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Sample records for 1a disease cmt1a

  1. Identification of Drug Modulators Targeting Gene-Dosage Disease CMT1A

    PubMed Central

    Jang, Sung-Wook; Lopez-Anido, Camila; MacArthur, Ryan; Svaren, John; Inglese, James

    2012-01-01

    The structural integrity of myelin formed by Schwann cells in the peripheral nervous system (PNS) is required for proper nerve conduction and is dependent on adequate expression of myelin genes including peripheral myelin protein 22 (PMP22). Consequently, excess PMP22 resulting from its genetic duplication and overexpression has been directly associated with the peripheral neuropathy called Charcot-Marie-Tooth disease type 1A (CMT1A), the most prevalent type of CMT. Here, in an attempt to identify transcriptional inhibitors with therapeutic value towards CMT1A, we developed a cross-validating pair of orthogonal reporter - firefly luciferase (FLuc) and β-lactamase (βLac) - assays capable of recapitulating PMP22 expression, utilizing the intronic regulatory element of the human PMP22 gene. Each compound from a collection of approximately 3,000 approved drugs was tested at multiple titration points to achieve a pharmacological endpoint in a 1536-well plate quantitative high-throughput screen (qHTS) format. In conjunction with an independent counter-screen for cytotoxicity, the design of our orthogonal screen platform effectively contributed to selection and prioritization of active compounds, among which three drugs (fenretinide, olvanil, and bortezomib) exhibited marked reduction of endogenous Pmp22 mRNA and protein. Overall, the findings of this study provide a strategic approach to assay development for gene-dosage diseases such as CMT1A. PMID:22530759

  2. The LITAF/SIMPLE I92V sequence variant results in an earlier age of onset of CMT1A/HNPP diseases.

    PubMed

    Sinkiewicz-Darol, Elena; Lacerda, Andressa Ferreira; Kostera-Pruszczyk, Anna; Potulska-Chromik, Anna; Sokołowska, Beata; Kabzińska, Dagmara; Brunetti, Craig R; Hausmanowa-Petrusewicz, Irena; Kochański, Andrzej

    2015-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) represent the most common heritable neuromuscular disorders. Molecular diagnostics of CMT1A/HNPP diseases confirm clinical diagnosis, but their value is limited to the clinical course and prognosis. However, no biomarkers of CMT1A/HNPP have been identified. We decided to explore if the LITAF/SIMPLE gene shared a functional link to the PMP22 gene, whose duplication or deletion results in CMT1A and HNPP, respectively. By studying a large cohort of CMT1A/HNPP-affected patients, we found that the LITAF I92V sequence variant predisposes patients to an earlier age of onset of both the CMT1A and HNPP diseases. Using cell transfection experiments, we showed that the LITAF I92V sequence variant partially mislocalizes to the mitochondria in contrast to wild-type LITAF which localizes to the late endosome/lysosomes and is associated with a tendency for PMP22 to accumulate in the cells. Overall, this study shows that the I92V LITAF sequence variant would be a good candidate for a biomarker in the case of the CMT1A/HNPP disorders. PMID:25342198

  3. Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMT1A duplication

    SciTech Connect

    Wise, C.A.; Davis, S.N.; Heju, Z.; Pentao, L.; Patel, P.I.; Lupski, J.R. ); Garcia, C.A. )

    1993-10-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. One form of CMT, CMT type 1A, is characterized by uniformly decreased nerve conduction velocities, usually shows autosomal dominant inheritance, and is associated with a large submicroscopic duplication of the p11.2-p12 region of chromosome 17. A cohort of 75 unrelated patients diagnosed clinically with CMT and evaluated by electrophysiological methods were analyzed molecularly for the presence of the CMT1A DNA duplication. Three methodologies were used to assess the duplication: Measurement of dosage differences between RFLP alleles, analysis of polymorphic (GT)[sub n] repeats, and detection of a junction fragment by pulsed-field gel electrophoresis. The CMT1A duplication was found in 68% of the 63 unrelated CMT patients with electrophysiological studies consistent with CMT type 1 (CMT1). The CMT1A duplication was detected as a de novo event in two CMT1 families. Twelve CMT patients who did not have decreased nerve conduction velocities consistent with a diagnosis of CMT type 2 (CMT2) were found not to have the CMT1A duplication. The most informative molecular method was the detection of the CMT1A duplication-specific junction fragment. Given the high frequency of the CMT1A duplication in CMT patients and the high frequency of new mutations, the authors conclude that a molecular test for the CMT1A DNA duplication is very useful in the differential diagnosis of patients with peripheral neuropathies. 61 refs., 4 figs.

  4. PMP22 expression in dermal nerve myelin from patients with CMT1A.

    PubMed

    Katona, Istvan; Wu, Xingyao; Feely, Shawna M E; Sottile, Stephanie; Siskind, Carly E; Miller, Lindsey J; Shy, Michael E; Li, Jun

    2009-07-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a 1.4 Mb duplication on chromosome 17p11.2, which contains the peripheral myelin protein-22 (PMP22) gene. Increased levels of PMP22 in compact myelin of peripheral nerves have been demonstrated and presumed to cause the phenotype of CMT1A. The objective of the present study was to determine whether an extra copy of the PMP22 gene in CMT1A disrupts the normally coordinated expression of PMP22 protein in peripheral nerve myelin and to evaluate PMP22 over-expression in patients with CMT1A and determine whether levels of PMP22 are molecular markers of disease severity. PMP22 expression was measured by taking skin biopsies from patients with CMT1A (n = 20) and both healthy controls (n = 7) and patients with Hereditary Neuropathy with liability to Pressure Palsies (HNPP) (n = 6), in which patients have only a single copy of PMP22. Immunological electron microscopy was performed on the skin biopsies to quantify PMP22 expression in compact myelin. Similar biopsies were analysed by real time PCR to measure PMP22 mRNA levels. Results were also correlated with impairment in CMT1A, as measured by the validated CMT Neuropathy Score. Most, but not all patients with CMT1A, had elevated PMP22 levels in myelin compared with the controls. The levels of PMP22 in CMT1A were highly variable, but not in HNPP or the controls. However, there was no correlation between neurological disabilities and the level of over-expression of PMP22 protein or mRNA in patients with CMT1A. The extra copy of PMP22 in CMT1A results in disruption of the tightly regulated expression of PMP22. Thus, variability of PMP22 levels, rather than absolute level of PMP22, may play an important role in the pathogenesis of CMT1A. PMID:19447823

  5. PMP22 expression in dermal nerve myelin from patients with CMT1A

    PubMed Central

    Katona, Istvan; Wu, Xingyao; Feely, Shawna M. E.; Sottile, Stephanie; Siskind, Carly E.; Miller, Lindsey J.; Shy, Michael E.

    2009-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a 1.4 Mb duplication on chromosome 17p11.2, which contains the peripheral myelin protein-22 (PMP22) gene. Increased levels of PMP22 in compact myelin of peripheral nerves have been demonstrated and presumed to cause the phenotype of CMT1A. The objective of the present study was to determine whether an extra copy of the PMP22 gene in CMT1A disrupts the normally coordinated expression of PMP22 protein in peripheral nerve myelin and to evaluate PMP22 over-expression in patients with CMT1A and determine whether levels of PMP22 are molecular markers of disease severity. PMP22 expression was measured by taking skin biopsies from patients with CMT1A (n = 20) and both healthy controls (n = 7) and patients with Hereditary Neuropathy with liability to Pressure Palsies (HNPP) (n = 6), in which patients have only a single copy of PMP22. Immunological electron microscopy was performed on the skin biopsies to quantify PMP22 expression in compact myelin. Similar biopsies were analysed by real time PCR to measure PMP22 mRNA levels. Results were also correlated with impairment in CMT1A, as measured by the validated CMT Neuropathy Score. Most, but not all patients with CMT1A, had elevated PMP22 levels in myelin compared with the controls. The levels of PMP22 in CMT1A were highly variable, but not in HNPP or the controls. However, there was no correlation between neurological disabilities and the level of over-expression of PMP22 protein or mRNA in patients with CMT1A. The extra copy of PMP22 in CMT1A results in disruption of the tightly regulated expression of PMP22. Thus, variability of PMP22 levels, rather than absolute level of PMP22, may play an important role in the pathogenesis of CMT1A. PMID:19447823

  6. Transgenic mouse models of CMT1A and HNPP.

    PubMed

    Suter, U; Nave, K A

    1999-09-14

    We have generated several PMP22 animal mutants with altered PMP22 gene dosage. A moderate increase in the number of PMP22 genes led to hypomyelination comparable to CMT1A, whereas high copy numbers of transgenic PMP22 resulted in phenotypes resembling more severe forms of hereditary motor and sensory neuropathies. In contrast, eliminating one of the two normal PMP22 genes by gene targeting caused unstable focal hypermyelination (tomacula) similar to the pathology in HNPP. A related but more severe phenotype was observed in mice that lack PMP22 completely. Detailed analysis of the different PMP22 mutants revealed, in addition to the obvious myelinopathy, distal axonopathy as a characteristic feature. We conclude that the maintenance of axons might be a promising target for therapeutic interventions in these demyelinating hereditary neuropathies. Furthermore, our results strongly support the concept that PMP22-related neuropathies (and most likely also other forms of inherited motor and sensory neuropathies) should be viewed as the consequence of impaired neuron-Schwann cell interactions that are likely already to be operative during development. Such considerations should be taken into account in the design of potential novel treatment strategies. PMID:10586249

  7. Selected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients.

    PubMed

    Mannil, Manoj; Solari, Alessandra; Leha, Andreas; Pelayo-Negro, Ana L; Berciano, José; Schlotter-Weigel, Beate; Walter, Maggie C; Rautenstrauss, Bernd; Schnizer, Tuuli J; Schenone, Angelo; Seeman, Pavel; Kadian, Chandini; Schreiber, Olivia; Angarita, Natalia G; Fabrizi, Gian Maria; Gemignani, Franco; Padua, Luca; Santoro, Lucio; Quattrone, Aldo; Vita, Giuseppe; Calabrese, Daniela; Young, Peter; Laurà, Matilde; Haberlová, Jana; Mazanec, Radim; Paulus, Walter; Beissbarth, Tim; Shy, Michael E; Reilly, Mary M; Pareyson, Davide; Sereda, Michael W

    2014-11-01

    This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. We then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures - the 10m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry - further improved discrimination between severely and mildly affected patients. From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials. PMID:25085517

  8. Detection of mosaicism in a CMT1a patient using FISH

    SciTech Connect

    Sourour, E.; Thompson, P.; MacMillan, J.; Upadhyaya, M.

    1994-09-01

    Charcot-Marie-Tooth disease type 1 (CMT1) is the most common hereditary motor and sensory neuropathy, and is characterized by peroneal muscular atrophy, pes cavus, loss of deep tendon reflexes and reduced motor nerve conduction velocities. CMT1a segregates as an autosomal dominant condition and shows complete linkage and association with a large submicroscopic duplication on chromosome 17p11.2-p12. We have detected a mosaicism in the father of an affected CMT1a patient. The affected individuals in this family were found to be homozygous with DNA markers YAW409, p132GBRI which are duplicated in CMT1a patients. FISH analysis with YAC clone (Y49H7), carried on 45 interphases from the affected father, revealed that the duplication was only present in 24 of these interphases. However, this duplication was found in all 50 interphases screened from the father`s affected son and, as expected, none of the 50 interphases derived from a non-CMT case had any evidence of this duplication. The affected father had had difficulty with his balance from age 40, with numerous falls. His median and motor nerve conduction velocities were normal. There was no obvious history fo the disorder in the previous generations. The affected boy had foot drop prior to his 10th birthday. He had loss of sensation in his feet and sensorineural deafness from childhood and had a median motor conduction velocity of 33 meters/second. The findings based on FISH analysis suggest that the mosaicism may have occurred early in embryogenesis leading to the disease in the father.

  9. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: Implications for testing in the cytogenetics laboratory

    SciTech Connect

    Shaffer, L.G.; Kennedy, G.M.; Spikes, A.S.

    1997-03-31

    Charcot-Marie-Tooth (CMT) disease type 1A is an inherited peripheral neuropathy characterized by slowly progressive distal muscle wasting and weakness, decreased nerve conduction velocities, and genetic linkage to 17p12. Most (>98%) CMT1A cases are caused by a DNA duplication of a 1.5-Mb region in 17p12 containing the PMP22 gene. The reciprocal product of the CMT1A duplication is a 1.5-Mb deletion which causes hereditary neuropathy with liability to pressure palsies (HNPP). The most informative current diagnostic testing requires pulsed-field gel electrophoresis to detect DNA rearrangement-specific junction fragments. We investigated the use of interphase FISH for the detection of duplications and deletions for these disorders in the clinical molecular cytogenetics laboratory. Established cell lines or blood specimens from 23 individuals with known molecular diagnoses and 10 controls were obtained and scored using a two-color FISH assay. At least 70%, of CMT1A cells displayed three signals consistent with duplications. Using this minimum expected percentile to make a CMT1A duplication diagnosis, all patients with CMT1A showed a range of 71-92% of cells displaying at least three signals. Of the HNPP cases, 88% of cells displayed only one hybridization signal, consistent with deletions. The PMP22 locus from normal control individuals displayed a duplication pattern in {approximately}9% of cells, interpreted as replication of this locus. The percentage of cells showing replication was significantly lower than in those cells displaying true duplications. We conclude that FISH can be reliably used to diagnose CMT1A and HNPP in the clinical cytogenetics laboratory and to readily distinguish the DNA rearrangements associated with these disorders from individuals without duplication or deletion of the PMP22 locus. 43 refs., 4 figs., 2 tabs.

  10. Computational Analysis Reveals the Association of Threonine 118 Methionine Mutation in PMP22 Resulting in CMT-1A

    PubMed Central

    Swetha, Rayapadi G.

    2014-01-01

    The T118M mutation in PMP22 gene is associated with Charcot Marie Tooth, type 1A (CMT1A). CMT1A is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Mutations in CMT related disorder are seen to increase the stability of the protein resulting in the diseased state. We performed SNP analysis for all the nsSNPs of PMP22 protein and carried out molecular dynamics simulation for T118M mutation to compare the stability difference between the wild type protein structure and the mutant protein structure. The mutation T118M resulted in the overall increase in the stability of the mutant protein. The superimposed structure shows marked structural variation between the wild type and the mutant protein structures. PMID:25400662

  11. Non-radioactive detection of 17p11.2 duplication in CMT1A: a study of 78 patients.

    PubMed Central

    Schiavon, F; Mostacciuolo, M L; Saad, F; Merlini, L; Siciliano, G; Angelini, C; Danieli, G A

    1994-01-01

    Charcot-Marie-Tooth disease type 1 (CMT1) is a peripheral neuropathy characterised by progressive distal muscular atrophy and sensory loss with markedly decreased nerve conduction velocity, mostly inherited as an autosomal dominant trait. The most common form, type 1A, is associated with a 1.5Mb DNA duplication in region p11.2-p12 of chromosome 17 in many patients. In this study a non-radioactive test for detection of the CMT1A duplication based on an RM11-GT microsatellite polymorphism is presented. Although different methods have been devised for this purpose, the present method has the advantage of being rapid, informative, economical, easily interpretable, and, therefore, it represents a very useful tool for diagnosis of CMT1A, especially before clear manifestation of clinical symptoms. Seventy-eight patients diagnosed clinically as having CMT and evaluated by electrophysiological methods were tested with an RM11-GT microsatellite and with probe pVAW409R3. The CMT1A duplication was found in 76% of the 56 unrelated patients. RM11-GT was the most informative marker with a heterozygosity of 89%. Images PMID:7853375

  12. Application of whole-exome sequencing for detecting copy number variants in CMT1A/HNPP.

    PubMed

    Jo, H-Y; Park, M-H; Woo, H-M; Han, M H; Kim, B-Y; Choi, B-O; Chung, K W; Koo, S K

    2016-08-01

    Large insertions and deletions (indels), including copy number variations (CNVs), are commonly seen in many diseases. Standard approaches for indel detection rely on well-established methods such as qPCR or short tandem repeat (STR) markers. Recently, a number of tools for CNV detection based on next-generation sequencing (NGS) data have also been developed; however, use of these methods is limited. Here, we used whole-exome sequencing (WES) in patients previously diagnosed with CMT1A or HNPP using STR markers to evaluate the ability of WES to improve the clinical diagnosis. Patients were evaluated utilizing three CNV detection tools including CONIFER, ExomeCNV and CEQer, and array comparative genomic hybridization (aCGH). We identified a breakpoint region at 17p11.2-p12 in patients with CMT1A and HNPP. CNV detection levels were similar in both 6 Gb (mean read depth = 80×) and 17 Gb (mean read depth = 190×) data. Taken together, these data suggest that 6 Gb WES data are sufficient to reveal the genetic causes of various diseases and can be used to estimate single mutations, indels, and CNVs simultaneously. Furthermore, our data strongly indicate that CNV detection by NGS is a rapid and cost-effective method for clinical diagnosis of genetically heterogeneous disorders such as CMT neuropathy. PMID:26662885

  13. Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.

    PubMed

    Zhang, Feng; Seeman, Pavel; Liu, Pengfei; Weterman, Marian A J; Gonzaga-Jauregui, Claudia; Towne, Charles F; Batish, Sat Dev; De Vriendt, Els; De Jonghe, Peter; Rautenstrauss, Bernd; Krause, Klaus-Henning; Khajavi, Mehrdad; Posadka, Jan; Vandenberghe, Antoon; Palau, Francesc; Van Maldergem, Lionel; Baas, Frank; Timmerman, Vincent; Lupski, James R

    2010-06-11

    Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previous studies showed that >99% of these rearrangements are recurrent and mediated by nonallelic homologous recombination (NAHR). Rare copy number variations (CNVs) generated by nonrecurrent rearrangements also exist in 17p12, but their underlying mechanisms are not well understood. We investigated 21 subjects with rare CNVs associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analyses, and we identified 17 unique CNVs, including two genomic deletions, ten genomic duplications, two complex rearrangements, and three small exonic deletions. Each of these CNVs includes either the entire PMP22 gene, or exon(s) only, or ultraconserved potential regulatory sequences upstream of PMP22, further supporting the contention that PMP22 is the critical gene mediating the neuropathy phenotypes associated with 17p12 rearrangements. Breakpoint sequence analysis reveals that, different from the predominant NAHR mechanism in recurrent rearrangement, various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms (e.g., FoSTeS and/or MMBIR), can generate nonrecurrent 17p12 rearrangements associated with neuropathy. We document a multitude of ways in which gene function can be altered by CNVs. Given the characteristics, including small size, structural complexity, and location outside of coding regions, of selected rare CNVs, their identification remains a challenge for genome analysis. Rare CNVs may potentially represent an important portion of "missing heritability" for human diseases. PMID:20493460

  14. Tolerability and efficacy study of P2X7 inhibition in experimental Charcot-Marie-Tooth type 1A (CMT1A) neuropathy.

    PubMed

    Sociali, Giovanna; Visigalli, Davide; Prukop, Thomas; Cervellini, Ilaria; Mannino, Elena; Venturi, Consuelo; Bruzzone, Santina; Sereda, Michael W; Schenone, Angelo

    2016-11-01

    Charcot-Marie-Tooth 1A (CMT1A) is a demyelinating hereditary neuropathy for which pharmacological treatments are not yet available. An abnormally high intracellular Ca(2+) concentration was observed in Schwann cells (SC) from CMT1A rats, caused by the PMP22-mediated overexpression of the P2X7 purinoceptor. The purpose of this study was to investigate the tolerability and therapeutic potential of a pharmacological antagonist of the P2X7 receptor (A438079) in CMT1A. A438079 ameliorated in vitro myelination of organotypic DRG cultures from CMT1A rats. Furthermore, we performed an experimental therapeutic trial in PMP22 transgenic and in wild-type rats. A preliminary dose-escalation trial showed that 3mg/kg A438079 administered via intraperitoneal injection every 24h for four weeks was well tolerated by wild type and CMT1A rats. Affected rats treated with 3mg/kg A438079 revealed a significant improvement of the muscle strength, when compared to placebo controls. Importantly, histologic analysis revealed a significant increase of the total number of myelinated axons in tibial nerves. Moreover, a significant decrease of the hypermyelination of small caliber axons and a significant increase of the frequency and diameter of large caliber myelinated axons was highlighted. An improved distal motor latencies was recorded, whereas compound muscle action potentials (CMAP) remained unaltered. A438079 reduced the SC differentiation defect in CMT1A rats. These results show that pharmacological inhibition of the P2X7 receptor is well tolerated in CMT1A rats and represents a proof-of-principle that antagonizing this pathway may correct the molecular derangements and improve the clinical phenotype in the CMT1A neuropathy. PMID:27431093

  15. A 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region in 17p11.2-p12

    SciTech Connect

    Murakami, Tatsufumi; Lupski, J.R.

    1996-05-15

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1.5-Mb tandem duplication in chromosome 17p11.2-p12, and hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. Both diseases appear to result from an altered copy number of the peripheral myelin protein-22 gene, PMP22, which maps within the critical region. To identify additional genes and characterize chromosomal elements, a 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region was assembled using a yeast artificial chromosome (YAC)-based isolation and binning strategy. Whole YAC probes were used for screening a high-density arrayed chromosome 17-specific cosmid library. Selected cosmids were spotted on dot blots and assigned to bins defined by YACs. This binning of cosmids facilitated the subsequent fingerprint analysis. The 1.5-Mb region was covered by 137 cosmids with a minimum overlap set of 52 cosmids assigned to 17 bins and 9 contigs. 20 refs., 2 figs.

  16. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment.

    PubMed

    Mandel, Jonas; Bertrand, Viviane; Lehert, Philippe; Attarian, Shahram; Magy, Laurent; Micallef, Joëlle; Chumakov, Ilya; Scart-Grès, Catherine; Guedj, Mickael; Cohen, Daniel

    2015-01-01

    CMT1A is the most common inherited peripheral neuropathy. There is currently no approved treatment. We performed a meta-analysis including four randomized, double-blind, Placebo-controlled clinical trials to assess the disease progression after one year under Placebo, Ascorbic Acid (AA) or PXT3003, a combination of three repurposed drugs. We observed a weak deterioration in patients under Placebo, well below the reported natural disease progression. Patients treated with AA were stable after one year but not significantly different from Placebo. Patients undergoing PXT3003 treatment showed an improvement in CMTNS and ONLS, statistically significant versus Placebo and potentially precursory of a meaningful change in the disease course. PMID:26070802

  17. Overlap phenotype between CMT1A and hereditary neuropathy with liability to pressure palsies caused by the novel small in-frame deletion c.407_418del12 in PMP22 gene.

    PubMed

    Vill, Katharina; Kuhn, Marius; Gläser, Dieter; Müller-Felber, Wolfgang

    2015-02-01

    We report monozygotic twins, who presented with a clinical picture of Charcot-Marie-Tooth disease type 1 (CMT1) with bilateral foot drop, pes cavus, thoracic kyphosis, and scoliosis. Hereditary neuropathy with liability to pressure palsies (HNPP) showed up in one of them. Neurography showed demyelinating neuropathy, typical for CMT1, and transient conduction block in the ulnar nerve correlating with clinical ulnar palsy due to minor mechanical stress in only one of them. Genetic analysis revealed novel small de novo deletion c.407_418del12 in the PMP22 gene. Our patient shows the rarely reported combination of CMT1A and HNPP, caused by an in-frame deletion in the PMP22 gene. HNPP is in the majority of cases correlated with heterozygous deletion of the whole PMP22 gene or other mutations leading to functional haploinsufficiency. The cases give further evidence that pathogenesis of HNPP is not completely understood and can obviously result from existence of a defective protein, too. The intrafamiliar phenotypic variability, even in monozygotic twins, confirms the well-known fact that factors apart from genetics contribute to the clinical course. PMID:25265422

  18. An essential role of MAG in mediating axon-myelin attachment in Charcot-Marie-Tooth 1A disease

    PubMed Central

    Kinter, Jochen; Lazzati, Thomas; Schmid, Daniela; Zeis, Thomas; Erne, Beat; Lützelschwab, Roland; Steck, Andreas J.; Pareyson, Davide; Peles, Elior; Schaeren-Wiemers, Nicole

    2012-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy caused by the duplication of the PMP22 gene. Demyelination precedes the occurrence of clinical symptoms that correlate with axonal degeneration. It was postulated that a disturbed axon-glia interface contribute to altered myelination consequently leading to axonal degeneration. In this study, we examined the expression of MAG and Necl4, two critical adhesion molecules that are present at the axon-glia interface, in sural nerve biopsies of CMT1A patients and in peripheral nerves of mice overexpressing human PMP22, an animal model for CMT1A. We show an increase in the expression of MAG and a strong decrease of Necl4 in biopsies of CMT1A patients as well as in CMT1A mice. Expression analysis revealed that MAG is strongly upregulated during peripheral nerve maturation, whereas Necl4 expression remains very low. Ablating MAG in CMT1A mice results in separation of axons from their myelin sheath. Our data show that MAG is important for axon-glia contact in a model for CMT1A, and suggest that its increased expression in CMT1A disease has a compensatory role in the pathology of the disease. Thus, we demonstrate that MAG together with other adhesion molecules such as Necl4 is important in sustaining axonal integrity. PMID:22940629

  19. Nerve Excitability Properties in Charcot-Marie-Tooth Disease Type 1A

    ERIC Educational Resources Information Center

    Nodera, Hiroyuki; Bostock, Hugh; Kuwabara, Satoshi; Sakamoto, Takashi; Asanuma, Kotaro; Jia-Ying, Sung; Ogawara, Kazue; Hattori, Naoki; Hirayama, Masaaki; Kaji, Ryuji

    2004-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the "in vivo" assessment of…

  20. Recombination hot spot in 3.2-kb region of the Charcot-Marie Tooth type 1A repeat sequences: New tools for molecular diagnosis of hereditary neuropathy with liability to pressure palsies and of Charcot-Marie-Tooth type 1A

    SciTech Connect

    Lopes, J.; LeGuern, E.; Gouider, R.; Tardieu, S.; Abbas, N.

    1996-06-01

    Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP) are autosomal dominant neuropathies, associated, respectively, with duplications and deletions of the same 1.5-Mb region on 17p11.2-p12. These two rearrangements are the reciprocal products of an unequal meiotic crossover between the two chromosome 17 homologues, caused by the misalignment of the CMT1A repeat sequences (CMT1A-REPs), the homologous sequences flanking the 1.5-Mb CMT1A/HNPP monomer unit. In order to map recombination breakpoints within the CMT1A-REPs, a 12.9-kb restriction map was constructed from cloned EcoRI fragments of the proximal and distal CMT1A-REPs. Only 3 of the 17 tested restriction sites were present in the proximal CMT1A-REP but absent in the distal CMT1A-REP, indicating a high degree of homology between these sequences. The rearrangements were mapped in four regions of the CMT1A-REPs by analysis of 76 CMT1A index cases and 38 HNPP patients, who were unrelated. A hot spot of crossover breakpoints located in a 3.2-kb region accounted for three-quarters of the rearrangements, detected after EcoRI/SacI digestion, by the presence of 3.2-kb and 7.8-kb junction fragments in CMT1A and HNPP patients, respectively. These junction fragments, which can be detected on classical Southern blots, permit molecular diagnosis. Other rearrangements can also be detected by gene dosage on the same Southern blots. 25 refs., 4 figs., 2 tabs.

  1. Peripheral myelin protein 22 gene duplication with atypical presentations: a new example of the wide spectrum of Charcot-Marie-Tooth 1A disease.

    PubMed

    Mathis, Stéphane; Corcia, Philippe; Tazir, Meriem; Camu, William; Magdelaine, Corinne; Latour, Philippe; Biberon, Julien; Guennoc, Anne-Marie; Richard, Laurence; Magy, Laurent; Funalot, Benoît; Vallat, Jean-Michel

    2014-06-01

    Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype-phenotype correlations in Charcot-Marie-Tooth diseases. PMID:24792522

  2. Prevalence and origin of De Novo duplications in Charcot-Marie-Tooth disease type 1A: First report of a De Novo duplication with a maternal origin

    SciTech Connect

    Blair, I.P.; Nash, J.; Gordon, M.J.; Nicholson, G.A.

    1996-03-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Sporadic cases of CMT have been described since the earliest reports of the disease. The most frequent form of the disorder, CMT1A, is associated with a 1.5-Mb DNA duplication on chromosome 17p11.2, which segregates with the disease. In order to investigate the prevalence of de novo CMT1A duplications, this study examined 118 duplication-positive CMT1A families. In 10 of these families it was demonstrated that the disease had arisen as the result of a de novo mutation. By taking into account the ascertainment of families, it can be estimated that {>=}10% of autosomal dominant CMT1 families are due to de novo duplications. The CMT1A duplication is thought to be the product of unequal crossing over between parental chromosome 17 homologues during meiosis. Polymorphic markers from within the duplicated region were used to determine the parental origin of these de novo duplications in eight informative families. Seven were of paternal and one of maternal origin. This study represents the first report of a de novo duplication with a maternal origin and indicates that it is not a phenomenon associated solely with male meioses. Recombination fractions for the region duplicated in CMT1A are larger in females than in males. That suggests that oogenesis may be afforded greater protection from misalignment during synapsis, and/or that there may be lower activity of those factors or mechanisms that lead to unequal crossing over at the CMT1A locus. 41 refs., 2 figs.

  3. Charcot-Marie-Tooth type 1A disease from patient to laboratory.

    PubMed

    Perveen, Shazia; Mannan, Shazia; Hussain, Abrar; Kanwal, Sumaira

    2015-02-01

    Charcot-Marie-Tooth (CMT) disease is a well-known neural or spinal type of muscular atrophy. It is the most familiar disease within a group of conditions called Hereditary Motor and Sensory Neuropathies (HMSN). The disease was discovered by three scientists several years ago. Several genes are involved as the causative agents for the disease. Hundreds of causative mutations have been found and research work for the identification of a novel locus and for the treatment of CMT1A is going on. This review article was planned to gather information on CMT disease and updates on its treatment.National Center for Biotechnology Information (NCBI) and PubMed were searched for data retrieval. Molgen database, which is the exclusive site for CMT mutation, was the other source of articles. Different aspects of the CMT disease were compared.Advancements in the finding of the causative gene, discovery of the novel Loci are the current issues in this regard.CMT disease is incurable, but researchers are trying to get some benefits from different natural compounds and several therapeutic agents.Various groups are working on the treatment projects of CMT1A. Major step forward in CMT research was taken in 2004 when ascorbic acid was used for transgenic mice treatment. Gene therapy for constant neurotrophin-3 (NT- 3) delivery by secretion by muscle cells for the CMT1A is also one of the possible treatments under trial. PMID:25842560

  4. PMP22 messenger RNA levels in skin biopsies: testing the effectiveness of a Charcot-Marie-Tooth 1A biomarker.

    PubMed

    Nobbio, Lucilla; Visigalli, Davide; Radice, Davide; Fiorina, Elisabetta; Solari, Alessandra; Lauria, Giuseppe; Reilly, Mary M; Santoro, Lucio; Schenone, Angelo; Pareyson, Davide

    2014-06-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with increased gene dosage for PMP22. Therapeutic approaches are currently aiming at correcting PMP22 over-expression. It is unknown whether PMP22 can be used as a biological marker of disease progression and therapy efficacy. We performed quantitative real-time polymerase chain reaction on skin biopsies of 45 patients with CMT1A, obtained at study entry and after 24-months of treatment either with ascorbic acid or placebo. Data of a subgroup of patients were also compared with matched healthy subjects. Finally, we analysed PMP22 messenger RNA levels in sural nerve biopsies. We did not find significant differences in the levels of any known PMP22 transcripts in treated or untreated patients with CMT1A, thus confirming that ascorbic acid does not impact on the molecular features of CMT1A. Most importantly, we did not observe any correlation between PMP22 messenger RNA levels and the different clinical and electrophysiological outcome measures, underscoring the weakness of PMP22 to mirror the phenotypic variability of patients with CMT1A. We did not find increased PMP22 messenger RNA levels in skin and sural nerve biopsies of patients with CMT1A compared with relative controls. In conclusion, this study shows that ascorbic acid does not impact on PMP22 transcriptional regulation and PMP22 is not a suitable biomarker for CMT1A. PMID:24812204

  5. Charcot-Marie-Tooth Disease

    MedlinePlus

    ... a different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused ... PMP-22 gene result in episodic, recurrent demyelinating neuropathy. CMT1B is an autosomal dominant disease caused by ...

  6. Charcot-Marie-Tooth 1A concurrent with schwannomas of the spinal cord and median nerve.

    PubMed

    Kwon, Joo Young; Chung, Ki Wha; Park, Eun Kyung; Park, Sun Wha; Choi, Byung-Ok

    2009-08-01

    We identified Charcot-Marie-Tooth disease type 1A (CMT1A) in a family with schwannomas in the spinal cord and median nerve. The CMT1A in this family showed an autosomal dominant pattern, like other CMT patients with PMP22 duplication, and the family also indicated a possible genetic predisposition to schwannomas by 'mother-to-son' transmission. CMT1A is mainly caused by duplication of chromosome 17p11.2-p12 (PMP22 gene duplication). A schwannoma is a benign encapsulated tumor originating from a Schwann cell. A case of hereditary neuropathy with liability to pressure palsies (HNPP) concurrent with schwannoma has been previously reported. Although it seems that the co-occurrence of CMT1A and schwannomas in a family would be the result of independent events, we could not completely ignore the possibility that the coincidence of two diseases might be due to a shared genetic background. PMID:19654968

  7. Charcot-Marie-Tooth (CMT) disease 1A with superimposed inflammatory polyneuropathy in children.

    PubMed

    Desurkar, A; Lin, J-P; Mills, K; Al-Sarraj, S; Jan, W; Jungbluth, H; Wraige, E

    2009-04-01

    Charcot-Marie-Tooth (CMT) disease is genetically heterogeneous and subdivided into demyelinating (CMT 1) and axonal (CMT 2) types based on neurophysiology findings. CMT1A, the commonest form associated with duplication of the PMP22 segment on chromosome 17p, often arises in childhood but is generally a slowly progressive disease. We report 2 children presenting with clinical features of an acute inflammatory demyelinating polyneuropathy (AIDP) who were subsequently diagnosed with underlying CMT1A. Both children had neurophysiology and histopathology features consistent with CMT1. Immunoglobulin treatment was initiated considering the evidence of superimposed inflammation and appeared to modify disease progression. Our findings indicate that CMT1A predisposes to a superimposed inflammatory neuropathy. Recognition of this association is difficult, particularly in children without clear family history, but of great importance as immunomodulatory treatment may improve outcome. In addition, we postulate that an underlying genetic polyneuropathy should be suspected if the recovery from AIDP is slower than expected, or incomplete. PMID:19809938

  8. Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family.

    PubMed

    Sun, A-Ping; Tang, Lu; Liao, Qin; Zhang, Hui; Zhang, Ying-Shuang; Zhang, Jun

    2015-10-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only four had clinical features of polyneuropathy. All CMT1A patients with a clinical phenotype also presented with type 2 diabetes mellitus. The other three individuals had no signs of CMT1A or type 2 diabetes mellitus. We believe that there may be a genetic link between these two diseases. PMID:26692872

  9. Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family

    PubMed Central

    Sun, A-ping; Tang, Lu; Liao, Qin; Zhang, Hui; Zhang, Ying-shuang; Zhang, Jun

    2015-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only four had clinical features of polyneuropathy. All CMT1A patients with a clinical phenotype also presented with type 2 diabetes mellitus. The other three individuals had no signs of CMT1A or type 2 diabetes mellitus. We believe that there may be a genetic link between these two diseases. PMID:26692872

  10. Severe phenotypes in a Charcot-Marie-Tooth 1A patient with PMP22 triplication.

    PubMed

    Kim, Sung Min; Lee, Jinho; Yoon, Bo Ram; Kim, Ye Jin; Choi, Byung-Ok; Chung, Ki Wha

    2015-02-01

    Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous hereditary motor and sensory neuropathy signified by a distal symmetric polyneuropathy. The most frequent subtype is type 1A (CMT1A) caused by duplication in chromosome 17p12 that includes PMP22. This study reports a woman with a family history of CMT1A due to PMP22 duplication. However, she presented with a more severe phenotype than her sibling or ancestors and was found to have a PMP22 triplication instead of the duplication. This was caused by de novo mutation on her affected mother's duplication chromosome. Her lower limb magnetic resonance imaging revealed severe diffused atrophy and fatty replacement. However, her affected sister with typical PMP22 duplication showed almost intact lower limb. Triplication patient's median motor nerve conduction velocity was far lower compared with her sister. Her onset age was faster (8 years) than her sister (42 years). CMT1A triplication might be generated by a female-specific chromosomal rearrangement mechanism that is different from the frequent paternal-originated CMT1A duplication. It also suggests that the wide phenotypic variation of CMT1A might be partly caused by unstable genomic rearrangement, including PMP22 triplication. PMID:25500726

  11. Coexistence of Charcot-Marie-Tooth disease type 1A and anti-MAG neuropathy.

    PubMed

    Piscosquito, Giuseppe; Salsano, Ettore; Ciano, Claudia; Palamara, Luisa; Morbin, Michela; Pareyson, Davide

    2013-06-01

    At age 35, a man with a genetic diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM-kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti-myelin associated glycoprotein (anti-MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a "double hit". Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate. PMID:23781967

  12. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

    PubMed Central

    2014-01-01

    PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal. PMID:24646194

  13. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies.

    PubMed

    van Paassen, Barbara W; van der Kooi, Anneke J; van Spaendonck-Zwarts, Karin Y; Verhamme, Camiel; Baas, Frank; de Visser, Marianne

    2014-01-01

    PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal. PMID:24646194

  14. Efficacy of focal mechanic vibration treatment on balance in Charcot-Marie-Tooth 1A disease: a pilot study.

    PubMed

    Pazzaglia, Costanza; Camerota, F; Germanotta, M; Di Sipio, E; Celletti, C; Padua, L

    2016-07-01

    Patients affected by Charcot-Marie-Tooth (CMT) disease experience an impaired balance. Although the causes of the postural instability are not fully understood, somatosensory system seems to play a key role. Mechanical vibration seems to act on the somatosensory system and to improve its function. The aim of our study was to evaluate the effects of focal mechanical vibration (fMV) on the balance of CMT 1A patients. We enrolled 14 genetically confirmed CMT 1A patients (8 female and 6 male, mean age 492 years, range 32-74, mean duration of disease: 13 years, range 1-30). Patients underwent a 3-day fMV treatment on quadriceps and triceps surae and were evaluated before the treatment as well as 1 week and 1 month after the end of the treatment. The primary outcome measure was the Berg Balance Scale (BBS) and the secondary were the Dynamic Gait Index (DGI), the 6 Min Walking Test (6MWT), the muscular strength of lower limbs, the Quality of Life (QoL) questionnaire and the stabilometric variables. The statistical analysis showed a significant modification of the BBS due to the effect of treatment (p < 0.05). A significant modification was also found in the DGI (p < 0.05). Concerning the stabilometric variables we found significant changes only for the eyes closed condition; in particular, a significant decrease was found in VelocityML (p < 0.05) and Sway path length (p < 0.05). The fMV treatment applied on lower limbs of CMT 1A patients determined an improvement of balance as detected by the BBS. The concurrent improvement of stabilometric variables in the eyes closed condition only suggests that fMV acts mostly on somatosensory afferences. Further studies are needed to confirm these data on a larger sample of CMT patients. PMID:27177999

  15. Respiratory dysfunction in Charcot-Marie-Tooth disease type 1A.

    PubMed

    de Carvalho Alcântara, Mônica; Nogueira-Barbosa, Marcello H; Fernandes, Regina Maria França; da Silva, Geruza Alves; Lourenço, Charles Marques; Sander, Heide H; Marques Junior, Wilson

    2015-05-01

    We aimed to investigate the relationship between neurological compromise, respiratory parameters in wakefulness and in sleep, physiology, and morphology of phrenic nerves in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Sixteen patients with CMT1A were evaluated by spirometry, maximal expiratory and maximal inspiratory pressures (MEP, MIP), polysomnography, phrenic nerve compound muscle action potential (CMAP), and ultrasonography (roots C3,C4,C5 and phrenic nerves). Clinical disability was measured with Charcot-Marie-Tooth neuropathy score (CMT-NS; range 0-36). Two control groups, comprising 30 individuals matched for age, sex, and body mass index, were used for comparison. Ten patients were female (62%), mean age was 37.88 years (range 24-76); and CMT-NS range was 7-34. MIP was reduced in five (31%) and MEP in 12 patients (75%), although only one had restrictive respiratory dysfunction in spirometry. Apnoea-hypopnea index (AHI) was significantly higher in patients (12.01 ± 11.57/h × 5.89 ± 8.36/h; p value = 0.05) and increased in REM sleep compared with NREM (9.94 ± 10.96/h × 19.13 ± 19.93/h; p value = 0.01). There were significant correlations between CMT-NS and AHI (Pearson = 0.69; p value = 0.03); CMT-NS and MIP (Pearson = -0.691, p value = 0.003); and CMT-NS and MEP (Pearson = -0.603, p value = 0.013). Also, AHI showed negative correlation with MIP (Pearson = -0.52, p value = 0.036) and MEP (Pearson = -0.55, p value = 0.026). Phrenic nerves were enlarged in ultrasonography in all patients and presented significant correlations with CMAPs (right: Pearson = -0.554, p value = 0.026; left: Pearson = -0.558, p value = 0.025). We suggest that axonal degeneration of nerves directed to muscles of respiration might explain the high prevalence of respiratory weakness in patients with CMT1A. Clinical manifestations are frequent during sleep, where the diaphragm alone can only partially surpass the overload in breathing apparatus. PMID:25761374

  16. Changes of gait pattern in children with Charcot-Marie-Tooth disease type 1A: a 18 months follow-up study

    PubMed Central

    2013-01-01

    Background In a previous study we identified 3 different gait patterns in a group of children with CMT1A disease: Normal-like (NL), Foot-drop (FD), Foot-drop and Push-off Deficit (FD&POD). Goal of the present study was to perform a follow-up evaluation of the same group of patients to analyze possible changes of gait features in relation to disease progression or specific therapy. Methods Nineteen children with CMT1A were evaluated clinically (CMT-Examination Score and Overall Neuropathy Limitation Scale) and through gait analysis 18.2±1.5 months after a baseline evaluation. Meanwhile, 3 of them had foot surgery. Results Fifteen out of the 16 non-operated patients significantly changed at least one of the two parameters associated to primary signs (FD and/or POD). Eleven participants worsened at least one parameter and 9 improved one parameter. CMTES significantly worsened for the group of non-operated patients. However, there was no change in CMTES score in 4 patients and in ONLS score in 11. At subgroup level, participants originally belonging to NL group showed a trend towards a foot-drop deficit (−15%, ns); FD and FD&POD subgroups did not change their primary signs, although significant changes were identified individually. All 3 patients operated have improved push-off and proximal joint patterns during walking. Clinical scores did not change within any sub-group. Conclusions Subtle changes occurring in 1.5 year in gait features of CMT1A children can be instrumentally identified. Such changes show a large inter-subject variability, with some patients even improving their walking pattern. There is anecdotal evidence that foot surgery may improve the push-off phase of gait. PMID:23819439

  17. Postural stabilization and balance assessment in Charcot–Marie–Tooth 1A subjects

    PubMed Central

    Lencioni, T.; Rabuffetti, M.; Piscosquito, G.; Pareyson, D.; Aiello, A.; Di Sipio, E.; Padua, L.; Stra, F.; Ferrarin, M.

    2014-01-01

    The aim of the present study was to assess postural stabilization skill in adult subjects affected by Charcot–Marie–Tooth disease (CMT) type 1A. For this purpose ground reaction force (GRF) was measured by means of a piezoelectric force platform during the sit-to-stand (STS) movement, until a steady state erect posture was achieved. Specific indexes to quantify Centre of Mass acceleration, both during postural stabilization and during quiet standing, were computed using a mathematical model. Forty-seven CMT1A subjects were recruited for the study, and the control group was formed by forty-one age- and sex-matched healthy subjects. The results show that CMT1A subjects are less stable than controls during the quiet stance. Greater difficulty (high values of Yinf, the final instability rate) to maintain erect posture appears to be mainly associated with plantar-flexor muscle weakness, rather than to damage of the proprioceptive system. The worst performances shown by CMT1A subjects in the stabilization phase (high values of I, the global index of postural stabilization performance) seem to be associated with reduced muscle strength and the loss of large sensory nerve fibres. Distal muscle weakness appears to affect both postural stabilization and quiet erect posture. The presented protocol and the analysis of postural stabilization parameters provide useful information on CMT1A balance disorders. PMID:25082324

  18. Postural stabilization and balance assessment in Charcot-Marie-Tooth 1A subjects.

    PubMed

    Lencioni, T; Rabuffetti, M; Piscosquito, G; Pareyson, D; Aiello, A; Di Sipio, E; Padua, L; Stra, F; Ferrarin, M

    2014-09-01

    The aim of the present study was to assess postural stabilization skill in adult subjects affected by Charcot-Marie-Tooth disease (CMT) type 1A. For this purpose ground reaction force (GRF) was measured by means of a piezoelectric force platform during the sit-to-stand (STS) movement, until a steady state erect posture was achieved. Specific indexes to quantify Centre of Mass acceleration, both during postural stabilization and during quiet standing, were computed using a mathematical model. Forty-seven CMT1A subjects were recruited for the study, and the control group was formed by forty-one age- and sex-matched healthy subjects. The results show that CMT1A subjects are less stable than controls during the quiet stance. Greater difficulty (high values of Yinf, the final instability rate) to maintain erect posture appears to be mainly associated with plantar-flexor muscle weakness, rather than to damage of the proprioceptive system. The worst performances shown by CMT1A subjects in the stabilization phase (high values of I, the global index of postural stabilization performance) seem to be associated with reduced muscle strength and the loss of large sensory nerve fibres. Distal muscle weakness appears to affect both postural stabilization and quiet erect posture. The presented protocol and the analysis of postural stabilization parameters provide useful information on CMT1A balance disorders. PMID:25082324

  19. Charcot-Marie-Tooth disease and related inherited neuropathies.

    PubMed

    Murakami, T; Garcia, C A; Reiter, L T; Lupski, J R

    1996-09-01

    Charcot-Marie-Tooth disease (CMT) was initially described more than 100 years ago by Charcot, Marie, and Tooth. It was only recently, however, that molecular genetic studies of CMT have uncovered the underlying causes of most forms of the diseases. Most cases of CMT1 are associated with a 1.5-Mb tandem duplication in 17p11.2-p12 that encompasses the PMP22 gene. Although many genes may exist in this large duplicated region, PMP22 appears to be the major dosage-sensitive gene. CMT1A is the first autosomal dominant disease associated with a gene dosage effect due to an inherited DNA rearrangement. There is no mutant gene, but instead the disease phenotype results from having 3 copies of a normal gene. Furthermore, these findings suggest that therapeutic intervention in CMT1A duplication patients may be possible by normalizing the amount of PMP22 mRNA levels. Alternatively, CMT1A can be caused by mutations in the PMP22 gene. Other forms of CMT are associated with mutations in the MPZ (CMT1B) and Cx32 (CMTX) genes. Thus, mutations in different genes can cause similar CMT phenotypes. The related but more severe neuropathy, Dejerine-Sottas syndrome (DSS), can also be caused by mutations in the PMP22 and MPZ genes. All 3 genes thus far identified by CMT researchers appear to play an important role in the myelin formation or maintenance of peripheral nerves. CMT1A, CMT1B, CMTX, hereditary neuropathy with liability to pressure palsies (HNPP), and DSS have been called myelin disorders or "myelino-pathies." Other demyelinating forms, CMT1C and CMT-AR, may be caused by mutations of not yet identified myelin genes expressed in Schwann cells. The clinically distinct disease HNPP is caused by a 1.5-Mb deletion in 17p11.2-p12, which spans the same region duplicated in most CMT1A patients. Underexpression of the PMP22 gene causes HNPP just as overexpression of PMP22 causes CMT1A. Thus, 2 different phenotypes can be caused by dosage variations of the same gene. It is apparent that

  20. Behavioural profiling of a murine Charcot-Marie-Tooth disease type 1A model.

    PubMed

    Norreel, J C; Jamon, M; Riviere, G; Passage, E; Fontes, M; Clarac, F

    2001-04-01

    Different features of motor behaviour were studied on a transgenic mouse model of Charcot-Marie-Tooth's disease (CMT). Mutants with 4 or 7 copies of the human PMP22 gene leading to a phenotype significantly close to CMT's disease type 1A were compared with control animals. The aim of the study was to validate this transgenic model and to characterise the impairments occurring in the various lines. Three main types of analysis were performed in 2-month-old mice without any peculiar visible deficit: (i) a study of standardised clinical tests (SHIRPA protocol) demonstrated that only a few motor deficits were expressed; (ii) a measurement of general spontaneous activity by means of a commercial video-tracking system was performed and revealed that the main spontaneous activities were identical in the three lines with, however, some slight localised modifications; and, (iii) by contrast, the three lines respond very differently to the footprints, grip strength, splay test and rotarod test. Even in lines with a significantly limited copy number of the transgene, we observed and quantified impairments. In conclusion, mutants of CMT1A seem to be a very pertinent model of this human pathology and will certainly be useful for therapeutic procedures and for theoretical studies on this disease. PMID:11328356

  1. The 5' regulatory sequence of the PMP22 in the patients with Charcot-Marie-Tooth disease.

    PubMed

    Sinkiewicz-Darol, Elena; Kabzińska, Dagmara; Moszyńska, Izabela; Kochański, Andrzej

    2010-01-01

    Little is known about the molecular background of clinical variability of Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A and HNPP disorders result from duplication and deletion of the PMP22 gene respectively. In a series of studies performed on affected animal transgenic models of CMT1A disease, expression of the PMP22 gene (gene dosage) was shown to correlete with severity of CMT course (gene dosage effect). In this study we hypothesized that single nucleotide polymorphisms (SNPs) located within the 5' regulatory sequence of PMP22 gene may be responsible for the CMT1A/HNPP clinical variability. We have sequenced the PMP22 5' upstream regulatory sequence in a group of 45 CMT1A/HNPP patients harboring the PMP22 duplication (37) /deletion (8). We have identified five SNPs in the regulatory sequence of the PMP22 gene. Three of them i.e. -819C>T, -4785G>T, -4800C>T were detected both in the patients and in the control group. Thus, their pathogenic role in the regulation of the expression of the PMP22 gene seems not to be significant. Two SNPs i.e. -4210T>C and -4759T>A were found only in the CMT patients. Their role in the regulation of the PMP22 gene expression can not be excluded. Additionally we have detected the Thr118Met variant in exon 4 of the PMP22 gene, which was previously reported by other authors, in one patient. We conclude that the 5' regulatory sequence of the PMP22 gene is conserved at the nucleotiode level, however rarely occurring SNPs variant in the PMP22 regulatory sequence may be associated with the gene dosage effect. PMID:20842290

  2. Mechanism, Prevalence, and More Severe Neuropathy Phenotype of the Charcot-Marie-Tooth Type 1A Triplication

    PubMed Central

    Liu, Pengfei; Gelowani, Violet; Zhang, Feng; Drory, Vivian E.; Ben-Shachar, Shay; Roney, Erin; Medeiros, Adam C.; Moore, Rebecca J.; DiVincenzo, Christina; Burnette, William B.; Higgins, Joseph J.; Li, Jun; Orr-Urtreger, Avi; Lupski, James R.

    2014-01-01

    Copy-number variations cause genomic disorders. Triplications, unlike deletions and duplications, are poorly understood because of challenges in molecular identification, the choice of a proper model system for study, and awareness of their phenotypic consequences. We investigated the genomic disorder Charcot-Marie-Tooth disease type 1A (CMT1A), a dominant peripheral neuropathy caused by a 1.4 Mb recurrent duplication occurring by nonallelic homologous recombination. We identified CMT1A triplications in families in which the duplication segregates. The triplications arose de novo from maternally transmitted duplications and caused a more severe distal symmetric polyneuropathy phenotype. The recombination that generated the triplication occurred between sister chromatids on the duplication-bearing chromosome and could accompany gene conversions with the homologous chromosome. Diagnostic testing for CMT1A (n = 20,661 individuals) identified 13% (n = 2,752 individuals) with duplication and 0.024% (n = 5 individuals) with segmental tetrasomy, suggesting that triplications emerge from duplications at a rate as high as ∼1:550, which is more frequent than the rate of de novo duplication. We propose that individuals with duplications are predisposed to acquiring triplications and that the population prevalence of triplication is underascertained. PMID:24530202

  3. De Novo duplication in Charcot-Marie-Tooth Type 1A

    SciTech Connect

    Mandich, P.; Bellone, E.; Ajmar, F.

    1996-09-01

    We read with interest the paper on {open_quotes}Prevalence and Origin of De Novo Duplications in Charcot-Marie-Tooth Disease Type 1A: First Report of a De Novo Duplication with a Maternal Origin,{close_quotes}. They reported their experience with 10 sporadic cases of Charcot-Marie-Tooth type 1A (CMT1A) in which it was demonstrated that the disease had arisen as the result of a de novo duplication. They analyzed the de novo-duplication families by using microsatellite markers and identified the parental origin of the duplication in eight cases. In one family the duplication was of maternal origin, whereas in the remaining seven cases it was of paternal origin. The authors concluded that their report was the first evidence of a de novo duplication of maternal origin, suggesting that this is not a phenomenon associated solely with male meiosis. 7 refs.

  4. [Pathology of Charcot-Marie-Tooth Disease].

    PubMed

    Oka, Nobuyuki

    2016-01-01

    Although genetic testing is available, nerve biopsy is useful in selected patients for the diagnosis of Charcot-Marie-Tooth disease (CMT). These are sporadic cases of hereditary neuropathy, or familial cases in which genetic testing is negative. CMT is caused by mutations of various genes. The pathological features of CMT have mostly been investigated using nerve biopsy, which may shed light on the presumed functions of mutated gene products. PMP22 duplication in CMT1A induces numerous large onion bulb lesions (OB). Compared to chronic inflammatory demyelinating polyradiculoneuropathy, the differential features of CMT1A are patchy distribution of OB and non-inflammatory lesions. CMT1B also manifests as OB, but presents abnormal compaction of myelin sheaths caused by uncompacted myelin or excessive myelin folding. CMT2 includes axonal neuropathies and many causative genes have been found. CMT2A (MFN2 mutation) shows abnormal mitochondria with a spherical morphology instead of tubular in the longitudinal direction. CMT4 consists of autosomal recessive forms with demyelinating pathology. Most subtypes have mutations of genes relating to myelin maintenance, and pathologically, they show abnormal folding of the myelin structure. PMID:26764296

  5. Mutation analysis of PMP22 in Slovak patients with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies.

    PubMed

    Resko, Peter; Radvansky, Jan; Odnogova, Zuzana; Baldovic, Marian; Minarik, Gabriel; Polakova, Helena; Palffy, Roland; Kadasi, Ludevit

    2011-12-01

    Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies are the most commonly inherited neurological disorders in humans, characterized by clinical and genetic heterogeneity. The most prevalent clinical entities belonging to this group of disorders are CMT type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). CMT1A and HNPP are predominantly caused by a 1.5 Mb duplication and deletion in the chromosomal region 17p11.2, respectively, and less frequently by other mutations in the peripheral myelin protein 22 (PMP22) gene. Despite being relatively common diseases, they haven't been previously studied in the Slovak population. Therefore, the aim of this study was to identify the spectrum and frequency of PMP22 mutations in the Slovak population by screening 119 families with CMT and 2 families with HNPP for causative mutations in this gene. The copy number determination of PMP22 resulted in the detection of CMT1A duplication in 40 families and the detection of HNPP deletion in 7 families, 6 of which were originally diagnosed as CMT. Consequent mutation screening of families without duplication or deletion using dHPLC and sequencing identified 6 single base changes (3 unpublished to date), from which only c.327C>A (Cys109X) present in one family was provably causative. These results confirm the leading role of PMP22 mutation analysis in the differential diagnosis of CMT and show that the spectrum and frequency of PMP22 mutations in the Slovak population is comparable to that seen in the global population. PMID:22131320

  6. Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update.

    PubMed

    Tazir, Meriem; Hamadouche, Tarik; Nouioua, Sonia; Mathis, Stephane; Vallat, Jean-Michel

    2014-12-15

    Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment. PMID:25454638

  7. Charcot-Marie-Tooth disease

    PubMed Central

    Manganelli, Fiore; Nolano, Maria; Pisciotta, Chiara; Provitera, Vincenzo; Fabrizi, Gian M.; Cavallaro, Tiziana; Stancanelli, Annamaria; Caporaso, Giuseppe; Shy, Michael E.

    2015-01-01

    Objective: To evaluate, by skin biopsy, dermal nerve fibers in 31 patients with 3 common Charcot-Marie-Tooth (CMT) genotypes (CMT1A, late-onset CMT1B, and CMTX1), and rarer forms of CMT caused by mutations in RAB7 (CMT2B), TRPV4 (CMT2C), and GDAP1 (AR-CMT2K) genes. Methods: We investigated axonal loss by quantifying Meissner corpuscles and intrapapillary myelinated endings and evaluated morphometric changes in myelinated dermal nerve fibers by measuring fiber caliber, internodal, and nodal gap length. Results: The density of both Meissner corpuscles and intrapapillary myelinated endings was reduced in skin samples from patients with CMT1A and all the other CMT genotypes. Nodal gaps were larger in all the CMT genotypes though widening was greater in CMT1A. Perhaps an altered communication between axons and glia may be a common feature for multiple forms of CMT. Internodal lengths were shorter in all the CMT genotypes, and patients with CMT1A had the shortest internodes of all our patients. The uniformly shortened internodes in all the CMT genotypes suggest that mutations in both myelin and axon genes may developmentally impede internode formation. The extent of internodal shortening and nodal gap widening are likely both important in determining nerve conduction velocities in CMT. Conclusions: This study extends the information gained from skin biopsies on morphologic abnormalities in various forms of CMT and provides insights into potential pathomechanisms of axonal and demyelinating CMT. PMID:26362287

  8. Calcium kinetics in glycogen storage disease type 1a.

    PubMed

    Goans, R E; Weiss, G H; Vieira, N E; Sidbury, J B; Abrams, S A; Yergey, A L

    1996-12-01

    Glycogen storage disease type 1a (Von Gierke's disease) is one of the more common glycogen storage diseases (GSD). GSD 1a patients can have severe idiopathic osteopenia, often beginning at a young age. Since calcium tracer studies offer a sensitive probe of the bone microenvironment and of calcium deposition, kinetics might be disturbed in patients with GSD 1a. Plasma dilution kinetics obtained using the stable isotope 42Ca are shown in this paper to be quite different between GSD 1a patients and age-matched controls. Comparison of kinetic parameters in these two populations is made using a new binding site model for describing calcium dynamics at the plasma-bone interface. This model describes reversible binding of calcium ions to postulated short-term and long-term sites by a retention probability density function psi (t). Using this analysis, adult GSD subjects exhibited a significant decrease (P = 0.023) in the apparent half-life of a calcium ion on the longer-term site compared with controls. The general theory of calcium tracer dilution kinetics is then discussed in terms of a new model of short-term calcium homeostasis recently proposed by Bronner and Stein [5]. PMID:8939770

  9. [Acute vincristine neurotoxicity in a non-Hodgkin's lymphoma patient with Charcot-Marie-Tooth disease].

    PubMed

    Uno, S; Katayama, K; Dobashi, N; Hirano, A; Ogihara, A; Yamazaki, H; Usui, N; Kobayashi, T; Inoue, K; Kuraishi, Y

    1999-05-01

    A 44-year-old, previously healthy man with a diagnosis of non-Hodgkin's lymphoma (NHL, diffuse large B-cell type, stage IIA) was treated with combination chemotherapy including vincristine (VCR). After receiving a cumulative dose of VCR, he experienced rapid and marked weakening which progressed to quadriplegia and bulbar palsy. Prior to this therapy, the patient had no neurological problems, and his siblings were asymptomatic. Physical examination identified pes cavus (hollow foot), and electrodiagnostic studies showed markedly slower nerve conduction velocity of myelinated fibers, with abundant "onion bulb" formations. Chromosomal analysis detected 17p11.2-12 duplication, thus yielding a diagnosis of Charcot-Marie-Tooth (CMT) 1A. CMT disease is a familial neuromuscular disorder, and the incidence is approximately 1 in 2,500. We concluded that if CMT disease is diagnosed, vincristine should be avoided due to the potential severity of neurotoxicity to small doses. PMID:10390891

  10. Biomarkers research in neuromuscular disease Charcot-Marie-Tooth.

    PubMed

    Seco-Cervera, Marta; Ibañez-Cabellos, Jose Santiago; Garcia-Gimenez, Jose Luis; Espinos, Carmen; Palau, Francesc; Pallardo, Federico V

    2014-10-01

    Charcot-Marie-Tooth disease (CMT) (ORPHA166) is the most frequent hereditary neuropathy. CMT is a heterogeneous group of disorders which, despite some variability in their clinical features, share the same general phenotype, usually characterized by wasting and weakness of distal limb muscles, decreased to absent deep tendon reflexes, distal sensory loss, and frequent skeletal deformities. Despite the clinical and molecular description of this disease in the last 20 years, there is no effective drug or advanced therapy available. Here we have pretend the identification of metabolic and oxidative stress biomarkers in plasmas from patients with duplication at PMP22 gene, the most frequent mutation causing CMT, and clinically characterized as CMT1A. The samples were collected in the neuropathy units from "La Fe" Hospital of Valencia, "Bellvitge" Hospital of Barcelona, "La Paz" Hospital of Madrid, and "Virgen del Rocío" Hospital of Sevilla. The metabolic biomarkers research was performed using 2D-DIGE analysis (Typhoon TRIO, GE) and DeCyder software (GE). Protein identification was made by mass spectrometry by MALDI-TOF-TOF (ABSciex) and liquid Chromatography analysis (ABSciex). The oxidative stress biomarkers research consisted in carbonylated proteins analysis by reaction with DNPH and Dot-blot. Total antioxidant capacity and GSSG/GSH ratio were analyzed with Antioxidant Assay kit (Cayman) and Glutathione Fluorescent detection Kit (Arbor Assays), respectively. Finally now we are performing the MDA levels by HPLC-UV. We found 8, 13 and 36 proteins with differential expression in mild, moderate and severely affected patients, respectively compared with their own matched controls. Also we found differences on oxidative stress parameters between de different groups analyzed. Our results suggest differences in the oxidative stress profile between the studied phenotypes in CMT1A patients. PMID:26461392

  11. Parkinson's disease and CYP1A2 activity

    PubMed Central

    Forsyth, J T; Grünewald, R A; Rostami-Hodjegan, A; Lennard, M S; Sagar, H J; Tucker, G T

    2000-01-01

    Aims MPTP, a neurotoxin which induces parkinsonism is partially metabolized by the enzyme CYP1A2. Smoking appears to protect against Parkinson's disease (PD) and cigarette smoke induces CYP1A2 activity. Thus, we investigated the hypothesis that idiopathic PD is associated with lower CYP1A2 activity using caffeine as a probe compound. Methods CYP1A2 activity was assessed using saliva paraxanthine (PX) to caffeine (CA) ratios. Caffeine half-life was also estimated from salivary concentrations of caffeine at 2 and 5 h post dose. 117 treated and 40 untreated patients with PD and 105 healthy control subjects were studied. Results PX/CA ratios were 0.57, 0.93 and 0.77 in treated patients, untreated patients and healthy control subjects, respectively, with no significant differences between study groups (95% CI: treated patients vs controls −0.24, 0.57; untreated patients vs controls −0.75, 0.35). However, patients with PD (treated or untreated) had caffeine half-lives shorter than that in controls (treated patients: 262 min, untreated patients: 244 min, controls: 345 min; 95% CI: controls vs treated patients 23, 143 (P = 0.003); controls vs untreated patients 19, 184 (P = 0.011)). Amongst the patients with PD, caffeine half-life was also inversely related to the age of onset of disease (P = 0.012); gender and concomitant drugs did not influence this significantly. Conclusions Based on PX/CA ratio, there was no evidence of decreased CYP1A2 activity in patients compared with control subjects. The observed decrease in the elimination half-life of caffeine in PD may be caused by increased CYP2E1 activity, an enzyme that also contributes to the metabolism of caffeine. The latter warrants further investigation. PMID:11012552

  12. [Therapy for Charcot-Marie-Tooth Disease: From the Standpoint of Neurologists].

    PubMed

    Nakagawa, Masanori

    2016-01-01

    To date, there is no approved pharmacologic treatment for any form of Charcot-Marie-Tooth disease (CMT). However, some clinical or preclinical trials for CMT1A have been undertaken, for example Neurotrophin-3, PXT3003, and neuregulin-1. Gene therapy for CMT1X, CMT2F and Giant axonal neuropathy using animal model or culture cells have been reported with some interesting results. Stem cell research for example iPS cells derived from patients with CMT2A or CMT2E, is being conducted to clarify the mechanism of CMT and find therapeutic clues. The development of new surrogate markers for clinical trials is also needed. Additionally, steps should be taken to improve the quality of life of patients with CMT, including pain control and life style enhancement. PMID:26764298

  13. Japanese neuropathy patients with peripheral myelin protein-22 gene aneuploidy

    SciTech Connect

    Lebo, R.V.; Li, L.Y.; Flandermeyer, R.R.

    1994-09-01

    Peripheral myelin protein (PMP-22) gene aneuploidy results in Charcot-Marie-Tooth disease Type 1A (CMT1A) and the Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) in Japanese patients as well as Caucasian Americans. Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, results when expression of one of at least seven genes is defective. CMT1A, about half of all CMT mutations, is usually associated with a duplication spanning the peripheral myelin protein-22 gene on distal chromosome band 17p11.2. Autosomal dominant HNPP (hereditary pressure and sensory neuropathy, HPSN) results from a deletion of the CMT1A gene region. Multicolor in situ hybridization with PMP-22 gene region probe characterized HNPP deletion reliably and detected all different size duplications reported previously. In summary, 72% of 28 Japanese CMT1 (HMSNI) patients tested had the CMT1A duplication, while none of the CMT2 (HMSNII) or CMT3 (HMSNIII) patients had a duplication. Three cases of HNPP were identified by deletion of the CMT1A gene region on chromosome 17p. HNPP and CMT1A have been reported to result simultaneously from the same unequal recombination event. The lower frequency of HNPP compared to CMT1A suggests that HNPP patients have a lower reproductive fitness than CMT1A patients. This result, along with a CMT1A duplication found in an Asian Indian family, demonstrates the broad geographic distribution and high frequency of PMP-22 gene aneuploidy.

  14. Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases

    PubMed Central

    Dethrage, Lindsey M.; Gore, John C.; Smith, Seth A.; Li, Jun

    2014-01-01

    Objective: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases. Methods: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n = 10), CMT type 2A (CMT2A, n = 3), hereditary neuropathy with liability to pressure palsies (n = 3), and healthy controls (n = 21). Additional patients without a genetically confirmed subtype (n = 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated. Results: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 ± 3.3 percent units) and CMT2A (31.5 ± 1.9 percent units) relative to controls (37.2 ± 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p = 0.01 for genetically confirmed patients only, p = 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels. Conclusions: MTR measurements may be a viable biomarker of proximal nerve pathology in patients with CMT. PMID:25253751

  15. Charcot-Marie-Tooth disease

    PubMed Central

    Sivera, Rafael; Vílchez, Juan Jesús; Martínez-Rubio, Dolores; Chumillas, María José; Vázquez, Juan Francisco; Muelas, Nuria; Bataller, Luis; Millán, José María; Palau, Fancesc; Espinós, Carmen

    2013-01-01

    Objectives: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area. Methods: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups. Results: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically. Conclusions: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region. PMID:24078732

  16. Charcot-Marie-Tooth 1A: A narrative review with clinical and anatomical perspectives.

    PubMed

    McGrath, M C

    2016-07-01

    Charcot-Marie-Tooth 1A (CMT1A) is regarded as the most common hereditary peripheral neurodegenerative disorder. This narrative review highlights perspectives around the historically well-established and characteristic anatomical manifestations of CMT1A seen in the feet, legs and hands, in addition to a clinical diagnosis that may be confirmed by electrophysiology, genetic or molecular markers together with the presence of a typical family history. A less well-known perspective is the potential for systemic manifestations and wider complication. The condition is characterised by a progressive clinical picture with unmistakable anatomical and neurological features that have been described since the late 19th century. There remains no cure although supportive, rehabilitative, and surgical regimes may provide helpful management or amelioration of symptoms. Most recently, the emergence of a pleotherapeutic approach suggests distinct promise. Future research focused on a detailed elucidation of the underlying molecular mechanisms underpinning myelin and axonal function may eventually hold the key to successful treatment of CMT1A. Genetic modification would potentially present a cure. Clin. Anat. 29:547-554, 2016. © 2015 Wiley Periodicals, Inc. PMID:26457477

  17. Myelin protein zero gene sequencing diagnoses Charcot-Marie-Tooth Type 1B disease

    SciTech Connect

    Su, Y.; Zhang, H.; Madrid, R.

    1994-09-01

    Charcot-Marie-Tooth disease (CMT), the most common genetic neuropathy, affects about 1 in 2600 people in Norway and is found worldwide. CMT Type 1 (CMT1) has slow nerve conduction with demyelinated Schwann cells. Autosomal dominant CMT Type 1B (CMT1B) results from mutations in the myelin protein zero gene which directs the synthesis of more than half of all Schwann cell protein. This gene was mapped to the chromosome 1q22-1q23.1 borderline by fluorescence in situ hybridization. The first 7 of 7 reported CMT1B mutations are unique. Thus the most effective means to identify CMT1B mutations in at-risk family members and fetuses is to sequence the entire coding sequence in dominant or sporadic CMT patients without the CMT1A duplication. Of the 19 primers used in 16 pars to uniquely amplify the entire MPZ coding sequence, 6 primer pairs were used to amplify and sequence the 6 exons. The DyeDeoxy Terminator cycle sequencing method used with four different color fluorescent lables was superior to manual sequencing because it sequences more bases unambiguously from extracted genomic DNA samples within 24 hours. This protocol was used to test 28 CMT and Dejerine-Sottas patients without CMT1A gene duplication. Sequencing MPZ gene-specific amplified fragments identified 9 polymorphic sites within the 6 exons that encode the 248 amino acid MPZ protein. The large number of major CMT1B mutations identified by single strand sequencing are being verified by reverse strand sequencing and when possible, by restriction enzyme analysis. This protocol can be used to distringuish CMT1B patients from othre CMT phenotypes and to determine the CMT1B status of relatives both presymptomatically and prenatally.

  18. ASK1: a new therapeutic target for kidney disease.

    PubMed

    Tesch, Greg H; Ma, Frank Y; Nikolic-Paterson, David J

    2016-08-01

    Stress-induced activation of p38 MAPK and JNK signaling is a feature of both acute and chronic kidney disease and is associated with disease progression. Inhibitors of p38 MAPK or JNK activation provide protection against inflammation and fibrosis in animal models of kidney disease; however, clinical trials of p38 MAPK and JNK inhibitors in other diseases (rheumatoid arthritis and pulmonary fibrosis) have been disappointing. Apoptosis signal-regulating kinase 1 (ASK1) acts as an upstream regulator for the activation of p38 MAPK and JNK in kidney disease. Mice lacking the Ask1 gene are healthy with normal homeostatic functions and are protected from acute kidney injury induced by ischemia-reperfusion and from renal interstitial fibrosis induced by ureteric obstruction. Recent studies have shown that a selective ASK1 inhibitor substantially reduced renal p38 MAPK activation and halted the progression of nephropathy in diabetic mice, and this has led to a current clinical trial of an ASK1 inhibitor in patients with stage 3 or 4 diabetic kidney disease. This review explores the rationale for targeting ASK1 in kidney disease and the therapeutic potential of ASK1 inhibitors based on current experimental evidence. PMID:27226108

  19. TRPV1: A Potential Drug Target for Treating Various Diseases

    PubMed Central

    Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, Vickram

    2014-01-01

    Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically. PMID:24861977

  20. Psychotropics regulate Skp1a, Aldh1a1, and Hspa8 transcription--potential to delay Parkinson's disease.

    PubMed

    Lauterbach, Edward C

    2013-01-10

    Recently, the genes p19 S-phase kinase-associated protein 1A (SKP1), huntingtin interacting protein-2 (UBE2K), aldehyde dehydrogenase family 1 subfamily A1 (ALDH1A1), 19 S proteasomal protein PSMC4, and heat shock 70-kDa protein 8 (HSPA8) have been found to predict the onset and progression of Parkinson's disease (PD). These findings prompted a review of the effects of commonly prescribed psychiatric medicines, drugs that are used in treating PD, on the expression of these genes. Findings in the published medical literature were reviewed and gene expression data in the Gene Expression Omnibus Profiles database were analyzed. The results indicate that fluoxetine upregulated the risk-attenuating genes Skp1a and Aldh1a1 and olanzapine downregulated risk-enhancing Hspa8 while also downregulating Aldh1a1. Less conclusive evidence suggested that fluoxetine might also downregulate Hspa8 and clozapine might downregulate risk-enhancing Ube2k, but that olanzapine might upregulate Ube2k. Together, the present findings suggest that these psychotropics may delay PD onset (fluoxetine, olanzapine, and perhaps clozapine) and progression (fluoxetine, clozapine, and perhaps olanzapine). These gene expression findings should be replicated by RT-PCR studies in humans and, if confirmed, these drugs should then be studied in animal models and PD patients. PMID:23046827

  1. The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator.

    PubMed

    Richard, Arianne C; Ferdinand, John R; Meylan, Françoise; Hayes, Erika T; Gabay, Odile; Siegel, Richard M

    2015-09-01

    Originally described in 2002 as a T cell-costimulatory cytokine, the tumor necrosis factor family member TNF-like factor 1A (TL1A), encoded by the TNFSF15 gene, has since been found to affect multiple cell lineages through its receptor, death receptor 3 (DR3, encoded by TNFRSF25) with distinct cell-type effects. Genetic deficiency or blockade of TL1A-DR3 has defined a number of disease states that depend on this cytokine-receptor pair, whereas excess TL1A leads to allergic gastrointestinal inflammation through stimulation of group 2 innate lymphoid cells. Noncoding variants in the TL1A locus are associated with susceptibility to inflammatory bowel disease and leprosy, predicting that the level of TL1A expression may influence host defense and the development of autoimmune and inflammatory diseases. PMID:26188076

  2. The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator

    PubMed Central

    Richard, Arianne C.; Ferdinand, John R.; Meylan, Françoise; Hayes, Erika T.; Gabay, Odile; Siegel, Richard M.

    2015-01-01

    Originally described in 2002 as a T cell-costimulatory cytokine, the tumor necrosis factor family member TNF-like factor 1A (TL1A), encoded by the TNFSF15 gene, has since been found to affect multiple cell lineages through its receptor, death receptor 3 (DR3, encoded by TNFRSF25) with distinct cell-type effects. Genetic deficiency or blockade of TL1A-DR3 has defined a number of disease states that depend on this cytokine-receptor pair, whereas excess TL1A leads to allergic gastrointestinal inflammation through stimulation of group 2 innate lymphoid cells. Noncoding variants in the TL1A locus are associated with susceptibility to inflammatory bowel disease and leprosy, predicting that the level of TL1A expression may influence host defense and the development of autoimmune and inflammatory diseases. PMID:26188076

  3. Neuromuscular Hip Dysplasia in Charcot-Marie-Tooth Disease Type 1A

    ERIC Educational Resources Information Center

    Bamford, Nigel S.; White, Klane K.; Robinett, Stephanie A.; Otto, Randolph K.; Gospe, Sidney M., Jr.

    2009-01-01

    Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting 36 in 100,000 people. CMT type 1A (hereditary motor and sensory neuropathy) is the most frequent form of this disease, affecting 60 to 80% of the CMT population, but its diagnosis may be delayed because of inconsistent clinical signs and…

  4. A putative disease-associated haplotype within the SCN1A gene in Dravet syndrome.

    PubMed

    Fendri-Kriaa, Nourhène; Boujilbene, Salma; Kammoun, Fatma; Mkaouar-Rebai, Emna; Ben Mahmoud, Afif; Hsairi, Ines; Rebai, Ahmed; Triki, Chahnez; Fakhfakh, Faiza

    2011-05-20

    Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is one of the most severe forms of childhood epilepsy. DS is caused by a mutation in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A). However, 25-30% of patients with DS are negative for the SCN1A mutation screening, suggesting that other molecular mechanisms may account for these disorders. Recently, the first case of DS caused by a mutation in the neuronal voltage-gated sodium-channel beta-subunit gene (SCN1B) was also reported. In this report we aim to make the molecular analysis of the SCN1A and SCN1B genes in two Tunisian patients affected with DS. The SCN1A and SCN1B genes were tested for mutations by direct sequencing. No mutation was revealed in the SCN1A and SCN1B genes by sequencing analyses. On the other hand, 11 known single nucleotide polymorphisms were identified in the SCN1A gene and composed a putative disease-associated haplotype in patients with DS phenotype. One of the two patients with putative disease-associated haplotype in SCN1A had also one known single nucleotide polymorphism in the SCN1B gene. The sequencing analyses of the SCN1A gene revealed the presence of a putative disease-associated haplotype in two patients affected with Dravet syndrome. PMID:21531204

  5. UGT1A1 variation and gallstone formation in sickle cell disease.

    PubMed

    Haverfield, Eden V; McKenzie, Colin A; Forrester, Terrence; Bouzekri, Nourdine; Harding, Rosalind; Serjeant, Graham; Walker, Thomas; Peto, Tim E A; Ward, Ryk; Weatherall, David J

    2005-02-01

    Pigment gallstones are a common clinical complication of sickle cell (SS) disease. Genetic variation in the promoter of uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) underlies Gilbert syndrome, a chronic form of unconjugated hyperbilirubinemia, and appears to be a risk factor for gallstone formation. We investigated the association between UGT1A1 (TA)(n) genotype, hyperbilirubinemia, and gallstones in a sample of Jamaicans with SS disease. Subjects were from the Jamaican Sickle Cell Cohort Study (cohort sample, n = 209) and the Sickle Cell Clinic at the University of the West Indies, Kingston, Jamaica (clinic sample, n = 357). The UGT1A1 (TA)(n) promoter region was sequenced in 541 SS disease subjects and 111 healthy controls (control sample). Indirect bilirubin levels for (TA)(7)/(TA)(7) and (TA)(7)/(TA)(8) genotypes were elevated compared with (TA)(6)/(TA)(6) (clinic sample, P < 10(-5); cohort sample, P < 10(-3)). The (TA)(7)/(TA)(7) genotype was also associated with symptomatic presentation and gallstones in the clinic sample (odds ratio [OR] = 11.3; P = 7.0 x 10(-4)) but not in the younger cohort sample. These unexpected findings indicate that the temporal evolution of symptomatic gallstones may involve factors other than the bilirubin level. Although further studies of the pathogenesis of gallstones in SS disease are required, the (TA)(7)/(TA)(7) genotype may be a risk factor for symptomatic gallstones in older people with SS disease. PMID:15388579

  6. Misdiagnosis as steatohepatitis in a family with mild glycogen storage disease type 1a.

    PubMed

    Shieh, Jeng-Jer; Lu, Yung-Hsiu; Huang, Shi-Wei; Huang, Yu-Hsiu; Sun, Chih-Hao; Chiou, Hong-Jen; Liu, Chinsu; Lo, Ming-Yu; Lin, Ching-Yuang; Niu, Dau-Ming

    2012-11-01

    The manifestations of glycogen storage disease type 1a (GSD 1a) are usually so prominent in childhood that it is readily diagnosed by pediatricians. However, a mild form of the disease may only become apparent during adolescence or adulthood. We observed a brother and sister with subtle manifestations of the disease, which was discovered after the brother's son was diagnosed with typical GSD 1a. The adult siblings never suffered from hypoglycemia, had normal fasting blood glucose and liver transaminases at the time of diagnosis, and were taller than average for Chinese. Their only notable disease manifestations were recurrent gouty arthritis associated with hyperuricemia and hyperlipidemia during adolescence. When diagnosed, the brother had multiple benign and malignant hepatic tumors, and died of fulminant metastatic hepatocellular carcinoma 6 months after liver transplantation. p.M121V/p.R83H and p.M121V/p.M121V genotypic constellations of the G6PC gene were identified in this family. Both siblings were homozygous for the newly identified p.M121V mutation. The infant had compound heterozygous mutations, p.R83H and p.M121V. We recommend that mild GSD should be considered in the adolescents with unexplained hyperuricemia and hyperlipidemia, despite the presence of normal blood glucose levels. This report also reminds us that hepatocellular carcinoma could develop even in very mild GSD 1a patients. PMID:22909800

  7. Plasma DYRK1A as a novel risk factor for Alzheimer's disease.

    PubMed

    Janel, N; Sarazin, M; Corlier, F; Corne, H; de Souza, L C; Hamelin, L; Aka, A; Lagarde, J; Blehaut, H; Hindié, V; Rain, J-C; Arbones, M L; Dubois, B; Potier, M C; Bottlaender, M; Delabar, J M

    2014-01-01

    To determine whether apparent involvement of DYRK1A in Alzheimer's disease (AD) pathology makes it a candidate plasma biomarker for diagnosis, we developed a method to quantify plasma DYRK1A by immunoblot in transgenic mouse models having different gene dosages of Dyrk1a, and, consequently, different relative protein expression. Then, we measured plasma DYRK1A levels in 26 patients with biologically confirmed AD and 25 controls (negative amyloid imaging available on 13). DYRK1A was detected in transgenic mouse brain and plasma samples, and relative levels of DYRK1A correlated with the gene copy number. In plasma from AD patients, DYRK1A levels were significantly lower compared with controls (P<0.0001). Results were similar when we compared AD patients with the subgroup of controls confirmed by negative amyloid imaging. In a subgroup of patients with early AD (CDR=0.5), lower DYRK1A expression was confirmed. In contrast, no difference was found in levels of DYRK1B, the closest relative of DYRK1A, between AD patients and controls. Further, AD patients exhibited a positive correlation between plasma DYRK1A levels and cerebrospinal fluid tau and phosphorylated-tau proteins, but no correlation with amyloid-β42 levels and Pittsburgh compound B cortical binding. DYRK1A levels detected in lymphoblastoid cell lines from AD patients were also lower when compared with cells from age-matched controls. These findings suggest that reduced DYRK1A expression might be a novel plasma risk factor for AD. PMID:25116835

  8. Patient Identification of the Symptomatic Impact of Charcot Marie Tooth Disease Type 1A

    PubMed Central

    Johnson, Nicholas E; Heatwole, Chad R.; Ferguson, Michele; Sowden, Janet E.; Jeanat, Shanie; Herrmann, David N.

    2013-01-01

    Objective The burden of Charcot Marie Tooth type 1A, the most common inherited peripheral neuropathy, including impact on patient quality of life is not well understood. This study aims to qualitatively describe the range of symptoms associated with Charcot Marie Tooth type 1A and impact on quality of life. Methods We performed qualitative interviews with 16 adult Charcot Marie Tooth type 1A patients. Each interview was analyzed using a qualitative framework technique to identify and index symptoms by theme. Results Sixteen patients provided 656 quotes. One hundred and forty-five symptoms of importance were identified representing 20 symptomatic themes. Symptoms associated with difficulty with mobility and ambulation, specific activity impairment, and emotional distress were the most frequently mentioned. Conclusions Multiple symptoms contribute to Charcot Marie Tooth type 1A disease burden, some previously under-recognized. Improved recognition of under-recognized symptoms will optimize patient care and quality of life. PMID:23965405

  9. Detection of copy number variation by SNP-allelotyping.

    PubMed

    Parker, Brett; Alexander, Ryan; Wu, Xingyao; Feely, Shawna; Shy, Michael; Schnetz-Boutaud, Nathalie; Li, Jun

    2015-03-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by an abnormal copy number variation (CNV) with a trisomy of chromosome 17p12. The increase of the DNA-segment copy number is expected to alter the allele frequency of single nucleotide polymorphism (SNP) within the duplicated region. We tested whether SNP allele frequency determined by a Sequenom MassArray can be used to detect the CMT1A mutation. Our results revealed distinct patterns of SNP allele frequency distribution, which reliably differentiated CMT1A patients from controls. This finding suggests that this technique may serve as an alternative approach to identifying CNV in certain diseases, including CMT1A. PMID:24830919

  10. Occurrence of Optic Neuritis and Cervical Cord Schwannoma with Charcot-Marie-Tooth Type 4B1 Disease

    PubMed Central

    Scott, Patrick; Bruwer, Zandre; Al-Kharusi, Khalsa; Meftah, Douja; Al-Murshedi, Fathiya

    2016-01-01

    Charcot-Marie-Tooth neuropathy type 4B1 (CMT4B1) disease is a rare subtype of CMT4 with reported association of facial weakness, vocal cord paresis, chest deformities, and claw hands. We report the unusual occurrence of optic neuritis and cervical cord schwannoma in a male individual with confirmed CMT4B1 disease. Sequencing of the MTMR2 gene revealed a novel nonsense homozygous mutation c.1768C>T (p.Gln590*). The mutation was identified in affected relatives of the proband and a second, apparently unrelated, family. The rare association of optic neuritis or schwannoma with genetically confirmed CMT1A has been individually observed, but never with recessive CMT. To the best of our knowledge, the occurrence of optic neuritis and cervical cord schwannoma in the same patient has never been reported with any form of CMT including CMT4B1. In similar cases, we recommend immediate medical attention to rule out the possibility of schwannomas in patients with all demyelinating CMT subtypes in case of the development of focal neurological signs or acute worsening of clinical status. PMID:27162595

  11. Cleaving for growth: threonine aspartase 1-a protease relevant for development and disease.

    PubMed

    Stauber, Roland H; Hahlbrock, Angelina; Knauer, Shirley K; Wünsch, Désirée

    2016-03-01

    From the beginning of life, proteases are key to organismal development comprising morphogenesis, cellular differentiation, and cell growth. Regulated proteolytic activity is essential for the orchestration of multiple developmental pathways, and defects in protease activity can account for multiple disease patterns. The highly conserved protease threonine aspartase 1 is a member of such developmental proteases and critically involved in the regulation of complex processes, including segmental identity, head morphogenesis, spermatogenesis, and proliferation. Additionally, threonine aspartase 1 is overexpressed in numerous liquid as well as in solid malignancies. Although threonine aspartase 1 is able to cleave the master regulator mixed lineage leukemia protein as well as other regulatory proteins in humans, our knowledge of its detailed pathobiological function and the underlying molecular mechanisms contributing to development and disease is still incomplete. Moreover, neither effective genetic nor chemical inhibitors for this enzyme are available so far precluding the detailed dissection of the pathobiological functions of threonine aspartase 1. Here, we review the current knowledge of the structure-function relationship of threonine aspartase 1 and its mechanistic impact on substrate-mediated coordination of the cell cycle and development. We discuss threonine aspartase 1-mediated effects on cellular transformation and conclude by presenting a short overview of recent interference strategies.-Stauber, R. H., Hahlbrock, A., Knauer, S. K., Wünsch, D. Cleaving for growth: threonine aspartase 1-a protease relevant for development and disease. PMID:26578689

  12. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

    PubMed Central

    May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M. Arfan; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G.; Cilio, Maria Roberta; Kunz, Wolfram S.; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R.; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A.

    2016-01-01

    Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10−4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions. PMID:26990884

  13. The influence of somatosensory and muscular deficits on postural stabilization: Insights from an instrumented analysis of subjects affected by different types of Charcot–Marie–Tooth disease

    PubMed Central

    Lencioni, Tiziana; Piscosquito, Giuseppe; Rabuffetti, Marco; Bovi, Gabriele; Calabrese, Daniela; Aiello, Alessia; Di Sipio, Enrica; Padua, Luca; Diverio, Manuela; Pareyson, Davide; Ferrarin, Maurizio

    2015-01-01

    Charcot–Marie–Tooth (CMT) disease is the most common hereditary neuromuscular disorder. CMT1 is primarily demyelinating, CMT2 is primarily axonal, and CMTX1 is characterized by both axonal and demyelinating abnormalities. We investigated the role of somatosensory and muscular deficits on quiet standing and postural stabilization in patients affected by different forms of CMT, comparing their performances with those of healthy subjects. Seventy-six CMT subjects (CMT1A, CMT2 and CMTX1) and 41 healthy controls were evaluated during a sit-to-stand transition and the subsequent quiet upright posture by means of a dynamometric platform. All CMT patients showed altered balance and postural stabilization compared to controls. Multivariate analysis showed that in CMT patients worsening of postural stabilization was related to vibration sense deficit and to dorsi-flexor's weakness, while quiet standing instability was related to the reduction of pinprick sensibility and to plantar-flexor's weakness. Our results show that specific sensory and muscular deficits play different roles in balance impairment of CMT patients, both during postural stabilization and in static posture. An accurate evaluation of residual sensory and muscular functions is therefore necessary to plan for the appropriate balance rehabilitation treatment for each patient, besides the CMT type. PMID:26028275

  14. The influence of somatosensory and muscular deficits on postural stabilization: Insights from an instrumented analysis of subjects affected by different types of Charcot-Marie-Tooth disease.

    PubMed

    Lencioni, Tiziana; Piscosquito, Giuseppe; Rabuffetti, Marco; Bovi, Gabriele; Calabrese, Daniela; Aiello, Alessia; Di Sipio, Enrica; Padua, Luca; Diverio, Manuela; Pareyson, Davide; Ferrarin, Maurizio

    2015-08-01

    Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder. CMT1 is primarily demyelinating, CMT2 is primarily axonal, and CMTX1 is characterized by both axonal and demyelinating abnormalities. We investigated the role of somatosensory and muscular deficits on quiet standing and postural stabilization in patients affected by different forms of CMT, comparing their performances with those of healthy subjects. Seventy-six CMT subjects (CMT1A, CMT2 and CMTX1) and 41 healthy controls were evaluated during a sit-to-stand transition and the subsequent quiet upright posture by means of a dynamometric platform. All CMT patients showed altered balance and postural stabilization compared to controls. Multivariate analysis showed that in CMT patients worsening of postural stabilization was related to vibration sense deficit and to dorsi-flexor's weakness, while quiet standing instability was related to the reduction of pinprick sensibility and to plantar-flexor's weakness. Our results show that specific sensory and muscular deficits play different roles in balance impairment of CMT patients, both during postural stabilization and in static posture. An accurate evaluation of residual sensory and muscular functions is therefore necessary to plan for the appropriate balance rehabilitation treatment for each patient, besides the CMT type. PMID:26028275

  15. Adjunctive treatment with oral AKL1, a botanical nutraceutical, in chronic obstructive pulmonary disease

    PubMed Central

    Brockwell, Claire; Ampikaipakan, Sundari; Sexton, Darren W; Price, David; Freeman, Daryl; Thomas, Mike; Ali, Muzammil; Wilson, Andrew M

    2014-01-01

    Purpose The objective of this pilot trial was to evaluate the safety and efficacy of AKL1, a patented botanical formulation containing extracts of Picrorhiza kurroa, Ginkgo biloba, and Zingiber officinale, as add-on therapy for patients with chronic obstructive pulmonary disease (COPD) and chronic cough. Patients and methods This randomized, double-blind, placebo-controlled trial enrolled male and female patients >18 years old with COPD and Leicester Cough Questionnaire (LCQ) score of <18. The 10-week study period comprised a 2-week single-blind placebo run-in period followed by add-on treatment with AKL1 or placebo twice daily for 8 weeks. The primary study endpoint was the change from week 0 to week 8 in cough-related health status, as assessed by the LCQ. Results Of 33 patients enrolled, 20 were randomized to AKL1 and 13 to placebo. Patients included 19 (58%) men and 14 (42%) women of mean (standard deviation [SD]) age of 67 (9.4) years; 15 (45%) patients were smokers and 16 (49%) were ex-smokers. The mean (SD) change from baseline in LCQ score at 8 weeks was 2.3 (4.9) in the AKL1 group and 0.6 (3.7) in the placebo group, with mean difference in change of 1.8 (95% confidence interval: −1.5 to 5.1; P=0.28). The St George’s Respiratory Questionnaire score improved substantially in the AKL1 treatment group by a mean (SD) of −7.7 (11.7) versus worsening in the placebo group (+1.5 [9.3]), with mean difference in change of −9.2 (95% confidence interval: −19.0 to 0.6; P=0.064). There were no significant differences between treatment groups in change from baseline to week 8 in other patient-reported measures, lung function, or the 6-minute walk distance. Conclusion Further study is needed with a larger patient population and over a longer duration to better assess the effects of add-on therapy with AKL1 in COPD. PMID:25031533

  16. Microbial Induction of Inflammatory Bowel Disease Associated Gene TL1A (TNFSF15) in Antigen Presenting Cells

    PubMed Central

    Shih, David Q.; Kwan, Lola Y.; Chavez, Valerie; Cohavy, Offer; Gonsky, Rivkah; Chang, Elmer Y.; Chang, Christopher; Elson, Charles O.; Targan, Stephan R.

    2010-01-01

    Summary TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease (IBD) patients. Neutralizing anti-mouse TL1A Ab attenuates chronic colitis in two T cell driven murine models, suggesting that TL1A is a central modulator of gut mucosal inflammation in IBD. We showed previously that TL1A is induced by immune complexes (IC) via the FcγR signaling pathway. In this study, we report that multiple bacteria, including gram negative organisms (E. coli, E. coli Nissle 1917, S. typhimurium), gram positive organisms (L. monocytogenes, S. epidermidis), partial anaerobes (C. jejuni), and obligate anaerobes (B. thetaiotaomicron, B. breve, Clostridium A4) activate TL1A expression in human APC, including monocytes and monocyte-derived DC. Bacterially induced TL1A mRNA expression correlates with the detection of TL1A protein levels. TL1A induced by bacteria is mediated in part by the TLR signaling pathway and inhibited by downstream blockade of p38 MAPK and NF-κB activation. Microbial induction of TL1A production by human APC potentiated CD4+ T cell effector function by augmenting IFN-γ production. Our findings suggest a role for TL1A in pro-inflammatory APC-T cell interactions and implicate TL1A in host responses to enteric microorganisms. PMID:19839006

  17. UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia.

    PubMed

    Carpenter, Shannon L; Lieff, Susan; Howard, Thad A; Eggleston, Barry; Ware, Russell E

    2008-10-01

    Genetic modifiers contribute to phenotypic variability in patients with sickle cell anemia (SCA). The influence of the bilirubin UDP-glucuronosyltransferase (UGT) 1A1 (TA)(n)TAA promoter polymorphism on bilirubin levels and gallbladder disease in SCA was examined using prospectively collected data from the Cooperative Study of Sickle Cell Disease. A total of 324 children with HbSS (median age 6.9 years) had UGT1A1 genotyping; 243 (75%) had common (TA)(6) or (TA)(7) alleles, whereas 81 (25.0%) had variant (TA)(5) or (TA)(8) alleles. The UGT1A1 genotype significantly influenced average bilirubin levels for the common alleles: 6/6 genotype = 2.36 +/- 1.13 mg/dL, 6/7 genotype = 2.90 +/- 1.54 mg/dL, and 7/7 genotype = 4.24 +/- 2.11 mg/dL (P < 0.0001). Thirty-nine percent of children with the 7/7 genotype had documented gallbladder disease, compared with 18.2% with the 6/7 genotype and only 9.9% with the wildtype 6/6 UGT1A1 genotype (P = 0.001). To analyze the (TA)(5) and (TA)(8) variant alleles, three groups were generated, showing increasing bilirubin levels with increasing TA repeats and age. Group 3 (genotypes 6/8, 7/7, and 7/8) had a significantly greater rate of bilirubin change than Groups 1 (genotypes 5/6, 5/7, and 6/6) or 2 (genotype 6/7). These results validate previous smaller studies and confirm that the UGT1A1 promoter polymorphism exerts a powerful influence on bilirubin levels and the development of gallbladder disease in children with SCA. UGT1A1 genotyping should be considered as a screening tool for predicting children most likely to develop gallbladder disease at a young age. PMID:18756540

  18. ATG16L1: A multifunctional susceptibility factor in Crohn disease

    PubMed Central

    Salem, Mohammad; Ammitzboell, Mette; Nys, Kris; Seidelin, Jakob Benedict; Nielsen, Ole Haagen

    2015-01-01

    Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease. PMID:25906181

  19. Pathologic studies of the osteoporosis of Von Gierke's disease (glycogenosis 1a).

    PubMed

    Soejima, K; Landing, B H; Roe, T F; Swanson, V L

    1985-01-01

    Pathologic and point count-morphometric studies of ribs, vertebrae, and iliac crests of 7 patients with Von Gierke's glycogenesis type Ia aged 5 months to 30 years were performed. The bone lesion is a pure osteoporosis (reduction in mass of bone matrix) with no evidences of significant physeal cartilage abnormality or of osteitis fibrosa or osteomalacia (reduced mineralization of bone matrix). The osteoporosis was already marked in the youngest patient studied (5 months). The discrepancy between normal and glycogen storage disease (GSD) bones increased progressively with age for ribs and was less severe for vertebrae. Available biochemical data give no indication of primary disturbance of calcium or phosphate metabolism, of parathyroid activity, or of vitamin D metabolism. Clinical data suggest that the osteoporosis of Von Gierke's disease is due to hypoglycemia or a metabolic sequela thereof, such as insulinopenia, but pathologic study of patients treated by newer techniques of maintaining euglycemia in GSD is needed. PMID:3867867

  20. Do Positive Psychosocial Factors Predict Disease Progression in HIV-1? A Review of the Evidence

    PubMed Central

    Ironson, Gail H.; Hayward, H’sien

    2008-01-01

    Adding to a traditional stress perspective, behavioral medicine has been focusing increasingly on investigating the potential impact of positive psychosocial factors on disease course in HIV. Dispositional optimism, active coping, and spirituality show the most evidence for predicting slower disease progression, although the data are not entirely consistent. Findings for the role of social support are mixed, although indications are that it may be particularly helpful at later stages of illness. Many of the other constructs (positive affect, finding meaning, emotional expression/processing, openness, extraversion, conscientiousness, altruism, and self-efficacy) have only been examined in one or two studies; results are preliminary but suggestive of protective effects. Plausible behavioral and biological mechanisms are discussed (including health behaviors, neurohormones, and immune measures) as well as suggestions for clinicians, limitations, future directions, and a discussion of whether these constructs can be changed. In conclusion, investigating the importance and usefulness of positive psychosocial factors in predicting disease progression in HIV is in its beginning scientific stages and shows good initial evidence and future promise. PMID:18541905

  1. Human PON1, a biomarker of risk of disease and exposure.

    PubMed

    Furlong, C E; Suzuki, S M; Stevens, R C; Marsillach, J; Richter, R J; Jarvik, G P; Checkoway, H; Samii, A; Costa, L G; Griffith, A; Roberts, J W; Yearout, D; Zabetian, C P

    2010-09-01

    Human paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme that exhibits a broad substrate specificity. In addition to protecting against exposure to some organophosphorus (OP) pesticides by hydrolyzing their toxic oxon metabolites, PON1 is important in protecting against vascular disease by metabolizing oxidized lipids. Recently, PON1 has also been shown to play a role in inactivating the quorum sensing factor N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) of Pseudomonas aeruginosa. Native, untagged engineered recombinant human PON1 (rHuPON1) expressed in Escherichia coli and purified by conventional column chromatographic purification is stable, active, and capable of protecting PON1 knockout mice (PON1(-/-)) from exposure to high levels of the OP compound diazoxon. The bacterially derived rHuPON1 can be produced in large quantities and lacks the glycosylation of eukaryotic systems that can produce immunogenic complications when inappropriately glycosylated recombinant proteins are used as therapeutics. Previous studies have shown that the determination of PON1 status, which reveals both PON1(192) functional genotype and serum enzyme activity level, is required for a meaningful evaluation of PON1's role in risk of disease or exposure. We have developed a new two-substrate assay/analysis protocol that provides PON1 status without use of toxic OP substrates, allowing for use of this protocol in non-specialized laboratories. Factors were also determined for inter-converting rates of hydrolysis of different substrates. PON1 status also plays an important role in revealing changes in HDL-associated PON1 activities in male patients with Parkinson disease (PD). Immunolocalization studies of PONs 1, 2 and 3 in nearly all mouse tissues suggest that the functions of PONs 1 and 3 extend beyond the plasma and the HDL particle. PMID:20338154

  2. Glycogen Storage Disease type 1a – a secondary cause for hyperlipidemia: report of five cases

    PubMed Central

    2013-01-01

    Background and aims Glycogen storage disease type Ia (GSD Ia) is a rare metabolic disorder, caused by deficient activity of glucose-6-phosphatase-α. It produces fasting induced hypoglycemia and hepatomegaly, usually manifested in the first semester of life. Besides, it is also associated with growth delay, anemia, platelet dysfunction, osteopenia and sometimes osteoporosis. Hyperlipidemia and hyperuricemia are almost always present and hepatocellular adenomas and renal dysfunction frequent late complications. Methods The authors present a report of five adult patients with GSD Ia followed in internal medicine appointments and subspecialties. Results Four out of five patients were diagnosed in the first 6 months of life, while the other one was diagnosed in adult life after the discovery of hepatocellular adenomas. In two cases genetic tests were performed, being identified the missense mutation R83C in one, and the mutation IVS4-3C > G in the intron 4 of glucose-6-phosphatase gene, not previously described, in the other. Growth retardation was present in 3 patients, and all of them had anemia, increased bleeding tendency and hepatocellular adenomas; osteopenia/osteoporosis was present in three cases. All but one patient had marked hyperlipidemia and hyperuricemia, with evidence of endothelial dysfunction in one case and of brain damage with refractory epilepsy in another case. Proteinuria was present in two cases and end-stage renal disease in another case. There was a great variability in the dietary measures; in one case, liver transplantation was performed, with correction of the metabolic derangements. Conclusions Hyperlipidemia is almost always present and only partially responds to dietary and drug therapy; liver transplantation is the only definitive solution. Although its association with premature atherosclerosis is rare, there have been reports of endothelial dysfunction, raising the possibility for increased cardiovascular risk in this group of

  3. SORLA/SORL1, a neuronal sorting receptor implicated in Alzheimer's disease.

    PubMed

    Willnow, Thomas E; Carlo, Anne-Sophie; Rohe, Michael; Schmidt, Vanessa

    2010-01-01

    The proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid-beta peptides in the brain has been recognized as a major pathological pathway in Alzheimer's disease (AD). Yet, the factors that control the processing of APP and their potential contribution to the common sporadic form of AD remain poorly understood. Here, we review recent findings from studies in patients and in animal models that led to the identification of a unique sorting receptor for APP in neurons, designated SORLA/SORL1, that emerges as a key player in amyloidogenic processing and as major genetic risk factor for AD. PMID:21086763

  4. Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.

    PubMed

    Cougnoux, A; Cluzeau, C; Mitra, S; Li, R; Williams, I; Burkert, K; Xu, X; Wassif, C A; Zheng, W; Porter, F D

    2016-01-01

    Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID:26986514

  5. Necroptosis in Niemann–Pick disease, type C1: a potential therapeutic target

    PubMed Central

    Cougnoux, A; Cluzeau, C; Mitra, S; Li, R; Williams, I; Burkert, K; Xu, X; Wassif, C A; Zheng, W; Porter, F D

    2016-01-01

    Niemann–Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID:26986514

  6. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a

    SciTech Connect

    Chou, J.Y.; Lei, K.J.; Shelly, L.L.

    1994-09-01

    Glycogen storage disease (GSD) type la (von Gierke disease) is caused by the deficiency of glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. The disease presents with clinical manifestations of severe hypoglycemia, hepatomegaly, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. We have succeeded in isolating a murine G6Pase cDNA from a normal mouse liver cDNA library by differentially screening method. We then isolated the human G6Pase cDNA and gene. To date, we have characterized the G6Pase genes of twelve GSD type la patients and uncovered a total of six different mutations. The mutations are comprised of R83C (an Arg at codon 83 to a Cys), Q347X (a Gly at codon 347 to a stop codon), 459insTA (a two basepair insertion at nucleotide 459 yielding a truncated G6Pase of 129 residues), R295C (an Arg at codon 295 to a Cys), G222R (a Gly at codon 222 to an Arg) and {delta}F327 (a codon deletion for Phe-327 at nucleotides 1058 to 1060). The relative incidences of these mutations are 37.5% (R83C), 33.3% (Q347X), 16.6% (459insTA), 4.2% (G222R), 4.2% (R295C) and 4.2% ({delta}F327). Site-directed mutagenesis and transient expression assays demonstrated that the R83C, Q347X, R295C, and {delta}F327 mutations abolished whereas the G222R mutation greatly reduced G6Pase activity. We further characterized the structure-function requirements of amino acids 83, 222, and 295 in G6Pase catalysis. The identification of mutations in GSD type la patients has unequivocally established the molecular basis of the type la disorder. Knowledge of the mutations may be applied to prenatal diagnosis and opens the way for developing and evaluating new therapeutic approaches.

  7. Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

    PubMed Central

    Miyazaki, Ikuko; Asanuma, Masato

    2016-01-01

    Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson’s disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration. PMID:26795196

  8. Hypoxia-Inducible Factor-1 (HIF-1): A Potential Target for Intervention in Ocular Neovascular Diseases

    PubMed Central

    Vadlapatla, Ramya Krishna; Vadlapudi, Aswani Dutt; Mitra, Ashim K.

    2015-01-01

    Constant oxygen supply is essential for proper tissue development, homeostasis and function of all eukaryotic organisms. Cellular response to reduced oxygen levels is mediated by the transcriptional regulator hypoxia-inducible factor-1 (HIF-1). It is a heterodimeric complex protein consisting of an oxygen dependent subunit (HIF-1α) and a constitutively expressed nuclear subunit (HIF-1β). In normoxic conditions, de novo synthesized cytoplasmic HIF-1α is degraded by 26S proteasome. Under hypoxic conditions, HIF-1α is stabilized, binds with HIF-1β and activates transcription of various target genes. These genes play a key role in regulating angiogenesis, cell survival, proliferation, chemotherapy, radiation resistance, invasion, metastasis, genetic instability, immortalization, immune evasion, metabolism and stem cell maintenance. This review highlights the importance of hypoxia signaling in development and progression of various vision threatening pathologies such as diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration and glaucoma. Further, various inhibitors of HIF-1 pathway that may have a viable potential in the treatment of oxygen-dependent ocular diseases are also discussed. PMID:23701276

  9. Sickle cell disease increases high mobility group box 1: a novel mechanism of inflammation

    PubMed Central

    Xu, Hao; Wandersee, Nancy J.; Guo, YiHe; Jones, Deron W.; Holzhauer, Sandra L.; Hanson, Madelyn S.; Machogu, Evans; Brousseau, David C.; Hogg, Neil; Densmore, John C.; Kaul, Sushma; Hillery, Cheryl A.

    2014-01-01

    High mobility group box 1 (HMGB1) is a chromatin-binding protein that maintains DNA structure. On cellular activation or injury, HMGB1 is released from activated immune cells or necrotic tissues and acts as a damage-associated molecular pattern to activate Toll-like receptor 4 (TLR4). Little is known concerning HMGB1 release and TLR4 activity and their role in the pathology of inflammation of sickle cell disease (SCD). Circulating HMGB1 levels were increased in both humans and mice with SCD compared with controls. Furthermore, sickle plasma increased HMGB1-dependent TLR4 activity compared with control plasma. HMGB1 levels were further increased during acute sickling events (vasoocclusive crises in humans or hypoxia/reoxygenation injury in mice). Anti-HMGB1 neutralizing antibodies reduced the majority of sickle plasma-induced TLR4 activity both in vitro and in vivo. These findings show that HMGB1 is the major TLR4 ligand in SCD and likely plays a critical role in SCD-mediated inflammation. PMID:25339362

  10. Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease

    PubMed Central

    Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D.; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

    2009-01-01

    Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance. PMID:19320048

  11. DYRK1A genetic variants are not linked to Alzheimer's disease in a Spanish case-control cohort

    PubMed Central

    2009-01-01

    Background As dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. Methods We examined genetic variations of DYRK1A by genotyping haplotype tagging SNPs (htSNPs) (rs11701483, rs2835740, rs1137600, rs2835761, rs2835762, rs2154545 and rs8132976) in a group of 634 Spanish AD cases and 733 controls. Results There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE ε4 allele. Conclusion Our negative findings in the Spanish population argue against the hypothesis that DYRK1A genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between DYRK1A gene and AD risk in the Japanese population exists. PMID:19995442

  12. Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism.

    PubMed

    Martins, Rute; Morais, Anabela; Dias, Alexandra; Soares, Isabel; Rolão, Cristiana; Ducla-Soares, J L; Braga, Lígia; Seixas, Teresa; Nunes, Baltazar; Olim, Gabriel; Romão, Luísa; Lavinha, João; Faustino, Paula

    2008-01-01

    Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA)n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in a group of 153 young SCD patients (mean age 12.0 +/- 9.0 years) predominantly of Bantu beta S haplotype. The concomitant effect of alpha thalassaemia was also analysed. Among the several UGT1A1 genotypes found, the most frequent were the (TA)6/(TA)6 (n = 37), (TA)6/(TA)7 (n = 60) and (TA)7/(TA)7 (n = 29). These groups of patients did not significantly differ in age, gender ratio and haemoglobin, foetal haemoglobin and reticulocyte levels. On the other hand, total bilirubin levels were significantly different between groups, with an increased (TA) repeat number being associated with higher bilirubinaemia. Furthermore, both cholelithiasis and cholecystectomy were more frequent in groups with higher (TA) repeat number, although the former association was not statistically significant. None of the mentioned parameters is statistically different within UGT1A1 groups with the presence of alpha thalassaemia. Thus, the UGT1A1 promoter polymorphism may represent an important nonglobin genetic modifier of Bantu SCD patients' clinical manifestations, even at a young age. PMID:18392554

  13. Detection of tandam duplications and implications for linkage analysis

    SciTech Connect

    Matise, T.C.; Weeks, D.E. ); Chakravarti, A. ); Patel, P.I.; Lupski, J.R. ); Nelis, E.; Timmerman, V.; Van Broeckhoven, C. )

    1994-06-01

    The first demonstration of an autosomal dominant human disease caused by segmental trisomy came in 1991 for Charcot-Marie-Tooth disease type 1A (CMT1A). For this disorder, the segmental trisomy is due to a large tandem duplication of 1.5 Mb of DNA located on chromosome 17p11.2-p12. The search for the CMT1A disease gene was misdirected and impeded because some chromosome 17 genetic markers that are linked to CMT1A lie within this duplication. To better understand how such a duplication might affect genetic analyses in the context of disease gene mapping, the authors studied the effects of marker duplication on transmission probabilities of marker alleles, on linkage analysis of an autosomal dominant disease, and on tests of linkage homogeneity. They demonstrate that the undetected presence of a duplication distorts transmission ratios, hampers fine localization of the disease gene, and increases false evidence of linkage heterogeneity. In addition, they devised a likelihood-based method for detecting the presence of a tandemly duplicated marker when one is suspected. They tested their methods through computer simulations and on CMT1A pedigrees genotyped at several chromosome 17 markers. On the simulated data, the method detected 96% of duplicated markers (with a false-positive rate of 5%). On the CMT1A data the method successfully identified two of three loci that are duplicated (with no false positives). This method could be used to identify duplicated markers in other regions of the genome and could be used to delineate the extent of duplications similar to that involved in CMT1A. 18 refs., 5 figs., 6 tabs.

  14. Detection of tandem duplications and implications for linkage analysis.

    PubMed

    Matise, T C; Chakravarti, A; Patel, P I; Lupski, J R; Nelis, E; Timmerman, V; Van Broeckhoven, C; Weeks, D E

    1994-06-01

    The first demonstration of an autosomal dominant human disease caused by segmental trisomy came in 1991 for Charcot-Marie-Tooth disease type 1A (CMT1A). For this disorder, the segmental trisomy is due to a large tandem duplication of 1.5 Mb of DNA located on chromosome 17p11.2-p12. The search for the CMT1A disease gene was misdirected and impeded because some chromosome 17 genetic markers that are linked to CMT1A lie within this duplication. To better understand how such a duplication might affect genetic analyses in the context of disease gene mapping, we studied the effects of marker duplication on transmission probabilities of marker alleles, on linkage analysis of an autosomal dominant disease, and on tests of linkage homogeneity. We demonstrate that the undetected presence of a duplication distorts transmission ratios, hampers fine localization of the disease gene, and increases false evidence of linkage heterogeneity. In addition, we devised a likelihood-based method for detecting the presence of a tandemly duplicated marker when one is suspected. We tested our methods through computer simulations and on CMT1A pedigrees genotyped at several chromosome 17 markers. On the simulated data, our method detected 96% of duplicated markers (with a false-positive rate of 5%). On the CMT1A data our method successfully identified two of three loci that are duplicated (with no false positives). This method could be used to identify duplicated markers in other regions of the genome and could be used to delineate the extent of duplications similar to that involved in CMT1A. PMID:8198134

  15. Defective IL-1A expression in patients with Crohn's disease is related to attenuated MAP3K4 signaling.

    PubMed

    van der Pouw Kraan, C T M; Baggen, J M; van Bodegraven, A A; Mulder, C J J; Zwiers, A; Geerts, D; Kraal, G; Horrevoets, A J; Bouma, G

    2012-09-01

    Crohn's disease (CD) is characterized by an aberrant immune response to bacterial products stimulating TLR, in genetically susceptible hosts. Next to mutations in the TLR signaling molecule NOD2, several other immune response- and autophagy-genes contribute to CD. Since only 10-20% of cases can be explained by a NOD2 defect, we searched for additional TLR-related disease-causing factors. We analyzed the LPS response of peripheral blood mononuclear cells from 23 CD patients in remission, compared to 16 controls in a time course experiment. Individuals with any of the three major contributing NOD2 mutations were excluded. Overall, the LPS-responsive gene transcript levels, determined by low density arrays, were significantly lower in CD patients. In particular IL-1A expression was severely reduced in CD patients (ninefold reduction, p=0.001). Quantification of several important TLR4 signal transducers and cytokines identified MAP3K4 as a candidate signaling molecule with reduced expression in CD patients, which might explain the low IL-1A expression. Silencing of MAP3K4 by lentiviral shRNA transduction indeed showed that the expression of IL-1A was specifically dependent on this kinase. Furthermore, the expression of GSK3β, an inhibitor of MAP3K4, was increased in CD patients. In conclusion, we identified a novel TLR signaling defect in CD patients involving MAP3K4 and IL-1A. This confirms the hypothesis that CD patients, despite their massive intestinal inflammation, suffer from a relative immune deficiency in TLR-mediated cytokine production. PMID:22732089

  16. ATP1A2 Mutations in Migraine: Seeing through the Facets of an Ion Pump onto the Neurobiology of Disease

    PubMed Central

    Friedrich, Thomas; Tavraz, Neslihan N.; Junghans, Cornelia

    2016-01-01

    Mutations in four genes have been identified in familial hemiplegic migraine (FHM), from which CACNA1A (FHM type 1) and SCN1A (FHM type 3) code for neuronal voltage-gated calcium or sodium channels, respectively, while ATP1A2 (FHM type 2) encodes the α2 isoform of the Na+,K+-ATPase's catalytic subunit, thus classifying FHM primarily as an ion channel/ion transporter pathology. FHM type 4 is attributed to mutations in the PRRT2 gene, which encodes a proline-rich transmembrane protein of as yet unknown function. The Na+,K+-ATPase maintains the physiological gradients for Na+ and K+ ions and is, therefore, critical for the activity of ion channels and transporters involved neuronal excitability, neurotransmitter uptake or Ca2+ signaling. Strikingly diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations which frequently lead to changes in the enzyme's voltage-dependent properties, kinetics, or apparent cation affinities, but some mutations are truly deleterious for enzyme function and thus cause full haploinsufficiency. Here, we summarize structural and functional data about the Na+,K+-ATPase available to date and an overview is provided about the particular properties of the α2 isoform that explain its physiological relevance in electrically excitable tissues. In addition, current concepts about the neurobiology of migraine, the correlations between primary brain dysfunction and mechanisms of headache pain generation are described, together with insights gained recently from modeling approaches in computational neuroscience. Then, a survey is given about ATP1A2 mutations implicated in migraine cases as documented in the literature with focus on mutations that were described to completely destroy enzyme function, or lead to misfolded or mistargeted protein in particular model cell lines. We also discuss whether or not there are correlations between these most severe mutational effects and clinical phenotypes. Finally, perspectives

  17. ATP1A2 Mutations in Migraine: Seeing through the Facets of an Ion Pump onto the Neurobiology of Disease.

    PubMed

    Friedrich, Thomas; Tavraz, Neslihan N; Junghans, Cornelia

    2016-01-01

    Mutations in four genes have been identified in familial hemiplegic migraine (FHM), from which CACNA1A (FHM type 1) and SCN1A (FHM type 3) code for neuronal voltage-gated calcium or sodium channels, respectively, while ATP1A2 (FHM type 2) encodes the α2 isoform of the Na(+),K(+)-ATPase's catalytic subunit, thus classifying FHM primarily as an ion channel/ion transporter pathology. FHM type 4 is attributed to mutations in the PRRT2 gene, which encodes a proline-rich transmembrane protein of as yet unknown function. The Na(+),K(+)-ATPase maintains the physiological gradients for Na(+) and K(+) ions and is, therefore, critical for the activity of ion channels and transporters involved neuronal excitability, neurotransmitter uptake or Ca(2+) signaling. Strikingly diverse functional abnormalities have been identified for disease-linked ATP1A2 mutations which frequently lead to changes in the enzyme's voltage-dependent properties, kinetics, or apparent cation affinities, but some mutations are truly deleterious for enzyme function and thus cause full haploinsufficiency. Here, we summarize structural and functional data about the Na(+),K(+)-ATPase available to date and an overview is provided about the particular properties of the α2 isoform that explain its physiological relevance in electrically excitable tissues. In addition, current concepts about the neurobiology of migraine, the correlations between primary brain dysfunction and mechanisms of headache pain generation are described, together with insights gained recently from modeling approaches in computational neuroscience. Then, a survey is given about ATP1A2 mutations implicated in migraine cases as documented in the literature with focus on mutations that were described to completely destroy enzyme function, or lead to misfolded or mistargeted protein in particular model cell lines. We also discuss whether or not there are correlations between these most severe mutational effects and clinical phenotypes

  18. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

    PubMed Central

    Fridman, V; Bundy, B; Reilly, M M; Pareyson, D; Bacon, C; Burns, J; Day, J; Feely, S; Finkel, R S; Grider, T; Kirk, C A; Herrmann, D N; Laurá, M; Li, J; Lloyd, T; Sumner, C J; Muntoni, F; Piscosquito, G; Ramchandren, S; Shy, R; Siskind, C E; Yum, S W; Moroni, I; Pagliano, E; Zuchner, S; Scherer, S S; Shy, M E

    2015-01-01

    Background The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. Methods We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). Results 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. Conclusions Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. Clinical trial registration ID number NCT01193075. PMID:25430934

  19. A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro.

    PubMed

    Coutadeur, Séverine; Benyamine, Hélène; Delalonde, Laurence; de Oliveira, Catherine; Leblond, Bertrand; Foucourt, Alicia; Besson, Thierry; Casagrande, Anne-Sophie; Taverne, Thierry; Girard, Angélique; Pando, Matthew P; Désiré, Laurent

    2015-05-01

    The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Aβ) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Aβ production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Aβ-induced Tau phosphorylation and DYRK1A-stimulated Aβ production. DYRK1A is thus as a key element of Aβ-mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies. Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high-potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Aβ production and Aβ effects on phospho-Tau, including Tau aggregation. PMID:25556849

  20. Peginterferon Lambda-1a Is Associated with a Low Incidence of Autoimmune Thyroid Disease in Chronic Hepatitis C.

    PubMed

    Fredlund, Paul; Hillson, Jan; Gray, Todd; Shemanski, Lynn; Dimitrova, Dessislava; Srinivasan, Subasree

    2015-11-01

    Peginterferon alfa (alfa) increases the risk of autoimmune disease. Peginterferon lambda-1a (Lambda) acts through a receptor with a more liver-specific distribution compared to the alfa receptor. In a phase-2b study, 525 treatment-naive patients with chronic hepatitis C virus (HCV) infection received ribavirin and Lambda interferon (120, 180, or 240 μg) or alfa interferon (180 μg) for 24 (genotypes 2 and 3) or 48 (genotypes 1 and 4) weeks. Retrospective analysis found that adverse events of MedDRA-coded thyroid dysfunction and abnormal levels of thyroid-stimulating hormone (TSH) were significantly more frequent with alfa versus Lambda (12% versus 2.6% and 15.2% versus 3.4%, respectively, both P<0.0001). Most Lambda recipients with abnormal TSH had levels below the lower limit of normal; the frequency of low and high TSH was similar in alfa recipients with abnormal TSH. Blinded review by an endocrinologist found that new-onset primary hypothyroidism or painless thyroiditis was less frequent with Lambda versus alfa (0.5% and 1.8% versus 5.3% and 7.5%, respectively, P<0.0001). Most TSH elevations reflected new-onset hypothyroidism requiring treatment, while most markedly suppressed TSH values reflected probable painless thyroiditis and resolved without sequelae. In conclusion, HCV-infected patients treated with Lambda/ribavirin experienced fewer adverse events of thyroid dysfunction compared with patients treated with alfa/ribavirin. PMID:26376344

  1. A 1.5-Mb deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    SciTech Connect

    Lorenzetti, D.; Pandolfo, M. |; Pareyson, D.; Sghirlanzoni, A.; Di Donato, S.; Roa, B.B.; Abbas, N.E.; Lupski, J.R.

    1995-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies. A 1.5-Mb deletion in chromosome 17p11.2-p12 has been associated with HNPP. Duplication of the same 1.5-Mb region is known to be associated with Charcot-Marie-Tooth disease type 1 (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity (NCV). The CMT1A duplication and HNPP deletion appear to be the reciprocal products of a recombination event involving a repeat element (CMT1A-REP) that flanks the 1.5-Mb region involved in the duplication/deletion. Patients from nine unrelated Italian families who were diagnosed with HNPP on the basis of clinical, electrophysiological, and histological evaluations were analyzed by molecular methods for DNA deletion on chromosome 17p. In all nine families, Southern analysis using a CMT1A-REP probe detected a reduced hybridization signal of a 6.0-kb EcoRI fragment mapping within the distal CMT1A-REP, indicating deletion of one copy of CMT1A-REP in these HNPP patients. Families were also typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125, and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, providing an independent indication for deletion. Furthermore, pulsed-field gel electrophoresis analysis of SacII-digested genomic DNA detected junction fragments specific to the 1.5-Mb HNPP deletion in seven of nine Italian families included in this study. These findings suggest that a 1.5-Mb deletion on 17p11.2-p12 is the most common mutation associated with HNPP. 51 refs., 5 figs., 1 tab.

  2. Cell fate determination, neuronal maintenance and disease state: The emerging role of transcription factors Lmx1a and Lmx1b.

    PubMed

    Doucet-Beaupré, Hélène; Ang, Siew-Lan; Lévesque, Martin

    2015-12-21

    LIM-homeodomain (LIM-HD) proteins are evolutionary conserved developmental transcription factors. LIM-HD Lmx1a and Lmx1b orchestrate complex temporal and spatial gene expression of the dopaminergic pathway, and evidence shows they are also involved in adult neuronal homeostasis. In this review, the multiple roles played by Lmx1a and Lmx1b will be discussed. Controlled Lmx1a and Lmx1b expression and activities ensure the proper formation of critical signaling centers, including the embryonic ventral mesencephalon floor plate and sharp boundaries between lineage-specific cells. Lmx1a and Lmx1b expression persists in mature dopaminergic neurons of the substantia nigra pars compacta and the ventral tegmental area, and their role in the adult brain is beginning to be revealed. Notably, LMX1B expression was lower in brain tissue affected by Parkinson's disease. Actual and future applications of Lmx1a and Lmx1b transcription factors in stem cell production as well as in direct conversion of fibroblast into dopaminergic neurons are also discussed. A thorough understanding of the role of LMX1A and LMX1B in a number of disease states, including developmental diseases, cancer and neurodegenerative diseases, could lead to significant benefits for human healthcare. PMID:26526610

  3. Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

    PubMed Central

    2012-01-01

    With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer’s disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer’s disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer’s disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors. PMID:23173067

  4. Spinal and bulbar muscular atrophy and Charcot-Marie-Tooth type 1A: Co-existence of two rare neuromuscular genetic diseases in the same patient.

    PubMed

    Sagnelli, Anna; Scaioli, Vidmer; Piscosquito, Giuseppe; Salsano, Ettore; Dalla Bella, Eleonora; Gellera, Cinzia; Pareyson, Davide

    2015-10-01

    Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by a trinucleotide CAG repeat expansion in the androgen receptor gene; it is clinically characterized by adult-onset, slowly progressive weakness and atrophy mainly affecting proximal limb and bulbar muscles. Charcot-Marie-Tooth disease type 1A is an autosomal dominant polyneuropathy due to peripheral myelin protein 22 gene duplication and characterized by slowly progressive distal limb muscle weakness, atrophy and sensory loss with foot deformities. Here we report the co-occurrence of both neuromuscular genetic diseases in the same male patient. Difficulties in climbing stairs and jaw weakness were presenting symptoms consistent with SBMA. However, predominant distal weakness and bilateral pes cavus were rather suggestive of a hereditary polyneuropathy. The combination of two diseases, even if extremely rare, should be considered in the presence of atypical symptoms; in the case of genetic diseases this event may have important implications on family members' counseling. PMID:26298608

  5. DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease

    PubMed Central

    Barallobre, M J; Perier, C; Bové, J; Laguna, A; Delabar, J M; Vila, M; Arbonés, M L

    2014-01-01

    In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a+/− mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a+/− mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that

  6. Are elevated levels of soluble ICAM-1 a marker of chronic graft disease in heart transplant recipients?

    PubMed

    Campana, E; Parlapiano, C; Borgia, M C; Papalia, U; Laurenti, A; Pantone, P; Giovanniello, T; Marangi, M; Sanguigni, S

    2000-02-01

    Positivity for circulating intercellular adhesion molecule-1 (ICAM-1) in heart transplant recipients has been claimed to predict the development of coronary artery disease and risk of graft failure. Soluble ICAM-1 were evaluated in 32 heart transplant recipients. Five of these patients, who had undergone transplantation several years before, were positive for soluble ICAM-1 but did not present any clinical sign of graft rejection. Furthermore, although heart graft coronary disease was diagnosed in 15 of the 32 patients, they did not show significantly higher titres of soluble ICAM-1 compared to the remaining patients. These findings suggest that major caution is necessary when considering ICAM-1 positivity as a marker of graft disease. PMID:10657564

  7. Spectrum and Consequences of SMC1A Mutations: The Unexpected Involvement of a Core Component of Cohesin in Human Disease

    PubMed Central

    Mannini, Linda; Liu, Jinglan; Krantz, Ian D.; Musio, Antonio

    2009-01-01

    SMC1A encodes a structural component of the cohesin complex, which isnecessary for sister chromatid cohesion. In addition to its canonical role, cohesin has been shown to be involved in gene expression regulation and maintenance of genome stability. Recently, it has been demonstrated that mutations in the SMC1A gene are responsible for Cornelia de Lange syndrome (CdLS). CdLS is a genetically heterogeneous multisystem developmental disorder with variable expressivity, typically characterized by consistent facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, gastrointestinal abnormalities and other systemic involvement. SMC1A mutations have also been identified in colorectal cancers. So far a total of 26 different mutations of the SMC1A gene have been reported. All mutations reported to date are either missense or small in frame deletions that maintain the open reading frame and presumably result in a protein with residual function. The mutations involve all domains of the protein but appear to cluster in key functional loci. At the functional level, elucidation of the effects that specific SMC1A mutations have on cohesin activity will be necessary to understand the etiopathology of CdLS and its possible involvement in tumorigenesis. In this review, we summarize the current knowledge of SMC1A mutations. PMID:19842212

  8. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity.

    PubMed

    Maruta, Hiroshi

    2014-05-01

    Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular PAK1 has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic PAK1-blockers have been recently developed, no FDA-approved PAK1 blockers are available on the market as yet. Thus, patients suffering from these PAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block PAK1 without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and PAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activated PAK1 and a list of herbal therapeutics that block PAK1, but cause no side (harmful) effect on healthy people or animals. PMID:23943274

  9. PPARGC1A Variations Associated with DNA Damage, Diabetes, and Cardiovascular Diseases: The Boston Puerto Rican Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Technical Abstract Type 2 diabetes, a major risk factor for cardiovascular disease (CVD) and other age-related ailments, affects over 200 million people worldwide. Patients with type 2 diabetes exhibit higher levels of oxidative DNA damage measured as 8-OHdG concentration in leukocytes or urine. How...

  10. TOC1: a valuable tool in assessing disease progression in the rTg4510 mouse model of tauopathy.

    PubMed

    Ward, Sarah M; Himmelstein, Diana S; Ren, Yan; Fu, Yifan; Yu, Xiao-Wen; Roberts, Kaleigh; Binder, Lester I; Sahara, Naruhiko

    2014-07-01

    All tauopathies result in various forms of cognitive decline and neuronal loss. Although in some diseases, tau mutations appear to cause neurodegeneration, the toxic "form" of tau remains elusive. Tau is the major protein found within neurofibrillary tangles (NFTs) and therefore it seemed rational to assume that aggregation of tau monomers into NFTs was causal to the disease process. However, the appearance of oligomers rather than NFTs coincides much better with the voluminous neuronal loss in many of these diseases. In this study, we utilized the bigenic mouse line (rTg4510) which conditionally expresses P301L human tau. A novel tau antibody, termed Tau Oligomer Complex 1 (TOC1) was employed to probe mouse brains and assess disease progression. TOC1 selectively recognizes dimers/oligomers and appears to constitute an early stage marker of tau pathology. Its peak reactivity is coincident with other well-known early stage pathological markers such as MC1 and the early-stage phospho-marker CP13. TOC1's reactivity depends on the conformation of the tau species since it does not react with monomer under native conditions, although it does react with monomers under SDS-denaturation. This indicates a conformational change must occur within the tau aggregate to expose its epitope. Tau oligomers preferentially form under oxidizing conditions and within this mouse model, we observe tau oligomers forming at an increased rate and persisting much longer, most likely due to the aggressive P301L mutation. With the help of other novel antibodies, the use of this antibody will aid in providing a better understanding of tau toxicity within Alzheimer's disease and other tauopathies. PMID:24631720

  11. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    PubMed

    Eda, Homare; Santo, Loredana; Wein, Marc N; Hu, Dorothy Z; Cirstea, Diana D; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E; Kuhstoss, Stuart Allen; Munshi, Nikhil C; Kronenberg, Henry M; Raje, Noopur S

    2016-06-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease

  12. Mmp 1a and Mmp 1b Are Not Functional Orthologs to Human MMP1 in Cigarette Smoke Induced Lung Disease

    PubMed Central

    Carver, Phillip I.; Anguiano, Vincent; D’Armiento, Jeanine M.; Shiomi, Takayuki

    2014-01-01

    Matrix Metalloproteinase 1 (MMP1, collagenase-1) expression is implicated in a number of diseased states including emphysema and malignant tumors. The cigarette-smoke induced expression of this interstitial collegenase has been studied extensively and its inhibition proposed as a novel therapeutic treatment for tobacco related diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. However, a limitation in MMP1 research is the inability to take advantage of natural in vivo studies as most research has been performed in vitro or via animal models expressing human forms of the gene due to the lack of a rodent ortholog of MMP1. The present study examines the function of two possible mouse orthologs of human MMP1 known as Mmp 1a and Mmp 1b. Using genomic sequence analysis and expression analysis of these enzymes, the data demonstrate that neither MMP 1a nor MMP 1b behave in the same manner as human MMP1 in the presence of cigarette smoke. These findings establish that the two commonly proposed orthologs of MMP1, MMP 1a and MMP 1b, provide substantial limitations for use in examining MMP1 induced lung disease in mouse models of cigarette smoke emphysema. PMID:25497407

  13. Mmp1a and Mmp1b are not functional orthologs to human MMP1 in cigarette smoke induced lung disease.

    PubMed

    Carver, Phillip I; Anguiano, Vincent; D'Armiento, Jeanine M; Shiomi, Takayuki

    2015-02-01

    Matrix Metalloproteinase 1 (MMP1, collagenase-1) expression is implicated in a number of diseased states including emphysema and malignant tumors. The cigarette-smoke induced expression of this interstitial collegenase has been studied extensively and its inhibition proposed as a novel therapeutic treatment for tobacco related diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. However, a limitation in MMP1 research is the inability to take advantage of natural in vivo studies as most research has been performed in vitro or via animal models expressing human forms of the gene due to the lack of a rodent ortholog of MMP1. The present study examines the function of two possible mouse orthologs of human MMP1 known as Mmp1a and Mmp1b. Using genomic sequence analysis and expression analysis of these enzymes, the data demonstrate that neither MMP1a nor MMP1b behave in the same manner as human MMP1 in the presence of cigarette smoke. These findings establish that the two commonly proposed orthologs of MMP1, Mmp1a and Mmp1b, provide substantial limitations for use in examining MMP1 induced lung disease in mouse models of cigarette smoke emphysema. PMID:25497407

  14. Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligase implicated in Alzheimer's disease.

    PubMed

    Saito, Ryo; Kaneko, Masayuki; Kitamura, Yoshihisa; Takata, Kazuyuki; Kawada, Koichi; Okuma, Yasunobu; Nomura, Yasuyuki

    2014-01-01

    The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane of brain neurons and is involved in endoplasmic reticulum-associated degradation. We previously demonstrated that suppression of HRD1 expression in neurons causes accumulation of amyloid precursor protein, resulting in amyloid β production associated with endoplasmic reticulum stress and apoptosis. Furthermore, HRD1 levels are significantly decreased in the cerebral cortex of Alzheimer's disease patients because of its insolubility. The mechanisms that affect HRD1 solubility are not well understood. We here show that HRD1 protein was insolubilized by oxidative stress but not by other Alzheimer's disease-related molecules and stressors, such as amyloid β, tau, and endoplasmic reticulum stress. Furthermore, we raise the possibility that modifications of HRD1 by 4-hydroxy-2-nonenal, an oxidative stress marker, decrease HRD1 protein solubility and the oxidative stress led to the accumulation of HRD1 into the aggresome. Thus, oxidative stress-induced HRD1 insolubilization might be involved in a vicious cycle of increased amyloid β production and amyloid β-induced oxidative stress in Alzheimer's disease pathogenesis. PMID:24788773

  15. Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas' disease

    SciTech Connect

    Lountos, George T.; Tropea, Joseph E.; Waugh, David S.

    2013-06-05

    Chagas’ disease, a neglected tropical affliction transmitted by the flagellated protozoan Trypanosoma cruzi, is prevalent in Latin America and affects nearly 18 million people worldwide, yet few approved drugs are available to treat the disease. Moreover, the currently available drugs exhibit severe toxicity or are poorly effective in the chronic phase of the disease. This limitation, along with the large population at risk, underscores the urgent need to discover new molecular targets and novel therapeutic agents. Recently, the T. cruzi protein tyrosine phosphatase TcPTP1 has been implicated in the cellular differentiation and infectivity of the parasite and is therefore a promising target for the design of novel anti-parasitic drugs. Here, we report the X-ray crystal structure of TcPTP1 refined to a resolution of 2.18 Å, which provides structural insights into the active site environment that can be used to initiate structure-based drug design efforts to develop specific TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also discussed.

  16. Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas’ disease

    PubMed Central

    Lountos, George T.; Tropea, Joseph E.; Waugh, David S.

    2014-01-01

    Chagas’ disease, a neglected tropical affliction transmitted by the flagellated protozoan Trypanosoma cruzi, is prevalent in Latin America and affects nearly 18 million people worldwide, yet few approved drugs are available to treat the disease. Moreover, the currently available drugs exhibit severe toxicity or are poorly effective in the chronic phase of the disease. This limitation, along with the large population at risk, underscores the urgent need to discover new molecular targets and novel therapeutic agents. Recently, the T. cruzi protein tyrosine phosphatase TcPTP1 has been implicated in the cellular differentiation and infectivity of the parasite and is therefore a promising target for the design of novel anti-parasitic drugs. Here, we report the X-ray crystal structure of TcPTP1 refined to a resolution of 2.18 Å, which provides structural insights into the active site environment that can be used to initiate structure-based drug design efforts to develop specific TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also discussed. PMID:23137716

  17. Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients★

    PubMed Central

    Li, Xiaobo; Zi, Xiaohong; Li, Lin; Zhan, Yajing; Huang, Shunxiang; Li, Jin; Li, Xuning; Li, Xigui; Hu, Zhengmao; Xia, Kun; Tang, Beisha; Zhang, Ruxu

    2012-01-01

    We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 (PMP22) to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ‘onion-like’ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ‘mouse-nibbled’-like changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced. PMID:25337104

  18. Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing.

    PubMed

    Nam, Soo Hyun; Hong, Young Bin; Hyun, Young Se; Nam, Da Eun; Kwak, Geon; Hwang, Sun Hee; Choi, Byung-Ok; Chung, Ki Wha

    2016-05-31

    Inherited peripheral neuropathies (IPN), which are a group of clinically and genetically heterogeneous peripheral nerve disorders including Charcot-Marie-Tooth disease (CMT), exhibit progressive degeneration of muscles in the extremities and loss of sensory function. Over 70 genes have been reported as genetic causatives and the number is still growing. We prepared a targeted gene panel for IPN diagnosis based on next generation sequencing (NGS). The gene panel was designed to detect mutations in 73 genes reported to be genetic causes of IPN or related peripheral neuropathies, and to detect duplication of the chromosome 17p12 region, the major genetic cause of CMT1A. We applied the gene panel to 115 samples from 63 non-CMT1A families, and isolated 15 pathogenic or likely-pathogenic mutations in eight genes from 25 patients (17 families). Of them, eight mutations were unreported variants. Of particular interest, this study revealed several very rare mutations in the SPTLC2, DCTN1, and MARS genes. In addition, the effectiveness of the detection of CMT1A was confirmed by comparing five 17p12-nonduplicated controls and 15 CMT1A cases. In conclusion, we developed a gene panel for one step genetic diagnosis of IPN. It seems that its time- and cost-effectiveness are superior to previous tiered-genetic diagnosis algorithms, and it could be applied as a genetic diagnostic system for inherited peripheral neuropathies. PMID:27025386

  19. Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy.

    PubMed

    Scurry, Alexandra N; Heredia, Dante J; Feng, Cheng-Yuan; Gephart, Gregory B; Hennig, Grant W; Gould, Thomas W

    2016-04-01

    Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity, and muscle weakness. APMP22point mutation in L16P (leucine 16 to proline) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (Tr(J)) die early postnatally, fail to make peripheral myelin, and, therefore, are more similar to patients with congenital hypomyelinating neuropathy than those with CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, we examined the structure and function of NMJs inTr(J)mice. Although synapses appeared to be normally innervated even in end-stageTr(J)mice, the growth and maturation of the NMJs were altered. In addition, the amplitudes of nerve-evoked muscle endplate potentials were reduced and there was transmission failure during sustained nerve stimulation. These results suggest that the severe congenital hypomyelinating neuropathy that characterizesTr(J)mice results in structural and functional deficits of the developing NMJ. PMID:26921370

  20. Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing

    PubMed Central

    Nam, Soo Hyun; Hong, Young Bin; Hyun, Young Se; Nam, Da Eun; Kwak, Geon; Hwang, Sun Hee; Choi, Byung-Ok; Chung, Ki Wha

    2016-01-01

    Inherited peripheral neuropathies (IPN), which are a group of clinically and genetically heterogeneous peripheral nerve disorders including Charcot-Marie-Tooth disease (CMT), exhibit progressive degeneration of muscles in the extremities and loss of sensory function. Over 70 genes have been reported as genetic causatives and the number is still growing. We prepared a targeted gene panel for IPN diagnosis based on next generation sequencing (NGS). The gene panel was designed to detect mutations in 73 genes reported to be genetic causes of IPN or related peripheral neuropathies, and to detect duplication of the chromosome 17p12 region, the major genetic cause of CMT1A. We applied the gene panel to 115 samples from 63 non-CMT1A families, and isolated 15 pathogenic or likely-pathogenic mutations in eight genes from 25 patients (17 families). Of them, eight mutations were unreported variants. Of particular interest, this study revealed several very rare mutations in the SPTLC2, DCTN1, and MARS genes. In addition, the effectiveness of the detection of CMT1A was confirmed by comparing five 17p12-nonduplicated controls and 15 CMT1A cases. In conclusion, we developed a gene panel for one step genetic diagnosis of IPN. It seems that its time- and cost-effectiveness are superior to previous tiered-genetic diagnosis algorithms, and it could be applied as a genetic diagnostic system for inherited peripheral neuropathies. PMID:27025386

  1. SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease

    PubMed Central

    Tang, Weibing; Tang, Junwei; He, Jun; Zhou, Zhigang; Qin, Yufeng; Qin, Jingjing; Li, Bo; Xu, Xiaoqun; Geng, Qiming; Jiang, Weiwei; Wu, Wei; Wang, Xinru; Xia, Yankai

    2015-01-01

    Hirschsprung's disease (HSCR) is a rare congenital disease caused by impaired proliferation and migration of neural crest cells. We investigated changes in expression of microRNAs (miRNAs) and the genes they regulate in tissues of patients with HSCR. Quantitative real-time PCR and immunoblot analyses were used to measure levels of miRNA, mRNAs, and proteins in colon tissues from 69 patients with HSCR and 49 individuals without HSCR (controls). Direct interactions between miRNAs and specific mRNAs were indentified in vitro, while the function role of miR-218-1 was investigated by using miR-218 transgenic mice. An increased level of miR-218-1 correlated with increased levels of SLIT2 and decreased levels of RET and PLAG1mRNA and protein. The reductions in RET and PLAG1 by miR-218-1 reduced proliferation and migration of SH-SY5Y cells. Overexpression of the secreted form of SLIT2 inhibited cell migration via binding to its receptor ROBO1. Bowel tissues from miR-218-1 transgenic mice had nerve fibre hyperplasia and reduced numbers of gangliocytes, compared with wild-type mice. Altered miR-218-1 regulation of SLIT2, RET and PLAG1 might be involved in the pathogenesis of HSCR. PMID:25786906

  2. SLIT2/ROBO1-miR-218-1-RET/PLAG1: a new disease pathway involved in Hirschsprung's disease.

    PubMed

    Tang, Weibing; Tang, Junwei; He, Jun; Zhou, Zhigang; Qin, Yufeng; Qin, Jingjing; Li, Bo; Xu, Xiaoqun; Geng, Qiming; Jiang, Weiwei; Wu, Wei; Wang, Xinru; Xia, Yankai

    2015-06-01

    Hirschsprung's disease (HSCR) is a rare congenital disease caused by impaired proliferation and migration of neural crest cells. We investigated changes in expression of microRNAs (miRNAs) and the genes they regulate in tissues of patients with HSCR. Quantitative real-time PCR and immunoblot analyses were used to measure levels of miRNA, mRNAs, and proteins in colon tissues from 69 patients with HSCR and 49 individuals without HSCR (controls). Direct interactions between miRNAs and specific mRNAs were indentified in vitro, while the function role of miR-218-1 was investigated by using miR-218 transgenic mice. An increased level of miR-218-1 correlated with increased levels of SLIT2 and decreased levels of RET and PLAG1 mRNA and protein. The reductions in RET and PLAG1 by miR-218-1 reduced proliferation and migration of SH-SY5Y cells. Overexpression of the secreted form of SLIT2 inhibited cell migration via binding to its receptor ROBO1. Bowel tissues from miR-218-1 transgenic mice had nerve fibre hyperplasia and reduced numbers of gangliocytes, compared with wild-type mice. Altered miR-218-1 regulation of SLIT2, RET and PLAG1 might be involved in the pathogenesis of HSCR. PMID:25786906

  3. The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease.

    PubMed

    Vasavda, Nisha; Menzel, Stephan; Kondaveeti, Sheila; Maytham, Emma; Awogbade, Moji; Bannister, Sybil; Cunningham, Juliette; Eichholz, Andrew; Daniel, Yvonne; Okpala, Iheanyi; Fulford, Tony; Thein, Swee Lay

    2007-07-01

    Serum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)-glucuronosyltransferase (UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase (HMOX1), a rate-limiting enzyme upstream of UGT1A in the haem catabolic pathway, and alpha-thalassaemia could explain some of the inconsistent effects. The UGT1A1 [TA](n) and HMOX1 [GT](n) promoter polymorphisms and alpha globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/beta(0), 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects (P < 0.0001 and P < 0.01, respectively). While HMOX1 genotype had no effect, co-inheritance of alpha-thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD. PMID:17593033

  4. BcGs1, a glycoprotein from Botrytis cinerea, elicits defence response and improves disease resistance in host plants.

    PubMed

    Zhang, Yi; Zhang, Yunhua; Qiu, Dewen; Zeng, Hongmei; Guo, Lihua; Yang, Xiufen

    2015-02-20

    In this study, a necrosis-inducing protein was purified from the culture filtrate of the necrotrophic fungus Botrytis cinerea BC-98 strain. Secreted proteins were collected and fractionated by liquid chromatography. The fraction with the highest necrosis-inducing activity was further purified. A glycoprotein named BcGs1 was identified by 2D electrophoresis and mass spectrometry. The BcGs1 protein consisted of 672 amino acids with a theoretical molecular weight of 70.487 kDa. Functional domain analysis indicated that BcGs1 was a glucan 1,4-alpha-glucosidase, a cell wall-degrading enzyme, with a Glyco_hydro_15 domain and a CBM20_glucoamylase domain. The BcGs1 protein caused necrotic lesions that mimicked a typical hypersensitive response and H2O2 production in tomato and tobacco leaves. BcGs1-treated plants exhibited resistance to B. cinerea, Pseudomonas syringae pv. tomato DC3000 and tobacco mosaic virus in systemic leaves. In addition, BcGs1 triggered elevation of the transcript levels of the defence-related genes PR-1a, TPK1b and Prosystemin. This is the first report of a Botrytis glucan 1,4-alpha-glucosidase triggering host plant immunity as an elicitor. These results lay a foundation for further study of the comprehensive interaction between plants and necrotrophic fungi. PMID:25613865

  5. Expression pattern in retinal photoreceptors of POMGnT1, a protein involved in muscle-eye-brain disease

    PubMed Central

    Uribe, Mary Luz; Haro, Carmen; Campello, Laura; Cruces, Jesús; Martín-Nieto, José

    2016-01-01

    Purpose The POMGNT1 gene, encoding protein O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1, is associated with muscle-eye-brain disease (MEB) and other dystroglycanopathies. This gene’s lack of function or expression causes hypoglycosylation of α-dystroglycan (α-DG) in the muscle and the central nervous system, including the brain and the retina. The ocular symptoms of patients with MEB include retinal degeneration and detachment, glaucoma, and abnormal electroretinogram. Nevertheless, the POMGnT1 expression pattern in the healthy mammalian retina has not yet been investigated. In this work, we address the expression of the POMGNT1 gene in the healthy retina of a variety of mammals and characterize the distribution pattern of this gene in the adult mouse retina and the 661W photoreceptor cell line. Methods Using reverse transcription (RT)–PCR and immunoblotting, we studied POMGNT1 expression at the mRNA and protein levels in various mammalian species, from rodents to humans. Immunofluorescence confocal microscopy analyses were performed to characterize the distribution profile of its protein product in mouse retinal sections and in 661W cultured cells. The intranuclear distribution of POMT1 and POMT2, the two enzymes preceding POMGnT1 in the α-DG O-mannosyl glycosylation pathway, was also analyzed. Results POMGNT1 mRNA and its encoded protein were expressed in the neural retina of all mammals studied. POMGnT1 was located in the cytoplasmic fraction in the mouse retina and concentrated in the myoid portion of the photoreceptor inner segments, where the protein colocalized with GM130, a Golgi complex marker. The presence of POMGnT1 in the Golgi complex was also evident in 661W cells. However, and in contrast to retinal tissue, POMGnT1 additionally accumulated in the nucleus of the 661W photoreceptors. Colocalization was found within this organelle between POMGnT1 and POMT1/2, the latter associated with euchromatic regions of the nucleus. Conclusions

  6. A combined omics approach to evaluate the effects of dietary curcumin on colon inflammation in the Mdr1a(-/-) mouse model of inflammatory bowel disease.

    PubMed

    Cooney, Janine M; Barnett, Matthew P G; Dommels, Yvonne E M; Brewster, Diane; Butts, Christine A; McNabb, Warren C; Laing, William A; Roy, Nicole C

    2016-01-01

    The aim of this study was to provide insight into how curcumin reduces colon inflammation in the Mdr1a(-/-) mouse model of human inflammatory bowel disease using a combined transcriptomics and proteomics approach. Mdr1a(-/-) and FVB control mice were randomly assigned to an AIN-76A (control) diet or AIN-76A+0.2% curcumin. At 21 or 24weeks of age, colonic histological injury score (HIS) was determined, colon mRNA transcript levels were assessed using microarrays and colon protein expression was measured using 2D gel electrophoresis and LCMS protein identification. Colonic HIS of Mdr1a(-/-) mice fed the AIN-76A diet was higher (P<.001) than FVB mice fed the same diet; the curcumin-supplemented diet reduced colonic HIS (P<.05) in Mdr1a(-/-) mice. Microarray and proteomics analyses combined with new data analysis tools, such as the Ingenuity Pathways Analysis regulator effects analysis, showed that curcumin's antiinflammatory activity in Mdr1a(-/-) mouse colon may be mediated by activation of α-catenin, which has not previously been reported. We also show evidence to support curcumin's action via multiple molecular pathways including reduced immune response, increased xenobiotic metabolism, resolution of inflammation through decreased neutrophil migration and increased barrier remodeling. Key transcription factors and other regulatory molecules (ERK, FN1, TNFSF12 and PI3K complex) activated in inflammation were down-regulated by dietary intervention with curcumin. PMID:26437580

  7. Exon redefinition by a point mutation within exon 5 of the glucose-6-phosphatase gene is the major cause of glycogen storage disease type 1a in Japan

    SciTech Connect

    Kajihara, Susumu; Yamamoto, Kyosuke; Kido, Keiko

    1995-09-01

    Glycogen storage disease (GSD) type 1a (von Gierke disease) is an autosomal recessive disorder caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase). We have identified a novel mutation in the G6Pase gene of a individual with GSD type 1a. The cDNA from the patient`s liver revealed a 91-nt deletion in exon 5. The genomic DNA from the patient`s white blood cells revealed no deletion or mutation at the splicing junction of intron 4 and exon 5. The 3{prime} splicing occurred 91 bp from the 5{prime} site of exon 5 (at position 732 in the coding region), causing a substitution of a single nucleotide (G to T) at position 727 in the coding region. Further confirmation of the missplicing was obtained by transient expression of allelic minigene constructs into animal cells. Another eight unrelated families of nine Japanese patients were all found to have this mutation. This mutation is a new type of splicing mutation in the G6Pase gene, and 91% of patients and carriers suffering from GSD1a in Japan are detectable with this splicing mutation. 28 refs., 5 figs., 2 tabs.

  8. A 1.5 Mb submicroscopic deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    SciTech Connect

    Lorenzetti, D.; Roa, B.B.; Abbas, N.E.

    1994-09-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies that was recently associated with a 1.5 Mb deletion in chromosome 17p11.2-p12. Duplication of the same region is known to be associated with Charcot-Marie-Tooth disease type 1A (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity. The CMT1A duplication and HNPP deletion are reciprocal recombination products involving a repeat element (CMT1A-REP) which flanks the 1.5 Mb region involved in the duplication/deletion. Patients from 9 unrelated HNPP Italian families were clinically, electrophysiologically and histologically evaluated. Families were typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125 and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, suggesting the presence of deletion. Southern blot analysis of EcoRI digested genomic DNA from HNPP patients and control subjects was performed using a probe mapping within the CMT1A-REP elements. A reduced hybridization signal of a 6.0 kb EcoRI fragment, mapping within the distal CMT1A-REP, was observed in all HNPP patients suggesting the loss of one copy of this fragment in the HNPP-deleted chromosome. PFGE analysis of SacII digested genomic DNA from selected HNPP subjects showed the presence of a junction fragment which has previously been found in association with the 1.5 Mb HNPP deletion. Evidence for deletion could be demonstrated in all 9 families suggesting that the 17p11.2-p12 deletion is commonly associated with HNPP.

  9. Molecular characteristics of penicillin-binding protein 2b, 2x and 1a sequences in Streptococcus pneumoniae isolates causing invasive diseases among children in Northeast China.

    PubMed

    Zhou, X; Liu, J; Zhang, Z; Liu, Y; Wang, Y; Liu, Y

    2016-04-01

    Streptococcus pneumoniae is one of the common pathogens causing severe invasive infections in children. This study aimed to investigate the serotype distribution and variations of penicillin-binding proteins (PBPs) 2b, 2x and 1a in S. pneumoniae isolates causing invasive diseases in Northeast China. A total of 256 strains were isolated from children with invasive pneumococcal disease (IPD) from January 2000 to October 2014. All strains were serotyped and determined for antibiotic resistance. The amplicons of penicillin-binding domains in pbp1a, pbp2b and pbp2x genes were sequenced for variation identification. The most prevalent serotypes of isolates in IPD children were 19A, 14, 19F, 23F and 6B. 19A and 19F were the most frequent serotypes of penicillin-resistant S. pneumoniae (PRSP), which present with high resistance to amoxicillin, cefotaxime, ceftriaxone and meropenem. The numbers of amino acid substitutions of penicillin-non-susceptible S. pneumoniae (PNSP) isolates were higher than those of penicillin-sensitive S. pneumoniae isolates in all the PBP genes (p < 0.01). The patterns of amino acid mutation in PBP2b, PBP2x and PBP1a were unique and different from those of other countries. All of the serotype 19A and 19F PRSP isolates carried 25 amino acid mutations, including Ala618 → Gly between positions 560 and 675 in PBP2b and Thr338 → Ala substitutions in PBP2x. The amino acid alterations in PBP2b, PBP2x and PBP1a from S. pneumoniae were closely associated with resistance to β-lactam antibiotics. This study provides new data for further monitoring of genetic changes related to the emergence and spread of resistance to β-lactam antibiotics in China. PMID:26972430

  10. Reduced Alzheimer's disease β-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin

    PubMed Central

    Meckler, Xavier; Roseman, Jelita; Das, Pritam; Cheng, Haipeng; Pei, Susan; Keat, Marcia; Kassarjian, Breanne; Golde, Todd E.; Parent, Angèle T.; Thinakaran, Gopal

    2010-01-01

    Sequential cleavage of amyloid precursor protein by β- and γ-secretases generates β-amyloid peptides (Aβ), which accumulate in the brains of patients with Alzheimer's disease. We recently identified S-palmitoylation of two γ-secretase subunits, APH1 and nicastrin. S-palmitoylation is an essential post-translational modification for the proper trafficking and function of many neuronal proteins. In cultured cell lines, lack of S-palmitoylation causes instability of nascent APH1 and nicastrin, but does not affect γ-secretase processing of amyloid precursor protein. To determine the importance of γ-secretase S-palmitoylation for Aβ deposition in the brain, we generated transgenic mice co-expressing human wild-type or S-palmitoylation-deficient APH1aL and nicastrin in neurons in the forebrain. We found that lack of S-palmitoylation did not impair the ability of APH1aL and nicastrin to form enzymatically active protein complexes with endogenous presenilin 1 and PEN2, or affect the localization of γ-secretase subunits in dendrites and axons of cortical neurons. When we crossed these mice with 85Dbo transgenic mice, which co-express familial Alzheimer's disease-causing amyloid precursor protein and presenilin 1 variants, we found that co-expression of wild-type or mutant APH1aL and nicastrin led to marked stabilization of transgenic presenilin 1 in the brains of double transgenic mice. Interestingly, we observed a moderate, but significant, reduction in amyloid deposits in the forebrain of mice expressing S-palmitoylation-deficient γ-secretase subunits as compared with mice overexpressing wild-type subunits, as well as a reduction in the levels of insoluble Aβ40-42. These results indicate that γ-secretase S-palmitoylation modulates Aβ deposition in the brain. PMID:21123562

  11. Reduced Alzheimer's disease ß-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin.

    PubMed

    Meckler, Xavier; Roseman, Jelita; Das, Pritam; Cheng, Haipeng; Pei, Susan; Keat, Marcia; Kassarjian, Breanne; Golde, Todd E; Parent, Angèle T; Thinakaran, Gopal

    2010-12-01

    Sequential cleavage of amyloid precursor protein by β- and γ-secretases generates β-amyloid peptides (Aβ), which accumulate in the brains of patients with Alzheimer's disease. We recently identified S-palmitoylation of two γ-secretase subunits, APH1 and nicastrin. S-Palmitoylation is an essential posttranslational modification for the proper trafficking and function of many neuronal proteins. In cultured cell lines, lack of S-palmitoylation causes instability of nascent APH1 and nicastrin but does not affect γ-secretase processing of amyloid precursor protein. To determine the importance of γ-secretase S-palmitoylation for Aβ deposition in the brain, we generated transgenic mice coexpressing human wild-type or S-palmitoylation-deficient APH1aL and nicastrin in neurons in the forebrain. We found that lack of S-palmitoylation did not impair the ability of APH1aL and nicastrin to form enzymatically active protein complexes with endogenous presenilin 1 and PEN2 or affect the localization of γ-secretase subunits in dendrites and axons of cortical neurons. When we crossed these mice with 85Dbo transgenic mice, which coexpress familial Alzheimer's disease-causing amyloid precursor protein and presenilin 1 variants, we found that coexpression of wild-type or mutant APH1aL and nicastrin led to marked stabilization of transgenic presenilin 1 in the brains of double-transgenic mice. Interestingly, we observed a moderate, but significant, reduction in amyloid deposits in the forebrain of mice expressing S-palmitoylation-deficient γ-secretase subunits compared with mice overexpressing wild-type subunits, as well as a reduction in the levels of insoluble Aβ(40-42). These results indicate that γ-secretase S-palmitoylation modulates Aβ deposition in the brain. PMID:21123562

  12. A Large Family with Carney Complex Caused by the S147G PRKAR1A Mutation Shows a Unique Spectrum of Disease Including Adrenocortical Cancer

    PubMed Central

    Anselmo, João; Medeiros, Sandra; Carneiro, Victor; Greene, Elizabeth; Levy, Isaac; Nesterova, Maria; Lyssikatos, Charalampos; Horvath, Anelia; Carney, J. Aidan

    2012-01-01

    Context: Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC. Objective: We studied the genotype-phenotype correlation in CNC. Design and Setting: We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center. Patients: Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations. Results: Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro. Conclusions: In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD

  13. CYP1A induction and blue sac disease in early life stages of white suckers (Catostomus commersoni) exposed to oil sands.

    PubMed

    Colavecchia, Maria V; Hodson, Peter V; Parrott, Joanne L

    2006-05-01

    The objectives of this study were to evaluate the influence of natural oil sands on the early developmental stages of white sucker (Catostomus commersoni) and to determine whether biochemical responses in this species were similar to native fish caught in the Athabasca Oil Sands area. Early life stage (ELS) sediment toxicity tests were conducted using controls, reference sediments, natural oil sands, and industrially contaminated (wastewater pond) sediments collected from sites along the Athabasca River, Alberta (Canada). Eggs and larvae were observed for mortality, hatching, deformities, growth, and cytochrome P-4501A (CYP1A) activity using immunohistochemistry. E-Nat-, S-Nat-, and wastewater pond sediment-exposed groups showed significant premature hatching, reduced growth, and exposure-dependent increases in ELS mortality and larval malformations relative to controls. The most common larval deformities included edemas (pericardial, yolk sac, and subepidermal), hemorrhages, and spinal defects. Juveniles exposed to oil sands and wastewater pond sediments (96 h) demonstrated significantly increased 7-ethoxyresorufin-O-deethylase (EROD) activity (30- to 50-fold) as compared to controls. Reference sediment-exposed groups and water controls demonstrated reliable embryo and larval survival, minimal malformations, and negligible CYP1A staining. These observed signs of blue sac disease (ELS mortality, malformations, growth reductions, CYP1A activity induction) may produce deleterious reproductive effects in natural fish populations exposed to oil sands mixtures. PMID:16728374

  14. Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer's disease: A post-mortem study with PET radiopharmaceuticals.

    PubMed

    Vidal, Benjamin; Sebti, Johan; Verdurand, Mathieu; Fieux, Sylvain; Billard, Thierry; Streichenberger, Nathalie; Troakes, Claire; Newman-Tancredi, Adrian; Zimmer, Luc

    2016-10-01

    PET imaging studies using 5-HT1A receptor radiotracers show a decreased density of this receptor in hippocampi of patients with Alzheimer's disease (AD) at advanced stages. However, current 5-HT1A receptor radiopharmaceuticals used in neuroimaging are antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radiotracer, which binds selectively to functional receptors, with the PET imaging obtained using an antagonist radiotracer would therefore provide original information on 5-HT1A receptor impairment during AD. Quantitative autoradiography using [(18)F]F13640 and [(18)F]MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of patients with AD (n = 25, at different Braak stages) and control subjects (n = 9). The neuronal density was measured in the same tissues by NeuN immunohistochemistry. The specific binding of both radiotracers was determined by addition of WAY-100635, a selective 5-HT1A receptor antagonist. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was in the pyramidal layer of CA1. Incubation with Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [(18)F]F13640 binding in hippocampal regions, confirming its preferential interaction with G-coupled receptors, and slightly increased [(18)F]MPPF binding. In the CA1 subfield, [(18)F]F13640 binding was significantly decreased at Braak stages I/II (-19%), Braak stages III/IV (-23%), and Braak stages V/VI (-36%) versus control. In contrast, [(18)F]MPPF binding was statistically reduced only at the most advanced Braak stages V/VI compared to control (-33%). Since [(18)F]F13640 and [(18)F]MPPF can be used in vivo in humans, this

  15. A Novel Mutation in the type Iα Regulatory Subunit of Protein Kinase A (PRKAR1A) in a Cushing's Syndrome Patient with Primary Pigmented Nodular Adrenocortical Disease.

    PubMed

    Mineo, Ryohei; Tamba, Sachiko; Yamada, Yuya; Okita, Tomonori; Kawachi, Yusuke; Mori, Reiko; Kyo, Mitsuaki; Saisho, Kenji; Kuroda, Yohei; Yamamoto, Koji; Furuya, Akiko; Mukai, Tokuo; Maekawa, Takashi; Nakamura, Yasuhiro; Sasano, Hironobu; Matsuzawa, Yuji

    2016-01-01

    A 40-year-old man presented with Cushing's syndrome due to bilateral adrenal hyperplasia with multiple nodules. Computed tomography scan results were atypical demonstrating an enlargement of the bilateral adrenal glands harboring multiple small nodules, but the lesion was clinically diagnosed to be primary pigmented nodular adrenocortical disease (PPNAD) based on both endocrinological test results and his family history. We performed bilateral adrenalectomy and confirmed the diagnosis histologically. An analysis of the patient and his mother's genomic DNA identified a novel mutation in the type Iα regulatory subunit of protein kinase A (PRKAR1A) gene; p.E17X (c.49G>T). This confirmed the diagnosis of PPNAD which is associated with Carney Complex. PMID:27580546

  16. In vivo hepatic lipid quantification using MRS at 7 Tesla in a mouse model of glycogen storage disease type 1a

    PubMed Central

    Ramamonjisoa, Nirilanto; Ratiney, Helene; Mutel, Elodie; Guillou, Herve; Mithieux, Gilles; Pilleul, Frank; Rajas, Fabienne; Beuf, Olivier; Cavassila, Sophie

    2013-01-01

    The assessment of liver lipid content and composition is needed in preclinical research to investigate steatosis and steatosis-related disorders. The purpose of this study was to quantify in vivo hepatic fatty acid content and composition using a method based on short echo time proton magnetic resonance spectroscopy (MRS) at 7 Tesla. A mouse model of glycogen storage disease type 1a with inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc−/−) mice and control mice were fed a standard diet or a high-fat/high-sucrose (HF/HS) diet for 9 months. In control mice, hepatic lipid content was found significantly higher with the HF/HS diet than with the standard diet. As expected, hepatic lipid content was already elevated in L-G6pc−/− mice fed a standard diet compared with control mice. L-G6pc−/− mice rapidly developed steatosis which was not modified by the HF/HS diet. On the standard diet, estimated amplitudes from olefinic protons were found significantly higher in L-G6pc−/− mice compared with that in control mice. L-G6pc−/− mice showed no noticeable polyunsaturation from diallylic protons. Total unsaturated fatty acid indexes measured by gas chromatography were in agreement with MRS measurements. These results showed the great potential of high magnetic field MRS to follow the diet impact and lipid alterations in mouse liver. PMID:23596325

  17. Malignant Transformation of Hepatic Adenoma in Glycogen Storage Disease Type-1a: Report of an Exceptional Case Diagnosed on Surveillance Imaging

    PubMed Central

    Baheti, Akshay D.; Yeh, Matthew M.; O'Malley, Ryan; Lalwani, Neeraj

    2015-01-01

    Hepatocellular adenoma is a heterogeneous group of benign neoplasms arising from hepatocellular cells and can be subclassified into four major groups based on genotypic and phenotypic characteristics. These four subtypes are hepatocyte nuclear factor (HNF) 1α-inactivated, β-catenin–activated, inflammatory, and unclassified adenomas. Immunohistochemistry studies have demonstrated that since β-catenin–activated adenomas have a higher risk of malignant transformation, the identification of the subtype of adenoma remains crucial in patient management. However, malignant transformation of hepatic adenoma without β-catenin overexpression can be seen in 30–65% cases. We report a case of malignant transformation of hepatic adenoma without overexpression of β-catenin in a 31-year-old man with a known glycogen storage disease (GSD) Type-1a, which was diagnosed on surveillance magnetic resonance imaging (MRI). The MRI showed a mild interval increase in one lesion with relative stability of the other adenomas. The lesion was presumed to be suspicious for a hepatocellular carcinoma (HCC) and was confirmed on pathology. PMID:26430540

  18. The PMP22 gene and its related diseases.

    PubMed

    Li, Jun; Parker, Brett; Martyn, Colin; Natarajan, Chandramohan; Guo, Jiasong

    2013-04-01

    Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50 % of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While overexpression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene. PMID:23224996

  19. The PMP22 Gene and Its Related Diseases

    PubMed Central

    Li, Jun; Parker, Brett; Martyn, Colin; Natarajan, Chandramohan; Guo, Jiasong

    2012-01-01

    Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50% of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While over-expression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene. PMID:23224996

  20. Peginterferon Beta-1a Injection

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS, a disease in which ... peginterferon beta-1a injection at around the same time of day each time you inject it. Follow ...

  1. Identification and characterization of the carboxy-terminal region of Sip-1, a novel autoantigen in Behçet's disease

    PubMed Central

    Delunardo, Federica; Conti, Fabrizio; Margutti, Paola; Alessandri, Cristiano; Priori, Roberta; Siracusano, Alessandra; Riganò, Rachele; Profumo, Elisabetta; Valesini, Guido; Sorice, Maurizio; Ortona, Elena

    2006-01-01

    Given the lack of a serological test specific for Behçet's disease, its diagnosis rests upon clinical criteria. The clinical diagnosis is nevertheless difficult because the disease manifestations vary widely, especially at the onset of disease. The aim of this study was to identify molecules specifically recognized by serum autoantibodies in patients with Behçet's disease and to evaluate their diagnostic value. We screened a cDNA library from human microvascular endothelial cells with serum IgG from two patients with Behçet's disease and isolated a reactive clone specific to the carboxy-terminal subunit of Sip1 (Sip1 C-ter). Using ELISA, we measured IgG, IgM and IgA specific to Sip1 C-ter in patients with various autoimmune diseases characterized by the presence of serum anti-endothelial cell antibodies, such as Behçet's disease, systemic lupus erythematosus, systemic sclerosis and various forms of primary vasculitis, as well as in patients with diseases that share clinical features with Behçet's disease, such as inflammatory bowel disease and uveitis. IgM immunoreactivity to Sip1 C-ter was significantly higher in patients with Behçet's disease and in patients with primary vasculitis than in the other groups of patients and healthy subjects tested (P < 10-4 by Mann-Whitney test). ELISA detected IgG specific to Sip1 C-ter in sera from 11/56 (20%) patients with Behçet's disease, IgM in 23/56 (41%) and IgA in 9/54 (17%). No sera from patients with systemic lupus erythematosus, systemic sclerosis, inflammatory bowel disease, uveitis or healthy subjects but 45% of sera from patients with primary vasculitis contained IgM specific to Sip1 C-ter. Serum levels of soluble E-selectin, a marker of endothelial activation and inflammation, correlated with levels of serum IgM anti Sip-1 C-ter in patients with Behçet's disease (r = 0.36, P = 0.023). In conclusion, Sip1 C-ter is a novel autoantigen in Behçet's disease. IgM specific to Sip1 C-ter might be useful in clinical

  2. An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes

    SciTech Connect

    Zhang, Liqun; Teng, Yen-Tung; Melet, F.

    1995-12-01

    This report describes how expression of the proto-oncogene Fli-1 is involved in the regulation of lymphopoiesis. Transgenic mice were generated which overexpressed the oncogene, leading to a high incidence of immunological renal diseases and death. The data suggests that overexpression of Fli-1 perturbs normal lymphoid cell function and programmed cell death, making these transgenic mice suitable as a biological model for autoimmune disease in humans. 35 refs., 6 figs., 4 tabs.

  3. The disease-linked Glu-26-Lys mutant version of Coronin 1A exhibits pleiotropic and pathway-specific signaling defects

    PubMed Central

    Ojeda, Virginia; Robles-Valero, Javier; Barreira, María; Bustelo, Xosé R.

    2015-01-01

    Coronin 1A (Coro1A) is involved in cytoskeletal and signaling events, including the regulation of Rac1 GTPase– and myosin II–dependent pathways. Mutations that generate truncated or unstable Coro1A proteins cause immunodeficiencies in both humans and rodents. However, in the case of the peripheral T-cell–deficient (Ptcd) mouse strain, the immunodeficiency is caused by a Glu-26-Lys mutation that targets a surface-exposed residue unlikely to affect the intramolecular architecture and stability of the protein. Here we report that this mutation induces pleiotropic effects in Coro1A protein, including the exacerbation of Coro1A-dependent actin-binding and -bundling activities; the formation of large meshworks of Coro1AE26K-decorated filaments endowed with unusual organizational, functional, and staining properties; and the elimination of Coro1A functions associated with both Rac1 and myosin II signaling. By contrast, it does not affect the ability of Coro1A to stimulate the nuclear factor of activated T-cells (NF-AT). Coro1AE26K is not a dominant-negative mutant, indicating that its pathological effects are derived from the inability to rescue the complete loss of the wild-type counterpart in cells. These results indicate that Coro1AE26K behaves as either a recessive gain-of-function or loss-of-function mutant protein, depending on signaling context and presence of the wild-type counterpart in cells. PMID:26108624

  4. UGT1A1*28 polymorphism in chronic lymphocytic leukemia: the first investigation of the polymorphism in disease susceptibility and its specific cytogenetic abnormalities.

    PubMed

    Karakosta, Maria; Kalotychou, Vassiliki; Kostakis, Alkiviadis; Pantelias, Gabriel; Rombos, Ioannis; Kouraklis, Gregory; Manola, Kalliopi N

    2014-01-01

    Chronic lymphocytic leukemia (CLL) has been recently attributed to a combination of genetic predisposition and exposure to environmental factors. UDP-glucuronosyltransferase (UGT)1A1*28 is an inborn polymorphism that results in significant downregulation of uridine diphosphate glucuronyltransferase 1-1 (UGT1A1) activity, one of the most critical metabolizing enzymes involved in the detoxification of toxic substances, some of which contribute to CLL pathogenesis. Here, for the first time, we investigated the putative impact of UGT1A1*28 on CLL incidence and on the formation of the most common chromosomal abnormalities of CLL. UGT1A1*28 was investigated in 109 CLL patients and 108 healthy controls, and was associated with karyotypic and fluorescence in situ hybridization (FISH) results. A significant high frequency of the mutant genotype was observed in patients carrying abnormal FISH patterns, especially del(11q) and +12, which are CLL-specific abnormalities. We also observed a significant association between UGT1A1*28 and the intermediate to unfavorable cytogenetic CLL risk groups. No difference, though, was observed in genotypes between patients and controls. Therefore, we could suggest that UGT-deficient individuals may be at a greater risk for developing CLL-specific abnormalities. Our study might serve as a starting point to consider UGT1A1*28 polymorphism as one of the possible predisposing factors of CLL pathogenesis. PMID:24458221

  5. Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.

    PubMed

    Yuan, Bo; Harel, Tamar; Gu, Shen; Liu, Pengfei; Burglen, Lydie; Chantot-Bastaraud, Sandra; Gelowani, Violet; Beck, Christine R; Carvalho, Claudia M B; Cheung, Sau Wai; Coe, Andrew; Malan, Valérie; Munnich, Arnold; Magoulas, Pilar L; Potocki, Lorraine; Lupski, James R

    2015-11-01

    The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability. PMID:26544804

  6. Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome

    PubMed Central

    Yuan, Bo; Harel, Tamar; Gu, Shen; Liu, Pengfei; Burglen, Lydie; Chantot-Bastaraud, Sandra; Gelowani, Violet; Beck, Christine R.; Carvalho, Claudia M.B.; Cheung, Sau Wai; Coe, Andrew; Malan, Valérie; Munnich, Arnold; Magoulas, Pilar L.; Potocki, Lorraine; Lupski, James R.

    2015-01-01

    The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability. PMID:26544804

  7. NDR1, a locus of Arabidopsis thaliana that is required for disease resistance to both a bacterial and a fungal pathogen.

    PubMed Central

    Century, K S; Holub, E B; Staskawicz, B J

    1995-01-01

    We have employed Arabidopsis thaliana as a model host plant to genetically dissect the molecular pathways leading to disease resistance. A. thaliana accession Col-0 is susceptible to the bacterial pathogen Pseudomonas syringae pv. tomato strain DC3000 but resistant in a race-specific manner to DC3000 carrying any one of the cloned avirulence genes avrB, avrRpm1, avrRpt2, and avrPph3. Fast-neutron-mutagenized Col-0 M2 seed was screened to identify mutants susceptible to DC3000(avrB). Disease assays and analysis of in planta bacterial growth identified one mutant, ndr1-1 (nonrace-specific disease resistance), that was susceptible to DC3000 expressing any one of the four avirulence genes tested. Interestingly, a hypersensitive-like response was still induced by several of the strains. The ndr1-1 mutation also rendered the plant susceptible to several avirulent isolates of the fungal pathogen Peronospora parasitica. Genetic analysis of ndr1-1 demonstrated that the mutation segregated as a single recessive locus, located on chromosome III. Characterization of the ndr1-1 mutation suggests that a common step exists in pathways of resistance to two unrelated pathogens. Images Fig. 1 PMID:11607554

  8. The global burden of myocarditis: part 1: a systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study.

    PubMed

    Cooper, Leslie T; Keren, Andre; Sliwa, Karen; Matsumori, Akira; Mensah, George A

    2014-03-01

    Myocarditis contributes to the global burden of cardiovascular disease primarily through sudden death and dilated cardiomyopathy. A systematic approach to identify the cardiovascular mortality and major morbidity attributable to myocarditis has not been performed. A writing group convened by the GBD 2010 (Global Burden of Diseases, Injuries and Risk Factors) Study systematically reviewed the world's literature by a manual review of all titles since 1966 on myocarditis identified using Ovid Medline, development of a disease model, and provision of estimates when possible of the incidence, prevalence, risk of death, and major morbidity for the world regions. Accurate population-based estimates of myocarditis incidence and prevalence are not directly available in any world region. However, a model that quantitates the risk of acute death and chronic heart failure following myocarditis was derived from the published data. Using hospital dismissal data, the burden of myocarditis as a percentage of prevalent heart failure varied by age and region from approximately 0.5% to 4.0%. The novel combination of multiple data sources may provide an estimate of the years of life lost and years of life disabled from myocarditis. Pending the integration of these data sources, the burden of dilated cardiomyopathy and myocarditis were reported together in the 2010 GBD report. The 2013 GBD project may refine these estimates with the inclusion of more comprehensive payor databases and more precise case definitions. PMID:25432122

  9. AAV1.NT-3 Gene Therapy for Charcot–Marie–Tooth Neuropathy

    PubMed Central

    Sahenk, Zarife; Galloway, Gloria; Clark, Kelly Reed; Malik, Vinod; Rodino-Klapac, Louise R; Kaspar, Brian K.; Chen, Lei; Braganza, Cilwyn; Montgomery, Chrystal; Mendell, Jerry R

    2014-01-01

    Charcot–Marie–Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the tremblerJ (TrJ) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the TrJ model of demyelinating CMT, rAAV1.NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for functional improvement and established the therapeutic dose and a preferential muscle-specific promoter to achieve sustained NT-3 levels. These studies of intramuscular (i.m.) delivery of rAAV1.NT-3 serve as a template for future CMT1A clinical trials with a potential to extend treatment to other nerve diseases with impaired nerve regeneration. PMID:24162799

  10. FC-TRIPLEX Chagas/Leish IgG1: a multiplexed flow cytometry method for differential serological diagnosis of chagas disease and leishmaniasis.

    PubMed

    Teixeira-Carvalho, Andréa; Campos, Fernanda Magalhães Freire; Geiger, Stefan Michael; Rocha, Roberta Dias Rodrigues; de Araújo, Fernanda Fortes; Vitelli-Avelar, Danielle Marquete; Andrade, Mariléia Chaves; Araújo, Márcio Sobreira Silva; Lemos, Elenice Moreira; de Freitas Carneiro Proietti, Anna Bárbara; Sabino, Ester Cerdeira; Caldas, Rafaella Gaiotti; Freitas, Carolina Renata Camargos; Campi-Azevedo, Ana Carolina; Elói-Santos, Silvana Maria; Martins-Filho, Olindo Assis

    2015-01-01

    Differential serological diagnosis of Chagas disease and leishmaniasis is difficult owing to cross-reactivity resulting from the fact that the parasites that cause these pathologies share antigenic epitopes. Even with optimized serological assays that use parasite-specific recombinant antigens, inconclusive test results continue to be a problem. Therefore, new serological tests with high sensitivity and specificity are needed. In the present work, we developed and evaluated the performance of a new flow cytometric serological method, referred to as FC-TRIPLEX Chagas/Leish IgG1, for the all-in-one classification of inconclusive tests. The method uses antigens for the detection of visceral leishmaniasis, localized cutaneous leishmaniasis, and Chagas disease and is based on an inverted detuned algorithm for analysis of anti-Trypanosomatidae IgG1 reactivity. First, parasites were label with fluorescein isothiocyanate or Alexa Fluor 647 at various concentrations. Then serum samples were serially diluted, the dilutions were incubated with suspensions of mixed labeled parasites, and flow cytometric measurements were performed to determine percentages of positive fluorescent parasites. Using the new method, we obtained correct results for 76 of 80 analyzed serum samples (95% overall performance), underscoring the outstanding performance of the method. Moreover, we found that the fluorescently labeled parasite suspensions were stable during storage at room temperature, 4 °C, and -20 °C for 1 year. In addition, two different lots of parasite suspensions showed equivalent antigen recognition; that is, the two lots showed equivalent categorical segregation of anti-Trypanosomatidae IgG1 reactivity at selected serum dilutions. In conclusion, we have developed a sensitive and selective method for differential diagnosis of Chagas disease, visceral leishmaniasis, and localized cutaneous leishmaniasis. PMID:25875961

  11. FC-TRIPLEX Chagas/Leish IgG1: A Multiplexed Flow Cytometry Method for Differential Serological Diagnosis of Chagas Disease and Leishmaniasis

    PubMed Central

    Teixeira-Carvalho, Andréa; Campos, Fernanda Magalhães Freire; Geiger, Stefan Michael; Rocha, Roberta Dias Rodrigues; de Araújo, Fernanda Fortes; Vitelli-Avelar, Danielle Marquete; Andrade, Mariléia Chaves; Araújo, Márcio Sobreira Silva; Lemos, Elenice Moreira; de Freitas Carneiro Proietti, Anna Bárbara; Sabino, Ester Cerdeira; Caldas, Rafaella Gaiotti; Freitas, Carolina Renata Camargos; Campi-Azevedo, Ana Carolina; Elói-Santos, Silvana Maria; Martins-Filho, Olindo Assis

    2015-01-01

    Differential serological diagnosis of Chagas disease and leishmaniasis is difficult owing to cross-reactivity resulting from the fact that the parasites that cause these pathologies share antigenic epitopes. Even with optimized serological assays that use parasite-specific recombinant antigens, inconclusive test results continue to be a problem. Therefore, new serological tests with high sensitivity and specificity are needed. In the present work, we developed and evaluated the performance of a new flow cytometric serological method, referred to as FC-TRIPLEX Chagas/Leish IgG1, for the all-in-one classification of inconclusive tests. The method uses antigens for the detection of visceral leishmaniasis, localized cutaneous leishmaniasis, and Chagas disease and is based on an inverted detuned algorithm for analysis of anti-Trypanosomatidae IgG1 reactivity. First, parasites were label with fluorescein isothiocyanate or Alexa Fluor 647 at various concentrations. Then serum samples were serially diluted, the dilutions were incubated with suspensions of mixed labeled parasites, and flow cytometric measurements were performed to determine percentages of positive fluorescent parasites. Using the new method, we obtained correct results for 76 of 80 analyzed serum samples (95% overall performance), underscoring the outstanding performance of the method. Moreover, we found that the fluorescently labeled parasite suspensions were stable during storage at room temperature, 4°C, and –20°C for 1 year. In addition, two different lots of parasite suspensions showed equivalent antigen recognition; that is, the two lots showed equivalent categorical segregation of anti-Trypanosomatidae IgG1 reactivity at selected serum dilutions. In conclusion, we have developed a sensitive and selective method for differential diagnosis of Chagas disease, visceral leishmaniasis, and localized cutaneous leishmaniasis. PMID:25875961

  12. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease.

    PubMed

    Fujita, Kyota; Motoki, Kazumi; Tagawa, Kazuhiko; Chen, Xigui; Hama, Hiroshi; Nakajima, Kazuyuki; Homma, Hidenori; Tamura, Takuya; Watanabe, Hirohisa; Katsuno, Masahisa; Matsumi, Chiemi; Kajikawa, Masunori; Saito, Takashi; Saido, Takaomi; Sobue, Gen; Miyawaki, Atsushi; Okazawa, Hitoshi

    2016-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis is predominantly attributed to the aggregation and transmission of two molecules, Aβ and tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network, occurs at Ser46 prior to aggregation of Aβ and is sustained throughout the course of AD in human and mouse brains. Furthermore, HMGB1 released from necrotic or hyperexcitatory neurons binds to TLR4, triggers the specific phosphorylation of MARCKS via MAP kinases, and induces neurite degeneration, the classical hallmark of AD pathology. Subcutaneous injection of a newly developed monoclonal antibody against HMGB1 strongly inhibits neurite degeneration even in the presence of Aβ plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and Aβ mutually affect polymerization of the other molecule, and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by Aβ-dependent and Aβ-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with Aβ and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD. PMID:27557632

  13. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease

    PubMed Central

    Fujita, Kyota; Motoki, Kazumi; Tagawa, Kazuhiko; Chen, Xigui; Hama, Hiroshi; Nakajima, Kazuyuki; Homma, Hidenori; Tamura, Takuya; Watanabe, Hirohisa; Katsuno, Masahisa; Matsumi, Chiemi; Kajikawa, Masunori; Saito, Takashi; Saido, Takaomi; Sobue, Gen; Miyawaki, Atsushi; Okazawa, Hitoshi

    2016-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis is predominantly attributed to the aggregation and transmission of two molecules, Aβ and tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network, occurs at Ser46 prior to aggregation of Aβ and is sustained throughout the course of AD in human and mouse brains. Furthermore, HMGB1 released from necrotic or hyperexcitatory neurons binds to TLR4, triggers the specific phosphorylation of MARCKS via MAP kinases, and induces neurite degeneration, the classical hallmark of AD pathology. Subcutaneous injection of a newly developed monoclonal antibody against HMGB1 strongly inhibits neurite degeneration even in the presence of Aβ plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and Aβ mutually affect polymerization of the other molecule, and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by Aβ-dependent and Aβ-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with Aβ and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD. PMID:27557632

  14. A lentiviral vector with expression controlled by E2F-1: A potential tool for the study and treatment of proliferative diseases

    SciTech Connect

    Strauss, Bryan E.; Vieira de Carvalho, Anna Carolina; Bajgelman, Marcio C.

    2006-10-06

    We have constructed a lentiviral vector with expression limited to cells presenting active E2F-1 protein, a potential advantage for gene therapy of proliferative diseases. For the FE2FLW vector, the promoter region of the human E2F-1 gene was utilized to drive expression of luciferase cDNA, included as a reporter of viral expression. Primary, immortalized, and transformed cells were transduced with the FE2FLW vector and cell cycle alterations were induced with serum starvation/replacement, contact inhibition or drug treatment, revealing cell cycle-dependent changes in reporter activity. Forced E2F-1 expression, but not E2F-2 or E2F-3, increased reporter activity, indicating a major role for this factor in controlling expression from the FE2FLW virus. We show the utility of this vector as a reporter of E2F-1 and proliferation-dependent cellular alterations upon cytotoxic/cytostatic treatment, such as the introduction of tumor suppressor genes. We propose that the FE2FLW vector may be a starting point for the development of gene therapy strategies for proliferative diseases, such as cancer or restinosis.

  15. A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis.

    PubMed

    Torices, Silvia; Alvarez-Rodríguez, Lorena; Grande, Lara; Varela, Ignacio; Muñoz, Pedro; Pascual, Dora; Balsa, Alejandro; López-Hoyos, Marcos; Martinez-Taboada, Víctor; Fernández-Luna, Jose L

    2015-12-01

    Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-κB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-κB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-κB target genes (TRAIL, TNF-α, cIAP-1, IL8) and blocks activation of a NF-κB-luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-κB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-κB and the secretion of TNF-α in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-κB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA. PMID:26503956

  16. Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

    PubMed Central

    Wilson, Caroline L.; Murphy, Lindsay B.; Leslie, Jack; Kendrick, Stuart; French, Jeremy; Fox, Christopher R.; Sheerin, Neil S.; Fisher, Andrew; Robinson, John H.; Tiniakos, Dina G.; Gray, Douglas A.; Oakley, Fiona; Mann, Derek A.

    2016-01-01

    Background & Aims Ubiquitination is a reversible protein modification involved in the major cellular processes that define cell phenotype and behaviour. Ubiquitin modifications are removed by a large family of proteases named deubiquitinases. The role of deubiquitinases in hepatic stellate cell (HSC) activation and their contribution to fibrogenesis are poorly defined. We have identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation, determined its function in activated HSC and its potential as a therapeutic target for fibrosis. Methods Deubiquitinase expression was determined in day 0 and day 10 HSC. Increased UCHL1 expression was confirmed in human HSC and in an alcoholic liver disease (ALD) patient liver. The importance of UCHL1 in hepatic fibrosis was investigated in CCl4 and bile duct ligation injured mice using a pharmacological inhibitor (LDN 57444). The effects of UCHL1 inhibition on HSC proliferation were confirmed by Western blot and 3H thymidine incorporation. Results Here we report that pharmacological inhibition of UCHL1 blocks progression of established fibrosis in CCl4 injured mice. UCHL1 siRNA knockdown, LDN 57444 treatment, or HSC isolated from UCHL1–/– mice show attenuated proliferation in response to the mitogen, platelet-derived growth factor. Additionally, we observed changes in the phosphorylation of the cell cycle regulator retinoblastoma protein (Rb) in the absence of UCHL1 highlighting a potential mechanism for the reduced proliferative response. Conclusions UCHL1 expression is highly upregulated upon HSC activation and is involved in the regulation of HSC proliferation. This study highlights therapeutic opportunities for pharmacological targeting of UCHL1 in chronic liver disease. PMID:26264933

  17. Rer1 and calnexin regulate endoplasmic reticulum retention of a peripheral myelin protein 22 mutant that causes type 1A Charcot-Marie-Tooth disease

    PubMed Central

    Hara, Taichi; Hashimoto, Yukiko; Akuzawa, Tomoko; Hirai, Rika; Kobayashi, Hisae; Sato, Ken

    2014-01-01

    Peripheral myelin protein 22 (PMP22) resides in the plasma membrane and is required for myelin formation in the peripheral nervous system. Many PMP22 mutants accumulate in excess in the endoplasmic reticulum (ER) and lead to the inherited neuropathies of Charcot-Marie-Tooth (CMT) disease. However, the mechanism through which PMP22 mutants accumulate in the ER is unknown. Here, we studied the quality control mechanisms for the PMP22 mutants L16P and G150D, which were originally identified in mice and patients with CMT. We found that the ER-localised ubiquitin ligase Hrd1/SYVN1 mediates ER-associated degradation (ERAD) of PMP22(L16P) and PMP22(G150D), and another ubiquitin ligase, gp78/AMFR, mediates ERAD of PMP22(G150D) as well. We also found that PMP22(L16P), but not PMP22(G150D), is partly released from the ER by loss of Rer1, which is a Golgi-localised sorting receptor for ER retrieval. Rer1 interacts with the wild-type and mutant forms of PMP22. Interestingly, release of PMP22(L16P) from the ER was more prominent with simultaneous knockdown of Rer1 and the ER-localised chaperone calnexin than with the knockdown of each gene. These results suggest that CMT disease-related PMP22(L16P) is trapped in the ER by calnexin-dependent ER retention and Rer1-mediated early Golgi retrieval systems and partly degraded by the Hrd1-mediated ERAD system. PMID:25385046

  18. The levels of 7,8-dihydrodeoxyguanosine (8-oxoG) and 8-oxoguanine DNA glycosylase 1 (OGG1) - A potential diagnostic biomarkers of Alzheimer's disease.

    PubMed

    Sliwinska, Agnieszka; Kwiatkowski, Dominik; Czarny, Piotr; Toma, Monika; Wigner, Paulina; Drzewoski, Jozef; Fabianowska-Majewska, Krystyna; Szemraj, Janusz; Maes, Michael; Galecki, Piotr; Sliwinski, Tomasz

    2016-09-15

    Evidence indicates that oxidative stress contributes to neuronal cell death in Alzheimer's disease (AD). Increased oxidative DNA damage l, as measured with 8-oxoguanine (8-oxoG), and reduced capacity of proteins responsible for removing of DNA damage, including 8-oxoguanine DNA glycosylase 1 (OGG1), were detected in brains of AD patients. In the present study we assessed peripheral blood biomarkers of oxidative DNA damage, i.e. 8- oxoG and OGG1, in AD diagnosis, by comparing their levels between the patients and the controls. Our study was performed on DNA and serum isolated from peripheral blood taken from 100 AD patients and 110 controls. For 8-oxoG ELISA was employed. The OGG1 level was determined using ELISA and Western blot technique. Levels of 8-oxoG were significantly higher in DNA of AD patients. Both ELISA and Western blot showed decreased levels of OGG1 in serum of AD patients. Our results show that oxidative DNA damage biomarkers detected in peripheral tissue could reflect the changes occurring in the brain of patients with AD. These results also suggest that peripheral blood samples may be useful to measure oxidative stress biomarkers in AD. PMID:27538622

  19. Hologram QSAR Models of a Series of 6-Arylquinazolin-4-Amine Inhibitors of a New Alzheimer’s Disease Target: Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase-1A Enzyme

    PubMed Central

    Leal, Felipe Dias; da Silva Lima, Camilo Henrique; de Alencastro, Ricardo Bicca; Castro, Helena Carla; Rodrigues, Carlos Rangel; Albuquerque, Magaly Girão

    2015-01-01

    Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A) is an enzyme directly involved in Alzheimer’s disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based) models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test) of DYRK1A. The best HQSAR model (q2 = 0.757; SEcv = 0.493; R2 = 0.937; SE = 0.251; R2pred = 0.659) presents high goodness-of-fit (R2 > 0.9), as well as high internal (q2 > 0.7) and external (R2pred > 0.5) predictive power. The fragments that increase and decrease the biological activity values were addressed using the colored atomic contribution maps provided by the method. The HQSAR contribution map of the best model is an important tool to understand the activity profiles of new derivatives and may provide information for further design of novel DYRK1A inhibitors. PMID:25756379

  20. Interferon Beta-1a Intramuscular Injection

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS, a disease in which ... interferon beta-1a intramuscular at around the same time of day on your injection days. Follow the ...

  1. Elephant Endotheliotropic Herpesviruses EEHV1A, EEHV1B, and EEHV2 from Cases of Hemorrhagic Disease Are Highly Diverged from Other Mammalian Herpesviruses and May Form a New Subfamily

    PubMed Central

    Richman, Laura K.; Zong, Jian-Chao; Latimer, Erin M.; Lock, Justin; Fleischer, Robert C.; Heaggans, Sarah Y.

    2014-01-01

    ABSTRACT A family of novel endotheliotropic herpesviruses (EEHVs) assigned to the genus Proboscivirus have been identified as the cause of fatal hemorrhagic disease in 70 young Asian elephants worldwide. Although EEHV cannot be grown in cell culture, we have determined a total of 378 kb of viral genomic DNA sequence directly from clinical tissue samples from six lethal cases and two survivors. Overall, the data obtained encompass 57 genes, including orthologues of 32 core genes common to all herpesviruses, 14 genes found in some other herpesviruses, plus 10 novel genes, including a single large putative transcriptional regulatory protein (ORF-L). On the basis of differences in gene content and organization plus phylogenetic analyses of conserved core proteins that have just 20% to 50% or less identity to orthologues in other herpesviruses, we propose that EEHV1A, EEHV1B, and EEHV2 could be considered a new Deltaherpesvirinae subfamily of mammalian herpesviruses that evolved as an intermediate branch between the Betaherpesvirinae and Gammaherpesvirinae. Unlike cytomegaloviruses, EEHV genomes encode ribonucleotide kinase B subunit (RRB), thymidine kinase (TK), and UL9-like origin binding protein (OBP) proteins and have an alphaherpesvirus-like dyad symmetry Ori-Lyt domain. They also differ from all known betaherpesviruses by having a 40-kb large-scale inversion of core gene blocks I, II, and III. EEHV1 and EEHV2 DNA differ uniformly by more than 25%, but EEHV1 clusters into two major subgroups designated EEHV1A and EEHV1B with ancient partially chimeric features. Whereas large segments are nearly identical, three nonadjacent loci totaling 15 kb diverge by between 21 and 37%. One strain of EEHV1B analyzed is interpreted to be a modern partial recombinant with EEHV1A. IMPORTANCE Asian elephants are an endangered species whose survival is under extreme pressure in wild range countries and whose captive breeding populations in zoos are not self-sustaining. In 1999, a

  2. Mitochondrial Genomic Analysis of Late Onset Alzheimer’s Disease Reveals Protective Haplogroups H6A1A/H6A1B: The Cache County Study on Memory in Aging

    PubMed Central

    Ridge, Perry G.; Maxwell, Taylor J.; Corcoran, Christopher D.; Norton, Maria C.; Tschanz, JoAnn T.; O’Brien, Elizabeth; Kerber, Richard A.; Cawthon, Richard M.; Munger, Ronald G.; Kauwe, John S. K.

    2012-01-01

    Background Alzheimer’s disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain. Methodology/Principal Findings We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. Conclusions/Significance Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary. PMID:23028804

  3. Amylase α-1A (AMY1A)

    PubMed Central

    Jain, Sarika; Roy, Somak; Amin, Milon; Acquafondata, Marie; Yin, Ming; LaFramboise, William; Bastacky, Sheldon; Pantanowitz, Liron; Dhir, Rajiv; Parwani, Anil

    2014-01-01

    Chromophobe renal cell carcinoma (ChRCC) and oncocytoma present with a perplexing overlap of morphologic and immunohistochemical features. ChRCC have deletions in the 1p21.1 region including the amylase α-1A gene (AMY1A). No such deletions are found in oncocytoma. Instead, oncocytomas shared other deletions on chromosome 1: 1p31.3, 1q25.2, and 1q44. We performed AMY1A immunostaining on 75 oncocytomas (57 tissue microarray [TMA] cores, 18 whole slides) and 54 ChRCCs (20 TMA cores, 34 whole slides). Staining was assessed using the H-score method. The intensity was graded as follows: no staining=0, weak=1, moderate=2, and strong=3. The AMY1A immunostain preferentially stained the distal tubules and collecting ducts of normal kidney. All oncocytomas (100%) expressed AMY1A with an H-score that varied from 100 to 300 (mean 205). Mild to moderate heterogeneity in staining intensity was noted within a given oncocytoma. For oncocytomas, 87% (65/75) cases had H-scores of at least 120 with a mean score of 221. Notably, the 13% (10/75) of oncocytoma cases that had an H-score of 100 were derived from the TMA. A total of 87% (47/54) of the ChRCC cases were negative for the AMY1A immunostain. Of the ChRCC cases, 4% (2/54) showed very weak cytoplasmic staining (H-score of 70 each), which was less than the lowest H-score of oncocytoma cases. All 5 cases of ChRCC, which showed an H-score of 100 or more, were referred to as eosinophilic variants of ChRCC. Three of these 5 cases showed a very nondescript, diffuse staining of the cytoplasm. Two of these 5 cases showed an H-score of 130. We think that as the staining pattern of these 2 cases is similar to that of oncocytoma, they should be put in a category of renal oncocytic neoplasms favoring oncocytoma. This result shows that AMY1A staining could be very helpful in further classifying even a subset of the eosinophilic variants of ChRCC. The difference between ChRCC and oncocytoma was statistically significant (χ2 test, P<0

  4. The modified ultrasound pattern sum score mUPSS as additional diagnostic tool for genetically distinct hereditary neuropathies.

    PubMed

    Grimm, Alexander; Rasenack, Maria; Athanasopoulou, Ioanna M; Dammeier, Nele Maria; Lipski, Christina; Wolking, Stefan; Vittore, Debora; Décard, Bernhard F; Axer, Hubertus

    2016-02-01

    The objective of this study is to evaluate the nerve ultrasound characteristics in genetically distinct inherited neuropathies, the value of the modified ultrasound pattern sum score (mUPSS) to differentiate between the subtypes and the correlation of ultrasound with nerve conduction studies (NCS), disease duration and severity. All patients underwent a standardized neurological examination, ultrasound, and NCS. In addition, genetic testing was performed. Consequently, mUPSS was applied, which is a sum-score of cross-sectional areas (CSA) at predefined anatomical points in different nerves. 31 patients were included (10xCharcot-Marie-Tooth (CMT)1a, 3xCMT1b, 3xCMTX, 9xCMT2, 6xHNPP [Hereditary neuropathy with liability to pressure palsies]). Generalized, homogeneous nerve enlargement and significantly increased UPS scores emphasized the diagnosis of demyelinating neuropathy, particularly CMT1a and CMT1b. The amount of enlargement did not depend on disease duration, symptom severity, height and weight. In CMTX the nerves were enlarged, as well, however, only in the roots and lower limbs, most prominent in men. In CMT2 no significant enlargement was detectable. In HNPP the CSA values were increased at entrapped sites, and not elsewhere. However, a distinction from CMT1, which also showed enlarged CSA values at entrapment sites, was only possible by calculating the entrapment ratios and entrapment score. The mUPSS allowed distinction between CMT1a (increased UPS scores, entrapment ratios <1.0) and HNPP (low UPS scores, entrapment ratios >1.4), while CMT1b and CMTX showed intermediate UPS types and entrapment ratios <1.0. Although based on few cases, ultrasound revealed consistent and homogeneous nerve alteration in certain inherited neuropathies. The modified UPSS is a quantitative tool, which may provide useful information for diagnosis, differentiation and follow-up evaluation in addition to NCS and molecular testing. PMID:26559821

  5. Inherited neuropathies.

    PubMed

    Chance, P F; Reilly, M

    1994-10-01

    Charcot-Marie-Tooth neuropathy (CMT) type 1 is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX), and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-Mb duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. CMTX is associated with mutations in the connexin 32 gene. CMT2 is an axonal neuropathy of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A). Dejerine-Sottas disease is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the P0 gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. Most examples of CMT1A and HNPP are reciprocal duplication or deletion syndromes originating from unequal crossover during germ cell meiosis. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disorder that classically presents with a sensory peripheral neuropathy and early autonomic involvement. Transthyretin (TTR) is the most common constituent amyloid fibril protein deposited in FAP, and there are now 28 point mutations in the TTR gene described in TTR-related FAP. Liver transplantation looks promising as a treatment for TTR-related FAP. PMID:7804455

  6. MIL1A

    Atmospheric Science Data Center

    2014-09-03

    ... MISR Level 1A camera charge-coupled device (CCD) Science Data: Reformatted Annotated Level 1A product of the CCD science data. ... :  Data Product Specification Versioning History:  Ellipsoid, Terrain, Browse, CCD, Radiance SCAR-B ...

  7. Interferon Beta-1a Intramuscular Injection

    MedlinePlus

    ... symptoms flare up from time to time) of multiple sclerosis (MS, a disease in which the nerves do not ... known how interferon beta-1a works to treat MS. ... doctor.Interferon beta-1a controls the symptoms of MS but does not cure it. Continue to use ...

  8. Clinical implications of peripheral myelin protein 22 for nerve compression and neural regeneration: a review.

    PubMed

    Hui-Chou, Helen G; Hashemi, Sharyhar S; Hoke, Ahmet; Dellon, A Lee

    2011-01-01

    Peripheral myelin protein 22 (PMP22) is a major component of the peripheral myelin sheath. The PMP22 gene is located on chromosome 17p11.2, and defects in PMP22 gene have been implicated in several common inherited peripheral neuropathies. Hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie Tooth disease type 1A (CMT1A), Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy are all associated with defects in PMP22 gene. The disease phenotypes mirror the range of expression of PMP22 due to the corresponding genetic defect. HNPP, characterized by a milder recurrent episodic focal demyelinating neuropathy, is attributed to a deletion leading to PMP22 underexpression. On the other end of the spectrum, CMT1A leads to a more uniform demyelination and axonal loss, resulting in severe progressive distal weakness and paresthesias; it is due to a duplication at 17p11.2 leading to PMP22 overexpression. Additional point mutations result in varying phenotypes due to dysfunction of the resultant PMP22 protein. All inherited neuropathies are diagnosed with a combination of physical findings on examination, electromyography, sural nerve biopsies, and genetic testing. Treatment and management of these disorders differ depending on the underlying genetic defect, nerves involved, and resulting functional impairments. A review of current literature elucidates clinical, microsurgical implications, and management of patients with PMP22-related neuropathy. PMID:20976668

  9. U1A Complex

    SciTech Connect

    2014-10-28

    Some of the most sophisticated experiments in the stockpile stewardship program are conducted in an environmentally safe manner, nearly 1000 feet below the ground at the site. The U1a complex a sprawling underground laboratory and tunnel complex is home to a number of unique capabilities.

  10. U1A Complex

    ScienceCinema

    None

    2015-01-09

    Some of the most sophisticated experiments in the stockpile stewardship program are conducted in an environmentally safe manner, nearly 1000 feet below the ground at the site. The U1a complex a sprawling underground laboratory and tunnel complex is home to a number of unique capabilities.

  11. A Chromosomal Rearrangement Hotspot Can Be Identified from Population Genetic Variation and Is Coincident with a Hotspot for Allelic Recombination

    PubMed Central

    Lindsay, Sarah J.; Khajavi, Mehrdad; Lupski, James R.; Hurles, Matthew E.

    2006-01-01

    Insights into the origins of structural variation and the mutational mechanisms underlying genomic disorders would be greatly improved by a genomewide map of hotspots of nonallelic homologous recombination (NAHR). Moreover, our understanding of sequence variation within the duplicated sequences that are substrates for NAHR lags far behind that of sequence variation within the single-copy portion of the genome. Perhaps the best-characterized NAHR hotspot lies within the 24-kb-long Charcot-Marie-Tooth disease type 1A (CMT1A)–repeats (REPs) that sponsor deletions and duplications that cause peripheral neuropathies. We investigated structural and sequence diversity within the CMT1A-REPs, both within and between species. We discovered a high frequency of retroelement insertions, accelerated sequence evolution after duplication, extensive paralogous gene conversion, and a greater than twofold enrichment of SNPs in humans relative to the genome average. We identified an allelic recombination hotspot underlying the known NAHR hotspot, which suggests that the two processes are intimately related. Finally, we used our data to develop a novel method for inferring the location of an NAHR hotspot from sequence variation within segmental duplications and applied it to identify a putative NAHR hotspot within the LCR22 repeats that sponsor velocardiofacial syndrome deletions. We propose that a large-scale project to map sequence variation within segmental duplications would reveal a wealth of novel chromosomal-rearrangement hotspots. PMID:17033965

  12. RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases γ-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model.

    PubMed

    Rivers, Angela; Vaitkus, Kestis; Ruiz, Maria Armila; Ibanez, Vinzon; Jagadeeswaran, Ramasamy; Kouznetsova, Tatiana; DeSimone, Joseph; Lavelle, Donald

    2015-07-01

    Increased levels of fetal hemoglobin are associated with decreased symptoms and increased lifespan in patients with sickle cell disease (SCD). Hydroxyurea, the only drug currently approved for SCD, is not effective in a large fraction of patients, and therefore, new agents are urgently needed. Recently it was found that lysine demethylase 1, an enzyme that removes monomethyl and dimethyl residues from the lysine 4 residue of histone H3, is a repressor of γ-globin gene expression. In this article, we have compared the ability of tranylcypromine (TCP) and a more potent TCP derivative, RN-1, to increase γ-globin expression in cultured baboon erythroid progenitor cells and in the SCD mouse model. The results indicate that the ability of RN-1 to induce F cells and γ-globin mRNA in SCD mice is similar to that of decitabine, the most powerful fetal hemoglobin-inducing drug known, and greater than that of either TCP or hydroxyurea. We conclude that RN-1 and other lysine demethylase 1 inhibitors may be promising new γ-globin-inducing agents for the treatment of SCD that warrant further studies in other preclinical models, such as nonhuman primates. PMID:25931013

  13. The proteolipid protein gene: Double, double, . . . and trouble

    SciTech Connect

    Hodes, M.E.; Dlouhy, S.R.

    1996-07-01

    That more of a good thing may be too much has been apparent at least since the discovery that Down syndrome is caused by three copies of chromosome 21 instead of the normal two. Duplications of myelin genes also lead to trouble. An extra dose of PMP22, the gene for a protein of peripheral nervous system myelin, causes Charcot-Marie Tooth type 1A disease (CMT1A). Increased dosage of the proteolipid protein gene, PLP, which encodes the chief protein of CNS myelin, can cause Pelizaeus-Merzbacher disease (PMD). The work of Inoue et al. is of particular importance because they found the duplication in four of five families with {open_quotes}classical{close_quotes} PMD, whereas other changes in PLP, such as missense mutations, are found in no more than one in four or five patients with the disease. 27 refs.

  14. Phosphodiesterase 1A Modulates Cystogenesis in Zebrafish

    PubMed Central

    Ward, Christopher J.; Leightner, Amanda C.; Smith, Jordan L.; Agarwal, Reema; Harris, Peter C.; Torres, Vicente E.

    2014-01-01

    Substantial evidence indicates the importance of elevated cAMP in polycystic kidney disease (PKD). Accumulation of cAMP in cystic tissues may be, in part, caused by enhanced adenylyl cyclase activity, but inhibition of cAMP degradation by phosphodiesterases (PDE) likely has an important role, because cAMP is inactivated much faster than it is synthesized. PDE1 is the only PDE family activated by Ca2+, which is reduced in PKD cells. To assess the contribution of the PDE1A subfamily to renal cyst formation, we examined the expression and function of PDE1A in zebrafish. We identified two splice isoforms with alternative starts corresponding to human PDE1A1 and PDE1A4. Expression of the two isoforms varied in embryos and adult tissues, and both isoforms hydrolyzed cAMP with Ca2+/calmodulin dependence. Depletion of PDE1A in zebrafish embryos using splice- and translation-blocking morpholinos (MOs) caused pronephric cysts, hydrocephalus, and body curvature. Human PDE1A RNA and the PKA inhibitors, H89 and Rp-cAMPS, partially rescued phenotypes of pde1a morphants. Additionally, MO depletion of PDE1A aggravated phenotypes in pkd2 morphants, causing more severe body curvature, and human PDE1A RNA partially rescued pkd2 morphant phenotypes, pronephric cysts, hydrocephalus, and body curvature. Together, these data indicate the integral role of PDE1A and cAMP signaling in renal development and cystogenesis, imply that PDE1A activity is altered downstream of polycystin-2, and suggest that PDE1A is a viable drug target for PKD. PMID:24700876

  15. Human TBK1: A Gatekeeper of Neuroinflammation.

    PubMed

    Ahmad, Liyana; Zhang, Shen-Ying; Casanova, Jean-Laurent; Sancho-Shimizu, Vanessa

    2016-06-01

    The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases. PMID:27211305

  16. B-1a Lymphocytes Attenuate Insulin Resistance

    PubMed Central

    Shen, Lei; Chng, MH; Alonso, Michael N.; Yuan, Robert

    2015-01-01

    Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell–derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell–deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell–activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell–depleting, B-1a cell–sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance. PMID:25249575

  17. MISR Level 1A Products

    Atmospheric Science Data Center

    2013-04-01

    ... MISR Level 1A Products Level 1A Engineering Data File Type 1 and Level 1A Navigation Data Processing ... Product Specification Rev K  (PDF). Transparent software rebuild with Irix 6.5.2 OS. F01_0007 (FM_ENG), ...

  18. Distinct neurological disorders with ATP1A3 mutations

    PubMed Central

    Heinzen, Erin L.; Arzimanoglou, Alexis; Brashear, Allison; Clapcote, Steven J.; Gurrieri, Fiorella; Goldstein, David B.; Jóhannesson, Sigurður H.; Mikati, Mohamad A.; Neville, Brian; Nicole, Sophie; Ozelius, Laurie J.; Poulsen, Hanne; Schyns, Tsveta; Sweadner, Kathleen J.; van den Maagdenberg, Arn; Vilsen, Bente

    2014-01-01

    Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na+/K+-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in vitro and animal model systems, and the role of Na+/K+-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases. PMID:24739246

  19. Distinct neurological disorders with ATP1A3 mutations.

    PubMed

    Heinzen, Erin L; Arzimanoglou, Alexis; Brashear, Allison; Clapcote, Steven J; Gurrieri, Fiorella; Goldstein, David B; Jóhannesson, Sigurður H; Mikati, Mohamad A; Neville, Brian; Nicole, Sophie; Ozelius, Laurie J; Poulsen, Hanne; Schyns, Tsveta; Sweadner, Kathleen J; van den Maagdenberg, Arn; Vilsen, Bente

    2014-05-01

    Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases. PMID:24739246

  20. Animal models for inherited peripheral neuropathies

    PubMed Central

    MARTINI, RUDOLF

    1997-01-01

    Recent progress in human genetics and neurobiology has led to the identification of various mutations in particular myelin genes as the cause for many of the known inherited demyelinating peripheral neuropathies. Mutations in 3 distinct myelin genes, PMP22, P0, and connexin 32 cause the 3 major demyelinating subtypes of Charcot-Marie-Tooth (CMT) disease, CMT1A, CMT1B and CMTX, respectively. In addition, a reduction in the gene dosage of PMP22 causes hereditary neuropathy with liability to pressure palsies (HNPP), while particular point mutations in PMP22 and P0 cause the severe Dejerine-Sottas (DS) neuropathy. A series of spontaneous and genetically engineered rodent mutants for genes for the above-mentioned myelin constituents are now available and their suitability to serve as models for these still untreatable diseases is an issue of particular interest. The spontaneous mutants Trembler-J and Trembler, with point mutations in PMP22, reflect some of the pathological alterations seen in CMT1A and DS patients, respectively. Furthermore, engineered mutants that either over or underexpress particular myelin genes are suitable models for patients who are similarly compromised in the gene dosage of the corresponding genes. In addition, engineered mutants heterozygously or homozygously deficient in the myelin component P0 show the pathology of distinct CMT1B and DS patients, respectively, while Cx32 deficient mice develop pathological abnormalities similar to those of CMTX patients. Mutants that mimic human peripheral neuropathies might allow the development of strategies to alleviate the symptoms of the diseases, and help to define environmental risk factors for aggravation of the disease. In addition, such mutants might be instrumental in the development of strategies to cure the diseases by gene therapy. PMID:9418989

  1. Animal models for inherited peripheral neuropathies.

    PubMed

    Martini, R

    1997-10-01

    Recent progress in human genetics and neurobiology has led to the identification of various mutations in particular myelin genes as the cause for many of the known inherited demyelinating peripheral neuropathies. Mutations in 3 distinct myelin genes, PMP22, P0, and connexin 32 cause the 3 major demyelinating subtypes of Charcot-Marie-Tooth (CMT) disease, CMT1A, CMT1B and CMTX, respectively. In addition, a reduction in the gene dosage of PMP22 causes hereditary neuropathy with liability to pressure palsies (HNPP), while particular point mutations in PMP22 and P0 cause the severe Dejerine-Sottas (DS) neuropathy. A series of spontaneous and genetically engineered rodent mutants for genes for the above-mentioned myelin constituents are now available and their suitability to serve as models for these still untreatable diseases is an issue of particular interest. The spontaneous mutants Trembler-J and Trembler, with point mutations in PMP22, reflect some of the pathological alterations seen in CMT1A and DS patients, respectively. Furthermore, engineered mutants that either over or underexpress particular myelin genes are suitable models for patients who are similarly compromised in the gene dosage of the corresponding genes. In addition, engineered mutants heterozygously or homozygously deficient in the myelin component P0 show the pathology of distinct CMT1B and DS patients, respectively, while Cx32 deficient mice develop pathological abnormalities similar to those of CMTX patients. Mutants that mimic human peripheral neuropathies might allow the development of strategies to alleviate the symptoms of the diseases, and help to define environmental risk factors for aggravation of the disease. In addition, such mutants might be instrumental in the development of strategies to cure the diseases by gene therapy. PMID:9418989

  2. TRPA1: A Gatekeeper for Inflammation

    PubMed Central

    Bautista, Diana M.; Pellegrino, Maurizio; Tsunozaki, Makoto

    2014-01-01

    Tissue damage evokes an inflammatory response that promotes the removal of harmful stimuli, tissue repair, and protective behaviors to prevent further damage and encourage healing. However, inflammation may outlive its usefulness and become chronic. Chronic inflammation can lead to a host of diseases, including asthma, itch, rheumatoid arthritis, and colitis. Primary afferent sensory neurons that innervate target organs release inflammatory neuropeptides in the local area of tissue damage to promote vascular leakage, the recruitment of immune cells, and hypersensitivity to mechanical and thermal stimuli. TRPA1 channels are required for neuronal excitation, the release of inflammatory neuropeptides, and subsequent pain hypersensitivity. TRPA1 is also activated by the release of inflammatory agents from nonneuronal cells in the area of tissue injury or disease. This dual function of TRPA1 as a detector and instigator of inflammatory agents makes TRPA1 a gatekeeper of chronic inflammatory disorders of the skin, airways, and gastrointestinal tract. PMID:23020579

  3. X-1A impact site

    NASA Technical Reports Server (NTRS)

    1955-01-01

    A photo taken on 8 August 1955, showing the remains of the Bell X-1A The Bell X-1A (Serial # 48-1384) was designed for aerodynamic stability and air load research. It was delivered to Edwards Air Force Base on 7 January 1953. The aircraft made its first glide flight on 14 February with Bell test pilot Jean 'Skip' Ziegler at the controls. Ziegler also flew the first powered flight in the X-1A on 21 February. Contractor flights in the aircraft continued through April, at which time the X-1A was temporarily grounded for modifications. Flight operations were resumed on 21 November 1953 with Maj. Charles 'Chuck' Yeager at the controls. During a flight on 12 December, Yeager took the X-1A to a record-breaking speed of Mach 2.44 at an altitude of 75,000 feet. He then encountered the unpleasant phenomemon of inertia coupling. The X-1A tumbled out of control, knocking Yeager unconscious briefly before entering an inverted spin. Fortunately Yeager regained his senses and control of the aircraft 60 miles from Edwards at an altitude of 25,000 feet. Shaken, but unharmed, he brought the rocket plane in for a safe landing on Rogers Dry Lake. Next, the X-1A was used for a series of high-altitude missions piloted by Maj. Arthur 'Kit' Murray. Fourteen flights proved necessary to meet the program requirements, with only four being successful. During the test series, Murray set several unofficial world altitude records. The highest (90,440 feet) was set on 26 August 1954. Following completion of the altitude program, the aircraft was turned over to the National Advisory Committee for Aeronautics (NACA). The X-1A underwent more modifications and was returned to flight status in July 1955. The first NACA-sponsored flight, piloted by Joseph A. Walker, took place on 20 July. The second NACA mission was to be the 25th flight of the X-1A. The flight began normally on 8 August 1955, with the X-1A shackled to the underside of a JTB-29A (45-21800) piloted by Stanley Butchart and John 'Jack' Mc

  4. Secretoglobin 1A1 and 1A1A Differentially Regulate Neutrophil Reactive Oxygen Species Production, Phagocytosis and Extracellular Trap Formation

    PubMed Central

    Côté, Olivier; Clark, Mary Ellen; Viel, Laurent; Labbé, Geneviève; Seah, Stephen Y. K.; Khan, Meraj A.; Douda, David N.; Palaniyar, Nades; Bienzle, Dorothee

    2014-01-01

    Secretoglobin family 1A member 1 (SCGB 1A1) is a small protein mainly secreted by mucosal epithelial cells of the lungs and uterus. SCGB 1A1, also known as club (Clara) cell secretory protein, represents a major constituent of airway surface fluid. The protein has anti-inflammatory properties, and its concentration is reduced in equine recurrent airway obstruction (RAO) and human asthma. RAO is characterized by reversible airway obstruction, bronchoconstriction and neutrophilic inflammation. Direct effects of SCGB 1A1 on neutrophil functions are unknown. We have recently identified that the SCGB1A1 gene is triplicated in equids and gives rise to two distinct proteins. In this study we produced the endogenously expressed forms of SCGBs (SCGB 1A1 and 1A1A) as recombinant proteins, and analyzed their effects on reactive oxygen species production, phagocytosis, chemotaxis and neutrophil extracellular trap (NET) formation ex vivo. We further evaluated whether NETs are present in vivo in control and inflamed lungs. Our data show that SCGB 1A1A but not SCGB 1A1 increase neutrophil oxidative burst and phagocytosis; and that both proteins markedly reduce neutrophil chemotaxis. SCGB 1A1A reduced chemotaxis significantly more than SCGB 1A1. NET formation was significantly reduced in a time- and concentration-dependent manner by SCGB 1A1 and 1A1A. SCGB mRNA in bronchial biopsies, and protein concentration in bronchoalveolar lavage fluid, was lower in horses with RAO. NETs were present in bronchoalveolar lavage fluid from horses with exacerbated RAO, but not in fluid from horses with RAO in remission or in challenged healthy horses. These findings indicate that SCGB 1A1 and 1A1A have overlapping and diverging functions. Considering disparities in the relative abundance of SCGB 1A1 and 1A1A in airway secretions of animals with RAO suggests that these functional differences may contribute to the pathogenesis of RAO and other neutrophilic inflammatory lung diseases. PMID:24777050

  5. Association between endometriosis and the interleukin 1A (IL1A) locus

    PubMed Central

    Sapkota, Yadav; Low, Siew-Kee; Attia, John; Gordon, Scott D.; Henders, Anjali K.; Holliday, Elizabeth G.; MacGregor, Stuart; Martin, Nicholas G.; McEvoy, Mark; Morris, Andrew P.; Takahashi, Atsushi; Scott, Rodney J.; Kubo, Michiaki; Zondervan, Krina T.; Montgomery, Grant W.; Nyholt, Dale R.

    2015-01-01

    STUDY QUESTION Are single-nucleotide polymorphisms (SNPs) at the interleukin 1A (IL1A) gene locus associated with endometriosis risk? SUMMARY ANSWER We found evidence for strong association between IL1A SNPs and endometriosis risk. WHAT IS KNOWN ALREADY Genetic factors contribute substantially to the complex aetiology of endometriosis and the disease has an estimated heritability of ∼51%. We, and others, have conducted genome-wide association (GWA) studies for endometriosis, which identified a total of nine independent risk loci. Recently, two small Japanese studies reported eight SNPs (rs6542095, rs11677416, rs3783550, rs3783525, rs3783553, rs2856836, rs1304037 and rs17561) at the IL1A gene locus as suggestively associated with endometriosis risk. There is also evidence of a link between inflammation and endometriosis. STUDY DESIGN, SIZE, DURATION We sought to further investigate the eight IL1A SNPs for association with endometriosis using an independent sample of 3908 endometriosis cases and 8568 controls of European and Japanese ancestry. The study was conducted between October 2013 and July 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS By leveraging GWA data from our previous multi-ethnic GWA meta-analysis for endometriosis, we imputed variants in the IL1A region, using a recent 1000 Genomes reference panel. After combining summary statistics for the eight SNPs from our European and Japanese imputed data with the published results, a fixed-effect meta-analysis was performed. An additional meta-analysis restricted to endometriosis cases with moderate-to-severe (revised American Fertility Society stage 3 or 4) disease versus controls was also performed. MAIN RESULTS AND THE ROLE OF CHANCE All eight IL1A SNPs successfully replicated at P < 0.014 in the European imputed data with concordant direction and similar size to the effects reported in the original Japanese studies. Of these, three SNPs (rs6542095, rs3783550 and rs3783525) also showed association with

  6. Variable phenotypes are associated with PMP22 missense mutations.

    PubMed

    Russo, M; Laurá, M; Polke, J M; Davis, M B; Blake, J; Brandner, S; Hughes, R A C; Houlden, H; Bennett, D L H; Lunn, M P T; Reilly, M M

    2011-02-01

    Charcot-Marie-Tooth disease (CMT) is the commonest hereditary neuropathy encompassing a large group of clinically and genetically heterogeneous disorders. The commonest form of CMT, CMT1A, is usually caused by a 1.4 megabase duplication of chromosome 17 containing the PMP22 gene. Mutations of PMP22 are a less common cause of CMT. We describe clinical, electrophysiological and molecular findings of 10 patients carrying PMP22 missense mutations. The phenotype varied from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe CMT1. We identified six different point mutations, including two novel mutations. Three families were also found to harbour a Thr118Met mutation. Although PMP22 point mutations are not common, our findings highlight the importance of sequencing the PMP22 gene in patients with variable CMT phenotypes and also confirm that the PMP22 Thr118Met mutation is associated with a neuropathy albeit with reduced penetrance. PMID:21194947

  7. Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies.

    PubMed

    Carreño, Oriel; Corominas, Roser; Serra, Selma Angèlica; Sintas, Cèlia; Fernández-Castillo, Noèlia; Vila-Pueyo, Marta; Toma, Claudio; Gené, Gemma G; Pons, Roser; Llaneza, Miguel; Sobrido, María-Jesús; Grinberg, Daniel; Valverde, Miguel Ángel; Fernández-Fernández, José Manuel; Macaya, Alfons; Cormand, Bru

    2013-11-01

    Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing. PMID:24498617

  8. Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies

    PubMed Central

    Carreño, Oriel; Corominas, Roser; Serra, Selma Angèlica; Sintas, Cèlia; Fernández-Castillo, Noèlia; Vila-Pueyo, Marta; Toma, Claudio; Gené, Gemma G; Pons, Roser; Llaneza, Miguel; Sobrido, María-Jesús; Grinberg, Daniel; Valverde, Miguel Ángel; Fernández-Fernández, José Manuel; Macaya, Alfons; Cormand, Bru

    2013-01-01

    Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing. PMID:24498617

  9. Abiotic and biotic stress tolerance in Arabidopsis overexpressing the multiprotein bridging factor 1a (MBF1a) transcriptional coactivator gene.

    PubMed

    Kim, Min-Jung; Lim, Gah-Hyun; Kim, Eun-Seon; Ko, Chang-Beom; Yang, Kwang-Yeol; Jeong, Jin-An; Lee, Myung-Chul; Kim, Cheol Soo

    2007-03-01

    We conducted a genetic yeast screen to identify salt tolerance (SAT) genes in a maize kernel cDNA library. During the screening, we identified a maize clone (SAT41) that seemed to confer elevated salt tolerance in comparison to control cells. SAT41 cDNA encodes a 16-kDa protein which is 82.4% identical to the Arabidopsis Multiprotein bridging factor 1a (MBF1a) transcriptional coactivator gene. To further examine salinity tolerance in Arabidopsis, we functionally characterized the MBF1a gene and found that dehydration as well as heightened glucose (Glc) induced MBF1a expression. Constitutive expression of MBF1a in Arabidopsis led to elevated salt tolerance in transgenic lines. Interestingly, plants overexpressing MBF1a exhibited insensitivity to Glc and resistance to fungal disease. Our results suggest that MBF1a is involved in stress tolerance as well as in ethylene and Glc signaling in Arabidopsis. PMID:17234157

  10. Flowability of JSC-1a

    NASA Technical Reports Server (NTRS)

    Rame, Enrique; Wilkinson, Allen; Elliot, Alan; Young, Carolyn

    2009-01-01

    We have done a complete flowability characterization of the lunar soil simulant, JSC-1a, following closely the ASTM-6773 standard for the Schulze ring shear test. The measurements, which involve pre-shearing the material before each yield point, show JSC-1a to be cohesionless, with an angle of internal friction near 40 deg. We also measured yield loci after consolidating the material in a vibration table which show it to have significant cohesion (approximately equal to 1 kPa) and an angle of internal friction of about 60 deg. Hopper designs based on each type of flowability test differ significantly. These differences highlight the need to discern the condition of the lunar soil in the specific process where flowability is an issue. We close with a list not necessarily comprehensive of engineering rules of thumb that apply to powder flow in hoppers.

  11. Are electrophysiological criteria useful in distinguishing childhood demyelinating neuropathies?

    PubMed

    Potulska-Chromik, Anna; Ryniewicz, Barbara; Aragon-Gawinska, Karolina; Kabzinska, Dagmara; Seroka, Andrzej; Lipowska, Marta; Kaminska, Anna M; Kostera-Pruszczyk, Anna

    2016-03-01

    Childhood chronic inflammatory demyelinating polyneuropathy (CIDP) needs to be differentiated from hereditary neuropathy. We aimed to validate existing CIDP nerve conduction study (NCS) criteria in a group of children with demyelinating neuropathies of chronic or subacute onset. Retrospective analysis of clinical and NCS results in 18 children with CIDP, 7 with hereditary neuropathy with pressure palsy (HNPP), and 24 with Charcot-Marie-Tooth 1a (CMT1a). AAN and EFNS electrodiagnostic CIDP criteria were fulfilled in 17 of 18 CIDP, 3 of 7 HNPP, and 23 of 24 CMT1a patients. A distal compound muscle action potential (dCMAP) of >9 ms was observed in 14 of 18 CIDP patients but not in any patients with HNPP. Abnormal median/normal sural SNAP (AMNS) and a 10 m/s difference between conduction velocities (CV) of two corresponding nerves were not observed in any CMT1a patients. NCS in CMT1a, HNPP, and CIDP reflect demyelination. dCMAP duration, sensory AMNS, and a 10 m/s CV difference parameter are most useful in the differential diagnosis of pediatric CIDP. PMID:26663344

  12. Kawasaki disease

    SciTech Connect

    Shulman, S.T. )

    1987-01-01

    This book contains over 70 selections. Some of the titles are: Genetic analysis of Kawasaki disease; Late onset valvular dysfunction in Kawasaki disease; ischemic heart disease in Kawasaki disease; Evaluation of evidence related to streptococci in the etiology of Kawasaki disease; and Immune complexes and cytotoxicity.

  13. Infectious Diseases

    MedlinePlus

    Infectious diseases kill more people worldwide than any other single cause. Infectious diseases are caused by germs. Germs are tiny living ... to live NIH: National Institute of Allergy and Infectious Diseases

  14. Celiac Disease

    MedlinePlus

    ... small intestine. People with celiac disease cannot eat gluten, a protein found in wheat, barley, and rye. ... Disease Doctors treat celiac disease by prescribing a gluten-free diet. Symptoms significantly improve for most people ...

  15. Alzheimer's Disease

    MedlinePlus

    Alzheimer's disease (AD) is the most common form of dementia among older people. Dementia is a brain disorder that ... higher if a family member has had the disease. No treatment can stop the disease. However, some ...

  16. Fifth Disease

    MedlinePlus

    ... Search The CDC Cancel Submit Search The CDC Parvovirus B19 and Fifth Disease Note: Javascript is disabled or ... this page: About CDC.gov . Parvovirus Home About Parvovirus B19 Fifth Disease Pregnancy and Fifth Disease Photos of ...

  17. Hookworm Disease

    MedlinePlus

    ... Parasitic Roundworm Diseases Laboratory of Parasitic Diseases National Library of Medicine, MedlinePlus World Health Organization ​​ Hookworm Disease Skip Content Marketing Share this: JavaScript is disabled in your browser. ...

  18. Farber's Disease

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Farber's Disease Information Page Synonym(s): Ceramidase Deficiency Table of Contents ( ... Trials Related NINDS Publications and Information What is Farber's Disease? Farber’s disease, also known as Farber's lipogranulomatosis, describes ...

  19. Wilson Disease

    MedlinePlus

    ... Share External Link Disclaimer Digestive Diseases Wilson Disease Alternate Versions Wilson Disease (444 KB) You can also ... things psychosis—when a person loses contact with reality Other Signs and Symptoms Other signs and symptoms ...

  20. Hodgkin Disease

    MedlinePlus

    ... far the disease has spread. It often includes radiation therapy or chemotherapy. The earlier the disease is diagnosed, the more effective the treatment. In most cases, Hodgkin disease can be cured. NIH: National Cancer Institute

  1. Kawasaki Disease

    MedlinePlus

    Kawasaki disease is a rare childhood disease. It makes the walls of the blood vessels in the ... veins, and capillaries. No one knows what causes Kawasaki disease. Symptoms include High fever that lasts longer ...

  2. Hirschsprung Disease

    MedlinePlus

    ... For Kids For Parents MORE ON THIS TOPIC Irritable Bowel Syndrome (IBS) Digestive System X-Ray Exam: Upper Gastrointestinal ... Bowel Disease Inflammatory Bowel Disease Your Digestive System Irritable Bowel Syndrome Upper GI (Video) Inflammatory Bowel Disease Digestive System ...

  3. Crohn's Disease

    MedlinePlus

    Crohn's disease causes inflammation of the digestive system. It is one of a group of diseases called inflammatory ... small intestine called the ileum. The cause of Crohn's disease is unknown. It may be due to an ...

  4. Infectious Diseases

    MedlinePlus

    Infectious diseases kill more people worldwide than any other single cause. Infectious diseases are caused by germs. Germs are tiny living ... live NIH: National Institute of Allergy and Infectious Diseases

  5. Bladder Diseases

    MedlinePlus

    ... frequent, urgent urination Bladder cancer Doctors diagnose bladder diseases using different tests. These include urine tests, x- ... National Institute of Diabetes and Digestive and Kidney Diseases

  6. Clinical utility of a DNA probe to 17p11.2 in screening of patients with a peripheral neuropathy

    SciTech Connect

    Blancato, J.; Precht, K.; Meck, J.

    1994-09-01

    We assessed the usefulness of in situ hybridization with a DNA probe to the area of chromosome 17 at p11.2 as a diagnostic tool for screening for Charcot Marte Tooth 1A (CMT 1A). In situ hybridization with a probe to 17p11.2 was performed on fixed lymphocytes from the following groups of individuals: (1) normal controls; (2) patients evoking a strong clinical suspicion of CMT 1A; and (3) 3 families with an apparent autosomal dominant peripheral neuropathy of unknown diagnoses. Group 2 patients had evidence of demyelination as defined by nerve conduction of less that 50% of the normal mean or terminal latency greater than 50% of the normal mean in conduction studies. Analysis of interphase cells hybridized with a cosmid DNA probe to 17p11.2 requires inclusion of a normal control with each trial and masked observer. Due to the size of the target DNA and the nature of the centromeric heterochromatin, the scoring of this probe is more subjective than centromere probes. For example, if the two 17 chromosomes are decondensed as in interphase, two tandem signals may be visualized as one. Results from duplication positive patients demonstrate a large proportion of cells with two closely aligned, but separate, signals with an additional single signal. Normal results demonstrate a majority of cells with two separate signals representing both normal homologues. None of the 3 families with questionable diagnosis revealed a duplication at the region, reinforcing our belief that a clinical diagnosis is the most discriminating tool available for diagnosis of CMT 1A. We concur with Boylan that molecular analysis for CMT 1A is useful for establishing a diagnosis of CMT 1A, but is not a primary differential diagnostic test. The yield in screening patients without physiologic evidence of demyelination is likely to be low. We further find that the use of in situ hybridization is a simple method of performing the duplication analysis.

  7. Scutellarin inhibits cytochrome P450 isoenzyme 1A2 (CYP1A2) in rats.

    PubMed

    Jian, Tun-Yu; He, Jian-Chang; He, Gong-Hao; Feng, En-Fu; Li, Hong-Liang; Bai, Min; Xu, Gui-Li

    2012-08-01

    Scutellarin is the most important flavone glycoside in the herbal drug Erigeron breviscapus (Vant.) Hand.-Mazz. It is used frequently in the clinic to treat ischemic vascular diseases in China. However, the direct relationship between scutellarin and cytochrome P450 (CYP450) is unclear. The present study investigated the in vitro and in vivo effects of scutellarin on cytochrome P450 1A2 (CYP 1A2) metabolism. According to in vitro experiments, scutellarin (10-250 µM) decreased the formation of 4-acetamidophenol in a concentration-dependent manner, with an IC₅₀ value of 108.20 ± 0.657 µM. Furthermore, scutellarin exhibited a weak mixed-type inhibition against the activity of CYP1A2 in rat liver microsomes, with a K(i) value of 95.2 µM. Whereas in whole animal studies, scutellarin treatment for 7 days (at 5, 15, 30 mg/kg, i.p.) decreased the clearance (CL), and increased the T(1/2) (at 15, 30 mg/kg, i.p.), it did not affect the V(d) of phenacetin. Scutellarin treatment (at 5, 15, 30 mg/kg, i.p.) increased the AUC(0-∞) by 14.3%, 67.3% and 159.2%, respectively. Scutellarin at 30 mg/kg also weakly inhibited CYP1A2 activity, in accordance with our in vitro study. Thus, the results indicate that CYP1A2 is inhibited directly, but weakly, by scutellarin in vivo, and provide useful information on the safe and effective use of scutellarin in clinical practice. PMID:22228482

  8. Heart Diseases

    MedlinePlus

    ... you're like most people, you think that heart disease is a problem for others. But heart disease is the number one killer in the ... of disability. There are many different forms of heart disease. The most common cause of heart disease ...

  9. Kawasaki Disease

    MedlinePlus

    ... As a result, some children who have Kawasaki disease may develop serious heart problems. Overview The cause of Kawasaki disease ... Early treatment helps reduce the risk of Kawasaki disease affecting the coronary arteries and causing serious problems. Outlook Kawasaki disease can't be prevented. ...

  10. Heart Diseases

    MedlinePlus

    ... re like most people, you think that heart disease is a problem for others. But heart disease is the number one killer in the U.S. ... disability. There are many different forms of heart disease. The most common cause of heart disease is ...

  11. Newcastle disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Newcastle disease (ND), referred to as Exotic Newcastle disease (END) in the U. S., is an acute viral disease of domestic poultry and many other bird species and a recognized worldwide problem. Occurrence of END is due to an infection with virulent strains of Newcastle disease virus (NDV) and is a ...

  12. 7 CFR 1a.4 - Limitations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Limitations. 1a.4 Section 1a.4 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.4 Limitations. The powers granted by §§ 1a.2(a) and 1a.2(b) shall be exercised only when a designated official is engaged in an...

  13. 7 CFR 1a.4 - Limitations.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false Limitations. 1a.4 Section 1a.4 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.4 Limitations. The powers granted by §§ 1a.2(a) and 1a.2(b) shall be exercised only when a designated official is engaged in an...

  14. 7 CFR 1a.2 - Authorization.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Authorization. 1a.2 Section 1a.2 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.2 Authorization. Any official of the Office of Inspector General who is designated by the Inspector General according to §§ 1a.3 and 1a.5...

  15. Impact of Dyrk1A level on alcohol metabolism.

    PubMed

    Renon, Marjorie; Legrand, Béatrice; Blanc, Etienne; Daubigney, Fabrice; Bokobza, Cindy; Mortreux, Marie; Paul, Jean-Louis; Delabar, Jean-Maurice; Rouach, Hélène; Andreau, Karine; Janel, Nathalie

    2016-09-01

    Alcoholic liver diseases arise from complex phenotypes involving many genetic factors. It is quite common to find hyperhomocysteinemia in chronic alcoholic liver diseases, mainly due to deregulation of hepatic homocysteine metabolism. Dyrk1A, involved in homocysteine metabolism at different crossroads, is decreased in liver of hyperhomocysteinemic mice. Here, we hypothesized that Dyrk1A contributes to alcohol-induced hepatic impairment in mice. Control, hyperhomocysteinemic and mice overexpressing Dyrk1A were fed using a Lieber-DeCarli liquid diet with or without ethanol (5% v/v ethanol) for one month, and liver histological examination and liver biochemical function tests were performed. Plasma alanine aminotransferase and homocysteine levels were significantly decreased in mice overexpressing Dyrk1A compared to control mice with or without alcohol administration. On the contrary, the mean plasma alanine aminotransferase and homocysteine levels were significantly higher in hyperhomocysteinemic mice than that of control mice after alcohol administration. Paraoxonase 1 and CYP2E1, two phase I xenobiotic metabolizing enzymes, were found increased in the three groups of mice after alcohol administration. However, NQO1, a phase II enzyme, was only found increased in hyperhomocysteinemic mice after alcohol exposure, suggesting a greater effect of alcohol in liver of hyperhomocysteinemic mice. We observed positive correlations between hepatic alcohol dehydrogenase activity, Dyrk1A and ADH4 protein levels. Importantly, a deleterious effect of alcohol consumption on hepatic Dyrk1A protein level was found. Our study reveals on the one hand a role of Dyrk1A in ethanol metabolism and on the other hand a deleterious effect of alcohol administration on hepatic Dyrk1A level. PMID:27216978

  16. Interferon Beta-1a Subcutaneous Injection

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS, a disease in which ... under the skin). It is usually injected three times a week. You should inject this medication on ...

  17. Menkes Disease

    MedlinePlus

    ... therapy approaches to Menkes disease. 3 1. Kaler, SG. The neurology of STPAT copper transporter disease: emerging ... Reviews Neurology , 2001:7:15-19.. 2. Kaler SG, et al. Neonatal Diagnosis and Treatment of Menkes ...

  18. Bone Diseases

    MedlinePlus

    ... also avoid smoking and drinking too much alcohol. Bone diseases can make bones easy to break. Different kinds ... Bones can also develop cancer and infections Other bone diseases, which are caused by poor nutrition, genetics, or ...

  19. Sandhoff Disease

    MedlinePlus

    ... Sandhoff Disease? Sandhoff disease is a rare, inherited lipid storage disorder that progressively destroys nerve cells in ... results in the harmful accumulation of certain fats (lipids) in the brain and other organs of the ...

  20. Gaucher Disease

    MedlinePlus

    ... one of the inherited metabolic disorders known as lipid storage diseases. Lipids are fatty materials that include oils, fatty acids, ... research to find ways to treat and prevent lipid storage disorders such as Gaucher disease. For example, ...

  1. Kidney Disease

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Kidney Disease KidsHealth > For Teens > Kidney Disease Print A ... Syndrome Coping With Kidney Conditions What Do the Kidneys Do? You might never think much about some ...

  2. Legionnaire disease

    MedlinePlus

    ... features on this page, please enable JavaScript. Legionnaire disease is an infection of the lungs and airways. It is caused by Legionella bacteria. Causes The bacteria that cause Legionnaire disease have ...

  3. Chagas disease

    MedlinePlus

    Kirchhoff LV. Chagas' disease. In: Goldman L, Schafer AI, eds. Cecil Medicine . 24th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 355. Kirchhoff LV. Trypanosoma species (American trypanosomiasis, Chagas' disease): Biology ...

  4. Huntington's Disease

    MedlinePlus

    ... express emotions. If one of your parents has Huntington's disease, you have a 50 percent chance of getting it. A blood test can tell you if have the HD gene and will develop the disease. Genetic counseling can ...

  5. Behcet's Disease

    MedlinePlus

    ... neurological disorders such as Behcet's disease. The National Human Genome Research Institute, another Institute of the National Institutes of Health, conducts research into the genomic basis of Behcet's disease. This research is aimed ...

  6. Digestive diseases

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/007447.htm Digestive diseases To use the sharing features on this page, please enable JavaScript. Digestive diseases are disorders of the digestive tract, which ...

  7. Liver Diseases

    MedlinePlus

    ... remove poisons. There are many kinds of liver diseases. Viruses cause some of them, like hepatitis A, ... the skin, can be one sign of liver disease. Cancer can affect the liver. You could also ...

  8. Kidney Diseases

    MedlinePlus

    ... until you go to the bathroom. Most kidney diseases attack the nephrons. This damage may leave kidneys ... medicines. You have a higher risk of kidney disease if you have diabetes, high blood pressure, or ...

  9. Meniere's Disease

    MedlinePlus

    Meniere's disease is a disorder of the inner ear. It can cause severe dizziness, a roaring sound in your ... together over several days. Some people with Meniere's disease have "drop attacks" during which the dizziness is ...

  10. Legionnaires' Disease

    MedlinePlus

    Legionnaires' disease is a type of pneumonia caused by bacteria. You usually get it by breathing in mist from ... spread from person to person. Symptoms of Legionnaires' disease include high fever, chills, a cough, and sometimes ...

  11. Eye Diseases

    MedlinePlus

    ... the back of the eye Macular degeneration - a disease that destroys sharp, central vision Diabetic eye problems ... defense is to have regular checkups, because eye diseases do not always have symptoms. Early detection and ...

  12. Parkinson's Disease

    MedlinePlus

    Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't ... coordination As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple ...

  13. Endocrine Diseases

    MedlinePlus

    ... low, you may have a hormone disorder. Hormone diseases also occur if your body does not respond ... In the United States, the most common endocrine disease is diabetes. There are many others. They are ...

  14. Raynaud's Disease

    MedlinePlus

    Raynaud's disease is a rare disorder of the blood vessels, usually in the fingers and toes. It causes the ... secondary Raynaud's, which is caused by injuries, other diseases, or certain medicines. People in colder climates are ...

  15. Addison Disease

    MedlinePlus

    ... blood pressure and water and salt balance. Addison disease happens if the adrenal glands don't make ... problem with your immune system usually causes Addison disease. The immune system mistakenly attacks your own tissues, ...

  16. Chagas Disease

    MedlinePlus

    Chagas disease is caused by a parasite. It is common in Latin America but not in the United States. ... nose, the bite wound or a cut. The disease can also spread through contaminated food, a blood ...

  17. Wilson Disease

    MedlinePlus

    Wilson disease is a rare inherited disorder that prevents your body from getting rid of extra copper. You need ... copper into bile, a digestive fluid. With Wilson disease, the copper builds up in your liver, and ...

  18. Fifth disease

    MedlinePlus

    Parvovirus B19; Erythema infectiosum; Slapped cheek rash ... Fifth disease is caused by human parvovirus B19. It often affects preschoolers or school-age children during the spring. The disease spreads through the fluids in the nose and mouth ...

  19. Tickborne Diseases

    MedlinePlus

    ... for tickborne diseases ranges from studying the basic biology of the microbes that cause these diseases to ... Nucleotide Polymorphism Phylogenetics & Ontology Proteomics & Protein Analysis Systems Biology Data Portals Software Applications BCBB Mobyle Interface Designer ( ...

  20. Graves' Disease

    MedlinePlus

    ... our online catalog. ​ Additional Links Hashimoto's Disease Hyperthyroidism Hypothyroidism Pregnancy & Thyroid Disease Thyroid Tests Find a Specialist ... everyone who receives radioactive iodine treatment eventually develops hypothyroidism, which occurs when the thyroid does not make ...

  1. Lyme Disease

    MedlinePlus

    Lyme disease is a bacterial infection you get from the bite of an infected tick. The first symptom ... Muscle and joint aches A stiff neck Fatigue Lyme disease can be hard to diagnose because you may ...

  2. Gilbert disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000301.htm Gilbert disease To use the sharing features on this page, please enable JavaScript. Gilbert disease is a common disorder passed down through ...

  3. Celiac Disease

    MedlinePlus

    ... immune disease in which people can't eat gluten because it will damage their small intestine. If you have celiac disease and eat foods with gluten, your immune system responds by damaging the small ...

  4. Pneumococcal Disease

    MedlinePlus

    ... pneumococcal disease. Quick Facts About Pneumococcal Disease and Vaccination According to WHO, pneumococcal pneumonia and meningitis are ... of antibiotic treatment. (9, 10, 11) Conjugate pneumococcal vaccination is safe and effective for preventing severe childhood ...

  5. Celiac Disease

    MedlinePlus

    ... having celiac disease? Yes, you can have gluten sensitivity without the immune system attack on the small ... gluten causes in celiac disease. Symptoms of gluten sensitivity are generally milder than those seen in celiac ...

  6. Fifth Disease

    MedlinePlus

    Fifth disease is a viral infection caused by parvovirus B19. The virus only infects humans; it's not the same parvovirus that dogs and cats can get. Fifth disease mostly affects children. Symptoms can include a low ...

  7. Bone Diseases

    MedlinePlus

    ... avoid smoking and drinking too much alcohol. Bone diseases can make bones easy to break. Different kinds ... break Osteogenesis imperfecta makes your bones brittle Paget's disease of bone makes them weak Bones can also ...

  8. Gaucher Disease

    MedlinePlus

    Gaucher disease is a rare, inherited disorder in which you do not have enough of an enzyme called glucocerebrosidase. ... It usually starts in childhood or adolescence. Gaucher disease has no cure. Treatment options for types 1 ...

  9. Kidney Diseases

    MedlinePlus

    ... until you go to the bathroom. Most kidney diseases attack the nephrons. This damage may leave kidneys ... medicines. You are at greater risk for kidney disease if you have diabetes, high blood pressure, or ...

  10. Parasitic Diseases

    MedlinePlus

    ... a bug bite, or sexual contact. Some parasitic diseases are easily treated and some are not. Parasites ... be seen with the naked eye. Some parasitic diseases occur in the United States. Contaminated water supplies ...

  11. Binswanger's Disease

    MedlinePlus

    ... and Information What is Binswanger's Disease? Binswanger's disease (BD), also called subcortical vascular dementia , is a type ... and brain tissue dies. A characteristic pattern of BD-damaged brain tissue can be seen with modern ...

  12. Wilson Disease

    MedlinePlus

    Wilson disease is a rare inherited disorder that prevents your body from getting rid of extra copper. You ... extra copper into bile, a digestive fluid. With Wilson disease, the copper builds up in your liver, and ...

  13. Heart Disease

    MedlinePlus

    ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ... this? Submit What's this? Submit Button Related CDC Web Sites Division for Heart Disease and Stroke Prevention ...

  14. Liver disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000205.htm Liver disease To use the sharing features on this page, please enable JavaScript. The term "liver disease" applies to many conditions that stop the liver ...

  15. Parasitic Diseases

    MedlinePlus

    ... water, a bug bite, or sexual contact. Some parasitic diseases are easily treated and some are not. Parasites ... can be seen with the naked eye. Some parasitic diseases occur in the United States. Contaminated water supplies ...

  16. Lyme disease

    MedlinePlus

    Lyme disease is a bacterial infection that is spread through the bite of one of several types of ... Lyme disease is caused by bacteria called Borrelia burgdorferi ( B burgdorferi ). Blacklegged ticks and other species of ticks ...

  17. Kennedy's Disease

    MedlinePlus

    ... to prevent, treat, and cure them. NIH Patient Recruitment for Kennedy's Disease Clinical Trials At NIH Clinical Center Throughout the U.S. and Worldwide NINDS Clinical Trials Organizations Column1 Column2 Kennedy's Disease Association P.O. Box ...

  18. Parkinson disease

    MedlinePlus

    American Parkinson Disease Association. Parkinson's Disease Handbook: A Guide for Patients and Their Families. Revised 2009. Available at: www.apdaparkinson.org/uploads/files/MP51919AmParkinsonHBK-vaU.pdf . Accessed September 15, ...

  19. Brain Diseases

    MedlinePlus

    ... know what causes some brain diseases, such as Alzheimer's disease. The symptoms of brain diseases vary widely depending on the specific problem. In some cases, damage is permanent. In other cases, treatments such as surgery, medicines, or physical therapy can correct the source of the problem or ...

  20. Behcet's Disease

    MedlinePlus

    ... with Behçet’s disease keep their joints strong and flexible. What Is the Prognosis for a Person With Behçet’s Disease? Most people with Behçet’s disease can lead productive lives and control symptoms with proper medicine, rest, and exercise. Doctors ...

  1. Meniere's Disease.

    ERIC Educational Resources Information Center

    Schessel, David A.

    1997-01-01

    Meniere's disease is characterized by unpredictable spells of severe vertigo and fluctuations in hearing and tinnitus. This article discusses the incidence of Meniere's disease, the present status of our understanding of this disease, controversies in its diagnosis, and the multiple therapeutic modalities recruited in its treatment. (Contains…

  2. Crinkle Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crinkle disease of hop was first described in Europe in 1930, and subsequent reports of the disease appear in literature published in the 1960s and 1970s. The disease appears to be of little importance in most regions of hop production. A fastidious rickettsia-like organism (RLO) is thought to cau...

  3. Celiac Disease

    MedlinePlus

    Celiac disease is an immune disease in which people can't eat gluten because it will damage their small intestine. If you have celiac disease and eat foods with gluten, your immune system responds by damaging the small intestine. Gluten ...

  4. Lyme Disease.

    ERIC Educational Resources Information Center

    Taylor, George C.

    1991-01-01

    This overview of the public health significance of Lyme disease includes the microbiological specifics of the infectious spirochete, the entomology and ecology of the ticks which are the primary disease carrier, the clinical aspects and treatment stages, the known epidemiological patterns, and strategies for disease control and for expanded public…

  5. Alzheimer disease

    MedlinePlus

    ... of brain function that occurs with certain diseases. Alzheimer disease (AD) is one form of dementia. It affects ... The exact cause of Alzheimer disease (AD) is not known. Research shows that certain changes in the brain lead to AD. You are more likely to ...

  6. Parkinson Disease.

    PubMed

    Capriotti, Teri; Terzakis, Kristina

    2016-06-01

    Parkinson disease (PD) is a progressive neurodegenerative disease that affects one million people in the United States. This article reviews the etiology and pathophysiology of PD, risk factors, clinical manifestations, diagnostic criteria, and treatment of this common disease. Implications for home care clinicians are included. PMID:27243427

  7. Prostate Diseases

    MedlinePlus

    ... our e-newsletter! Aging & Health A to Z Prostate Diseases Basic Facts & Information What are Prostate Diseases? The prostate—one of the components of ... out anything serious. The Most Common Types of Prostate Diseases Benign prostatic hyperplasia (BPH) Prostatitis Prostate cancer ...

  8. Prion Diseases

    PubMed Central

    Geschwind, Michael D.

    2016-01-01

    Purpose of Review This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations. Recent Findings Prion diseases, a group of disorders caused by abnormally shaped proteins called prions, occur in sporadic (Jakob-Creutzfeldt disease), genetic (genetic Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia), and acquired (kuru, variant Jakob-Creutzfeldt disease, and iatrogenic Jakob-Creutzfeldt disease) forms. This article presents updated information on the clinical features and diagnostic methods for human prion diseases. New antemortem potential diagnostic tests based on amplifying prions in order to detect them are showing very high specificity. Understanding of the diversity of possible presentations of human prion diseases continues to evolve, with some genetic forms progressing slowly over decades, beginning with dysautonomia and neuropathy and progressing to a frontal-executive dementia with pathology of combined prionopathy and tauopathy. Unfortunately, to date, all human prion disease clinical trials have failed to show survival benefit. A very rare polymorphism in the prion protein gene recently has been identified that appears to protect against prion disease; this finding, in addition to providing greater understanding of the prionlike mechanisms of neurodegenerative disorders, might lead to potential treatments. Summary Sporadic Jakob-Creutzfeldt disease is the most common form of human prion disease. Genetic prion diseases, resulting from mutations in the prion-related protein gene (PRNP), are classified based on the mutation, clinical phenotype, and neuropathologic features and can be difficult to diagnose because of their varied presentations. Perhaps most relevant to this Continuum issue on neuroinfectious diseases, acquired prion diseases are caused by accidental transmission to humans, but fortunately, they are the least common form and

  9. Glomerular disease.

    PubMed

    Vaden, Shelly L

    2011-08-01

    Glomerular diseases are a leading cause of chronic kidney disease in dogs but seem to be less common in cats. Glomerular diseases are diverse, and a renal biopsy is needed to determine the specific glomerular disease that is present in any animal. Familial glomerulopathies occur in many breeds of dogs. However, most dogs with glomerular disease have acquired glomerular injury that is either immune-complex mediated or due to systemic factors, both of which are believed to be the result of a disease process elsewhere in the body (i.e., neoplastic, infectious, and noninfectious inflammatory disorders). A thorough clinical evaluation is indicated in all dogs suspected of having glomerular disease and should include an extensive evaluation for potential predisposing disorders. Nonspecific management of dogs with glomerular disease can be divided into 3 major categories: (1) treatment of potential predisposing disorders, (2) management of proteinuria, and (3) management of uremia and other complications of glomerular disease and chronic kidney disease. Specific management of specific glomerular diseases has not been fully studied in dogs. However, it may be reasonable to consider immunosuppressive therapy in dogs that have developed a form of glomerulonephritis secondary to a steroid-responsive disease (e.g., systemic lupus erythematosus) or have immune-mediated lesions that have been documented in renal biopsy specimens. Appropriate patient monitoring during therapy is important for maximizing patient care. The prognosis for dogs and cats with glomerular disease is variable and probably dependent on a combination of factors. The purpose of this article is to discuss the general diagnosis and management of dogs with glomerular disease. PMID:21782143

  10. [Social diseases, civilization diseases or lifestyle diseases?].

    PubMed

    Betlejewski, Stansław

    2007-01-01

    In general, the development of civilization is viewed as a positive step for the well-being of the human species, leading to an increased duration and quality of life. The accelerated progress of civilization (mainly industrialization, urbanization and nutrition) has lead to new possibilities for adverse effects on human health. In former high civilization--like old Egypt, Greece, Roman, Chinese, Indian, Maya civilizations--the "modem civilization diseases" were unknown. Modem science through improved sanitation, vaccination and antibiotics as well as improved social and economical conditions, has eliminated the threat of death from most infectious diseases. In the years after World War II the social, economic and health conditions changed. Most deaths have resulted from heart disease, stroke, cancer and other diseases as a result of an inappropriate relationship of people with their environment and changed lifestyle. Lifestyle diseases are different from other diseases because they are potentially preventable and can be lowered with changes in diet, lifestyle and environment. PMID:18350729

  11. The 5-HT1A receptor in Major Depressive Disorder.

    PubMed

    Kaufman, Joshua; DeLorenzo, Christine; Choudhury, Sunia; Parsey, Ramin V

    2016-03-01

    Major Depressive Disorder (MDD) is a highly prevalent psychiatric diagnosis that is associated with a high degree of morbidity and mortality. This debilitating disorder is currently one of the leading causes of disability nationwide and is predicted to be the leading cause of disease burden by the year 2030. A large body of previous research has theorized that serotonergic dysfunction, specifically of the serotonin (5-HT) 1A receptor, plays a key role in the development of MDD. The purpose of this review is to describe the evolution of our current understanding of the serotonin 1A (5-HT1A) receptor and its role in the pathophysiology MDD through the discussion of animal, post-mortem, positron emission tomography (PET), pharmacologic and genetic studies. PMID:26851834

  12. PRKAR1A and the evolution of pituitary tumors.

    PubMed

    Kirschner, Lawrence S

    2010-09-15

    Carney complex (CNC) is an inherited tumor predisposition associated with pituitary tumors, including GH-producing pituitary adenomas and rare reports of prolactinomas. This disease is caused by mutations in PRKAR1A, which encodes the type 1A regulatory subunit of the cAMP-dependent protein kinase, PKA. Loss of PRKAR1A causes enhanced PKA signaling, which leads to pituitary tumorigenesis. Mutations in the gene have not been detected in sporadic pituitary tumors, but there is some data to suggest that non-genomic mechanisms may cause loss of protein expression. Unlike CNC patients, mice heterozygous for Prkar1a mutations do not develop pituitary tumors, although complete knockout of the gene in the Pit1 lineage of the pituitary produces GH-secreting pituitary adenomas. These data indicate that complete loss of Prkar1a/PRKAR1A is able to cause pituitary tumors in mice and men. The pattern of tumors is likely related to the signaling pathways employed in specific pituitary cell types. PMID:20451576

  13. Borna disease.

    PubMed Central

    Hatalski, C. G.; Lewis, A. J.; Lipkin, W. I.

    1997-01-01

    Borna disease virus, a newly classified nonsegmented negative-strand RNA virus with international distribution, infects a broad range of warm-blooded animals from birds to primates. Infection causes movement and behavioral disturbances reminiscent of some neuropsychiatric syndromes. The virus has not been clearly linked to any human disease; however, an association between infection with the virus and selected neuropsychiatric disorders has been suggested. We reviewed recent advances in Borna disease virus research, focusing on evidence of infection in humans. PMID:9204293

  14. Gaucher Disease

    PubMed Central

    Nagral, Aabha

    2014-01-01

    Gaucher disease is the commonest lysosomal storage disease seen in India and worldwide. It should be considered in any child or adult with an unexplained splenohepatomegaly and cytopenia which are seen in the three types of Gaucher disease. Type 1 is the non-neuronopathic form and type 2 and 3 are the neuronopathic forms. Type 2 is a more severe neuronopathic form leading to mortality by 2 years of age. Definitive diagnosis is made by a blood test–the glucocerebrosidase assay. There is no role for histological examination of the bone marrow, liver or spleen for diagnosis of the disease. Molecular studies for mutations are useful for confirming diagnosis, screening family members and prognosticating the disease. A splenectomy should not be performed except for palliation or when there is no response to enzyme replacement treatment or no possibility of getting any definitive treatment. Splenectomy may worsen skeletal and lung manifestations in Gaucher disease. Enzyme replacement therapy (ERT) has completely revolutionized the prognosis and is now the standard of care for patients with this disease. Best results are seen in type 1 disease with good resolution of splenohepatomegaly, cytopenia and bone symptoms. Neurological symptoms in type 3 disease need supportive care. ERT is of no benefit in type 2 disease. Monitoring of patients on ERT involves evaluation of growth, blood counts, liver and spleen size and biomarkers such as chitotriosidase which reflect the disease burden. Therapy with ERT is very expensive and though patients in India have so far got the drug through a charitable access programme, there is a need for the government to facilitate access to treatment for this potentially curable disease. Bone marrow transplantation is an inferior option but may be considered when access to expensive ERT is not possible. PMID:25755533

  15. 9 CFR 73.1a - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false 73.1a Section 73.1a Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1a...

  16. 9 CFR 73.1a - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false 73.1a Section 73.1a Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1a...

  17. 9 CFR 73.1a - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false 73.1a Section 73.1a Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1a...

  18. 9 CFR 73.1a - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false 73.1a Section 73.1a Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1a...

  19. 9 CFR 73.1a - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false 73.1a Section 73.1a Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS SCABIES IN CATTLE § 73.1a...

  20. [Moyamoya disease].

    PubMed

    Esin, R G; Isayeva, Yu N; Gorobets, E A; Tokareva, N V; Esin, O R

    2016-01-01

    Moya-moya is a rare cerebrovascular disease characterized by the progressive occlusion of cerebral vessels with partial switching off the circle of Willis and arteries that feed it. The article provides a review of literature, modern diagnostic criteria and a description of a single clinical case. The onset of the disease in this patient was characterized by headache and speech disorders.An analysis of speech disorders showed that they were systemic. They were registered at all language levels (phonetic, lexical,morphological, syntactic). A long diagnostic search may be explained by clinical manifestations that are atypical for other cerebrovascular diseases and by the rarity of the disease. PMID:27386589

  1. Coeliac disease.

    PubMed

    Green, Peter H R; Jabri, Bana

    2003-08-01

    Coeliac disease is a genetically-determined chronic inflammatory intestinal disease induced by an environmental precipitant, gluten. Patients with the disease might have mainly non-gastrointestinal symptoms, and as a result patients present to various medical practitioners. Epidemiological studies have shown that coeliac disease is very common and affects about one in 250 people. The disease is associated with an increased rate of osteoporosis, infertility, autoimmune diseases, and malignant disease, especially lymphomas. The mechanism of the intestinal immune-mediated response is not completely clear, but involves an HLA-DQ2 or HLA-DQ8 restricted T-cell immune reaction in the lamina propria as well as an immune reaction in the intestinal epithelium. An important component of the disease is the intraepithelial lymphocyte that might become clonally expanded in refractory sprue and enteropathy-associated T-cell lymphoma. Study of the mechanism of the immune response in coeliac disease could provide insight into the mechanism of inflammatory and autoimmune responses and lead to innovations in treatment. PMID:12907013

  2. Celiac disease.

    PubMed

    Holtmeier, Wolfgang; Caspary, Wolfgang F

    2006-01-01

    Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen); often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years. PMID:16722573

  3. Huntington's Disease

    PubMed Central

    Finkbeiner, Steven

    2011-01-01

    Huntington's disease (HD) is the most common inherited neurodegenerative disease and is characterized by uncontrolled excessive motor movements and cognitive and emotional deficits. The mutation responsible for HD leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, which confers one or more toxic functions to mutant Htt leading to neurodegeneration. The polyQ expansion makes Htt prone to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins tend to slow disease progression in HD models. This article will focus on HD and the evidence that it is a conformational disease. PMID:21441583

  4. Whipworm Disease

    MedlinePlus

    ... About NIAID News & Events Volunteer NIAID > Health & Research Topics > Whipworm Disease Skip Website Tools Website Tools Print this page Get email updates Order publications Volunteer for Clinical ...

  5. Moyamoya disease.

    PubMed Central

    Farrugia, M.; Howlett, D. C.; Saks, A. M.

    1997-01-01

    Moyamoya disease is a rare cerebrovascular condition of uncertain aetiology commonly affecting young persons. The disease is mainly seen in Japanese patients. We report two cases of moyamoya disease in Caucasian women and review the postulated aetiological factors and associated conditions as well as the spectrum of invasive and non-invasive imaging modalities useful in the diagnosis and follow-up of the disease, with particular reference to the developing role of magnetic resonance imaging and angiography. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:9373593

  6. Alpers' Disease

    MedlinePlus

    ... caused by mutation in the gene for the mitochondrial DNA polymerase POLG. The disease occurs in about one in 100,000 persons. ... typically occur months before tissue samples show the mitochondrial DNA depletion, so ... with Alpers' disease develop symptoms in the first two years of ...

  7. Sever's Disease

    MedlinePlus

    ... Tests How do I know if my child's heel pain is caused by Sever's disease? In Sever's disease, heel pain can be in one or both heels. It ... cut down or stop any activity that causes heel pain. Apply ice to the injured heel for 20 ...

  8. Kidney Disease

    MedlinePlus

    ... version of this page please turn Javascript on. Kidney Disease What is Kidney Disease? What the Kidneys Do Click for more information You have two ... damaged, wastes can build up in the body. Kidney Function and Aging Kidney function may be reduced ...

  9. Cardiovascular Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cardiovascular disease (CVD), particularly CHD (coronary heart disease) and stroke, remain the leading causes of death of women in America and most developed countries. In recent years the rate of CVD has declined in men but not in women. This is contributed to by an under-recognition of women’s C...

  10. Addison's Disease

    MedlinePlus

    ... is Addison’s disease? Addison’s disease affects your body’s adrenal glands. The adrenal glands are part of the endocrine system. The endocrine ... your moods, growth, metabolism, and tissue function. The adrenal glands are located just above your kidneys. They produce ...

  11. Disease management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soilborne pathogens that cause root diseases spend most of their life cycle in or on the soil. Soil management decisions will influence the survival, growth of these pathogens and severity of disease. Many of the cultural methods that growers have relied on in the past to reduce the impact of the...

  12. Endocrine Diseases

    MedlinePlus

    ... high or too low, you may have an endocrine disease or disorder. Endocrine diseases and disorders also occur if your body does not respond to hormones the way it is supposed to. Featured Topics Adrenal Insufficiency ... Topics Research Discoveries & News Children with Cushing ...

  13. Chagas Disease

    MedlinePlus

    ... to see whether the disease has affected your intestines and heart. Medicines can kill the parasite, especially early on. You can also treat related problems. For example, a pacemaker helps with certain heart ... practice food safety. Centers for Disease Control and Prevention

  14. Whipple's disease

    MedlinePlus

    ... include: Complete blood count ( CBC ) Polymerase chain reaction (PCR) test to check for the bacteria that cause the disease Small bowel biopsy Upper GI endoscopy (viewing the intestines with a flexible, lighted tube in a process called enteroscopy ) This disease may ...

  15. Prion Diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prion diseases comprise a set of rare fatal neurological diseases found in humans and other mammals. A prion is a protein capable of converting a normal cellular protein (PrPC) into a prion and thereby propagating an infection. A prion and PrPC differ solely in their conformation. There are differen...

  16. Mitochondrial Diseases

    PubMed Central

    Lee, Young-Mock

    2012-01-01

    Mitochondria contain the respiratory chain enzyme complexes that carry out oxidative phosphorylation and produce the main part of cellular energy in the form of ATP. Although several proteins related with signalling, assembling, transporting, and enzymatic function can be impaired in mitochondrial diseases, most frequently the activity of the respiratory chain protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. Mitochondrial diseases usually show a chronic, slowly progressive course and present with multiorgan involvement with varying onset between birth and late adulthood. Neuromuscular system is frequently affected in mitochondrial diseases. Although there is actually no specific therapy and cure for mitochondrial diseases, the understanding of the pathophysiology may further facilitate the diagnostic approach and open perspectives to future in mitochondrial diseases. PMID:24649452

  17. Gaucher disease

    PubMed Central

    Rizk, Tamer M.; Ariganjoye, Rafiu O.; Alsaeed, Gihad I.

    2015-01-01

    We aim to describe an 8-year-old boy with an unusual clinical presentation of Gaucher disease (GD). Gaucher disease is a progressive lysosomal storage disorder due to deficiency of the specific enzyme glucocerebrosidase with varying clinical features, but often involving the monocytes-macrophages systems. This child ran a progressive course with a devastating outcome. Three distinct GD subtypes have been described with varying clinical features based on the presence or absence of neurologic involvement. Gaucher disease diagnosis is obtained via: enzyme activity assay, gene mutation study, bone marrow aspiration in addition to multiple other tests that have been successfully used in diagnosis of cases of GD. Treatment modalities include enzyme replacement treatment, substrate reduction therapy, bone marrow transplantation, blood transfusion, and surgery are available management modalities for GD. Gaucher disease is a chronic disease requiring a multidisciplinary team approach with regular follow up with multiple subspecialties. PMID:26166597

  18. Expression and function of the TL1A/DR3 axis in chronic lymphocytic leukemia

    PubMed Central

    Cavallini, Chiara; Lovato, Ornella; Bertolaso, Anna; Zoratti, Elisa; Malpeli, Giorgio; Mimiola, Elda; Tinelli, Martina; Aprili, Fiorenza; Tecchio, Cristina; Perbellini, Omar; Scarpa, Aldo; Zamò, Alberto; Cassatella, Marco Antonio; Pizzolo, Giovanni; Scupoli, Maria Teresa

    2015-01-01

    TNF-like ligand 1A (TL1A) and its unique receptor death receptor 3 (DR3) acts as broad T-cell costimulator involved in regulatory mechanisms of adaptive immune response under physiological and pathological settings. Moreover, we have recently shown that TL1A negatively regulates B-cell proliferation. Despite increasing interest on the TL1A/DR3-axis functions, very little is known on its expression and role in leukemia. In this study, we investigated the expression and function of TL1A/DR3 axis in chronic lymphocytic leukemia (CLL). DR3 was differentially expressed in activated CLL cells and predominantly detected in patients with early clinical stage disease. Soluble TL1A has been revealed in the sera of CLL patients where higher TL1A levels were associated with early stage disease. T cells, monocytes and leukemic B cells have been identified as major sources of TL1A in CLL. The relevance of these findings has been sustained by functional data showing that exogenous TL1A reduces CLL proliferation induced by stimulation of the B cell receptor. Overall, these data document the expression of the TL1A/DR3 axis in early-stage CLL. They also identify a novel function for TL1A as a negative regulator of leukemic cell proliferation that may influence the CLL physiopathology and clinical outcome at an early-stage disease. PMID:26393680

  19. Alzheimer's disease.

    PubMed

    Scheltens, Philip; Blennow, Kaj; Breteler, Monique M B; de Strooper, Bart; Frisoni, Giovanni B; Salloway, Stephen; Van der Flier, Wiesje Maria

    2016-07-30

    Although the prevalence of dementia continues to increase worldwide, incidence in the western world might have decreased as a result of better vascular care and improved brain health. Alzheimer's disease, the most prevalent cause of dementia, is still defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality as proposed in the original amyloid hypothesis. Age-related, protective, and disease-promoting factors probably interact with the core mechanisms of the disease. Amyloid β42, and tau proteins are established core cerebrospinal biomarkers; novel candidate biomarkers include amyloid β oligomers and synaptic markers. MRI and fluorodeoxyglucose PET are established imaging techniques for diagnosis of Alzheimer's disease. Amyloid PET is gaining traction in the clinical arena, but validity and cost-effectiveness remain to be established. Tau PET might offer new insights and be of great help in differential diagnosis and selection of patients for trials. In the search for understanding the disease mechanism and keys to treatment, research is moving increasingly into the earliest phase of disease. Preclinical Alzheimer's disease is defined as biomarker evidence of Alzheimer's pathological changes in cognitively healthy individuals. Patients with subjective cognitive decline have been identified as a useful population in whom to look for preclinical Alzheimer's disease. Moderately positive results for interventions targeting several lifestyle factors in non-demented elderly patients and moderately positive interim results for lowering amyloid in pre-dementia Alzheimer's disease suggest that, ultimately, there will be a future in which specific anti-Alzheimer's therapy will be combined with lifestyle interventions targeting general brain health to jointly combat the disease. In this Seminar, we discuss the main developments in Alzheimer's research. PMID:26921134

  20. Lyme disease.

    PubMed

    Nat, Laura Bogdana; Simiti, Adriana Liana; Poanta, Laura Irina

    2014-01-01

    Lyme disease (Borreliosis), also called the "disease of 1000 faces", is produced by a bacterium called Borrelia burgdorferi, transmitted by the Ixodes tick. The clinical picture is non-specific and polymorph, with multisystemic involvement. Diagnosis is most often one of exclusion, and certain diagnosis is based on the presence of Borellia antibodies. The treatment is done differently depending on the stage of the disease and the severity of injuries, being used antibiotics like Doxycycline, Amoxicillin, Erythromycin or Penicillin. Under treatment the disease quickly heals without sequel, in the early stages, but advanced stages are usually resistant to treatment and chronic injuries can occur. Symptoms get worse without treatment and become chronic. We present the case of a woman of 66-year-old with a complex history of disease, which began one year prior to admission, through multiple and nonspecific symptoms; she presented herself in numerous medical services (gastroenterology, rheumatology--where an immunosuppressive treatment was initiated, hematology) without determining a final diagnosis. She was admitted in our service with altered general state and worsening symptoms, predominantly fever, muscle pain, joint pain, the patient being immobilized in bed. After multiple investigations and the problem of differential diagnosis with multiple pathologies, we finally established the diagnosis of Lyme disease. The peculiarities of the case are represented by the severity of the clinical manifestations and fulminant disease evolution under the unjustified administration of immunosuppressive treatment, and atypical joint involvement regarding localization and evolution that raised the issue of differential diagnosis with osteosarcoma or bone tuberculosis. PMID:25726630

  1. [Segawa disease].

    PubMed

    Segawa, Masaya

    2008-01-01

    The first report of Segawa disease was a report of two girls, cousin each other, with dystonic posture, under the title of "Hereditary progressive basal ganglia disorder" in 1971. After accumulation of cases with an adult case, I confirmed this disease does not transform to Parkinson's disease in adulthood and published with a nomenclature of "Hereditary progressive dystonia with marked diurnal fluctuation" in 1976. Polysomnographical examination for evaluating the sleep effects and correlation of the natural course to the age variation of the tyrosine hydroxylase activities in the striatum, these speculated this is a particular disorder caused by non-progressive decrement of the tyrosine hydroxylase at the terminal of the nigrostriatal dopamine neuron. This was supported by PET studies in early 1990's. Evaluation of pteridine metabolites in cerebrospinal fluid revealed partial decrement of the GTP cyclohydrolase I as the cause of this disease and induced the discovery of the causative gene. After the discovery of the gene, an autopsied case with dopa-responsive dystonia was confirmed as Segawa disease and the neuropathological and histochemical findings confirmed the hypothesis. Furthermore, these showed rather selective involvement the D1-direct pathways in the disease. However, it was also clarified existence of two types, one, classic type, postural dystonia and the other action dystonia with vigorous dystonic movements besides dystonic posture, which, is postulated to be caused by the dopamine neuron innervating to the subthalamic nucleus with D1 neuron. Existence of these two phenotypes also provides phenotypical variation of Segawa disease. PMID:18232327

  2. Lyme disease.

    PubMed

    Kalish, R

    1993-05-01

    The clinical features of Lyme disease have been well documented since its description as a distinct clinical entity in 1975. A better understanding of the diversity of Borrelia strains and species that cause the disease as well as new insights into the immunology and pathogenesis of Lyme disease help explain some of the observed variations in clinical manifestations. The diagnosis of Lyme disease may be straightforward when patients in endemic areas present with typical clinical features; however, the diagnosis should be in doubt when the clinical picture is nonspecific or atypical, or a feasible exposure history cannot be obtained. Laboratory diagnosis is primarily based on serologic techniques, but interpretation of test results can be fraught with uncertainty. Treatment with appropriate antibiotics is successful in the majority of cases of Lyme disease. However, some patients may not respond, and in these cases multiple repeated courses are usually ineffective and unwarranted. More data are needed to determine the appropriate treatment of Lyme disease during pregnancy, and the appropriate management of ixodes tick bites. A suitable arthropod vector and a competent animal reservoir host are essential for perpetuating Lyme disease in a geographic location. The intricate ecologic forces at work are well understood in certain endemic areas but are poorly defined elsewhere, particularly where the disease is sporadic or its existence is in question. Prevention of Lyme disease is best achieved through education regarding avoidance of the tick vector. A vaccine using a recombinant form of the OspA protein of B. burgdorferi has been successful in animal models. Whether an effective human vaccine can be developed remains unknown. PMID:8502779

  3. [CELIAC DISEASE].

    PubMed

    Malamut, Georgia; Cellier, Christophe

    2015-12-01

    Celiac disease is an inflammatory enteropathy, autoimmune-like, due to gluten intake in genetically predisposed persons with HLA-DQ2/DQ8 genotyping. Prevalence rates are approaching 1% of population in Europe and USA. Clinical expression of celiac disease is extremely various. Screening is based on detection of serum celiac antibodies and diagnosis is confirmed with duodenal biopsy. Treatment relies on gluten free diet (GFD) with eviction of wheat, barley and rye. GFD allows prevention of osteopenia, autoimmune diseases and malignant complications. The main cause of resistance to GFD because is its bad observance. PMID:26979028

  4. Fabry Disease

    MedlinePlus

    ... kidneys may become progressively impaired, leading to renal failure. Other signs include decreased sweating, fever, and gastrointestinal ... of complications from strokes, heart disease, or kidney failure. What research is being done? The mission of ...

  5. Graves disease

    MedlinePlus

    ... is called hyperthyroidism. (An underactive thyroid leads to hypothyroidism .) Graves disease is the most common cause of ... these treatments, you will have an underactive thyroid (hypothyroidism). You will need to take replacement thyroid hormones ...

  6. Wilson Disease

    MedlinePlus

    ... Wilson disease. Growing knowledge of the copper transporting gene ATP7B, which in its mutated form causes WD, should lead to the design of better therapies for this disorder. NIH Patient Recruitment for Wilson ...

  7. Lyme disease.

    PubMed

    Evans, J

    1994-07-01

    In the United States, Lyme disease is the most common arthropod-borne infection. The majority of cases occur in the Northeast, the Midwest, and California, which are areas with established foci of Borrelia burgdorferi. Phenotypic and genotypic diversity of B. burgdorferi has resulted in its classification into three separate genospecies and may account for differences in disease expression. Clinical features of Lyme disease have expanded to include a flulike illness without erythema migrans and the persistence of intrathecal antibody responses after successful antibiotic therapy in neuroborreliosis. Better understanding of the pathogenic mechanisms of Lyme arthritis will help guide future treatment decisions, and recent progress made in assessing the risk of infection from tick bites and vaccine development may help calm public anxiety about Lyme disease. PMID:8068513

  8. Behcet's Disease

    MedlinePlus

    ... Old Silk Route,” which spans the region from Japan and China in the Far East to the ... the disease’s epidemiology is not well understood. In Japan, Behcet’s disease ranks as a leading cause of ...

  9. Lung Diseases

    MedlinePlus

    ... on Carcinogens: Captafol A Human Health Perspective on Climate Change (Full Report) (4MB) Certain Glass Wool Fibers (Inhalable) ( ... Environmental Public Health (PEPH) (1MB) Programs and Initiatives: Climate Change and Human Health Respiratory Disease and the Environment ( ...

  10. Pick disease

    MedlinePlus

    ... disease and their family may need to seek legal advice early in the course of the disorder. Advance care directive , power of attorney, and other legal actions can make it easier to make decisions ...

  11. Stargardt Disease

    MedlinePlus

    ... ways to prevent it. A decrease in color perception also occurs in Stargardt disease. This is because photoreceptor cells involved in color perception are concentrated in the macula. Back to top ...

  12. Crohn's Disease

    MedlinePlus

    ... can help control symptoms, and may include medicines, nutrition supplements, and/or surgery. Some people have long periods of remission, when they are free of symptoms. NIH: National Institute of Diabetes and Digestive and Kidney Diseases

  13. Whipple's disease

    MedlinePlus

    ... fatal. Treatment relieves symptoms and can cure the disease. ... Brain damage Heart valve damage (from endocarditis ) Nutritional deficiencies Symptoms return (which may be because of drug resistance) Weight loss

  14. Sever's Disease

    MedlinePlus

    ... Are Reading Upsetting News Reports? What to Say Vaccines: Which Ones & When? Smart School Lunches Emmy-Nominated Video "Cerebral Palsy: Shannon's Story" 5 Things to Know About Zika & Pregnancy Sever's Disease KidsHealth > ...

  15. Endocrine Diseases

    MedlinePlus

    Your endocrine system includes eight major glands throughout your body. These glands make hormones. Hormones are chemical messengers. They ... levels. In the United States, the most common endocrine disease is diabetes. There are many others. They ...

  16. Lung Diseases

    MedlinePlus

    ... many disorders affecting the lungs, such as asthma, COPD, infections like influenza, pneumonia and tuberculosis, lung cancer, and many other breathing problems. Some lung diseases can lead to respiratory failure. Dept. of Health and Human Services Office on Women's Health

  17. Moyamoya Disease

    MedlinePlus

    ... to prevent repeated strokes in children. NIH Patient Recruitment for Moyamoya Disease Clinical Trials At NIH Clinical Center Throughout the U.S. and Worldwide NINDS Clinical Trials Organizations Column1 Column2 National Rehabilitation Information Center (NARIC) 8400 ...

  18. Planning Diseases.

    ERIC Educational Resources Information Center

    Gabel, Medard

    1984-01-01

    To solve societal problems, both local and global, a global approach is needed. Serious diseases that are crippling present-day problem solving and planning are discussed, and the characteristics of a healthy, effective planning approach are described. (RM)

  19. Prion Diseases

    MedlinePlus

    ... and sometimes polymerize in neurodegenerative disorders. Credit: NIAID Biology & Genetics Scientists are examining how abnormal prion protein ... the abnormal form. Read more about prion diseases biology and genetics Therapeutic Approaches Although there are no ...

  20. Graves disease

    MedlinePlus

    ... is called hyperthyroidism . (An underactive thyroid leads to hypothyroidism .) Graves disease is the most common cause of ... radioactive iodine often will cause an underactive thyroid (hypothyroidism). Without getting the correct dosage of thyroid hormone ...

  1. Chagas disease

    MedlinePlus

    ... help control the spread of the disease. Blood banks in Central and South America screen donors for ... if the donor has the parasite. Most blood banks in the United States began screening for Chagas ...

  2. Krabbe disease

    MedlinePlus

    ... Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment . 5th ed. New York, NY: Springer; 2012:chap 39. Read ... by: Chad Haldeman-Englert, MD, FACMG, Wake Forest School of Medicine, Department of Pediatrics, Section on ...

  3. Vascular Diseases

    MedlinePlus

    ... heart and blood vessels, such as diabetes or high cholesterol Smoking Obesity Losing weight, eating healthy foods, being active and not smoking can help vascular disease. Other treatments include medicines and surgery.

  4. Alzheimer disease

    MedlinePlus

    Senile dementia - Alzheimer type (SDAT); SDAT; Dementia - Alzheimer ... The exact cause of Alzheimer disease (AD) is not known. Research shows that certain changes in the brain lead to AD. You are more likely ...

  5. Zoonotic Diseases

    MedlinePlus

    ... gov . One Health About One Health Zoonotic Diseases History of One Health One Health in Action The Story of the Rift Valley Fever Virus Vaccine Lead Poisoning Investigation in Northern Nigeria Domestic One Health Activities "Friends" Magazine Global One ...

  6. Heart Disease

    MedlinePlus

    ... with heart disease? What do my cholesterol and triglyceride numbers mean? How can I lower my cholesterol? ... weight Know your numbers (blood pressure, cholesterol, and triglycerides) You can reduce your chances of getting heart ...

  7. Pilonidal Disease

    MedlinePlus

    Skip to main content ASCRS Patients Educational Resources Diseases and Conditions Patient Education Library Patient Success Stories Treatments and Screening Resources Find a Surgeon Hereditary Colorectal Cancer Registries Helpful Links Physicians ...

  8. Batten Disease

    MedlinePlus

    ... gene codes has not been identified. In addition, research scientists are working with NCL animal models to improve understanding and treatment of these disorders. One research team, for example, is ... for scientists to study the genetics of these diseases. NIH ...

  9. Huntington disease

    MedlinePlus

    ... physical exam and may ask about the patient's family history and symptoms. An exam of the nervous system ... Genetic counseling is advised if there is a family history of Huntington disease. Experts also recommend genetic counseling ...

  10. Alzheimer's Disease

    MedlinePlus

    ... risk of urinary tract and other serious infections. Malnutrition or dehydration: People who have Alzheimer’s disease may ... swallow. It’s important to watch for signs of malnutrition. If you think that a loved one might ...

  11. Hirschsprung's disease

    MedlinePlus

    Muscle contractions in the gut help digested foods and liquids move through the intestine. This is called peristalsis. Nerves between the muscle layers trigger the contractions. In Hirschsprung's disease, the nerves are missing from ...

  12. Canavan Disease

    MedlinePlus

    ... fibers in the brain, as well as providing nutritional support for nerve cells. In Canavan disease, many oligodendrocytes ... There is no cure, nor is there a standard course of treatment. Treatment is symptomatic and supportive. ...

  13. Gum Disease

    MedlinePlus

    ... disease. It ranges from simple gum inflammation, called gingivitis, to serious damage to the tissue and bone ... the worst cases, you can lose teeth. In gingivitis, the gums become red and swollen. They can ...

  14. Parkinson's Disease

    MedlinePlus

    ... about 5 to 10 percent of people with Parkinson's have "early-onset" disease which begins before the age of 50. Early-onset forms of Parkinson's are often inherited, though not always, and some ...

  15. Meningococcal Disease

    MedlinePlus

    ... at increased risk of meningococcal disease. This includes college students, military personnel, international travelers to areas where meningococcal ... You May Also Like An 18-Year-Old College Student’s Battle with Meningitis Meningococcal Serogroup B Cases and ...

  16. Lung disease

    MedlinePlus

    ... the lungs to take in oxygen and release carbon dioxide. People with this type of lung disorder often ... the lungs to take up oxygen and release carbon dioxide. These diseases may also affect heart function. An ...

  17. Wilson Disease

    MedlinePlus

    ... too much copper is poisonous. Normally, the liver filters extra copper and releases it into bile. Bile ... tract. In Wilson disease, the liver does not filter copper correctly and copper builds up in the ...

  18. Lyme disease

    MedlinePlus

    ... symptoms develop. A single dose of the antibiotic doxycycline may be given to someone soon after being ... the disease and the symptoms. Common choices include doxycycline, amoxicillin, azithromycin, cefuroxime, and ceftriaxone. Pain medicines, such ...

  19. Lyme Disease

    MedlinePlus

    ... It has also been reported in China, Europe, Japan, Australia, and the parts of the former Soviet ... bacterium can affect the joints, heart, and nervous system. The late phase of Lyme disease can also ...

  20. Parkinson disease

    MedlinePlus

    Nerve cells use a brain chemical called dopamine to help control muscle movement. With Parkinson disease, the brain cells that make dopamine slowly die. Without dopamine, the cells that control movement ...

  1. Parkinson's Disease

    MedlinePlus

    ... cells make and use a brain chemical called dopamine (say: DOH-puh-meen) to send messages to ... coordinate body movements. When someone has Parkinson's disease, dopamine levels are low. So, the body doesn't ...

  2. Hirschsprung disease

    MedlinePlus

    ... a condition that can lead to malnourishment and dehydration. When to Contact a Medical Professional Call your child's provider if: Your child develops symptoms of Hirschsprung disease Your child has abdominal pain ...

  3. Addison disease

    MedlinePlus

    ... genetic defects may also cause adrenal insufficiency. Symptoms Symptoms of Addison disease include: Chronic diarrhea, nausea, and vomiting Darkening of the skin in some places Dehydration Dizziness when standing up Paleness Extreme weakness , fatigue , ...

  4. Mitochondrial Diseases

    MedlinePlus

    ... in your body tissues. If you have a metabolic disorder, something goes wrong with this process. Mitochondrial diseases are a group of metabolic disorders. Mitochondria are small structures that produce energy in ...

  5. Crohn disease

    PubMed Central

    Stappenbeck, Thaddeus S.; Rioux, John D.; Mizoguchi, Atsushi; Saitoh, Tatsuya; Huett, Alan; Darfeuille-Michaud, Arlette; Wileman, Tom; Mizushima, Noboru; Carding, Simon; Akira, Shizuo; Parkes, Miles; Xavier, Ramnik J.

    2011-01-01

    Crohn disease (CD) is a chronic and debilitating inflammatory condition of the gastrointestinal tract.1 Prevalence in western populations is 100–150/100,000 and somewhat higher in Ashkenazi Jews. Peak incidence is in early adult life, although any age can be affected and a majority of affected individuals progress to relapsing and chronic disease. Medical treatments rely significantly on empirical corticosteroid therapy and immunosuppression, and intestinal resectional surgery is frequently required. Thus, 80% of patients with CD come to surgery for refractory disease or complications. It is hoped that an improved understanding of pathogenic mechanisms, for example by studying the genetic basis of CD and other forms of inflammatory bowel diseases (IBD), will lead to improved therapies and possibly preventative strategies in individuals identified as being at risk. PMID:20729636

  6. Liver Diseases

    MedlinePlus

    Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. There are many kinds of liver diseases. Viruses cause some of them, like hepatitis ...

  7. [Kawasaki disease].

    PubMed

    Gliwińska, E

    1995-01-01

    Kawasaki disease (KD), first described in Japan in 1967 by Dr. Tomisaku Kawasaki, is an acute multi system vasculitis of infancy and early childhood characterised by high fever, rash, conjunctivitis, inflammation of the mucous membranes, erythematous induration of the hands and feet and cervical lymphadenopathy. Synonyms for Kawasaki disease include "Kawasaki syndrome" and "mucocutaneous lymph node syndrome" (MCLS, MLNS, MCLNS). Kawasaki disease was initially presumed to occur only in Japan; but now this disease is known in the whole world. The first cases in the United States were reported in Hawaii in 1976. In poland 5 cases were recognized, and first time described in 1981. The etiology of Kawasaki disease remains unknown. Toxic, allergic and immunologic causes have been suspected, but most investigators favor an infectious cause or an immune response to an infectious agent. Among classes of microorganism suspected of causing Kawasaki disease were bacteria, leptospires, fungi, rickettsiae and a number of viruses. Recently, there has been considerable interest in the possibility, that Kawasaki disease is caused by RETROVIRUSES. Although the disease is generally benign and self-limited, about 20% of children develop coronary artery aneurysms. In 5% of cases, giant aneurysm/more then 8 mm/develop, predisposing the patient to acute coronary artery thrombosis, myocardial infarction and sudden death. This is the most serious complication of KD. Other manifestations of hearth involvement, include pericarditis, myocarditis, myocardial failure and mitral regurgitation. Besides this many other clinical findings are commonly noted in KD; such as: pneumonia, diarrhea, arthritis, aseptic meningitis, otitis media, obstructive jaundice, hydrops of gallbladder and others.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7545822

  8. Pharmacogenetics of SULT1A1

    PubMed Central

    Daniels, Jaclyn; Kadlubar, Susan

    2015-01-01

    Cytosolic SULT1A1 participates in the bioconversion of a plethora of endogenous and xenobiotic substances. Genetic variation in this important enzyme such as SNPs can vary by ethnicity and have functional consequences on its activity. Most SULT1A1 genetic variability studies have been centered on the SULT1A1*1/2 SNP. Highlighted here are not only this SNP, but other genetic variants associated with SULT1A1 that could modify drug efficacy and xenobiotic metabolism. Some studies have investigated how differential metabolism of xenobiotic substances influences susceptibility to or protection from cancer in multiple sites. This review will focus primarily on the impact of SULT1A1 genetic variation on the response to anticancer therapeutic agents and subsequently how it relates to environmental and dietary exposure to both cancer-causing and cancer-preventative compounds. PMID:25493573

  9. Legionnaires' disease.

    PubMed

    Cunha, Burke A; Burillo, Almudena; Bouza, Emilio

    2016-01-23

    Since first identified in early 1977, bacteria of the genus Legionella are recognised as a common cause of community-acquired pneumonia and a rare cause of hospital-acquired pneumonia. Legionella bacteria multisystem manifestations mainly affect susceptible patients as a result of age, underlying debilitating conditions, or immunosuppression. Water is the major natural reservoir for Legionella, and the pathogen is found in many different natural and artificial aquatic environments such as cooling towers or water systems in buildings, including hospitals. The term given to the severe pneumonia and systemic infection caused by Legionella bacteria is Legionnaires' disease. Over time, the prevalence of legionellosis or Legionnaires' disease has risen, which might indicate a greater awareness and reporting of the disease. Advances in microbiology have led to a better understanding of the ecological niches and pathogenesis of the condition. Legionnaires' disease is not always suspected because of its non-specific symptoms, and the diagnostic tests routinely available do not offer the desired sensitivity. However, effective antibiotics are available. Disease notification systems provide the basis for initiating investigations and limiting the scale and recurrence of outbreaks. This report reviews our current understanding of this disease. PMID:26231463

  10. Legionella pneumophila glucosyltransferase inhibits host elongation factor 1A

    PubMed Central

    Belyi, Yury; Niggeweg, Ricarda; Opitz, Bastian; Vogelsgesang, Martin; Hippenstiel, Stefan; Wilm, Matthias; Aktories, Klaus

    2006-01-01

    Legionella pneumophila, the causal agent of Legionnaires' disease, is an intracellular parasite and invades and proliferates within different eukaryotic cells, including human alveolar macrophages. After several 100-fold multiplication within host cells, the pathogens are released for new invasion by induction of apoptosis or necrosis. Here we report that L. pneumophila produces a glucosyltransferase, which selectively modifies an ≈50-kDa mammalian protein by using UDP-glucose as a cosubstrate. MS analysis identified the protein substrate as the mammalian elongation factor (EF)1A. Legionella glucosyltransferase modifies its eukaryotic protein substrate at serine-53, which is located in the GTPase domain of the EF. Glucosylation of EF1A results in inhibition of eukaryotic protein synthesis and death of target cells. Our findings show a mode of inhibition of protein synthesis by microbial pathogens and offer a perspective for understanding of the host-pathogen interaction of L. pneumophila. PMID:17068130

  11. Aortic Valve Disease

    MedlinePlus

    ... Disease Tricuspid Valve Disease Cardiac Rhythm Disturbances Thoracic Aortic Aneurysm Pediatric and Congenital Heart Disease Heart abnormalities that ... Disease Tricuspid Valve Disease Cardiac Rhythm Disturbances Thoracic Aortic Aneurysm Aortic Valve Disease Overview The human heart has ...

  12. Neuronal loss of Drosophila NPC1a causes cholesterol aggregation and age-progressive neurodegeneration.

    PubMed

    Phillips, Scott E; Woodruff, E A; Liang, Ping; Patten, Meaghan; Broadie, Kendal

    2008-06-25

    The mistrafficking and consequent cytoplasmic accumulation of cholesterol and sphingolipids is linked to multiple neurodegenerative diseases. One class of disease, the sphingolipid storage diseases, includes Niemann-Pick disease type C (NPC), caused predominantly (95%) by mutation of the NPC1 gene. A disease model has been established through mutation of Drosophila NPC1a (dnpc1a). Null mutants display early lethality attributable to loss of cholesterol-dependent ecdysone steroid hormone production. Null mutants rescued to adults by restoring ecdysone production mimic human NPC patients with progressive motor defects and reduced life spans. Analysis of dnpc1a null brains shows elevated overall cholesterol levels and progressive accumulation of filipin-positive cholesterol aggregates within brain and retina, as well as isolated cultured brain neurons. Ultrastructural imaging of dnpc1a mutant brains reveals age-progressive accumulation of striking multilamellar and multivesicular organelles, preceding the onset of neurodegeneration. Consistently, electroretinogram recordings show age-progressive loss of phototransduction and photoreceptor synaptic transmission. Early lethality, movement impairments, neuronal cholesterol deposits, accumulation of multilamellar bodies, and age-dependent neurodegeneration are all rescued by targeted neuronal expression of a wild-type dnpc1a transgene. Interestingly, targeted expression of dnpc1a in glia also provides limited rescue of adult lethality. Generation of dnpc1a null mutant neuron clones in the brain reveals cell-autonomous requirements for dNPC1a in cholesterol and membrane trafficking. These data demonstrate a requirement for dNPC1a in the maintenance of neuronal function and viability and show that loss of dNPC1a in neurons mimics the human neurodegenerative condition. PMID:18579730

  13. Neuronal Loss of Drosophila NPC1a Causes Cholesterol Aggregation and Age-Progressive Neurodegeneration

    PubMed Central

    Phillips, Scott E.; Woodruff, E. A.; Liang, Ping; Patten, Meaghan; Broadie, Kendal

    2009-01-01

    The mistrafficking and consequent cytoplasmic accumulation of cholesterol and sphingolipids is linked to multiple neurodegenerative diseases. One class of disease, the sphingolipid storage diseases, includes Niemann-Pick Disease Type C (NPC) caused predominantly (95%) by mutation of the NPC1 gene. A disease model has been established through mutation of Drosophila NPC1a (dnpc1a). Null mutants display early lethality due to loss of cholesterol-dependent ecdysone steroid hormone production. Null mutants rescued to adults by restoring ecdysone production mimic human NPC patients with progressive motor defects and reduced life spans. Analysis of dnpc1a null brains shows elevated overall cholesterol levels and progressive accumulation of filipin-positive cholesterol aggregates within brain and retina, as well as isolated cultured brain neurons. Ultrastructural imaging of dnpc1a mutant brains reveals age-progressive accumulation of striking multilamellar and multivesicular organelles, preceding the onset of neurodegeneration. Consistently, electroretinogram (ERG) recordings show age-progressive loss of phototransduction and photoreceptor synaptic transmission. Early lethality, movement impairments, neuronal cholesterol deposits, accumulation of multilamellar bodies and age-dependent neurodegeneration are all rescued by targeted neuronal expression of a wildtype dnpc1a transgene. Interestingly, targeted expression of dnpc1a in glia also provides limited rescue of adult lethality. Generation of dnpc1a null mutant neuron clones in the brain reveals cell autonomous requirements for dNPC1a in cholesterol and membrane trafficking. These data demonstrate a requirement for dNPC1a in the maintenance of neuronal function and viability, and show that loss of dNPC1a in neurons mimics the human neurodegenerative condition. PMID:18579730

  14. [Eales' disease].

    PubMed

    Errera, M-H; Pratas, A; Goldschmidt, P; Sedira, N; Sahel, J-A; Benesty, J

    2016-05-01

    The syndrome of recurrent vitreous hemorrhages in young men was described for the first time by Henry Eales in 1880. The association with a clinical manifestation of ocular inflammation was reported 5years later. Eales disease affects young adults who present with ischemic retinal vasculitis, with the peripheral retina most commonly affected. Most cases have been reported in South Asia. Although the etiology of this abnormality is unknown, it may be related to an immune sensitivity to Mycobacterium tuberculosis antigens. Its pathogenesis is related to extensive ischemia that affects the retina, secondary to an obliterative retinal vasculopathy with release of angiogenic factors of the VEGF type. Involvement of the retina is the hallmark of the disease, which manifests as follows: periphlebitis, retinal capillary ischemia most often affecting the periphery with secondary proliferative retinopathy and retinal and/or papillary neovascularization, recurrent vitreous hemorrhages and tractional retinal detachment. These complications are potentially blinding. The natural history of Eales disease varies, with temporary or permanent remission in some cases and continuous progression in others. Progression is often bilateral, which necessitates regular follow-up. The treatment of Eales disease depends on the stage of the disease and is not well defined. Observation only, pars plana vitrectomy surgery and/or intravitreal injections of anti-VEGF are recommended in cases of vitreous hemorrhage, associated with corticosteroids when retinal vasculitis is present. Laser pan-retinal photocoagulation is necessary when neovascularization is present. PMID:27185661

  15. Infection and Cardiovascular Disease

    ClinicalTrials.gov

    2016-02-17

    Cardiovascular Diseases; Coronary Disease; Cerebrovascular Accident; Heart Diseases; Myocardial Infarction; Infection; Chlamydia Infections; Cytomegalovirus Infections; Helicobacter Infections; Atherosclerosis

  16. The phenotype range of achondrogenesis 1A.

    PubMed

    Grigelioniene, Giedre; Geiberger, Stefan; Papadogiannakis, Nikos; Mäkitie, Outi; Nishimura, Gen; Nordgren, Ann; Conner, Peter

    2013-10-01

    Achondrogenesis 1A (ACG1A; OMIM 200600) is an autosomal recessive perinatally lethal skeletal dysplasia comprising intrauterine growth failure, micromelia, minor facial anomalies, deficient ossification of the skull, absent or extremely defective spinal ossification, short beaded ribs, and short deformed long bones with a stellate appearance. ACG1A is caused by mutations in the TRIP11 gene, resulting in deficiency of the Golgi microtubule associated protein 210. In this study we describe dizygotic twins with a clinical and radiological phenotype of ACG1A who were homozygous for a novel nonsense mutation in the TRIP11 gene. In addition, another patient with a milder manifestation, not readily distinguishable from those of other lethal skeletal dysplasias, was found to be a compound heterozygote for a nonsense mutation and a deletion of the 3' end of the TRIP11 gene. We conclude that mutations of the TRIP11 gene may encompass a wider phenotypic range than previously recognized. PMID:23956106

  17. The Alpha-1A Adrenergic Receptor in the Rabbit Heart

    PubMed Central

    Myagmar, Bat-Erdene; Swigart, Philip M.; Baker, Anthony J.; Simpson, Paul C.

    2016-01-01

    The alpha-1A-adrenergic receptor (AR) subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR) on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse. PMID:27258143

  18. The Alpha-1A Adrenergic Receptor in the Rabbit Heart.

    PubMed

    Thomas, R Croft; Cowley, Patrick M; Singh, Abhishek; Myagmar, Bat-Erdene; Swigart, Philip M; Baker, Anthony J; Simpson, Paul C

    2016-01-01

    The alpha-1A-adrenergic receptor (AR) subtype is associated with cardioprotective signaling in the mouse and human heart. The rabbit is useful for cardiac disease modeling, but data on the alpha-1A in the rabbit heart are limited. Our objective was to test for expression and function of the alpha-1A in rabbit heart. By quantitative real-time reverse transcription PCR (qPCR) on mRNA from ventricular myocardium of adult male New Zealand White rabbits, the alpha-1B was 99% of total alpha-1-AR mRNA, with <1% alpha-1A and alpha-1D, whereas alpha-1A mRNA was over 50% of total in brain and liver. Saturation radioligand binding identified ~4 fmol total alpha-1-ARs per mg myocardial protein, with 17% alpha-1A by competition with the selective antagonist 5-methylurapidil. The alpha-1D was not detected by competition with BMY-7378, indicating that 83% of alpha-1-ARs were alpha-1B. In isolated left ventricle and right ventricle, the selective alpha-1A agonist A61603 stimulated a negative inotropic effect, versus a positive inotropic effect with the nonselective alpha-1-agonist phenylephrine and the beta-agonist isoproterenol. Blood pressure assay in conscious rabbits using an indwelling aortic telemeter showed that A61603 by bolus intravenous dosing increased mean arterial pressure by 20 mm Hg at 0.14 μg/kg, 10-fold lower than norepinephrine, and chronic A61603 infusion by iPRECIO programmable micro Infusion pump did not increase BP at 22 μg/kg/d. A myocardial slice model useful in human myocardium and an anthracycline cardiotoxicity model useful in mouse were both problematic in rabbit. We conclude that alpha-1A mRNA is very low in rabbit heart, but the receptor is present by binding and mediates a negative inotropic response. Expression and function of the alpha-1A in rabbit heart differ from mouse and human, but the vasopressor response is similar to mouse. PMID:27258143

  19. Peripheral artery disease - legs

    MedlinePlus

    ... if they have a history of: Abnormal cholesterol Diabetes Heart disease (coronary artery disease) High blood pressure ( hypertension ) Kidney disease involving hemodialysis Smoking Stroke ( cerebrovascular disease )

  20. Kawasaki Disease.

    PubMed

    Newburger, Jane W; Takahashi, Masato; Burns, Jane C

    2016-04-12

    Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 in 5 children develop coronary artery aneurysms; this risk is reduced 5-fold if intravenous immunoglobulin is administered within 10 days of fever onset. Coronary artery aneurysms evolve dynamically over time, usually reaching a peak dimension by 6 weeks after illness onset. Almost all the morbidity and mortality occur in patients with giant aneurysms. Risk of myocardial infarction from coronary artery thrombosis is greatest in the first 2 years after illness onset. However, stenosis and occlusion progress over years. Indeed, Kawasaki disease is no longer a rare cause of acute coronary syndrome presenting in young adults. Both coronary artery bypass surgery and percutaneous intervention have been used to treat Kawasaki disease patients who develop myocardial ischemia as a consequence of coronary artery aneurysms and stenosis. PMID:27056781

  1. Crohn's disease

    PubMed Central

    2011-01-01

    Introduction Crohn's disease is a chronic condition of the gastrointestinal tract. It is characterised by transmural, granulomatous inflammation that occurs in a discontinuous pattern, with a tendency to form fistulae. The cause is unknown but may depend on interactions between genetic predisposition, environmental triggers, and mucosal immunity. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments to induce remission in adults with Crohn's disease? What are the effects of surgical interventions to induce and maintain remission in adults with small-bowel Crohn's disease? What are the effects of surgical interventions to induce remission in adults with colonic Crohn's disease? What are the effects of medical interventions to maintain remission in adults with Crohn's disease; and to maintain remission following surgery? What are the effects of lifestyle interventions to maintain remission in adults with Crohn's disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 93 systematic reviews, RCTs, or observational studies that met our inclusion criteria. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: aminosalicylates, antibiotics, azathioprine/mercaptopurine, ciclosporin, corticosteroids (oral), enteral nutrition, fish oil, infliximab, methotrexate, probiotics, resection, segmental colectomy, smoking cessation, and strictureplasty. PMID:21524318

  2. Crohn's disease

    PubMed Central

    2007-01-01

    Introduction Crohn's disease is a long-term chronic condition of the gastrointestinal tract. It is characterised by transmural, granulomatous inflammation that occurs in a discontinuous pattern, with a tendency to form fistulae. The cause is unknown but may depend on interactions between genetic predisposition, environmental triggers, and mucosal immunity. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments in adults to induce remission in Crohn's disease? What are the effects of lifestyle interventions in adults with Crohn's disease to maintain remission? What are the effects of surgical interventions in adults with small-bowel Crohn's disease to induce remission? What are the effects of surgical interventions in adults with colonic Crohn's disease to induce remission? What are the effects of medical interventions to maintain remission in adults with Crohn's disease; and to maintain remission following surgery? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 60 systematic reviews, RCTs, or observational studies that met our inclusion criteria. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: aminosalicylates, antibiotics, azathioprine/mercaptopurine, ciclosporin, corticosteroids (oral), enteral nutrition, fish oil, infliximab, methotrexate, probiotics, resection, segmental colectomy, smoking cessation, and strictureplasty. PMID:19450352

  3. Dupuytren's disease.

    PubMed

    Worrell, Michael

    2012-01-01

    Dupuytren's disease is a benign contractile disorder of the hand. The condition commonly affects older men of Celtic descent. Although fibroproliferation and collagen alteration play a role in its etiology, defining a cause remains elusive. Nonoperative intervention for advanced disease has shown only short-term benefit. Therefore, open fasciectomy has become the mainstay of treatment. Associated morbidity and recurrence have prompted investigation into less invasive techniques, including needle aponeurotomy and enzymatic fasciotomy. Data from phase III studies using injectable collagenase are changing treatment algorithms. Postoperative rehabilitation includes nighttime splinting and immediate active range of motion exercises to facilitate return to function. PMID:22229922

  4. Dent's disease

    PubMed Central

    2010-01-01

    Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl-/H+ exchanger ClC-5, which belongs to the CLC family of Cl- channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and the prevention of

  5. Casein Kinase 2 Is a Novel Regulator of the Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2) Trafficking.

    PubMed

    Chan, Ting; Cheung, Florence Shin Gee; Zheng, Jian; Lu, Xiaoxi; Zhu, Ling; Grewal, Thomas; Murray, Michael; Zhou, Fanfan

    2016-01-01

    Human organic anion transporting polypeptides (OATPs) mediate the influx of many important drugs into cells. Casein kinase 2 (CK2) is a critical protein kinase that phosphorylates >300 protein substrates and is dysregulated in a number of disease states. Among the CK2 substrates are several transporters, although whether this includes human OATPs has not been evaluated. The current study was undertaken to evaluate the regulation of human OATP1A2 by CK2. HEK-239T cells in which OATP1A2 was overexpressed were treated with CK2 specific inhibitors or transfected with CK2 specific siRNA, and the activity, expression, and subcellular trafficking of OATP1A2 was evaluated. CK2 inhibition decreased the uptake of the prototypic OATP1A2 substrate estrone-3-sulfate (E3S). Kinetic studies revealed that this was due to a decrease in the maximum velocity (Vmax) of E3S uptake, while the Michaelis constant was unchanged. The cell surface expression, but not the total cellular expression of OATP1A2, was impaired by CK2 inhibition and knockdown of the catalytic α-subunits of CK2. CK2 inhibition decreased the internalization of OATP1A2 via a clathrin-dependent pathway, decreased OATP1A2 recycling, and likely impaired OATP1A2 targeting to the cell surface. Consistent with these findings, CK2 inhibition also disrupted the colocalization of OATP1A2 and Rab GTPase (Rab)4-, Rab8-, and Rab9-positive endosomal and secretory vesicles. Taken together, CK2 has emerged as a novel regulator of the subcellular trafficking and stability of OATP1A2. Because OATP1A2 transports many molecules of physiological and pharmacological importance, the present data may inform drug selection in patients with diseases in which CK2 and OATP1A2 are dysregulated. PMID:26580496

  6. Ostrich diseases.

    PubMed

    Verwoerd, D J

    2000-08-01

    Scientific knowledge of ostrich diseases is incomplete and very fragmented, with specific details on technical aspects of diagnostic and/or screening tests completely absent in most cases. Salmonella Typhimurium is common in multispecies collections and causes mortality in chicks younger than three months on commercial farms, but is rarely found in chicks older than six months, or slaughter birds of twelve to fourteen months in southern Africa. Campylobacter jejuni and Chlamydia psittaci are occasionally reported, mainly in young ostriches, but both remain a diagnostic challenge. Crimean-Congo haemorrhagic fever is transmitted to domestic animals including ostriches, principally by ticks of the genus Hyalomma. In the ostrich, the disease causes no clinical symptoms during a viraemia of approximately four days. Spongiform encephalopathy has not been reliably reported in ostriches, while anthrax has occurred rarely in modern times but was reportedly an important cause of death approximately 100 years ago in South Africa. Salmonella Gallinarum and S. Pullorum are unknown in ostriches. Pasteurella multocida occurs but is easily contained with antibiotics. Mycoplasma spp. are regularly found in an upper respiratory disease syndrome complicated by opportunistic bacterial pathogens. Ostriches of all ages are susceptible to challenge by velogenic Newcastle disease virus (NDV), but standard inactivated La Sota poultry vaccines can stimulate protective immunity lasting over six months. The viraemic period in vaccinated slaughter ostriches is between nine and eleven days and there are no indications of a carrier state or presence of the virus in the meat or any other tissues after this period, with peak immunoglobulin G response reached on day fourteen post infection. Haemagglutination inhibition tests are significantly less sensitive and less specific than enzyme-linked immunosorbent assays. Cloacal and choanal swabs used for direct virological screening in clinically

  7. Celiac disease.

    PubMed

    Rivera, E; Assiri, A; Guandalini, S

    2013-10-01

    Celiac disease, with a prevalence around 1% of the general population, is the most common genetically-induced food intolerance in the world. Triggered by the ingestion of gluten in genetically predisposed individuals, this enteropathy may appear at any age, and is characterized by a wide variety of clinical signs and symptoms. Among them, gastrointestinal presentations include chronic diarrhea, abdominal pain, weight loss or failure to thrive in children; but extra-intestinal manifestations are also common, and actually appear to be on the rise. They include a large variety of ailments, such as dermatitis Herpetiformis, anemia, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminases, and even female infertility. For the clinician interested in oral diseases, celiac disease can lead to delayed tooth eruption, dental enamel hypoplasia, recurrent oral aphthae. Diagnosing celiac disease requires therefore a high degree of suspicion followed by a very sensitive screening test: serum levels of the autoantibody anti-tissue transglutaminase. A positive subject will then be confirmed by an intestinal biopsy, and will then be put on a strict gluten-free diet, that in most cases will bring a marked improvement of symptoms. Newer forms of treatment which in the future will probably be available to the non-responsive patients are currently being actively pursued. PMID:23496382

  8. Lyme disease.

    PubMed

    Duffy, J

    1990-07-01

    Lyme disease is a complex multisystem disorder recognized on six continents that is epidemic in some parts of the world during spring, summer, and fall seasons. It is an infectious disease caused by a spirochete, B. burgdorferi, which is transmitted chiefly by I. dammini and pacificus ticks in the United States and I. ricinis in Europe. It is a disease with early and late cutaneous manifestations plus involvement of the nervous system, heart, eye, and joints in variable combinations. Diagnosis is based on patient contact with an endemic area, one or more characteristic clinical features, particularly erythema migrans rash, and a positive serologic test for B. burgdorferi infection in the majority of cases with illness greater than 4 to 6 weeks' duration. Although infection is the primary cause, immune mechanisms almost certainly play a synergistic role in some manifestations during late stages. Prompt diagnosis and treatment are important for full recovery. Therapy with doxycycline or amoxicillin is effective in the earliest stages but serious late complications require high doses of intravenous penicillin or ceftriaxone. Some sequelae respond well to antibiotic therapy while others such as chronic arthritis or advanced central nervous system disease may not. Anti-B. burgdorferi antibodies appear to be protective in certain experimental studies but data are limited and inconclusive in humans. PMID:2195920

  9. Wilson Disease

    MedlinePlus

    ... or 414–961–0533 Email: info@wilsonsdisease.org Internet: www.wilsonsdisease.org National Organization for Rare Disorders ... or 203–744–0100 Fax: 203–798–2291 Internet: www.rarediseases.org Office of Rare Diseases Research ...

  10. Neurologic Diseases

    MedlinePlus

    The brain, spinal cord, and nerves make up the nervous system. Together they control all the workings of the body. When something goes wrong ... develops, such as spina bifida Degenerative diseases, where nerve cells are ... to the spinal cord and brain Seizure disorders, such as epilepsy ...

  11. Cement disease.

    PubMed

    Jones, L C; Hungerford, D S

    1987-12-01

    Does "cement disease" exist? The bony environment surrounding a loosened cemented prosthesis is an abnormal pathologic condition which, if left unattended, will progress to a total failure of the joint including an inhibition of function and immobilizing pain. That biomaterial properties of the cement used for fixation also contribute to the pathologic state separates this disease from other modes of loosening. This leads inevitably to the conclusion that "cement disease" does exist. Methyl methacrylate has revolutionized the treatment of severe joint dysfunction. There can be no doubt that improving surgical technique, cement handling, and the cement itself will continue to improve the results and reduce the incidence of failure due to loosening. Cement is undoubtedly satisfactory for elderly patients with low activity levels and relatively short life expectancies. However, because of the inherent biologic and biomechanical properties of methyl methacrylate, it is unlikely that it can be rendered satisfactory in the long run for the young, the active, or the overweight patient, for whom alternatives are currently being sought. In such cases, the elimination of "cement disease" can only occur with the elimination of cement. Alternatives include the search for other grouting materials and the development of prostheses with satisfactory surfaces for either press-fit or biologic ingrowth. PMID:3315375

  12. Foodborne Diseases

    MedlinePlus

    ... Centers for Disease Control and Prevention Foodsafety.gov ​​ Javascript Error Your browser JavaScript is turned off causing certain features of the ... incorrectly. Please visit your browser settings and turn JavaScript on. Read more information on enabling JavaScript. Top ...

  13. Autoinflammatory Diseases

    MedlinePlus

    ... Behçet’s Disease Progress and Promise Key Words The Immune System When your body is attacked—perhaps by a virus or other germs—your immune system defends you. It “sees” and kills the germs ...

  14. Gaucher disease

    MedlinePlus

    ... signs of swelling in the liver and spleen, bone changes, lung disease, eye movement problems, heart problems, or hearing loss. The following tests may be done: Blood test to look for enzyme activity Bone marrow aspiration Biopsy of your spleen MRI CT ...

  15. Castleman disease

    PubMed Central

    Al-Amri, Ali M.

    2012-01-01

    Castleman and Towne described a disease presenting as a mediastinal mass resembling thymoma. It is also known as "giant lymph node hyperplasia", "lymph node hamartoma", "angiofollicular mediastinal lymph node hyperplasia", and "angiomatous lymphoid hyperplasia". The pathogenesis is unknown, but the bulk of evidence points toward faulty immune regulation, resulting in excessive B-lymphocyte and plasma-cell proliferation in lymphatic tissue. In addition to the mediastinal presentation, extrathoracic involvement in the neck, axilla, mesentery, pelvis, pancreas, adrenal gland, and retroperitoneum also have been described. There are 2 major pathologic variations of Castleman disease: (1) hyaline-vascular variant, the most frequent, characterized by small hyaline-vascular follicles and capillary proliferation; and (2) the plasma-cell variant, in which large lymphoid follicles are separated by sheets of plasma cells. The hyaline-vascular cases usually are largely asymptomatic, whereas the less common plasma-cell variant may present with fever, anemia, weight loss, and night sweats, along with polyclonal hypergamma-globulinemia. Castleman disease is a rare lymphoproliferative disorders. Few cases have been described world widely. In this article we reviewed the classification, pathogenesis, pathology, radiological features and up to date treatment with special emphasis on the role of viral stimulation, recent therapeutic modalities and the HIV-associated disease. PMID:23071471

  16. Huntington's Disease

    MedlinePlus

    ... rather than by the loss of individual cells, scientists are using cutting-edge methods such as optogenetics (where neurons are activated or silenced in the brains of living animals using light beams) to probe the cause ... defects in HD. Scientists are also using stem cells to study disease ...

  17. Sunflower diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The sunflower disease chapter is part of the Sunflower Oilseeds Monograph, which will be a new publication in the AOCS Oilseeds Monograph series. The monograph contains an overview and history of sunflower crop development, how the oilseed is cultivated, how the oilseed is produced, how the seed is...

  18. SMUT DISEASES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A COMPREHENSIVE REVIEW OF MOST ASPECTS OF COMMON BUNT AND DWARF BUNT DISEASES OF WHEAT IS PRESENTED. INCLUDED ARE SECTIONS ON HISTORY, DISTRIBUTION AND ECONOMIC IMPORTANCE, TAXONOMY, MORPHOLOGY, SPORE GERMINATION, CULTURE, AND PHYSIOLOGY. EXTENSIVE SECTIONS DEAL WITH RESEARCH METHODOLOGY AND DISEA...

  19. Lung Diseases

    MedlinePlus

    When you breathe, your lungs take in oxygen from the air and deliver it to the bloodstream. The cells in your body need oxygen to ... you breathe nearly 25,000 times. People with lung disease have difficulty breathing. Millions of people in ...

  20. Blount Disease

    MedlinePlus

    ... Fitness Diseases & Conditions Infections Q&A School & Jobs Drugs & Alcohol Staying Safe Recipes En Español Making a Change – Your Personal Plan Hot Topics Meningitis Choosing Your Mood Prescription Drug Abuse Healthy School Lunch Planner How Can I ...

  1. Lyme disease.

    PubMed

    Chomel, B

    2015-08-01

    Lyme disease is among the most frequently diagnosed zoonotic tick-borne diseases worldwide. The number of human cases has been on the increase since the first recognition of its aetiological agent. Lyme disease is caused by spirochete bacteria belonging to the genus Borrelia, with B. burgdorferi sensu stricto (s.s.) found in the Americas, and B. afzelii and B. garinii, in addition to B. burgdorferi s.s., in Europe and Asia. Environmental factors, such as human encroachment onto habitats favourable to ticks and their hosts, reduced deforestation, increased human outdoor activities, and climatic factors favouring a wider distribution of tick vectors, have enhanced the impact of the disease on both humans and animals. Clinical manifestations in humans include, in the early phases, erythema migrans, followed several weeks later by neuro-borreliosis (meningo-radiculitis, meningitis or meningo-encephalitis), Lyme arthritis and/or Borrelia lymphocytoma. In dogs, acute signs include fever, general malaise, lameness, lymph node enlargement and polyarthritis, as well as neuro-borreliosis in the chronic form. Diagnosis is mainly serological in both humans and animals, based on either a two-tier approach (an immunoenzymatic test followed by a Western blot confirmatory test) in humans or C(6) peptide, only in dogs. Early treatment with antibiotics, such as doxycycline or amoxicillin, for three weeks usually reduces the risk of chronic disease. Tick control, including the use of tick repellents for both humans and animals, particularly dogs, is highly reliable in preventing transmission. Vaccines are not available to prevent human infection, whereas several vaccines are available to reduce transmission and the clinical manifestations of infection in dogs. PMID:26601457

  2. Celiac disease

    PubMed Central

    Rodrigo, Luis

    2006-01-01

    Celiac disease (CD) is a common autoimmune disorder, induced by the intake of gluten proteins present in wheat, barley and rye. Contrary to common belief, this disorder is a protean systemic disease, rather than merely a pure digestive alteration. CD is closely associated with genes that code HLA-II antigens, mainly of DQ2 and DQ8 classes. Previously, it was considered to be a rare childhood disorder, but is actually considered a frequent condition, present at any age, which may have multiple complications. Tissue transglutaminase-2 (tTG), appears to be an important component of this disease, both, in its pathogenesis and diagnosis. Active CD is characterized by intestinal and/or extra-intestinal symptoms, villous atrophy and crypt hyperplasia, and strongly positive tTG auto-antibodies. The duodenal biopsy is considered to be the “gold standard” for diagnosis, but its practice has significant limitations in its interpretation, especially in adults. Occasionally, it results in a false-negative because of patchy mucosal changes and the presence of mucosal villous atrophy is often more severe in the proximal jejunum, usually not reached by endoscopic biopsies. CD is associated with increased rates of several diseases, such as iron deficiency anemia, osteoporosis, dermatitis herpetiformis, several neurologic and endocrine diseases, persistent chronic hypertransami-nasemia of unknown origin, various types of cancer and other autoimmune disorders. Treatment of CD dictates a strict, life-long gluten-free diet, which results in remission for most individuals, although its effect on some associated extraintestinal manifestations remains to be established.

  3. Polyclonal T-Cells Express CD1a in Langerhans Cell Histiocytosis (LCH) Lesions

    PubMed Central

    West, Jennifer A.; Olsen, Sharon L.; Mitchell, Jenée M.; Priddle, Ross E.; Luke, Jennifer M.; Åkefeldt, Selma Olsson; Henter, Jan-Inge; Turville, Christopher; Kannourakis, George

    2014-01-01

    Langerhans cell histiocytosis (LCH) is a complex and poorly understood disorder that has characteristics of both inflammatory and neoplastic disease. By using eight-colour flow cytometry, we have identified a previously unreported population of CD1a+/CD3+ T-cells in LCH lesions. The expression of CD1a is regarded as a hallmark of this disease; however, it has always been presumed that it was only expressed by pathogenic Langerhans cells (LCs). We have now detected CD1a expression by a range of T-cell subsets within all of the LCH lesions that were examined, establishing that CD1a expression in these lesions is no longer restricted to pathogenic LCs. The presence of CD1a+ T-cells in all of the LCH lesions that we have studied to date warrants further investigation into their biological function to determine whether these cells are important in the pathogenesis of LCH. PMID:25343480

  4. Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis.

    PubMed

    Zheng, Ye; Khan, Zaraq; Zanfagnin, Valentina; Correa, Luiz F; Delaney, Abigail A; Daftary, Gaurang S

    2016-04-01

    Progressive fibrosis is recalcitrant to conventional therapy and commonly complicates chronic diseases and surgical healing. We evaluate here a novel mechanism that regulates scar-tissue collagen (COL1A1/Col1a1) expression and characterizes its translational relevance as a targeted therapy for fibrosis in an endometriosis disease model. Endometriosis is caused by displacement and implantation of uterine endometrium onto abdominal organs and spreads with progressive scarring. Transcription factor KLF11 is specifically diminished in endometriosis lesions. Loss of KLF11-mediated repression of COL1A1/Col1a1 expression resulted in increased fibrosis. To determine the biological significance of COL1A1/Col1a1 expression on fibrosis, we modulated its expression. In human endometrial-stromal fibroblasts, KLF11 recruited SIN3A/HDAC (histone deacetylase), resulting in COL1A1-promoter deacetylation and repression. This role of KLF11 was pharmacologically replicated by a histone acetyl transferase inhibitor (garcinol). In contrast, opposite effects were obtained with a HDAC inhibitor (suberoyl anilide hydroxamic acid), confirming regulatory specificity for these reciprocally active epigenetic mechanisms. Fibrosis was concordantly reversed in Klf11(-/-)animals by histone acetyl transferase inhibitor and in wild-type animals by HDAC inhibitor treatments. Aberrant lesional COL1A1 regulation is significant because fibrosis depended on lesion rather than host genotype. This is the first report demonstrating feasibility for targeted pharmacological reversal of fibrosis, an intractable phenotype of diverse chronic diseases. PMID:26935598

  5. UDP-glucuronosyltransferases 1A6 and 1A10 catalyze reduced menadione glucuronidation

    SciTech Connect

    Nishiyama, Takahito; Ohnuma, Tomokazu; Inoue, Yuu; Kishi, Takehiko; Ogura, Kenichiro; Hiratsuka, Akira

    2008-06-27

    Menadione (2-methyl-1,4-naphthoquine), also known as vitamin K3, has been widely used as a model compound in the field of oxidative stress-related research. The metabolism of menadione has been studied, and it is known that menadione undergoes a two-electron reduction by NAD(P)H:Quinone oxidoreductase 1 (NQO1) after which the reduced form of menadione (2-methyl-1,4-naphthalenediol, menadiol) is glucuronidated and excreted in urine. To investigate which human UDP-glucuronosyltransferase (UGT) isoforms participate in the glucuronidation of menadiol reduced by NQO1 from menadione, we first constructed heterologously expressed NQO1 in Sf9 cells and tested the menadiol glucuronidating activity of 16 human recombinant UGT isoforms. Of the 16 UGT isoforms, UGTs 1A6, 1A7, 1A8, 1A9, and 1A10 catalyzed menadiol glucuronidation, and, of these, UGTs 1A6 and 1A10 catalyzed menadiol glucuronidation at much higher rates than the other UGTs. Menadiol was regioselectively glucuronidated in the manner of 4-position > 1-position by UGTs 1A7, 1A8, 1A9, and 1A10. In contrast to these UGTs, only UGT1A6 exhibited 1-menadiol-preferential glucuronidating activity. The results suggest possible detoxification pathways for quinones via NQO1 reduction followed by UGT glucuronidation.

  6. Fabry disease

    PubMed Central

    2010-01-01

    Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs

  7. Incomplete penetrance of biallelic ALDH1A3 mutations.

    PubMed

    Plaisancié, Julie; Brémond-Gignac, Dominique; Demeer, Bénédicte; Gaston, Véronique; Verloes, Alain; Fares-Taie, Lucas; Gerber, Sylvie; Rozet, Jean-Michel; Calvas, Patrick; Chassaing, Nicolas

    2016-04-01

    The formation of a properly shaped eye is a complex developmental event that requires the coordination of many induction processes and differentiation pathways. Microphthalmia and anophthalmia (MA) represent the most severe defects that can affect the ocular globe during embryonic development. When genetic, these ocular disorders exhibit large genetic heterogeneity and extreme variable expressivity. Around 20 monogenic diseases are known to be associated with MA as main phenotype and the penetrance of mutations is usually full in the patients. Some of these genes encode proteins involved in the vitamin A pathway, tightly regulated during eye development. One of those retinoic acid synthesis genes is ALDH1A3 and biallelic mutations in that gene have been recently found to lead to MA phenotype in patients. Interestingly, we report here the lack of ocular defect in a girl carrying the same homozygous mutation in the ALDH1A3 gene than the affected members of her family. Thus, this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families. Furthermore, these data contribute to the more general understanding that we have for the complex genetic inheritance of these MA phenotypes. PMID:26873617

  8. Mutations in COL1A1 Gene Change Dentin Nanostructure.

    PubMed

    Duan, Xiaohong; Liu, Zhenxia; Gan, Yunna; Xia, Dan; Li, Qiang; Li, Yanling; Yang, Jiaji; Gao, Shan; Dong, Mingdong

    2016-04-01

    Although many studies have attempted to associate specific gene mutations with dentin phenotypic severity, it remains unknown how the mutations in COL1A1 gene influence the mechanical behavior of dentin collagen and matrix. Here, we reported one osteogenesis imperfecta (OI) pedigree caused by two new inserting mutations in exon 5 of COL1A1 (NM_000088.3:c.440_441insT;c.441_442insA), which resulted in the unstable expression of COL1A1 mRNA and half quantity of procollagen production. We investigated the morphological and mechanical features of proband's dentin using atomic force microscope (AFM), scanning electron microscope, and transmission electron microscope. Increased D-periodic spacing, variably enlarged collagen fibrils coating with fewer minerals were found in the mutated collagen. AFM analysis demonstrated rougher dentin surface and sparsely decreased Young's modulus in proband's dentin. We believe that our findings provide new insights into the genetic-/nano- mechanisms of dentin diseases, and may well explain OI dentin features with reduced mechanical strength and a lower crosslinked density. Anat Rec, 299:511-519, 2016. © 2015 Wiley Periodicals, Inc. PMID:26694865

  9. DSCOVR_EPIC_L1A

    Atmospheric Science Data Center

    2015-09-29

    DSCOVR_EPIC_L1A Full sun-light Earth images calibrated with ... 680NM 688NM 551NM LAGRANGE L1B IMAGERY EPIC DSCOVR 325NM Order Data:  ASDC Order Tool: Order Data Readme Files:  EPIC Data Format Control Book Read Software Files :  ...

  10. Modeling Environment for Total Risk-1A

    EPA Science Inventory

    MENTOR-1A uses an integrated, mechanistically consistent source-to-dose modeling framework to quantify inhalation exposure and dose for individuals and/or populations due to co-occurring air pollutants. It uses the "One Atmosphere" concept to characterize simultaneous exposures t...

  11. Smoothed particle hydrodynamics with GRAPE-1A

    NASA Technical Reports Server (NTRS)

    Umemura, Masayuki; Fukushige, Toshiyuki; Makino, Junichiro; Ebisuzaki, Toshikazu; Sugimoto, Daiichiro; Turner, Edwin L.; Loeb, Abraham

    1993-01-01

    We describe the implementation of a smoothed particle hydrodynamics (SPH) scheme using GRAPE-1A, a special-purpose processor used for gravitational N-body simulations. The GRAPE-1A calculates the gravitational force exerted on a particle from all other particles in a system, while simultaneously making a list of the nearest neighbors of the particle. It is found that GRAPE-1A accelerates SPH calculations by direct summation by about two orders of magnitudes for a ten thousand-particle simulation. The effective speed is 80 Mflops, which is about 30 percent of the peak speed of GRAPE-1A. Also, in order to investigate the accuracy of GRAPE-SPH, some test simulations were executed. We found that the force and position errors are smaller than those due to representing a fluid by a finite number of particles. The total energy and momentum were conserved within 0.2-0.4 percent and 2-5 x 10 exp -5, respectively, in simulations with several thousand particles. We conclude that GRAPE-SPH is quite effective and sufficiently accurate for self-gravitating hydrodynamics.

  12. Hirschprung's disease.

    PubMed Central

    Sullivan, P B

    1996-01-01

    Current evidence on the pathogenesis of Hirschprung's disease, then, favours the 'abnormal microenvironment' hypothesis wherein the developing and migrating normal neural crest cells confront a segmentally abnormal and hostile microenvironment in the colon. This hypothesis would account both for the congenital absence of ganglion cells in the wall of colon and also for the range of enteric neuronal abnormalities encountered including neuronal dysplasia, hypoganglionosis, and zonal aganglionosis. The abnormal constitution of the mesenchymal and basement membrane extracellular matrix in the affected segment of colon is presumably genetically determined and further understanding of the pathogenesis of this disorder will emerge as molecular geneticists characterise the specific genes and gene products associated with Hirschprung's disease. Advances in this field should permit gene probes to be developed to facilitate prenatal and postnatal diagnosis. PMID:8660047

  13. Thyroid disease

    SciTech Connect

    Falk, S.

    1990-01-01

    Presenting a multidisciplinary approach to the diagnosis and treatment of thyroid disease, this volume provides a comprehensive picture of current thyroid medicine and surgery. The book integrates the perspectives of the many disciplines that deal with the clinical manifestations of thyroid disorders. Adding to the clinical usefulness of the book is the state-of-the-art coverage of many recent developments in thyroidology, including the use of highly sensitive two-site TSH immunoradionetric measurements to diagnose thyroid activity; thyroglobulin assays in thyroid cancer and other diseases; new diagnostic applications of MRI and CT; treatment with radionuclides and chemotherapy; new developments in thyroid immunology, pathology, and management of hyperthyroidism; suppressive treatment with thyroid hormone; and management of Graves' ophthalmopathy. The book also covers all aspects of thyroid surgery, including surgical treatment of hyperthyroidism; papillary, follicular, and other carcinomas; thyroidectomy; and prevention and management of complications.

  14. Morgellons disease?

    PubMed

    Accordino, Robert E; Engler, Danielle; Ginsburg, Iona H; Koo, John

    2008-01-01

    Morgellons disease, a pattern of dermatologic symptoms very similar, if not identical, to those of delusions of parasitosis, was first described many centuries ago, but has recently been given much attention on the internet and in the mass media. The present authors present a history of Morgellons disease, in addition to which they discuss the potential benefit of using this diagnostic term as a means of building trust and rapport with patients to maximize treatment benefit. The present authors also suggest "meeting the patient halfway" and creating a therapeutic alliance when providing dermatologic treatment by taking their cutaneous symptoms seriously enough to provide both topical ointments as well as antipsychotic medications, which can be therapeutic in these patients. PMID:18318880

  15. Coronary heart disease

    MedlinePlus

    Heart disease, Coronary heart disease, Coronary artery disease; Arteriosclerotic heart disease; CHD; CAD ... Coronary heart disease is the leading cause of death in the United States for men and women. Coronary heart ...

  16. Peripheral Artery Disease

    MedlinePlus

    ... Physician Resources Professions Site Index A-Z Peripheral Artery Disease (PAD) Peripheral artery disease (PAD) refers to ... is peripheral artery disease treated? What is peripheral artery disease (PAD)? Peripheral artery disease, or PAD, refers ...

  17. Fifth Disease

    MedlinePlus

    ... Don’t worry! Fifth disease is caused by parvovirus, but it isn’t the same type of “parvo” that infects dogs and cats, so you aren’t at risk of catching it from pets. ... the pattern of the rash. A blood test also can be used to check for the antibody to parvovirus. An antibody is a type of protein that ...

  18. Lyme Disease.

    PubMed

    Hu, Linden T

    2016-05-01

    This issue provides a clinical overview of Lyme disease, focusing on prevention, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers. PMID:27136224

  19. Beryllium disease

    SciTech Connect

    Not Available

    1991-12-20

    After two workers at the nuclear weapons plant at Oak Ridge National Laboratory in Tennessee were diagnosed earlier this year with chronic beryllium disease (CBD), a rare and sometimes fatal scarring of the lungs, the Department of Energy ordered up a 4-year probe. Now, part of that probe has begun - tests conducted by the Oak Ridge Associated Universities' Center for Epidemiological Research measuring beryllium sensitivity in 3,000 people who've been exposed to the metal's dust since Manhattan Project managers opened the Y-12 plant at Oak Ridge in 1943. Currently, 119 Y-12 employees process beryllium, which has a number of industrial uses, including rocket heat shields and nuclear weapon and electrical components. The disease often takes 20 to 25 years to develop, and the stricken employees haven't worked with beryllium for years. There is no cure for CBD, estimated to strike 2% of people exposed to the metal. Anti-inflammatory steroids alleviate such symptoms as a dry cough, weight loss, and fatigue. Like other lung-fibrosis diseases that are linked to lung cancer, some people suspect CBD might cause some lung cancer. While difficult to diagnose, about 900 cases of CBD have been reported since a Beryllium Case Registry was established in 1952. The Department of Energy (DOE) estimates that about 10,000 DOE employees and 800,000 people in private industry have worked with beryllium.

  20. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.

    PubMed

    Weedon, Michael N; Cebola, Inês; Patch, Ann-Marie; Flanagan, Sarah E; De Franco, Elisa; Caswell, Richard; Rodríguez-Seguí, Santiago A; Shaw-Smith, Charles; Cho, Candy H-H; Lango Allen, Hana; Houghton, Jayne A L; Roth, Christian L; Chen, Rongrong; Hussain, Khalid; Marsh, Phil; Vallier, Ludovic; Murray, Anna; Ellard, Sian; Ferrer, Jorge; Hattersley, Andrew T

    2014-01-01

    The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ~400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease. PMID:24212882

  1. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis

    PubMed Central

    Flanagan, Sarah E.; De Franco, Elisa; Caswell, Richard; Rodríguez-Seguí, Santiago A.; Shaw-Smith, Charles; Cho, Candy H-H.; Allen, Hana Lango; Houghton, Jayne AL.; Roth, Christian L.; Chen, Rongrong; Hussain, Khalid; Marsh, Phil; Vallier, Ludovic; Murray, Anna

    2014-01-01

    The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole genome sequencing can identify all non-coding variants, yet discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in hESC-derived embryonic pancreatic progenitor cells to guide the interpretation of whole genome sequences from patients with isolated pancreatic agenesis. This uncovered six different recessive mutations in a previously uncharacterized ~400bp sequence located 25kb downstream of PTF1A (pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can uncover novel non-coding elements underlying human development and disease. PMID:24212882

  2. Venereal Disease. Consumer Health Education.

    ERIC Educational Resources Information Center

    Arkansas Univ., Fayetteville, Cooperative Extension Service.

    Designed to be used by health educators when teaching youths and their parents about the control of veneral disease (syphilis and gonorrhea), this booklet includes the following: (1) a two-page teaching plan consisting of objectives for both youths and adults along with notes on subject matter, methods (including titles of films and printed…

  3. Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T-lineage tumours.

    PubMed

    Longville, Brooke A C; Anderson, Denise; Welch, Mathew D; Kees, Ursula R; Greene, Wayne K

    2015-01-01

    The class 1A aldehyde dehydrogenase (ALDH1A) subfamily of genes encode enzymes that function at the apex of the retinoic acid (RA) signalling pathway. We detected aberrant expression of ALDH1A genes, particularly ALDH1A2, in a majority (72%) of primary paediatric T cell acute lymphoblastic leukaemia (T-ALL) specimens. ALDH1A expression was almost exclusive to T-lineage, but not B-lineage, ALL. To determine whether ALDH1A expression may have relevance to T-ALL cell growth and survival, the effect of inhibiting ALDH1A function was measured on a panel of human ALL cell lines. This revealed that T-ALL proliferation had a higher sensitivity to modulation of ALDH1A activity and RA signalling as compared to ALL cell lines of B-lineage. Consistent with these findings, the genes most highly correlated with ALDH1A2 expression were involved in cell proliferation and apoptosis. Evidence that such genes may be targets of regulation via RA signalling initiated by ALDH1A activity was provided by the TNFRSF10B gene, encoding the apoptotic death receptor TNFRSF10B (also termed TRAIL-R2), which negatively correlated with ALDH1A2 and showed elevated transcription following treatment of T-ALL cell lines with the ALDH1A inhibitor citral (3,7-dimethyl-2,6-octadienal). These data indicate that ALDH1A expression is a common event in T-ALL and supports a role for these enzymes in the pathobiology of this disease. PMID:25208926

  4. Acid-sensing ion channels 1a (ASIC1a) inhibit neuromuscular transmission in female mice

    PubMed Central

    Lino, Noelia G.; González-Inchauspe, Carlota M. F.; González, Laura E.; Colettis, Natalia; Vattino, Lucas G.; Wunsch, Amanda M.; Wemmie, John A.; Uchitel, Osvaldo D.

    2013-01-01

    Acid-sensing ion channels (ASIC) open in response to extracellular acidosis. ASIC1a, a particular subtype of these channels, has been described to have a postsynaptic distribution in the brain, being involved not only in ischemia and epilepsy, but also in fear and psychiatric pathologies. High-frequency stimulation of skeletal motor nerve terminals (MNTs) can induce presynaptic pH changes in combination with an acidification of the synaptic cleft, known to contribute to muscle fatigue. Here, we studied the role of ASIC1a channels on neuromuscular transmission. We combined a behavioral wire hanging test with electrophysiology, pharmacological, and immunofluorescence techniques to compare wild-type and ASIC1a lacking mice (ASIC1a −/− knockout). Our results showed that 1) ASIC1a −/− female mice were weaker than wild type, presenting shorter times during the wire hanging test; 2) spontaneous neurotransmitter release was reduced by ASIC1a activation, suggesting a presynaptic location of these channels at individual MNTs; 3) ASIC1a-mediated effects were emulated by extracellular local application of acid saline solutions (pH = 6.0; HEPES/MES-based solution); and 4) immunofluorescence techniques revealed the presence of ASIC1a antigens on MNTs. These results suggest that ASIC1a channels might be involved in controlling neuromuscular transmission, muscle contraction and fatigue in female mice. PMID:24336653

  5. [Renal disease].

    PubMed

    Espinosa-Cuevas, María de Los Ángeles

    2016-09-01

    Chronic renal failure in its various stages, requires certain nutritional restrictions associated with the accumulation of minerals and waste products that cannot be easily eliminated by the kidneys. Some of these restrictions modify the intake of proteins, sodium, and phosphorus. Milk and dairy products are sources of these nutrients. This article aims to inform the reader about the benefits including milk and dairy products relying on a scientific and critical view according to the clinical conditions and the stage of renal disease in which the patient is. PMID:27603894

  6. Infectious disease.

    PubMed

    Jaworski, Carrie A; Donohue, Brian; Kluetz, Joshua

    2011-07-01

    Athletes are susceptible to the same infections as the general population. However, special considerations often need to be taken into account when dealing with an athlete who has contracted an infectious disease. Health care providers need to consider how even common illnesses can affect an athlete's performance, the communicability of the illness to team members, and precautions/contraindications related to athletic participation. Recent advances in the prevention, diagnosis, and/or management of frequently encountered illnesses, as well as certain conditions that warrant special attention in the athletic setting, are discussed in detail. PMID:21658549

  7. [Bone diseases].

    PubMed

    Uebelhart, Brigitte; Rizzoli, René

    2016-01-13

    Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw. PMID:26946704

  8. LR1: a candidate RNA virus of Leishmania.

    PubMed Central

    Tarr, P I; Aline, R F; Smiley, B L; Scholler, J; Keithly, J; Stuart, K

    1988-01-01

    Although viruses are important biological agents and useful molecular tools, little is known about the viruses of parasites. We report here the discovery of a candidate for an RNA virus in a kinetoplastid parasite. This potential virus, which we term LR1, is present in the promastigote form of the human pathogen Leishmania braziliensis guyanensis CUMC1-1A but not in 11 other stocks of Leishmania that were examined nor in Trypanosoma brucei. The candidate viral RNA has a size of approximately 6000 nucleotides, is single-stranded, and is largely, if not exclusively, located in the cytoplasm. No homologous LR1 sequences are detected in genomic DNA. The candidate viral RNA is associated with a spherical particle 32 nm in diameter that has a sedimentation coefficient of approximately 130 S. There is as yet no evident effect of this potential virus on parasite physiology or the disease caused by the parasite. Images PMID:3200841

  9. Chagas' disease.

    PubMed Central

    Tanowitz, H B; Kirchhoff, L V; Simon, D; Morris, S A; Weiss, L M; Wittner, M

    1992-01-01

    Chagas' disease, caused by Trypanosoma cruzi, is an important cause of morbidity in many countries in Latin America. The important modes of transmission are by the bite of the reduviid bug and blood transfusion. The organism exists in three morphological forms: trypomastigotes, amastigotes, and epimastigotes. The mechanism of transformation and differentiation is currently being explored, and signal transduction pathways of the parasites may be involved in this process. Parasite adherence to and invasion of host cells is a complex process involving complement, phospholipase, penetrin, neuraminidase, and hemolysin. Two clinical forms of the disease are recognized, acute and chronic. During the acute stage pathological damage is related to the presence of the parasite, whereas in the chronic stage few parasites are found. In recent years the roles of tumor necrosis factor, gamma interferon, and the interleukins in the pathogenesis of this infection have been reported. The common manifestations of chronic cardiomyopathy are arrhythmias and thromboembolic events. Autoimmune, neurogenic, and microvascular factors may be important in the pathogenesis of the cardiomyopathy. The gastrointestinal tract is another important target, and "mega syndromes" are common manifestations. The diagnosis and treatment of this infection are active areas of investigation. New serological and molecular biological techniques have improved the diagnosis of chronic infection. Exacerbations of T. cruzi infection have been reported for patients receiving immuno-suppressive therapy and for those with AIDS. Images PMID:1423218

  10. [Morton's disease].

    PubMed

    Isomoto, Shinji; Tanaka, Yasuhito

    2014-12-01

    Morton's disease refers to neuralgia at the web space of the toes with a pseudo-neuroma. It commonly occurs in the third web space of the foot in middle-aged and older women. The pseudo-neuroma is thought to be a secondary change after entrapment or repeated microtrauma. Patients complain of forefoot pain while walking. Typically, symptoms are caused by tight high-heeled shoes. The physical examination includes palpation of the web spaces and Mulder's test. Weight bearing foot radiographs are used to evaluate the deformity of the foot, especially at metatarsophalangeal (MTP) joints. MRI is useful for differential diagnosis of pseudo-neuroma, MTP joint arthritis, and interdigital bursitis. Conservative treatments are shoe modification, use of orthotic insoles, and injection of corticosteroids and local anesthesia. The injections are useful not only for the treatment but also for diagnosis of Morton's disease. If the local injection is not temporally effective, surgical treatment is not indicated. If the conservative treatment fails, surgical treatment is indicated. The most common surgery is excision of the pseudo-neuroma. The surgery is usually performed using a dorsal approach. PMID:25475032

  11. Shiga Toxin (Stx) Type 1a Reduces the Oral Toxicity of Stx Type 2a

    PubMed Central

    Russo, Lisa M.; Melton-Celsa, Angela R.; O'Brien, Alison D.

    2016-01-01

    Background. Shiga toxin (Stx) is the primary virulence factor of Stx-producing Escherichia coli (STEC). STEC can produce Stx1a and/or Stx2a, which are antigenically distinct. However, Stx2a-producing STEC are associated with more severe disease than strains producing both Stx1a and Stx2a. Methods and Results. To address the hypothesis that the reason for the association of Stx2a with more severe disease is because Stx2a crosses the intestinal barrier with greater efficiency that Stx1a, we covalently labeled Stx1a and Stx2a with Alexa Fluor 750 and determined the ex vivo fluorescent intensity of murine systemic organs after oral intoxication. Surprisingly, both Stxs exhibited similar dissemination patterns and accumulated in the kidneys. We next cointoxicated mice to determine whether Stx1a could impede Stx2a. Cointoxication resulted in increased survival and an extended mean time to death, compared with intoxication with Stx2a only. The survival benefit was dose dependent, with the greatest effect observed when 5 times more Stx1a than Stx2a was delivered, and was amplified when Stx1a was delivered 3 hours prior to Stx2a. Cointoxication with an Stx1a active site toxoid also reduced Stx2a toxicity. Conclusions. These studies suggest that Stx1a reduces Stx2a-mediated toxicity, a finding that may explain why STEC that produce only Stx2a are associated with more severe disease than strains producing Stx1a and Stx2a. PMID:26743841

  12. Deletion and duplication within the p11.2 region of chromosome 17

    SciTech Connect

    McCorquodale, D.J.; McCorquodale, M.; Bereziouk, O.

    1994-09-01

    A 7 1/2-year-old male patient presented with mild mental retardation, speech delay, hyperactivity, behavioral problems, mild facial hypoplasia, short broad hands, digital anomalies, and self-injurious behavior. Chromosomes obtained from peripheral blood cells revealed a deletion of 17p11.2 in about 40% of the metaphases examined, suggesting that the patient had Smith-Magenis Syndrome. A similar pattern of mosaicism in peripheral blood cells, but not in fibroblasts in which all cells displayed the deletion, has been previously reported. Since some cases of Smith-Magenis Syndrome have a deletion that extends into the region associated with Charcot-Marie-Tooth (CMT) Syndrome, we examined interphase cells with a CMT1A-specific probe by the method of fluorescence in situ hybridization. The CMT1A region was not deleted, but about 40% of the cells gave signals indicating a duplication of the CMT1A region. The patient has not presented neuropathies associated with CMT at this time. Future tracking of the patient should be informative.

  13. CYP1B1: a unique gene with unique characteristics.

    PubMed

    Faiq, Muneeb A; Dada, Rima; Sharma, Reetika; Saluja, Daman; Dada, Tanuj

    2014-01-01

    CYP1B1, a recently described dioxin inducible oxidoreductase, is a member of the cytochrome P450 superfamily involved in the metabolism of estradiol, retinol, benzo[a]pyrene, tamoxifen, melatonin, sterols etc. It plays important roles in numerous physiological processes and is expressed at mRNA level in many tissues and anatomical compartments. CYP1B1 has been implicated in scores of disorders. Analyses of the recent studies suggest that CYP1B1 can serve as a universal/ideal cancer marker and a candidate gene for predictive diagnosis. There is plethora of literature available about certain aspects of CYP1B1 that have not been interpreted, discussed and philosophized upon. The present analysis examines CYP1B1 as a peculiar gene with certain distinctive characteristics like the uniqueness in its chromosomal location, gene structure and organization, involvement in developmentally important disorders, tissue specific, not only expression, but splicing, potential as a universal cancer marker due to its involvement in key aspects of cellular metabolism, use in diagnosis and predictive diagnosis of various diseases and the importance and function of CYP1B1 mRNA in addition to the regular translation. Also CYP1B1 is very difficult to express in heterologous expression systems, thereby, halting its functional studies. Here we review and analyze these exceptional and startling characteristics of CYP1B1 with inputs from our own experiences in order to get a better insight into its molecular biology in health and disease. This may help to further understand the etiopathomechanistic aspects of CYP1B1 mediated diseases paving way for better research strategies and improved clinical management. PMID:25658124

  14. Intracranial ROSAI-DORFMAN Disease

    PubMed Central

    Mahzoni, Parvin; Zavareh, Mohsen Hani Tabaei; Bagheri, Marzie; Hani, Neda; Moqtader, Babak

    2012-01-01

    Rosai-Dorfman disease is a benign lymphohistiocytosis that often involve lymph nodes and present as massive lymphadenopathy with sinus histiocytosis. The disease is rarely associated with intracranial involvement. Herein, we report a 33-years-old man with recent onset of unconsciousness. According to his past medical history, he was suffering from frontal headache, ataxia and dizziness with no sensory or motor defect since August 2010. At initial work up, MRI showed infiltrating mass in the left parietal region. Microscopically, the mass consisted of infiltration of abundant lymphoplasma cells, neutrophils and some histiocytes scattered in fibrotic background. Emperipolesis (lymphocytophagocytosis) of histiocytic cells made the diagnosis of Rosai-Dorfman disease. Rosai-Dorfman disease should be added in the list of differential diagnosis for a dural mass mimicking meningioma or cerebral mass mimicking glioma, therefore, immunohistochemical staining for EMA, S100 and CD1a should be performed to rule out the differential diagnosis. PMID:23267385

  15. ARID1A Is Essential for Endometrial Function during Early Pregnancy

    PubMed Central

    Wang, Zhong; Lydon, John P.; Khatri, Shikha; Hawkins, Shannon M.; Leach, Richard E.; Fazleabas, Asgerally T.; Young, Steven L.; Lessey, Bruce A.; Ku, Bon Jeong; Jeong, Jae-Wook

    2015-01-01

    AT-rich interactive domain 1A gene (ARID1A) loss is a frequent event in endometriosis-associated ovarian carcinomas. Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus, and 50% of women with endometriosis are infertile. ARID1A protein levels were significantly lower in the eutopic endometrium of women with endometriosis compared to women without endometriosis. However, an understanding of the physiological effects of ARID1A loss remains quite poor, and the function of Arid1a in the female reproductive tract has remained elusive. In order to understand the role of Arid1a in the uterus, we have generated mice with conditional ablation of Arid1a in the PGR positive cells (Pgr cre/+ Arid1a f/f; Arid1a d/d). Ovarian function and uterine development of Arid1a d/d mice were normal. However, Arid1a d/d mice were sterile due to defective embryo implantation and decidualization. The epithelial proliferation was significantly increased in Arid1a d/d mice compared to control mice. Enhanced epithelial estrogen activity and reduced epithelial PGR expression, which impedes maturation of the receptive uterus, was observed in Arid1a d/d mice at the peri-implantation period. The microarray analysis revealed that ARID1A represses the genes related to cell cycle and DNA replication. We showed that ARID1A positively regulates Klf15 expression with PGR to inhibit epithelial proliferation at peri-implantation. Our results suggest that Arid1a has a critical role in modulating epithelial proliferation which is a critical requisite for fertility. This finding provides a new signaling pathway for steroid hormone regulation in female reproductive biology and furthers our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in human reproductive disorders such as endometriosis. PMID:26378916

  16. Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model

    PubMed Central

    Jackson, D J; Eastlake, J L; Kumpel, B M

    2014-01-01

    Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs most frequently when human platelet antigen (HPA)-1a-positive fetal platelets are destroyed by maternal HPA-1a immunoglobulin (Ig)G antibodies. Pregnancies at risk are treated by administration of high-dose intravenous Ig (IVIG) to women, but this is expensive and often not well tolerated. Peptide immunotherapy may be effective for ameliorating some allergic and autoimmune diseases. The HPA-1a/1b polymorphism is Leu/Pro33 on β3 integrin (CD61), and the anti-HPA-1a response is restricted to HPA-1b1b and HLA-DRB3*0101-positive pregnant women with an HPA-1a-positive fetus. We investigated whether or not HPA-1a antigen-specific peptides that formed the T cell epitope could reduce IgG anti-HPA-1a responses, using a mouse model we had developed previously. Peripheral blood mononuclear cells (PBMC) in blood donations from HPA-1a-immunized women were injected intraperitoneally (i.p.) into severe combined immunodeficient (SCID) mice with peptides and HPA-1a-positive platelets. Human anti-HPA-1a in murine plasma was quantitated at intervals up to 15 weeks. HPA-1a-specific T cells in PBMC were identified by proliferation assays. Using PBMC of three donors who had little T cell reactivity to HPA-1a peptides in vitro, stimulation of anti-HPA-1a responses by these peptides occurred in vivo. However, with a second donation from one of these women which, uniquely, had high HPA-1a-specific T cell proliferation in vitro, marked suppression of the anti-HPA-1a response by HPA-1a peptides occurred in vivo. HPA-1a peptide immunotherapy in this model depended upon reactivation of HPA-1a T cell responses in the donor. For FNAIT, we suggest that administration of antigen-specific peptides to pregnant women might cause either enhancement or reduction of pathogenic antibodies. PMID:24261689

  17. INSAT-1A launch on Delta

    NASA Technical Reports Server (NTRS)

    1982-01-01

    The INSAT-1A, the first in a series of 12 transponder communications satellites developed for India, is described as well as the launch plans. The launch vehicle will be the Delta 3910 configuration which incorporates an extended long tank Thor booster, nine Castor IV strap-on motors, a TR-201 second stage, and an 8 foot fairing. The satellite will be placed in a suborbital trajectory. A DAM-D stage will then thrust it into a synchronous transfer orbit. An apogee kick motor will be fired to circularize its orbit at a geosynchronous altitude of 19,300 nautical miles.

  18. X-1A in flight over lakebed

    NASA Technical Reports Server (NTRS)

    1953-01-01

    The Bell Aircraft Corporation X-1A (48-1384) returning from an Air Force test flight over Edwards Air Force Base, California in late 1953. A North American F-86A Sabre as chase plane will follow the X-1A to touchdown. The Rogers Dry Lake is the whitish area under the planes with the airfield at the edge of the dry lake. Bell test pilot Jean 'Skip' Ziegler made six flights between 14 February and 25 April 1953. Air Force test pilots Maj. Charles 'Chuck' Yeager and Maj. Arthur 'Kit' Murray made 18 test flights between 21 November 1953 and 26 August 1954. NACA test pilot Joseph Walker made one successful flight on 20 July 1955. During a second flight attempt, on 8 August 1955, an explosion damaged the aircraft shortly before launch. Walker, unhurt, climbed up into the JTB-29A mothership, and the X-1A was jettisoned over the Edwards AFB bombing range. There were five versions of the Bell X-1 rocket-powered research aircraft that flew at the NACA High-Speed Flight Research Station, Edwards, California. The bullet-shaped X-1 aircraft were built by Bell Aircraft Corporation, Buffalo, N.Y. for the U.S. Army Air Forces (after 1947, U.S. Air Force) and the National Advisory Committee for Aeronautics (NACA). The X-1 Program was originally designated the XS-1 for EXperimental Sonic. The X-1's mission was to investigate the transonic speed range (speeds from just below to just above the speed of sound) and, if possible, to break the 'sound barrier.' Three different X-1s were built and designated: X-1-1, X-1-2 (later modified to become the X-1E), and X-1-3. The basic X-1 aircraft were flown by a large number of different pilots from 1946 to 1951. The X-1 Program not only proved that humans could go beyond the speed of sound, it reinforced the understanding that technological barriers could be overcome. The X-1s pioneered many structural and aerodynamic advances including extremely thin, yet extremely strong wing sections; supersonic fuselage configurations; control system

  19. Avian Paramyxovirus Serotype-1: A Review of Disease Distribution, Clinical Symptoms, and Laboratory Diagnostics

    PubMed Central

    Hines, Nichole L.; Miller, Cathy L.

    2012-01-01

    Avian paramyxovirus serotype-1 (APMV-1) is capable of infecting a wide range of avian species leading to a broad range of clinical symptoms. Ease of transmission has allowed the virus to spread worldwide with varying degrees of virulence depending on the virus strain and host species. Classification systems have been designed to group isolates based on their genetic composition. The genetic composition of the fusion gene cleavage site plays an important role in virulence. Presence of multiple basic amino acids at the cleavage site allows enzymatic cleavage of the fusion protein enabling virulent viruses to spread systemically. Diagnostic tests, including virus isolation, real-time reverse-transcription PCR, and sequencing, are used to characterize the virus and identify virulent strains. Genetic diversity within APMV-1 demonstrates the need for continual monitoring for changes that may arise requiring modifications to the molecular assays to maintain their usefulness for diagnostic testing. PMID:22577610

  20. Genomic and clinical characteristics of microduplications in chromosome 17.

    PubMed

    Shchelochkov, Oleg A; Cheung, S W; Lupski, J R

    2010-05-01

    Genomic disorders have been increasingly recognized as a significant source of clinically relevant phenotypes largely fostered by advances in technologies for genome-wide analyses. Molecular and clinical studies of copy number variants involving chromosome 17 began with locus-specific studies of Charcot-Marie-Tooth disease type 1A (CMT1A, OMIM #118220) and hereditary neuropathy with liability to pressure palsies (HNPP, OMIM #162500), which laid the foundation for the paradigm of duplication/deletion and gene-dosage for our understanding of genomic disorders. With the clinical introduction of high-resolution array comparative genomic hybridization (aCGH) the number of recognized genomic disorders including microduplications has been increasing rapidly. A relatively high proportion of disease-associated copy number variants map to chromosome 17. This may result from its unique structural features, such as relative abundance of segmental duplications and interspersed repetitive elements, high gene content, and the presence of dosage-sensitive genes. These genomic rearrangements are mediated by diverse mechanisms including Non-Allelic Homologous Recombination (NAHR), Non-Homologous End-Joining (NHEJ), and Fork Stalling and Template Switching (FoSTeS). We provide specific examples of chromosome 17 microduplications with the emphasis on their phenotype, specific clinical features aiding in their diagnosis, and counseling. PMID:20425816

  1. PREVENTION OF TYPE 1A DIABETES

    PubMed Central

    Eisenbarth, George S.

    2016-01-01

    Objective Review prediction of Type 1 diabetes in light of current trials for prevention and preclinical novel therapist. Methods We estimate from islet autoantibody testing of random cadaveric donors that approximately ½ million individuals in the United States express multiple islet autoantibodies and are developing Type 1A (immune mediated) diabetes. It is now possible to predict not only risk for Type 1A diabetes but also the approximate age of diabetes onset of children followed from birth. Results In animal models diabetes can be prevented and some of the immunologic therapies effective in animal models are able to delay loss of insulin secretion in man. Conclusion Unfortunately none of the therapies studied to date in man can completely arrest progressive loss of insulin secretion from destruction of islet beta cells. Nevertheless current knowledge of pathogenesis (targeting trimolecular recognition complex: MHC- peptide- T cell receptor) and natural history combined with newer diagnostic methods allows accurate diagnosis and has stimulated the search for novel safe and effective preventive therapies. PMID:22548954

  2. [Pancreatic Diseases].

    PubMed

    Schöfl, Rainer

    2016-06-22

    The author presents his personal choice of practical relevant papers of pancreatic diseases from 2014 to 2015. Nutritional factors and hypertriglycidemia are discussed as causes of acute pancreatitis. Tools to avoid post-ERCP(endoscopic retrograde cholangiopancreatography) pancreatitis are described and the natural course of fluid collections and pseudocysts is demonstrated. The value of secretin-MRCP(magnetic resonance cholangiopancreatography) for diagnosis of chronic pancreatitis is illustrated. Data help to choose the minimally effective prednisolone dose in autoimmune pancreatitis. The increased prevalence of fractures in patients with chronic pancreatitis highlights the necessity of screening for bone density loss. The association of vitamin D intake with pancreatic cancer is described. The probability of cancer in IPNM is shown and innovative surgical concepts to reduce the loss of pancreatic function are presented. Finally neoadjuvant concepts for the treatment of pancreatic cancer are highlighted. PMID:27329710

  3. Disease Activity Measures in Paediatric Rheumatic Diseases

    PubMed Central

    Luca, Nadia J.; Feldman, Brian M.

    2013-01-01

    Disease activity refers to potentially reversible aspects of a disease. Measurement of disease activity in paediatric rheumatic diseases is a critical component of patient care and clinical research. Disease activity measures are developed systematically, often involving consensus methods. To be useful, a disease activity measure must be feasible, valid, and interpretable. There are several challenges in quantifying disease activity in paediatric rheumatology; namely, the conditions are multidimensional, the level of activity must be valuated in the context of treatment being received, there is no gold standard for disease activity, and it is often difficult to incorporate the patient's perspective of their disease activity. To date, core sets of response variables are defined for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, and juvenile dermatomyositis, as well as definitions for improvement in response to therapy. Several specific absolute disease activity measures also exist for each condition. Further work is required to determine the optimal disease activity measures in paediatric rheumatology. PMID:24089617

  4. Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage.

    PubMed

    Souchet, Benoit; Guedj, Fayçal; Sahún, Ignasi; Duchon, Arnaud; Daubigney, Fabrice; Badel, Anne; Yanagawa, Yuchio; Barallobre, Maria Jose; Dierssen, Mara; Yu, Eugene; Herault, Yann; Arbones, Mariona; Janel, Nathalie; Créau, Nicole; Delabar, Jean Maurice

    2014-09-01

    Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations. PMID:24801365

  5. Polycystic Kidney Disease (PKD)

    MedlinePlus

    MENU Return to Web version Polycystic Kidney Disease Overview What is polycystic kidney disease? Polycystic kidney disease (PKD) is an inherited disease that affects the kidneys. Sacs of fluid (called ...

  6. Undifferentiated Connective Tissue Disease

    MedlinePlus

    ... Home Conditions Undifferentiated Connective Tissue Disease (UCTD) Undifferentiated Connective Tissue Disease (UCTD) Make an Appointment Find a Doctor ... L. Goldstein, MD, MMSc (February 01, 2016) Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This ...

  7. Interstitial Lung Diseases

    MedlinePlus

    Interstitial lung disease is the name for a large group of diseases that inflame or scar the lungs. The inflammation and ... is responsible for some types of interstitial lung diseases. Specific types include Black lung disease among coal ...

  8. Motor Neuron Diseases

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Motor Neuron Diseases Information Page Condensed from Motor Neuron Diseases ... and Information Publicaciones en Español What are Motor Neuron Diseases? The motor neuron diseases (MNDs) are a ...

  9. Anti-wrinkle effect of bone morphogenetic protein receptor 1a-extracellular domain (BMPR1a-ECD)

    PubMed Central

    Yoon, Byung-Hak; Jeon, Yun-Hui; Hwang, Byunghee; Kwon, Hyuknam; Choe, Senyon; Yang, Zungyoon

    2013-01-01

    Bone morphogenetic proteins (BMPs) have diverse and important roles in the proliferation and differentiation of adult stem cells in our tissues. Especially, BMPs are well known to be the main inducers of bone formation, by facilitating both proliferation and differentiation of bone stem cells. Interestingly, in skin stem cells, BMPs repress their proliferation but are indispensable for the proper differentiation into several lineages of skin cells. Here, we tested whether BMP antagonists have an effect on the prevention of wrinkle formation. For this study we used an in vivo wrinkle-induced mouse model. As a positive control, retinoic acid, one of the top anti-wrinkle effectors, showed a 44% improvement compared to the non-treated control. Surprisingly, bone morphogenetic protein receptor 1a extracellular domain (BMPR1a-ECD) exhibited an anti-wrinkle effect which was 6-fold greater than that of retinoic acid. Our results indicate that BMP antagonists will be good targets for skin or hair diseases. [BMB Reports 2013; 46(9): 465-470] PMID:24064062

  10. Total syntheses of disulphated glycosphingolipid SB1a and the related monosulphated SM1a

    PubMed Central

    Hirose, Haruka; Tamai, Hideki; Gao, Chao; Imamura, Akihiro; Ando, Hiromune; Ishida, Hideharu; Feizi, Ten; Kiso, Makoto

    2016-01-01

    Total syntheses of two natural sulphoglycolipids, disulphated glycosphingolipid SB1a and the structurally related monosulphated SM1a, are described. They have common glycan sequences and ceramide moiety and are associated with human epithelial carcinomas. The syntheses featured efficient glycan assembly and the glucosyl ceramide cassette as a versatile building block. The binding of the synthetic sulphoglycolipids by the carcinoma-specific monoclonal antibody AE3 was investigated using carbohydrate microarray technology. PMID:26399908

  11. Rat Organic Anion Transporting Protein 1A1 (OATP1A1)

    PubMed Central

    Xiao, Yansen; Nieves, Edward; Angeletti, Ruth H.; Orr, George A.; Wolkoff, Allan W.

    2008-01-01

    Rat organic anion transporting protein 1a1 (oatp1a1), a hepatocyte basolateral plasma membrane protein, mediates transport of various amphipathic compounds. Our previous studies indicated that serine phosphorylation of a single tryptic peptide inhibits its transport activity without changing its cell surface content. The site of phosphorylation is unknown and was the subject of the present study. Following immunoaffinity chromatographic purification from rat liver, oatp1a1 was subjected to trypsin digestion and MALDI-TOF. Except for predicted N-glycosylated peptides, 97% of oatp1a1 tryptic peptides were observed. A single tryptic phosphopeptide was found in the C-terminus (aa 626-647), existing in unphosphorylated, singly, or doubly phosphorylated forms, and sensitive to alkaline phosphatase treatment. β-elimination reaction resulted in mass loss of 98 or 196 Da from this peptide, and subsequent Michael addition with cysteamine increased masses by the predicated 77 and 154 Da, indicating that oatp1a1 can be singly or doubly phosphorylated at serine or threonine residues in the C-terminal sequence SSATDHT (aa 634-640). Subsequent tandem MS/MS analysis revealed that phosphorylation at S634 accounted for all singly phosphorylated peptide, while phosphorylation at S634 and S635 accounted for all doubly phosphorylated peptide. These findings identify the site of oatp1a1 phosphorylation and demonstrate that it is an ordered process, in which phosphorylation at S634 precedes that at S635. The mechanism by which phosphorylation results in loss of transport activity in hepatocytes remains to be established. Whether phosphorylation near the C-terminus inhibits C-terminal oligomerization of oatp1a1, required for normal transport function, can be speculated upon, but is as yet unknown. PMID:16519530

  12. Heme Oxygenase-1: A Metabolic Nike

    PubMed Central

    Nemeth, Zsuzsanna; Correa-Costa, Matheus; Bulmer, Andrew C.; Otterbein, Leo E.

    2014-01-01

    Abstract Significance: Heme degradation, which was described more than 30 years ago, is still very actively explored with many novel discoveries on its role in various disease models every year. Recent Advances: The heme oxygenases (HO) are metabolic enzymes that utilize NADPH and oxygen to break apart the heme moiety liberating biliverdin (BV), carbon monoxide (CO), and iron. Heme that is derived from hemoproteins can be toxic to the cells and if not removed immediately, it causes cell apoptosis and local inflammation. Elimination of heme from the milieu enables generation of three products that influences numerous metabolic changes in the cell. Critical Issues: CO has profound effects on mitochondria and cellular respiration and other hemoproteins to which it can bind and affect their function, while BV and bilirubin (BR), the substrate and product of BV, reductase, respectively, are potent antioxidants. Sequestration of iron into ferritin and its recycling in the tissues is a part of the homeodynamic processes that control oxidation-reduction in cellular metabolism. Further, heme is an important component of a number of metabolic enzymes, and, therefore, HO-1 plays an important role in the modulation of cellular bioenergetics. Future Directions: In this review, we describe the cross-talk between heme oxygenase-1 (HO-1) and its products with other metabolic pathways. HO-1, which we have labeled Nike, the goddess who personified victory, dictates triumph over pathophysiologic conditions, including diabetes, ischemia, and cancer. Antioxid. Redox Signal. 20, 1709–1722. PMID:24180257

  13. In vitro activity of CAY-1, a saponin from Capsicum frutescens, against microsporum and trichophyton species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dermatomycoses are among the world’s most common diseases. The incidence of dermatomycoses has increased over recent years, particularly in immunosuppressed patients. In previous studies, the saponin CAY-1, a saponin from cayenne pepper (Capsicum frutenses), has shown antifungal activities against...

  14. Meniere's disease.

    PubMed

    Nakashima, Tsutomu; Pyykkö, Ilmari; Arroll, Megan A; Casselbrant, Margaretha L; Foster, Carol A; Manzoor, Nauman F; Megerian, Cliff A; Naganawa, Shinji; Young, Yi-Ho

    2016-01-01

    Meniere's disease (MD) is a disorder of the inner ear that causes vertigo attacks, fluctuating hearing loss, tinnitus and aural fullness. The aetiology of MD is multifactorial. A characteristic sign of MD is endolymphatic hydrops (EH), a disorder in which excessive endolymph accumulates in the inner ear and causes damage to the ganglion cells. In most patients, the clinical symptoms of MD present after considerable accumulation of endolymph has occurred. However, some patients develop symptoms in the early stages of EH. The reason for the variability in the symptomatology is unknown and the relationship between EH and the clinical symptoms of MD requires further study. The diagnosis of MD is based on clinical symptoms but can be complemented with functional inner ear tests, including audiometry, vestibular-evoked myogenic potential testing, caloric testing, electrocochleography or head impulse tests. MRI has been optimized to directly visualize EH in the cochlea, vestibule and semicircular canals, and its use is shifting from the research setting to the clinic. The management of MD is mainly aimed at the relief of acute attacks of vertigo and the prevention of recurrent attacks. Therapeutic options are based on empirical evidence and include the management of risk factors and a conservative approach as the first line of treatment. When medical treatment is unable to suppress vertigo attacks, intratympanic gentamicin therapy or endolymphatic sac decompression surgery is usually considered. This Primer covers the pathophysiology, symptomatology, diagnosis, management, quality of life and prevention of MD. PMID:27170253

  15. Biochemical and Structural Characterization of the Human TL1A Ectodomain

    SciTech Connect

    Zhan, C.; Yan, Q; Patskovsky, Y; Li, Z; Toro, R; Meyer, A; Cheng, H; Brenowitz, M; Nathenson, S; Almo, S

    2009-01-01

    TNF-like 1A (TL1A) is a newly described member of the TNF superfamily that is directly implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis. We report the crystal structure of the human TL1A extracellular domain at a resolution of 2.5 {angstrom}, which reveals a jelly-roll fold typical of the TNF superfamily. This structural information, in combination with complementary mutagenesis and biochemical characterization, provides insights into the binding interface and the specificity of the interactions between TL1A and the DcR3 and DR3 receptors. These studies suggest that the mode of interaction between TL1A and DcR3 differs from other characterized TNF ligand/receptor complexes. In addition, we have generated functional TL1A mutants with altered disulfide bonding capability that exhibit enhanced solution properties, which will facilitate the production of materials for future cell-based and whole animal studies. In summary, these studies provide insights into the structure and function of TL1A and provide the basis for the rational manipulation of its interactions with cognate receptors.

  16. Aldehyde Dehydrogenase 1A1: Friend or Foe to Female Metabolism?

    PubMed Central

    Petrosino, Jennifer M.; DiSilvestro, David; Ziouzenkova, Ouliana

    2014-01-01

    In this review, we summarize recent advances in understanding vitamin A-dependent regulation of sex-specific differences in metabolic diseases, inflammation, and certain cancers. We focus on the characterization of the aldehyde dehydrogenase-1 family of enzymes (ALDH1A1, ALDH1A2, ALDH1A3) that catalyze conversion of retinaldehyde to retinoic acid. Additionally, we propose a “horizontal transfer of signaling” from estrogen to retinoids through the action of ALDH1A1. Although estrogen does not directly influence expression of Aldh1a1, it has the ability to suppress Aldh1a2 and Aldh1a3, thereby establishing a female-specific mechanism for retinoic acid generation in target tissues. ALDH1A1 regulates adipogenesis, abdominal fat formation, glucose tolerance, and suppression of thermogenesis in adipocytes; in B cells, ALDH1A1 plays a protective role by inducing oncogene suppressors Rara and Pparg. Considering the conflicting responses of Aldh1a1 in a multitude of physiological processes, only tissue-specific regulation of Aldh1a1 can result in therapeutic effects. We have shown through successful implantation of tissue-specific Aldh1a1−/− preadipocytes that thermogenesis can be induced in wild-type adipose tissues to resolve diet-induced visceral obesity in females. We will briefly discuss the emerging role of ALDH1A1 in multiple myeloma, the regulation of reproduction, and immune responses, and conclude by discussing the role of ALDH1A1 in future therapeutic applications. PMID:24594504

  17. Phosphatase PPM1A is a novel prognostic marker in pancreatic ductal adenocarcinoma.

    PubMed

    Fan, Jie; Yang, Michelle X; Ouyang, Qi; Fu, Deliang; Xu, Zude; Liu, Xiuping; Mino-Kenudson, Mari; Geng, Jiang; Tang, Feng

    2016-09-01

    Pancreatic ductal adenocarcinoma (PDAC) harbors complex molecular alterations and remains a lethal disease. Aberrant TGF-β/Smads signaling is a well-known mechanism involved in the progression of PDACs. However, loss of Smad4 expression is reported in only ~50% of PDACs and is generally associated with worse prognosis. Investigating additional prognostic markers is warranted. PPM1A is a phosphatase that dephosphorylates TGF-β-activated Smad2/3 and inactivates the TGF-β signaling. Little is known about the clinical significance of PPM1A in PDACs and its functional relationship to Smad4. In this study, PPM1A and Smad4 immunohistochemistry was assessed in 180 R0 resected human PDACs. PPM1A was lost in 41.7% cases, whereas Smad4 was lost in 45.7% cases. The median survival rate with negative and positive PPM1A was 10.9 and 16.8 months, respectively. Loss of PPM1A was significantly associated with larger tumor size and higher stage and was an independent predictor of unfavorable outcomes. Intriguingly, the overall survival of this cohort was divided into 3 groups based on the expression pattern of PPM1A and Smad4, with the Smad4+/PPM1A+ pattern associated with favorable survival, the Smad4+/PPM1A- or Smad4-/PPM1A- pattern associated with unfavorable, and the PPM1A+/Smad4- pattern fell between these 2 groups. In 82 cases with negative Smad4, PPM1A or P-Smad2/3 expression was retained. Using a SMAD4-deficient human PDAC cell line, BxPC3, we further demonstrated that TGF-β1 treatment induced PPM1A and P-Smad2/3 expression in this cell line. PPM1A and Smad4 immunohistochemistry in surgical specimens may provide more accurate prognostic stratification for patients with PDAC. PMID:27195906

  18. Effects of ρ-Da1a a peptidic α1A-adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats

    PubMed Central

    Palea, S; Maiga, A; Guilloteau, V; Rekik, M; Guérard, M; Rouget, C; Rischmann, P; Botto, H; Camparo, P; Lluel, P; Gilles, N

    2013-01-01

    Background and Purpose ρ-Da1a, a 65 amino-acid peptide, has subnanomolar affinity and high selectivity for the human α1A-adrenoceptor subtype. The purpose of this study was to characterize the pharmacological effects of ρ-Da1a on prostatic function, both in vivo and in vitro. Experimental Approach ρ-Da1a was tested as an antagonist of adrenaline-induced effects on COS cells transfected with the human α1A-adrenoceptor as well as on human isolated prostatic adenoma obtained from patients suffering from benign prostatic hyperplasia. Moreover, we compared the effects of ρ-Da1a and tamsulosin on phenylephrine (PHE)-induced increases in intra-urethral (IUP) and arterial pressures (AP) in anaesthetized rats, following i.v. or p.o. administration. Key Results On COS cells expressing human α1A-adrenoceptors and on human prostatic strips, ρ-Da1a inhibited adrenaline- and noradrenaline-induced effects. In anaesthetized rats, ρ-Da1a and tamsulosin administered i.v. 30 min before PHE significantly antagonized the effects of PHE on IUP. The pKB values for tamsulosin and ρ-Da1a for this effect were similar. With regards to AP, ρ-Da1a only reduced the effect of PHE on AP at the lowest dose tested (10 μg·kg−1), whereas tamsulosin significantly reduced PHE effects at doses between 10 and 150 μg·kg−1. Conclusions and Implications ρ-Da1a exhibited a relevant effect on IUP and a small effect on AP. In contrast, tamsulosin antagonized the effects of PHE on both IUP and AP. We conclude that ρ-Da1a is more uroselective than tamsulosin. ρ-Da1a is the most selective peptidic antagonist for α1A-adenoceptors identified to date and could be a new treatment for various urological diseases. PMID:23005263

  19. Muscle disease.

    PubMed

    Tsao, Chang-Yong

    2014-02-01

    On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15) PMID:24488829

  20. Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy.

    PubMed

    Chance, Phillip F

    2006-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often

  1. Glomerulocystic kidney disease

    PubMed Central

    Siroky, Brian J.; Yin, Hong

    2010-01-01

    Glomerulocystic disease is a rare renal cystic disease with a long descriptive history. Findings from recent studies have significantly advanced the pathophysiological understanding of the disease processes leading to this peculiar phenotype. Many genetic syndromes associated with glomerulocystic disease have had their respective proteins localized to primary cilia or centrosomes. Transcriptional control of renal developmental pathways is dysregulated in obstructive diseases that also lead to glomerulocystic disease, emphasizing the importance of transcriptional choreography between renal development and renal cystic disease. PMID:20091054

  2. ARID1A immunohistochemistry improves outcome prediction in invasive urothelial carcinoma of urinary bladder.

    PubMed

    Faraj, Sheila F; Chaux, Alcides; Gonzalez-Roibon, Nilda; Munari, Enrico; Ellis, Carla; Driscoll, Tina; Schoenberg, Mark P; Bivalacqua, Trinity J; Shih, Ie-Ming; Netto, George J

    2014-11-01

    AT-rich interactive domain 1A (ARID1A) is tumor suppressor gene that interacts with BRG1 adenosine triphosphatase to form a SWI/SNF chromatin remodeling protein complex. Inactivation of ARID1A has been described in several neoplasms, including epithelial ovarian and endometrial carcinomas, and has been correlated with prognosis. In the current study, ARID1A expression in urothelial carcinoma (UC) of the bladder and its association with clinicopathological parameters and outcome are addressed. Five tissue microarrays were constructed from 136 cystectomy specimens performed for UC at our institution. Nuclear ARID1A staining was evaluated using immunohistochemistry. An H-score was calculated as the sum of the products of intensity (0-3) multiplied by extent of expression (0%-100%). Average H-score per case was used for statistical analysis. ARID1A expression was categorized in low and high using Youden index to define the cut point. ARID1A expression significantly increased from normal to noninvasive UC to invasive UC. For both tumor progression and cancer death, Youden index yielded an H-score of 288 as the optimal cut point for ARID1A expression. Low ARID1A expression showed a tendency for lower risk of tumor progression and cancer mortality. Adding ARID1A expression to pathologic features offers a better model for predicting outcome than pathologic features alone. Low ARID1A expression was more frequently seen in earlier stage disease. There was a tendency for low ARID1A expression to predict better outcome. More importantly, the findings indicate that adding ARID1A expression to pathologic features increases the goodness of fit of the predictive model. PMID:25175170

  3. Various ARID1A expression patterns and their clinical significance in gastric cancers.

    PubMed

    Kim, Young-Bae; Ham, In-Hye; Hur, Hoon; Lee, Dakeun

    2016-03-01

    AT-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancers, and loss of ARID1A expression is considered a poor prognostic factor in various cancers. However, in practice, ARID1A shows various expression patterns, and our understanding of its significance is limited. We performed immunohistochemistry for ARID1A, MLH1, and pS6 using whole tissue blocks of 350 gastric cancers and classified the ARID1A expression as follows: retained (63.7%), reduced (17.7%), complete loss (14.9%), and partial loss (3.7%). Complete/partial loss was more common in poorly differentiated histology (P < .001), and reduced or complete loss of ARID1A was frequent in cases with MLH1 loss (P < .001). The ARID1A-reduced group showed only slightly inferior disease-free survival (DFS; P = .254) and overall survival (OS; P = .377) compared to those of the ARID1A-retained group, whereas the group with complete loss showed significantly worse DFS (hazard ratio [HR], 1.732; P = .015) and OS (HR, 1.751; P = .013). Worse DFS (HR, 2.672; P = .005) and OS (HR, 2.531; P = .002) were also noted in the group with partial loss. High expression of pS6 was observed more frequently in groups showing altered ARID1A expression patterns (P < .001). In conclusion, reduced ARID1A expression is not a major prognostic determinant, although it may lead to AKT pathway activation. Tumor cells lacking ARID1A expression may influence the prognosis even if they constitute only a small proportion of the tumor sample. Our data provide an enhanced roadmap for understanding ARID1A with implications for future research and therapeutics. PMID:26826411

  4. Understanding the Multifaceted Role of Human Down Syndrome Kinase DYRK1A.

    PubMed

    Kay, L J; Smulders-Srinivasan, T K; Soundararajan, M

    2016-01-01

    The dual-specificity tyrosine (Y) phosphorylation-regulated kinase DYRK1A, also known as Down syndrome (DS) kinase, is a dosage-dependent signaling kinase that was originally shown to be highly expressed in DS patients as a consequence of trisomy 21. Although this was evident some time ago, it is only in recent investigations that the molecular roles of DYRK1A in a wide range of cellular processes are becoming increasingly apparent. Since initial knowledge on DYRK1A became evident through minibrain mnb, the Drosophila homolog of DYRK1A, this review will first summarize the scientific reports on minibrain and further expand on the well-established neuronal functions of mammalian and human DYRK1A. Recent investigations across the current decade have provided rather interesting and compelling evidence in establishing nonneuronal functions for DYRK1A, including its role in infection, immunity, cardiomyocyte biology, cancer, and cell cycle control. The latter part of this review will therefore focus in detail on the emerging nonneuronal functions of DYRK1A and summarize the regulatory role of DYRK1A in controlling Tau and α-synuclein. Finally, the emerging role of DYRK1A in Parkinson's disease will be outlined. PMID:27567487

  5. A brief review of recent Charcot-Marie-Tooth research and priorities

    PubMed Central

    Ekins, Sean; Litterman, Nadia K.; Arnold, Renée J.G.; Burgess, Robert W.; Freundlich, Joel S.; Gray, Steven J.; Higgins, Joseph J.; Langley, Brett; Willis, Dianna E.; Notterpek, Lucia; Pleasure, David; Sereda, Michael W.; Moore, Allison

    2015-01-01

    This brief review of current research progress on Charcot-Marie-Tooth (CMT) disease is a summary of discussions initiated at the Hereditary Neuropathy Foundation (HNF) scientific advisory board meeting on November 7, 2014. It covers recent published and unpublished in vitro and in vivo research. We discuss recent promising preclinical work for CMT1A, the development of new biomarkers, the characterization of different animal models, and the analysis of the frequency of gene mutations in patients with CMT. We also describe how progress in related fields may benefit CMT therapeutic development, including the potential of gene therapy and stem cell research. We also discuss the potential to assess and improve the quality of life of CMT patients. This summary of CMT research identifies some of the gaps which may have an impact on upcoming clinical trials. We provide some priorities for CMT research and areas which HNF can support. The goal of this review is to inform the scientific community about ongoing research and to avoid unnecessary overlap, while also highlighting areas ripe for further investigation. The general collaborative approach we have taken may be useful for other rare neurological diseases. PMID:25901280

  6. Hereditary motor and sensory neuropathies: Understanding molecular pathogenesis could lead to future treatment strategies.

    PubMed

    Jerath, Nivedita U; Shy, Michael E

    2015-04-01

    Inherited peripheral neuropathies, like many other degenerative disorders, have been challenging to treat. At this point, there is little specific therapy for the inherited neuropathies other than genetic counseling as well as symptomatic treatment and rehabilitation. In the past, ascorbic acid, progesterone antagonists, and subcutaneous neurotrophin-3 (NT3) injections have demonstrated improvement in animal models of CMT 1A, the most common inherited neuropathy, but have failed to translate any effect in humans. Given the difficulty in treatment, it is important to understand the molecular pathogenesis of hereditary neuropathies in order to strategize potential future therapies. The hereditary neuropathies are in an era of molecular insight and over the past 20 years, more than 78 subtypes of Charcot Marie Tooth disease (CMT) have been identified and extensively studied to understand the biological pathways in greater detail. Next generation molecular sequencing has also improved the diagnosis as well as the understanding of CMT. A greater understanding of the molecular pathways will help pave the way to future therapeutics of CMT. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID:25108281

  7. Molecular diagnosis of PMP22 gene duplications and deletions: comparison of different methods.

    PubMed

    Stangler Herodez, Spela; Zagradisnik, B; Erjavec Skerget, A; Zagorac, A; Kokalj Vokac, N

    2009-01-01

    Several techniques can be used to diagnose Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuro pathy with liability to pressure palsies (HNPP), but no technique combines simplicity with high sensitivity. Multiplex ligation-dependent probe amplification (MLPA) was applied to develop an efficient and sensitive test for the detection of duplication/deletion of the peripheral myelin protein 22 (PMP22) gene. The study sample included 70 probands that had each been previously analysed by fluorescence in situ hibridization (FISH) and the restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) assay, both of which detect a unique recombination fragment uniquely present in most patients with the duplication. A total of nine duplications and 19 deletions were detected in the 70 probands using MLPA, and there was 100% concordance between MPLA and FISH. A single duplication was missed by the RFLP-PCR assay, which accords with the lower sensitivity of this method. It is concluded that the MLPA allows accurate detection of PMP22 gene duplications/deletions and could be used for the molecular diagnosis of these two neuropathies. PMID:19930872

  8. Two patients with duplication of 17p11.2: The reciprocal of the Smith-Magenis syndrome deletion?

    SciTech Connect

    Brown, A. |; Phelan, M.C.; Rogers, R.C.

    1996-05-17

    J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magenis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/ duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A). 30 refs., 3 figs., 1 tab.

  9. Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis.

    PubMed

    Asano, Yoshihide

    2015-10-01

    Systemic sclerosis (SSc) is a multisystem connective tissue disease featured by immune abnormalities, vasculopathy and tissue fibrosis with unknown etiology. A series of studies on disease-susceptibility genes and twins have demonstrated the association of genetic factors with autoimmunity and disease severity and the contribution of environmental factors to the induction of clinical features in this disease. Friend leukemia virus integration 1 (Fli1), a member of Ets transcription factor family, is epigenetically suppressed in the lesional skin of SSc patients, suggesting that Fli1 is a potential predisposing factor of SSc reflecting the influence of environmental factors. Consistent with this idea, Fli1 deficiency induces SSc-like phenotypes in dermal fibroblasts and dermal microvascular endothelial cells in vivo and in vitro at molecular levels. Furthermore, Fli1 haploinsufficiency recapitulates tissue fibrosis, vascular activation and inflammation characteristic of SSc to a greater extent in bleomycin-treated mice. Importantly, bosentan, a dual endothelin receptor antagonist with a potential disease-modifying effect on SSc vasculopathy, reverses the expression of Fli1 protein by increasing its protein stability. Therefore, Fli1 may serve as a predisposing factor of SSc and can be a promising therapeutic target of this incurable and devastating disease. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID:26055516

  10. Testing for Kidney Disease

    MedlinePlus

    ... Education Program > Learn About Kidney Disease > What Causes Kidney Disease? > Testing for Kidney Disease | Share External Link Disclaimer What ... from our online catalog . Alternate Language URL Español Testing for Kidney Disease Page Content Early kidney disease usually does not ...

  11. RARE DISEASES LIST

    EPA Science Inventory

    The rare disease list includes rare diseases and conditions for which information requests have been made to the Office of Rare Diseases. A rare disease is defined as a disease or condition for which there are fewer than 200,000 affected persons alive in the United States. The Of...

  12. Celiac disease and metabolic bone disease.

    PubMed

    Xing, Yanming; Morgan, Sarah L

    2013-01-01

    Celiac disease is a common autoimmune gastrointestinal disorder affecting multiple organs, precipitated in genetically vulnerable persons by the ingestion of gluten. Gluten is poorly digested and is presented to the intestinal mucosa as a large polypeptide. Binding to human leukocyte antigen-DQ2 and human leukocyte antigen-DQ8 molecules on antigen-presenting cells stimulates cellular and humeral immune reactions. Although common serological tests are available to diagnose celiac disease, the diagnosis of celiac disease is often delayed or missed because of lack of recognition as the disease presentation in adults is highly variable and may be asymptomatic. Celiac disease is a common secondary cause of metabolic bone disease and delayed treatment with gluten-free diet affects bone mineral density and fracture risk, so it is crucial to diagnose and treat celiac disease promptly. In this article, we will review recent studies of celiac disease in adults and provide practical, easily accessible information for busy clinicians. PMID:24090646

  13. A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition

    PubMed Central

    Kim, Hyeongki; Lee, Kyu-Sun; Kim, Ae-Kyeong; Choi, Miri; Choi, Kwangman; Kang, Mingu; Chi, Seung-Wook; Lee, Min-Sung; Lee, Jeong-Soo; Lee, So-Young; Song, Woo-Joo; Yu, Kweon

    2016-01-01

    ABSTRACT DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases. PMID:27483355

  14. A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition.

    PubMed

    Kim, Hyeongki; Lee, Kyu-Sun; Kim, Ae-Kyeong; Choi, Miri; Choi, Kwangman; Kang, Mingu; Chi, Seung-Wook; Lee, Min-Sung; Lee, Jeong-Soo; Lee, So-Young; Song, Woo-Joo; Yu, Kweon; Cho, Sungchan

    2016-08-01

    DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases. PMID:27483355

  15. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis.

    PubMed

    Radue, Ernst-Wilhelm; Stuart, William H; Calabresi, Peter A; Confavreux, Christian; Galetta, Steven L; Rudick, Richard A; Lublin, Fred D; Weinstock-Guttman, Bianca; Wynn, Daniel R; Fisher, Elizabeth; Papadopoulou, Athina; Lynn, Frances; Panzara, Michael A; Sandrock, Alfred W

    2010-05-15

    The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p<0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p<0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p<0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone. PMID:20236661

  16. Altered striatal function in a mutant mouse lacking D1A dopamine receptors.

    PubMed Central

    Drago, J; Gerfen, C R; Lachowicz, J E; Steiner, H; Hollon, T R; Love, P E; Ooi, G T; Grinberg, A; Lee, E J; Huang, S P

    1994-01-01

    Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway. Images Fig. 2 Fig. 4 PMID:7809078

  17. Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis.

    PubMed

    Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

    2015-01-01

    Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1(+) tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the "classical-like" (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients' outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1(+) cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1(-) cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1(+) cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

  18. Spinal Cord Diseases

    MedlinePlus

    ... this can also injure the spinal cord. Other spinal cord problems include Tumors Infections such as meningitis and polio Inflammatory diseases Autoimmune diseases Degenerative diseases such as amyotrophic lateral ...

  19. United Mitochondrial Disease Foundation

    MedlinePlus

    ... Caregivers! Want to help? Enroll now in the Mitochondrial Disease Community Registry to advance the development of treatments and cures. HOME What is Mitochondrial Disease Types of Mitochondrial Disease Possible Symptoms Getting a ...

  20. Treatment of Celiac Disease

    MedlinePlus

    ... Mission Statement Press Releases 2015 CSA Youth Ambassador PEER Grants Awarded Bountiful Pantry DNI Group, LLC Earth ... for Celiac Disease International Symposium Celiac Disease 2013 Peer Review Research Application History of Gluten Induced Diseases ...

  1. Lipid Storage Diseases

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Lipid Storage Diseases Information Page Condensed from Lipid Storage ... en Español Additional resources from MedlinePlus What are Lipid Storage Diseases? Lipid storage diseases are a group ...

  2. Tay-Sachs Disease

    MedlinePlus

    ... metabolic disease caused by the harmful buildup of lipids (fatty materials such as oils and acids) in ... management, and therapy of rare diseases, including the lipid storage diseases. Additional research funded by the NINDS ...

  3. Niemann-Pick disease

    MedlinePlus

    Niemann-Pick disease is a group of diseases passed down through families (inherited) in which fatty substances called lipids ... Niemann-Pick disease types A and B occur when cells in the body do not have an enzyme called ...

  4. Peripheral Vascular Disease

    MedlinePlus

    ... Information Center Back to previous page En español Aneurysms and Dissections Angina Arrhythmia Bundle Branch Block Cardiomyopathy ... blockage including peripheral artery disease or PAD Aortic aneurysms Buerger's Disease Raynaud's Phenomenon Disease of the veins ...

  5. Chronic obstructive pulmonary disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000091.htm Chronic obstructive pulmonary disease To use the sharing features on this page, please enable JavaScript. Chronic obstructive pulmonary disease (COPD) is a common lung disease. Having COPD ...

  6. Digestive Diseases Materials

    MedlinePlus

    ... NIDDK Health Information NIDDK Home NIDDK Image Library Digestive Disease, Nutrition, and Weight-control Materials Healthy eating, ... Materials Statistics Tip Sheets Catalog Home | Diabetes Materials | Digestive Diseases Materials | Kidney and Urologic Diseases Materials Online ...

  7. Adult Still's disease

    MedlinePlus

    Still's disease - adult; AOSD ... than 1 out of 100,000 people develop adult-onset Still's disease each year. It affects women more often than men. The cause of adult Still's disease is unknown. No risk factors for ...

  8. Paget's Disease of Bone

    MedlinePlus

    ... page please turn Javascript on. Paget's Disease of Bone What is Paget's Disease of Bone? Click for more information Enlarged and Misshapen Bones Paget's disease of bone causes affected bones to ...

  9. Carotid Artery Disease

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Carotid Artery Disease? Carotid artery disease is a disease in ... blood to your face, scalp, and neck. Carotid Arteries Figure A shows the location of the right ...

  10. Heart disease - resources

    MedlinePlus

    Resources - heart disease ... The following organizations are good resources for information on heart disease: American Heart Association -- www.heart.org Centers for Disease Control and Prevention -- www.cdc.gov/heartdisease

  11. Kidney disease - resources

    MedlinePlus

    Resources - kidney disease ... The following organizations are good resources for information on kidney disease: National Kidney Disease Education Program -- www.nkdep.nih.gov National Kidney Foundation -- www.kidney.org National ...

  12. Lyme disease (image)

    MedlinePlus

    Lyme disease is an acute inflammatory disease characterized by skin changes, joint inflammation and symptoms similar to ... that is caused by the bacterium Borrelia burgdorferi . Lyme disease is transmitted by the bite of a ...

  13. Acid Lipase Disease

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Acid Lipase Disease Information Page Synonym(s): Cholesterol Ester Storage ... Trials Related NINDS Publications and Information What is Acid Lipase Disease ? Acid lipase disease or deficiency occurs ...

  14. Childhood Interstitial Lung Disease

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Childhood Interstitial Lung Disease? Childhood interstitial (in-ter-STISH-al) lung disease, ... with similar symptoms—it's not a precise diagnosis. Interstitial lung disease (ILD) also occurs in adults. However, the cause ...

  15. Lyme disease (image)

    MedlinePlus

    Lyme disease is an acute inflammatory disease characterized by skin changes, joint inflammation and symptoms similar to the ... that is caused by the bacterium Borrelia burgdorferi . Lyme disease is transmitted by the bite of a deer ...

  16. Parkinson disease - discharge

    MedlinePlus

    Your doctor has told you that you have Parkinson disease . This disease affects the brain and leads ... have you take different medicines to treat your Parkinson disease and many of the problems that may ...

  17. Tay-Sachs disease

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001417.htm Tay-Sachs disease To use the sharing features on this page, please enable JavaScript. Tay-Sachs disease is a life-threatening disease of the ...

  18. Parkinson disease - discharge

    MedlinePlus

    Your doctor has told you that you have Parkinson disease . This disease affects the brain and leads to ... have you take different medicines to treat your Parkinson disease and many of the problems that may come ...

  19. Degenerative Nerve Diseases

    MedlinePlus

    Degenerative nerve diseases affect many of your body's activities, such as balance, movement, talking, breathing, and heart function. Many ... viruses. Sometimes the cause is not known. Degenerative nerve diseases include Alzheimer's disease Amyotrophic lateral sclerosis Friedreich's ...

  20. Ebola Virus Disease

    MedlinePlus

    ... 2014 Fact sheets Features Commentaries 2014 Multimedia Contacts Ebola virus disease Fact sheet Updated January 2016 Key ... for survivors of Ebola virus disease Symptoms of Ebola virus disease The incubation period, that is, the ...

  1. Alzheimer's Disease Medications

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... Plan National Alzheimer's Project Act (NAPA) About ADEAR Alzheimer's Disease Medications Fact Sheet Treatment for Mild to ...

  2. Understanding Alzheimer's Disease

    MedlinePlus

    ... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... National Alzheimer's Project Act (NAPA) About ADEAR Understanding Alzheimer's Disease: What You Need to Know Introduction Many ...

  3. Diabetes and Kidney Disease

    MedlinePlus

    ... Disease, and Other Dental Problems Diabetic Eye Disease Diabetes and Kidney Disease What are my kidneys and ... urine until releasing it through urination. How can diabetes affect my kidneys? Too much glucose , also called ...

  4. Sickle Cell Disease Quiz

    MedlinePlus

    ... False: People with sickle cell disease cannot get malaria. A True B False 4. True or False: ... False: People with sickle cell disease cannot get malaria. False People with sickle cell disease can get ...

  5. Autoimmune liver disease panel

    MedlinePlus

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cirrhosis. This group of tests helps your health care provider diagnose ...

  6. Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits

    PubMed Central

    Zha, Xiang-ming; Wang, Runping; Collier, Dan M.; Snyder, Peter M.; Wemmie, John A.; Welsh, Michael J.

    2009-01-01

    The acid-sensing ion channel-1a (ASIC1a) is composed of 3 subunits and is activated by a decrease in extracellular pH. It plays an important role in diseases associated with a reduced pH and production of oxidants. Previous work showed that oxidants reduce ASIC1a currents. However, the effects on channel structure and composition are unknown. We found that ASIC1a formed inter-subunit disulfide bonds and the oxidant H2O2 increased this link between subunits. Cys-495 in the ASIC1a C terminus was particularly important for inter-subunit disulfide bond formation, although other C-terminal cysteines contributed. Inter-subunit disulfide bonds also produced some ASIC1a complexes larger than trimers. Inter-subunit disulfide bond formation reduced the proportion of ASIC1a located on the cell surface and contributed to the H2O2-induced decrease in H+-gated current. These results indicate that channel function is controlled by disulfide bond formation between intracellular residues on distinct ASIC1a subunits. They also suggest a mechanism by which the redox state can dynamically regulate membrane protein activity by forming intracellular bridges. PMID:19218436

  7. Histone methyltransferase KMT1A restrains entry of alveolar rhabdomyosarcoma cells into a myogenic differentiated state.

    PubMed

    Lee, Min-Hyung; Jothi, Mathivanan; Gudkov, Andrei V; Mal, Asoke K

    2011-06-01

    Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric muscle cancer, which arrested during the process of skeletal muscle differentiation. In muscle myoblast cells, ectopic expression of the histone H3 lysine 9 (H3K9) methytransferase KMT1A blocks differentiation by repressing a myogenic gene expression program. In this study, we tested the hypothesis that activation of a KMT1A-mediated program of transcriptional repression prevents ARMS cells from differentiating. We investigated whether KMT1A represses the expression of differentiation-associated genes in ARMS cells, thereby blocking muscle differentiation. Our results show that expression of KMT1A is induced in human ARMS cancer cell lines when cultured under differentiation-permissible conditions. shRNA-mediated knockdown of KMT1A decreased anchorage dependent and independent cell proliferation and tumor xenograft growth, increased expression of differentiation-associated genes, and promoted the appearance of a terminally differentiated-like phenotype. Finally, shRNA-directed KMT1A knockdown restored the impaired transcriptional activity of the myogenic regulator MyoD. Together, our results suggested that high levels of KMT1A in ARMS cells under differentiation conditions impairs MyoD function, thereby arresting myogenic differentiation in these tumor cells. Thus, targeting KMT1A may be a novel strategy for the treatment of this disease. PMID:21493592

  8. A gene for Usher syndrome type I (USH1A) maps to chromosome 14q

    SciTech Connect

    Kaplan, J.; Gerber, S.; Rozet, J.M.; Delrieu, O.; Briard, M.L.; Dollfus, H.; Frezal, J.; Munnich, A. ); Bonneau, D. ); Ghazi, I. )

    1992-12-01

    Usher syndrome (US) is an autosomal recessive disease characterized by congenital hearing impairment and retinitis pigmentosa. It is the most frequent cause of deaf-blindness in adults and accounts for 3 to 6% of deaf children. Here, the authors report the genetic mapping of a gene for US type I (USH1A), the most severe form of the disease, to the long arm of chromosome 14, by linkage to probe MLJ14 at the D14S13 locus in 10 families of Western France ancestry ([cflx Z] = 4.13 at [cflx [theta

  9. [Interferon beta 1-a in multiple sclerosis: 1-year experience in 62 patients].

    PubMed

    Tilbery, C P; Felipe, E; Moreira, M A; Mendes, M F; França, A S

    2000-06-01

    We report the results of a trial of interferon beta 1-a in 62 ambulatory patients with relapsing-remitting multiple sclerosis. Entry criteria included EDSS of 0 to 5.5 and at least two exacerbations in the previous 2 years. The patients received 3 million international units by subcutaneous injections three times a week. The end points were differences in exacerbation rate and treatment effect on disease progression. The annual exacerbation rate for patients that did not take the interferon beta 1-a was 1.32 and for the patients under medication 0.63. The EDSS score in patients that did not take the mediaction was 4.7 and 2.0 for the patients with interferon beta 1-a. Interferon beta 1-a was well tolerated and 85% of patients completed 1 year treatment. PMID:10920406

  10. Diabetes and kidney disease

    MedlinePlus

    Diabetic nephropathy; Nephropathy - diabetic; Diabetic glomerulosclerosis; Kimmelstiel-Wilson disease ... Diabetic kidney disease is a major cause of sickness and death in people with diabetes. It can ...

  11. Polymorphisms of UGT1A1*6, UGT1A1*27 & UGT1A1*28 in three major ethnic groups from Malaysia

    PubMed Central

    Teh, L. K.; Hashim, H.; Zakaria, Z. A.; Salleh, M. Z.

    2012-01-01

    Background & objectives: Genetic polymorphisms of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) have been associated with a wide variation of responses among patients prescribed with irinotecan. Lack of this enzyme is known to be associated with a high incidence of severe toxicity. The objective of this study was to investigate the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28), which are associated with reduced enzyme activity and increased irinotecan toxicity, in the three main ethnic groups in Malaysia (Malays, Chinese and Indians). Methods: A total of 306 healthy unrelated volunteers were screened for UGT1A1*28, UGT1A1*6 and UGT1A1*27. Blood samples (5 ml) were obtained from each subject and DNA was extracted. PCR based methods were designed and validated for detection of UGT1A1*6, UGT1A1*27 and UGT1A1*28. Direct DNA sequencing was performed to validate the results of randomly selected samples. Results: Malays and Indian have two-fold higher frequency of homozygous of UGT1A1*28 (7TA/7TA) which was 8 and 8.8 per cent, respectively compared to the Chinese (4.9%). However, the distribution of UGT1A1*6 and UGT1A1*27 showed no significant differences among them. UGT1A1*27 which has not been detected in Caucasian and African American population, was found in the Malaysian Malays (3.33%) and Malaysian Chinese (2.0%). Interpretation & conclusions: There was interethnic variability in the frequency of UGT1A1*28 in the Malaysian population. Our results suggest that genotyping of UGT1A1*6, UGT1A1*28 and UGT1A1*27 need to be performed before patients are prescribed with irinotecan due to their high prevalence of allelic variant which could lead to adverse drug reaction. PMID:22960892

  12. Differences in frequencies of UGT1A9, 1A7, and 1A1 genetic polymorphisms in Chinese Tibetan versus Han Chinese populations.

    PubMed

    Yan, W; Wang, Y W; Yang, F F; Wang, M; Zhang, X Q; Dong, J; Chen, E; Yang, J

    2013-01-01

    As part of a series of pharmacogenomics studies of the Chinese population, we investigated genetic polymorphisms of some UGT1A regions. The three genes that were analyzed were UGT1A9, 1A7, and 1A1; we sequenced their exons, together with promoters, surrounding introns and 3'-untranslated regions (3'UTR) in 100 unrelated-healthy Chinese Tibetan individuals. We compared the data with information on Han Chinese of the same region, which we downloaded from the HapMap database. We identified 40 polymorphisms; 16 of them were shared by the two populations. We then analyzed their linkage disequilibrium map. The UGT1As cluster can be divided into two linkage blocks in the Tibetan population: Block 1 (UGT1A9, UGT1A7), Block 2 (3'-UTR). Furthermore, we identified haplotypes and selected their tagSNPs. In exon 1 of UGT1A7 gene, 393G>A (Arg131Gln, rs17868324) was found at a frequency of 44.4% in the Tibetan population, compared to only 0.7% in the Han population. The linkage blocks in the Han Chinese sample differed from that of the Chinese Tibetan group; the former had Block 1 (UGT1A9, UGT1A7), Block 2 (UGT1A7), and Block 3 (3'-UTR). These findings provide fundamental information for future molecular genetic studies of the UGT1A gene cluster as well as for personalized medicine in Chinese. PMID:24390994

  13. Dimerization of human uridine diphosphate glucuronosyltransferase allozymes 1A1 and 1A9 alters their quercetin glucuronidation activities.

    PubMed

    Liu, Yan-Qing; Yuan, Ling-Min; Gao, Zhang-Zhao; Xiao, Yong-Sheng; Sun, Hong-Ying; Yu, Lu-Shan; Zeng, Su

    2016-01-01

    Uridine diphosphate glucuronosyltransferase 1A (UGT1A) is a major phase II drug-metabolism enzyme superfamily involved in the glucuronidation of endobiotics and xenobiotics in humans. Many polymorphisms in UGT1A genes are reported to inhibit or decrease UGT1A activity. In this study, two UGT1A1 allozymes, UGT1A1 wild-type and a splice mutant, as well as UGT1A9 wild-type and its three UGT1A9 allozymes, UGT1A9*2(C3Y), UGT1A9*3(M33T), and UGT1A9*5(D256N) were single- or double-expressed in a Bac-to-Bac expression system. Dimerization of UGT1A1 or UGT1A9 allozymes was observed via fluorescence resonance energy transfer (FRET) and co-immunoprecipitation analysis. SNPs of UGT1A altered the ability of protein-protein interaction, resulting in differential FRET efficiencies and donor-acceptor r distances. Dimerization changed the chemical regioselectivity, substrate-binding affinity, and enzymatic activity of UGT1A1 and UGT1A9 in glucuronidation of quercetin. These findings provide molecular insights into the consequences of homozygous and heterozygous UGT1A1 and UGT1A9 allozymes expression on quercetin glucuronidation. PMID:27025983

  14. Dimerization of human uridine diphosphate glucuronosyltransferase allozymes 1A1 and 1A9 alters their quercetin glucuronidation activities

    PubMed Central

    Liu, Yan-Qing; Yuan, Ling-Min; Gao, Zhang-Zhao; Xiao, Yong-Sheng; Sun, Hong-Ying; Yu, Lu-Shan; Zeng, Su

    2016-01-01

    Uridine diphosphate glucuronosyltransferase 1A (UGT1A) is a major phase II drug-metabolism enzyme superfamily involved in the glucuronidation of endobiotics and xenobiotics in humans. Many polymorphisms in UGT1A genes are reported to inhibit or decrease UGT1A activity. In this study, two UGT1A1 allozymes, UGT1A1 wild-type and a splice mutant, as well as UGT1A9 wild-type and its three UGT1A9 allozymes, UGT1A9*2(C3Y), UGT1A9*3(M33T), and UGT1A9*5(D256N) were single- or double-expressed in a Bac-to-Bac expression system. Dimerization of UGT1A1 or UGT1A9 allozymes was observed via fluorescence resonance energy transfer (FRET) and co-immunoprecipitation analysis. SNPs of UGT1A altered the ability of protein-protein interaction, resulting in differential FRET efficiencies and donor-acceptor r distances. Dimerization changed the chemical regioselectivity, substrate-binding affinity, and enzymatic activity of UGT1A1 and UGT1A9 in glucuronidation of quercetin. These findings provide molecular insights into the consequences of homozygous and heterozygous UGT1A1 and UGT1A9 allozymes expression on quercetin glucuronidation. PMID:27025983

  15. Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity

    PubMed Central

    Sidharthan, Neelima P.; Minchin, Rodney F.; Butcher, Neville J.

    2013-01-01

    Dopamine neurotoxicity is associated with several neurodegenerative diseases, and neurons utilize several mechanisms, including uptake and metabolism, to protect them from injury. Metabolism of dopamine involves three enzymes: monoamine oxidase, catechol O-methyltransferase, and sulfotransferase. In primates but not lower order animals, a sulfotransferase (SULT1A3) is present that can rapidly metabolize dopamine to dopamine sulfate. Here, we show that SULT1A3 and a closely related protein SULT1A1 are highly inducible by dopamine. This involves activation of the D1 and NMDA receptors. Both ERK1/2 phosphorylation and calcineurin activation are required for induction. Pharmacological agents that inhibited induction or siRNA targeting SULT1A3 significantly increased the susceptibility of cells to dopamine toxicity. Taken together, these results show that dopamine can induce its own metabolism and protect neuron-like cells from damage, suggesting that SULT1A3 activity may be a risk factor for dopamine-dependent neurodegenerative diseases. PMID:24136195

  16. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells

    PubMed Central

    Khor, Bernard; Gagnon, John D; Goel, Gautam; Roche, Marly I; Conway, Kara L; Tran, Khoa; Aldrich, Leslie N; Sundberg, Thomas B; Paterson, Alison M; Mordecai, Scott; Dombkowski, David; Schirmer, Melanie; Tan, Pauline H; Bhan, Atul K; Roychoudhuri, Rahul; Restifo, Nicholas P; O'Shea, John J; Medoff, Benjamin D; Shamji, Alykhan F; Schreiber, Stuart L; Sharpe, Arlene H; Shaw, Stanley Y; Xavier, Ramnik J

    2015-01-01

    The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. DOI: http://dx.doi.org/10.7554/eLife.05920.001 PMID:25998054

  17. Inhibitory effects of commonly used herbal extracts on UDP-glucuronosyltransferase 1A4, 1A6, and 1A9 enzyme activities.

    PubMed

    Mohamed, Mohamed-Eslam F; Frye, Reginald F

    2011-09-01

    The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC(50)) and the volume in which the dose could be diluted to generate an IC(50)-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC(50) value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC(50) values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC(50) values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC(50)-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions. PMID:21632963

  18. Variable Phenotype of Diabetes Mellitus in Siblings with a Homozygous PTF1A Enhancer Mutation.

    PubMed

    Gonc, E Nazlı; Ozon, Alev; Alikasifoglu, Ayfer; Haliloğlu, Mithat; Ellard, Sian; Shaw-Smith, Charles; Kandemir, Nurgun

    2015-01-01

    Neonatal diabetes is a rare form of diabetes, characterized by onset in the first 6 months of life. A number of cases are due to pancreas agenesis. Recently, PTF1A enhancer mutations have been shown to cause neonatal diabetes associated with pancreatic agenesis. Herein, we report the clinical features of two siblings with PTF1A enhancer mutations, one of whom had neonatal diabetes, whereas the elder sister had a milder form of the disease with onset of diabetes at 9 years of age. PMID:26184423

  19. Diseases of Dairy Animals: Infectious Diseases: Johne's Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Johne's disease is a chronic, debilitating intestinal disorder in cattle, sheep and wild ruminants, characterized by diarrhea, weight loss and death. Animals usually become infected when they are young by ingesting feces or milk containing the causative bacteria. However, clinical signs of disease...

  20. Biomarker for Glycogen Storage Diseases

    ClinicalTrials.gov

    2016-08-25

    Fructose Metabolism, Inborn Errors; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VI; Glycogen Storage Disease Type VII; Glycogen Storage Disease Type VIII