Microchip in situ electrosynthesis of silver metallic oxide clusters for ultra-FAST detection of galactose in galactosemic newborns' urine samples.

Analyst. 2016 Sep 23;:

Authors: García-Carmona L, Rojas D, González MC, Escarpa A

Abstract
This work describes for the first time the coupling of microfluidic chips (MC) to electrosynthetized silver metallic oxide clusters (AgMOCs). As an early demonstration of this novel approach, the ultrafast detection of galactose in galactosemic newborns' urine samples is proposed. AgMOCs were in situ electrosynthetized on integrated microchip platinum electrodes using a double pulse technique and characterized in full using scanning electronic microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS) and electrochemical techniques revealing the presence of silver oxides and electrocatalysis towards galactose as a galactosemia biomarker. Galactose detection in galactosemic newborns' urine samples proceeded in less than 30 s, differentiating between ill and healthy urine samples and requiring negligible urine sample consumption. The significance of the newborns' urine samples confirmed the analytical potency of the MC-AgMOCs approach for future implementation of screening for rare disease diagnosis such as galactosemia.

PMID: 27704089 [PubMed - as supplied by publisher]

Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease.

Hum Mol Genet. 2016 Oct 3;:

Authors: Tang CS, Gui H, Kapoor A, Kim JH, Luzón-Toro B, Pelet A, Burzynski G, Lantieri F, So MT, Berrios C, Shin HD, Fernández RM, Le TL, Verheij JB, Matera I, Cherny SS, Nandakumar P, Cheong HS, Antiñolo G, Amiel J, Seo JM, Kim DY, Oh JT, Lyonnet S, Borrego S, Ceccherini I, Hofstra RM, Chakravarti A, Kim HY, Sham PC, Tam PK, Garcia-Barceló MM

Abstract
Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 (odds ratio (OR)=5.2, P=4.7x10(-10)). Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR=20.3, conditional P=4.1x10(-14)). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs.

PMID: 27702942 [PubMed - as supplied by publisher]

Primary Biliary Cholangitis: Medical and Specialty Pharmacy Management Update.

J Manag Care Spec Pharm. 2016 Oct;22(10-a-s Suppl):S3-S15

Authors: Bowlus CL, Kenney JT, Rice G, Navarro R

Abstract
BACKGROUND: Chronic liver disease and cirrhosis are a leading cause of morbidity and mortality in the United States. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis and which has been designated an orphan condition, is a chronic autoimmune disease resulting in the destruction of the small bile ducts in the liver. Without effective treatment, disease progression frequently leads to liver failure and death. Until May 2016, the only FDA-approved treatment for PBC was ursodiol (UDCA), an oral hydrophilic bile acid, which can slow progression of liver damage due to PBC. However, 1 out of 3 patients taking UDCA has an inadequate biochemical response, leading to increased risk of disease progression, liver transplantation, and mortality. Given this unmet clinical need, new therapies are in development for the treatment of PBC. To provide pharmacists with an overview of the latest research on the pathophysiology of PBC and potential new treatment options and to highlight medical and specialty pharmacy approaches to managing access to drugs to treat orphan diseases such as PBC, a 2-hour satellite symposium was presented in conjunction with the 2015 Academy of Managed Care Pharmacy (AMCP) Nexus meeting. Although obeticholic acid was approved by the FDA for the treatment of PBC in May 2016, this development occurred after the symposium presentation. The symposium was supported by an independent educational grant from Intercept Pharmaceuticals and was managed by Analysis Group. Robert Navarro, PharmD, moderated the CPE-accredited symposium titled "Medical and Specialty Pharmacy Management Update on Primary Biliary Cirrhosis." Expert panelists included Christopher L. Bowlus, MD; James T. Kenney, RPh, MBA; and Gary Rice, RPh, MS, MBA, CSP.
OBJECTIVE: To summarize the educational satellite symposium presentations and discussions.
SUMMARY: Autoimmune liver diseases, including PBC, are responsible for 15% of all liver transplants performed and an equal percentage of deaths related to liver disease. UDCA is the only FDA-approved therapy for treatment of PBC and is considered the standard of care. Nevertheless, many patients do not respond to UDCA, creating the need for new therapeutic options to improve clinical outcomes for PBC patients with inadequate response to treatment. While several agents are being studied in combination with UDCA, monotherapy with the novel agent obeticholic acid, a farnesoid X receptor agonist, has also shown promising results. Health plans are anticipated to assign any newly introduced therapy for the treatment of PBC to specialty pharmacy given its orphan disease status. This assignment enables the health plan to receive disease education, which is particularly important when new drugs are indicated for orphan diseases, and assistance with designing appropriate prior authorization criteria. The clinical value of any new therapeutic options that will inform formulary decisions and prior authorization criteria will be assessed based on evidence of efficacy, safety, and tolerability, among other factors, such as the potential to reduce or delay medical resource utilization (e.g., liver transplant). Key considerations for prior authorization of a new therapy will be determining which PBC patients are appropriate candidates for the new therapy and developing criteria for that determination. These are likely to include clinical diagnostic criteria and degree of response to prior treatment with UDCA. Initially, any new therapy would likely be positioned as noncovered until appropriate prior authorization criteria are established.
CONCLUSIONS: PBC is a chronic liver disease with significant morbidity and mortality, as well as a significant burden on the health care system if the disease progresses to the point at which a liver transplant is needed. Although UDCA, the current standard of care, has improved outcomes for many patients, others have an inadequate response to this treatment. This symposium discussed these issues and also addressed the overall treatment paradigm for orphan drug therapies, key implications for patient management, and the role of specialty pharmacy management and any associated needs both in general and specifically for new therapeutic options for PBC.

PMID: 27700211 [PubMed - in process]

Epidemiologic Analysis of Onychomycosis in the San Diego Pediatric Population.

Pediatr Dermatol. 2016 Oct 4;:

Authors: Totri CR, Feldstein S, Admani S, Friedlander SF, Eichenfield LF

Abstract
BACKGROUND: Onychomycosis (OM) is thought to be a rare disease in children, although there are few epidemiologic studies.
METHODS: This 3-year retrospective case series of nearly 400 children seen at Rady Children's Hospital-San Diego (RCHSD) describes the characteristics of OM found in this pediatric population.
RESULTS: From 2011 to 2013, the Pediatric and Adolescent Dermatology Clinic at RCHSD saw a total of 36,634 unique patients, of whom 433 were unique patients with OM. Thirty-four patients met exclusion criteria, leaving 399 (1.1%) with a diagnosis of OM by a pediatric dermatologist. Nail cultures were obtained in 242 cases (60.7%), 116 (48.0%) of which were positive. Trichophyton rubrum was the most commonly isolated pathogen, responsible for 106 cases (91.3%) of positive cultures in the cohort.
CONCLUSIONS: Our study provides important regional information regarding epidemiologic data in pediatric onychomycosis, highlighting the diagnostic methods most commonly used and the pathogens most frequently encountered in our practice.

PMID: 27699839 [PubMed - as supplied by publisher]

Parent training education program: a pilot study, involving families of children with Prader-Willi syndrome.

Ann Ist Super Sanita. 2016 Jul-Sep;52(3):428-433

Authors: Kodra Y, Kondili LA, Ferraroni A, Serra MA, Caretto F, Ricci MA, Taruscio D

Abstract
INTRODUCTION: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by severe hypotonia during the neonatal period and the first two years of life, the onset of hyperphagia with a risk of obesity during infancy and adulthood, learning difficulties and behavioral or severe psychiatric problems. This complex disease has severe consequences and difficult management issues also for patients' families. Parents of children with PWS need appropriate psychoeducational intervention in order to better manage their children with PWS. The purpose of this study was the implementation and evaluation of a PWS psychoeducational parent training program.
METHODS: The Italian National Center for Rare Diseases implemented a pilot parent training program offered to parents of children with PWS. The intervention's effects was evaluated using questionnaires comprised of 11 items rated on a 7 point Likert scale.
RESULTS: The intervention was offered to 43 parents. The behavior problems management, dietary restrictions, autonomy and relationships were indicated by parents as the priority topics which needed to be addressed. Evaluations, immediately post-intervention and after 6 months, were reported by parents, fulfilling specific questionnaires. 90% of parents involved in the study, appreciated the methodology, 86% felt more informed about PWS, 47-62% felt more capable to better approach behaviour's problems, 20-25% felt better about the child's health situation and future expectations. Feeling more capable to help the child autonomy and relationships were reported in 62% and 63% of parents respectively, which decreased significantly (p < 0.05) according to the evaluation 6 months after the intervention. Younger age of parents (< 44 years of age) was significantly correlated with better understanding on how to help the child's autonomy (OR: 0.05; CI: 0.04-0.8) and to better collaborate with the child's teachers (OR: 0.02; CI: 0.001-0.9).
CONCLUSION: Parent training is a promising intervention for parents of children with behavior's problems. Interventions with a behaviorally oriented program, addressed to parents of PWS affected children, is a useful tool in increasing their ability to manage the problems related to the disease.

PMID: 27698302 [PubMed - in process]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/30

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22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/28

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/27

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Investigating Alternative Transport of Integral Plasma Membrane Proteins from the ER to the Golgi: Lessons from the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Methods Mol Biol. 2016;1459:105-126

Authors: Amaral MD, Farinha CM, Matos P, Botelho HM

Abstract
Secretory traffic became a topical field because many important cell regulators are plasma membrane proteins (transporters, channels, receptors), being thus key targets in biomedicine and drug discovery. Cystic fibrosis (CF), caused by defects in a single gene encoding the CF transmembrane conductance regulator (CFTR), constitutes the most common of rare diseases and certainly a paradigmatic one.Here we focus on five different approaches that allow biochemical and cellular characterization of CFTR from its co-translational insertion into the ER membrane to its delivery to the plasma membrane.

PMID: 27665554 [PubMed - as supplied by publisher]

Hypertrophic cardiomyopathy with Jeune syndrome: The first reported case.

Turk Kardiyol Dern Ars. 2016 Sep;44(6):503-506

Authors: Güvenç O, Sündüs Uygun S, Çimen D, Aslan E, Annagür A

Abstract
Jeune syndrome (Asphyxiating thoracic dysplasia) is a rare dystrophy of the skeleton, inherited as an autosomal recessive condition. Patients develop a narrowed thorax, rhizomelic dwarfism, and hepatic, renal, and pancreatic abnormalities. High rates of pulmonary hypoplasia and pulmonary hypertension have been reported. Some patients die in early stages of life due to respiratory failure. The case of a patient referred with a history of severe asphyxiating birth, who had been diagnosed with Jeune syndrome and later hypertrophic cardiomyopathy (HCM) upon echocardiographic examination is described in the present report. This rare disease is discussed with respect to the current literature, as the present is the first reported case to be accompanied by HCM.

PMID: 27665332 [PubMed - as supplied by publisher]

Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.

Rev Neurol (Paris). 2016 Sep 21;

Authors: De Antonio M, Dogan C, Hamroun D, Mati M, Zerrouki S, Eymard B, Katsahian S, Bassez G, French Myotonic Dystrophy Clinical Network

Abstract
The broad clinical spectrum of myotonic dystrophy type 1 (DM1) creates particular challenges for both medical care and design of clinical trials. Clinical onset spans a continuum from birth to late adulthood, with symptoms that are highly variable in both severity and nature of the affected organ systems. In the literature, this complex phenotype is divided into three grades (mild, classic, and severe) and four or five main clinical categories (congenital, infantile/juvenile, adult-onset and late-onset forms), according to symptom severity and age of onset, respectively. However, these classifications are still under discussion with no consensus thus far. While some specific clinical features have been primarily reported in some forms of the disease, there are no clear distinctions. As a consequence, no modifications in the management of healthcare or the design of clinical studies have been proposed based on the clinical form of DM1. The present study has used the DM-Scope registry to assess, in a large cohort of DM1 patients, the robustness of a classification divided into five clinical forms. Our main aim was to describe the disease spectrum and investigate features of each clinical form. The five subtypes were compared by distribution of CTG expansion size, and the occurrence and onset of the main symptoms of DM1. Analyses validated the relevance of a five-grade model for DM1 classification. Patients were classified as: congenital (n=93, 4.5%); infantile (n=303, 14.8%); juvenile (n=628, 30.7%); adult (n=694, 34.0%); and late-onset (n=326, 15.9%). Our data show that the assumption of a continuum from congenital to the late-onset form is valid, and also highlights disease features specific to individual clinical forms of DM1 in terms of symptom occurrence and chronology throughout the disease course. These results support the use of the five-grade model for disease classification, and the distinct clinical profiles suggest that age of onset and clinical form may be key criteria in the design of clinical trials when considering DM1 health management and research.

PMID: 27665240 [PubMed - as supplied by publisher]

A genetic cluster of xeroderma pigmentosum variant patients with two different founder mutations.

Br J Dermatol. 2016 Sep 24;

Authors: Munford V, Castro LP, Souto R, Lerner LK, Vilar JB, Quayle C, Asif H, Schuch AP, de Souza TA, Ienne S, Alves FI, Moura LM, Galante PA, Camargo AA, Liboredo R, Pena SD, Sarasin A, Chaibub SC, Menck CF

Abstract
BACKGROUND: Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumors at an early age. We identified a community in the state of Goias (central Brazil), a very sunny and tropical region, with a high incidence of XP (17 patients among approximately 1,000 inhabitants).
OBJECTIVES: To identify the gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes.
METHODS: Functional analyses of DNA repair capacity and cell cycle responses after ultraviolet exposure were investigated in cells from local XP patients, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community.
RESULTS: Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by the POLH gene. We detected two different POLH mutations: one at the splice donor site of intron 6, c.764 +1 G>A, and the other in exon 8, c.907 C>T, p.Arg303X. The mutation at intron 6 is novel, whereas the mutation at exon 8 was previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease.
CONCLUSIONS AND RELEVANCE: This work describes a genetic cluster involving the POLH gene, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe. This article is protected by copyright. All rights reserved.

PMID: 27664908 [PubMed - as supplied by publisher]

Parathyroid carcinoma in tertiary hyperparathyroidism.

Asian J Surg. 2016 Oct;39(4):255-259

Authors: Kim BS, Ryu HS, Kang KH, Park SJ

Abstract
Parathyroid carcinoma is a rare disease of unknown etiology. This study presents a case of parathyroid carcinoma in a patient with tertiary hyperparathyroidism. Despite a successful kidney transplantation, the intact parathyroid hormone (iPTH) level of the patient was elevated consistently and could not be controlled by medical therapy. Due to the development of tertiary hyperparathyroidism with bone pain and osteoporosis, subtotal parathyroidectomy was performed 4 months after the kidney transplantation. Histological evaluation revealed that one of four parathyroid lesions was a parathyroid carcinoma, while the others were diffuse hyperplasia. Postoperative laboratory studies indicated a decreased level of iPTH. A positron emission tomography-computed tomography performed 6 months after the operation revealed no evidence of local recurrence or distant metastasis.

PMID: 27664600 [PubMed - as supplied by publisher]

The Inherited p53 Mutation in the Brazilian Population.

Cold Spring Harb Perspect Med. 2016 Sep 23;

Authors: Achatz MI, Zambetti GP

Abstract
A common criticism of studying rare diseases is the often-limited relevance of the findings to human health. Here, we review ∼15 years of research into an unusual germline TP53 mutation (p.R337H) that began with its detection in children with adrenocortical carcinoma (ACC), a remarkably rare childhood cancer that is associated with poor prognosis. We have come to learn that the p.R337H mutation exists at a very high frequency in Southern and Southeastern Brazil, occurring in one of 375 individuals within a total population of ∼100 million. Moreover, it has been determined that carriers of this founder mutation display variable tumor susceptibility, ranging from isolated cases of pediatric ACC to Li-Fraumeni or Li-Fraumeni-like (LFL) syndromes, thus representing a significant medical issue for this country. Studying the biochemical and molecular consequences of this mutation on p53 tumor-suppressor activity, as well as the putative additional genetic alterations that cooperate with this mutation, is advancing our understanding of how p53 functions in tumor suppression in general. These studies, which originated with a rare childhood tumor, are providing important information for guiding genetic counselors and physicians in treating their patients and are already providing clinical benefit.

PMID: 27663983 [PubMed - as supplied by publisher]

Familial amyloid polyneuropathy: When does it stop to be asymptomatic and need a treatment?

Rev Neurol (Paris). 2016 Sep 20;

Authors: Adams D, Beaudonnet G, Adam C, Lacroix C, Théaudin M, Cauquil C, Labeyrie C

Abstract
Transthyretin familial amyloid polyneuropathy (FAP) is a rare disease with autosomal transmission due to point mutation of the transthyretin (TTR) gene. It is the most disabling hereditary neuropathy affecting sensory, motor and autonomic nerves, and is irreversible and fatal within 7 to 12 years of onset in the absence of therapy. Diagnosis is usually delayed for 1-5 years because the onset is usually insidious, and a positive family history is lacking in 50% of late-onset cases. Penetrance is variable, and depends of the age of the carrier and age of onset in family members. Two treatments are available: liver transplantation, to suppress the main source of systemic production of mutant TTR; and TTR tetramer stabilizer drugs, to avoid the release of highly amyloidogenic monomers and oligomers. These therapies are able to stop or slow the progression of the disease in its early stages. Genetic counseling is crucial to detect carriers at risk of developing the disease. The European network for TTR-FAP recommends careful baseline assessment by questionnaire, clinical examination and neurophysiological tests, and periodic consultations to detect the onset of disease in time to start anti-amyloid therapy after biopsy findings of amyloid deposition. A therapeutic educational program is important for improving patients' awareness. Patients are considered symptomatic and ill when they themselves perceive symptoms or changes, including changes from baseline measurements on neurophysiological tests, followed by findings of amyloid deposition on biopsy. The most sensitive biopsies are from the labial salivary gland and skin.

PMID: 27663057 [PubMed - as supplied by publisher]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/24

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

25 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/23

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/09/22

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.