14 after pSNL. Conversely, the increment of FosB positive neurons was significantly attenuated in Trpv1-/- than WT mice on days 7 and 14 after pSNL. These results suggest that TRPV1 may modulate thermal perception via increased astrocytes in the dorsal horn of the spinal cord.
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http://dx.doi.org/10.1016/j.neures.2020.12.007DOI Listing
January 2021

[Giant Left Atrial Myxoma Found with Congestive Heart Failure;Report of a Case].

Kyobu Geka 2020 Dec;73(13):1113-1116

Department of Cardiovascular Surgery, Mie Prefectural General Medical Center, Yokkaichi, Japan.

We report a case of giant left atrial myxoma in a 52-year-old woman who developed congestive heart failure. By echocardiography, not only the myxoma but moderate degree of mitral and tricuspid regurgitation was also found. The tumor was extensively attached to the left atrial endocardium, and was excised completely together with the endocardium. No valve surgery was added. Postoperative echocardiography showed no myxoma and no mitral valve regurgitation. She was discharged in good condition on postoperative day 14.
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December 2020

[Surgical Repair of Giant Coronary Artery Aneurysm Associated with Coronary-pulmonary Artery Fistulae;Report of a Case].

Kyobu Geka 2020 Nov;73(12):1018-1021

Department of Cardiovascular Surgery, Mie Prefectural General Medical Center, Yokkaichi, Japan.

A 61-year-old woman was referred to our hospital with a complaint of chest compression. Coronary angiography revealed a giant coronary artery aneurysm, located in the middle of a coronary-pulmonary artery fistula originating from the right coronary artery. Another fistula was also shown between the left anterior descending artery and the pulmonary artery. Surgical correction was indicated due to the risks of the aneurysmal rupture and coronary events. Under cardiopulmonary bypass, suture-closure of the coronary artery aneurysm and ligations of the fistulae were carried. Postoperative coronary angiography showed no aneurysm or fistula, and she was discharged uneventfully on the 12th postoperative day.
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November 2020

Mouse Hair Significantly Lightened Through Replacement of the Cysteine Residue in the N-Terminal Domain of Mc1r Using the CRISPR/Cas9 System.

J Hered 2020 12;111(7):640-645

and Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo, Kumamoto, Japan.

A loss-of-function mutation in the melanocortin 1 receptor gene (MC1R), which switches off the eumelanin production, causes yellowish coat color variants in mammals. In a wild population of sables (Martes zibellina) in Hokkaido, Japan, the mutation responsible for a bright yellow coat color variant was inferred to be a cysteine replacement at codon 35 of the N-terminal extracellular domain of the Mc1r receptor. In the present study, we validated these findings by applying genome editing on Mc1r in mouse strains C3H/HeJ and C57BL/6N, altering the codon for cysteine (Cys33Phe). The resulting single amino acid substitution (Cys33Phe) and unintentionally generated frameshift mutations yielded a color variant exhibiting substantially brighter body color, indicating that the Cys35 replacement produced sufficient MC1R loss of function to confirm that this mutation is responsible for producing the Hokkaido sable yellow color variant. Notably, the yellowish mutant mouse phenotype exhibited brown coloration in subapical hair on the dorsal side in both the C3H/HeJ and C57BL/6N strains, despite the inability of the latter to produce the agouti signaling protein (Asip). This darker hair and body coloration was not apparent in the Hokkaido sable variant, implying the presence of an additional genetic system shaping yellowish hair variability.
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http://dx.doi.org/10.1093/jhered/esaa054DOI Listing
December 2020

[Severe Calcification on Glutaraldehyde-treated Autologous Pericardium after Mitral Valve Repair by Leaflet Augmentation;Report of a Case].

Kyobu Geka 2020 Oct;73(11):944-946

Department of Cardiovascular Surgery, Mie Prefectural General Medical Center, Yokkaichi, Japan.

We report a case of surgical treatment of mitral valve stenosis due to severe calcification on the glutaraldehyde-treated autologous pericardium. A 39-year-old woman presented with progressive dyspnea. She had undergone mitral valve repair by leaflet augmentation with a glutaraldehyde-treated autologous pericardium for mitral regurgitation 3 years before. Transthoracic echocardiography showed mitral valve stenosis with limited movement of the anterior leaflet. At redo surgery, severe calcification was observed of the glutaraldehyde-treated autologous pericardium patch on the anterior mitral leaflet. Mitral valve replacement was performed successfully, and she was discharged on postoperative day 14.
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October 2020

Structural elasticity for tensile deformation of a single human hair and the comparison with it for the bending deformation.

J Mech Behav Biomed Mater 2021 01 26;113:104166. Epub 2020 Oct 26.

Department of Finemechanics, Tohoku University, Sendai 980-8579, Japan.

Human hair is a multi-layered structure, which consists of the inner medulla, middle cortex, and outer cuticle. Therefore, the mechanical properties of the hair are related not only to the Young's modulus of each layer but also to the internal structures. Although the tensile test of a human hair has been performed elsewhere, the deformability of the hair for the tensile deformation is determined as the Young's modulus of the hair structure, which is similar to that of metals. In this paper, the structural elasticity of a single human hair for the tensile deformation, which expresses the deformability of a hair by tension without being dependent on external dimensions and shape, is defined based on the theoretical model, and is measured by performing the tensile test under the digital microscope observation. The values of the structural elasticity for the tensile deformation of the hair samples collected from healthy persons are compared with the values obtained for bending deformation. The structural elasticity for the tensile deformation of the hair sample is found to be lesser than that of the bending deformation, and this is verified to be always valid provided the Young's modulus of the outer cuticle is greater than that of the middle cortex.
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http://dx.doi.org/10.1016/j.jmbbm.2020.104166DOI Listing
January 2021

Factors associated with mortality among patients with necrotizing soft tissue infections: An analysis of 4597 cases using the Diagnosis Procedure Combination Database.

Int J Infect Dis 2021 Jan 13;102:73-78. Epub 2020 Oct 13.

Department of Orthopedics, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi, Kitakyushu, 8078555, Japan. Electronic address:

Objective: This study aimed to determine the factors associated with mortality among patients with necrotizing soft tissue infection (NSTI) in Japan using inpatient data from the Diagnosis Procedure Combination (DPC) Database.

Methods: We conducted a cross-sectional study using a population retrieved from the Japanese DPC inpatient database of patients who underwent surgical operations from 2014 through 2017. The associations between the covariates and mortality were estimated using multivariate logistic regression models.

Results: In total, 4597 patients were registered in this study, with an overall mortality rate of 6.9%. Multilevel logistic regression analysis revealed that higher age, lower body mass index (BMI < 18.5 kg/m), pre-existing cancer diagnosis, sepsis at admission, maintenance dialysis, antithrombin III use, and anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotic use were associated with a high mortality rate among NSTI patients. However, sex, underlying diabetes mellitus, ambulance use at admission, intravenous immunoglobulin use, higher hospital case volume, and frequency of operations were not associated with mortality.

Conclusion: This study is the first to report the association of lower BMI, antithrombin III use, and anti-MRSA antibiotic use with a higher mortality rate among NSTI patients.
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http://dx.doi.org/10.1016/j.ijid.2020.10.019DOI Listing
January 2021

Genetic Diversity and Phylogeography of () in Asian House Shrew () in Eurasia.

Front Cell Infect Microbiol 2020 27;10:438. Epub 2020 Aug 27.

Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan.

Murid and cricetid rodents were previously believed to be the principal reservoir hosts of hantaviruses. Recently, however, multiple newfound hantaviruses have been discovered in shrews, moles, and bats, suggesting a complex evolutionary history. Little is known about the genetic diversity and geographic distribution of the prototype shrew-borne hantavirus, (TPMV), carried by the Asian house shrew (), which is widespread in Asia, Africa, and the Middle East. Comparison of TPMV genomic sequences from two Asian house shrews captured in Myanmar and Pakistan with TPMV strains in GenBank revealed that the Myanmar TPMV strain (H2763) was closely related to the prototype TPMV strain (VRC66412) from India. In the L-segment tree, on the other hand, the Pakistan TPMV strain (PK3629) appeared to be the most divergent, followed by TPMV strains from Nepal, then the Indian-Myanmar strains, and finally TPMV strains from China. The Myanmar strain of TPMV showed sequence similarity of 79.3-96.1% at the nucleotide level, but the deduced amino acid sequences showed a high degree of conservation of more than 94% with TPMV strains from Nepal, India, Pakistan, and China. Cophylogenetic analysis of host cytochrome and TPMV strains suggested that the Pakistan TPMV strain was mismatched. Phylogenetic trees, based on host cytochrome and cytochrome c oxidase subunit I genes of mitochondrial DNA, and on host recombination activating gene 1 of nuclear DNA, suggested that the Asian house shrew and Asian highland shrew () comprised a species complex. Overall, the geographic-specific clustering of TPMV strains in Asian countries suggested local host-specific adaptation. Additional in-depth studies are warranted to ascertain if TPMV originated in Asian house shrews on the Indian subcontinent.
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http://dx.doi.org/10.3389/fcimb.2020.00438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481397PMC
June 2021

Genetic Diversity of Isopods in Hokkaido and Niigata, Northern Japan, Based on Mitochondrial DNA Analysis.

Zoolog Sci 2020 Oct;37(5):417-428

Graduate School of Environmental Science, Hokkaido University, Kita-ku, Sapporo 060-0810, Japan.

The genetic diversity of the genus in Hokkaido and Niigata, northern Japan, was investigated by analyzing the cytochrome c oxidase subunit 1 (CO1) region in the mitochondrial DNA (mtDNA). The genetic diversity in Hokkaido was much lower than that in Niigata. Nine different operational taxonomic units (OTUs) were identified. Only a single OTU, most likely , was found in Hokkaido, whereas all nine OTUs were found in Niigata. Using the mtDNA evolutionary rate determined for the marine invertebrate (Miers, 1880), population expansion for OTU1 in Hokkaido was estimated to have occurred at 12,600 years BP, suggesting that underwent a bottleneck due to glacial cooling, and the population then expanded after postglacial warming. Assuming that the expansion of the OTU1 population occurred at 9600 years BP, when the sea surface temperature rose offshore of Tokachi in the Northwestern Pacific, the evolutionary rate (µ) of the mtDNA CO1 region in is calculated as: 0.087 (95% confidence intervals: min: 0.042-max: 0.12) (substitutions/site/million years). The presence of a haplotype common to Hokkaido and Niigata implies that the haplotype migrated across the Tsugaru Strait. Considering that geological evidence indicates that the Tsugaru Strait was continuously present even during the last glacial maximum when the sea level was at its lowest, accidental transport by human beings or animals might have been critical to the migration of .
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http://dx.doi.org/10.2108/zs200017DOI Listing
October 2020

Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases.

BMC Nephrol 2020 09 18;21(1):402. Epub 2020 Sep 18.

Department of Nephrology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Background: Dipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear.

Methods: The localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte.

Results: DPP-4 activity under normal conditions was observed in some Bowman's capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA. Saxagliptin also improved the detachment of podocytes.

Conclusions: DPP-4 activity induces degradation of synaptopodin and reduction of RhoA, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.
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http://dx.doi.org/10.1186/s12882-020-02060-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501714PMC
September 2020

House mouse Mus musculus dispersal in East Eurasia inferred from 98 newly determined complete mitochondrial genome sequences.

Heredity (Edinb) 2021 Jan 15;126(1):132-147. Epub 2020 Sep 15.

Graduate School of Environmental Science, Hokkaido University, North 10, West 5, Kita-ku, Sapporo, 060-0810, Japan.

The Eurasian house mouse Mus musculus is useful for tracing prehistorical human movement related to the spread of farming. We determined whole mitochondrial DNA (mtDNA) sequences (ca. 16,000 bp) of 98 wild-derived individuals of two subspecies, M. m. musculus (MUS) and M. m. castaneus (CAS). We revealed directional dispersals reaching as far as the Japanese Archipelago from their homelands. Our phylogenetic analysis indicated that the eastward movement of MUS was characterised by five step-wise regional extension events: (1) broad spatial expansion into eastern Europe and the western part of western China, (2) dispersal to the eastern part of western China, (3) dispersal to northern China, (4) dispersal to the Korean Peninsula and (5) colonisation and expansion in the Japanese Archipelago. These events were estimated to have occurred during the last 2000-18,000 years. The dispersal of CAS was characterised by three events: initial divergences (ca. 7000-9000 years ago) of haplogroups in northernmost China and the eastern coast of India, followed by two population expansion events that likely originated from the Yangtze River basin to broad areas of South and Southeast Asia, including Sri Lanka, Bangladesh and Indonesia (ca. 4000-6000 years ago) and to Yunnan, southern China and the Japanese Archipelago (ca. 2000-3500). This study provides a solid framework for the spatiotemporal movement of the human-associated organisms in Holocene Eastern Eurasia using whole mtDNA sequences, reliable evolutionary rates and accurate branching patterns. The information obtained here contributes to the analysis of a variety of animals and plants associated with prehistoric human migration.
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http://dx.doi.org/10.1038/s41437-020-00364-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852662PMC
January 2021

The effectiveness of very slow switching to aripiprazole in schizophrenia patients with dopamine supersensitivity psychosis: a case series from an open study.

Int Clin Psychopharmacol 2020 11;35(6):338-344

Department of Psychiatry, Chiba University Graduate School of Medicine.

Dopamine supersensitivity psychosis (DSP) in patients with schizophrenia is induced by treatment with a high dosage of antipsychotics for a long time period, and it is characterized by unstable psychotic symptoms. The upregulation of dopamine D2 receptor (DRD2) provoked by antipsychotics underlies DSP. Aripiprazole does not cause an excessive blockade of DRD2 and is less likely to upregulate DRD2 by aripiprazole's dopamine partial agonistic profile. Aripiprazole; however, has a potential risk of inducing severe rebound psychosis in patients who have already developed dopamine supersensitivity. Recently, an animal model study suggested that aripiprazole could attenuate established dopamine supersensitivity. The present study was conducted to examine whether very slowly switching to aripiprazole could help patients with schizophrenia with dopamine supersensitivity while avoiding rebound psychosis. This study was a single-armed and open-labeled study in which patients were observed over a period of 2 years. Only 11 patients were ultimately recruited. Five patients were successfully switched to a sufficient dose of aripiprazole and completed the study protocol. These five patients did not present with severe DSP over the study period, but only one patient showed a large improvement in psychopathology. Five patients dropped out of the study, and one of these five showed a severe worsening of psychosis. The present study indicated that the introduction of aripiprazole in patients with DSP was difficult, but suggested that aripiprazole could contribute to attaining a stable state in psychosis if it was applied with careful observation.
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http://dx.doi.org/10.1097/YIC.0000000000000322DOI Listing
November 2020

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia.

Clin Exp Nephrol 2021 Jan 28;25(1):1-8. Epub 2020 Aug 28.

Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

Background: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria.

Methods: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation.

Results: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls.

Conclusion: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia.

Trial Registration: Trial registration number: jRCTs042180076.
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http://dx.doi.org/10.1007/s10157-020-01959-9DOI Listing
January 2021

The neurohypophysial oxytocin and arginine vasopressin system is activated in a knee osteoarthritis rat model.

J Neuroendocrinol 2020 08 6;32(8):e12892. Epub 2020 Aug 6.

Department of Orthopaedics Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Osteoarthritis (OA) causes chronic joint pain and significantly impacts daily activities. Hence, developing novel treatment options for OA has become an increasingly important area of research. Recently, studies have reported that exogenous, as well as endogenous, hypothalamic-neurohypophysial hormones, oxytocin (OXT) and arginine-vasopressin (AVP), significantly contribute to nociception modulation. Moreover, the parvocellular OXT neurone (parvOXT) extends its projection to the superficial spinal dorsal horn, where it controls the transmission of nociceptive signals. Meanwhile, AVP produced in the magnocellular AVP neurone (magnAVP) is released into the systemic circulation where it contributes to pain management at peripheral sites. The parvocellular AVP neurone (parvAVP), as well as corticotrophin-releasing hormone (CRH), suppresses inflammation via activation of the hypothalamic-pituitary adrenal (HPA) axis. Previously, we confirmed that the OXT/AVP system is activated in rat models of pain. However, the roles of endogenous hypothalamic-neurohypophysial hormones in OA have not yet been characterised. In the present study, we investigated whether the OXT/AVP system is activated in a knee OA rat model. Our results show that putative parvOXT is activated and the amount of OXT-monomeric red fluorescent protein 1 positive granules in the ipsilateral superficial spinal dorsal horn increases in the knee OA rat. Furthermore, both magnAVP and parvAVP are activated, concurrent with HPA axis activation, predominantly modulated by AVP, and not CRH. The OXT/AVP system in OA rats was similar to that in systemic inflammation models, including adjuvant arthritis; however, magnocellular OXT neurones (magnOXT) were not activated in OA. Hence, localised chronic pain conditions, such as knee OA, activate the OXT/AVP system without impacting magnOXT.
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http://dx.doi.org/10.1111/jne.12892DOI Listing
August 2020

Influence of post-disaster evacuation on incidence of hyperuricemia in residents of Fukushima Prefecture: the Fukushima Health Management Survey.

Clin Exp Nephrol 2020 Nov 26;24(11):1025-1032. Epub 2020 Jul 26.

Radiation Medical Science Center, Fukushima Health Management Survey, Fukushima Medical University, Fukushima, Japan.

Aim: After the Great East Japan Earthquake, over 160,000 residents in Fukushima Prefecture were forced to evacuate the area around the Fukushima Daiichi power plant following nuclear accident there. Health problems in these evacuees have since become a major issue. We have examined the association between evacuation and incidence of hyperuricemia among residents in Fukushima.

Methods: We conducted a cohort study of residents aged 40-90 years without hyperuricemia at the time of the Fukushima disaster. Among 8173 residents who met the inclusion criteria before the disaster, 4789 residents (men: 1971, women: 2818; follow-up duration: 1.38 years; and follow-up rate: 58.6%) remained available for follow-up examinations at the end of March 2013. The main endpoint was incidence of hyperuricemia, defined by the Japanese committee guidelines, using local health data from before and after the disaster. We divided participants by evacuation status and compared outcomes between groups. Using a logistic regression model, we estimated the odds ratio for incidence of hyperuricemia, adjusting for potential confounders, age, gender, waist circumference, physical activity, and alcohol consumption.

Results: Incidence of hyperuricemia was higher in evacuees (men 10.1%; women 1.1%) than in non-evacuees (men 7.4%, women 1.0%). Evacuees had higher body mass index, waist circumference, triglycerides, LDL-cholesterol, fasting plasma glucose, HbA1c, and lower HDL-cholesterol after the disaster than non-evacuees. We found that evacuation was associated with incidence of hyperuricemia (adjusted odds ratio: 1.38; 95% confidence interval: 1.03-1.86).

Conclusion: This is the first study to demonstrate an association between evacuation after a disaster and increased incidence of hyperuricemia.
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http://dx.doi.org/10.1007/s10157-020-01924-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524849PMC
November 2020

Presynaptic glutamatergic transmission and feedback system of oxytocinergic neurons in the hypothalamus of a rat model of adjuvant arthritis.

Mol Pain 2020 Jan-Dec;16:1744806920943334

Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

The neurohypophysial hormone oxytocin (OXT) is synthesized in the hypothalamic paraventricular and supraoptic nuclei. Recently, some studies have considered OXT to be important in sensory modulation and that the OXT protein is upregulated by acute and chronic nociception. However, the mechanism by which OXT is upregulated in neurons is unknown. In this study, we examined the resting membrane potentials and excitatory postsynaptic currents in OXT-ergic neurons in the paraventricular nucleus in adjuvant arthritis rat model, a model of chronic inflammation, using whole-cell patch-clamping. Transgenic rats expressing OXT and monomeric red fluorescent protein 1 (mRFP1) fusion protein to visualize the OXT-ergic neurons were used, and the OXT-mRFP1 transgenic rat model of adjuvant arthritis was developed by injection of heat-killed . Furthermore, the feedback system of synthesized OXT was also examined using the OXT receptor antagonist L-368,899. We found that the resting membrane potentials and frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-monomeric red fluorescent protein 1 neurons in the paraventricular nucleus were significantly increased in adjuvant arthritis rats. Furthermore, L-368,899 dose-dependently increased the frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-ergic neurons. Following bath application of the GABA receptor antagonist picrotoxin and the cannabinoid receptor 1 antagonist AM 251, L-368,899 still increased the frequency of miniature excitatory postsynaptic currents. However, following bath application of the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride, L-368,899 did not alter the miniature excitatory postsynaptic current frequency. Thus, it is suggested that OXT-ergic neuron activity is upregulated via an increase in glutamate release, and that the upregulated OXT neurons have a feedback system with released endogenous OXT. It is possible that nitric oxide, but not GABA, may contribute to the feedback system of OXT neurons in chronic inflammation.
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http://dx.doi.org/10.1177/1744806920943334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372626PMC
June 2021

Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.

CEN Case Rep 2021 02 16;10(1):17-22. Epub 2020 Jul 16.

Department of Nephrology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
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http://dx.doi.org/10.1007/s13730-020-00508-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829275PMC
February 2021

Rapid progression to end-stage renal disease in a child with IgA-dominant infection-related glomerulonephritis associated with parvovirus B19.

CEN Case Rep 2020 11 3;9(4):423-430. Epub 2020 Jul 3.

Department of Pediatric Nephrology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.

Parvovirus B19 (PVB19) has been known to cause acute glomerulonephritis and nephrotic syndrome with various renal histologic patterns, such as endocapillary glomerulonephritis and collapsing glomerulopathy. Remission is achieved spontaneously or by treatment with steroid and/or immunosuppressants in most patients, except those with sickle cell anemia or two APOL1 risk alleles. In this study, we report the case of a previously healthy 5-year-old boy with infection-related glomerulonephritis (IRGN) associated with PVB19 that progressed to end-stage renal disease (ESRD). He presented with macrohematuria, nephrotic-range proteinuria, and progressive renal dysfunction despite treatment with methylprednisolone pulse therapy, plasmapheresis, and intravenous immunoglobulin. The kidney biopsy specimens exhibited endocapillary infiltration and mesangiolysis with cellular crescent formation. Immunofluorescence analysis revealed that IgA was dominantly positive in the glomeruli, with some co-localized with KM55, which is a specific monoclonal antibody for galactose-deficient IgA1 (Gd-IgA1). The intensity of the KM55 signal in the present patient was weaker than that in patients with IgA nephropathy. To our knowledge, this is the first report of IRGN associated with PVB19 that progressed to ESRD without any underlying diseases. Further investigations are needed to determine the significance of IgA and Gd-IgA1 deposition in IRGN associated with PVB19.
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http://dx.doi.org/10.1007/s13730-020-00501-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502115PMC
November 2020

Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy.

J Am Soc Nephrol 2020 09 1;31(9):2013-2024. Epub 2020 Jul 1.

Department of Nephrology, Juntendo University, Tokyo, Japan

Background: IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition.

Methods: We established an AIM-deficient IgAN model ( gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model ( gddY) was also generated to further determine the role of AIM.

Results: In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45 leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in gddY mice.

Conclusions: AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.
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http://dx.doi.org/10.1681/ASN.2019100987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461693PMC
September 2020

Penetrating nail-gun injury of the thoracic descending aorta.

Acute Med Surg 2020 Jan-Dec;7(1):e530. Epub 2020 Jun 19.

Mie General Medical Center, Emergency and Critical Care Center Yokkaichi Mie Japan.

Penetrating injury of the descending aorta due to accidental discharge of a nail gun.
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http://dx.doi.org/10.1002/ams2.530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305459PMC
June 2020

Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy.

Kidney Dis (Basel) 2020 May 16;6(3):168-180. Epub 2020 Apr 16.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objectives: IgA nephropathy (IgAN) is thought to involve an autoimmune process wherein galactose-deficient IgA1 (Gd-IgA1), recognized as autoantigen by autoantibodies, forms pathogenic immune complexes. Mounting evidence has implicated abnormal activation of some protein-tyrosine kinases (PTKs) in IgAN. Furthermore, genome-wide association studies (GWAS) of IgAN provided insight into disease pathobiology and genetics. A GWAS locus on chromosome 22q12 contains genes encoding leukemia inhibitory factor (LIF) and oncostatin M, interleukin (IL)-6-related cytokines implicated in mucosal immunity and inflammation. We have previously shown that IL-6 mediates overproduction of Gd-IgA1 through aberrant STAT3 activation. Here, we show that LIF enhanced production of Gd-IgA1 in IgA1-secreting cells of patients with IgAN and provide initial analyses of LIF signaling.

Methods: We characterized LIF signaling that is involved in the overproduction of Gd-IgA1, using IgA1-secreting cell lines derived from peripheral blood of patients with IgAN and healthy controls (HC). We used global PTK activity profiling, immunoblotting, lectin ELISA, and siRNA knock-down.

Results: LIF stimulation did not significantly affect production of total IgA1 in IgA1-secreting cells from patients with IgAN or HC. However, LIF increased production of Gd-IgA1, but only in the cells from patients with IgAN. LIF stimulation enhanced phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN to a higher degree than in the cells from HC. siRNA knock-down of STAT1 blocked LIF-mediated overproduction of Gd-IgA1. Unexpectedly, this abnormal phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN was not mediated by JAK, but rather involved activation of Src-family PTKs (SFKs).

Conclusion: Abnormal LIF/STAT1 signaling represents another pathway potentially leading to overproduction of Gd-IgA1 in IgAN, providing possible explanation for the phenotype associated with chromosome 22q12 GWAS locus. Abnormal LIF/STAT1 signaling and the associated SFKs may represent potential diagnostic and/or therapeutic targets in IgAN.
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http://dx.doi.org/10.1159/000505748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265702PMC
May 2020