Fukuoka University Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

Emmprin (basigin, CD147) is a cell surface glycoprotein that belongs to the immunoglobulin superfamily. It is highly expressed on the surface of tumor cells and stimulates adjacent fibroblasts or tumor cells to produce matrix metalloproteinases. Moreover, it has recently been shown that emmprin also stimulates expression of vascular endothelial growth factor and hyaluronan, which leads to angiogenesis and anchorage-independent growth/multidrug resistance, respectively. These findings have made emmprin an important molecule in tumor progression and, thus, more attractive as a target for antitumor treatment. However, other functions of emmprin, including as an activator of T cells, a chaperone for monocarboxylate transporters, a receptor for cyclophilin A and a neural recognition molecule, are also being identified in physiological and pathological conditions. Therefore, it is essential to develop specific means to control particular functions of emmprin, for which elucidation of each mechanism is crucial. This review will discuss the role of emmprin in tumor progression and recent advances in the molecular mechanisms of diverse phenomena regulated by emmprin.

BACKGROUND AND PURPOSE: It has been speculated that the same type of hypertensive small-artery disease can cause either intracerebral hemorrhages or ischemic lesions, depending on the circumstances. METHODS: To test this hypothesis, we examined the association between spontaneous intracerebral hematomas and both small chronic hemorrhages and ischemic lesions using echo planar and T2-weighted MRI. We considered a hypointense area to represent a hemorrhage and a hyperintense area to represent an ischemic lesion. RESULTS: We identified small hypointense lesions in 56.7% of 30 patients with intracerebral hematomas (mean age, 62.2 years; total number of lesions, 108) and in 25.4% of 59 patients without hematomas (mean age, 67.6 years; total lesions, 28). The incidence of hypertension was 88.3% in patients with intracerebral hematomas and 42.3% in those without. The hypointense lesions were found in 56.0% of 50 patients with hypertension, whereas they were found only in 10.3% of 39 patients without hypertension. The hypointense lesions were most common in the subcortex, followed by the putamen, pons, thalamus, and cerebellum. The hyperintense lesions were of a higher grade in patients with intracerebral hematomas than in those without. The hypointense lesions were commonly surrounded by hyperintense areas. Additionally, in 3 of 3 autopsied brains, we found hemosiderin deposits around arteriosclerotic microvessels and a surrounding small infarction in areas that had appeared as small hypointense lesions surrounded by hyperintensity on MRI. One specimen also had an organized miliary pseudoaneurysm. CONCLUSIONS: Our findings indicate that spontaneous intracerebral hematomas are frequently associated with small chronic hemorrhages, ischemic lesions, and hypertension. We speculate that hypertensive intracerebral hemorrhage may have the same microangiopathic basis as cerebral infarction.

PAD peripheral arterial disease PCI percutaneous coronary intervention peak V O2 peak oxygen uptake PH pulmonary hypertension PVCs premature ventricular contraction QOL quality of life RCT randomized controlled trial RPE rating of perceived exertion SGA Subjective Global Assessment STEMI ST elevation myocardial infarction TG triglyceride TAVI transcatheter aortic valve implantation VAD ventricular assist device V CO2 carbon dioxide output V E minute ventilation V E/V CO2 ventilatory equivalent for carbon dioxide V E vs. V CO2 slope minute ventilation vs. carbon dioxide output slope V O2 oxygen uptake V O2/HR oxygen pulse capacity is assessed by cardiopulmonary exercise testing (CPX), an exercise prescription is prepared based on the risk in terms of severity of illness, and then a treatment and CR plan is established. If CPX cannot be performed due to complications, low physical fitness, or low left ventricular function, exercise capacity should be confirmed by the 6-minute walk test.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

Background: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. Methods: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks’ treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring). Results: One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m 2 ). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (–6.3 mm Hg; P =0.004); between-group difference in change from baseline was –4.3 mm Hg ( P =0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (–9.5, –7.7, –7.5, and –8.6 mm Hg, respectively; all P ≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (–1.3 kg and –0.33%; both P <0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (–12.1%; P =0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (–8.2% [ P =0.008] and –9.7% [ P =0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups. Conclusions: Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03050229.

BACKGROUND: Laparoscopic cholecystectomy is now accepted as a surgical procedure for acute cholecystitis when it is performed by an expert surgeon. There are several lines of strong evidence, such as randomized controlled trials (RCTs) and meta-analyses, supporting the introduction of laparoscopic cholecystectomy for patients with acute cholecystitis. The updated Tokyo Guidelines 2013 (TG13) describe the surgical treatment for acute cholecystitis according to the grade of severity, the timing, and the procedure used for cholecystitis in a question-and-answer format using the evidence concerning surgical management of acute cholecystitis. METHODS AND MATERIALS: Forty-eight publications were selected for a careful examination of their full texts, and the types of surgical management of acute cholecystitis were investigated using this evidence. The items concerning the surgical management of acute cholecystitis were the optimal surgical treatment for acute cholecystitis according to the grade of severity, optimal timing for the cholecystectomy, surgical procedure used for cholecystectomy, optimal timing of the conversion of cholecystectomy from laparoscopic to open surgery, and the complications of laparoscopic cholecystectomy. RESULTS: There were eight RCTs and four meta-analyses concerning the optimal timing of the cholecystectomy. Consequently, it was found that cholecystectomy is preferable early after admission. There were three RCTs and two meta-analyses concerning the surgical procedure, which concluded that laparoscopic cholecystectomy is preferable to open procedures. Literature concerning the surgical treatment according to the grade of severity could not be quoted, because there have been no publications on this topic. Therefore, the treatment was determined based on the general opinions of professionals. CONCLUSION: Surgical management of acute cholecystitis in the updated TG13 is fundamentally the same as in the Tokyo Guidelines 2007 (TG07), and the concept of a critical view of safety and the existence of extreme vasculobiliary injury are added in the text to call the surgeon's attention to the need to reduce the incidence of bile duct injury. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.

Basic fibroblast growth factor (bFGF) has been shown to promote wound healing. The present trial evaluated the clinical efficacy of bFGF for diabetic ulcer, a type of refractory skin ulcer, and the dose-response relationship. This was designed as a randomized, double-blind, dose-ranging, placebo-controlled trial. A total of 150 patients with non-ischaemic diabetic ulcers measuring 900 mm2 or less were randomized into a placebo group (n = 51), a 0.001% bFGF group (n = 49) and a 0.01% bFGF group (n = 50), and 148 of these patients received treatment for 8 weeks or less. The efficacy evaluation was carried out on 139 patients who met the protocol in this trial. The primary outcome was the percentage of patients showing 75% or greater reductions in the area of ulcer. The area of ulcer decreased by 75% or more in 57.5% (27/47), 72.3% (34/47), and 82.2% (37/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively, and differences were significant between the 0.01% bFGF and placebo groups (p = 0.025). The cure rate was 46.8% (22/47), 57.4% (27/47), and 66.7% (30/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively. The findings obtained in this trial showed wound healing accelerating effects of bFGF on diabetic ulcers.

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.

BACKGROUND AND AIMS: Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S-methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA. METHODS: The frequency of TPMT mutations was investigated in 147 Japanese inflammatory bowel disease (IBD) patients retrospectively. In these subjects, the presence of four mutant alleles (TPMT*2, *3B, *3C and *8) was determined by direct sequencing. The incidence of adverse reactions among patients carrying wild-type TPMT was investigated. The blood level of 6-thioguanine nucleotide (6-TGN) was measured and analyzed in 47 patients with wild-type TPMT. The results were analyzed in relation to the concomitant use of aminosalicylates (ASA). RESULTS: Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/*1) and three (2.0%) carried a mutant TPMT allele (TPMT*1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC < or = 3000/microL) was seen in 15.8% of the patients with wild-type TPMT. 6-TGN levels varied among 47 patients with wild-type TPMT. The blood levels of 6-TGN were significantly higher in the patients receiving concomitant ASA treatment compared with those not receiving concomitant ASA treatment (P = 0.0033). CONCLUSION: The frequency of TPMT gene mutations is low among Japanese IBD patients. The incidence of adverse reactions to AZA was high, even in patients carrying wild-type TPMT. It is concluded that determination of TPMT genotype may not be useful in Japanese IBD patients to predict adverse reactions to AZA.

Proteolytic shedding is an important step in the functional down-regulation and turnover of most membrane proteins at the cell surface. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a multifunctional glycoprotein that has two Ig-like domains in its extracellular portion and functions in cell adhesion as an inducer of matrix metalloproteinase (MMP) expression in surrounding cells. Although the shedding of EMMPRIN is reportedly because of cleavage by metalloproteinases, the responsible proteases, cleavage sites, and stimulants are not yet known. In this study, we found that human tumor HT1080 and A431 cells shed a 22-kDa EMMPRIN fragment into the culture medium. The shedding was enhanced by phorbol 12-myristate 13-acetate and inhibited by TIMP-2 but not by TIMP-1, suggesting the involvement of membrane-type MMPs (MT-MMPs). Indeed, down-regulation of the MT1-MMP expression in A431 cells using small interfering RNA inhibited the shedding. The 22-kDa fragment was purified, and the C-terminal amino acid was determined. A synthetic peptide spanning the cutting site was cleaved by MT1-MMP in vitro. The cleavage site is located in the linker region connecting the two Ig-like domains. The N-terminal Ig-like domain is important for the MMP inducing activity of EMMPRIN and for cell-cell interactions, presumably through its ability to engage in homophilic interactions, and the 22-kDa fragment retained the ability to augment MMP-2 expression in human fibroblasts. Thus, the MT1-MMP-dependent cleavage eliminates the functional N-terminal domain of EMMPRIN from the cell surface, which is expected to down-regulate its function. At the same time, the released 22-kDa fragment may mediate the expression of MMPs in tumor tissues.

The annual all-cause mortality in chronic dialysis patients in our country is within 10%, indicating that the outcome of dialysis therapy in Japan is one of the best in the world. It is nothing short of extraordinary to maintain favorable survival like this despite challenging conditions such as aging of the patients and increase in the proportion of patients on long-term dialysis and with diabetes mellitus. We can be proud of our achievement. Novel therapeutic strategies for dialysis patients have been developed, such as antihypertensive drugs (e.g. angiotensin II receptor blockers, calcium channel blockers and beta blockers), treatment of anemia (e.g. erythropoiesis stimulating agents), and management of chronic kidney disease-mineral and bone disorder (CKD-MBD) (e.g. activated vitamin D, calcimimetics, and new phosphate binders). While the beneficial effect of these new approaches is well acknowledged, we must not forget that the favorable outcome is also due to the considerable efforts and excellence in management of all the medical staff, including physicians, nurses, and clinical engineers, who are engaged in dialysis therapy in Japan. While mortality due to infectious diseases is increasing at present, about half of dialysis patients die from cardiovascular disease (CVD). Thus, the management of CVD has become the most challenging clinical issue in dialysis patients. With regard to CVD, the main focus has so far been on blood vessel diseases of the heart and brain; however, peripheral artery disease (PAD) is now also attracting attention because the number of patients with atherosclerotic obstruction of the peripheral arteries in the lower extremities has increased in recent years and endovascular catheter therapy has been introduced and developed. The number of specialists in the field of PAD has increased along with the development of new biomedical technology and expansion of their use. Endovascular catheter therapy is currently offered to patients with chronic dialysis and we expected an increase in the number of patients benefiting from this therapy. Evidence suggests that the pathological process of CVD is also involved in the aggravation of systemic atherosclerosis associated with renal dysfunction, prompting the use of potent anti-atherogenic agents, such as statins in dialysis patients similar to the general population. With regard to CVD in dialysis patients, unfortunately, there is little clinical evidence to justify the compilation of clinical guidelines. For example, the appropriate blood pressure level in such patients remains unknown, and the target blood pressure level for management of hypertension has not yet been defined even in the guidelines issued by Western countries. Although we discussed this issue in detail in several committee meetings, we only agreed on setting the target blood pressure though we presented this as an opinion rather than guideline by the committee. There is no doubt that we need to validate in the future whether the level is appropriate or not. In fact, we do not know whether any statement on the clinical guideline is right or not especially when evidence is insufficient, and any statement is nothing but "themes of clinical questions". We need to validate this issue by prospective high-evidence grade studies. The Japanese Society for Dialysis Therapy (JSDT) maintains a patient registry database kept with the standing committee responsible for statistics and investigation. We used the data stored in this database to generate the present guideline. We stress that we should continue to maintain this important registry system in order to revise the clinical guidelines in the future. The chapters on cardiac failure, ischemic heart disease, arrhythmia, valvular heart disease, cerebrovascular disease, and peripheral artery disease in the guideline are separated into those for "renal dialysis physicians" and "cardiologists (or strokologists)" in order to demonstrate the importance of cooperation between these two specialties. We think that the excellent outcome of dialysis therapy in Japan is in part attributed to the implementation of excellent daily clinical procedures, which are based on "evidence" and/or "experience" in each dialysis facility. We have to validate the daily procedures and present them as treatment guidelines. We hope this guideline is useful in daily clinical practice. We determined the grading evidence and recommendation levels according to the position statement from Kidney Disease: Improving Global Outcomes (1,2). In dialysis patients, dyslipidemia is an independent risk factor for cardiovascular diseases, particularly incident myocardial infarction (B). We recommend measurement of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, and triglyceride (TG) before dialysis (casual blood sampling) for routine evaluation (1B). We suggest the control target levels should be LDL-C < 120 mg/dL or non-HDL-C < 150 mg/dL for the primary prevention, and LDL-C < 100 mg/dL or non-HDL-C < 130 mg/dL for the secondary prevention of ischemic heart disease (2C). We suggest that administration of statin should be considered if lipid control cannot be achieved by dietary/exercise therapy (2B). We suggest that the evaluation and intervention of undernutrition should be considered if hypolipidemia is present. Observational studies in Japan have demonstrated a close relationship between dyslipidemia (hyper-LDL-cholesterolemia, hypo-HDL-cholesterolemia, hypertriglyceridemia, and/or hyper-non-HDL-cholesterolemia) and the severity of atherosclerosis (1,2) and also the risk of myocardial infarction (3) in dialysis patients. In addition, dyslipidemia is more closely related to coronary artery disease than cerebrovascular disorders. However, observational cohort studies of dialysis patients showed a higher risk of death due to all causes (4) or death due to cardiovascular disease (5) in patients with low total cholesterol (TC) level, reflecting a reverse tendency compared with epidemiological data in the general population. Such relationship is, however, not observed in dialysis patients who are free of inflammation or are not undernourished (as defined by the levels of C-reactive protein [CRP] and serum albumin, respectively) (4,6). In Western countries, the survival curve of dialysis patients who develop acute coronary syndrome is poorer in patients with low body mass index (BMI) than in those with high BMI (7). Similarly, in Japanese dialysis patients, old age, low BMI, and high CRP are reported to be factors that enhance the risk of death after a cardiovascular event (3). These reports suggest that undernutrition, represented by hypoalbuminemia, low BMI, and hypocholesterolemia, correlates with increased risk of death by increasing the risk of death after an event (fatality rate), although hypocholesterolemia per se is not considered to promote atherosclerosis (8). Dyslipidemia can be classified into primary and secondary dyslipidemia, depending on the cause. Primary dyslipidemia includes familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL), with a reported respective prevalence of each type of 1:500 and 1:100. Secondary dyslipidemia is caused by various conditions such as diabetes, endocrine (thyroid, adrenal) disorders, liver diseases, kidney diseases, and drugs. Hypercholesterolemia associated with nephrotic syndrome and hypertriglyceridemia and hypo-HDL-cholesterolemia associated with chronic kidney failure are well-known dyslipidemias caused by kidney diseases. Low lipoprotein lipase activity (high apo C-III levels), low hepatic lipase level, and low lecithin cholesterol acyltransferase (LCAT) activity contribute to dyslipidemia in patients with chronic renal failure. According to the Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases by the Japan Atherosclerosis Society (9), hyper-LDL-cholesterolemia is defined as LDL-C ≥140mg/dL, hypo-HDL-cholesterolemia as HDL-C <40 mg/dL, and hypertriglyceridemia as TG ≥150 mg/dL in fasting blood samples. However, fasting blood samples are often difficult to obtain from dialysis patients. In general, post-prandial changes in TC or HDL-C level are very small, compared with the increase in TG levels. Thus, LDL-C level calculated by the Friedewald equation decreases while little change is observed in non-HDL-C level (TC minus HDL-C). Also, since non-HDL-C level is the sum of LDL-C and cholesterol present in TG-rich lipoproteins (Fig. 1), it is regarded as an integrated index of the atherogenic lipoprotein level. Therefore, for routine evaluation in dialysis patients, non-HDL-C level in a casual blood sample is considered acceptable in addition to the standard fasting LDL-C level. Serum total cholesterol and its components. Serum contains a mixture of lipoproteins of different densities (specific gravity), and the total sum of cholesterol in the various lipoproteins represents serum total cholesterol. Several methods are used to fractionate lipoproteins. HDL has an anti-atherosclerotic properties, and all other fractions apart from HDL (collectively called non-HDL) are atherogenic. The cholesterol present in non-HDL is expressed as non-HDL-C. Thus, non-HDL-C is the sum of cholesterol in atherogenic lipoproteins. In subjects with dyslipidemia in general, secondary dyslipidemia is usually excluded first, followed by recommendations for long-term dietary/exercise therapy. Drug treatment is also considered if the target level cannot be achieved. However, in patients with coronary artery disease, the first option should be drug treatment. A strict target lipid level is set in patients that have not developed coronary artery disease but are at high risk, while a stricter target is set for patients with established coronary artery disease (secondary prevention group). According to the recent epidemiological study of the Japanese Society for Dialysis Therapy (3), the risk of occurrence of acute myocardial infarction increases 1.24 times (95% confidence interval: 1.14–1.35) with every increase in non-HDL-C level of 1 mmol/L (38.7 mg/dL). Based on the results of this observational study, the present guidelines propose a target level of LDL-C <120 mg/dL or non-HDL-C <150 mg/dL for primary prevention, and LDL-C < 100 mg/dL or non-HDL-C level <130 mg/dL for secondary prevention. There are only a few randomized controlled trials in dialysis patients regarding whether lipid lowering therapy significantly reduces the risk of cardiovascular events. The 4D (Die Deutsche Diabetes Dialyse) study using atorvastatin (10) and AURORA Study using rosuvastatin (11) suggested that the risk of all cardiovascular diseases (including those not directly related to atherosclerosis such as heart failure and cerebral hemorrhage) can only be reduced slightly even by lipid lowering therapy using statins. However, the risk of ischemic cardiac accidents decreased significantly by 18% in the 4D Study. Taking these results and the results of the observational cohort study in Japan into consideration, it would be reasonable to treat dialysis patients with high LDL-C or non-HDL-C levels with statins to reduce the risk of ischemic heart disease. Furthermore, there is little medical basis for discontinuation of statins therapy, since statin use is reported to associate with better survival in both incident (12) and prevalent dialysis patients (13). In conducting drug therapy, statins are the first choice. Statins reduce LDL-C level by 25–40% although this effect varies with the drug and dose. In the above 4D (10) and AURORA (11) studies, the frequency of adverse effects were comparable between the statins and placebo groups, suggesting no safety problems with the use of statins. Excluding clinofibrate, fibrates available in Japan are contraindicated in patients with renal failure due to the high risk of rhabdomyolysis based on their excretion via the kidney. Bile acid-binding resins, eicosapentaenoic acid preparations, and intestinal cholesterol transporter inhibitors can also be used in dialysis patients. Niceritrol, a nicotinic acid derivative, reduces serum phosphate levels but could cause anemia and thrombocytopenia and must be administered with caution in dialysis patients. Many patients are treated with more than one drug. For safe treatment, one should monitor symptoms and laboratory tests including serum creatine kinase, aspartate aminotransferase and alanine aminotransferase, and also pay attention to drug interactions. If the patient develops hypolipidemia, a nutritional disorder should be suspected, and measures to improve the nutritional state should be considered. The following issues are proposed as topics of future studies; whether a very high TG level is a risk factor of acute pancreatitis in dialysis patients, and whether patients undergoing peritoneal dialysis and children with renal failure should be treated in a manner similar to that of adult hemodialysis patients. We expect further data from sub-analyses and meta-analysis of the 4D, AURORA, and Study of Heart and Renal Protection (SHARP) studies.* Papers on subanalyses of the 4D Study (14) and AURORA Study (15), and the original report of SHARP (16) appeared during the publication of the guidelines, on which the present simplified guidelines are based, and the preparation of this simplified version. The subanalyses of 4D and AURORA studies suggested that lipid lowering therapy prevents atherosclerotic cardiovascular events in diabetic patients on dialysis, and that it significantly prevents such events more effectively in patients with higher LDL-C levels before the treatment. SHARP also showed that lipid lowering therapy using the combination of simvastatin and ezetimibe significantly reduced the risk of atherosclerotic cardiovascular events and that such reduction showed no significant heterogeneity between the patient groups before and after the initiation of dialysis therapy. To evaluate the risk of cardiovascular death in dialysis patients, we recommend the inclusion of risk factors specific to renal failure (e.g. anemia, inflammation, undernutrition, abnormal mineral metabolism), in addition to classic risk factors (1C). The extent of arterial wall thickening, arterial wall stiffening, and vascular calcification may be used for the evaluation of cardiovascular risk (Opinion). In dialysis patients, the risk of death due to cardiovascular disease (CVD) such as ischemic heart disease, cerebrovascular diseases, and heart failure is markedly increased, and the relative risk compared to the general population is reported to be 10–30 (1). Dialysis patients are characterized by a high risk of CVD events and low survival rate after the onset (high fatality rate). Compared to the general population, dialysis patients show 2–5 times higher risk of incident acute myocardial infarction and poorer survival rate after acute myocardial infarction (2). This is also true for cerebrovascular diseases (3). The high incidence and high fatality rate are considered to synergistically increase the risk of death due to CVD (4). One of the reasons for the high risk of CVD in dialysis patients is advanced atherosclerosis before the initiation of dialysis. About half of the patients have significant coronary artery stenosis at the initiation of dialysis (5,6), and the presence or absence of coronary artery disease at the initiation of dialysis is a strong predictor of cardiovascular events after the initiation of dialysis (7). Vascular calcification is classified into atherosclerotic calcification affecting the intimal layer of the artery and Mönckeberg's sclerosis affecting the medial layer of the artery, especially the latter is more frequently observed in dialysis patients. Both types of calcification are significant predictors of death in dialysis patients. Abnormal mineral and bone metabolism including vascular calcification associated with chronic kidney diseases (CKD) has been integrated as a new concept named CKD-mineral and bone disorder (CKD-MBD) (8), and it is considered important in clinical practice of dialysis patients. Because the risk of CVD in dialysis patients is significantly high even after correction for classic risk factors such as old age, hypertension, dyslipidemia, and diabetes, factors specific to CKD are considered to be involved in the elevated risk of CVD (9). Sarnak et al. (10) noted many factors including anemia, inflammation, undernutrition, and abnormal mineral metabolism as non-classic risk factors. Among them, undernutrition (wasting) is diagnosed in daily clinical practice based on the presence of hypoalbuminemia or low BMI. According to reports from Japan, low BMI is a predictor of all-cause death (11,12) and CVD death (11), but not a predictor of future myocardial infarction (12). A report from the United States (13) observed that the survival curve after the onset of acute coronary syndrome was poorer in the low BMI group. In Japan, also, low BMI is independently related to the risk of death after CVD including myocardial infarction, cerebral infarction, and cerebral hemorrhage (12). Thus, certain non-classic risk factors are considered factors that enhance the fatality rate after the onset of CVD. Clinically, atherosclerosis-arteriosclerosis can be evaluated quantitatively and qualitatively by examination of the thickness and stiffness of the arterial wall and vascular calcification (Table 1). These measurements may serve as surrogate markers between risk factors and CVD events. Carotid artery intima-medial thickness is measured by B mode ultrasonography, which provides quantitative evaluation of arterial wall thickening, and is a predictor of the risk of CVD death and total death in dialysis patients (14). Aortic pulse wave velocity (cfPWV, hfPWV) is a representative index of arterial stiffness and a predictor of CVD death and total death in dialysis patients (15). While a high baPWV measured in the brachium and ankle is also a prognostic factor in dialysis patients (16), its value falsely decreases in patients with obstructive arteriosclerosis in the lower limbs. Therefore, caution is needed and simultaneous measurement of the ankle brachial pressure index (ABI) may be helpful. The Cardio-ankle vascular index (CAVI) and augmentation index (AI) have also been used as new indices of arterial stiffness. Various methods are available to evaluate vascular calcification. Among these, electron beam computed tomography (EBCT) has excellent temporal resolution and provides specific assessment of the heart and large blood vessels. Coronary artery calcification is usually evaluated using the coronary artery calcification score (CACS) calculated by Agatston's method. CACS has been reported to be a predictor of cardiovascular events (cardiac death, non-fatal myocardial infarction) in non-dialysis patients with coronary artery disease (17). However, while dialysis patients with high CACS have poor survival, CACS is not necessarily related to cardiovascular events (18). The sensitivity of multi-detector computed tomography (MDCT) has improved in recent years, and this modality has become the mainstay of coronary artery computed tomography (CT). Abdominal plain CT is used to measure the area of aortic calcification, using the aortic calcification index (ACI), which is determined in 10 slices at 1-cm intervals above the origin of the common iliac artery. In dialysis patients, there is a strong correlation between ACI and coronary artery calcification (19). The presence or absence of vascular calcification examined by thoracoabdominal CT (20,21) has also been shown to be an independent predictor of all-cause death and CVD death in dialysis patients and is considered to be useful in daily clinical practice. Although evaluation of these non-invasive surrogate indices may help estimate the individual CVD risk, the criteria used for their evaluation or appropriate frequency of their use have not been established. Longitudinal changes in these measures are not well known in dialysis patients. We propose that the evaluation method(s) should be selected taking into consideration the characteristics of individual patients and availability in the medical facilities, and to the measurement every if We do not the treatment for each risk factors and their effects on atherosclerosis-arteriosclerosis because are discussed in detail in for other including and at an appropriate for each patient are considered Furthermore, if treatment of CVD are particularly important in dialysis patients. In dialysis patients, we recommend blood pressure should be evaluated not only in the dialysis but also at (1B). In patients long-term dialysis with no of the cardiac we suggest the target of antihypertensive treatment should be blood pressure before dialysis at the of the (Opinion). We recommend should be set in the target blood pressure (1B). We recommend antihypertensive should be administered when the reduction in blood pressure is even after of (1B). According to reports on the present state of chronic dialysis therapy in Japan at the of of all dialysis patients were based on blood pressure measured at the initiation of dialysis and the criteria of the Japanese Society of (1). hypertension is a cause of ischemic heart disease, heart failure, and death, and the control of hypertension is important in dialysis patients (2). However, a in blood pressure during dialysis not only have effects on outcome (3), it may also the of or In dialysis patients, aortic calcification also has a on as pulse and and The outcome is poorer in patients with low pressure but pressure and also in patients with high pressure with pressure Also, the mortality rate is reported to significantly if the blood pressure of the pulse pressure measured before and after dialysis times a and at daily at and before to (7). This is also true for various other including the and blood blood pressure and blood pressure it is important to blood pressure in the evaluation It is more important to any clinical or therapeutic on the of measurements than a casual blood pressure measurement Many cohort studies demonstrated poorer of patients with high blood pressure compared with patients. This is due to the inclusion the of patients with or those with chronic heart failure reverse prospective studies are needed to further evaluate patients Many factors are to be responsible for hypertension in dialysis patients. blood pressure is reported to in more than of patients following strict management of body of is and the present guidelines propose should be of blood pressure measurement is for the of blood pressure of blood pressure pressure should be measured conditions although it can be measured in the or position depending on the at each facility. the of dialysis therapy, blood pressure should be measured after a of of at before the of dialysis. should from before the measurement and from during the pressure should be measured with the heart rate at every the of dialysis, the blood pressure should be measured in a similar manner before of blood and within after the of of and pressure measured before of blood at the of dialysis is called pressure at of setting or blood pressure should be measured also in the standing position at the of dialysis. blood pressure should be measured as by the guidelines of the Japanese Society of before to at and at in the are While has also been reported to be useful it cannot be due to the use of one for In dialysis patients with changes in body it is important to evaluate blood pressure not only in the dialysis but also at In dialysis patients, evaluation on a basis is because dialysis is after pressure decreases from the to the of the on the blood pressure should be evaluated or used are very The blood pressure represents the blood pressure measured before and after dialysis times a and daily blood in the and observational studies demonstrated that is a more significant predictor of and cardiovascular than casual or blood pressure measured at the of the pressure measured at on a non-dialysis in the of the could be also used since it correlates with In dialysis patients, a relationship is observed between blood pressure and However, this relationship that is, it is important to the subjects and when the target blood pressure of antihypertensive treatment. The of antihypertensive treatment is to reduce the long-term risk of cardiovascular diseases in patients on chronic dialysis, rather than reduce all-cause mortality Therefore, patients with cardiac dysfunction, for example, are The target level should be set after evaluation of cardiac in both patients with markedly reduced and those with reduced due to In since the outcome is reported to in patients with increased aortic stiffness due to aortic calcification, by in blood pressure and increase in pulse caution reduction in blood pressure is in consideration of the effects of the blood pressure on various conditions such as chronic heart failure and coronary blood For these the criteria for blood pressure control should not be to all patients but by patients with reduced cardiac for example, and further evaluated at While it is difficult to propose specific target blood pressure in the present guidelines due to the of a dialysis blood pressure than at the of the is as a However, a in blood pressure or in during dialysis and after dialysis are reported to and further studies are the other observational studies that blood pressure not with the effect of in blood pressure during dialysis The target blood pressure is set to reduce the long-term risk of cardiovascular diseases in patients on dialysis, and should not be to patients with cardiovascular disorders. In patients, the blood pressure during dialysis correlates significantly with the risk of death within years (3). One of antihypertensive treatment is appropriate of dialysis, and the conditions of dialysis such as blood and dialysis need to be should an appropriate be and This should be followed by administration of appropriate antihypertensive drugs when If a in blood pressure is observed during dialysis, antihypertensive should be or its the should be set the patient should be followed and antihypertensive if control of and of are the most important of during dialysis. To the target of antihypertensive treatment, the must be set first issue is discussed in a different It is to control changes in body between to any in blood pressure during

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 6th edition was published in 2009, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2009. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women.

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K(+) conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1-4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.

BACKGROUND: Homozygous deletion of 9p21 detected by fluorescence in situ hybridization (FISH) and loss of BRCA1-associated protein 1 (BAP1) expression detected by immunohistochemistry (IHC) are useful for the differentiation between malignant pleural mesothelioma (MPM) and reactive mesothelial hyperplasia. The authors previously described that IHC expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, was correlated with the deletion status of 9p21 FISH in MPM tissues. In the current study, the authors investigated whether a combination of MTAP and BAP1 IHC could distinguish MPM from reactive mesothelial cells (RMC) in cell blocks obtained from pleural effusions. METHODS: The authors examined IHC expression of MTAP and BAP1 in cell blocks obtained from pleural effusions of 45 cases of MPM and 21 cases of reactive mesothelial hyperplasia. Furthermore, IHC expression of MTAP was compared with the deletion status of 9p21 FISH. RESULTS: MTAP and BAP1 IHC differentiated MPM from RMC with 100% specificity for both and sensitivities of 42.2% and 60.0%, respectively. The combination of MTAP and BAP1 IHC yielded a sensitivity of 77.8%, which was higher than that of BAP1 IHC alone or 9p21 FISH alone (62.2%). Moreover, a high degree of concordance was observed between the results of MTAP IHC and 9p21 FISH in cell blocks. CONCLUSIONS: A combination of MTAP and BAP1 IHC in cell blocks from pleural effusions appears to be a reliable and useful method for differentiating MPM cells from RMC and can be used in the routine diagnosis of MPM. Cancer Cytopathol 2018;126:54-63. © 2017 American Cancer Society.

OBJECTIVE: We tried to identify indications for cerebrospinal fluid shunting in patients with normal pressure hydrocephalus. METHODS: We studied the cerebral blood flow (CBF) and vascular response to acetazolamide in the white matter, cortex, and thalamus of 21 patients with normal pressure hydrocephalus, comparing patients who improved clinically after shunting with those who did not. We used xenon-enhanced computed tomography for the CBF measurements. RESULTS: Preoperatively, both groups had globally reduced CBF, but the reduction was more pronounced in the unimproved patients. The vascular response was impaired only in the white matter of the patients who improved later. After shunting, restoration of CBF, more marked in the white matter, and recovery of vascular response in the white matter paralleled clinical improvement and a reduction in ventricular dilation and periventricular lucency on computed tomographic scans in nine patients. The CBF reduction, however, deteriorated in the 12 patients who did not improve clinically. CONCLUSION: We conclude that the underlying disease in the improved patients was ischemia, with a loss of autoregulatory capacity in the periventricular white matter caused by cerebrospinal fluid diffusion. Those who did not improve had irreversible brain damage in which the CBF reduction was secondary to metabolic depression and autoregulation was preserved. We also conclude that patients suspected of having normal pressure hydrocephalus will improve clinically after shunting if preoperative hemispheric CBF is greater than 20 ml/100 g per minute and the vascular response to acetazolamide is impaired only in the periventricular white matter. They will not improve, however, if the preoperative CBF is less than 20 ml/100 g per minute and the vascular response to acetazolamide is intact.

After stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

BACKGROUND: Laparoscopic surgery for rectal cancer is widely performed all over the world and several randomized controlled trials have been reported. However, the usefulness of laparoscopic surgery compared with open surgery has not been demonstrated sufficiently, especially for the low rectal area. OBJECTIVE: The aim of this study was to investigate the hypothesis that laparoscopic primary tumor resection is safe and effective when compared with the open approach for locally advanced low rectal cancer. PATIENTS AND METHODS: Data from patients with clinical stage II to III low rectal cancer below the peritoneal reflection were collected and analyzed. The operations were performed from 2010 to 2011. Short-term outcomes and long-term prognosis were analyzed with propensity score matching. RESULTS: Of 1608 cases collated from 69 institutes, 1500 cases were eligible for analysis. The cases were matched into 482 laparoscopic and 482 open cases. The mean height of the tumor from the anal verge was 4.6 cm. Preoperative treatment was performed in 35% of the patients. The conversion rate from laparoscopic to open surgery was 5.2%. Estimated blood loss during laparoscopic surgery was significantly less than that during open surgery (90 vs 625 mL, P < 0.001). Overall, the occurrence of complications after laparoscopic surgeries was less than that after open surgeries (30.3% vs 39.2%, P = 0.005). Three-year overall survival rates were 89.9% [95% confidence interval (95% CI) 86.7-92.4] and 90.4% (95% CI 87.4-92.8) in the laparoscopic and open groups, respectively, and no significant difference was seen between the 2 groups. No significant difference was observed in recurrence-free survival (RFS) between the 2 groups (3-year RFS: 70.9%, 68.4 to 74.2 vs 71.8%, 67.5 to 75.7). CONCLUSION: Laparoscopic surgery could be considered as a treatment option for advanced, low rectal cancer below the peritoneal reflection, based on the short-term and long-term results of this large cohort study (UMIN-ID: UMIN000013919).