Research Infrastructure for Collaborative Team Science: Challenges in Technology-Supported Workflows in and Across Laboratories, Institutions, and Geographies.

Semin Nephrol. 2015 May;35(3):291-302

Authors: Mirel B, Luo A, Harris M

Abstract
Collaborative research has many challenges. One under-researched challenge is how to align collaborators' research practices and evolving analytical reasoning with technologies and configurations of technologies that best support them. The goal of such alignment is to enhance collaborative problem solving capabilities in research. Toward this end, we draw on our own research and a synthesis of the literature to characterize the workflow of collaborating scientists in systems-level renal disease research. We describe the various phases of a hypothetical workflow among diverse collaborators within and across laboratories, extending from their primary analysis through secondary analysis. For each phase, we highlight required technology supports, and. At time, complementary organizational supports. This survey of supports matching collaborators' analysis practices and needs in research projects to technological support is preliminary, aimed ultimately at developing a research capability framework that can help scientists and technologists mutually understand workflows and technologies that can help enable and enhance them.

PMID: 26215866 [PubMed - indexed for MEDLINE]

APOL1 Kidney Disease Risk Variants: An Evolving Landscape.

Semin Nephrol. 2015 May;35(3):222-36

Authors: Dummer PD, Limou S, Rosenberg AZ, Heymann J, Nelson G, Winkler CA, Kopp JB

Abstract
Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.

PMID: 26215860 [PubMed - indexed for MEDLINE]

Data-based Reconstruction of Gene Regulatory Networks of Fungal Pathogens.

Front Microbiol. 2016;7:570

Authors: Guthke R, Gerber S, Conrad T, Vlaic S, Durmuş S, Çakır T, Sevilgen FE, Shelest E, Linde J

Abstract
In the emerging field of systems biology of fungal infection, one of the central roles belongs to the modeling of gene regulatory networks (GRNs). Utilizing omics-data, GRNs can be predicted by mathematical modeling. Here, we review current advances of data-based reconstruction of both small-scale and large-scale GRNs for human pathogenic fungi. The advantage of large-scale genome-wide modeling is the possibility to predict central (hub) genes and thereby indicate potential biomarkers and drug targets. In contrast, small-scale GRN models provide hypotheses on the mode of gene regulatory interactions, which have to be validated experimentally. Due to the lack of sufficient quantity and quality of both experimental data and prior knowledge about regulator-target gene relations, the genome-wide modeling still remains problematic for fungal pathogens. While a first genome-wide GRN model has already been published for Candida albicans, the feasibility of such modeling for Aspergillus fumigatus is evaluated in the present article. Based on this evaluation, opinions are drawn on future directions of GRN modeling of fungal pathogens. The crucial point of genome-wide GRN modeling is the experimental evidence, both used for inferring the networks (omics 'first-hand' data as well as literature data used as prior knowledge) and for validation and evaluation of the inferred network models.

PMID: 27148247 [PubMed]

Disease models for the development of therapies for lysosomal storage diseases.

Ann N Y Acad Sci. 2016 May 4;

Authors: Xu M, Motabar O, Ferrer M, Marugan JJ, Zheng W, Ottinger EA

Abstract
Lysosomal storage diseases (LSDs) are a group of rare diseases in which the function of the lysosome is disrupted by the accumulation of macromolecules. The complexity underlying the pathogenesis of LSDs and the small, often pediatric, population of patients make the development of therapies for these diseases challenging. Current treatments are only available for a small subset of LSDs and have not been effective at treating neurological symptoms. Disease-relevant cellular and animal models with high clinical predictability are critical for the discovery and development of new treatments for LSDs. In this paper, we review how LSD patient primary cells and induced pluripotent stem cell-derived cellular models are providing novel assay systems in which phenotypes are more similar to those of the human LSD physiology. Furthermore, larger animal disease models are providing additional tools for evaluation of the efficacy of drug candidates. Early predictors of efficacy and better understanding of disease biology can significantly affect the translational process by focusing efforts on those therapies with the higher probability of success, thus decreasing overall time and cost spent in clinical development and increasing the overall positive outcomes in clinical trials.

PMID: 27144735 [PubMed - as supplied by publisher]

Exploring Rare Diseases in South Africa, a Personal Journey: Time for Electronic Record-keeping.

Ann Med Health Sci Res. 2016 Jan-Feb;6(1):1-3

Authors: Ross IL

PMID: 27144070 [PubMed]

Successful Surgical Excision of a Large Cardiac Fibroma in an Asymptomatic Child: A Case Report.

World J Pediatr Congenit Heart Surg. 2016 May 3;

Authors: Borodinova O, Ostras O, Raad T, Yemets I

Abstract
Cardiac fibroma is a rare disease, and the management of asymptomatic patients is controversial. We report a case of successful surgical excision of a large cardiac fibroma in an asymptomatic child. Surgery should be considered for such a patient, as sudden cardiac death may occur in the absence of premonitory symptoms.

PMID: 27143716 [PubMed - as supplied by publisher]

Natural history of mevalonate kinase deficiency: a literature review.

Pediatr Rheumatol Online J. 2016;14(1):30

Authors: Zhang S

Abstract
Mevalonate kinase deficiency (MKD), a very rare autosomal recessive autoinflammatory disease with multiple organ involvement, presents clinically as hyperimmunoglobulinemia D syndrome (HIDS), a less severe phenotype and more common form, and mevalonic aciduria (MVA), a more severe phenotype and rare form. MKD is characterized by recurrent febrile attacks that are frequently accompanied by lymphadenopathy, gastrointestinal symptoms, arthralgia, myalgia, skin rash, and aphthous ulcers. Patients with MVA also have intrauterine growth retardation, congenital defects (cataracts, shortened limbs, and dysmorphic craniofacial features), neurological disease, and failure to thrive. Mean age at onset of symptoms is within the first year of life. There is a delay by several years between symptom onset and diagnosis, which is in part attributable to the initial misdiagnosis due to the rarity and nonspecific clinical manifestations of disease. The frequency of recurrent febrile attacks is highest in childhood and gradually decreases after adolescence. MKD is associated with rare long-term complications such as type AA amyloidosis, joint contractures, abdominal adhesions, renal angiomyolipoma, and severe pneumococcal infections. Frequent febrile attacks significantly impair several aspects of patients' and caregivers' quality of life, with an adverse impact on patients' daily activities, education, and employment. Lifespan is generally normal for HIDS whereas MVA can be fatal in early childhood.

PMID: 27142780 [PubMed - in process]

Enrichment of rare variants in population isolates: single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland.

Eur J Hum Genet. 2016 May 4;

Authors: Trotta L, Hautala T, Hämäläinen S, Syrjänen J, Viskari H, Almusa H, Lepisto M, Kaustio M, Porkka K, Palotie A, Seppänen M, Saarela J

Abstract
Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T>C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P<0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P<0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.European Journal of Human Genetics advance online publication, 4 May 2016; doi:10.1038/ejhg.2016.37.

PMID: 27142677 [PubMed - as supplied by publisher]

Fatal Primary Capillary Leak Syndrome in a Late Preterm Newborn.

Indian J Pediatr. 2016 May 4;

Authors: Kulihova K, Prochazkova M, Semberova J, Janota J

Abstract
Primary capillary leak syndrome is a rare disease of unknown etiology, characterized by episodes of vascular collapse and plasma extravasation, which may lead to multiple organ failure. Primary capillary leak is extremely rare in children. The authors report a case of a late preterm newborn with fatal capillary leak syndrome of unknown etiology, manifesting as hypotension unresponsive to treatment, extravasation leading to generalised edema, disseminated intravascular coagulation and finally, multiple organ dysfunction syndrome. Aggressive volumotherapy and a combination of inotropes and high doses of terlipressin did not influence systemic vascular collapse and plasma extravasation. The newborn developed multiple organ failure and died on day 27 of life. Investigations performed failed to reveal any specific cause of capillary leak. This is the first report of a fatal primary capillary leak syndrome in a newborn.

PMID: 27142601 [PubMed - as supplied by publisher]

[Pharmacogenetics in anesthesia and intensive care medicine : Clinical and legal challenges exemplified by malignant hyperthermia].

Anaesthesist. 2016 May 3;

Authors: Klingler W, Pfenninger E

Abstract
Pharmacotherapy is a key component of anesthesiology and intensive care medicine. The individual genetic profile influences not only the effect of pharmaceuticals but can also completely alter the mode of action. New technologies for genetic screening (e.g. next generation sequencing) and increasing knowledge of molecular pathways foster the disclosure of pharmacogenetic syndromes, which are classified as rare diseases. Taking into account the high genetic variability in humans and over 8000 known rare diseases, up to 20 % of the population may be affected. In summary, rare diseases are not rare. Most pharmacogenetic syndromes lead to a weakening or loss of pharmacological action. In contrast, malignant hyperthermia (MH), which is the most relevant pharmacogenetic syndrome for anesthesia, is characterized by a pharmacologically induced overactivation of calcium metabolism in skeletal muscle. Volatile anesthetic agents and succinylcholine trigger life-threatening hypermetabolic crises. Emergency treatment is based on inhibition of the calcium release channel of the sarcoplasmic reticulum by dantrolene. After an adverse pharmacological event patients must be informed and a clarification consultation must be carried out during which the hereditory character of MH is explained. The patient should be referred to a specialist MH center where a predisposition can be diagnosed by the functional in vitro contracture test from a muscle biopsy. Additional molecular genetic investigations can yield mutations in the genes for calcium-regulating proteins in skeletal muscle, e.g. ryanodine receptor 1 (RyR1) and calcium voltage-gated channel subunit alpha 1S (CACNA1S). Currently, an association to MH has only been shown for 35 mutations out of more than 400 known and probably hundreds of unknown genetic variations. Furthermore, MH predisposition is not excluded by negative mutation screening. For anesthesiological patient safety it is crucial to identify individuals at risk and warn genetic relatives; however, the legal requirements of the Patients Rights Act and the Human Genetic Examination Act must be strictly adhered to. Specific features of insurance and employment law must be respected under consideration of the Human Genetic Examination Act.

PMID: 27142362 [PubMed - as supplied by publisher]

Non-cholesterol Sterols in the Diagnosis and Treatment of Dyslipidemias: A Review.

Curr Med Chem. 2016 May 3;

Authors: Baila-Rueda L, Cenarro A, Civeira F

Abstract
Non-cholesterol sterols have been used as markers of cholesterol intestinal absorption and hepatic synthesis, leading to a better understanding of cholesterol homeostasis in humans. This review discusses the main non-cholesterol sterols that are clinically useful, different methods to quantify the factors associated with blood concentration, and the potential role of non-cholesterol sterols in the diagnosis and treatment of different types of dyslipidemia. The main indication is the use of non-cholesterol sterols for the diagnosis of rare diseases associated with defects in cholesterol synthesis or anomalies in the absorption and/or elimination of phytosterols. However, other potential uses, including the diagnosis of certain hypercholesterolemias and the individualization of lipid-lowering therapies, are promising as they could help treat a wider population.

PMID: 27142287 [PubMed - as supplied by publisher]

Clinicopathological features and prognosis of Kimura's disease with renal involvement in Chinese patients.

Clin Nephrol. 2016 May 4;

Authors: Chen Y, Wang J, Xu F, Zeng C, Liu Z

Abstract
AIMS: Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.
MATERIALS AND METHODS: Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.
RESULTS: The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.
CONCLUSIONS: KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

PMID: 27142199 [PubMed - as supplied by publisher]

Challenges of access to medicine and the responsibility of pharmaceutical companies: a legal perspective.

Daru. 2016;24(1):13

Authors: Ahmadiani S, Nikfar S

Abstract
The right to health as a basic human right- and access to medicine as a part of it- have been a matter of attention for several decades. Also the responsibilities of different parties- particularly pharmaceutical companies- in realization of this right has been emphasized by World Health Organization. This is while many companies find no incentive for research and development of medicines related to rare diseases. Also some legal structures such as "patent agreements" clearly cause huge difficulties for access to medicine in many countries. High prices of brand medicine and no legal production of generics can increase the catastrophic costs- as well as morbidity-mortality of medication in lower income countries. Here we evidently review the current challenges in access to medicine and critically assess its legal roots. How societies/governors can make the pharmaceutical companies responsible is also discussed to have a look on possible future and actions that policy makers- in local or global level- can take.

PMID: 27141958 [PubMed - in process]

The Undiagnosed Diseases Program--Reply.

JAMA. 2016 May 3;315(17):1904

Authors: Gahl WA, Wise AL, Ashley EA

PMID: 27139070 [PubMed - indexed for MEDLINE]

The Undiagnosed Diseases Program.

JAMA. 2016 May 3;315(17):1903-4

Authors: Drolet BC, Brower JP

PMID: 27139068 [PubMed - indexed for MEDLINE]

Policymaking for Orphan Drugs and Its Challenges.

AMA J Ethics. 2015 Aug;17(8):776-9

Authors: Rhee TG

PMID: 26270879 [PubMed - indexed for MEDLINE]

Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain.

Brain. 2015 Dec;138(Pt 12):e400

Authors: Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hernández I, Rojas-García R, García-Redondo A, Povedano M, Lladó A, Álvarez V, Sánchez-Juan P, Pardo J, Jericó I, Vázquez-Costa J, Sevilla T, Cardona F, Indakoechea B, Moreno F, Fernández-Torrón R, Muñoz-Llahuna L, Moreno-Grau S, Rosende-Roca M, Vela Á, Muñoz-Blanco JL, Combarros O, Coto E, Alcolea D, Fortea J, Lleó A, Sánchez-Valle R, Esteban-Pérez J, Ruiz A, Pastor P, López De Munain A, Pérez-Tur J, Clarimón J, Dementia Genetics Spanish Consortium (DEGESCO)

PMID: 26152333 [PubMed - indexed for MEDLINE]

Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis.

PLoS One. 2015;10(6):e0128113

Authors: Andersson C, Kvist PH, McElhinney K, Baylis R, Gram LK, Pelzer H, Lauritzen B, Holm TL, Hogan S, Wu D, Turpin B, Miller W, Palumbo JS

Abstract
The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII-sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII-sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

PMID: 26098308 [PubMed - indexed for MEDLINE]

Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping.

PLoS One. 2015;10(6):e0128074

Authors: Cutler DJ, Zwick ME, Okou DT, Prahalad S, Walters T, Guthery SL, Dubinsky M, Baldassano R, Crandall WV, Rosh J, Markowitz J, Stephens M, Kellermayer R, Pfefferkorn M, Heyman MB, LeLeiko N, Mack D, Moulton D, Kappelman MD, Kumar A, Prince J, Bose P, Mondal K, Ramachandran D, Bohnsack JF, Griffiths AM, Haberman Y, Essers J, Thompson SD, Aronow B, Keljo DJ, Hyams JS, Denson LA, PRO-KIIDS Research Group, Kugathasan S

Abstract
BACKGROUND: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.
METHODS: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.
CONCLUSIONS: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

PMID: 26098103 [PubMed - indexed for MEDLINE]

The Telehealth Enhancement of Adherence to Medication (TEAM) in pediatric IBD trial: Design and methodology.

Contemp Clin Trials. 2015 Jul;43:105-13

Authors: Hommel KA, Gray WN, Hente E, Loreaux K, Ittenbach RF, Maddux M, Baldassano R, Sylvester F, Crandall W, Doarn C, Heyman MB, Keljo D, Denson LA

Abstract
Medication nonadherence is a significant health care issue requiring regular behavioral treatment. Lack of sufficient health care resources and patient/family time commitment for weekly treatment are primary barriers to receiving appropriate self-management support. We describe the methodology of the Telehealth Enhancement of Adherence to Medication (TEAM) trial for medication nonadherence in pediatric inflammatory bowel disease (IBD). For this trial, participants 11-18 years of age will be recruited from seven pediatric hospitals and will complete an initial 4-week run in to assess adherence to a daily medication. Those who take less than 90% of their prescribed medication will be randomized. A total of 194 patients with IBD will be randomized to either a telehealth behavioral treatment (TBT) arm or education only (EO) arm. All treatments will be delivered via telehealth video conferencing. The patients will be assessed at baseline, post-treatment, 3, 6, and 12 months. We anticipate that participants in the TBT arm will demonstrate a statistically significant improvement at post-treatment and 3-, 6-, and 12-month follow-up compared to participants in the EO arm for both medication adherence and secondary outcomes (i.e., disease severity, patient quality of life, and health care utilization). If efficacious, the TEAM intervention could be disseminated broadly and reduce health care access barriers so that the patients could receive much needed self-management intervention.

PMID: 26003436 [PubMed - indexed for MEDLINE]