All Articles

Ammouri W*, Harmouche H, Alaoui M, Tazi ZM, Maamar MM and Adnaoui M

Internal Medicine Department, CHU Ibn Sina, University of Medicine Rabat, Morocco

 Gayet-Wernicke encephalopathy is an acute, reversible neuropsychiatric emergency due to thiamine defciency. Chronic alcoholism is recognized as the most common cause of Wernicke’s encephalopathy, but other causes, including fasting/starvation and malnutrition, have been documented within the scientific literature. These causes may not be readily recognized by healthcare professionals and may lead to Wernicke’s encephalopathy being overlooked as a diagnosis when a nonalcoholic patient presents with classic signs and symptoms of the disorder.

The diagnosis of the disease is clinical and magnetic resonance imaging confirms the diagnosis by the presence of hypersignals most frequently in the periaqueductal level of thalami and mammilary bodies. Urgent and adequate thiamine replacement is necessary to avoid death or progression to Korsakoff syndrome with largely irreversible brain damage. Wernicke Korsakoff syndrome refers to a condition where features of Wernicke encephalopathy are mixed with those of Korsakoff syndrome. Although thiamine is the cornerstone of treatment of Wernicke encephalopathy, there are no universally accepted guidelines with regard to its optimal dose, mode of administration, frequency of administration or duration of treatment. We present recommendations for the clinical management of Gayet-Wernicke encephalopathy based on literature review.

Na Zhang^1,2, Xing Gao^1,3 Yingchao Zhao^1,4, Meenal Datta^1,5, Pinan Liu⁶ and Lei Xu^1*

¹Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
²Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing China, 100730.
³Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁴Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430023, China.
⁵Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA.
⁶Neural Reconstructional Department, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China, 100050.

 Neurofibromatosis type 2 is characterized by bilateral vestibular schwannomas, which are benign tumors that originate from the nerve sheath and damage the nerve as they grow, causing neurological dysfunction such as hearing loss. Current standard radiation therapy can further augment hearing loss by inducing local damage to mature nerve tissue. Treatment with bevacizumab, a Vascular Endothelial Growth Factor (VEGF)-specific antibody, is associated with tumor control and hearing improvement in NF2 patients; however, its effect is not durable and its mechanism of action on improving nerve function is unknown. Anti-VEGF treatment can normalize the tumor vasculature, improving vessel perfusion and delivery of oxygen. It is known that oxygen is a potent radiosensitizer; therefore, combining anti-VEGF treatment with radiation therapy can achieve better tumor control and allow for the use of lower radiation doses, thus minimizing treatment-related neurological toxicity.

Narayan Subramanian¹, Wayne N. Frankel^1,2*

¹Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA
²Department of Genetics & Development, Columbia University Medical Center, New York, NY 10032, USA

Annie Killoran^1* and Kevin Biglan²

¹Department of Neurology, University of Iowa, IA, USA
²Department of Neurology, University of Rochester, New York, USA

 Huntington’s disease (HD) causes progressive neurological deterioration that leads to death. It is inherited in an autosomal dominant fashion, and individuals with a positive family history can be tested for the presence of the HD mutation prior to the development of the overt features that subjectively define disease onset. An objective biomarker denoting this time point would improve onset accuracy, and ideally be sufficiently sensitive to monitor progression leading up to this juncture. Once manifestations arise, patients are treated symptomatically. There are no disease-modifying treatments available for HD, but many are in development. A major goal is to develop a therapy that will delay the onset of the disease or to potentially even prevent the disease from occurring altogether. However, how does one assess the efficacy of these experimental therapeutics in individuals who carry the HD gene mutation, but are clinically-unaffected? Sensitive and reliable outcome measures are required for preventative clinical trials. Candidate biomarkers include subtle, but quantifiable abnormalities detected on clinical exam, findings on brain imaging, and levels of pathologically-relevant molecules collected in bodily fluids.

Makhosazane Zungu-Edmondson and Yuichiro J. Suzuki*

Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057

 Right ventricular (RV) failure is the major cause of death among patients with pulmonary hypertension. However, differences between the RV and left ventricle (LV) of the adult heart have not been defined, despite myocytes from these two ventricles originate from different progenitor cells. The lack of such knowledge interferes with developing therapeutic strategies to protect the RV. The goal of this study was to identify possible differences between stress responses in the RV and LV free walls of adult rats. We found that levels of angiogenesis and autophagy/mitophagy proteins are higher in the LV than in the RV. Thus, the LV may be more resistant to stress-induced damage. To test this, isolated rat hearts were subjected to biventricular working heart perfusion and ischemia/reperfusion (I/R) injury. However, I/R was found to cause apoptosis in both LV and RV to a similar extent. One mechanism of cardiac apoptosis involves downregulation of GATA4 transcription factor that controls gene transcription of anti-apoptotic Bcl-xL. Interestingly, only in the RV, I/R caused downregulation of GATA4 and Bcl-xL, suggesting that mechanisms of apoptosis may be different between the two ventricles. Levels of tropomyosin and troponin T were also found to be decreased in response to I/R only in the RV, but not in the LV. Downregulation of the GATA4/Bcl-xL axis and the reduction of tropomyosin and troponin T are RV-specific events that occur in response to stress. This information may be useful for designing RV-specific therapeutic strategies to treat RV failure in pulmonary hypertension patients.

Pradeep Kumar Yadav^1,2 and Ram Rajasekharan^1,2*

¹Lipidomic Centre, Department of Lipid Science, CSIR-Central Food Technological Research Institute (CFTRI), Mysore 570020, Karnataka, India
²Academy of Scientific & Innovative Research, CSIR-CFTRI, Mysore, India

 The DDHD domain-containing lipases belong to the intracellular phospholipase A1 (iPLA1) family. Phospholipases have been implicated in the regulation of lipid metabolism, intracellular membrane trafficking, and signaling. In addition, phospholipases have been linked to the development of rare and neurodegenerative diseases. The rare and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have been focused on phospholipase A2. But there is a scarcity of literature on the role of PLA1 in rare and neurodegenerative diseases. Recently, in humans, mutation in DDHD1 and DDHD2 (iPLA1 members) has been identified as a cause of specific types of hereditary spastic paraplegia (HSP) termed as SPG28 and SPG54, respectively. Ddl1 (DDHD domain-containing lipase 1), a yeast homolog of human DDHD1/2, hydrolyzes cardiolipin (CL), phosphatidylethanolamine, and phosphatidylglycerol. Ddl1 has an important role in the mitochondrial phospholipids remodeling. Defects in phospholipids remodeling and mitochondrial functions have been implicated in the development of the Barth syndrome, HSPs, and other neurodegenerative disorders. Mutations in DDHD1 and DDHD2 produce DDL1-defective yeast strain like phenotypes (mitochondrial dysfunction and defects in lipid metabolism).

Therefore, the DDL1-defective yeast could be a good model system to understand hereditary spastic paraplegia.

Hernán Trimarchi*

Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina

Parul Rai¹ and Punam Malik^1,2*

¹Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
²Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA

 Gene therapy by either gene insertion or editing is an exciting curative therapeutic option for monogenic hemoglobin disorders like sickle cell disease and β-thalassemia. The safety and efficacy of gene transfer techniques has markedly improved with the use of lentivirus vectors. The clinical translation of this technology has met with good success, although key limitations include number of engraftable transduced hematopoietic stem cells and adequate transgene expression that results in complete correction of β0 thalassemia major. This highlights the need to identify and address factors that might be contributing to the in-vivo survival of the transduced hematopoietic stem cells or find means to improve expression from current vectors. In this review, we briefly discuss the gene therapy strategies specific to hemoglobinopathies, the success of the preclinical models and the current status of gene therapy clinical trials.

Yuichiro J. Suzuki¹, Yasmine F. Ibrahim^1,2 and Nataliia V. Shults^1*

¹Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington DC 20007 USA
²Department of Pharmacology, Minia University School of Medicine, Minia, Egypt

 Pulmonary arterial hypertension (PAH) is rare, but patients who are diagnosed with this disease still suffer from a lack of satisfactory treatment strategies to prolong survival. While currently approved drugs for PAH have some benefits, these vasodilators only have limited efficacy for eliminating pulmonary vascular remodeling and reducing mortality. Thus, our laboratory has been exploring the use of aggressive drugs, which are capable of causing apoptotic cell death, to treat PAH. We have so far found that three classes of anti-tumor agents, including anthracyclines, taxanes, and proteasome inhibitors, are capable of reducing pulmonary vascular thickness in rats with PAH. These drugs kill cells in remodeled pulmonary vessels without affecting the normal, healthy pulmonary vasculature, revealing that proliferating vascular cells in PAH patients are more sensitive to drug-induced apoptosis compared to the differentiated phenotype that is physiologically important for smooth muscle contraction. Since many apoptosis-inducing drugs cause cardiotoxicity in cancer patients, and because PAH patients already have a weakened heart, we focus on finding biological mechanisms that may reverse pulmonary vascular remodeling without promoting cardiotoxicity. We found two agents, dexrazoxane and pifithrin-α, that selectively inhibit cardiac muscle apoptosis without affecting the drug-induced apoptosis of the proliferating pulmonary vascular cells. Thus, we propose that the addition of apoptosis-inducing drugs and cardioprotectants to PAH therapies may be effective in treating patients and preventing right heart failure.

Emily Cockey and Nicole J Ullrich*

Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that predisposes patients to develop benign and malignant neoplasms, most often due to a loss of function mutation in the neurofibromatosis type 1 (NF1) gene. Neurofibromin, the protein product of NF1, regulates the inactivation of the Ras pathway, and thus acts as a tumor suppressor. Located in neurons, Schwann cells, and melanocytes, a decrease in neurofibromin predisposes patients with NF1 to tumors in both the central and peripheral nervous systems. Interestingly, brain tumors associated with NF1 often follow a more benign course than their sporadic counterparts and are often found in different locations. Thus, these tumors are often observed without tumor-directed therapy, unless clinical progression is noted, and then they are treated with surgery, chemotherapy or radiation. Current treatment trials seek to create more targeted therapies for specific tumor types associated with NF1 in order to increase efficacy and decrease treatment-related morbidity. This review will examine the most common types of brain tumors associated with NF1, including pilocytic astrocytomas, optic pathway gliomas, brainstem gliomas and glioblastomas, and will provide an overview of the clinical implications, current treatments, and ongoing clinical trials for these tumors.

Sumita Choudhury, William E. Plautz, Cosette Zacarias and Rinku Majumder*

Department of Biochemistry & Molecular Biology, LSU Health Science Center, 1901 Perdido Street, MEB-7114, New Orleans, LA-70112

Tonio Schoenfelder* and Hans-Holger Bleß

IGES Institut GmbH, Friedrichstraße 180, D-10117 Berlin, Germany

Jessica Bauer*, Jonas J Staudacher, Nancy L Krett and Barbara Jung

Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois, USA

Ilaria Fregno^1,2,3*, Maurizio Molinari^1,2,4*

¹Università della Svizzera italiana, CH-6900 Lugano, Switzerland
²Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
³Department of Biology, Swiss Federal Institute of Technology, CH-8093 Zurich, Switzerland
⁴Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, CH-1015 Lausanne, Switzerland

Maria Favia¹ and Anna Atlante^2*

¹Department of Biosciences, Biotechnology and Biopharmaceutics - University of Bari, Via E. Orabona 4, 70126, Bari, Italy
²Institute of Biomembrane and Bioenergetics - CNR, Via G. Amendola 165/A, 70126, Bari, Italy

 Cystic fibrosis is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. It results from different possible mutations in the CFTR gene, which encodes the CFTR chloride channel, a protein that controls the movement of salt and water in and out of your body's cells. It follows that the abnormal channel function of the expressed protein on the secretory cell membrane determines the clinical phenotype in its classical form. Novel and more recent studies on mitochondrial bioenergetics - aiming to rediscover a possible role of mitochondria in this disease - provide a springboard for upcoming research to further understand the molecular mechanisms responsible for the involvement of mitochondria in CF and identify the protein/s primarily responsible for the F508del-CFTR-dependent mitochondrial alterations. Here, we review these CFTR-driven mitochondrial defects, thus revealing potential new targets for therapy.

Eunice Mah¹ and DeAnn J Liska^1*

¹Biofortis Innovation Services, 211 E. Lake Street, Addison, IL 60101, USA

 Cranberries have long been associated with the prevention of urinary tract infection (UTI); however, meta-analyses of clinical trials on the effect of cranberry for UTI have provided conflicting results. Liska and colleagues recently examined these meta-analyses to better understand the reasons behind their disparate findings and found several methodological differences. Most notably, the populations influencing conclusions varied. For example, one analysis, which concluded cranberry was not effective for UTI (RR: 0.86; 95% CI: 0.71, 1.04), had the largest contribution of results from studies in patients with complicated UTI. In contrast, another review, which included many of the same studies but weighted the evidence relatively equally across populations with complicated and uncomplicated UTI, concluded cranberry was effective (RR: 0.62; 95% CI: 0.49, 0.80). In both reviews, a significant benefit was noted in healthy women with recurrent UTI, particularly when two or three small trials in this population were analyzed; but, inclusion of a larger study that used a lower bacterial cut-off threshold for UTI outcome definition led to significant heterogeneity and non-significant results. These findings not only impact how we design meta-analyses, but also indicate the importance in considering the patient characteristics when generalizing findings across populations. In addition, the findings suggest additional research on cranberries in healthy women with recurrent UTI may be warranted.

Linda D. Hazlett^1,2*, Sharon A. McClellan¹ and Sandamali A. Ekanayaka¹

¹Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA
²Department of Ophthalmology, Wayne State University, School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA

 Pseudomonas (P.) aeruginosa is a Gram negative bacterium widely dispersed in the environment which can cause acute and chronic infections in humans. According to the Centers for Disease Control and Prevention (CDC), the overall incidence of P. aeruginosa infections in USA hospitals averages about 0.4% (4/1000 discharges), and the bacterium is the fourth most commonly-isolated nosocomial pathogen accounting for 10.1% of all hospital-acquired infections. P. aeruginosa keratitis is a severe infection of the eye, progresses rapidly and remains a leading cause of corneal ulcers worldwide. Use of contact lenses is the major risk factor in the USA, while in less industrialized countries, trauma from agricultural accidents are of importance. Animal models of bacterial keratitis are of value in the study of this disease and suggest potential alternative therapeutic targets that are needed urgently due to increasing antibiotic resistance. Recently we have shown success and improved disease outcome after down-regulation of one promising target, high mobility group box(HMGB1) using small interfering RNA (siRNA). Testing more clinically relevant approaches are underway to reduce HMGB1 levels in P. aeruginosa keratitis which may hold promise for its treatment.

Moyra Smith*

University of California, Irvine, CA, USA

Khalil Charafeddine and Mohammad-Zouheir Habbal*

Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon

Hermann Gram*

Novartis Institutes of BioMedical Research, Forum 1, CH-4002 Basel, Switzerland

Inmaculada Martinez-Saguer^1* and Henriette Farkas²

¹Hemophilia Center Rhine Main, Germany
²Hungarian Angioedema Center, 3rd Department of Internal Medicine, Semmelweis University, Hungary

Sally Ann Lynch^1,2* & Jillian P Casey²

¹National Rare Disease Office, Mater Hospital Dublin 7, Ireland
²UCD Academic Centre of Rare Disease, School of Medicine and Medical Sciences, Belfield, Dublin 4, Ireland

 European Reference Networks are being established across the EU with the aim of improving the care of patients with rare diseases. Recognising that experts are rare, ERNs are tasked with the aim of encouraging collaboration of experts across individual member states. Membership of an ERN is dependent on fulfilling criteria to allow one to be described as a centre of expertise. ERNs will produce guidelines through consensus and the development of EU wide registries should help to facilitate clinical trials. However, the ERN entry requirements are such that some member states will struggle to fulfil the criteria. Investment in trained staff for rare diseases has been poor in some countries risking the possibility that ERN membership may be restricted to a limited number of member states.

Hugh James Freeman*

Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, BC, Canada

 A rarely diagnosed clinical and pathological disorder was historically characterized by multiple benign small intestinal ulcers, involving the mucosa and, occasionally, the submucosa of the small intestine, and histopathologically by non-specific inflammatory changes without granulomas. These early reports also noted that recurrent episodes of abdominal pain often developed due to obstructive events, sometimes associated with localized stricture formation. This usually responded to steroid treatment, intestinal resection, or both. Recent advances owing largely to emerging imaging methods have provided added criteria for separation of this entity from other disorders, including Crohn’s disease and medication-related small bowel ulceration. Most important, recent long-term follow-up studies have suggested a potential for confusion with other functional or motility-based clinical disorders and emphasize the likelihood of a much more benign clinical course.

Michel Lebel*

Centre de recherche du CHU de Québec, Faculty of Medicine, Université Laval, Quebec City Quebec, Canada

 Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a pro-oxidant/pro-inflammatory status, genomic instability, and by the premature onset of several age-associated diseases. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA replication, repair, and transcription. This review focuses on the beneficial impact of vitamin C treatment in mutant mouse and worm models of WS with an emphasis on serum metabolomic and cytokinome profiles in Wrn mutant mice. Vitamin C normalizes the health and life span of these mutant animals. More importantly, our recent results indicate that it will be possible to follow the beneficial impact of vitamin C at a systemic level by monitoring specific serum metabolites and inflammatory cytokines in a longitudinal study involving WS patients.

Paula G. Franco^1,2, Ana M. Adamo^1,2, Patricia Mathieu^1,2, María J. Pérez^1,2, Patricia C. Setton-Avruj^1,2 and Lucas Silvestroff^1,2*

¹Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica. Buenos Aires, Argentina
²Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química y Fisicoquímica

Biológicas (IQUIFIB) Profesor Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Argentina

 Lysosomal Storage Disorders (LSD) are rare diseases that as a whole have a combined incidence ranging from 1:1500 to 1:7000 live births. One of such diseases is Mucopolysaccharidosis VI (MPS VI), or Maroteaux Lamy Syndrome. MPS VI patients undergo devastating and irreversible skeletal alterations and multisystemic failure as from early childhood due to reduced Arylsulfatse B (ARSB) enzyme activity.

Reaching a final diagnosis is not always a short cut path, but rather a years-long battle against uncertainty and unnecessary medical interventions. Our aim is to contribute from the bench table with different approaches that could serve as alternatives to pre-existing assays for screening and diagnosing MPS VI and other LSD.

The present work is based on our research article authored by Franco et al.1 where we studied the effect of blood-derived hemoglobin, and other blood components, on the fluorescence of 4-Methylumbelliferone when measuring ARSB enzyme activity from dried blood spot (DBS) samples.

Our experience indicates that to date there are plenty of different approaches for measuring ARSB enzyme activity, although the sample type required or the assay in itself often make them more adaptable for either high throughput screening or small scale diagnostics.

As a whole, the fluorometric determinations seem to be the most accessible to low budget laboratories with equally valuable performances as a sophisticated mass spectrometry analysis for this disease. Furthermore, the DBS serves as an attractive sample type for screening the disease in large populations.