Eiji Ohashi*

Department of Biology, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan

DNA damage response (DDR) pathways play crucial roles in the maintenance of genome integrity, and defects in DDR proteins lead to genome instability and eventually cancer. Rad9-Hus1-Rad1 (9-1-1) is a ring-shaped heterotrimeric complex involved in multiple DDR pathways, especially the DNA damage checkpoint. Rad9 has an intrinsically disordered C-terminal region, called C-tail. The C-tail projects from the ring and has multiple phosphorylation sites and several protein-protein interaction sites, some of which are crucial for checkpoint activation. In addition, it was recently shown that C-tail binds to the 9-1-1 ring structure and is released from it upon binding to TopBP1, an activator of the DNA damage checkpoint. This review focuses on the regulatory roles of the Rad9 C-tail and discusses DNA damage checkpoint activation and the regulation of several DNA repair pathways via this region.

DOI: 10.29245/2572-9411/2017/3.1110 View / Download Pdf

Yuji Saitoh1,2 and Yoshitaka Nagai1,3*

1Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan
2Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8551, Japan
3Department of Neurotherapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

DOI: 10.29245/2572-9411/2017/3.1106 View / Download Pdf

Ellis J Powell1, Joan E Cunnick2, and Christopher K Tuggle1*

1Genetics and Genomics Graduate Program, Department of Animal Science, Iowa State University, Ames, IA 50011, USA
2Interdepartmental Microbiology Program, Department of Animal Science, Iowa State University, Ames, IA 50011, USA

Severe Combined ImmunoDeficiency (SCID) is defined as the lack or impairment of an adaptive immune system. Although SCID phenotypes are characteristically absent of T and B cells, many such SCID cellular profiles include the presence of NK cells. In human SCID patients, functional NK cells may impact the engraftment success of life saving procedures such as bone marrow transplantation. However, in animal models, a T cell-, B cell-, NK cell+ environment provides a valuable tool for asking specific questions about the extent of the innate immune system function as well as emerging NK targeted therapies against cancer. Physiologically and immunologically the pig is more similar to the human than common rodent research animals. This review discusses why the T- B- NK+ SCID pig may offer a more relevant model for development of human SCID patient therapies as well as provide an opportunity for systematic exploration of the role of NK cells in artiodactyl immunity.

DOI: 10.29245/2572-9411/2017/3.1103 View / Download Pdf

Caitlin Doherty1, Francyne Kubaski2,3, Shunji Tomatsu3,4,5*, and Thomas H. Shaffer3,6*

1University of Delaware, Newark, DE, USA
2Department of Biological Sciences, University of Delaware, Newark, DE, USA
3Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
4Department of Pediatrics, Gifu University, Gifu, Japan
5Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA
6Center for Pediatric Lung Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA

 Morquio patients, in many cases, present with severe tracheal narrowing and restrictive lung problems making them susceptible to high mortality arising from sleep apnea and related complications. Tracheal obstruction with growth imbalance, short neck, adeno and tonsillar hypertrophy, large mandible, and/or pectus carinatum also contributes to the challenges in managing the airway with intubation and extubation due to factors intrinsic to Morquio syndrome. Taken together, these issues lead to serious respiratory distress and life-threatening complications during anesthetic procedures. Furthermore, patients with Morquio syndrome frequently cannot perform standard pulmonary function tests as a result of their distinctive skeletal dysplasia and chest deformity, thus making diagnosis of incipient pulmonary disease difficult. In many cases, conventional spirometry is too difficult for patients to complete, deriving from issues with cooperation or clinical circumstance. Therefore, it is an unmet challenge to assess pulmonary insufficiency with standard pulmonary function test (PFT) with minimal effort. Non-invasive PFT such as respiratory inductance plethysmography, impulse oscillometry system, and pneumotachography were described in Morquio patients as compared with spirometry. Findings from our previous study indicate that these non-invasive tests are a reliable approach to evaluate lung function in a larger range of patients, and provide valuable clinical information otherwise unobtainable from invasive tests. In conclusion, the present study describes the utility of non-invasive (PFT) to accommodate a broad range of patients including intolerance to effort-dependent PFT.

DOI: 10.29245/2572-9411/2017/2.1097 View / Download Pdf

Vaishnavi Raja, Christian A. Reynolds, and Miriam L. Greenberg

Department of Biological Sciences, Wayne State University, USA

Barth syndrome (BTHS) is a rare X-linked genetic disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, and organic aciduria. The presence and severity of clinical manifestations are highly variable in BTHS, even among patients with identical gene mutations. Currently, less than 200 patients are diagnosed worldwide, but it is estimated that the disorder may be substantially under-diagnosed due to the variable spectrum of clinical manifestations. BTHS is caused by mutations in the gene tafazzin (TAZ), resulting in defective remodeling of cardiolipin (CL), the signature phospholipid of the mitochondrial membranes. Many of the clinical sequela associated with BTHS can be directly attributed to mitochondria defects. In 2008, a definitive biochemical test was described based on detection of the abnormal CL profile characteristic of BTHS. This mini-review provides an overview of the etiology of BTHS, as well as a description of common clinical phenotypes associated with the disorder.

DOI: 10.29245/2572-9411/2017/2.1087 View / Download Pdf

Mitsunori Higuchi1*, Tetsutaro Nemoto2, Hajime Matsuida2, Ikuro Oshibe2, Nobutoshi Soeta2, Toshiyuki Takeshige2, Takuro Saito2, and Hiroyuki Suzuki3

1Department of Thoracic Surgery, Aizu Medical Center, Fukushima Medical University, Fukushima, 969-3492, Japan
2Department of Surgery, Aizu Medical Center, Fukushima Medical University, Fukushima, 969-3492, Japan
3Department of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan

 Immune checkpoint inhibitors play crucial roles in the treatment of advanced and recurrent non-small cell lung caner (NSCLC). As yet, there are no biomarkers to help select patients that would benefit from this treatment. Currently, evaluation of the efficacy of immune checkpoint inhibitors is performed using Response Evaluation Criteria In Solid Tumors (RECIST) or immune-related response criteria on the basis of computed tomography (CT) scans, which are based only on anatomical changes and exclude a metabolic assessment. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) can add metabolic information, but is also subject to false-positive and false-negative findings in the presence of inflammation. In this review, we briefly discuss the optimal use of FDG-PET for the evaluation of checkpoint-based cancer immunotherapy and also discuss the relationship between immune checkpoint inhibitors and FDG-PET in NSCLC. We also introduce ongoing clinical studies and pre-clinical experiments involved in the development of diagnostic imaging and treatments for NSCLC.

DOI: 10.29245/2572-9411/2017/2.1098 View / Download Pdf

H.S. Natraj Setty*, J.R. Vijaykumar, C.M Nagesh, Shivanand S Patil, Santhosh Jadav, T.R. Raghu, C.N. Manjunath

Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India

Takayasu’s arteritis (TA) is a chronic inflammatory disease of unknown aetiology. The mechanism of this disease is not exactly defined. The inflammatory process is generally (but not exclusively) initiated in the second or third decade of life through the actions of non-specific inflammatory cells. As the disease progresses, fibrotic stenosis occurs in aorta and its main branches. The consequence of this inflammatory process can be stenosis, thrombosis, dilatation or aneurysm formation in aorta and/ or its branches. Majority of cases have been observed in Asia, Africa, and Latin America. In Asia, its incidence (2.69 in a million per year) has been reported to be 100 times higher than in Europe and North America. Because of the delay in diagnosing the disease, patients often experience claudication, absence of pulses, hypertension, myocardial infarction (MI), and cerebrovascular accidents (CVAs). Accurate and early diagnosis of TA can reduce the economic, social, and psychological burdens. Considering the fact that classical TA has mainly been described in Asia.

DOI: 10.29245/2572-9411/2017/2.1048 View / Download Pdf

Aintzane Urbizu1, Tahir N. Khan2, Allison E. Ashley-Koch1*

1Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA
2Duke Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA

 Chiari malformation type 1 is a heterogeneous disease characterized by cerebellar tonsillar herniation through the foramen magnum. Symptomatology is diverse, and diagnosis and treatment are controversial. Some evidence suggests the presence of a genetic component to the disease. However, the specific genetic factors involved remain relatively unknown. Previous reviews have broadly addressed different aspects (clinical manifestations, anatomical trails, treatment) of CM-1 by itself or compared it with other types of Chiari malformation. In this mini-review, we focus our attention on the heterogeneity of this disease and its impact on the study of the genetic etiology of classic CM-1. Patient stratification strategies and endophenotypes definitions are offered to help overcome the heterogeneity.

DOI: 10.29245/2572-9411/2017/2.1082 View / Download Pdf

Marina G. Yefimova1,2 and Nicolas Bourmeyster1*

1Université de Poitiers/CNRS, Laboratoire Signalisation et Transports Ioniques Membranaires, 1 rue Georges Bonnet, F-86022 Poitiers, France
2Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Maurice Thorez Prospekt, 194233 Saint Petersburg, Russia

 Myelinosomes are pleomorphic structures with huge diversity of form, specific hallmark of “lysosomal storage diseases”, but also present in other inborn errors of metabolism such as aggregation diseases HD and CF. In the original work “Myelinosomes act as natural secretory organelles to prevent accumulation of aggregate-prone mutant Huntingtin and CFTR” Yefimova et al., describe an unexpected role of myelinosomes as key regulators of proteostasis in the somatic Sertoli cells from the testis. By releasing myelinosomes loaded with undegraded misfolded proteins, Sertoli cells demonstrate a new aspect of protein quality control mechanism unrelated to catabolic degradation.

DOI: 10.29245/2572-9411/2017/2.1085 View / Download Pdf

Alfred Said Sife1, Tumaini Jonas Wapalila2 and Maulilio John Kipanyula3*

1Sokoine National Agricultural Library (SNAL), Sokoine University of Agriculture, P.O. Box 3022 Chuo Kikuu, Morogoro, Tanzania
2Morogoro Regional Commisioner's Office, Boma Road, P.O. Box 650 Boma Road, Morogoro, Tanzania
3Department of Anatomy Histology and Cell Biology, College of Veterinary and Medical Sciences, Sokoine University of Agriculture, P.O.Box 3016, Morogoro – Tanzania

 The CD4 T-cell count is an important laboratory indicator of the immune status in patients with HIV/AIDS. It is used in decision making to determine when antiretroviral therapy and a need of prophylaxis for opportunistic infections should be initiated. This study was carried out to assess the contribution of donor funded projects to the wellbeing of people living with HIV/AIDS as measured by improvement of CD4 count. A total of 120 respondents were randomly selected from Morogoro urban and Kilombero district, Tanzania. Based on panel data, individual observations were made four times across time and there were a total of 480 observations. The home based care TUNAJALI project provided various interventions including medical care and psychological support with the purpose of improving the health status of people living with HIV/AIDS. The effect of home based care TUNAJALI services was the only predictor of health status of people living with HIV/AIDS that was measured as an improvement of CD4 count over time. The average CD4 count before, one year, two years of home based care, and during the study were: 193.86; 258.83 (25.1%); 375.72 (31.2%); 487.57 respectively. A positive relationship was observed between home based care services and well-being. The findings from the present study show that the home based care positively improved the well-being of HIV/AIDS patients in the studied population. Improved wellbeing also improved CD4 count in patients.

DOI: 10.29245/2572-9411/2017/2.1091 View / Download Pdf

Ramy Sedhom1*, Daniel Sedhom1 and Roger Strair2

1Department of Internal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
2Division of Hematology and Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA

 IgG4-related disease is a fibroinflammatory condition that mimics many malignant, infectious, and inflammatory disorders. Histopathology is key to diagnosis and is hallmarked by tumor like infiltration of IgG4 positive plasma cells in tissues, with dense lymphoplasmacytic infiltrate, storiform fibrosis and oblierative phlebitis. Disease has been reported in virtually every organ system1-4. Though the underlying pathophysiology is still unclear, untreated disease ultimately leads to irreversible fibrosis. We describe the pathogenesis, diagnosis, and relevant features of IgG4-related disease and discuss current evidence regarding treatment.

DOI: 10.29245/2572-9411/2017/2.1089 View / Download Pdf

Breanna R Campbell, David Reynoso, and A Clinton White Jr*

Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA

 Neurocysticercosis, caused by Taenia solium, is a common cause of neurologic disease worldwide. Approximately 2,000 cases per year are diagnosed in the United States. Intraventricular neurocysticercosis is a severe form of the disease, in which cysticerci within the cerebral ventricles cause obstructive hydrocephalus. Symptoms of hydrocephalus include headache, nausea, vomiting, altered mental status, dizziness, and decreased visual acuity. In some cases, sudden onset of symptoms are associated with changes in head position leading to acute obstruction (Bruns’ syndrome). Diagnosis depends on neuroimaging studies, especially 3 dimensional MRI sequences. Optimal treatment involves relief of hydrocephalus by removal of the cysticerci. For cysticerci in the lateral and third ventricles, this can usually be accomplished via minimally invasive surgery (neuroendoscopy). However, this is not possible with adherent cysticerci. In some cases of cysticerci in the 4th ventricle, open surgical microdissection via an occipital approach may be safer. Mortality is rare with appropriate management.

DOI: 10.29245/2572-9411/2017/2.1084 View / Download Pdf

Bryan A. Wilson1,2 and Monte S. Willis1,3*

1McAllister Heart Institute, University of North Carolina, Chapel Hill, NC USA
2Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC USA
3Department of Pharmacology, Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC USA

 The 8th annual Rare Disease Scientific Workshop featured presentations on the topic of “Evaluating Models to Provide Early Access for Rare Disease Patients”. The workshop included presentations from and participation by experts in Industry, the Food and Drug Administration, and academia focused on case study examples of successful mechanisms for those seeking to provide early access to experimental therapies for patients. Current regulatory frameworks were discussed and evaluated, with an emphasis on rare and serious diseases with the goal of identifying best practices and useful ideas for a set of standard approaches to early access.

Date: Tuesday, September 13, 2016, Washington, DC

Location: Willard Intercontinental Hotel, Washington DC

Sponsor: The EveryLife Foundation for Rare Diseases

AAV, adeno-associated virus; ALS, Amyotrophic Lateral Sclerosis; CURES, Compassionate Use Reform and Enhancements; DMD, Duchenne Muscular Dystrophy; ERT, enzyme replacement therapy; FDA, US Food and Drug Administration; GLPs, good laboratory practices; ICU, intensive care unit; IND, FDA’s Investigational New Drug program; H.R., House of Representatives; IRB, institutional review boards; J&J, Johnson and Johnson; JAMA, Journal of the American Medical Association; MCT, Medium-chain triglyceride; MPS I, mucopolysaccharidosis I; MPS7, Mucopolysaccharidosis type 7; NYU, New York University; OHOP, Office of Hematology and Oncology Products; rhGUS, recombinant human beta-glucuronidase; RUF, Reagan-Udall Foundation; WT, WideTrial

DOI: 10.29245/2572-9411/2017/2.1095 View / Download Pdf

Matshidiso Moeti*

WHO regional office for Africa, Brazzaville, Congo

 This mini review on my previous article entitled, ‘Winning the battle against the scourge of poliomyelitis in the African Region’ published in Vaccine 34 (2016) 5142–5143 takes another look at the optimism expressed in that article about the success in eradicating poliomyelitis (Polio) from the African Region. Polio is a deadly and painful disease that afflicts mostly children less than 5 years. The struggle to eradicate it and get the African Region polio-free has been tortuous. The struggle has been protracted with a series of public health emergencies and political strife compromising the efforts of global partnership comprising of WHO and its key partners such as the United Nations Children’s Fund, the United States Centres for Disease Control and Prevention, Rotary International, and Bill and Melinda Gates Foundation, among others, as well as other stakeholders and national governments in the African Region. In a renewed effort, the partnership generated a huge amount of resources and skills deployed to interrupt polio transmission in the Region. For the first time since the struggle began in the early 80s, the Region reported no wild polio virus for two years. However, the recent success of the military campaign in Northeast Nigeria brought to the open the realities of reservoirs of transmission isolated in security compromised areas. Thus, after two years new cases of wild polio virus were reported in previously unreachable areas. The lesson here is in understanding the impact of political activities on the realization of health for all in our Region.

DOI: 10.29245/2572-9411/2017/1.1090 View / Download Pdf

Mira Sohn and Tamas Balla*

Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA

 Lenz-Majewski syndrome (LMS) is a rare disease presenting with complex physical and mental abnormalities. Whole exome sequencing performed on five LMS-affected individuals has identified gain-of-function mutations in the PTDSS1 gene encoding phosphatidylserine synthase 1 (PSS1) enzyme. These mutations all rendered PSS1 insensitive to PS-mediated product inhibition. In a recent study we showed that uncontrolled PS production by these mutant PSS1 enzymes lead to the accumulation of PS in the ER where it is not detected in normal cells. This increased PS in the ER in turn, activated the Sac1 phosphatase, which is responsible for the dephosphorylation of the minor lipid, phosphatidylinositol 4-phosphate (PI4P) in the ER. Increased Sac1 activity decreased PI4P levels both in the Golgi and the plasma membrane thereby dissipating the PI4P gradients set up by PI 4-kinase enzymes (PI4Ks) between these membranes and the ER. Such PI4P gradients at membrane contact sites have been shown to support the transports of structural lipids such as cholesterol and PS out of the ER by non-vesicular lipid transfer. Therefore, uncontrolled production of PS not only affects the PS status of cells but also initiates an avalanche of changes in the metabolism of other membrane lipids via affecting PI4P gradients throughout the cell. Recognition of the close metabolic interaction between PS synthesis and PI4P metabolism provided a new clue to better understand the molecular underpinning of this rare and severe disease.

DOI: 10.29245/2572-9411/2017/1.1080 View / Download Pdf

Ryuichi Mashima1* and Torayuki Okuyama1,2

1Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
2Center for Lysosomal Storage Disorders, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan

DOI: 10.29245/2572-9411/2017/1.1079 View / Download Pdf

Ayami Sato1,2, Nantiga Virgona2, Yuko Sekine1 and Tomohiro Yano2*

1Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba, Japan
2Research Institute of Life Innovation, Toyo University, Gunma, Japan

 Malignant mesothelioma (MM) is an aggressive cancer associated with exposure to asbestos. In recent years, despite restrictions on the use of asbestos, the incidence of MM has been increasing due to its long latency period. Owing to its poor prognosis, the treatment of MM requires innovative therapies. Tocotrienol (T3), one of the vitamin E analogues, has powerful antioxidant properties and anti-cancer effects. However, these effects have not been fully understood, and are mediated independent of its antioxidant activity. Therefore, we have synthesized a new redox-inactive derivative of T3 (T3E) that has shown a stronger anti-MM effect than its redox-sensitive mother compound. In this review, we discuss the potential for anti-MM effect of T3E as non-antioxidant functions of T3 by introducing our previous reports.

DOI: 10.29245/2572-9411/2017/1.1072 View / Download Pdf

Takeo Kato1*, Minako Ide1 and Masatoshi Nakata2

1Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
2Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto Japan

 Infantile spasms (IS) is the most recognized epileptic encephalopathy in early infancy, resulting in poor cognitive outcome. Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for IS, but the relapse rate is high. Relapse after initial ACTH therapy is a poor prognostic factor for long-term seizure control and outcome of cognitive function. Recently, several studies have reported on the long-lasting maintenance of the positive effects produced by an initial course of ACTH by using long-term weekly ACTH therapy for relapsed IS. Here, we review the clinical characteristics of five previously reported cases. Epileptic spasms and hypsarrhythmia remained completely resolved during the extended ACTH therapy and did not recur after ACTH discontinuation in all cases. Furthermore, no cognitive or neurodevelopment deterioration was observed, and no serious adverse events occurred in any patient. In conclusion, this therapy appears safe and may lead to improved psychomotor development. We believe that it may be a good alternative therapy when frequent relapses occur after a favorable response to an initial course of conventional ACTH therapy. However, further studies are required to examine the risks and benefits of this therapy for relapsed IS in a large population and in countries in addition to Japan.

DOI: 10.29245/2572-9411/2017/1.1068 View / Download Pdf

Patsy Thrasher1, Mahipal Singh1 and Krishna Singh1,2*

1Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
2James H Quillen Veterans Affairs Medical Center, Mountain Home, TN, USA

 Ataxia-telangiectasia mutated kinase (ATM) is a serine/threonine kinase. Mutations in the ATM gene cause a rare autosomal multisystemic disease known as Ataxia-telangiectasia (AT). Individuals with mutations in both copies of the ATM gene suffer from increased susceptibility to ionizing radiation, predisposition to cancer, insulin resistance, immune deficiency, and premature aging. Patients with one mutated allele make-up ~1.4 to 2% of the general population. These individuals are spared from most of the symptoms of the disease. However, they are predisposed to developing cancer or ischemic heart disease, and die 7-8 years earlier than the non-carriers. DNA double-strand breaks activate ATM, and active ATM is known to phosphorylate an extensive array of proteins involved in cell cycle arrest, DNA repair, and apoptosis. The importance of ATM in the regulation of DNA damage response signaling is fairly well-established. This review summarizes the role of ATM in the heart, specifically in cardiac remodeling following β-adrenergic receptor stimulation and myocardial infarction.

DOI: 10.29245/2572-9411/2017/1.1077 View / Download Pdf

David Badrudin, Pierre Dubé and Lucas Sideris*

Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, Université de Montréal, Montréal QC, Canada

 Background: Cytoreductive surgery combined to hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard of care for selected patients with peritoneal surface malignancies. Preclinical studies, especially when performed on animal models, provide a framework for improvement of this treatment. This study aims to present an overview of a single institution's experience in this setting.

Methods/Results: Review of all preclinical studies from a single center was conducted using PubMed and author databases. Multiple experiments were conducted using pig and rat models. These studies examined the impact of different surgical techniques, such as the electrovaporization of tumor nodules and the use of different suture material, in the context of HIPEC. The pharmacokinetics of multiple intraperitoneal cytotoxic agents – namely oxaliplatin, raltitrexed, irinotecan and pemetrexed – were also studied.

Conclusion: Experimental studies help guide future directions for the treatment of peritoneal surface malignancies with hyperthermic intraperitoneal chemotherapy.

DOI: 10.29245/2572-9411/2017/1.1064 View / Download Pdf

Michael Y. Soliman, Rima El-Abassi* and John D. England

Department of Neurology, South East Louisiana Veteran Health Care Sysytem (SELVHCS), Louisiana State University, New Orleans, Louisiana, 70112, United States

DOI: 10.29245/2572-9411/2017/1.1062 View / Download Pdf

Di-Fei Lu, and Xiao-Hui Guo*

Peking University First Hospital, Beijing, China

 Polycystic ovary syndrome (PCOS) is a prevalent female endocrine and metabolic disorder, and is typically presented with menstrual irregularity and an excess of androgen production. Obesity is a common comorbidity with PCOS, and accompanying insulin resistance is proved to be a key pathogenesis of PCOS. Several parameters have been applied to evaluate obesity, including body-mass index (BMI), waist circumference (WC), percentage of body fat (PBF) and lipid accumulation product (LAP) index. Accumulating studies were conducted to analyze the association between the markers of obesity and PCOS, as well as the cut-off level of each marker in order to detect higher risk of cardiovascular diseases or rule out metabolic syndrome. However, standards of obesity parameters to screen or diagnose PCOS are yet to be established. Herein we briefly review the association of obesity measuring methods and its diagnostic value with PCOS, which gives insight into the development of standard criteria for obesity in PCOS.

DOI: 10.29245/2572-9411/2017/1.1078 View / Download Pdf

Mark J C Nuijten1,2* and Jan Vis3

1A2M (Ars Accessus Medica), 1546 LG Amsterdam, The Netherlands
2H4V, 1546 LG Amsterdam, The Netherlands
3Talanton, Amsterdam, The Netherlands
4RSM, Erasmus University, Rotterdam, The Netherlands

 Rational: Many pharmaceutical companies, especially biotechnology companies, are now commercializing innovative so-called expensive medicinal products, e.g. biologicals, and especially orphan drugs, with an incremental cost-effectiveness ratio (ICER), which will probably exceed threshold values that are commonly regarded as acceptable for reimbursement.

Objective: The goal of this paper is to propose an additional methodology to evaluate and valuate innovative drugs from a broader perspective by applying concepts from business valuation, when the ICER exceeds the threshold.

Methods: Medical innovation relies on the market mechanisms in the finance market of biotechnology including the incentives of the various stakeholders, especially the capital providers, who demand a required return on investment. The justification of the orphan drug price can be based on the Discounted Cash Flow method, which is based on the expected free cash flows and the required cost of capital, and can be used to validate the price of the new drug from a narrow investor’s perspective.

Conclusion: We propose an alternative policy approach for the evaluation of ultra-innovative drugs from a broader perspective by bridging concepts from health economics and the economics of business (economic) valuation. This approach may justify a drug price, especially when ICER exceeds the threshold.

DOI: 10.29245/2572-9411/2017/1.1056 View / Download Pdf

Edgar M. Pera1*, Nadège Gouignard1 and Marco Maccarana2

1Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden
2Dept. Experimental Medical Science, Lund University, 221 84 Lund, Sweden

Musculocontractural Ehlers-Danlos syndrome (MC-EDS) is a rare recessive disorder that is characterized by connective tissue fragility, distinct craniofacial features and congenital malformations. MC-EDS patients have defects in the enzymes dermatan sulfate epimerase-1 and dermatan 4-O-sulfotransferase-1, which are involved in the biosynthesis of iduronic acid in the chondroitin sulfate/dermatan sulfate (CS/DS) chains of proteoglycans (PGs). While the connective tissue defect is a result of disturbed collagen fibril assembly based on a decreased iduronic acid content of interacting CS/DS-PGs, the cause of the developmental malformations in MC-EDS is not well understood. This review focuses on a new role of CS/DS-PGs in the development of multipotent and highly migratory neural crest (NC) cells in the Xenopus embryo model of MC-EDS. Single iduronic acid residues in CS/DS-PGs are involved in the formation of NC-derived craniofacial structures by facilitating the migration and adhesion of NC cells to fibronectin. Our results suggest a defect in NC development as cause of the craniofacial and other congenital anomalies in MC-EDS patients, which might contribute to an improved diagnosis and etiology-based therapy.

DOI: 10.29245/2572-9411/2016/3.1069 View / Download Pdf