Shinshu University Hospital

The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

Vitamin A circulates in human plasma as retinol bound to a specific transport protein. This protein differs from the known low and high density plasma lipoproteins and has a hydrated density greater than 1.21. In order to study this protein, volunteers were injected intravenously with retinol-15-(14)C. Plasma was collected 1-3 days later, and the purification of retinol-binding protein (RBP) was monitored by assaying for (14)C and also by following the fluorescence of the protein-bound retinol. Purification of RBP was effected by the sequence: Cohn fractionation, chromatography on columns of Sephadex G-200 and diethylaminoethyl (DEAE)-Sephadex, preparative polyacrylamide gel electrophoresis, and finally chromatography on Sephadex G-100. These procedures resulted in a preparation of RBP which was at least 98% pure and which had been purified more than 1500-fold. Purified RBP has alpha(1) mobility on electrophoresis and has a molecular weight of approximately 21,000-22,000. There appears to be one binding site for retinol per molecule of RBP. Solutions of RBP are fluorescent (characteristic of retinol) and have ultraviolet absorption spectra with peaks at 330 mmu (resulting from the bound retinol) and at 280 mmu. There are no fatty acid or fatty acyl chains present in purified RBP. The usual concentration of RBP in plasma is of the order of 3-4 mg/100 ml. In plasma, RBP apparently circulates as a complex, together with another, larger protein with prealbumin mobility on electrophoresis. The RBP-prealbumin complex remains intact during Cohn fractionation and during chromatography on Sephadex and on DEAE-Sephadex columns. The complex dissociates during gel electrophoresis, permitting the isolation and subsequent purification of each of the components. The complex is again formed by mixing together solutions of the separated RBP and of prealbumin. Retinol transport in plasma thus appears to involve both a lipid-protein (retinol-RBP) interaction and a protein-protein (RBP-prealbumin) interaction.

An epidemiological survey for the causes of a high incidence of primary liver cancer (PLC) in Haimen city, Jian-Su province and Fusui county, Guangxi province in China, found a close correlation between the incidence of PLC and the drinking of pond and ditch water. With an aim to clarify whether microcystins (MC), a hepatotoxic peptide produced by water bloom algae, contaminate the drinking water in the endemic areas of PLC in China, a highly sensitive enzyme-linked immunosorbent assay with a detection limit of 50 pg/ml, was introduced to monitor the MC. Three trials to survey the drinking water were carried out in 1993-1994. Samples, 1135 in total, were collected from different sources such as: ponds, ditches, rivers, shallow wells and deep wells in Haimen city. The first survey in September 1993 found that three out of 14 ditch water specimens were positive for MC, with a range of 90-460 pg/ml. Several toxic algae such as Oscillatoria agardhii were present in some of the ditches. In the second trial, samples were collected from five ponds/ditches, two rivers, two shallow wells and two deep wells monthly for the whole year of 1994. These data showed that MC was highest in June to September, with a range of 62-296 pg/ml. A third trial on the 989 different water samples collected from the different types of water sources in July 1994 revealed that 17% of the pond/ditch water, 32% of the river water, and 4% of the shallow-well water were positive for MC, with averages of 101, 160 and 68 pg/ml respectively. No MC was detected in deep well water. A similar survey on 26 drinking water samples in Fusui, Guangxi province, demonstrated a high contamination frequency of MC in the water of ponds/ditches and rivers but no MC in shallow and deep wells. These data support a hypothesis that the blue-green algal toxin MC in the drinking water of ponds/ditches and rivers, or both, is one of the risk factors for the high incidence of PLC in China. Based on previous findings on the epidemiology of PLC and the present results from the mass screening of MC in the drinking water, an advisory level of MC in drinking water was proposed to below 0.01 microg/l. The combined effect of a potent hepatocarcinogen AFB1 and an intermittent intake of MC in drinking water in the summer season was discussed as an etiology of PLC.

The aim of this study was to evaluate the usefulness of annual screening for lung cancer by low-dose computed tomography (CT) and the characteristics of identified lung cancers. Subjects consisted of 5483 general population aged 40-74 years, who received initial CT scans in 1996, followed by repeat annual scans for most subjects in 1997 and 1998, with a total of 13 786 scans taken during 1996-1998. Work-up examinations for patients with suspicious lesions were conducted using diagnostic CTs. The initial screening in 1996 detected suspicious nodules in 279 (5.1%) of 5483 subjects, and 22 (8%) were confirmed surgically to have lung cancer. Corresponding figures in 1997 and 1998 screening studies were 173 (3.9%) of 4425 and 25 (14%) of 173, and 136 (3.5%) of 3878 and 9 (7%) of 136, respectively. The sensitivity and specificity of detecting surgically confirmed lung cancer were 55% (22/40) and 95% (4960/5199) in 1996 and 83% (25/30) and 97% (4113/4252) in 1997 screening, respectively. 88% (55/60) of lung cancers identified on screening and surgically confirmed were AJCC stage IA. Our trial allowed detection of nearly 11 times the expected annual number of early lung cancers. Repeat CT allowed the detection of more aggressive, rapidly growing lung cancers, compared to those in the initial screening.

The 'Clinical Guidelines for Obstetrical Practice, 2011 edition' were revised and published as a 2014 edition (in Japanese) in April 2014 by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction of burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. The number of Clinical Questions and Answers items increased from 87 in the 2011 edition to 104 in the 2014 edition. The Japanese 2014 version included a Discussion, a List of References, and some Tables and Figures following the Answers to the 104 Clinical Questions; these additional sections covered common problems and questions encountered in obstetrical practice, helping Japanese readers to achieve a comprehensive understanding. Each answer with a recommendation level of A, B or C was prepared based principally on 'evidence' or a consensus among Japanese obstetricians in situations where 'evidence' was weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 104 Clinical Questions and Answers items, with the omission of the Discussion, List of References, and Tables and Figures, are presented herein to promote a better understanding among English readers of the current standard care practices for pregnant women in Japan.

BACKGROUND: IgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases. METHODS: The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012. RESULTS: The diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC. CONCLUSION: These diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.

Water/air, blood/air, oil/air, oil/water, and oil/blood partition (or solubility) coefficients of 17 aromatic hydrocarbons and ketones were measured by a newly developed vial-equilibration method, which needs no direct measurements of the concentration either in the liquid or in the air phase, but only the gas chromatographic peak heights of the air in the sample (in which a test material is contained) and reference vessels (containing no test material). It was found that the blood/air partition coefficients for aromatic hydrocarbons are correlated closely with the product of water/air and oil/air partitiion coefficients, whereas those for ketones are almost in the same range as the water/air, irrespective of the oil/air partition coefficients.

OBJECTIVE: To evaluate the feasibility of an aggressive surgical approach incorporating major hepatic resection after biliary drainage and preoperative portal vein embolization for patients with hilar bile duct cancer. SUMMARY BACKGROUND DATA: Although many surgeons have emphasized the importance of major hepatectomy in terms of curative resection for patients with hilar bile duct cancer, this procedure results in a high incidence of postoperative morbidity and mortality in patients with cholestasis-induced impaired liver function. METHODS: A retrospective cohort study was conducted in 140 patients with hilar bile duct cancer treated from 1990 through 2001. Resectional surgery was performed in 79 patients, 69 of whom underwent major hepatic resection. Thirteen patients underwent concomitant pancreaticoduodenectomy. Preoperative biliary drainage was carried out in all 65 patients who had obstructive jaundice. Portal vein embolization was conducted in 41 of 51 patients undergoing extended right hepatectomy. Short- and long-term outcomes were evaluated. RESULTS: No patient experienced postoperative liver failure (maximum total bilirubin level, 5.4 mg/dL). The in-hospital mortality rate was 1.3% (1 in 79, resulting from cerebral infarction). A histologically negative resection margin was obtained more frequently when the scheduled extended hepatic resection was conducted (75% vs 44%, P = 0.0178). The estimated 5-year survival rate was 40% when histologically negative resection margins were obtained, but only 6% if the margins were positive. Multivariate analysis identified the resection margin and nodal status as independent factors predictive of survival. CONCLUSIONS: Extensive resection, mainly extended right hemihepatectomy, after biliary drainage and preoperative portal vein embolization, when necessary, for patients with hilar bile duct cancer can be performed safely and is more likely to result in histologically negative margins than other resection methods.

Helicobacter pylori infects the stomachs of nearly a half the human population, yet most infected individuals remain asymptomatic, which suggests that there is a host defense against this bacterium. Because H. pylori is rarely found in deeper portions of the gastric mucosa, where O-glycans are expressed that have terminal alpha1,4-linked N-acetylglucosamine, we tested whether these O-glycans might affect H. pylori growth. Here, we report that these O-glycans have antimicrobial activity against H. pylori, inhibiting its biosynthesis of cholesteryl-alpha-D-glucopyranoside, a major cell wall component. Thus, the unique O-glycans in gastric mucin appeared to function as a natural antibiotic, protecting the host from H. pylori infection.

We conclude that auricular deformities of the early neonate are corrigible by nonsurgical correction. Ideally, the correction should be started immediately after birth (realistically, at latest by the third day after birth) in order to obtain satisfactory and irreversible results.

AIMS: To describe the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in hospitalized elderly patients with heart failure. METHODS AND RESULTS: The FRAGILE-HF study was a prospective multicentre cohort study enrolling consecutive hospitalized patients with heart failure aged ≥65 years. The study objectives were to examine the prevalence, overlap, and prognostic implications of the coexistence of multiple frailty domains. Physical frailty, social frailty, and cognitive dysfunction were evaluated by the Fried phenotype model, Makizako's 5 items, and Mini-Cog, respectively. The primary study outcome was the combined endpoint of heart failure rehospitalization and all-cause death within 1 year. Among 1180 enrolled hospitalized patients (median age, 81 years; 57.4% male), physical frailty, social frailty, and cognitive dysfunction were identified in 56.1%, 66.4%, and 37.1% of the patients, respectively. The number of identified frailty domains was 0, 1, 2, and 3 in 13.5%, 31.4%, 36.9%, and 18.2% of the patients, respectively. During follow-up, the combined endpoint occurred in 383 patients. Adjusted hazard ratios for 1, 2, and 3 domains, with 0 domains as the reference, were 1.38 [95% confidence interval (CI) 0.89-2.13; P = 0.15], 1.60 (95% CI 1.04-2.46; P = 0.034), and 2.04 (95% CI 1.28-3.24; P = 0.003), respectively. Incorporating the number of frailty domains into the pre-existing risk model yielded a 22.0% (95% CI 0.087-0.352; P = 0.001) net reclassification improvement for the primary outcome. CONCLUSIONS: The coexistence of multiple frailty domains is prevalent in hospitalized elderly patients with heart failure. Holistic assessment of multi-domain frailty provides additive value to known prognostic factors.

BACKGROUND AND AIMS: Histochemical analysis of the surface mucous gel layer of the human colon is difficult, as it dissolves in fixatives. This study was undertaken to explore the surface mucous gel layer on the normal mucosa and neoplastic tissues of the large intestine. In addition, the distribution of different mucins secreted from goblet cells was studied with a series of histochemical stains for mucins. METHODS: Twenty four surgically resected specimens were fixed in Carnoy's solution and embedded in paraffin. In four cases, the surface mucous gel layer was also studied in frozen sections. Serial sections were stained by a battery of histochemical techniques characterising mucins. RESULTS AND CONCLUSION: The surface mucous gel layer consisted of the inner and outer layers. The first covered the luminal surface of the mucosa, consisted of mucins, and showed a vertical striped pattern. The second overlaid the first, showed a lateral striped pattern, and was contaminated with bacteria and other substances. Their thickness in paraffin sections varied considerably among the sites in the large intestine, but was the thickest in the rectum and measured 12.7 (SEM 6.0) microns and 88.8 (SEM 80.1) microns respectively. Mucins forming the inner layer were obviously derived from goblet cells underlying it.

According to the IASLC/ATS/ERS classification, the lepidic predominant pattern consists of 3 subtypes: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and nonmucinous lepidic predominant invasive adenocarcinoma. We reviewed tumor slides from 1038 patients with stage I lung adenocarcinoma, recording the percentage of each histologic pattern and measuring the invasive tumor size. Tumors were classified according to the IASLC/ATS/ERS classification: 2 were AIS, 34 MIA, and 103 lepidic predominant invasive. Cumulative incidence of recurrence (CIR) was used to estimate the probability of recurrence. Patients with AIS and MIA experienced no recurrences. Patients with lepidic predominant invasive tumors had a lower risk for recurrence (5-y CIR, 8%) than nonlepidic predominant tumors (n=899; 19%; P=0.003). Patients with >50% lepidic pattern tumors experienced no recurrences (n=84), those with >10% to 50% lepidic pattern tumors had an intermediate risk for recurrence (n=344; 5-y CIR, 12%), and those with ≤10% lepidic pattern tumors had the highest risk (n=610; 22%; P<0.001). CIR was lower for patients with ≤2 cm tumors than for those with >2 to 3 cm tumors (for both total and invasive tumor size), with the difference more pronounced for invasive tumor size (5-y CIR, 13% vs. 21% [total size; P=0.022] and 12% vs. 27% [invasive size; P<0.001]). Most patients with lepidic predominant adenocarcinoma who experienced a recurrence had potential risk factors, including sublobar resection with close margins (≤0.5 cm; n=2), 20% to 30% micropapillary component (n=2), and lymphatic or vascular invasion (n=2). It therefore may be possible to identify lepidic predominant adenocarcinomas that carry a low or high risk for recurrence.

concentration via global cooling and sea ice formation in the North Atlantic, in addition to extended Northern Hemisphere ice sheets.

Recent studies have demonstrated that n-3 polyunsaturated fatty acids ameliorate nonalcoholic fatty liver disease. Although eicosapentaenoic acid (EPA), one of the major components of n-3 polyunsaturated fatty acids, is widely used as an antilipidemic agent, its single efficacy for nonalcoholic steatohepatitis (NASH) remains unclear. As such, we aimed to evaluate the efficacy and safety of EPA on 23 biopsy-proven NASH patients in a pilot trial. Highly purified EPA (2700 mg/d) was administered for 12 months and efficacy was assessed by biochemical parameters and liver histology. All patients completed the treatment with no adverse events, indicating acceptable tolerance to the treatment. After 12 months, serum alanine aminotransferase levels were significantly improved (from 79+/-36 to 50+/-20 U/L), and serum free fatty acids, plasma soluble tumor necrosis factor receptor 1 and 2 levels, and serum ferritin and thioredoxin levels, which may reflect hepatic oxidative stress, were significantly decreased. Body weight, blood glucose, insulin, and adiponectin concentrations remained unchanged. Seven of the 23 patients consented to undergo posttreatment liver biopsy, which showed improvement of hepatic steatosis and fibrosis, hepatocyte ballooning, and lobular inflammation in 6 patients. In conclusion, EPA treatment seems to be safe and efficacious for patients with NASH, largely due to its anti-inflammatory and antioxidative properties. To confirm these results, appropriately powered, controlled trials are needed.

The Ehlers-Danlos syndromes comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders, which are characterized by joint hypermobility, skin hyperextensibility, and tissue friability. In the Villefranche Nosology, six subtypes were recognized: The classical, hypermobile, vascular, kyphoscoliotic, arthrochalasis, and dermatosparaxis subtypes of EDS. Except for the hypermobile subtype, defects had been identified in fibrillar collagens or in collagen-modifying enzymes. Since 1997, a whole spectrum of novel, clinically overlapping, rare EDS-variants have been delineated and genetic defects have been identified in an array of other extracellular matrix genes. Advances in molecular testing have made it possible to now identify the causative mutation for many patients presenting these phenotypes. The aim of this literature review is to summarize the current knowledge on the rare EDS subtypes and highlight areas for future research. © 2017 Wiley Periodicals, Inc.

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTSafe Clinical Use of Carbon Nanotubes as Innovative BiomaterialsNaoto Saito*†, Hisao Haniu‡, Yuki Usui‡§, Kaoru Aoki‡, Kazuo Hara‡, Seiji Takanashi‡, Masayuki Shimizu‡, Nobuyo Narita‡, Masanori Okamoto‡, Shinsuke Kobayashi‡, Hiroki Nomura‡, Hiroyuki Kato‡, Naoyuki Nishimura⊥, Seiichi Taruta∥, and Morinobu Endo§∥View Author Information† Institute for Biomedical Sciences, Shinshu University, Asahi 3-1-1, Matsumoto 390-8621, Japan‡ Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan§ ∥ §Research Center for Exotic Nanocarbons, and ∥Faculty of Engineering, Shinshu University, Wakasato 4-17-1, Nagano 380-8553, Japan⊥ R&D Center, Nakashima Medical Co. Ltd., Haga 5322, Kita-ku, Okayama 701-1221, Japan*Tel.: +81 263 37 2409. Fax: +81 263 35 8844. E-mail: [email protected]Cite this: Chem. Rev. 2014, 114, 11, 6040–6079Publication Date (Web):April 10, 2014Publication History Received26 June 2013Published online10 April 2014Published inissue 11 June 2014https://doi.org/10.1021/cr400341hCopyright © 2014 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceArticle Views10601Altmetric-Citations169LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (24 MB) Get e-AlertsSUBJECTS:Biomaterials,Carbon nanotubes,Nanoparticles,Safety,Toxicity Get e-Alerts

The possible existence of a beta3-adrenergic receptor (beta3-AR) in the human detrusor muscle was investigated by in vitro functional studies and analysis of mRNA expression. Isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of the human detrusor. The rank order for their relaxing potencies was isoprenaline (pD2 6.37+/-0.07) > or = noradrenaline (pD2 6.07+/-0.12) > or = adrenaline (pD2 5.88< or =0.11). Neither dobutamine (beta1- and beta2-AR agonist) nor procaterol (beta2-AR agonist) produced any significant relaxation at concentrations up to 10(-5) M. BRL37344A, CL316243 and CGP-12177A (beta3-AR agonists), relaxed the preparations significantly at concentrations higher than 10(-6) M. The pD2 values for BRL37344A, CL316243 and CGP-12177A were 6.42+/-0.25, 5.53+/-0.09 and 5.74+/-0.14, respectively. CGP-20712A (10(-7) - 10(-5) M), a beta1-AR antagonist, did not affect the isoprenaline-induced relaxation. On the other hand, ICI-118,551, a beta2-AR antagonist, produced a rightward parallel shift of the concentration-relaxation curve for isoprenaline only at the highest concentration used (10(-5) > M) and its pKB value was 5.71+/-0.19. Moreover, SR58894A (10(-7) - 10(-5) M), a beta3-AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in a concentration-dependent manner. The pA2 value and slope obtained from Schild plots were 6.24+/-0.20 and 0.68+/-0.31. The beta1-, beta2- and beta3-AR mRNAs were all positively expressed in detrusor smooth muscle preparations in a reverse transcription polymerase chain reaction assay. In conclusion, the present results provide the first evidence for the existence of the beta3-AR subtype in the human detrusor. They also suggest that the relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through beta3-AR activation.

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.