A Case of Acute Kidney Injury Caused by Myoglobin Cast Nephropathy With Sars-Cov-2 Infection in a Living-Donor Kidney Transplant Recipient.

When COVID-19 affects patients with risk factors such as chronic kidney disease or on immunosuppressive drugs, they often rapidly become seriously ill. We describe a 50-year-old man who was affected with SARS-CoV-2 and had undergone an ABO-compatible living-donor kidney transplantation from his father 14 years ago because of end-stage renal failure due to hypertensive nephrosclerosis. He had continued on immunosuppressive drugs and completed vaccination twice (9 months ago and 6 months ago) with messenger RNA (mRNA) vaccines against SARS-CoV-2. However, he was temporarily on a mechanical ventilator due to respiratory failure and hemodialysis due to acute kidney injury (AKI). He was finally weaned from the ventilator and hemodialysis by taking steroid and antiviral drugs. Echo-guided renal biopsy revealed myoglobin cast nephropathy. We experienced 14 outpatients after living-donor kidney transplantation infected with SARS-CoV-2, but only this case developed AKI.

Lower body mass index potentiates the association between skipping breakfast and prevalence of proteinuria.

Background: Proteinuria is an important predictor of cardiovascular disease and mortality. Several studies reported the association between skipping breakfast and the prevalence of proteinuria. Furthermore, skipping breakfast was associated with an increased risk of obesity. Although proteinuria is highly prevalent in obese individuals, the association between the prevalence of proteinuria and low body mass index (BMI) was reported in a previous cross-sectional study in asymptomatic individuals without known kidney diseases. The aim of this cross-sectional study was to assess the clinical impact of BMI on the association between skipping breakfast and the prevalence of proteinuria in normal renal function subjects. Methods: The present study included 26,888 subjects (15,875 males and 11,013 females) with an estimated glomerular filtration rate ≥60 ml/min/1.73 m2 and no history of kidney disease who underwent a health checkup in Sumitomo Hospital. The association between skipping breakfast and the prevalence of proteinuria (defined as dipstick proteinuria of ≥1+) was assessed using logistic regression models adjusted for clinically relevant factors. Results: Skipping breakfast was reported in 3,306 males (20.8%) and 1,514 females (13.8%). Multivariable adjusted logistic regression models showed that skipping breakfast was significantly associated with the prevalence of proteinuria above 1+. This association was evident in lower BMI subjects, even after adjusting for clinically relevant factors (adjusted odds ratios of males and females were 1.67 [1.17-2.38] and 1.92 [1.31-2.82], respectively), whereas this association was not evident in higher BMI subjects. Conclusion: Lower BMI subjects with proteinuria might need to be careful about skipping breakfast.

The Combination of High Levels of Adiponectin and Insulin Resistance Are Affected by Aging in Non-Obese Old Peoples.

Background: Adipokine dysregulation is a key feature of insulin resistance and a metabolic syndrome associated with obesity. Low adiponectin levels are associated with higher risks of cardiovascular diseases (CVD). However, high adiponectin levels have also been associated with increased all-cause and cardiovascular mortality in the elderly. This adiponectin paradox has yet to be clarified, which has hindered our understanding of the biological role of adiponectin. Adipokine dysregulation and insulin resistance are also associated with energy-deprivation conditions, such as frailty in old age. The objective of this study was to investigate the association between plasma adiponectin and insulin resistance using the homeostasis model assessment for insulin resistance (HOMA-IR) classified by age. In particular, we sought to determine the factors of the subjects associated with both high adiponectin levels and HOMA-IR (H-adiponectin/H-HOMA) and high adiponectin levels and low HOMA-IR (H-adiponectin/L-HOMA). Methods: The eligible subjects in this cross-sectional study were 33,216 individuals who had undergone health checkups at the Physical Checkup Center of Sumitomo Hospital between April 2008 and December 2018. After excluding 26,371 individuals who were under 60 years old, 529 who had been taking medications for diabetes mellitus, and 690 with missing data, the present study included 5,673 (3,467 males, 2,206 females) subjects with no missing data. The relationship between serum adiponectin levels and HOMA-IR was assessed using logistic regression models adjusted by clinically relevant factors. Results: In the multivariable logistic regression analysis, age and low BMI were shown to positively correlate with the characteristics of H-adiponectin/H-HOMA. In females, systolic blood pressure was also shown to be an associated factor. Conclusion: In conclusion, this study showed that aging or a low BMI may contribute to high adiponectin levels and insulin resistance.

Two Cases of the MYH9 Disorder Fechtner Syndrome Diagnosed from Observation of Peripheral Blood Cells before End-Stage Renal Failure.

As a MYH9 disorder, Fechtner syndrome is characterized by nephritis, giant platelets, granulocyte inclusion bodies (Döhle-like bodies), cataract, and sensorineural deafness. Observation of peripheral blood smear for the presence of thrombocytopenia, giant platelets, and granulocyte inclusion bodies (Döhle-like bodies) is highly important for the early diagnosis of MYH9 disorders. In our two cases, sequencing analysis of the MYH9 gene indicated mutations in exon 24. Both cases were diagnosed as the MYH9 disorders Fechtner syndrome before end-stage renal failure on the basis of the observation of peripheral blood smear.

Budd-Chiari Syndrome with Multiple Thrombi due to a Familial Arg42Ser Mutation in the Protein C Gene.

A 34-year-old Japanese woman was admitted to our hospital complaining of developing bilateral pedal edema. Imaging studies led to a diagnosis of Budd-Chiari syndrome combined with internal jugular vein thrombus. We investigated the cause of thrombosis and found that the anticoagulant activity of protein C was decreased. Genetic analysis showed the presence of a c.125C>A (Arg42Ser) substitution in the protein C gene (PROC) of the proband, which generates an Arg42Ser mutation that replaces the scissile bond Arg42-Ala43 normally cleaved by a furin-like processing protease. Her father and younger brother also carried this mutation, although they had no evidence of thrombosis.

Takotsubo Cardiomyopathy in Two Patients without Any Cardiac Symptom on Maintenance Hemodialysis.

Takotsubo cardiomyopathy is a disorder characterized by left ventricular apical ballooning and electrocardiographic changes in the absence of coronary artery disease. While reversible in many cases, the mechanism of this disorder remains unclear. The most frequent clinical symptoms of takotsubo cardiomyopathy on admission are chest pain and dyspnea, resembling acute myocardial infarction. Here, we describe two cases of takotsubo cardiomyopathy without chest pain or dyspnea in patients on maintenance hemodialysis. The asymptomatic nature of these two cases may be due to the patients being on hemodialysis. Periodic electrocardiograms (ECG) may be helpful in screening this population for asymptomatic takotsubo cardiomyopathy and in evaluating its incidence.

The Efficacy of Mizoribine (Inosine Monophosphate Dehydrogenase Inhibitor) for ANCA-Associated Vasculitis with Hepatitis B Virus Carrier.

A 42-year-old female who was an asymptomatic carrier of hepatitis B virus (HBV) was diagnosed with antineutrophil cytoplasm antibody- (ANCA-) associated vasculitis and was induced to remission with 30 mg/day prednisolone nine years ago. Four years ago, she suffered recurrence of ANCA-associated vasculitis and with 30 mg/day prednisolone was induced to remission. This time, laboratory data showed 3-fold increase in myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) levels. Administration of 30 mg/day prednisolone was started. Three days later, she was admitted to our hospital suffering from fatigue. After admission, urinalysis showed glomerular hematuria. Despite administration of 30 mg/day prednisolone, MPO-ANCA titer had been of high level, ranging from 42 to 83 EU for 2.5 months. Furthermore, the adverse effects of steroid were seen. We decided the tapering of prednisolone (25 mg/day) and the start of mizoribine (4-carbamoyl-1-ß-D-ribofuranosyl imidazolium-5-olate) administration. After mizoribine treatment, MPO-ANCA titer was decreased without any mizoribine-related adverse effects. Six months later, MPO-ANCA titer was decreased to normal levels and she was induced to clinical remission without reactivation of HBV. We describe the effectiveness of mizoribine for the ANCA-associated vasculitis complicated with HBV-carrier.

Reelin signals survival through Src-family kinases that inactivate BAD activity.

Reelin plays an important role in the migration of embryonic neurons, but its continuing presence suggests additional functions in the brain. We now report a novel function where reelin protects P19 embryonal cells from apoptosis during retinoic acid-induced neuronal differentiation. This increased survival is associated with reelin activation of the phosphatidyl-inositol-3-kinase (PI3 K)/Akt pathway. When PI3 K was inhibited with LY294002, reelin failed to protect against this retinoic acid-induced apoptosis. The protective effect of reelin includes activating the Src-family kinases/PI3 K/Akt pathway which then led to selective phosphorylation of Bcl-2/Bcl-XL associated death promoter (BAD) at serine-136, while the phosphorylation-incompetent mutation of BAD (S136A) suppressed this protection. These and additional studies define a novel pathway where reelin binds apoE receptors, significantly activates the PI3 K/Akt pathway causing phosphorylation of BAD which helps to protect cells from apoptosing, thus serving an important role in promoting the survival of maturing neurons in the brain.

17-year follow-up study of a patient with obstructive hypertrophic cardiomyopathy with a deletion mutation in the cardiac myosin binding protein C gene.

A 60-year-old Japanese man with obstructive hypertrophic cardiomyopathy was found to have a mutation in the cardiac myosin binding protein C gene: a single base deletion of a thymidine residue at nucleotide 11645 (codon 593) in exon 18. He was diagnosed at the age of 43 and has been followed for 17 years. During this follow-up period, echocardiograms and mechanocardiograms revealed progressive hypertrophy until the age of 54, then gradual dilation of the left ventricle associated with a decrease in the obstruction. Paroxysmal atrial fibrillation occurred at the age of 52 and progressed to chronic atrial fibrillation at the age of 53. He had congestive heart failure at the age of 58.

NFkappaB regulates plasma apolipoprotein A-I and high density lipoprotein cholesterol through inhibition of peroxisome proliferator-activated receptor alpha.

The levels of plasma HDL cholesterol and apoA-I in NFkappaB p50 subunit-deficient mice were significantly higher than those in wild-type mice under regular and high fat diets, without any significant difference in the level of total cholesterol. To examine the role of NFkappaBin lipid metabolism, we studied its effect on the regulation of apoA-I secretion from human hepatoma HepG2 cells. Lipopolysaccharide-induced activation of NFkappaB reduced the expression of apoA-I mRNA and protein, whereas adenovirus-mediated expression of IkappaBalpha super-repressor ameliorated the reduction. This IkappaBalpha-induced apoA-I increase was blocked by preincubation with MK886, a selective inhibitor of peroxisome proliferator-activated receptor alpha (PPARalpha), suggesting that NFkappaB inactivation induces apoA-I through activation of PPARalpha. To further support this idea, the expression of IkappaBalpha increased apoA-I promoter activity, and this increase was blocked by preincubation with MK886. Mutations in the putative PPARalpha-binding site in the apoA-I promoter or lack of the site abrogated these changes. Taking these results together, inhibition of NFkappaB increases apoA-I and HDL cholesterol through activation of PPARalpha in vivo and in vitro. Our data suggest a new aspect of lipid metabolism and may lead to a new paradigm for prevention and treatment of atherosclerotic disease.

Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade.

Neurofibrillary tangles comprised of highly phosphorylated tau proteins are a key component of Alzheimer's disease pathology. Mice lacking Reelin (Reln), double-knockouts lacking the VLDL receptor (VLDLR) and ApoE receptor2 (ApoER2), and mice lacking disabled-1 (Dab1) display increased levels of phosphorylated tau. Because Reln binds to recombinant ApoE receptors, assembly of a Reln/ApoE-receptor/Dab1 (RAD) complex may initiate a signal transduction cascade that controls tau phosphorylation. Conversely, disruption of this RAD complex may increase tau phosphorylation and lead to neurodegeneration. To substantiate this concept, we mated Reln-deficient mice to ApoE-deficient mice and found that in the absence of Reln, tau phosphorylation increased as the amount of ApoE decreased. Paralleling the change in tau phosphorylation levels, we found that GSK-3beta activity increased in Reln-deficient mice and further increased in mice lacking both Reln and ApoE. CDK-5 activity was similar in mice lacking Reln, ApoE, or both. GSK-3beta and CDK-5 activity increased in Dab1-deficient mice, independent of ApoE levels. Further supporting the idea that increased tau phosphorylation results primarily from increased kinase activity, the activity of two phosphatases was similar in all conditions tested. These data support a novel, ligand-mediated signal transduction cascade--initiated by the assembly of a RAD complex that suppresses kinase activity and controls tau phosphorylation.

The 4,752 C/T polymorphism in the presenilin 1 gene increases the risk of Alzheimer's disease in apolipoprotein E4 carriers.

OBJECTIVE: We sought to establish an association between sporadic Alzheimer's disease (AD) and presenilin 1 (PSEN1) gene polymorphisms in the Japanese population. METHODS: A 5 kb fragment containing the putative promoter of the PSEN1 gene for randomly selected control subjects was subcloned into plasmid and sequenced to screen novel polymorphisms in this region. Patients and controls were genotyped for five polymorphic markers in the PSEN1 region. We then constructed haplotypes using the computer program HAPLO and compared the frequencies between cases and controls. SUBJECTS: A total of 189 AD cases (NINCDS-ADRDA criteria) and 240 controls were studied. RESULTS: We discovered a novel polymorphism with high heterozygosity on -4,752 of the PSEN1 promoter region. A significant association was observed between the -4,752 C/T polymorphism and late-onset AD. The odds ratio for AD associated with the CC vs non-CC genotype was 1.59 (95% CI = 1.01-2.51), while that of epsilon 4 vs non-epsilon 4 in APOE gene was 4.41 (95% CI = 2.72-7.16). The C allele was associated with a further increase in the risk of AD in APOE epsilon 4 carriers. We found 12 major haplotypes using five polymorphisms. The distribution pattern was significantly different between cases and controls. CONCLUSION: The PSEN1 gene -4,752 C/T polymorphism modifies the risk for AD.

Evidence of positive selection acting at the human dopamine receptor D4 gene locus.

Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2-11. Here we show by DNA resequencing/haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R-6R alleles can be explained by simple one-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5-10-fold "younger" than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.