Beyond "Cirrhosis" A Proposal From the International Liver Pathology Study Group

Cirrhosis is a moiphologic term that has been used for almost 200 years to denote the end stage of a variety of chronic liver diseases. The term implies a condition with adverse prognosis due to the well-known complications of portal hypertension, hepatocellular carcinoma, and liver failure. However, recent advances in the diagnosis and treatment of chronic liver diseases have changed the natural history of cirrhosis significantly. This consensus document by the International Liver Pathology Study Group challenges the usefulness of the word cirrhosis in modern medicine and suggests that this is an appropriate time to consider discontinuing the use of this term. The role of pathologists should evolve to the diagnosis of advanced stage of chronic liver disease, with emphasis on etiology, grade of activity, features suggestive of progression or regression, presence of other diseases, and risk factors for malignancy, within the perspective of an integrated clinicopathologic assessment.

GRBAS and Cape-V Scales: High Reliability and Consensus When Applied at Different Times

Objectives. To evaluate whether the overall dysphonia grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, and the Consensus Auditory Perceptual Evaluation-Voice (CAPE-V) scale show the same reliability and consensus when applied to the same vocal sample at different times. Study Design. Observational cross-sectional study. Methods. Sixty subjects had their voices recorded according to the tasks proposed in the CAPE-V scale. Vowels /a/ and /i/ were sustained between 3 and 5 seconds. Reproduction of six sentences and spontaneous speech from the request "Tell me about your voice" were analyzed. For the analysis of the GRBAS scale, the sustained vowel and reading tasks of the sentences was used. Auditory-perceptual voice analyses were conducted by three expert speech therapists with more than 5 years of experience and familiar with both the scales. Results. A strong correlation was observed in the intrajudge consensus analysis, both for the GRBAS scale as well as for CAPE-V, with intraclass coefficient values ranging from 0.923 to 0.985. A high degree of correlation between the general GRBAS and CAPE-V grades (coefficient = 0.842) was observed, with similarities in the grades of dysphonia distribution in both scales. The evaluators indicated a mild difficulty in applying the GRBAS scale and low to mild difficulty in applying the CAPE-V scale. The three evaluators agreed when indicating the GRBAS scale as the fastest and the CAPE-V scale as the most sensitive, especially for detecting small changes in voice. Conclusions. The two scales are reliable and are indicated for use in analyzing voice quality.

Coordination and Control of Autonomous Mobile Robots Swarms by using Particle Swarm Optimization Algorithm and Consensus Theory

This thesis presents some different techniques designed to drive a swarm of robots in an a-priori unknown environment in order to move the group from a starting area to a final one avoiding obstacles. The presented techniques are based on two different theories used alone or in combination: Swarm Intelligence (SI) and Graph Theory. Both theories are based on the study of interactions between different entities (also called agents or units) in Multi- Agent Systems (MAS). The first one belongs to the Artificial Intelligence context and the second one to the Distributed Systems context. These theories, each one from its own point of view, exploit the emergent behaviour that comes from the interactive work of the entities, in order to achieve a common goal. The features of flexibility and adaptability of the swarm have been exploited with the aim to overcome and to minimize difficulties and problems that can affect one or more units of the group, having minimal impact to the whole group and to the common main target. Another aim of this work is to show the importance of the information shared between the units of the group, such as the communication topology, because it helps to maintain the environmental information, detected by each single agent, updated among the swarm. Swarm Intelligence has been applied to the presented technique, through the Particle Swarm Optimization algorithm (PSO), taking advantage of its features as a navigation system. The Graph Theory has been applied by exploiting Consensus and the application of the agreement protocol with the aim to maintain the units in a desired and controlled formation. This approach has been followed in order to conserve the power of PSO and to control part of its random behaviour with a distributed control algorithm like Consensus.

Hereditary angioedema (HAE) in children and adolescents--a consensus on therapeutic strategies

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

A Comparative Study of Central and Eastern European Social Policy Concernig Mental Disability

The main goal of this project was to identity whether an imported system of social policy can be suitable for a host country, and if not why not. Romanian social policy concerning the mentally disabled represents a paradoxical situation in that while social policy is designed to ensure both an institutional structure and a juridical environment, in practice it is far from successful. The central question which Ms. Ciumageanu asked therefore was whether this failure was due to systemic factors, or whether the problem lay in reworking an imported social policy system to meet local needs. She took a comparative approach, also considering both the Scandinavian model of social policy, particularly the Danish model which has been adopted in Romania, and the Hungarian system, which has inherited a similar universal welfare system and perpetuated it to some extent. In order to verify her hypothesis, she also studied the transformation of the welfare system in Great Britain, which meant a shift from state responsibility towards community care. In all these she concentrated on two major aspects: the structural design within the different countries and, at a micro level, the societal response. Following her analyses of the various in the other countries concerned, Ms. Ciumageanu concluded that the major differences lie first in the difference between the stages of policy design. Here Denmark is the most advanced and Romania the most backwards. Denmark has a fairly elaborate infrastructure, Britain a system with may gaps to bridge, and Hungary and Romania are struggling with severe difficulties owing both to the inherited structure and the limits imposed by an inadequate GDP. While in Denmark and Britain, mental patients are integrated into an elaborate system of care, designed and administered by the state (in Denmark) or communities (in Britain), in Hungary and Romania, the state designs and fails to implement the policy and community support is minimal, partly due to the lack of a fully developed civil society. At the micro level the differences are similar. While in Denmark and Britain there is a consensus about the roles of the state and of civil societies (although at different levels in the two countries, with the state being more supportive in Denmark), in Romania and to a considerable extent in Hungary, civil society tends to expect too much from the state, which in its turn is withdrawing faster from its social roles than from its economic ones, generating a gap between the welfare state and the market economy and disadvantaging the expected transition from a welfare state to a welfare society and, implicitly, the societal response towards those mentally disabled persons in it. On an intermediate level, the factors influencing social policy as a whole were much the same for Hungary and Romania. Economic factors include the accumulated economic resources of both state and citizens, and the inherited pattern of redistribution, as well as the infrastructure; institutional resources include the role of the state and the efficiency of the state bureaucracy, the strength and efficiency of the state apparatus, political stability and the complexity of political democratisation, the introduction of market institutions, the strength of civil society and civic sector institutions. From the standpoint of the societal response, some factors were common to all countries, particularly the historical context, the collective and institutional memories and established patterns of behaviour. In the specific case of Romania, general structural and environmental factors - industrialisation and forced urbanisation - have had a definite influence on family structure, values and behavioural patterns. The analysis of Romanian social policy revealed several causes for failure to date. The first was the instability of the policy and the failure to consider the structural network involved in developing it, rather than just the results obtained. The second was the failure to take into account the relationship between the individual and the group in all its aspects, followed by the lack of active assistance for prevention, re-socialisation or professional integration of persons with mental disabilities. Finally, the state fails to recognise its inability to support an expensive psychiatric enterprise and does not provide any incentive to the private sector. This creates tremendous social costs for both the state and the individual. NGOs working in the field in Romania have been somewhat more successful but are still limited by their lack of funding and personnel and the idea of a combined system is as yet utopian in the circumstances in the country.

Novel sst2-selective somatostatin agonists. Three-dimensional consensus structure by NMR

The 3D NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form are described. These analogues, with the basic sequence H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Ala/Aph, exhibit potent and highly selective binding to human SRIF type 2 (sst2) receptors. The backbone of these sst2-selective analogues have the usual type-II' beta-turn reported in the literature for sst2/3/5-subtype-selective analogues. Correlating the biological results and NMR studies led to the identification of the side chains of DPhe2, DTrp8, and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show that the aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3 and sst5 binding. This pharmacophore is, therefore, different from that proposed by others for sst2/3/5 analogues.

European Working Group on Clinical Cell Analysis: Consensus protocol for the flow cytometric characterisation of platelet function

An increased or disturbed activation and aggregation of platelets plays a major role in the pathophysiology of thrombosis and haemostasis and is related to cardiovascular disease processes. In addition to qualitative disturbances of platelet function, changes in thrombopoiesis or an increased elimination of platelets, (e. g., in autoimmune thrombocytopenia), are also of major clinical relevance. Flow cytometry is increasingly used for the specific characterisation of phenotypic alterations of platelets which are related to cellular activation, haemostatic function and to maturation of precursor cells. These new techniques also allow the study of the in vitro response of platelets to stimuli and the modification thereof under platelet-targeted therapy as well as the characterisation of platelet-specific antibodies. In this protocol, specific flow cytometric techniques for platelet analysis are recommended based on a description of the current state of flow cytometric methodology. These recommendations are an attempt to promote the use of these new techniques which are at present broadly evaluated for diagnostic purposes. Furthermore, the definition of the still open questions primarily related to the technical details of the method should help to promote the multi-center evaluation of procedures with the goal to finally develop standardized operation procedures as the basis of interlaboratory reproducibility when applied to diagnostic testing.

The association between admission systolic blood pressure and mortality in significant traumatic brain injury: A multi-centre cohort study

INTRODUCTION Low systolic blood pressure (SBP) is an important secondary insult following traumatic brain injury (TBI), but its exact relationship with outcome is not well characterised. Although a SBP of <90mmHg represents the threshold for hypotension in consensus TBI treatment guidelines, recent studies suggest redefining hypotension at higher levels. This study therefore aimed to fully characterise the association between admission SBP and mortality to further inform resuscitation endpoints. METHODS We conducted a multicentre cohort study using data from the largest European trauma registry. Consecutive adult patients with AIS head scores >2 admitted directly to specialist neuroscience centres between 2005 and July 2012 were studied. Multilevel logistic regression models were developed to examine the association between admission SBP and 30 day inpatient mortality. Models were adjusted for confounders including age, severity of injury, and to account for differential quality of hospital care. RESULTS 5057 patients were included in complete case analyses. Admission SBP demonstrated a smooth u-shaped association with outcome in a bivariate analysis, with increasing mortality at both lower and higher values, and no evidence of any threshold effect. Adjusting for confounding slightly attenuated the association between mortality and SBP at levels <120mmHg, and abolished the relationship for higher SBP values. Case-mix adjusted odds of death were 1.5 times greater at <120mmHg, doubled at <100mmHg, tripled at <90mmHg, and six times greater at SBP<70mmHg, p<0.01. CONCLUSIONS These findings indicate that TBI studies should model SBP as a continuous variable and may suggest that current TBI treatment guidelines, using a cut-off for hypotension at SBP<90mmHg, should be reconsidered.

Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document

OBJECTIVES The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. BACKGROUND A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS Two in-person meetings (held in September 2011 in Washington, DC, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and noninterventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).

Consensus on melanonychia nail plate dermoscopy

This statement, focused on melanonychia and nail plate dermoscopy, is intended to guide medical professionals working with melanonychia and to assist choosing appropriate management for melanonychia patients. The International Study Group on Melanonychia was founded in 2007 and currently has 30 members, including nail experts and dermatopathologists with special expertise in nails. The need for common definitions of nail plate dermoscopy was addressed during the Second Meeting of this Group held in February 2008. Prior to this meeting and to date (2010) there have been no evidence-based guidelines on the use of dermoscopy in the management of nail pigmentation.

STUDY OF REST AS A NEGATIVE REGULATOR OF P16INK4A

STUDY OF REST AS A NEGATIVE REGULATOR OF P16INK4A Monica Gireud, B.S. Thesis Advisor: Vidya Gopalakrishnan, Ph.D. The RE1 Silencing Transcription Factor (REST) is a negative regulator of neuronal differentiation. It is expressed ubiquitously in early embryos, but downregulated in neural progenitors concomitant with onset of neuronal differentiation in these cells. REST has been widely studied as a negative regulator of neuronal differentiation genes. Our recent work identified a novel role for REST in control of cell proliferation. However, the underlying molecular mechanism(s) are not known and is a focus of the current thesis project. Here, we provide evidence that REST signaling controls the expression of the cyclin-dependent kinase inhibitor, p16Ink4a, a negative regulator of the cell cycle and passage through G1. We determined that REST expression in the proliferating granule progenitors of the cerebellum and its lack of expression in the differentiated neurons is reciprocally correlated with that of p16Ink4a. Decline in REST levels in differentiating primary and neural stem cells immortalized with v-myc (NSC-M) granule progenitors in vitro was also associated with upregulation of p16Ink4a expression. Conversely, constitutive human REST transgene expression in NSC-M cells (NSC-MRs) blocked p16Ink4 upregulation, even under neuronal differentiation conditions. However, the lack of a consensus REST DNA binding RE1 element in the regulatory regions of p16Ink4a locus suggested an indirect regulation of p16Ink4a by REST. Based on work from other groups that showed repression of p16Ink4a transcription by the polycomb protein Bmi-1, and its negative regulation by microRNA-203 (miR-203) and our identification of a RE1 element in the downstream regulatory region of miR-203, we asked if the p16Ink4a expression was controlled by REST through a series of negative regulatory events involving miR-203 and Bmi-1. We observed that Bmi1 -expression mirrored that of REST and inversely correlated with that of miR-203 in the postnatal cerebellum and in vitro differentiated granule and NSC-M progenitors. In contrast, forced REST transgene expression in NSC-MR cells abrogated the decrease in Bmi-1 levels and elevation in miR-203 expression. Significant REST binding to the miR-203 RE1 element was also observed in NSC-M cells, indicating that REST had the potential to directly regulate miR-203 expression. In conclusion, our studies suggest a role for REST in control of cell cycle transit in neural progenitors through negative regulation of p16Ink4a. Further validation of these results in REST knockout mice is needed, and is ongoing.

Practitioners' Views of Family Strengths: A Delphi Study

Reported is a research study to assess the opinions of family practitioners on the status of families in Oklahoma. Researchers employed the Delphi method to achieve consensus among key informants in the family practice field about the strengths and weaknesses of Oklahoma families, threats facing families in the state, and means to strengthening family life in Oklahoma. The study yielded qualitative data from the key informants, which the researchers then condensed into response categories to feed back to informants to rate. Family practitioners identified resilience, spirituality, and access to support systems as the greatest strengths, and listed substance abuse, poverty, and generational cycles of dysfunction as the greatest weaknesses of Oklahoma families. Recommendations by these practitioners are given for improvements in addressing family needs.

Structure and function study of prostaglandin H synthase

Prostaglandin H synthase (PGHS) is a key enzyme in biosynthesis of prostaglandins, thromboxane, and prostacyclin. It has two activities, cyclooxygenase and peroxidase. "PGHS" means PGHS-1. A current hypothesis considers the cyclooxygenase reaction to be a free radical chain reaction, initiated by interaction of the synthase peroxidase with hydroperoxides leading to the production of a tyrosyl free radical. According to this hypothesis, tyrosyl residue(s) may play a key role in the cyclooxygenase reaction. Tetranitromethane (TNM) can relatively selectively nitrate tyrosines at pH 8.0. The effect of TNM on both cyclooxygenase activity and peroxidase activity has been examined: reaction of the synthase holoenzyme with TNM at pH 8.0 led to inactivation of both activities, with the cyclooxygenase activity being lost rapidly and completely, while the peroxidase activity was lost more slowly. Indomethacin, a non-steroidal anti-inflammatory agent, can protect the synthase from the inactivation of TNM. Amino acid analyses indicated that a loss of tyrosine and formation of nitrotyrosine residues occurred during reaction with TNM, and that TNM-reacted holoenzyme with $<$10% residual cyclooxygenase activity had about 2.0 nitrotyrosine/subunit.^ PGH synthase is known to be an endoplasmic reticulum membrane-associated protein. Antibodies directed at particular PGHS peptide segments and indirect immunofluorescence have been used to characterize the membrane topology of crucial portions of PGHS. PGHS was expressed in COS-1 cells transfected with the appropriate cDNA. Stably-transfected human endothelial cells were also used for the topology study. The cells were treated with streptolysin-O, which selectively permeabilizes the plasma membrane, or with saponin to achieve general membrane disruption, before incubation with the antipeptide antibodies. Bound antipeptide antibody was stained by FITC-labelled secondary antibody and visualized by fluorescence microscopy. With the antipeptide antibodies against residues 51-66, 156-170 or 377-390, there was a significant reticular and perinuclear pattern of staining in cells permeabilized with saponin but not in cells permeabilized with SLO alone. Antibodies directed against the endogenous C-terminal peptide or against residues 271-284 produced staining in cells permeabilized with saponin, and also in a lower, but significant fraction of cells permeabilized with SLO. Similar results were obtained when COS-1 cells expressing recombinant PGHS with a viral reporter peptide inserted at the C-terminus were stained with antibody against the reporter epitope.^ The PGHS C-terminal sequence is similar to that of the consensus KDEL ER retention signal. The potential function of the PGHS C-terminus segment in ER retention was examined by mutating this segment and analyzing the subcellular distribution of the mutants expressed in COS-1 cells. None of the mutants had an altered subcellular distribution, although some had greatly diminished the enzyme activities. (Abstract shortened by UMI.) ^

New Patterns of Democracy in the Countries of the Comparative Study of Electoral Systems

The chapter introduces a new database on political-institutional patterns of democracy used in the contributions to the book. It provides an update and extension of Lijphart’s (1999, 2012) measurement of consensus and majoritarian democracy for the countries of the second wave of the CSES during the period 1997–2006, using 11 partly improved indicators. The chapter explores patterns of democracy by the means of factor analysis, construct additive indices, and present the resulting country scores of consensus and majoritarian democracy graphically. Two variants are presented, one featuring Lijphart’s (1999) classic ‘executives–parties’ and ‘federal–unitary’ dimensions, and another incorporating direct democracy into the framework, yielding an additional ‘cabinets–direct democracy’ dimension

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

BackgroundHepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 ¿M) and NTBC-levels in the therapeutic range (20¿40 ¿M). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.