Correlation Between Skeletal Muscle Mass Deficit and Poor Functional Outcome in Patients with Acute Ischemic Stroke.

BACKGROUND AND AIMS: To date, the correlation between sarcopenia, which exists before a stroke, and acute stroke outcome remains partially understood. This study aims to evaluate the skeletal muscle mass deficit using the bioelectrical impedance analysis in patients with acute ischemic stroke. METHODS: We enrolled 164 geriatric patients with acute ischemic stroke (108 males and 56 females) who underwent the bioelectrical impedance analysis. We evaluated clinical outcomes and their impact on patients with the skeletal muscle mass deficit determined using the skeletal muscle mass index. RESULTS: The skeletal muscle mass deficit was obtained using the bioelectrical impedance analysis in 101 patients. Patients with the skeletal muscle mass deficit determined by the skeletal muscle mass index exhibited severe neurological impairment and functional status on admission; moreover, they tended to display poor functional outcome and prolonged hospital stay. Logistic regression analysis revealed that the skeletal muscle mass deficit remained an independent poor outcome predictor. CONCLUSIONS: This study establishes the presence of the skeletal muscle mass deficit in over half patients with acute ischemic stroke. Furthermore, the skeletal muscle mass deficit correlates with neurological impairment owing to stroke with poorer functional prognosis.

[Development of an event scale for perceiving well-being in high school students].

Objective　This study aimed to develop an event scale for perceiving well-being in high school students (hereinafter called "the scale"). The scale includes ten items for one factor and measures the frequency with which students perceive experience-based well-being.Method　This study comprised two surveys. Survey I was conducted for constructive concept validity based on the factor structural model, reliability for internal consistency, and clarifying each item's performance. The survey contents comprised the event frequency of perceived well-being. The constructive concept validity of the scale was examined with confirmatory factor analysis by structural equation modeling using data of 1,095 students. The reliability was tested using McDonald ω reliability coefficients for internal consistency. Each item's performance was examined using the item response theory.　Survey II was conducted to examine constructive concept validity using hypotheses testing. The survey contents were as follows: event frequency of perceived well-being, satisfaction in life, and mood. For the measurement, the scale was used for event frequency of well-being, the life satisfaction scale was used for satisfaction, and the abridged version of mood scale was used for moods. For the statistical analysis, we constructed a model in which the event frequency of perceived well-being influences the level of life satisfaction, and a model where the event frequency of perceived well-being influences mood. We examined the fit of the models using data of 2,003 students following structural equation modeling.Result　The results of Survey I showed that the model fit for data assumed for the scale was as follows: CFI=0.932, RMSEA=0.098, and ω reliability coefficients were 0.828. Discernment of each item was 0.65~1.06, and the difficulty level was -1.99~2.27, thus all values were acceptable.　The results of Survey II showed that the mode fit for the data where event frequency of perceived well-being influences the level of life satisfaction was CFI=0.978, RMSEA=0.060; thus, the values were acceptable. Model fit for data where event frequency of perceived well-being influences mood was CFI=0.952, RMSEA=0.057; thus, values were acceptable.Conclusion　The scale developed in this study supported the following: constructive concept validity based on the factor structural model, reliability with each item performance tested for internal consistency, and constructive concept validity using hypotheses testing. We believe that the scale will be helpful in developing support methods that enhance high school students' subjective sense of well-being.

[Mitral Valve Infective Endocarditis Complicated with Meningitis in a Patient with Atopic Dermatitis;Report of a Case].

Meningitis has not been described to the same extent as other neurological complications of infective endocarditis(IE). The appropriate selection and dosing of antibiotics for patients with IE and meningitis do not exist. Herein, we described an instructive surgical case of mitral valve endocarditis and meningitis caused in a patient with atopic dermatitis, that was successfully treated using a multi-disciplinary approach.

Diagnosis and treatment of TMA based on Japanese clinical guides.

Patients with thrombotic microangiopathies (TMAs), which include thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), exhibit multiple symptoms. These include thrombocytopenia (platelet count <15×104/µl), microangiopathic hemolytic anemia (hemoglobin <10 g/dl), and organ damage, such as renal dysfunction or neurological abnormalities. Guidelines for the management of TTP, aHUS, and STEC-HUS have been published. Diagnosis of TTP, STEC-HUS, or aHUS requires ADAMTS13 activity <10%, the detection of STEC or Shiga toxins, or a genetic analysis to investigate the complement regulatory system, respectively. In the established management of TMAs, fresh frozen plasma is used for congenital TTP to supplement ADAMTS13. Plasma exchange (PE) is used in acquired TTP (ATTP) to remove inhibitors and replace ADAMTS13. Steroid therapy is administered in ATTP to suppress inhibitor production, and rituximab is administered in ATTP without response to PE or with high titers of ADAMTS13 inhibitors. Eculizumab, a monoclonal antibody for complement protein 5, is used for the treatment of aHUS. Supportive therapy is required for some TMAs, particularly STEC-HUS, but platelet transfusion is generally contraindicated for other TMAs, such as TTP. Treatments should be administered in accordance with these guidelines to improve the outcome of TMAs.

DIC: an update on diagnosis and treatment.

Disseminated intravascular coagulation (DIC) was considered to be a fatal disease. However, it has recently been suggested that very early DIC protects the host against microthrombosis and infection localization. Therefore, early treatment of DIC may be contraindicated in patients with sepsis. These factors suggest that the diagnosis and treatment of DIC will gain further importance. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG2016), which include details regarding the management of DIC, have been recently published. Differences in recommendations for DIC treatment, such as antithrombin and recombinant human thrombomodulin, between J-SSCG2016 and other guidelines, including the Japanese Society on Thrombosis and Hemostasis (JSTH), British Committee for Standards in Haematology (BCST), Italian Society for Thrombosis and Haemostasis (SISET), and International Society on Thrombosis and Haemostasis (ISTH) have been discussed. Furthermore, differences in the diagnostic criteria for DIC between the Japanese Ministry of Health, Labor and Welfare, ISTH overt, ISTH non-overt, Japanese Association for Acute Medicine, and JSTH have been discussed.

Analysis of senescence in gingival tissues and gingival fibroblast cultures.

OBJECTIVE: To determine senescence-associated changes in the gingival tissues of aged mice and gingival fibroblast cultures. MATERIALS AND METHODS: The production of senescence-associated ß-galactosidase (SA-ß-gal) and mRNA expression of p16, p21, interleukin (IL)-1ß, and tumor necrosis factor α (TNF-α) were evaluated in gingival tissues, gingival fibroblasts of 10- and 20-month-old C57BL/6NCrl mice, and multiple-passaged and hydrogen peroxide-stimulated human gingival fibroblasts (HGFs). Changes in molecular expression in HGF cultures due to senescent cell elimination by the senolytic drug ABT-263 (Navitoclax) were analyzed. RESULTS: Compared to 10-week-old mice, the 20-month-old mice had higher numbers of M1 macrophages. The proportion of cells expressing SA-ß-gal were also higher in 20- month-old mice than in 10-week-old-mice. Gingival fibroblasts in 20-month-old mice expressed less collagen 1a1, collagen 4a1, and collagen 4a2 mRNA than those in 10-week-old mice. Compared to control cells, H2O2 treated HGF cells expressed higher levels of SA-ß-gal and p16, p21, IL-1ß, and TNF-α. Furthermore, ABT-263 suppressed HGF cell expression of cytokines after senescence induction. CONCLUSIONS: Senescence-associated changes were observed in the gingival tissues of aged mice and HGF cultures. In addition, the potential of senolytic drugs to modify aging-related changes in the gingiva was shown.

Leucine-rich α-2-glycoprotein is a marker for idiopathic normal pressure hydrocephalus.

OBJECTIVE: Cerebrospinal fluid (CSF) shunting can improve symptoms of elderly patients' idiopathic normal pressure hydrocephalus (iNPH). However, adjunctive means for confirming the diagnosis remain unavailable. We have previously reported the specific increase of leucine-rich alpha-2-glycoprotein (LRG) in iNPH CSF, and the present study investigates its potential clinical applications. METHODS: We performed CSF tap test (TT) on 90 patients (mean age 73.4 years) and shunting in 52 patients (mean age 73.5 years), evaluating symptom improvement and higher cerebral functions-mini-mental state examination (MMSE) and Frontal Assessment Battery (FAB) before and 12 months after shunting. LRG and tau protein concentrations in TT CSF were simultaneously measured using enzyme-linked immunosorbent assay. We then compared the predictive value of these concentrations with TT results regarding successful shunting outcomes. RESULTS: Positive combinations of TT and LRG concentrations of 67 ng/ml or higher, gave 81.6% sensitivity and 78.6% specificity. Therefore we used LRG (67 ng/ml) and tau (200 pg/ml) cut-off values, dividing patients into four groups. In group A (LRG ≥ 67 ng/ml and tau < 200 pg/ml) 31 of 34 patients (91.2%) had a positive TT and all operated 22 patients were shunt responders. Dementia MMSE and FAB scores in them increased from a baseline of 22.05(SE ± 0.96) to 25.65 (±0.85) and 11.38 (±0.68) to 13.08 (±0.57) respectively. In group B, (LRG ≥ 67 ng/ml and tau ≥ 200 pg/ml), the mean MMSE score increased from 17.62 (±2.03) to 21.62 (±1.96), and the FAB decreased slightly from 9.25 (±1.15) to 10.5 (±1.59), without improvement beyond the range of dementia. In group C, (LRG < 67 ng/ml, tau < 200 pg/ml), the mean MMSE score improved from 22.06 (±1.25) to 24.29 (±1.23) and the FAB score improved slightly from 12.0 (±0.72) to 12.87 (±0.72). Finally, in group D, (LRG < 67 ng/ml, tau ≥ 200 pg/ml), there was almost no improvement in MMSE score CONCLUSIONS: A combination of positive TT and biomarkers quantification such as LRG and tau protein, can reliably predict shunting outcome in iNPH patients.

Adenovirus Biology, Recombinant Adenovirus, and Adenovirus Usage in Gene Therapy.

Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse "CRAs that can specifically target tumors with multiple factors" (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine.

Overproduction of IgE induces macrophage-derived chemokine (CCL22) secretion from basophils.

Macrophage-derived chemokine (MDC) CCL22 is a potent chemoattractant for Th2 cells and has been implicated in Th2-predominant allergic inflammation. In the present study, we demonstrated that basophils produce MDC in response to monomeric IgE. In trinitrophenyl (TNP)-IgE transgenic mice, serum levels of MDC were persistently higher than in wild-type mice. The i.v. administration of TNP-specific IgE to wild-type mice transiently induced an elevation in serum MDC, which appeared to be mediated by Fc epsilonRI, as no increase in serum MDC was observed after IgE administration in FcRgamma (-/-) mice. However, the IgE-mediated increase in MDC was observed in mast cell-deficient mice. Freshly isolated bone marrow cells and bone marrow-derived basophils secreted MDC in response to TNP-IgE without Ag stimulation. Furthermore, MDC production was not observed in bone marrow-derived basophils isolated from FcRgamma (-/-) mice. IgE activated Lyn and ERK 1/2 in bone marrow-derived basophils. Treatment of TNP-IgE transgenic mice with a basophil-depletion Ab (Ba103) resulted in decreased serum MDC levels. Thus, IgE appears to be capable of stimulating basophils to produce MDC in the absence of a specific Ag, which may contribute to IgE-mediated and/or Th2-predominant allergic inflammation.

Clinical Features of Painful Ophthalmoplegia with a High-Intensity Ring Appearance around the Optic Nerve on MRI: A Case Series.

OBJECTIVE: Painful ophthalmoplegia includes nonspecific magnetic resonance imaging (MRI) manifestations and various clinical features including orbital pain and cranial nerve palsies. Treatment for painful ophthalmoplegia remains controversial. The aim of this report was to describe detailed clinical features, MRI findings, treatments, and prognosis of patients with painful ophthalmoplegia. Patients and Methods. We retrospectively investigated four cases of patients with painful ophthalmoplegia diagnosed using the International Classification of Headache Disorders, 3rd edition. RESULTS: All patients experienced unilateral orbital pain and oculomotor nerve palsy with diplopia but no vision loss. One of the four patients was diagnosed with Tolosa-Hunt syndrome based on the appearance of a granulomatous inflammation of the cavernous sinus on MRI. No specific lesions were detected on brain MRI for the other three patients; therefore, their headaches were attributed to ischaemic ocular motor nerve palsy. In all patients, a high-intensity ring appearance around the ipsilateral optic nerve was observed on MRI. Steroid therapy was administered to these patients, and good prognoses were anticipated. CONCLUSION: These results indicate that prednisolone is a useful treatment for painful ophthalmoplegia that displays ipsilateral hyperintense ring lesions around the optic nerve on MRI, regardless of the presence of granulomatous inflammation of the cavernous sinus.

Successful treatment of drug-resistant status epilepticus in an adult patient with Mowat-Wilson syndrome: A case report.

Mowat-Wilson syndrome (MWS) is a rare genetic disorder characterized by intellectual disability, distinctive facial features, epilepsy, and multiple anomalies caused by heterozygous loss-of-function mutations in the zinc finger E-box-binding homeobox-2 gene (ZEB2). Treatment choice is very important as patients with MWS because patients sometimes develop drug-resistant epilepsy. Here, we report the case of a 45-year-old male patient with MWS who developed drug-resistant status epilepticus after a 26-years seizure-free period while taking multiple anti-seizure medications. He showed a characteristic magnetic resonance imaging finding with a focal lesion in his left thalamic pulvinar nucleus, a finding not previously reported in status epilepticus with MWS. We succeeded in controlling seizures in the patient after trying multiple new antiseizure drug combinations. These findings indicate that patients with MWS may develop drug-resistant status epilepticus with age, even after a long-term seizure-free period, which can be managed with anti-seizure medication. Therefore, careful monitoring of seizures is important for the treatment of people with MWS, even in patients who have not experienced seizures for a long time.

Simultaneous Development of Progressive Multifocal Leukoencephalopathy and Cryptococcal Meningitis during Methotrexate and Infliximab Treatment.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the JC virus under an immunosuppressed state. This condition carries a high risk of cryptococcal meningitis. We herein report a 65-year-old woman who simultaneously developed PML and cryptococcal meningitis and presented with bilateral sixth nerve palsy. She had been treated with methotrexate and infliximab for rheumatoid arthritis. Her symptoms improved with antifungal drug treatment and discontinuation of immunosuppression therapy. Although concurrent PML and cryptococcal meningitis is rare, it should be considered in immunosuppressed patients.

Hyperventilation and finger exercise increase venous-arterial Pco2 and pH differences.

INTRODUCTION: Since the invention of the pulse oximeter, physicians often or even routinely perform venous blood gas analysis (VBGA). However, it has not been generally agreed that the application of VBGA is practically meaningful in routine clinical situations such as in an ED. METHODS: We measured venous-arterial Pco(2) difference ((v-a)Pco(2)) and arterial-venous pH difference ((a-v)pH), and analyzed the physiological factors that affect these differences in healthy volunteers and hyperventilation patients. RESULTS: In healthy volunteers, both (v-a)Pco(2) and (a-v)pH increased during finger exercise or hyperventilation in an intensity-dependent manner. Doppler echography indicated that increases in (v-a)Pco(2) and (a-v)pH during hyperventilation are induced by reduction of peripheral blood flow. Approximately 40% of patients with untreated respiratory alkalosis were found to be incorrectly diagnosed if based only on VBGA. CONCLUSIONS: It must be noted that VBGA may lead to overestimation of acidosis and to underestimation of respiratory alkalosis when extremities muscles are active or patients are hyperventilating. Physicians should keep these limitations in mind when conducting VBGA.

Aceruloplasminemia with Abnormal Compound Heterozygous Mutations Developed Neurological Dysfunction during Phlebotomy Therapy.

Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in aceruloplasminemia patients with other gene mutations.

2-(1,3-Dithiolan-2-ylidene)-5-(1,3-dithian-2-ylidene)-1,3,4,6- tetrathiapentalene(DHDA-TTP), a hybrid of BDH-TTP and BDA-TTP, and its metallic cation-radical salts.

The synthesis and electrochemical properties of the DHDA-TTP donor, a hybrid of 2,5-bis(1,3-dithiolan-2-ylidene)-1,3,4,6-tetrathiapentalene (BDH-TTP) and 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP), has been investigated, and its ability to form metallic cation-radical salts is elucidated.

Uremic toxins overload accelerates renal damage in a rat model of chronic renal failure.

Uremic toxins have been suggested to promote progression of chronic renal failure by damaging tubular cells. Previous in vitro studies have indicated that some uremic toxins induce oxidative stress and activate NF-kappaB to upregulate plasminogen activator inhibitor-1 in tubular cells. These mechanisms may promote tubulointerstitial fibrosis. The present study examined whether uremic toxins induce glomerular and tubulointerstitial damage in vivo. Two uremic toxins, hippuric acid (HA) or indoleacetic acid (IAA), were tested in two independent experiments (HA-treated rats vs. non-HA-treated controls, IAA-treated rats vs. non-IAA-treated controls). The uremic toxins were administered to subtotally nephrectomized rats. Renal functions were measured periodically and glomerular sclerosis and interstitial fibrosis were examined at the end of the experimental period (18 and 24 weeks, respectively, after subtotal nephrectomy for HA and IAA treatments). Glomerular filtration rate (inulin clearance) at the end of the study period was significantly lower in uremic toxin-treated rats than in control rats (HA-treated rats: 0.090 +/- 0.004 ml/min/100 g body weight vs. non-HA-treated controls: 0.125 +/- 0.013, IAA-treated rats: 0.068 +/- 0.006 versus non-IAA-treated controls: 0.100 +/- 0.013; both p < 0.05). Beta-N-acetyl-glucoseamidase excretion was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.55 +/- 0.05 U/day vs. control: 0.39 +/- 0.04 at week 18, IAA-treated: 0.35 +/- 0.02 vs. control: 0.26 +/- 0.07 at week 16; both p < 0.05). Glomerular sclerosis index was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.85 +/- 0.16 versus control: 0.48 +/- 0.10, IAA-treated: 1.13 +/- 0.25 vs. control: 0.57 +/- 0.10; both p < 0.05). Significant enlargement of interstitial fibrosis was observed in indoleacetic acid-treated rats. These results indicate that overload of uremic toxins accelerates the loss of kidney function, glomerular sclerosis and tubulointerstitial injury in a rat model of chronic renal failure. The present study suggests the potential benefit of early intervention to remove various uremic toxins in delaying the onset of end-stage renal failure in patients with progressive renal disease.

Regulation of QT indices mediated by autonomic nervous function in patients with type 2 diabetes.

Both the QT interval and QT dispersion in diabetic patients have been reported to increase with the progression of cardiac autonomic neuropathy and to have a prognostic value. We assessed the cardiac autonomic influences on QT indices using the measurements of baroreflex sensitivity, heart rate variability, and cardiac (123)I-metaiodobenzylguanidine scintigraphic findings in patients with type 2 diabetes mellitus. Forty-two consecutive patients with type 2 diabetes (mean+/-SD: 54+/-10 years, 22 women and 20 men) were studied. Baroreflex sensitivity negatively correlated with the maximum and minimum QTc intervals as well as QT/QTc dispersion. However, the high-frequency power and the ratio of low-frequency power to high-frequency power of heart rate variability did not correlate with any QT indices. The percent washout rate of (123)I-metaiodobenzylguanidine positively correlated with QT/QTc dispersion, but not with maximum and minimum QTc intervals. Our findings suggest that cardiac vagal dysfunction is related to QT interval prolongation while both sympathetic and vagal dysfunctions are related to increased QT dispersion in type 2 diabetic patients. Baroreflex sensitivity and percent washout rate of (123)I-metaiodobenzylguanidine may be useful parameters indicating the abnormalities of the cardiac ventricular repolarization in this population.