Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy.

Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown. Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE. Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation. Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models. Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h. Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients. IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models. These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV. Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE.

Short term-efficacy and tolerability of Rheocarna, a novel direct hemoperfusion adsorptive column, for chronic limb-threatening ischemia in dialysis patients: A single-center case series.

INTRODUCTION: With population aging and lifestyle changes, the number of patients with chronic limb-threatening ischemia (CLTI) is increasing, and refractory or recurrent lesions are more common, especially in chronic dialysis patients. In March 2021, a new type of adsorptive cellulose bead column immobilized with dextran sulfate and L-tryptophan for direct hemoperfusion (DHP) was approved by Japan's medical insurance system as a treatment for CLTI. METHODS: We retrospectively analyzed 17 cases of CLTI in dialysis patients treated with DHP using the novel column (Rheocarna) (DHP-R) at our hospital from May 2021 to October 2022. The short-term of efficacy of DHP-R was judged qualitatively by the foot care team every 2 weeks based on the assessment of skin color, warmth, ulcer epithelialization or shrinkage of the ulcer area, and foot pain. The final judgment of efficacy was made after the final DHP-R session. RESULTS: The median age of patients was 66 years, the median dialysis duration was 10 years, 15 cases (88%) were male, and 15 cases (88%) had diabetes. The median total number of sessions was eight. In comparing the groups in which DHP-R was effective and ineffective, there was no significant difference in any factors including patient background data (i.e., age, diabetes, low-density lipoprotein cholesterol, hemoglobin, dialysis duration, etc.), type of anticoagulants, and presence of episodes of blood pressure drop or circuit clotting during session. Three cases with symptomatic hypotension during the session and two cases with circuit clotting that did not improve with increased heparin dose all resolved immediately after changing the anticoagulant from heparin to nafamostat mesylate (NM). CONCLUSION: Identification of patients' characteristics in which DHP-R is favorable and some reliable index that allow a rapid decision to continue DHP-R are needed. In addition, validating whether the use of NM as anticoagulant affects the efficacy of DHP-R for CTLI treatment remains a challenge to resolve.

Managing the symptom burden associated with maintenance dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Individuals with kidney failure undergoing maintenance dialysis frequently report a high symptom burden that can interfere with functioning and diminish life satisfaction. Until recently, the focus of nephrology care for dialysis patients has been related primarily to numerical targets for laboratory measures, and outcomes such as cardiovascular disease and mortality. Routine symptom assessment is not universal or standardized in dialysis care. Even when symptoms are identified, treatment options are limited and are initiated infrequently, in part because of a paucity of evidence in the dialysis population and the complexities of medication interactions in kidney failure. In May of 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference-Symptom-Based Complications in Dialysis-to identify the optimal means for diagnosing and managing symptom-based complications in patients undergoing maintenance dialysis. Participants included patients, physicians, behavioral therapists, nurses, pharmacists, and clinical researchers. They outlined foundational principles and consensus points related to identifying and addressing symptoms experienced by patients undergoing dialysis and described gaps in the knowledge base and priorities for research. Healthcare delivery and education systems have a responsibility to provide individualized symptom assessment and management. Nephrology teams should take the lead in symptom management, although this does not necessarily mean taking ownership of all aspects of care. Even when options for clinical response are limited, clinicians should focus on acknowledging, prioritizing, and managing symptoms that are most important to individual patients. A recognized factor in the initiation and implementation of improvements in symptom assessment and management is that they will be based on locally existing needs and resources.

Successful Use of Granulocyte and Monocyte Adsorptive Apheresis in a Patient with Post-COVID-19 Multisystem Inflammatory Syndrome in Adults.

Multisystem inflammatory syndrome in adults (MIS-A) is a life-threatening disease that can develop weeks after coronavirus disease 2019 (COVID-19). MIS-A symptoms include multiorgan involvement, especially gastrointestinal tract and heart involvement, and Kawasaki disease-like symptoms. We herein report a 44-year-old Japanese man with MIS-A who had contracted COVID-19 five weeks ago and went into shock after acute gastroenteritis, acute kidney injury, and Kawasaki disease-like symptoms. Methylprednisone pulse and high-dose intravenous immunoglobulin resulted in recovery of shock and his renal function, but diffuse ST-segment elevation on electrocardiography and pericardial effusion with a fever emerged after therapy. Additional granulocyte-monocyte adsorptive apheresis successfully ameliorated the cardiac involvement.

GCN2 kinase-mediated upregulation of ubiquitin C maintains intracellular glutamine level and tRNAGln (CUG) charging under amino acid starvation.

Each tRNA is aminoacylated (charged) with a genetic codon-specific amino acid. It remains unclear what factors are associated with tRNA charging and how tRNA charging is maintained. By using the individual tRNA acylation PCR method, we found that the charging ratio of tRNAGln (CUG) reflects cellular glutamine level. When uncharged tRNAGln (CUG) increased under amino acid starvation, the kinase GCN2, which is a key stimulator of the integrated stress response, was activated. Activation of GCN2 led to the upregulation of ubiquitin C (UBC) expression. Upregulated UBC, in turn, suppressed the further reduction in tRNAGln (CUG) charging levels. Thus, tRNA charging is sensitive to intracellular nutrient status and is an important initiator of intracellular signaling.

i-tRAP (individual tRNA acylation PCR): A convenient method for selective quantification of tRNA charging.

Each transfer RNA (tRNA) is aminoacylated (charged) with a genetic codon-specific amino acid at its 3' end. Charged tRNAs are primarily used for translation, whereas fluctuations in charged tRNA fractions are known to reflect cellular response to stress. Here we report the development of individual tRNA-acylation using PCR (i-tRAP), a convenient PCR-based method that can specifically quantify individual tRNA charging ratio. In this i-tRAP method, demethylases remove base methylations which are problematic for reverse transcription reaction, and ß-elimination reaction specifically removes the 3' end of adenine residue in uncharged tRNA. Subsequent TaqMan MGB qRT-PCR can distinguish between cDNA of charged tRNA and uncharged tRNA. By using this method, we revealed that the charging ratio of tRNAGln(CUG) was changed in response to amino acid starvation and also the charging ratio of tRNAGln(CUG) in senescent cells was lower than in young cells under starvation conditions. i-tRAP can be applicable to the quantification of charging ratio of various tRNAs, and provides a simple and convenient method for analyzing tRNA charging.

Development of IgA vasculitis with severe glomerulonephritis after COVID-19 vaccination: a case report and literature review.

With the worldwide spread of the COVID-19 vaccine program during the COVID-19 pandemic, the numbers of reported cases with new-onset or relapsed kidney disease/vasculitis such as minimal change nephrotic syndrome, immunoglobulinA (IgA) nephropathy, and IgA vasculitis (IgAV) that developed after COVID-19 vaccination are increasing. We present the case of a 67-year-old Japanese woman who developed IgAV with purpura on her extremities and trunk in the evening of the day that she received the second dose of the Pfizer-BioNTech COVID-19 vaccine. She subsequently presented with acute kidney injury and nephrotic syndrome, and a kidney biopsy performed 14 days after the second vaccination showed diffuse mesangial and endocapillary glomerulonephritis with necrotizing crescent formation, accompanied by IgA deposition. One steroid pulse plus four administrations of a monthly intravenous cyclophosphamide injection were applied, followed by oral azathioprine during oral steroid tapering. Her response to this treatment was unsatisfactory and intractable for some time. Eventually, her renal function improved and nephrotic syndrome was resolved, while microscopic hematuria and proteinuria at ~ 1 g/gCr remained at 6 months post-vaccination. Unlike the previous milder renal-involved IgAV cases following COVID-19 vaccination, our patient's case presented severe glomerulonephritis and took a long time to recover despite intensive initial immunosuppressive treatment.

d-Serine Mediates Cellular Proliferation for Kidney Remodeling.

Background: d-serine, a long-term undetected enantiomer of serine, is a biomarker that reflects kidney function and disease activity. The physiologic functions of d-serine are unclear. Methods: The dynamics of d-serine were assessed by measuring d-serine in human samples of living kidney donors using two-dimensional high-performance liquid chromatography, and by autoradiographic studies in mice. The effects of d-serine on the kidney were examined by gene expression profiling and metabolic studies using unilateral nephrectomy mice, and genetically modified cells. Results: Unilateral nephrectomy in human living kidney donors decreases urinary excretion and thus increases the blood level of d-serine. d-serine is quickly and dominantly distributed to the kidney on injection in mice, suggesting the kidney is a main target organ. Treatment of d-serine at a low dose promotes the enlargement of remnant kidney in mouse model. Mechanistically, d-serine activates the cell cycle for tissue remodeling through an mTOR-related pathway. Conclusions: d-serine is a physiologic molecule that promotes kidney remodeling. Besides its function as a biomarker, d-serine has a physiologic activity that influences kidney function.

Successful peritoneal dialysis for the end-stage kidney disease associated with Prader-Willi syndrome: a case report.

Prader-Willi Syndrome (PWS) is characterized by hyperphagia, severe obesity, and mental retardation from early childhood and occurs 1/10,000 to 1/15,000 live births in Japan. There is high prevalence of diabetes mellitus because of hyperphagia. The patient may sometimes face the necessity of renal replacement therapy (RRT) because of end-stage kidney disease (ESKD) caused by diabetes-associated kidney disease (DKD). Since mental retardation and extreme obesity usually prevent to introduce peritoneal dialysis (PD), hemodialysis (HD) has been the first choice of RRT. In this report, we experienced one case of patient with PWS suffering from ESKD due to DKD who started PD as an initial RRT and succeeded to continue for total of 40 months. The patient was 37-year-old man at the time of initiation of dialysis. PD was chosen for RRT because we suspected that he might have more technical difficulties for continuing HD. After several episodes of peritonitis, he successfully continues PD without peritonitis for next 27 months until the present time with good support by his family member. To our best knowledge, this is the first reported case of ESKD associated with PWS who was successfully treated with PD for long period.

2017 Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update Implementation: Asia Summit Conference Report.

Improving Global Outcomes (KDIGO) Clinical Practice Guideline on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) 2009 provided recommendations on the detection, evaluation, and treatment of CKD-MBD in patients CKD who are and are not undergoing dialysis. Because of the accumulation of evidence since this initial publication, the CKD-MBD Guideline underwent a selective update in 2017. In April 2018, KDIGO convened a CKD-MBD Guideline Implementation Summit in Japan with the key objective to discuss various barriers to the uptake and implementation of the CKD-MBD Guideline in 8 Asian countries/regions. These countries/regions were comparable according to their high-to-middle economic ranking assigned by the World Bank. The discussion took into account the availability of CKD-MBD medication therapies and government health policies that may influence reimbursement and practice patterns in the region. Most importantly, Summit participants developed a framework of multifaceted strategies aimed at overcoming barriers to guideline implementation. The Summit attendees suggested a shared decision-making approach between clinicians and patients in CKD-MBD management, as well as individualized care based on the treatment risk-benefit ratio. The Summit participants also discussed how KDIGO, as a guideline development organization, may work in partnership with local and national nephrology societies to provide education and facilitate implementation of the guideline by clinicians. The conclusions drawn from this Summit in Asia may serve as an important guide for other regions to follow.

Novel crystalline organic-inorganic hybrid silicate material composed of the alternate stacking of semi-layered zeolite and microporous organic layers.

A novel type of crystalline organic-inorganic hybrid microporous silicate material, KCS-5, was synthesized supposedly from a lamellar precursor composed of amphiphilic organosilicic acids. This well-ordered material has a crystalline structure, is thermally stable up to 500 °C and has lipophilic 1-dimensional micropores.

Adipokinetic hormone signaling determines dietary fatty acid preference through maintenance of hemolymph fatty acid composition in the cricket Gryllus bimaculatus.

Adipokinetic hormone (AKH), an analog of mammalian glucagon, functions in supplying the required energy by releasing lipids and carbohydrates from the fat body into the hemolymph. Our previous study showed that AKH receptor (AKHR) knockdown in the two-spotted cricket Gryllus bimaculatus decreased hemolymph lipid levels and increased its feeding frequency. To reveal underlying mechanisms by which AKH signaling modulates lipid homeostasis, we analyzed the fatty acid composition as the lipid structure in the crickets. AKH administration significantly increased the proportion of unsaturated fatty acids (USFAs) to total fatty acids with decrease of the saturated fatty acids (SFAs) in hemolymph, while these proportions were inversely changed in RNA interference-mediated AKHR-knockdowned (AKHRRNAi) crickets. Interestingly, knockdown of hormone-sensitive lipase (Hsl) by RNAi (HslRNAi) affected the proportion of USFAs and SFAs in a similar manner to that observed in AKHRRNAi crickets. AKH administration in HslRNAi crickets did not change hemolymph fatty acid composition, indicating that AKH signaling critically altered fatty acid composition in the hemolymph through Hsl. In addition, a choice assay revealed that AKHRRNAi significantly increases the preference of USFAs. These data indicate that hemolymph lipid level and composition were modulated by AKH signaling with a complementary feeding behavior toward USFAs.

Renal compensatory adaptation for water handling in a patient with adipsic diabetes insipidus after clipping of a ruptured aneurysm of the anterior communicating artery
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A 38-year-old Japanese man who had undergone clipping surgery for a ruptured aneurysm of the anterior communicating artery 2 days prior, suddenly developed refractory hypernatremia (serum sodium (Na) 156 - 162 mmol/L). Symptoms included low plasma vasopressin, fluctuating urine osmolality (120 - 710 mOsm/kg) and lack of thirst, all suggesting adipsic diabetes insipidus (ADI). Hypernatremia was corrected by scheduled water intake with desmopressin administration. During 1-year follow-up after the surgery, his serum Na level normalized despite the suspension of desmopressin, but neither thirst nor osmolality-dependent vasopressin release recovered. Meanwhile, his urine osmolality shifted to a constant high level. The present case suggests that renal compensatory adaptation, apparently independent of the circulating vasopressin level, plays a major role in water handling in longitudinal ADI.
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Erratum: A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis.

[This corrects the article on p. 424 in vol. 9, PMID: 27274828.].

The divide-and-conquer second-order proton propagator method based on nuclear orbital plus molecular orbital theory for the efficient computation of proton binding energies.

An efficient computational method to evaluate the binding energies of many protons in large systems was developed. Proton binding energy is calculated as a corrected nuclear orbital energy using the second-order proton propagator method, which is based on nuclear orbital plus molecular orbital theory. In the present scheme, the divide-and-conquer technique was applied to utilize local molecular orbitals. This use relies on the locality of electronic relaxation after deprotonation and the electron-nucleus correlation. Numerical assessment showed reduction in computational cost without the loss of accuracy. An initial application to model a protein resulted in reasonable binding energies that were in accordance with the electrostatic environment and solvent effects.

[Is it possible to-predict fracture in CKD patients?].

Routine examination of bone mineral density(BMD)by DXA(dual energy X-ray absorptiometry)is useful to predict bone fracture in both CKD nondialysis and dialysis patients. The cutoff value of BMD to predict bone fracture is different between genders and its predictive power is better in patients with lower serum PTH levels than higher counterpart. Increase in serum bone specific alkaline phosphatase is a better predictor of the bone fracture than serum PTH levels.

A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis.

A 40-year-old Japanese man who had a medical history of hypokalemic periodic paralysis 4 months prior was hospitalized to undergo a cholecystectomy. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. An ammonium chloride/furosemide-fludrocortisone/bicarbonate loading test demonstrated a remarkable disability in urinary H(+) excretion. A novel heterozygous mutation in the ATP6V0A4 gene encoding the vacuolar H(+)-ATPase (V-ATPase) a4 subunit p.S544L was detected. Among cases of V-ATPase a4 mutations, this is the first case in which a heterozygous mutation developed to an incomplete or latent form of dRTA.

Imbalanced Hemolymph Lipid Levels Affect Feeding Motivation in the Two-Spotted Cricket, Gryllus bimaculatus.

Insect feeding behavior is regulated by many intrinsic factors, including hemolymph nutrient levels. Adipokinetic hormone (AKH) is a peptide factor that modulates hemolymph nutrient levels and regulates the nutritional state of insects by triggering the transfer of lipids into the hemolymph. We recently demonstrated that RNA interference (RNAi)-mediated knockdown of the AKH receptor (AKHR) reduces hemolymph lipid levels, causing an increase in the feeding frequency of the two-spotted cricket, Gryllus bimaculatus. This result indicated that reduced hemolymph lipid levels might motivate crickets to feed. In the present study, to elucidate whether hemolymph lipid levels contribute to insect feeding behavior, we attempted to manipulate hemolymph lipid levels via the lipophorin (Lp)-mediated lipid transferring system in G. bimaculatus. Of the constituent proteins in Lp, we focused on apolipophorin-III (GrybiApoLp-III) because of its possible role in facilitating lipid mobilization. First, we used RNAi to reduce the expression of GrybiApoLp-III. RNAi-mediated knockdown of GrybiApoLp-III had little effect on basal hemolymph lipid levels and the amount of food intake. In addition, hemolymph lipid levels remained static even after injecting AKH into GrybiApoLp-IIIRNAi crickets. These observations indicated that ApoLp-III does not maintain basal hemolymph lipid levels in crickets fed ad libitum, but is necessary for mobilizing lipid transfer into the hemolymph following AKH stimulation. Second, Lp (containing lipids) was injected into the hemolymph to induce a temporary increase in hemolymph lipid levels. Consequently, the initiation of feeding was delayed in a dose-dependent manner, indicating that increased hemolymph lipid levels reduced the motivation to feed. Taken together, these data validate the importance of basal hemolymph lipid levels in the control of energy homeostasis and for regulating feeding behavior in crickets.

Newly identified allatostatin Bs and their receptor in the two-spotted cricket, Gryllus bimaculatus.

A cDNA encoding allatostatin Bs (ASTBs) containing the W(X)6W motif was identified using a database generated by a next generation sequencer (NGS) in the two-spotted cricket, Gryllus bimaculatus. The contig sequence revealed the presence of five novel putative ASTBs (GbASTBs) in addition to GbASTBs previously identified in G. bimaculatus. MALDI-TOF MS analyses revealed the presence of these novel and previously identified GbASTBs with three missing GbASTBs. We also identified a cDNA encoding G. bimaculatus GbASTB receptor (GbASTBR) in the NGS data. Phylogenetic analysis demonstrated that this receptor was highly conserved with other insect ASTBRs, including the sex peptide receptor of Drosophila melanogaster. Calcium imaging analyses indicated that the GbASTBR heterologously expressed in HEK293 cells exhibited responses to all identified GbASTBs at a concentration range of 10(-10)-10(-5)M.