Vol 1-3 Mini Review

Mechanism-based disease similarity

Mehdi B Hamaneh and Yi-Kuo Yu*

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA

 In recent years several methods have been proposed to assign pairwise mechanism-based similarity scores to human diseases. Despite their differences in approach and performance, these methods work in a somewhat similar manner: first a set of biomolecules (genes, proteins, chemicals, etc.) is associated with each disease, and then a measure is defined to calculate the similarity between the sets assigned to a pair of diseases. Since the similarity score between two diseases is defined based on the underlying molecular processes, a high score may hint at a shared cause, and therefore a similar treatment, for both diseases. This is of great practical importance especially when a rare or newly-discovered disease, for which limited information is available, is found to be related to a disease with a known treatment. Thus, in this mini-review we briefly discuss the recently developed methods for computing mechanism-based disease-disease similarities.

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Vol 1-3 Mini Review

Association of infantile-onset glaucoma with collagen disorders

Christian Apsey and Brenda L. Bohnsack*

Kellogg Eye Center and Department of Ophthalmology and Vision Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA

 Primary infantile-onset glaucoma is a rare, potentially blinding disease that is due to malformation of the trabecular meshwork and aqueous outflow tracts (goniotrabeculodysgenesis). While goniotrabeculodysgenesis is typically an isolated finding, there are reports of primary infantile-onset glaucoma in the setting of collagen disorders, specifically Stickler syndrome and osteogenesis imperfecta.

In Stickler syndrome, defects in type II or type XI collagen are commonly associated with craniofacial anomalies, hearing loss, hypermobile joints, and vitreoretinal abnormalities. Osteogenesis imperfecta is caused by disruption in type I collagen synthesis and is characterized by frequent bone fractures. Both type I and type II collagens are major structural proteins in the trabecular meshwork of the eye and both of these collagen disorders show higher incidences of adult-onset glaucoma. Herein we review the association between primary infantile-onset glaucoma and collagen disorders, which gives insight into the development of the trabecular meshwork and the aqueous outflow tracts of the eye.

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Vol 1-3 Mini Review

Usefulness of the endotoxin activity assay to evaluate the degree of lung injury

Yuichiro Sakamoto*

Department of Emergency and Critical Care Medicine Faculty of Medicine, Saga University, Saga, Japan

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Vol 1-3 Mini Review

Hepatocyte specific RNase H1 knockout mice: Clarifying functions of mammalian RNase H1

Stanley T. Crooke*, Wen Shen and Xue-hai Liang

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA

 Human RNase H1 cleaves RNA only when the RNA is present in a DNA-RNA heteroduplex. Previous efforts to create RNase H1 knockout mice resulted in embryonic lethality1, but demonstrated that RNase H1 is required for mitochondrial function. We constructed viable constitutive hepatocyte liver specific RNase H1 knock out mice by coupling the Cre recombinase to an albumin promoter as albumin is not expressed till late in gestation. We also constructed hepatocyte specific tamoxifen inducible hepatocyte knockout mice.

Our studies demonstrate that mammalian RNase H1 is required for transcription of mitochondrial ribosomal DNA and removal of R Loops. The absence of RNase H1 leads to mitochondrial dysfunction and hepatocyte apoptosis and liver dysfunction. Subsequently, a clone of hepatocytes that lost the Cre-recombinase and thereby regained RNase H1 expression emerged, supporting the analysis of events leading to liver regeneration. RNase H1 is confirmed to be responsible for the pharmacological effects of DNA-like antisense drugs as well.

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Vol 1-3 Mini Review

Idiopathic non-cirrhotic portal hypertension

Sith Siramolpiwat1,2, Susana Seijo3,*

1Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12120, Thailand
2Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand
3CTO, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disorder consisting of intrahepatic portal hypertension in the absence of other identifiable intrinsic liver diseases and/or splanchnic vein thrombosis. The exact pathophysiology of INCPH is yet to be determined. This disorder is linked with several conditions such as immunological disorders, chronic infections, prothrombotic disorders, genetic predisposition and/or toxins. There is no specific positive diagnostic test. The diagnosis of INCPH is based on a high index of suspicion, a set of clinical criteria and exclusion of other causes of portal hypertension. Liver biopsy is mandatory to firmly rule out cirrhosis or other causes of liver diseases. The patency of splanchnic venous system should be also demonstrated. Most patients present with signs or symptoms of portal hypertension (i.e. gastro-esophageal varices, variceal bleeding), which should receive the same management strategy as per the current accepted guidelines in cirrhosis. The prevalence of portal vein thrombosis in INCPH ranges from 13-46%. Although liver function is usually preserved and prognosis is generally good, some patients may develop liver-related complications that would eventually require liver transplantation and/or that would overshadow long-term prognosis. 

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Vol 1-3 Mini Review

Can we alter dietary macronutrient compositions and alleviate mitochondrial disease?

W.C. Aw, N. A. Youngson and J. W. O. Ballard

School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia

 Mitochondria are an important regulator of organismal fitness and the key energy converting organelle. The flow of energy in eukaryotes involves the conversion of macronutrients to form substrates that drive mitochondrial respiration. Changing the relative ratio of dietary macronutrients can influence metabolic flexibility and alter the production of mitochondrial metabolites, such as reactive oxygen species (ROS), which can influence mitochondrial functions and affect the organismal health. In this review, we describe the differences in mitochondrial output due to dietary macronutrient composition in individuals with Complex I mutations. Non-synonymous mutations in mitochondrial Complex I subunits are a common cause of early-onset mitochondrial diseases. We discuss the possibility of manipulating macronutrient ratios as a treatment for some cases of mild mitochondrial dysfunction.

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Vol 1-3 Mini Review

Rare disease models provide insight into inherited forms of neurodegeneration

Philippa C. Fowler#, Dwayne J. Byrne# and Niamh C. O’Sullivan*

UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Dublin 4, Ireland

 Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized in vivo loss of function models of two very rare forms of HSP caused by loss of the ER-shaping proteins ARL6IP1 (SPG61) and RTN2 (SPG12). These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.

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Vol 1-3 Commentary

Commentary on "Ferritins: Furnishing proteins with iron"

Justin M. Bradley, Nick E. Le Brun and Geoffrey R. Moore*

Centre for Molecular and Structural Biochemistry, School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK

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Vol 1-3 Mini Review

The challenges of cystinuria in the twenty-first century - a mini review

Louise F. Øbro1, Katja V. Pedersen2, Søren K. Lildal1, Susanne S. Osther1, Helene U. Jung1, Kim H. Andreassen1 and Palle J. S. Osther1,*

1Department of Urology, Urological Research Center, Lillebaelt Hospital, University of Southern Denmark, Fredericia, Denmark
2Department of Clinical Genetics, Lillebaelt Hospital, University of Southern Denmark, Vejle, Denmark

 Cystinuria is a rare genetic disorder caused by mutations in the genes that encode the two subunits of amino acid transport, resulting in failure of absorption of filtered dibasic amino acids including cystine in the proximal tubules. Despite new knowledge of the molecular basis of cystinuria, it continues to be one of the most challenging stone diseases. There is no curative treatment of cystinuria, and patients will have life-long risk of stone formation, repeated surgery, impaired renal function and quality of life. Management of cystinuria requires a multi-modal approach in dedicated centres to improve treatment outcome and patient compliance. Recent developments in cystine crystal growth inhibitors may hold promise for more effective stone prevention in the future.

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Vol 1-3 Research

Design and analysis of clinical trials for small rare disease populations

Ralf?Dieter Hilgers1*, FranzKönig2, Geert Molenberghs3 and Stephen Senn4

1Department of Medical Statistics, RWTH Universit Aachen, Pauwelstr 30, D? 52074 Aachen, Germany
2Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
3I?BioStat, Universiteit Hasselt, B?3590 Diepenbeek, Belgium
4Competence Centre for Methodology and Statistics, Luxembourg Institute of Health, L?1445 Strassen, Luxembourg

 The mostly unmet need as well as the pressure to show efficacy of new therapies to treat rare diseases contrasts with the limited possibility to use traditional statistical methods to design and analyse clinical trials in this setting. Within this paper, we will refer to the current state of design and analysis methods, as well as practical conditions to be considered when conducting a clinical trial for rare diseases. We will embed the research of the IDeAl project within this setting and give some first recommendations to improve the methodology for clinical trials in rare diseases.

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Vol 1-3 Mini Review

Personalising medicine: Feasibility and future implications from a payers' perspective

Brian Godman1,2,3*, Isabel Frost4, Richard Harrington5 and Finlayson AE6

1Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden
2Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
3Liverpool Health Economics Centre, University of Liverpool, Chatham Street, Liverpool, UK L69 7ZH
4Department of Zoology, University of Oxford, Oxford, OX1 3PS, United Kingdom
5Nuffield Department of Population Health, British Heart Foundation Centre on Population Approaches for NCD Prevention, University of Oxford, Oxford, United Kingdom
6Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom

 There are considerable differences in how patients respond to treatments due to a number of factors calling for personalised approaches to care, which is happening. However, the early promise of personalised medicine has not always translated into improved care for patients. Payers have concerns that current tests can be costly, requests for funding specific tests have subsequently been reversed as more information becomes available, and there is currently fragmentation in the funding of diagnostic tests. Payers also have concerns that pharmaceutical companies are exploiting the situation by seeking orphan status for their new targeted medicines driving up requested prices. It is also not clear who should fund biomarkers that accompany new expensive medicines. This is changing as the cost of tests come down, and payers develop new models to optimise the managed entry of new medicines as well as evaluate potential prices for new medicines for orphan diseases. There are also developments with ‘big data’ offering new understanding of disease complexity to enhance pipeline productivity and diagnosis as well as ongoing developments with drug resistance testing and research into the role of microbiomes to improve future health. Current challenges and concerns are being addressed. This will continue to improve patient care.

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Vol 1-3 Review

Transepithelial/endothelial Electrical Resistance (TEER) theory and applications for microfluidic body-on-a-chip devices

Daniel H. Elbrecht, Christopher J. Long and James J. Hickman*

NanoScience Technology Center, University of Central Florida, Orlando, Florida, 32826, USA

 Transepithelial/endothelial electrical resistance (TEER) is a valuable method for assaying in vitro barrier tissue integrity, and is becoming an important measurement for body-on-a-chip barrier tissue devices due to its usefulness and non-invasive nature. The measurement concept is relatively straightforward, with TEER measurements performed by applying an AC electrical signal across electrodes placed on both sides of a cellular monolayer and measuring voltage and current to calculate the electrical resistance of the barrier. However, details of the setup, measurement circuit, and applied electrical signal must be properly designed for accurate measurements. Several main factors contribute to errors and variability in the measurement of TEER values, and while many of these factors can be reasonably controlled with little effort in Transwell®-type culture conditions, these factors can become major issues in body-on-a-chip devices without proper design. This mini-review outlines several important aspects of TEER measurements, including the basic theory, commercial systems used to perform measurements, major factors that contribute to measurement errors, and the application of TEER measurements to current body-on-a-chip barrier tissue devices, with the aim of providing guidance for the design of novel body-on-a-chip systems.

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Vol 1-3 Mini Review

Mini-review on current strategies to knockdown long non-coding RNAs

Kim A Lennox and Mark A Behlke*

Integrated DNA Technologies, Inc., Coralville, IA, 52241, USA

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Vol 1-3 Mini Review
Vol 1-3 Commentary

Commentary: Primary cardiac lymphoma: Two Cases and a review of literature

Karolis Jonavicius1*, Kestutis Salcius2, Raimundas Meskauskas3, Nomeda Valeviciene4, Virgilijus Tarutis2 and Vytautas Sirvydis2

1Faculty of Medicine, Vilnius University, Vilnius, Lithuania
2Department of Cardiovascular Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
3National Center of Pathology, Affiliate of Vilnius University Hospital Santariskiu Clinics
4Department of Radiology, Nuclear medicine and Physics of Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania

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Vol 1-3 Case Report

An unusual complication and imaging of PTFE membrane: Report of a case

Tugba Avc1, Irfan Tasoglu, Emre Aygun and Mustafa Pac

Yuksek Ihtisas Egitim ve Arastlrma Hastanesi, Ankara, Turkey Department of Cardiovascular Surgery, Turkey

Background:There are many usage areas of the PTFE patch in cardiac surgery. In this report, we present an unusual complication which should be kept in mind about PTFE membranes.

Case presentation:The 20-year-old male patient had been operated for ascending aortic aneurysm. David Procedure was carried out. After (in)the procedure, before the sternal closure, the pericardial closure was applied with PTFE membrane to avoid the sternal adhesions. The sternal wound drainage occurred two months after the operation. After further evaluations, surgery was the choice. The cure was achieved by removing the PTFE membrane. The sternum closure was applied without pericardial closure. His wound healed fastly.

Conclusions:The complications about prosthetic materials are trouble for surgeons. In many cases, the cure is achieved by removing the prosthetic materials. In most times, radiology is helpful for diagnosis, but rarely, it might be a misleading procedure.

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