Vol 2-2 Mini Review

Intraventricular Neurocysticercosis and Bruns' Syndrome: A Review

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.

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Vol 2-2 Conference Summary

8th Annual rare disease scientific workshop: Evaluating early access models for patients: Flashpoints, frameworks & case studies for advancement: A summary

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

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Vol 2-2 Mini Review

IgG-4 related disease: A mini-review

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.

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Vol 2-2 Commentary

Myelinosome-driven secretion: Non-catabolic management of misfolded proteins - Lessons from the Sertoli cells

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.

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Vol 2-2 Review

CD4 count improvement as result of enhanced wellbeing of HIV/AIDS patients

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.

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Vol 2-2 Mini Review

Genetic dissection of Chiari malformation type 1 using endophenotypes and stratification

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.

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Vol 2-2 Mini Review

Current status and future prospects of PET/CT in NSCLC treated with checkpoint-based immunotherapy

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.

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Vol 2-2 Review

Non-invasive pulmonary function test on Morquio patients

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.

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Vol 2-2 Mini Review

Barth syndrome: A life-threating disorder caused by abnormal cardiolipin remodeling

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.

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