Compliance of Static Stretching and the Effect on Blood Pressure and Arteriosclerosis Index in Hypertensive Patients.

Background: Treatment of high blood pressure is a combination of lifestyle changes and medications, and appropriateexercise therapy is recommended as one of the lifestyle-related changes. Recently, stretching, a low-intensity exercise, was reported to be antihypertensive and effective for improving arteriosclerosis, in addition to aerobic exercise. The present study investigated the short-term effects of continuous stretching and rest-induced rebound on vascular endothelial function in hypertensive patients. Methods: This study was conducted as a single-arm prospective interventional study including patients between 30 and 70 years of age undergoing treatment for hypertension from October 2019 until May 2021. The intervention consisted of six months of daily stretching, one month of rest, and another three months of stretching. We measured arteriosclerosis indices such as cardio ankle vascular index (CAVI), ankle brachial pressure index (ABI) and reactive hyperemia index (RHI), and flexibility at the baseline and one, three, six, seven, and ten months from the baseline. Results: We included a total of ten patients (three males and seven females) with an average age of 60.10 ± 6.05 years. The exercise rate for the entire period was 90% or more, and the anteflexion measurement value improved significantly before and after the intervention (p < 0.001). Blood pressure and CAVI/ABI were well controlled throughout the study period. RHI did not show any significant improvement during the initial six months, and only slightly improved by the third month (p = 0.063). Even after the rest phase and resumption of stretching, RHI remained stable. Conclusions: The compliance of the stretching program we used, evaluated by the exercise implementation rate for the entire period, was 90% or more; therefore, easy to perform and continue by hypertensive patients. However, we did not observe a significant positive effect on arteriosclerosis index or blood pressure in this study.

Skeletal Muscle Index at Intensive Care Unit Admission Is a Predictor of Intensive Care Unit-Acquired Weakness in Patients With Sepsis.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) can be diagnosed using the Medical Research Council (MRC) score. However, such scoring may not be possible in ICU patients who may be sedated or delirious or have encephalopathy. Currently, a quantitative assessment of the cross-sectional area of the muscle is available to assess changes in skeletal muscle mass using computed tomography (CT) images. This assessment calculates the skeletal muscle index (SMI) (cm2/m2) by dividing the cross-sectional area (cm2) of the skeletal muscle at the level of the third lumbar vertebra by the square of the patient's height (m2) on CT. This study assessed the effectiveness of SMI, as measured by abdominal CT scans, in predicting the onset of ICU-AW in patients with sepsis admitted to the ICU. METHODS: We examined septic ICU patients admitted to the Niigata University Hospital ICU during 2012 - 2017 under mechanical ventilation. Patients were retrospectively divided into two groups by MRC score at ICU discharge: group AW comprised patients with an MRC score < 48, and group non-AW (NAW) comprised the remaining patients. Clinicopathological factors at ICU admission such as age, gender, underlying disease, body mass index, and SMI were compared between the two groups. Statistical analyses were performed using the Mann-Whitney U test, Fisher's exact test, receiver operator characteristic (ROC) analysis and multivariate analysis. RESULTS: A total of 31 septic patients were examined, and 23 patients met the criteria for ICU-AW. The prevalence of women was significantly higher in group AW (P < 0.05). All clinical factors, except for gender, were not significantly different between the two groups. SMI was significantly lower in group AW than in group NAW (P < 0.05). ROC analysis revealed that the cut-off value of SMI for predicting ICU-AW was 44.1, and the multivariate analysis revealed that only low SMI was a significant factor in predicting ICU-AW (P < 0.05). CONCLUSIONS: Our results show that SMI measurement at ICU admission is a valid predictive factor for ICU-AW progression in septic patients.

Efficacy of Physical Activity in Prevention of Muscle Weakness in Patients With Chronic Liver Disease.

BACKGROUND: Sarcopenia is a prognostic factor for patients with liver cirrhosis and hepatocellular carcinoma, and it affects the onset of hepatic encephalopathy. Therefore, the prevention of sarcopenia contributes to the improvement of the prognosis of patients with chronic liver disease (CLD). We focused on changes of hand grip strength (HGS), one of the indicators of sarcopenia. However, there are little data investigating the impact of physical activity (PA) on HGS in patients with CLD. This study aimed to clarify whether PA contributes to the prevention of muscle weakness in patients with CLD. METHODS: This was a prospective observational study. We examined the effect of PA on changes in HGS from the baseline to the endpoint in each group. Metabolic equivalents-hour/week (METs-h/w) was used to evaluate PA. In total, 183 outpatients with CLD were analyzed. We divided participants into four groups (low PA in younger patients (n = 20), high PA in younger patients (n = 33), low PA in elderly patients (n = 47), and high PA in elderly patients (n = 83)). RESULTS: Fifty-eight percent of patients were men, and the median (interquartile range) age was 69.0 (63.0, 75.0) years. The most common etiology of liver disease was hepatitis C (38%). The frequency of living alone and low exercise habit was significantly high, and sarcopenia was more obvious in elderly patients with low PA than in those with high PA. Additionally, the elderly with low PA showed significantly reduced HGS compared to that of the elderly with high PA (-1.00 (-2.27, 0.55) kg vs. 0.10 (-1.40, 1.10) kg, P < 0.05). However, changes in HGS in younger patients were not significant (-0.02 (1.83, 1.47) kg vs. 0.25 (-2.45, 2.05) kg, P = 0.96). Logistic regression analyses identified PA as the independent factor for prevention of decrease in HGS (odds ratio: 1.91, 95% confidence interval: 1.00 - 3.62, P = 0.049). CONCLUSIONS: Young patients with low PA were characterized by a long sedentary time; however, there was no loss of HGS. In contrast, elderly patients with CLD and low PA had significantly reduced HGS compared to that in elderly patients with CLD and high PA.

Treatment for renal anemia and outcomes in non-dialysis patients with chronic kidney disease: the current status of regional medicine according to the Kyoto Fushimi Renal Anemia (KFRA) study.

BACKGROUND: The baseline data obtained in the CKD-JAC demonstrated that insufficient treatment was being provided for renal anemia by institutions specializing in renal disease. The objective of this study was to investigate the status of treatment for renal anemia, including renal/cardiovascular outcomes and mortality, at regional medical facilities since the development of long-acting erythropoiesis-stimulating agents (LA-ESA). METHODS: Non-dialysis outpatients with chronic kidney disease and renal anemia were eligible. Anemia was treated based on the clinical condition of each patient and targeted hemoglobin (Hb) levels. RESULTS: A total of 283 patients from 21 institutions were enrolled and followed up for a maximum of 3 years. A doubling of the serum creatinine level was observed in 89 patients, and renal replacement therapy was initiated in 57 patients. Multivariate Cox regression analysis revealed that a lower mean Hb level (mHb) and receiving fewer frequency of ESA during the follow-up period were independent determinants of the composite renal outcome and overall mortality. During the follow-up period, the percentages of patients with mHb of 10-10.9 g/dL and ≥ 11 g/dL were increased. Similar trends were seen regardless of whether the patients were treated by nephrologists or non-nephrologists. The frequency of ESA treatment was increased among the patients treated by non-nephrologists; however, it was much lower than nephrologists. CONCLUSION: This study demonstrated that, in the era of LA-ESA treatment, higher Hb levels are associated with reduced composite renal outcomes at regional medical facilities. The importance of renal anemia management should be highlighted, even among non-nephrologists.

Elemental Diet Regulates Intestinal Permeability and Antibody Production in Indomethacin-Induced Intestinal Injury Rats.

Crohn's disease is a type of inflammatory bowel disease of unknown etiology. Administration of indomethacin (Indo) to rats induces acute mucosal lesions similar to those observed in Crohn's disease patients, but the damage can be prevented by feeding the animals an elemental diet (ED). In this study, we examined changes in intestinal macroscopic appearance, permeability, and immunoglobulin production after administration of Indo to male Sprague-Dawley rats fed normal lab chow or an ED. Intestinal damage was induced by subcutaneous injection of Indo on two successive days. Mucosal permeability, as measured by urinary excretion of phenolsulfonphthalein, peaked on day 2 after Indo injection, whereas the most severe intestinal damage, as scored by macroscopic inflammatory changes, was observed on day 3. Flow cytometric analysis of mesenteric lymph node cells revealed that the proportion of CD45RA+ cells was increased after Indo treatment. Furthermore, in vitro-cultured mesenteric lymph node and spleen lymphocytes from Indo-treated rats produced higher levels of IgA and IgG than did cells from vehicle-treated rats. In contrast, IgG and albumin concentrations in plasma were significantly decreased by Indo administration. Notably, none of the Indo-induced changes was observed in ED-fed rats. These findings suggest that an ED may prevent the appearance of Indo-induced mucosal lesions, at least in part, by modulating intestinal permeability and antibody production.

Membranoproliferative glomerulonephritis with unusual deposits of parallel arrangement striated structure: a new pathological entity?
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A 71-year-old male with a past history of lower limb arteriosclerosis obliterans developed nephrotic syndrome and renal dysfunction. Renal biopsy showed diffuse global endocapillary proliferative lesions with infiltration of mononuclear cells and occasional foam cells. An irregular double contour of the glomerular basement membrane and global mild-to-moderate mesangial proliferative lesions were observed, indicating membranoproliferative glomerulonephritis. Congo red staining was negative. Routine immunofluorescence studies showed no obvious immunoglobulin or complement depositions. Electron microscopy showed endocapillary proliferative lesions and infiltration of macrophages with abundant lysosomes. Irregular subepithelial, subendothelial, and mesangial electron-dense deposits were observed in glomeruli. In these electron-dense deposits, parallel arrangement striated structures were detected. All known disease entities with Congo red-negative and immunoglobulin-negative glomerular deposits were pathologically excluded. The glomerular lesion in our case might be a new disease entity.
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Thrombotic microangiopathy associated with cetuximab, an epidermal growth factor receptor inhibitor
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Cetuximab is a chimeric human-murine monoclonal antibody that binds competitively and with high affinity to the epidermal growth factor receptor (EGFR) and is used to treat advanced squamous cell carcinoma of the head and neck. After receiving a total of six doses of cetuximab, a 72-year-old male presented with pretibial edema, acne-like skin rash, and nephrotic syndrome. The renal biopsy findings revealed features of thrombotic microangiopathy (TMA), with the expansion of the subendothelial zone, reduplication of the glomerular basement, and swelling of the endothelial cells. Nine weeks after the discontinuation of cetuximab, his pretibial edema had disappeared and proteinuria decreased. To our knowledge, this is the first report in which kidney biopsy revealed evidence of TMA due to cetuximab administration. Our report suggests that it may be prudent to monitor patients receiving cetuximab closely for the possible development of nephrotic syndrome.
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[Viewpoint: Skill Certifications for Japanese Medical Technologists].

With the development of medicine, the field of clinical laboratory medicine evolves rapidly, and it will be more specialized in the near future. Medical technologists are required to hone their skills and knowledge, in order to keep up with the evolution. In recent years, board certifications by several medical societies are considered to indicate the skills of medical technologists. The number of board-certified medical technologists in populated areas such as Tokyo, Kanagawa, Osaka, and Fukuoka is greater than in less populated areas such as Kyusyu and Tohoku. The rate of certified medical technologists among prefectures is the highest in Mie (10.1%), followed by Nagasaki (8.8%). Tokyo, Ishikawa, Kyoto, and Osaka have acquisition rates greater than 7%. In contrast, prefectures of Miyazaki, Kumamoto, Yamanashi, and Akita have low acquisition rates of less than 4%. Being certified is not only an opportunity for personal career advancement, but also a chance to improve the laboratory. More technologists are being certified in our laboratory, and we are encouraging a future increase in their number. However, there are some problems to be overcome. Assignment of competent staff and long-term and premeditated rotation are considered to be important for staff to find the work rewarding, and the laboratory to be trusted by physicians.

Trade off situation between thymus and growth hormone: age-related decline of growth hormone is a cause of thymic involution but favorable for elongation of lifespan.

High level of growth hormone (GH) is necessary for the activation of thymic function to promote T cell differentiation in the early stage of animal life. In the later stage of the life, administration of GH promotes the development of immune system and rejuvenates declined immune function of elderly people. By contraries, GH deficiency is favorable for the longer lifespan, as hypo-pituitary dwarf mice such as Ames and Snell dwarf mice exhibit longer lifespan than control. Furthermore over-expression of heterologous or homologous GH in transgenic mice shortens the lifespan. Ecuadorians carrying mutations of GH receptor gene are short in height, but exhibited low frequency of malignancy and no cases of diabetes. These data indicate that GH is necessary for the development of thymus dependent immune system but GH deficiency is favorable for long life span and decreases occurrence of cancer and DM. This situation is a kind of trade off situation between the immune system and GH. Thus the early decline of high level of GH occurring shortly after the birth is a cause of early decline of thymic functions, but favorable for longer lifespan. This situation could be a kind of trade off situation between thymus and GH.

Post-infectious acute glomerulonephritis with vasculitis and pulmonary hemorrhage.

An 84-year-old male complained of fever, cough, sputum, and appetite loss. His renal function rapidly worsened, and he had hypoalbuminemia and hypocomplementemia. His condition worsened and C-reactive protein levels were elevated. Vasculitis syndrome was suspected and he was administered 40 mg of prednisolone, although myeloperoxidase antineutrophil cytoplasmic antibody (ANCA), proteinase-3 ANCA and antiglomerular basement membrane antibody tests were negative. His body temperature decreased and fatigue promptly resumed. On renal biopsy, light microscopy revealed endocapillary and extracapillary glomerulonephritis. Vasculitis was detected in interlobular arteries. Immunofluorescence studies revealed granular deposits of C3 and IgG along capillary walls. Electron microscopy revealed dome-shaped small electron-dense granular subepithelial deposits. Acute post-infectious glomerulonephritis was suspected. Although his renal function improved, he developed hemoptysis and was diagnosed with pulmonary hemorrhage. He received methylprednisolone and plasma exchange, and his respiratory status improved gradually. This is an extremely rare case and suggests the importance of considering a differential diagnosis.

Human mediator MED17 subunit plays essential roles in gene regulation by associating with the transcription and DNA repair machineries.

In eukaryotes, holo-Mediator consists of four modules: head, middle, tail, and CDK/Cyclin. The head module performs an essential function involved in regulation of RNA polymerase II (Pol II). We studied the human head module subunit MED17 (hMED17). Recent structural studies showed that yeast MED17 may function as a hinge connecting the neck and movable jaw regions of the head module to the fixed jaw region. Luciferase assays in hMED17-knockdown cells showed that hMED17 supports transcriptional activation, and pulldown assays showed that hMED17 interacted with Pol II and the general transcription factors TFIIB, TBP, TFIIE, and TFIIH. In addition, hMED17 bound to a DNA helicase subunit of TFIIH, XPB, which is essential for both transcription and nucleotide excision repair (NER). Because hMED17 associates with p53 upon UV-C irradiation, we treated human MCF-7 cells with either UV-C or the MDM2 inhibitor Nutlin-3. Both treatments resulted in accumulation of p53 in the nucleus, but hMED17 remained concentrated in the nucleus in response to UV-C. hMED17 colocalized with the NER factors XPB and XPG following UV-C irradiation, and XPG and XPB bound to hMED17 in vitro. These findings suggest that hMED17 may play essential roles in switching between transcription and NER.

Human mediator subunit MED15 promotes transcriptional activation.

In eukaryotes, the Mediator complex is an essential transcriptional cofactor of RNA polymerase II (Pol II). In humans, it contains up to 30 subunits and consists of four modules: head, middle, tail, and CDK/Cyclin. One of the subunits, MED15, is located in the tail module, and was initially identified as Gal11 in budding yeast, where it plays an essential role in the transcriptional regulation of galactose metabolism with the potent transcriptional activator Gal4. For this reason, we investigated the function of the human MED15 subunit (hMED15) in transcriptional activation. First, we measured the effect of hMED15 knockdown on cell growth in HeLa cells. The growth rate was greatly reduced. By immunostaining, we observed the colocalization of hMED15 with the general transcription factors TFIIE and TFIIH in the nucleus. We measured the effects of siRNA-mediated knockdown of hMED15 on transcriptional activation using two different transcriptional activators, VP16 and SREBP1a. Treatment with siRNAs reduced transcriptional activation, and this reduction could be rescued by overexpression of HA/Flag-tagged, wild-type hMED15. To investigate hMED15 localization, we treated human MCF-7 cells with the MDM2 inhibitor Nutlin-3, thus inducing p21 transcription. We found that hMED15 localized to both the p53 binding site and the p21 promoter region, along with TFIIE and TFIIH. These results indicate that hMED15 promotes transcriptional activation.

Decomposition of hydrazine by an organic fullerene-phthalocyanine p-n bilayer photocatalysis system over the entire visible-light region.

An organic p-n bilayer photocatalysis system successfully induced the oxidative decomposition of hydrazine (N2H4) into N2 and simultaneously yielded H2 from H(+). This demonstrates the first instance of the stoichiometric decomposition of N2H4 under visible-light irradiation.

Chaga mushroom-induced oxalate nephropathy.

Chaga mushrooms have been used in folk and botanical medicine as a remedy for cancer, gastritis, ulcers, and tuberculosis of the bones. A 72-year-old Japanese female had been diagnosed with liver cancer 1 year prior to presenting at our department. She underwent hepatectomy of the left lobe 3 months later. Chaga mushroom powder (4 - 5 teaspoons per day) had been ingested for the past 6 months for liver cancer. Renal function decreased and hemodialysis was initiated. Renal biopsy specimens showed diffuse tubular atrophy and interstitial fibrosis. Oxalate crystals were detected in the tubular lumina and urinary sediment and oxalate nephropathy was diagnosed. Chaga mushrooms contain extremely high oxalate concentrations. This is the first report of a case of oxalate nephropathy associated with ingestion of Chaga mushrooms.

Gamma 1-heavy chain deposition disease accompanied by IgG kappa in serum, urine, and bone marrow.

A 32-year-old Japanese woman presented with hypertension, nephrotic syndrome, microhematuria, and severe hypocomplementemia. Her serum creatinine concentration increased from 1.46 mg/dL (129.0 µmol/L) to 3.46 mg/dL (305.8 µmol/L) over 1 month. Renal biopsy revealed Congo red-negative nodular glomerulosclerosis accompanied by mesangial proliferation. There was extensive staining of immunoglobulin (Ig) G in the glomerular and tubular basement membranes and expanded mesangial regions. Staining was negative for IgA, IgM, and kappa and lambda light chains and positive for the gamma 1 IgG subclass. Staining for constant domains of the gamma heavy chains showed a deletion of the first constant domain (CH1). Electron microscopy revealed electron-dense deposits in the glomerular and tubular basement membranes and mesangium. These findings indicated gamma 1-heavy chain deposition disease (HCDD). Serum and urine immunoelectrophoresis revealed an IgG kappa monoclonal band, whereas bone marrow biopsy revealed monoclonal plasmacytosis with positive staining for kappa chains. HCDD associated with kappa light chain is extremely rare. We report the first case of HCDD with IgG kappa detected in the serum, urine, and bone marrow.

Glomerular endotheliosis in a pregnant woman with severe gestational proteinuria.

Preeclampsia is the most common hypertensive disorder to occur during pregnancy. A healthy 38-year-old primipara presented with pretibial edema at 33 weeks of gestation followed by the development of proteinuria at 36 weeks of gestation. She had no past medical history of hypertension and was normotensive during gestation. Her proteinuria persisted after delivery, and she was also hypoalbuminemic. A renal biopsy revealed a remodeling of the glomerular basement membrane (GBM) with double contours. Some of the glomerular segments showed endothelial swelling. Immunoperoxidase staining for C4b-binding protein was positive and Protein S was weakly detected in the GBM. Electron microscopy revealed an expansion of the subendothelial zone as well as mesangial cell interposition. This case suggests that glomerular endotheliosis may therefore sometimes be present despite the absence of hypertension.

A rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage.

Malignant-phase hypertension is characterized clinically by severe accelerating hypertension with neuroretinopathy or papilledema and by evidence of renal damage. A Japanese male in his early thirties presented with hemoptysis and general fatigue. He had a 5-year history of hypertension, but had not received any treatment. His blood pressure was 290/150 mmHg and his serum creatinine level was 8.24 mg/dL. Chest X-rays and computed tomography scans of the chest revealed a pulmonary alveolar hemorrhage. He was suspected of having vasculitis syndrome or Goodpasture's syndrome, but his renal biopsy specimen showed malignant nephrosclerosis. Myeloperoxidase antineutrophil cytoplasmic antibody (ANCA), proteinase-3 ANCA and antiglomerular basement membrane antibody were negative. He was treated with a calcium antagonist and a ß-blocker, followed by an angiotensin-converting enzyme inhibitor. After the administration of the ß-blocker, his blood pressure decreased and his renal function gradually improved. This is a rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage; this condition should be considered in the differential diagnosis in order to avoid unnecessary treatment such as immunosuppressive therapy.

Loss of the Gata1 gene IE exon leads to variant transcript expression and the production of a GATA1 protein lacking the N-terminal domain.

GATA1 is essential for the differentiation of erythroid cells and megakaryocytes. The Gata1 gene is composed of multiple untranslated first exons and five common coding exons. The erythroid first exon (IE exon) is important for Gata1 gene expression in hematopoietic lineages. Because previous IE exon knockdown analyses resulted in embryonic lethality, less is understood about the contribution of the IE exon to adult hematopoiesis. Here, we achieved specific deletion of the floxed IE exon in adulthood using an inducible Cre expression system. In this conditional knock-out mouse line, the Gata1 mRNA level was significantly down-regulated in the megakaryocyte lineage, resulting in thrombocytopenia with a marked proliferation of megakaryocytes. By contrast, in the erythroid lineage, Gata1 mRNA was expressed abundantly utilizing alternative first exons. Especially, the IEb/c and newly identified IEd exons were transcribed at a level comparable with that of the IE exon in control mice. Surprisingly, in the IE-null mouse, these transcripts failed to produce full-length GATA1 protein, but instead yielded GATA1 lacking the N-terminal domain inefficiently. With low level expression of the short form of GATA1, IE-null mice showed severe anemia with skewed erythroid maturation. Notably, the hematological phenotypes of adult IE-null mice substantially differ from those observed in mice harboring conditional ablation of the entire Gata1 gene. The present study demonstrates that the IE exon is instrumental to adult erythropoiesis by regulating the proper level of transcription and selecting the correct transcription start site of the Gata1 gene.

Indispensable function for embryogenesis, expression and regulation of the nonspecific form of the 5-aminolevulinate synthase gene in mouse.

The first step of heme biosynthesis in animals is catalyzed by 5-aminolevulinate synthase (ALAS), which controls heme supply in various tissues. To clarify the roles that the nonspecific isoform of ALAS (ALAS-N) plays in vivo, we prepared a green fluorescent protein (GFP) knock-in mouse line in which the Alas1 gene (encoding ALAS-N) is replaced with a gfp gene. We found that mice bearing a homozygous knock-in allele (Alas1(GFP/GFP)) were lethal by embryonic day 8.5, demonstrating that ALAS-N is essential for early embryogenesis. Fluorescence microscopic and flow cytometric analyses of heterozygous mouse (Alas1(+/GFP)) tissues showed that the Alas1 expression level differs substantially in tissues; Alas1 is highly expressed in testis Leydig cells, exocrine glands (including submandibular and parotid glands), endocrine glands (such as adrenal and thyroid glands) and hematopoietic lineage cells (including neutrophils and eosinophils). Quantitative analyses of GFP mRNA and ALAS-N mRNA in various tissues of Alas1(+/GFP) mice suggested that the destabilization of ALAS-N mRNA was not uniform in the various tissues. These results thus lay bare that elaborate control of the endogenous heme supply operates in various mouse tissues through regulation of the ALAS-N expression level and that this control is essential for heme homeostasis in animals.