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Sample records for resembling human sporadic

  1. A molecular model for sporadic human aneuploidy.

    PubMed

    Warren, William D; Gorringe, Kylie L

    2006-04-01

    Aneuploidy is a leading cause of birth defects and a significant contributor to infertility in humans. Maternal age is the only well-established risk factor for gametic aneuploidy in the general population, with the underlying cause(s) yet to be identified. Here we present an extension of the 'two-hit' model for sporadic human aneuploidy. An important implication of this model is that the genetic makeup of an individual will influence the threshold where recombinationally at-risk oocytes (hit-1 events) become sensitive to the effects of advancing age (hit-2 events). Consequently, the age-related risk of gametic aneuploidy in many individuals is likely to differ significantly from the population average, and single nucleotide polymorphisms (SNPs) associated with altered risk should be identifiable.

  2. Human Immunodeficiency Virus Associated Sporadic Nonfamilial Porphyria Cutanea Tarda

    PubMed Central

    Guha, Sibashish Kamal; Bandyopadhyay, Debabrata; Saha, Abanti; Lal, Niharika Ranjan

    2016-01-01

    Porphyria cutanea tarda (PCT), a relatively uncommon metabolic disease, is the most common cutaneous porphyria. Here, we present the case of a patient diagnosed with sporadic, nonfamilial PCT that presented with classical cutaneous findings and multiple risk factors, including alcohol abuse, human immunodeficiency virus/AIDS, that have been strongly associated with the sporadic form of PCT. PMID:27293254

  3. Differentiated human stem cells resemble fetal, not adult, β cells.

    PubMed

    Hrvatin, Sinisa; O'Donnell, Charles W; Deng, Francis; Millman, Jeffrey R; Pagliuca, Felicia Walton; DiIorio, Philip; Rezania, Alireza; Gifford, David K; Melton, Douglas A

    2014-02-25

    Human pluripotent stem cells (hPSCs) have the potential to generate any human cell type, and one widely recognized goal is to make pancreatic β cells. To this end, comparisons between differentiated cell types produced in vitro and their in vivo counterparts are essential to validate hPSC-derived cells. Genome-wide transcriptional analysis of sorted insulin-expressing (INS(+)) cells derived from three independent hPSC lines, human fetal pancreata, and adult human islets points to two major conclusions: (i) Different hPSC lines produce highly similar INS(+) cells and (ii) hPSC-derived INS(+) (hPSC-INS(+)) cells more closely resemble human fetal β cells than adult β cells. This study provides a direct comparison of transcriptional programs between pure hPSC-INS(+) cells and true β cells and provides a catalog of genes whose manipulation may convert hPSC-INS(+) cells into functional β cells.

  4. Ulipristal acetate resembles mifepristone in modulating human fallopian tube function.

    PubMed

    Li, Hang Wun Raymond; Liao, Su-Bin; Yeung, William Shu-Biu; Ng, Ernest Hung-Yu; O, Wai-Sum; Ho, Pak-Chung

    2014-10-10

    Do ulipristal acetate (UPA) and mifepristone have an effect on ciliary beat frequency and muscular contractions in the human Fallopian tube? UPA, in resemblance to mifepristone, inhibits ciliary beat and muscular contraction of the human Fallopian tube, probably through an agonistic effect on the tubal progesterone receptor. UPA, like mifepristone, acts as an emergency contraceptive mainly by inhibiting ovulation. Little is known about its effects on tubal function. This was an in vitro experimental study using Fallopian tube samples collected from 11 women undergoing hysterectomy for benign non-tubal gynaecological conditions. The tubal epithelium and longitudinal smooth muscle fibres were isolated, cultured and treated with UPA at graded concentrations of 0, 20, 200 and 2000 ng/ml, and mifepristone at graded concentrations of 0, 300, 3000 and 30 000 ng/ml, respectively. After treatment, ciliary beat frequency was determined using a photometric method. Basal tone, amplitude and frequency of muscular contraction were recorded through a force transducer. The mRNA expression of progesterone receptor (total and PR-B isoform), glycodelin and adrenomedullin were determined by real-time quantitative PCR. There was an overall dose-dependent suppressive effect on ciliary beat frequency (P < 0.0001) after treatment with UPA at all concentrations and with mifepristone at 3000 ng/ml or above. The basal tone, amplitude and frequency of muscular contractions were significantly reduced (P < 0.05) after treatment with UPA at 200 ng/ml or above, and with mifepristone at 3000 ng/ml or above. UPA treatment at 200 ng/ml or above significantly up-regulated the mRNA expression of progesterone receptor and glycodelin and down-regulated the mRNA expression of adrenomedullin in Fallopian tube tissue (P < 0.05). Whether or not the tubal effect may translate into additional mechanisms for contraceptive action in vivo is uncertain. The clinical relevance of UPA with regard to contraceptive

  5. Muscular dystrophy in a dog resembling human becker muscular dystrophy.

    PubMed

    Baroncelli, A B; Abellonio, F; Pagano, T B; Esposito, I; Peirone, B; Papparella, S; Paciello, O

    2014-05-01

    A 3-year-old, male Labrador retriever dog was presented with clinical signs of progressive exercise intolerance, bilateral elbow extension, rigidity of the forelimbs, hindlimb flexion and kyphosis. Microscopical examination of muscle tissue showed marked variability in myofibre size, replacement of muscle with mature adipose tissue and degeneration/regeneration of muscle fibres, consistent with muscular dystrophy. Immunohistochemical examination for dystrophin showed markedly reduced labelling with monoclonal antibodies specific for the rod domain and the carboxy-terminal of dystrophin, while expression of β-sarcoglycan, γ-sarcoglycan and β-dystroglycan was normal. Immunoblotting revealed a truncated dystrophin protein of approximately 135 kDa. These findings supported a diagnosis of congenital canine muscular dystrophy resembling Becker muscular dystrophy in man.

  6. Feline epidermal nevi resembling human inflammatory linear verrucous epidermal nevus.

    PubMed

    Sato, Masafumi; Kariya, Kazuhiro; Matsumoto, Munetaka; Itoh, Miyuki; Kobayashi, Yoshiyasu; Nishifuji, Koji; Kamiie, Junichi; Shirota, Kinji

    2012-10-01

    Multiple, pigmented, verrucous, cutaneous lesions in a 2-year-old female cat were pathologically examined. The lesions were linearly arranged on the right side of the body, and had developed along with moderate pruritus since infancy. Histologically, prominent exophytic, papillomatous outgrowths of the epidermis and acanthosis with intense ortho and parakeratotic hyperkeratosis were characteristic of the lesions. Dermal inflammation with mononuclear cells, neutrophils, and eosinophils was also noted. Inclusion bodies, cellular degeneration, and intranuclear viral particles suggesting papillomavirus infection in the keratinocytes were not observed. Papillomavirus antigen and DNA were not detected in the lesions by immunohistochemistry and polymerase chain reaction, respectively. In accordance with these clinical and histopathological features, the cutaneous lesions of the present cat were diagnosed as epidermal nevi, which were consistent with human inflammatory linear verrucous epidermal nevi.

  7. Equine skin tumours in 20 horses resembling three variants of human melanocytic naevi.

    PubMed

    Schöniger, Sandra; Summers, Brian A

    2009-06-01

    Melanocytic tumours are important in horses, especially grey horses. Intradermal common melanocytic naevi, cellular blue naevi and combined cellular blue naevi are subgroups of human melanocytic tumours, which have not been reported in horses. In this study, we describe 20 horses with skin tumours similar to these naevi of humans. These tumours represented individual skin masses in male and female horses of different breeds. Tumours resembling human intradermal common melanocytic naevi were noted in 12 horses aged between 2 and 17 years. Seven horses aged between 4 and 15 years developed cutaneous lesions similar to human cellular blue naevi. A combined cellular blue naevus-like tumour was diagnosed in a 20-year-old horse. All tumour types formed expansile, well-demarcated, non-encapsulated, symmetrical masses. Tumours similar to intradermal common melanocytic naevi were composed of nests of round and spindeloid neoplastic cells, often embedded in myxomatous stroma. Lesions resembling cellular blue naevi were formed by intradermal bundles of ovoid to elongated cells separated by collagen fibres. The combined cellular blue naevus-like tumour resembled human cellular blue naevus with in addition, an overlying junctional common melanocytic naevus. Neoplastic cells in all groups contained varying amounts of melanin pigment and were immunopositive for S100. These equine skin tumours differ from the commonly recognized equine melanocytic tumours by their cytomorphological features, random location and the absence of an increased tumour frequency in grey horses. The resemblance of these tumours to three distinct subgroups of human naevi expands the complexity of equine proliferative cutaneous melanocytic lesions.

  8. A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor.

    PubMed Central

    Rosen, D R; Martin-Morris, L; Luo, L Q; White, K

    1989-01-01

    We have isolated genomic and cDNA clones for a Drosophila gene resembling the human beta-amyloid precursor protein (APP). This gene produces a nervous system-enriched 6.5-kilobase transcript. Sequencing of cDNAs derived from the 6.5-kilobase transcript predicts an 886-amino acid polypeptide. This polypeptide contains a putative transmembrane domain and exhibits strong sequence similarity to cytoplasmic and extracellular regions of the human beta-amyloid precursor protein. There is a high probability that this Drosophila gene corresponds to the essential Drosophila locus vnd, a gene required for embryonic nervous system development. Images PMID:2494667

  9. A Drosophila gene encoding a protein resembling the human. beta. -amyloid protein precursor

    SciTech Connect

    Rosen, D.R.; Martin-Morris, L.; Luo, L.; White, K. )

    1989-04-01

    The authors have isolated genomic and cDNA clones for a Drosophila gene resembling the human {beta}-amyloid precursor protein (APP). This gene produces a nervous system-enriched 6.5-kilobase transcript. Sequencing of cDNAs derived from the 6.5-kilobase transcript predicts an 886-amino acid polypeptide. This polypeptide contains a putative transmembrane domain and exhibits strong sequence similarity to cytoplasmic and extracellular regions of the human {beta}-amyloid precursor protein. There is a high probability that this Drosophila gene corresponds to the essential Drosophila locus vnd, a gene required for embryonic nervous system development.

  10. American alligator proximal pedal phalanges resemble human finger bones: Diagnostic criteria for forensic investigators.

    PubMed

    Ferraro, Joseph V; Binetti, Katie M

    2014-07-01

    A scientific approach to bone and tooth identification requires analysts to pursue the goal of empirical falsification. That is, they may attribute a questioned specimen to element and taxon only after having ruled out all other possible attributions. This requires analysts to possess a thorough understanding of both human and non-human osteology, particularly so for remains that may be morphologically similar across taxa. To date, forensic anthropologists have identified several potential 'mimics' for human skeletal remains, including pig teeth and bear paws. Here we document another possible mimic for isolated human skeletal elements--the proximal pedal phalanges of American alligators (Alligator mississippiensis) closely resemble the proximal and intermediate hand phalanges of adult humans. We detail morphological similarities and differences between these elements, with the goal of providing sufficient information for investigators to confidently falsify the hypothesis that a questioned phalanx is derived from an American alligator. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Sclerosing cholangitis in baboons (Papio spp) resembling primary sclerosing cholangitis of humans.

    PubMed

    Arenas-Gamboa, A M; Bearss, J J; Hubbard, G B; Porter, B F; Owston, M A; Dick, E J

    2012-05-01

    Primary sclerosing cholangitis is a chronic and progressive cholestatic liver disease that has been extensively documented in the human literature. Although it shares many features in common with chronic lymphocytic cholangitis in cats, primary sclerosing cholangitis has never been reported in a nonhuman primate. Primary sclerosing cholangitis is characterized by the presence of intrahepatic and/or extrahepatic inflammation and concentric fibrosis of bile ducts, eventually leading to cirrhosis and hepatic failure. The pathogenesis and cause remain unknown, but the disease likely involves a multifactorial mechanism with genetic- and immune-mediated components. The authors report 2 cases that histologically resemble the condition in humans; they consist of 2 adult male baboons with a clinical history of chronic elevated liver enzymes. In both cases, the liver was histologically characterized by thick bands of fibrosis and mild lymphoplasmacytic periportal cholangiohepatitis with concentric periductal fibrosis, resulting in atrophy and loss of bile ducts. Immunohistochemical analysis revealed positivity of hepatocytes to cytokeratin 7. Masson stain demonstrated marked biliary fibrosis. This is the first report that resembles sclerosing cholangitis in a nonhuman primate, and it suggests that the baboon may provide a useful animal model for this condition in humans.

  12. Human endomembrane H sup + pump strongly resembles the ATP-synthetase of Archaebacteria

    SciTech Connect

    Suedhof, T.C.; Stone, D.K.; Johnston, P.A.; Xie, Xiaosong ); Fried, V.A. )

    1989-08-01

    Preparations of mammalian H{sup +} pumps that acidify intracellular vesicles contain eight or nine polypeptides, ranging in size from 116 to 17 kDa. Biochemical analysis indicates that the 70- and 58-kDa polypeptides are subunits critical for ATP hydrolysis. The amino acid sequences of the major catalytic subunits (58 and 70 kDa) of the endomembrane H{sup +} pump are unknown from animal cells. The authors report here the complete sequence of the 58-kDa subunit derived from a human kidney cDNA clone and partial sequences of the 70- and 58-kDa subunits purified from clathrin-coated vesicles of bovine brain. The amino acid sequences of both proteins strongly resemble the sequences of the corresponding subunits of the vacuolar H{sup +} pumps of Archaebacteria, plants, and fungi. The archaebacterial enzyme is believed to use a H{sup +} gradient to synthesize ATP. Thus, a common ancestral protein has given rise to a H{sup +} pump that synthesizes ATP in one organism and hydrolyzes it in another and is highly conserved from prokaryotes to humans. The same pump appears to mediate the acidification of intracellular organelles, including coated vesicles, lysosomes, and secretory granules, as well as extracellular fluids such as urine.

  13. A Mouse Model of Diet-Induced Obesity Resembling Most Features of Human Metabolic Syndrome

    PubMed Central

    Della Vedova, Maria C.; Muñoz, Marcos D.; Santillan, Lucas D.; Plateo-Pignatari, Maria G.; Germanó, Maria J.; Rinaldi Tosi, Martín E.; Garcia, Silvina; Gomez, Nidia N.; Fornes, Miguel W.; Gomez Mejiba, Sandra E.; Ramirez, Dario C.

    2016-01-01

    Increased chicken-derived fat and fructose consumption in the human diet is paralleled by an increasing prevalence of obesity and metabolic syndrome (MS). Herein, we aimed at developing and characterizing a mouse model of diet-induced obesity (DIO) resembling most of the key features of the human MS. To accomplish this, we fed male C57BL/6J mice for 4, 8, 12, and 16 weeks with either a low-fat diet (LFD) or a high-chicken-fat diet (HFD) and tap water with or without 10% fructose (F). This experimental design resulted in the following four experimental groups: LFD, LFD + F, HFD, and HFD + F. Over the feeding period, and on a weekly basis, the HFD + F group had more caloric intake and gained more weight than the other experimental groups. Compared to the other groups, and at the end of the feeding period, the HFD + F group had a higher adipogenic index, total cholesterol, low-density lipoprotein cholesterol, fasting basal glycemia, insulin resistance, hypertension, and atherogenic index and showed steatohepatitis and systemic oxidative stress/inflammation. A mouse model of DIO that will allow us to study the effect of MS in different organs and systems has been developed and characterized. PMID:27980421

  14. Response of mice to continuous 5-day passive hyperthermia resembles human heat acclimation.

    PubMed

    Sareh, Houtan; Tulapurkar, Mohan E; Shah, Nirav G; Singh, Ishwar S; Hasday, Jeffrey D

    2011-05-01

    Chronic repeated exposure to hyperthermia in humans results in heat acclimation (HA), an adaptive process that is attained in humans by repeated exposure to hyperthermia and is characterized by improved heat elimination and increased exercise capacity, and acquired thermal tolerance (ATT), a cellular response characterized by increased baseline heat shock protein (HSP) expression and blunting of the acute increase in HSP expression stimulated by re-exposure to thermal stress. Epidemiologic studies in military personnel operating in hot environments and elite athletes suggest that repeated exposure to hyperthermia may also exert long-term health effects. Animal models demonstrate that coincident exposure to mild hyperthermia or prior exposure to severe hyperthermia can profoundly affect the course of experimental infection and injury, but these models do not represent HA. In this study, we demonstrate that CD-1 mice continuously exposed to mild hyperthermia (ambient temperature ~37°C causing ~2°C increase in core temperature) for 5 days and then exposed to a thermal stress (42°C ambient temperature for 40 min) exhibited some of the salient features of human HA, including (1) slower warming during thermal stress and more rapid cooling during recovery and (2) increased activity during thermal stress, as well as some of the features of ATT, including (1) increased baseline expression of HSP72 and HSP90 in lung, heart, spleen, liver, and brain; and (2) blunted incremental increase in HSP72 expression following acute thermal stress. This study suggests that continuous 5-day exposure of CD-1 mice to mild hyperthermia induces a state that resembles the physiologic and cellular responses of human HA. This model may be useful for analyzing the molecular mechanisms of HA and its consequences on host responsiveness to subsequent stresses.

  15. Arteriovenous Malformation in the Adult Mouse Brain Resembling the Human Disease

    PubMed Central

    Walker, Espen J.; Su, Hua; Shen, Fanxia; Choi, Eun-Jung; Oh, S. Paul; Chen, Grant; Lawton, Michael T.; Kim, Helen; Chen, Yongmei; Chen, Wanqiu; Young, William L.

    2010-01-01

    Objective Brain arteriovenous malformations (bAVM) are an important cause of hemorrhagic stroke. The underlying mechanisms are not clear. No animal model for adult bAVM is available for mechanistic exploration. Patients with Hereditary Hemorrhagic Telangiectasia Type2 (HHT2) with activin receptor-like kinase 1 (ALK1; ACVRL1) mutations have a higher incidence of bAVM than the general population. We tested the hypothesis that VEGF stimulation with regional homozygous deletion of Alk1 induces severe dysplasia in the adult mouse brain, akin to human bAVM. Methods Alk12f/2f (exons 4–6 flanked by loxP sites) and wild-type (WT) mice (8–10 weeks old) were injected with Ad-Cre (2×107 PFU, adenoviral vector expressing Cre recombinase) and AAV-VEGF (2×109 genome copies, adeno-associated viral vectors expressing VEGF) into the basal ganglia. At 8 weeks, blood vessels were analyzed. Results Gross vascular irregularities were seen in Alk1 2f/2f mouse brain injected with Ad-Cre and AAV-VEGF. The vessels were markedly enlarged with abnormal patterning resembling aspects of the human bAVM phenotype, displayed altered expression of the arterial and venous markers (EphB4 and Jagged-1), and showed evidence of arteriovenous shunting. Vascular irregularities were not seen in similarly treated WT mice. Interpretation Our data indicate that post-natal, adult formation of the human disease bAVM is possible, and that both genetic mutation and angiogenic stimulation are necessary for lesion development. Our work not only provides a testable adult mouse bAVM model for the first time, but also suggests that specific medical therapy can be developed to slow bAVM growth and potentially stabilize the rupture-prone abnormal vasculature. PMID:21437931

  16. Mutations in human lymphocytes commonly involve gene duplication and resemble those seen in cancer cels.

    PubMed Central

    Turner, D R; Grist, S A; Janatipour, M; Morley, A A

    1988-01-01

    Mutations in human lymphocytes are commonly due to gene deletion. To investigate the mechanism of deletion for autosomal genes, we immunoselected lymphocytes mutated at the HLA-A locus and cloned them for molecular analysis. Of 36 mutant clones that showed deletion of the selected HLA-A allele, 8 had resulted from a simple gene deletion, whereas 28 had resulted from a more complex mutational event involving reduplication of the nonselected HLA-A allele as indicated by hybridization intensity on Southern blots. In 3 of the 28 clones, retention of heterozygosity at the HLA-B locus indicated that the reduplication was due to recombination between the two chromosomes 6; but in the remaining 25 clones, distinction could not be made between recombination and chromosome reduplication. The results indicate that mutations in normal somatic cells frequently result in hemizygosity or homozygosity at gene loci and, thereby, resemble the mutations thought to be important in the etiology of various forms of cancer. Images PMID:3258992

  17. Mutations in human lymphocytes commonly involve gene duplication and resemble those seen in cancer cells

    SciTech Connect

    Turner, D.R.; Grist, S.A.; Janatipour, M.; Morley, A.A.

    1988-05-01

    Mutations in human lymphocytes are commonly due to gene deletion. To investigate the mechanism of deletion for autosomal genes, the authors immunoselected lymphocytes mutated at the HLA-A locus and clones them for molecular analysis. Of 36 mutant clones that showed deletion of the selected HLA-A allele, 8 had resulted from a simple gene deletion, whereas 28 had resulted from a more complex mutational event involving reduplication of the nonselected HLA-A allele as indicated by hybridization intensity on Southern blots. In 3 of the 28 clones, retention of heterozygosity at the HLA-B locus indicated that the reduplication was due to recombination between the two chromosomes 6; but in the remaining 25 clones, distinction could not be made between recombination and chromosome reduplication. The results indicate that mutations in normal somatic cells frequently result in hemizygosity or homozygosity at gene loci and, thereby, resemble the mutations thought to be important in the etiology of various forms of cancer.

  18. Impaired Autophagy in Sporadic Inclusion-Body Myositis and in Endoplasmic Reticulum Stress-Provoked Cultured Human Muscle Fibers

    PubMed Central

    Nogalska, Anna; D'Agostino, Carla; Terracciano, Chiara; Engel, W. King; Askanas, Valerie

    2010-01-01

    The hallmark pathologies of sporadic inclusion-body myositis (s-IBM) muscle fibers are autophagic vacuoles and accumulation of ubiquitin-positive multiprotein aggregates that contain amyloid-β or phosphorylated tau in a β-pleated sheet amyloid configuration. Endoplasmic reticulum stress (ERS) and 26S proteasome inhibition, also associated with s-IBM, putatively aggrandize the accumulation of misfolded proteins. However, autophagosomal-lysosomal pathway formation and function, indicated by autophagosome maturation, have not been previously analyzed in this system. Here we studied the autophagosomal-lysosomal pathway using 14 s-IBM and 30 disease control and normal control muscle biopsy samples and our cultured human muscle fibers in a microenvironment modified to resemble aspects of s-IBM pathology. We report for the first time that in s-IBM, lysosomal enzyme activities of cathepsin D and B were decreased 60% (P < 0.01) and 40% (P < 0.05), respectively. We also detected two indicators of increased autophagosome maturation, the presence of LC3-II and decreased mammalian target of rapamycin-mediated phosphorylation of p70S6 kinase. Moreover, in cultured human muscle fibers, ERS induction significantly decreased activities of cathepsins D and B, increased levels of LC3-II, decreased phosphorylation of p70S6 kinase, and decreased expression of VMA21, a chaperone for assembly of lysosomal V-ATPase. We conclude that in s-IBM muscle, decreased lysosomal proteolytic activity might enhance accumulation of misfolded proteins, despite increased maturation of autophagosomes, and that ERS is a possible cause of s-IBM-impaired lysosomal function. Thus, unblocking protein degradation in s-IBM muscle fibers may be a desirable therapeutic strategy. PMID:20616343

  19. Facial resemblance enhances trust.

    PubMed

    DeBruine, Lisa M

    2002-07-07

    Organisms are expected to be sensitive to cues of genetic relatedness when making decisions about social behaviour. Relatedness can be assessed in several ways, one of which is phenotype matching: the assessment of similarity between others' traits and either one's own traits or those of known relatives. One candidate cue of relatedness in humans is facial resemblance. Here, I report the effects of an experimental manipulation of facial resemblance in a two-person sequential trust game. Subjects were shown faces of ostensible playing partners manipulated to resemble either themselves or an unknown person. Resemblance to the subject's own face raised the incidence of trusting a partner, but had no effect on the incidence of selfish betrayals of the partner's trust. Control subjects playing with identical pictures failed to show such an effect. In a second experiment, resemblance of the playing partner to a familiar (famous) person had no effect on either trusting or betrayals of trust.

  20. Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma.

    PubMed

    Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

    2014-01-01

    Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model.

  1. Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma

    PubMed Central

    Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

    2014-01-01

    Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. PMID:24128326

  2. Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

    PubMed

    Castillo, Sandra D; Tzouanacou, Elena; Zaw-Thin, May; Berenjeno, Inma M; Parker, Victoria E R; Chivite, Iñigo; Milà-Guasch, Maria; Pearce, Wayne; Solomon, Isabelle; Angulo-Urarte, Ana; Figueiredo, Ana M; Dewhurst, Robert E; Knox, Rachel G; Clark, Graeme R; Scudamore, Cheryl L; Badar, Adam; Kalber, Tammy L; Foster, Julie; Stuckey, Daniel J; David, Anna L; Phillips, Wayne A; Lythgoe, Mark F; Wilson, Valerie; Semple, Robert K; Sebire, Neil J; Kinsler, Veronica A; Graupera, Mariona; Vanhaesebroeck, Bart

    2016-03-30

    Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs. Copyright © 2016, American Association for the Advancement of Science.

  3. Deep Networks Can Resemble Human Feed-forward Vision in Invariant Object Recognition.

    PubMed

    Kheradpisheh, Saeed Reza; Ghodrati, Masoud; Ganjtabesh, Mohammad; Masquelier, Timothée

    2016-09-07

    Deep convolutional neural networks (DCNNs) have attracted much attention recently, and have shown to be able to recognize thousands of object categories in natural image databases. Their architecture is somewhat similar to that of the human visual system: both use restricted receptive fields, and a hierarchy of layers which progressively extract more and more abstracted features. Yet it is unknown whether DCNNs match human performance at the task of view-invariant object recognition, whether they make similar errors and use similar representations for this task, and whether the answers depend on the magnitude of the viewpoint variations. To investigate these issues, we benchmarked eight state-of-the-art DCNNs, the HMAX model, and a baseline shallow model and compared their results to those of humans with backward masking. Unlike in all previous DCNN studies, we carefully controlled the magnitude of the viewpoint variations to demonstrate that shallow nets can outperform deep nets and humans when variations are weak. When facing larger variations, however, more layers were needed to match human performance and error distributions, and to have representations that are consistent with human behavior. A very deep net with 18 layers even outperformed humans at the highest variation level, using the most human-like representations.

  4. Deep Networks Can Resemble Human Feed-forward Vision in Invariant Object Recognition

    PubMed Central

    Kheradpisheh, Saeed Reza; Ghodrati, Masoud; Ganjtabesh, Mohammad; Masquelier, Timothée

    2016-01-01

    Deep convolutional neural networks (DCNNs) have attracted much attention recently, and have shown to be able to recognize thousands of object categories in natural image databases. Their architecture is somewhat similar to that of the human visual system: both use restricted receptive fields, and a hierarchy of layers which progressively extract more and more abstracted features. Yet it is unknown whether DCNNs match human performance at the task of view-invariant object recognition, whether they make similar errors and use similar representations for this task, and whether the answers depend on the magnitude of the viewpoint variations. To investigate these issues, we benchmarked eight state-of-the-art DCNNs, the HMAX model, and a baseline shallow model and compared their results to those of humans with backward masking. Unlike in all previous DCNN studies, we carefully controlled the magnitude of the viewpoint variations to demonstrate that shallow nets can outperform deep nets and humans when variations are weak. When facing larger variations, however, more layers were needed to match human performance and error distributions, and to have representations that are consistent with human behavior. A very deep net with 18 layers even outperformed humans at the highest variation level, using the most human-like representations. PMID:27601096

  5. Genomic landscape of retinoblastoma in Rb(-/-) p130(-/-) mice resembles human retinoblastoma.

    PubMed

    Kooi, Irsan E; van Mil, Saskia E; MacPherson, David; Mol, Berber M; Moll, Annette C; Meijers-Heijboer, Hanne; Kaspers, Gertjan J L; Cloos, Jacqueline; Te Riele, Hein; Dorsman, Josephine C

    2017-03-01

    Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb(-/-) p107(-/-) retinoblastomas, somatic copy number alterations (SCNAs) like Mdm2 amplification or Cdkn2a deletion targeting the p53-pathway occur, which is uncommon for human retinoblastoma. In our study, we determined SCNAs in retinoblastomas developing in Rb(-/-) p130(-/-) mice and compared this to murine Rb(-/-) p107(-/-) tumors and human tumors. Chimeric mice were made by injection of 129/Ola-derived Rb(-/-) p130(-/-) embryonic stem cells into wild type C57BL/6 blastocysts. SCNAs of retinoblastoma samples were determined by low-coverage (∼0.5×) whole genome sequencing. In Rb(-/-) p130(-/-) tumors, SCNAs included gain of chromosomes 1 (3/23 tumors), 8 (1/23 tumors), 10 (1/23 tumors), 11 (2/23 tumors), and 12 (4/23 tumors), which could be mapped to frequently altered chromosomes in human retinoblastomas. While the altered chromosomes in Rb(-/-) p130(-/-) tumors were similar to those in Rb(-/-) p107(-/-) tumors, the alteration frequencies were much lower in Rb(-/-) p130(-/-) tumors. Most of the Rb(-/-) p130(-/-) tumors (16/23 tumors, 70%) were devoid of SCNAs, in strong contrast to Rb(-/-) p107(-/-) tumors, which were never (0/15 tumors) SCNA-devoid. Similarly, to human retinoblastoma, increased age at diagnosis significantly correlated with increased SCNA frequencies. Additionally, focal loss of Cdh11 was observed in one Rb(-/-) p130(-/-) tumor, which enforces studies in human retinoblastoma that identified CDH11 as a retinoblastoma suppressor. Moreover, based on a comparison of genes altered in human and murine retinoblastoma, we suggest exploring the role of HMGA1 and SRSF3 in retinoblastoma development. © 2016 Wiley Periodicals, Inc.

  6. Acute paretic syndrome in juvenile White Leghorn chickens resembles late stages of acute inflammatory demyelinating polyneuropathies in humans

    PubMed Central

    2010-01-01

    Background Sudden limb paresis is a common problem in White Leghorn flocks, affecting about 1% of the chicken population before achievement of sexual maturity. Previously, a similar clinical syndrome has been reported as being caused by inflammatory demyelination of peripheral nerve fibres. Here, we investigated in detail the immunopathology of this paretic syndrome and its possible resemblance to human neuropathies. Methods Neurologically affected chickens and control animals from one single flock underwent clinical and neuropathological examination. Peripheral nervous system (PNS) alterations were characterised using standard morphological techniques, including nerve fibre teasing and transmission electron microscopy. Infiltrating cells were phenotyped immunohistologically and quantified by flow cytometry. The cytokine expression pattern was assessed by quantitative real-time PCR (qRT-PCR). These investigations were accomplished by MHC genotyping and a PCR screen for Marek's disease virus (MDV). Results Spontaneous paresis of White Leghorns is caused by cell-mediated, inflammatory demyelination affecting multiple cranial and spinal nerves and nerve roots with a proximodistal tapering. Clinical manifestation coincides with the employment of humoral immune mechanisms, enrolling plasma cell recruitment, deposition of myelin-bound IgG and antibody-dependent macrophageal myelin-stripping. Disease development was significantly linked to a 539 bp microsatellite in MHC locus LEI0258. An aetiological role for MDV was excluded. Conclusions The paretic phase of avian inflammatory demyelinating polyradiculoneuritis immunobiologically resembles the late-acute disease stages of human acute inflammatory demyelinating polyneuropathy, and is characterised by a Th1-to-Th2 shift. PMID:20109187

  7. Resemblance of the properties of superimposed volume holograms to the properties of human memory

    NASA Astrophysics Data System (ADS)

    Orlov, V. V.

    2006-09-01

    According to current concepts in psychology, a collection of patterns stored in human memory has the property of integrity and contains new information not contained in the individual patterns. It is shown that superimposed volume holograms possess similar properties if the information in them is written by a method that excludes the appearance of crosstalk of the holograms.

  8. Assessing Prion Infectivity of Human Urine in Sporadic Creutzfeldt-Jakob Disease

    PubMed Central

    Notari, Silvio; Qing, Liuting; Pocchiari, Maurizio; Dagdanova, Ayuna; Hatcher, Kristin; Dogterom, Arend; Groisman, Jose F.; Lumholtz, Ib Bo; Puopolo, Maria; Lasmezas, Corinne; Chen, Shu G.; Kong, Qingzhong

    2012-01-01

    Prion diseases are neurodegenerative conditions associated with a misfolded and infectious protein, scrapie prion protein (PrPSc). PrPSc propagate prion diseases within and between species and thus pose risks to public health. Prion infectivity or PrPSc presence has been demonstrated in urine of experimentally infected animals, but there are no recent studies of urine from patients with Creutzfeldt-Jakob disease (CJD). We performed bioassays in transgenic mice expressing human PrP to assess prion infectivity in urine from patients affected by a common subtype of sporadic CJD, sCJDMM1. We tested raw urine and 100-fold concentrated and dialyzed urine and assessed the sensitivity of the bioassay along with the effect of concentration and dialysis on prion infectivity. Intracerebral inoculation of transgenic mice with urine from 3 sCJDMM1 patients failed to demonstrate prion disease transmission, indicating that prion infectivity in urine from sCJDMM1 patients is either not present or is <0.38 infectious units/mL. PMID:22260924

  9. Animal cognition. Number-space mapping in the newborn chick resembles humans' mental number line.

    PubMed

    Rugani, Rosa; Vallortigara, Giorgio; Priftis, Konstantinos; Regolin, Lucia

    2015-01-30

    Humans represent numbers along a mental number line (MNL), where smaller values are located on the left and larger on the right. The origin of the MNL and its connections with cultural experience are unclear: Pre-verbal infants and nonhuman species master a variety of numerical abilities, supporting the existence of evolutionary ancient precursor systems. In our experiments, 3-day-old domestic chicks, once familiarized with a target number (5), spontaneously associated a smaller number (2) with the left space and a larger number (8) with the right space. The same number (8), though, was associated with the left space when the target number was 20. Similarly to humans, chicks associate smaller numbers with the left space and larger numbers with the right space.

  10. Barrier function in reconstructed epidermis and its resemblance to native human skin.

    PubMed

    Ponec, M; Gibbs, S; Pilgram, G; Boelsma, E; Koerten, H; Bouwstra, J; Mommaas, M

    2001-01-01

    One of the prerequisites for the use of human skin equivalents for scientific and screening purposes is that their barrier function is similar to that of native skin. Using human epidermis reconstructed on de-epidermized dermis we demonstrated that the formation of the stratum corneum (SC) barrier in vitro proceeds similarly as in vivo as judged from the extensive production of lamellar bodies, their complete extrusion at the stratum granulosum/SC interface, and the formation of multiple broad lamellar structures in the intercorneocyte space. The presence of well-ordered lipid lamellar phases was confirmed by small-angle X-ray diffraction. Although the long periodicity lamellar phase was present in both the native and the reconstructed epidermis, the short periodicity lamellar phase was present only in native tissue. In addition, the SC lipids predominantly formed the hexagonal sublattice. Analysis of lipid composition revealed that all SC lipids are synthesized in vitro. Differences in SC lipid organization in reconstructed epidermis may be ascribed to the differences in fatty acid content and profile indicating that further improvement in culture conditions is required for generation of in vitro reconstructed epidermis with stratum barrier properties of the native tissue. Copyright 2001 S. Karger AG, Basel

  11. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans.

    PubMed

    Hathcock, Karen S; Padilla-Nash, Hesed M; Camps, Jordi; Shin, Dong-Mi; Triner, Daniel; Shaffer, Arthur L; Maul, Robert W; Steinberg, Seth M; Gearhart, Patricia J; Staudt, Louis M; Morse, Herbert C; Ried, Thomas; Hodes, Richard J

    2015-11-12

    The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M(+) B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors.

  12. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans

    PubMed Central

    Hathcock, Karen S.; Padilla-Nash, Hesed M.; Camps, Jordi; Shin, Dong-Mi; Triner, Daniel; Shaffer, Arthur L.; Maul, Robert W.; Steinberg, Seth M.; Gearhart, Patricia J.; Staudt, Louis M.; Morse, Herbert C.; Ried, Thomas

    2015-01-01

    The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M+ B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell–like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors. PMID:26400962

  13. The RNA Binding Specificity of Human APOBEC3 Proteins Resembles That of HIV-1 Nucleocapsid

    PubMed Central

    Errando, Manel; Bieniasz, Paul D.

    2016-01-01

    The APOBEC3 (A3) cytidine deaminases are antiretroviral proteins, whose targets include human immunodeficiency virus type-1 (HIV-1). Their incorporation into viral particles is critical for antiviral activity and is driven by interactions with the RNA molecules that are packaged into virions. However, it is unclear whether A3 proteins preferentially target RNA molecules that are destined to be packaged and if so, how. Using cross-linking immunoprecipitation sequencing (CLIP-seq), we determined the RNA binding preferences of the A3F, A3G and A3H proteins. We found that A3 proteins bind preferentially to RNA segments with particular properties, both in cells and in virions. Specifically, A3 proteins target RNA sequences that are G-rich and/or A-rich and are not scanned by ribosomes during translation. Comparative analyses of HIV-1 Gag, nucleocapsid (NC) and A3 RNA binding to HIV-1 RNA in cells and virions revealed the striking finding that A3 proteins partially mimic the RNA binding specificity of the HIV-1 NC protein. These findings suggest a model for A3 incorporation into HIV-1 virions in which an NC-like RNA binding specificity is determined by nucleotide composition rather than sequence. This model reconciles the promiscuity of A3 RNA binding that has been observed in previous studies with a presumed advantage that would accompany selective binding to RNAs that are destined to be packaged into virions. PMID:27541140

  14. Hydrogen-dependent organisms from the human gingival crevice resembling Vibrio succinogenes.

    PubMed

    Van Palenstein Helderman, W H; Rosman, I

    1976-01-01

    Twenty-eight strains of microaerophilic, motile, slightly curved gram-negative rods isolated from the gingival crevice of patients with gingivitis were studied. They seemed similar to Vibrio sputorum, though eleven strains differed in minor characters from Bergey's description under the new name Campylobacter sputorum, subspecies sputorum. The oral strains studied appeared to be closely related to several species of the genus Campylobacter and to Vibrio succinogenes. The oral strains were able to utilize gaseous hydrogen and to grow in a mineral medium with either nitrate of fumarate as hydrogen acceptor. Formate could replace hydrogen as hydrogen donor. In contrast the Campylobacter strains were not dependent on hydrogen or formate as energy source and grew poorly in mineral medium. In these nutritional and metabolic aspects the oral strains are more related to Vibrio succinogenes than to Campylobacter species. Serologically the oral strains differed from all the Campylobacter species. The GC ratio in the DNA of the oral strains varied between 48 and 50%, conform to the values described for Vibrio succinogenes. Vibrio sputorum seems a nomen conservandum and vibrio-like organisms from human infections should be tested for hydrogen-dependence before they are classified as Campylobacter species.

  15. Characterization of bone mineral-resembling biomaterials for optimizing human osteoclast differentiation and resorption.

    PubMed

    Nakamura, Miho; Hentunen, Teuvo; Salonen, Jukka; Nagai, Akiko; Yamashita, Kimihiro

    2013-11-01

    Bioresorption is a biological mechanism by which biomaterials are resorbed and thereby disappear from implantation sites partially or completely over a period of time. Osteoclast-medicated bioresorption is a possible new advantage to incorporate material degradation into remodeling in bone metabolism process. The purpose of this study was to investigate the osteoclastogenesis and bioresorption of synthesized calcium phosphate materials. Differentiation into mature human osteoclasts on carbonated hydroxyapatite (CA) was significantly enhanced compared to hydroxyapatite (HA) and β-tricalcium phosphate, based on the quantitative gene expressions of molecular markers for osteoclast differentiation. Osteoclasts adhered and differentiated into giant multinuclear TRAP-positive cells on every type of synthesized sample based on the histological analysis. Morphological observations using fluorescence and quantitative analysis revealed that the actin rings of osteoclasts on CA were thick, small in diameter and co-localized with vinculin, similar to the rings found on bone slices. In contrast, the actin rings of osteoclasts on HA and culture dishes were thin and large in diameter. Scanning electron microscopic images and quantitative analysis indicated that the resorption pits on CA were significantly deeper than those on HA due to the enhanced tight sealing ability between osteoclasts and their substrate. Copyright © 2013 Wiley Periodicals, Inc.

  16. Inclusion bodies in loggerhead erythrocytes are associated with unstable hemoglobin and resemble human Heinz bodies.

    PubMed

    Basile, Filomena; Di Santi, Annalisa; Caldora, Mercedes; Ferretti, Luigi; Bentivegna, Flegra; Pica, Alessandra

    2011-08-01

    The aim of this study was to clarify the role of the erythrocyte inclusions found during the hematological screening of loggerhead population of the Mediterranean Sea. We studied the erythrocyte inclusions in blood specimens collected from six juvenile and nine adult specimens of the loggerhead turtle, Caretta caretta, from the Adriatic and Tyrrhenian Seas. Our study indicates that the percentage of mature erythrocytes containing inclusions ranged from 3 to 82%. Each erythrocyte contained only one round inclusion body. Inclusion bodies stained with May Grünwald-Giemsa show that their cytochemical and ultrastructure characteristics are identical to those of human Heinz bodies. Because Heinz bodies originate from the precipitation of unstable hemoglobin (Hb) and cause globular osmotic resistance to increase, we analyzed loggerhead Hb using electrophoresis and high-performance liquid chromatography to detect and quantitate Hb fractions. We also tested the resistance of Hb to alkaline pH, heat, isopropanol denaturation, and globular osmosis. Our hemogram results excluded the occurrence of any infection, which could be associated with an inclusion body, in all the specimens. Negative Feulgen staining indicated that the inclusion bodies are not derived from DNA fragmentation. We hypothesize that amino acid substitutions could explain why loggerhead Hb precipitates under normal physiologic conditions, forming Heinz bodies. The identification of inclusion bodies in loggerhead erythrocytes allow us to better understand the haematological characteristics and the physiology of these ancient reptiles, thus aiding efforts to conserve such an endangered species. Copyright © 2011 Wiley-Liss, Inc., A Wiley Company.

  17. Human Glioma–Initiating Cells Show a Distinct Immature Phenotype Resembling but Not Identical to NG2 Glia

    PubMed Central

    Barrantes-Freer, Alonso; Kim, Ella; Bielanska, Joanna; Giese, Alf; Mortensen, Lena Sünke; Schulz-Schaeffer, Walter J.; Stadelmann, Christine; Brück, Wolfgang

    2013-01-01

    Abstract Glioma-initiating cells (GICs) represent a potential important therapeutic target because they are likely to account for the frequent recurrence of malignant gliomas; however, their identity remains unsolved. Here, we characterized the cellular lineage fingerprint of GICs through a combination of electrophysiology, lineage marker expression, and differentiation assays of 5 human patient-derived primary GIC lines. Most GICs coexpressed nestin, NG2 proteoglycan, platelet-derived growth factor receptor-α, and glial fibrillary acidic protein. Glioma-initiating cells could be partially differentiated into astrocytic but not oligodendroglial or neural lineages. We also demonstrate that GICs have a characteristic electrophysiologic profile distinct from that of well-characterized tumor bulk cells. Together, our results suggest that GICs represent a unique type of cells reminiscent of an immature phenotype that closely resembles but is not identical to NG2 glia with respect to marker expression and functional membrane properties. PMID:23481707

  18. A skeletal disorder in a dog resembling the Klippel-Feil Syndrome with Sprengel's Deformity in humans.

    PubMed

    Bertolini, G; Trotta, M; Caldin, M

    2015-03-01

    A five-year-old intact male golden retriever dog was evaluated for cervical pain and right hemiparesis. Clinical and computed tomography features suggested a caudal cervical instability and myelopathy due to a cervicoscapular malformation resembling the human Klippel-Feil Syndrome with Sprengel Deformity, a rare complex congenital disorder. Polymerase chain reaction (PCR) and direct sequencing of MEOX1, PAX1 and FGFR3 genes were performed in this dog to investigate a possible underlying genetic predisposition, but no mutations were detected in the coding regions of the three target genes evaluated. Other genes can be involved in this condition in dogs and require further investigation. This report describes a cervical vertebral fusion and complex scapular anomaly in a dog. The presence of an omovertebral bone should be considered in the setting of signs characteristic of myelopathy in dogs with or without obvious skeletal deformity.

  19. Nicotine Delivery to Rats via Lung Alveolar Region-Targeted Aerosol Technology Produces Blood Pharmacokinetics Resembling Human Smoking

    PubMed Central

    2013-01-01

    Introduction: Nicotine is a heavily used addictive drug acquired through smoking tobacco. Nicotine in cigarette smoke is deposited and absorbed in the lungs, which results in a rapidly peaked slowly declining arterial concentration. This pattern plays an important role in initiation of nicotine addiction. Methods: A method and device were developed for delivering nicotine to rodents with lung alveolar region-targeted aerosol technology. The dose of delivery can be controlled by the nicotine aerosol concentration and duration of exposure. Results: Our data showed that, in the breathing zone of the nose-only exposure chamber, the aerosol droplet size distribution was within the respirable diameter range. Rats were exposed to nicotine aerosol for 2min. The arterial blood nicotine concentration reached 43.2±15.7ng/ml (mean ± SD) within 1–4min and declined over the next 20min, closely resembling the magnitude and early pharmacokinetics of a human smoking a cigarette. The acute inhalation toxicity of nicotine: LC50 = 2.3mg/L was determined; it was affected by pH, suggesting that acidification decreases nicotine absorption and/or bioavailability. Conclusions: A noninvasive method and toolkit were developed for delivering nicotine to rodents that enable rapid delivery of a controllable amount of nicotine into the systemic circulation and brain-inducing dose-dependent pharmacological effects, even a lethal dose. Aerosol inhalation can produce nicotine kinetics in both arterial and venous blood resembling human smoking. This method can be applied to studies of the effects of chronic intermittent nicotine exposure, nicotine addiction, toxicology, tobacco-related diseases, teratogenicity, and for discovery of pharmacological therapeutics. PMID:23239844

  20. Anti-Lipid IgG Antibodies Are Produced via Germinal Centers in a Murine Model Resembling Human Lupus

    PubMed Central

    Wong-Baeza, Carlos; Reséndiz-Mora, Albany; Donis-Maturano, Luis; Wong-Baeza, Isabel; Zárate-Neira, Luz; Yam-Puc, Juan Carlos; Calderón-Amador, Juana; Medina, Yolanda; Wong, Carlos; Baeza, Isabel; Flores-Romo, Leopoldo

    2016-01-01

    Anti-lipid IgG antibodies are produced in some mycobacterial infections and in certain autoimmune diseases [such as anti-phospholipid syndrome, systemic lupus erythematosus (SLE)]. However, few studies have addressed the B cell responses underlying the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a murine model resembling human lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membranes of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which appear to be involved in the development of the mouse model of lupus. Of note, anti-NPA antibodies are also detected in patients with SLE and leprosy. We used this model of lupus to investigate in vivo the cellular mechanisms that lead to the production of anti-lipid, class-switched IgG antibodies. In this murine lupus model, we found plasma cells (Gr1−, CD19−, CD138+) producing NPA-specific IgGs in the draining lymph nodes, the spleen, and the bone marrow. We also found a significant number of germinal center B cells (IgD−, CD19+, PNA+) specific for NPA in the draining lymph nodes and the spleen, and we identified in situ the presence of NPA in these germinal centers. By contrast, very few NPA-specific, extrafollicular reaction B cells (B220+, Blimp1+) were found. Moreover, when assessing the anti-NPA IgG antibodies produced during the experimental protocol, we found that the affinity of these antibodies progressively increased over time. Altogether, our data indicate that, in this murine model resembling human lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers. PMID:27746783

  1. On the lack of evidence that non-human animals possess anything remotely resembling a 'theory of mind'.

    PubMed

    Penn, Derek C; Povinelli, Daniel J

    2007-04-29

    After decades of effort by some of our brightest human and non-human minds, there is still little consensus on whether or not non-human animals understand anything about the unobservable mental states of other animals or even what it would mean for a non-verbal animal to understand the concept of a 'mental state'. In the present paper, we confront four related and contentious questions head-on: (i) What exactly would it mean for a non-verbal organism to have an 'understanding' or a 'representation' of another animal's mental state? (ii) What should (and should not) count as compelling empirical evidence that a non-verbal cognitive agent has a system for understanding or forming representations about mental states in a functionally adaptive manner? (iii) Why have the kind of experimental protocols that are currently in vogue failed to produce compelling evidence that non-human animals possess anything even remotely resembling a theory of mind? (iv) What kind of experiments could, at least in principle, provide compelling evidence for such a system in a non-verbal organism?

  2. Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis.

    PubMed

    Matsuzaki, K

    2006-06-01

    Transforming growth factor-beta (TGF-beta) signaling occurring during human colorectal carcinogenesis involves a shift in TGF-beta function, reducing the cytokine's antiproliferative effect, while increasing actions that promote invasion and metastasis. TGF-beta signaling involves phosphorylation of Smad3 at serine residues 208 and 213 in the linker region and serine residues 423 and 425 in the C-terminal region. Exogenous TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), changing unphosphorylated Smad3 to its phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). Either pSmad3C or pSmad3L oligomerizes with Smad4, and translocates into nuclei. While the TbetaRI/pSmad3C pathway inhibits growth of normal epithelial cells in vivo, JNK/pSmad3L-mediated signaling promotes tumor cell invasion and extracellular matrix synthesis by activated mesenchymal cells. Furthermore, hepatocyte growth factor signaling interacts with TGF-beta to activate the JNK/pSmad3L pathway, accelerating nuclear transport of cytoplasmic pSmad3L. This reduces accessibility of unphosphorylated Smad3 to membrane-anchored TbetaRI, preventing Smad3C phosphorylation, pSmad3C-mediated transcription, and antiproliferative effects of TGF-beta on epithelial cells. As neoplasia progresses from normal colorectal epithelium through adenoma to invasive adenocarcinoma with distant metastasis, nuclear pSmad3L gradually increases while pSmad3C decreases. The shift from TbetaRI/pSmad3C-mediated to JNK/pSmad3L-mediated signaling is a major mechanism orchestrating a complex transition of TGF-beta signaling during sporadic human colorectal carcinogenesis. This review summarizes the recent understanding of Smad3 phosphoisoform-mediated signaling, particularly 'cross-talk' between Smad3 and JNK pathways that cooperatively promote oncogenic activities. Understanding of these actions should help to develop more effective

  3. Pneumonic Tularemia in Rabbits Resembles the Human Disease as Illustrated by Radiographic and Hematological Changes after Infection

    PubMed Central

    Reed, Douglas S.; Smith, Le'Kneitah; Dunsmore, Tammy; Trichel, Anita; Ortiz, Luis A.; Cole, Kelly Stefano; Barry, Eileen

    2011-01-01

    Background Pneumonic tularemia is caused by inhalation of the gram negative bacterium, Francisella tularensis. Because of concerns that tularemia could be used as a bioterrorism agent, vaccines and therapeutics are urgently needed. Animal models of pneumonic tularemia with a pathophysiology similar to the human disease are needed to evaluate the efficacy of these potential medical countermeasures. Principal Findings Rabbits exposed to aerosols containing Francisella tularensis strain SCHU S4 developed a rapidly progressive fatal pneumonic disease. Clinical signs became evident on the third day after exposure with development of a fever (>40.5°C) and a sharp decline in both food and water intake. Blood samples collected on day 4 found lymphopenia and a decrease in platelet counts coupled with elevations in erythrocyte sedimentation rate, alanine aminotransferase, cholesterol, granulocytes and monocytes. Radiographs demonstrated the development of pneumonia and abnormalities of intestinal gas consistent with ileus. On average, rabbits were moribund 5.1 days after exposure; no rabbits survived exposure at any dose (190–54,000 cfu). Gross evaluation of tissues taken at necropsy showed evidence of pathology in the lungs, spleen, liver, kidney and intestines. Bacterial counts confirmed bacterial dissemination from the lungs to the liver and spleen. Conclusions/Significance The pathophysiology of pneumonic tularemia in rabbits resembles what has been reported for humans. Rabbits therefore are a relevant model of the human disease caused by type A strains of F. tularensis. PMID:21931798

  4. Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof of principle study with colorectal cancer

    PubMed Central

    Tang, Jie; Li, Yaping; Lyon, Kenneth; Camps, Jordi; Dalton, Stephen; Ried, Thomas; Zhao, Shaying

    2014-01-01

    Herein we report a proof of principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver–passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human- and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, while PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A, and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals. PMID:23416983

  5. ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease

    PubMed Central

    Wu, Jer-Yuarn; Kao, Hsiao-Jung; Li, Sing-Chung; Stevens, Robert; Hillman, Steven; Millington, David; Chen, Yuan-Tsong

    2004-01-01

    Tandem mass spectrometry was applied to detect derangements in the pathways of amino acid and fatty acid metabolism in N-ethyl-N-nitrosourea–treated (ENU-treated) mice. We identified mice with marked elevation of blood branched-chain amino acids (BCAAs), ketoaciduria, and clinical features resembling human maple syrup urine disease (MSUD), a severe genetic metabolic disorder caused by the deficiency of branched-chain α-keto acid dehydrogenase (BCKD) complex. However, the BCKD genes and enzyme activity were normal. Sequencing of branched-chain aminotransferase genes (Bcat) showed no mutation in the cytoplasmic isoform (Bcat-1) but revealed a homozygous splice site mutation in the mitochondrial isoform (Bcat-2). The mutation caused a deletion of exon 2, a marked decrease in Bcat-2 mRNA, and a deficiency in both BCAT-2 protein and its enzyme activity. Affected mice responded to a BCAA-restricted diet with amelioration of the clinical symptoms and normalization of the amino acid pattern. We conclude that BCAT-2 deficiency in the mouse can cause a disease that mimics human MSUD. These mice provide an important animal model for study of BCAA metabolism and its toxicity. Metabolomics-guided screening, coupled with ENU mutagenesis, is a powerful approach in uncovering novel enzyme deficiencies and recognizing important pathways of genetic metabolic disorders. PMID:14755340

  6. Fetal Mesenchymal Stromal Cells Differentiating towards Chondrocytes Acquire a Gene Expression Profile Resembling Human Growth Plate Cartilage

    PubMed Central

    Leijten, Jeroen C. H.; Decker, Eva; Sticht, Carsten; van Houwelingen, Johannes C.; Goeman, Jelle J.; Kleijburg, Carin; Scherjon, Sicco A.; Gretz, Norbert; Wit, Jan Maarten; Rappold, Gudrun; Post, Janine N.; Karperien, Marcel

    2012-01-01

    We used human fetal bone marrow-derived mesenchymal stromal cells (hfMSCs) differentiating towards chondrocytes as an alternative model for the human growth plate (GP). Our aims were to study gene expression patterns associated with chondrogenic differentiation to assess whether chondrocytes derived from hfMSCs are a suitable model for studying the development and maturation of the GP. hfMSCs efficiently formed hyaline cartilage in a pellet culture in the presence of TGFβ3 and BMP6. Microarray and principal component analysis were applied to study gene expression profiles during chondrogenic differentiation. A set of 232 genes was found to correlate with in vitro cartilage formation. Several identified genes are known to be involved in cartilage formation and validate the robustness of the differentiating hfMSC model. KEGG pathway analysis using the 232 genes revealed 9 significant signaling pathways correlated with cartilage formation. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development. PMID:23144774

  7. PLTP secreted by HepG2 cells resembles the high-activity PLTP form in human plasma.

    PubMed

    Siggins, Sarah; Jauhiainen, Matti; Olkkonen, Vesa M; Tenhunen, Jukka; Ehnholm, Christian

    2003-09-01

    Plasma phospholipid transfer protein (PLTP) is an important regulator of plasma HDL levels and HDL particle distribution. PLTP is present in plasma in two forms, one with high and the other with low phospholipid transfer activity. We have used the human hepatoma cell line, HepG2, as a model to study PLTP secreted from hepatic cells. PLTP activity was secreted by the cells into serum-free culture medium as a function of time. However, modification of a previously established ELISA assay to include a denaturing sample pretreatment with the anionic detergent sodium dodecyl sulphate was required for the detection of the secreted PLTP protein. The HepG2 PLTP could be enriched by Heparin-Sepharose affinity chromatography and eluted in size-exclusion chromatography at a position corresponding to the size of 160 kDa. PLTP coeluted with apolipoprotein E (apoE) but not with apoB-100 or apoA-I. A portion of PLTP was retained by an anti-apoE immunoaffinity column together with apoE, suggesting an interaction between these two proteins. Furthermore, antibodies against apoE but not those against apoB-100 or apoA-I were capable of inhibiting PLTP activity. These results show that the HepG2-derived PLTP resembles in several aspects the high-activity form of PLTP found in human plasma.

  8. Epidemiological and virological differences in human clustered and sporadic infections with avian influenza A H7N9.

    PubMed

    Wu, Zuqun; Sha, Jianping; Yu, Zhao; Zhao, Na; Cheng, Wei; Chan, Ta-Chien; Amer, Said; Zhang, Zhiruo; Liu, Shelan

    2016-08-01

    Previous research has suggested that avian influenza A H7N9 has a greater potential pandemic risk than influenza A H5N1. This research investigated the difference in human clustered and sporadic cases of H7N9 virus and estimated the relative risk of clustered infections. Comparative epidemiology and virology studies were performed among 72 sporadic confirmed cases, 17 family clusters (FCs) caused by human-to-human transmission, and eight live bird market clusters (LCs) caused by co-exposure to the poultry environment. The case fatality of FCs, LCs and sporadic cases (36%, 26%, and 29%, respectively) did not differ among the three groups (p>0.05). The average age (36 years, 60 years, and 58 years), co-morbidities (31%, 60%, and 54%), exposure to birds (72%, 100%, and 83%), and H7N9-positive rate (20%, 64%, and 35%) in FCs, LCs, and sporadic cases, respectively, differed significantly (p<0.05). These higher risks were associated with increased mortality. There was no difference between primary and secondary cases in LCs (p>0.05). However, exposure to a person with confirmed avian influenza A H7N9 (primary 12% vs. secondary 95%), history of visiting a live bird market (100% vs. 59%), multiple exposures (live bird exposure and human-to-human transmission history) (12% vs. 55%), and median days from onset to antiviral treatment (6 days vs. 3 days) differed significantly between primary and secondary cases in FCs (p<0.05). Mild cases were found in 6% of primary cases vs. 32% of secondary cases in FCs (p<0.05). Twenty-five isolates from the three groups showed 99.1-99.9% homology and increased human adaptation. There was no statistical difference in the case fatality rate and limited transmission between FCs and LCs. However, the severity of the primary cases in FCs was much higher than that of the secondary cases due to the older age and greater underlying disease of the latter patients. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Molecular organization of the non-bilayer phospholipid arrangements that induce an autoimmune disease resembling human lupus in mice.

    PubMed

    Wong-Baeza, Carlos; Hernández-Pando, Rogelio; Reséndiz, Albany; Tescucano, Alonso; Bustos, Israel; Ibáñez, Miguel; Wong, Carlos; Baeza, Isabel

    2012-03-01

    Non-bilayer phospholipid arrangements are three-dimensional structures that can form when anionic phospholipids with an intermediate form of the tubular hexagonal phase II (H(II)), such as phosphatidic acid, phosphatidylserine or cardiolipin, are present in a bilayer of lipids. The drugs chlorpromazine and procainamide, which trigger a lupus-like disease in humans, can induce the formation of non-bilayer phospholipid arrangements, and we have previously shown that liposomes with non-bilayer arrangements induced by these drugs cause an autoimmune disease resembling human lupus in mice. Here we show that liposomes with non-bilayer phospholipid arrangements induced by Mn²⁺ cause a similar disease in mice. We extensively characterize the physical properties and immunological reactivity of liposomes made of the zwitterionic lipid phosphatidylcholine and a H(II)-preferring lipid, in the absence or presence of Mn²⁺, chlorpromazine or procainamide. We use an hapten inhibition assay to define the epitope recognized by sera of mice with the disease, and by a monoclonal antibody that binds specifically to non-bilayer phospholipid arrangements, and we report that phosphorylcholine and glycerolphosphorylcholine, which form part of the polar region of phosphatidylcholine, are the only haptens that block the binding of the tested antibodies to non-bilayer arrangements. We propose a model in which the negatively charged H(II)-preferring lipids form an inverted micelle by electrostatic interactions with the positive charge of Mn²⁺, chlorpromazine or procainamide; the inverted micelle is inserted into the bilayer of phosphatidylcholine, whose polar regions are exposed and become targets for antibody production. This model may be relevant in the pathogenesis of human lupus.

  10. Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes

    PubMed Central

    Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M. Shawkat; Nabeshima, Yo-ichi

    2014-01-01

    Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho-/- (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl-/- mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl-/- mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis. PMID:25080854

  11. Primary Follicular Dystrophy with Scarring Dermatitis in C57BL/6 Mouse Substrains Resembles Central Centrifugal Cicatricial Alopecia in Humans

    PubMed Central

    Sundberg, John P.; Taylor, Douglas; Lorch, Gwendolen; Miller, Jim; Silva, Kathleen A.; Sundberg, Beth A.; Roopenian, Derry; Sperling, Leonard; Ong, David; King, Lloyd E.; Everts, Helen

    2011-01-01

    A number of C57BL/6 (B6) substrains are commonly used by scientists for basic biomedical research. One of several B6 strain specific background diseases is focal alopecia that may resolve or progress to severe, ulcerative dermatitis. Clinical and progressive histologic changes of skin disease commonly observed in C57BL/6J and preliminary studies in other closely related substrains are presented. Lesions develop due to a primary follicular dystrophy with rupture of severely affected follicles leading to formation of secondary foreign body granulomas (trichogranulomas) in affected B6 substrains of mice. Histologically these changes resemble the human disease called central centrifugal cicatrical alopecia (CCCA). Four B6 substrains tested have a polymorphism in alcohol dehydrogenase 4 (Adh4) that reduces its activity and potentially affects removal of excess retinol. Using immunohistochemistry, differential expression of epithelial retinol dehydrogenase (DHRS9) was detected which may partially explain anecdotal reports of frequency differences between B6 substrains. The combination of these two defects have the potential to make high dietary vitamin A levels toxic in some B6 substrains while not affecting most other commonly used inbred strains. PMID:20861494

  12. Does Facial Resemblance Enhance Cooperation?

    PubMed Central

    Giang, Trang; Bell, Raoul; Buchner, Axel

    2012-01-01

    Facial self-resemblance has been proposed to serve as a kinship cue that facilitates cooperation between kin. In the present study, facial resemblance was manipulated by morphing stimulus faces with the participants' own faces or control faces (resulting in self-resemblant or other-resemblant composite faces). A norming study showed that the perceived degree of kinship was higher for the participants and the self-resemblant composite faces than for actual first-degree relatives. Effects of facial self-resemblance on trust and cooperation were tested in a paradigm that has proven to be sensitive to facial trustworthiness, facial likability, and facial expression. First, participants played a cooperation game in which the composite faces were shown. Then, likability ratings were assessed. In a source memory test, participants were required to identify old and new faces, and were asked to remember whether the faces belonged to cooperators or cheaters in the cooperation game. Old-new recognition was enhanced for self-resemblant faces in comparison to other-resemblant faces. However, facial self-resemblance had no effects on the degree of cooperation in the cooperation game, on the emotional evaluation of the faces as reflected in the likability judgments, and on the expectation that a face belonged to a cooperator rather than to a cheater. Therefore, the present results are clearly inconsistent with the assumption of an evolved kin recognition module built into the human face recognition system. PMID:23094095

  13. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.

    PubMed

    Undén, A B; Zaphiropoulos, P G; Bruce, K; Toftgård, R; Ståhle-Bäckdahl, M

    1997-06-15

    Recently, a human homologue of the Drosophila patched gene, PTCH, was identified as a putative tumor suppressor mutated in both hereditary and sporadic basal cell carcinomas. Because PTCH controls its own transcription, inactivating mutations in PTCH may lead to overexpression of mutant PTCH mRNA due to loss of autoregulation. The present study is aimed at evaluating whether deregulation of PTCH mRNA expression is a general feature of BCCs of varying histological growth pattern and malignant potential. Irrespective of histological subtype, PTCH mRNA was overexpressed consistently as determined by in situ hybridization in all of the sporadic (n = 16) and hereditary (n = 20) tumors examined. PTCH expression was found in all of the tumor cells but appeared stronger in the peripheral palisading cells. PTCH mRNA was not detected in adjacent nontumor epidermal cells or in other parts of the epidermis. In the majority of tumors (20 of 36), nuclear immunostaining for p53 was found in scattered cells, whereas seven tumors completely lacked p53 immunoreactivity. Our finding of an up-regulation of PTCH mRNA levels in all of the BCCs analyzed indicates that deregulation of the PTCH signaling pathway constitutes an early rate-limiting event in BCC development.

  14. Giardiasis in NSW: Identification of Giardia duodenalis assemblages contributing to human and cattle cases, and an epidemiological assessment of sporadic human giardiasis.

    PubMed

    Asher, A J; Hose, G; Power, M L

    2016-10-01

    Two genetic assemblages (A and B) of the protozoan parasite species, Giardia duodenalis, infect humans, domestic animals and wildlife. In New South Wales, Australia, over 2000 sporadic human giardiasis cases are reported annually, but parasite sources and links between sporadic cases are unknown. This study describes G. duodenalis assemblages contributing to human and cattle cases in NSW, and examines demographic, spatial, and temporal distributions of NSW human infections and G. duodenalis assemblages. Genotyping by PCR-restriction fragment length polymorphism of the glutamate dehydrogenase (gdh) gene identified G. duodenalis assemblage B as the most common (86%) cause of infection among human cases (n=165). Approximately 37% of cattle DNA samples were PCR positive (18S rRNA, gdh), and G. duodenalis assemblages E (69%) or B (31%) were identified from these samples. Human assemblage A was more common among older age groups, and seasonality in the geographic dispersal of human assemblage A was observed. The results of this study indicate G. duodenalis assemblage B is highly prevalent among humans in NSW, and the potential for cross-species transmission exists between humans and cattle in this region. Spatio-temporal and demographic distributions of human assemblage A and B are highlighted, and risk factors associated with these dispersal patterns warrants further research. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Population structure of Listeria monocytogenes serotype 4b isolates from sporadic human listeriosis cases in the United States from 2003 to 2008.

    PubMed

    Lee, Sangmi; Ward, Todd J; Graves, Lewis M; Tarr, Cheryl L; Siletzky, Robin M; Kathariou, Sophia

    2014-06-01

    Listeria monocytogenes can cause severe food-borne disease (listeriosis). Numerous outbreaks have involved three serotype 4b epidemic clones (ECs): ECI, ECII, and ECIa. However, little is known about the population structure of L. monocytogenes serotype 4b from sporadic listeriosis in the United States, even though most cases of human listeriosis are in fact sporadic. Here we analyzed 136 serotype 4b isolates from sporadic cases in the United States, 2003 to 2008, utilizing multiple tools including multilocus genotyping, pulsed-field gel electrophoresis, and sequence analysis of the inlAB locus. ECI, ECII, and ECIa were frequently encountered (32, 17, and 7%, respectively). However, annually 30 to 68% of isolates were outside these ECs, and several novel clonal groups were identified. An estimated 33 and 17% of the isolates, mostly among the ECs, were resistant to cadmium and arsenic, respectively, but resistance to benzalkonium chloride was uncommon (3%) among the sporadic isolates. The frequency of clonal groups fluctuated within the 6-year study period, without consistent trends. However, on several occasions, temporal clusters of isolates with indistinguishable genotypes were detected, suggesting the possibility of hidden multistate outbreaks. Our analysis suggests a complex population structure of serotype 4b L. monocytogenes from sporadic disease, with important contributions by ECs and several novel clonal groups. Continuous monitoring will be needed to assess long-term trends in clonality patterns and population structure of L. monocytogenes from sporadic listeriosis.

  16. Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration

    PubMed Central

    Alves, Chrystian J.; Dariolli, Rafael; Jorge, Frederico M.; Monteiro, Matheus R.; Maximino, Jessica R.; Martins, Roberto S.; Strauss, Bryan E.; Krieger, José E.; Callegaro, Dagoberto; Chadi, Gerson

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that leads to widespread motor neuron death, general palsy and respiratory failure. The most prevalent sporadic ALS form is not genetically inherited. Attempts to translate therapeutic strategies have failed because the described mechanisms of disease are based on animal models carrying specific gene mutations and thus do not address sporadic ALS. In order to achieve a better approach to study the human disease, human induced pluripotent stem cell (hiPSC)-differentiated motor neurons were obtained from motor nerve fibroblasts of sporadic ALS and non-ALS subjects using the STEMCCA Cre-Excisable Constitutive Polycistronic Lentivirus system and submitted to microarray analyses using a whole human genome platform. DAVID analyses of differentially expressed genes identified molecular function and biological process-related genes through Gene Ontology. REVIGO highlighted the related functions mRNA and DNA binding, GTP binding, transcription (co)-repressor activity, lipoprotein receptor binding, synapse organization, intracellular transport, mitotic cell cycle and cell death. KEGG showed pathways associated with Parkinson's disease and oxidative phosphorylation, highlighting iron homeostasis, neurotrophic functions, endosomal trafficking and ERK signaling. The analysis of most dysregulated genes and those representative of the majority of categorized genes indicates a strong association between mitochondrial function and cellular processes possibly related to motor neuron degeneration. In conclusion, iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadic ALS. Large gene profiling of differentiated motor neurons from sporadic ALS patients highlights mitochondrial participation in the establishment of autonomous mechanisms associated with sporadic ALS

  17. Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration.

    PubMed

    Alves, Chrystian J; Dariolli, Rafael; Jorge, Frederico M; Monteiro, Matheus R; Maximino, Jessica R; Martins, Roberto S; Strauss, Bryan E; Krieger, José E; Callegaro, Dagoberto; Chadi, Gerson

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that leads to widespread motor neuron death, general palsy and respiratory failure. The most prevalent sporadic ALS form is not genetically inherited. Attempts to translate therapeutic strategies have failed because the described mechanisms of disease are based on animal models carrying specific gene mutations and thus do not address sporadic ALS. In order to achieve a better approach to study the human disease, human induced pluripotent stem cell (hiPSC)-differentiated motor neurons were obtained from motor nerve fibroblasts of sporadic ALS and non-ALS subjects using the STEMCCA Cre-Excisable Constitutive Polycistronic Lentivirus system and submitted to microarray analyses using a whole human genome platform. DAVID analyses of differentially expressed genes identified molecular function and biological process-related genes through Gene Ontology. REVIGO highlighted the related functions mRNA and DNA binding, GTP binding, transcription (co)-repressor activity, lipoprotein receptor binding, synapse organization, intracellular transport, mitotic cell cycle and cell death. KEGG showed pathways associated with Parkinson's disease and oxidative phosphorylation, highlighting iron homeostasis, neurotrophic functions, endosomal trafficking and ERK signaling. The analysis of most dysregulated genes and those representative of the majority of categorized genes indicates a strong association between mitochondrial function and cellular processes possibly related to motor neuron degeneration. In conclusion, iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadic ALS. Large gene profiling of differentiated motor neurons from sporadic ALS patients highlights mitochondrial participation in the establishment of autonomous mechanisms associated with sporadic ALS.

  18. Regulation of human cerebrospinal fluid malate dehydrogenase 1 in sporadic Creutzfeldt-Jakob disease patients

    PubMed Central

    Schmitz, Matthias; Llorens, Franc; Pracht, Alexander; Thom, Tobias; Correia, Ângela; Zafar, Saima; Ferrer, Isidre; Zerr, Inga

    2016-01-01

    The identification of reliable diagnostic biomarkers in differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous two-dimensional proteomic study on cerebrospinal fluid (CSF) revealed an elevated level of an enzyme, mitochondrial malate dehydrogenase 1 (MDH1), in sporadic Creutzfeldt-Jakob disease (sCJD) patients. Here, we could demonstrate the expression of MDH1 in neurons as well as in the neuropil. Its levels are lower in sCJD brains than in control brains. An examination of CSF-MDH1 in sCJD patients by ELISA revealed a significant elevation of CSF-MDH1 levels in sCJD patients (independently from the PRNP codon 129 MV genotype or the prion protein scrapie (PrPSc) type) in comparison to controls. In combination with total tau (tau), CSF-MDH1 detection exhibited a high diagnostic accuracy for sCJD diagnosis with a sensitivity of 97.5% and a specificity of 95.6%. A correlation study of MDH1 level in CSF with other neurodegenerative marker proteins revealed a significant positive correlation between MDH1 concentration with tau, 14-3-3 and neuron specific enolase level. In conclusion, our study indicated the potential of MDH1 in combination with tau as an additional biomarker in sCJD improving diagnostic accuracy of tau markedly. PMID:27852982

  19. Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters.

    PubMed

    Ponomarenko, Petr; Chadaeva, Irina; Rasskazov, Dmitry A; Sharypova, Ekaterina; Kashina, Elena V; Drachkova, Irina; Zhechev, Dmitry; Ponomarenko, Mikhail P; Savinkova, Ludmila K; Kolchanov, Nikolay

    2017-01-01

    While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimer's disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: "What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?" Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: "What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?" As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may become

  20. Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

    PubMed Central

    Ponomarenko, Petr; Chadaeva, Irina; Rasskazov, Dmitry A.; Sharypova, Ekaterina; Kashina, Elena V.; Drachkova, Irina; Zhechev, Dmitry; Ponomarenko, Mikhail P.; Savinkova, Ludmila K.; Kolchanov, Nikolay

    2017-01-01

    While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimer's disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: “What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?” Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: “What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?” As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may

  1. Frequency and spectrum of c-Ki-ras mutations in human sporadic colon carcinoma, carcinomas arising in ulcerative colitis, and pancreatic adenocarcinoma

    SciTech Connect

    Burmer, G.C.; Rabinovitch, P.S.; Loeb, L.A. )

    1991-06-01

    Sporadic colon carcinomas, carcinomas arising in chronic ulcerative colitis, and pancreatic adenocarcinomas have been analyzed for the presence of c-Ki-ras mutations by a combination of histological enrichment, cell sorting, polymerase chain reaction, and direct sequencing. Although 60% (37/61) of sporadic colon carcinomas contained mutations in codon 12, only 1 of 17 specimens of dysplasia or carcinoma from ulcerative colitis patients contained c-Ki-ras mutations, despite a high frequency of aneuploid tumors. In contrast, a higher percentage (16/20 = 80%) of pancreatic adenocarcinomas contained mutations in c-Ki-ras 2, despite a lower frequency of DNA aneuploidy in these neoplasms. Moreover, the spectrum of mutations differed between sporadic colon carcinoma, where the predominant mutation was a G to A transition, and pancreatic carcinomas, which predominantly contained G to C or T transversions. These results suggest that the etiology of ras mutations is different in these three human neoplasms.

  2. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease

    PubMed Central

    Sánchez-Danés, Adriana; Richaud-Patin, Yvonne; Carballo-Carbajal, Iria; Jiménez-Delgado, Senda; Caig, Carles; Mora, Sergio; Di Guglielmo, Claudia; Ezquerra, Mario; Patel, Bindiben; Giralt, Albert; Canals, Josep M; Memo, Maurizio; Alberch, Jordi; López-Barneo, José; Vila, Miquel; Cuervo, Ana Maria; Tolosa, Eduard; Consiglio, Antonella; Raya, Angel

    2012-01-01

    Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type. PMID:22407749

  3. Species composition of phlebotomine sand fly fauna in an area with sporadic cases of Leishmania infantum human visceral leishmaniasis, Morocco.

    PubMed

    Kahime, Kholoud; Boussaa, Samia; Ouanaimi, Fouad; Boumezzough, Ali

    2015-08-01

    Visceral and cutaneous leishmaniases are the main endemic vector-born diseases in Morocco. Human visceral leishmaniasis (HVL), by Leishmania infantum, currently presents a significant health problem throughout the country and may constitute factor for death, especially among children with less than 15 years old. In the past, HVL has been basically absent or at least sporadic in Marrakesh-Tensift-Al Haouz region; however it became significant during the last decade. An entomological survey and a retrospective study on L. infantum HVL cases had been carried out to assess the risk of the disease apparition in this region. 7046 sand flies (Diptera: Psychodidae) were collected and studied from twelve localities within Marrakesh-Tensift-Al Haouz region. The result shows the presence of ten sand fly species, 58.76% from the genus Phlebotomus and 41.24% from genus Sergentomyia. A further analysis indicates that Phlebotomus perniciosus, Phlebotomus longicuspis and Phlebotomus ariasi species, incriminated vectors of L. infantum, are dominant (35.56%), so, we describe their spatial (according to altitude and biotopes) and temporal (seasonal activity) distribution in study area. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer's Disease (AD)-Novel and Unique Pathological Features.

    PubMed

    Zhao, Yuhai; Pogue, Aileen I; Lukiw, Walter J

    2015-12-17

    Of the approximately ~2.65 × 10³ mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset-about 35-40-are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA-mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer's disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS.

  5. Hemangiomatosis associated with osteolysis of the mandible in a dog resembling Gorham-Stout disease in humans.

    PubMed

    López Peña, M; Muñoz, F; Alemañ, N; González, A; Pereira, J L; Nieto, J M

    2005-07-01

    A 6-month-old female German Shepherd Dog died as a result of profuse oral bleeding. At postmortem examination, the oral cavity showed visible roots of the right mandibular fourth premolar and first molar teeth and, in addition, they were very mobile and compressible. Radiographs showed a generalized radiolucency in the body of the right mandible, with evidence of resorption of the affected alveolar bone. Histologically, the lesion of the right mandible was characterized by the lysis of bony structures and a non-malignant proliferation of blood-filled vascular spaces lined by a single layer of well-differentiated endothelial cells. The clinical, radiographic, and histologic presentation of this dog is consistent with that associated with Gorham-Stout disease, a rare bone disorder in humans.

  6. Genetic determinants for cadmium and arsenic resistance among Listeria monocytogenes serotype 4b isolates from sporadic human listeriosis patients

    USDA-ARS?s Scientific Manuscript database

    In Listeria monocytogenes serotype 4b from sporadic listeriosis, heavy metal resistance was primarily encountered in certain clonal groups (ECI, ECII, ECIa). All arsenic-resistant isolates harbored the arsenic resistance cassette previously identified in pLI100; ECIa harbored additional arsenic resi...

  7. Population Structure of Listeria monocytogenes Serotype 4b Isolates from Sporadic Human Listeriosis in the United States, 2003-2008

    USDA-ARS?s Scientific Manuscript database

    Listeria monocytogenes can cause severe foodborne disease (listeriosis). Serotype 4b strains have resulted in numerous outbreaks, repeatedly involving three epidemic clones (ECI, ECII, and ECIa). Little is known about population structure of L. monocytogenes serotype 4b from sporadic listeriosis, ev...

  8. Characterization of naturally occurring cutaneous neurofibromatosis in Holstein cattle. A disorder resembling neurofibromatosis type 1 in humans.

    PubMed Central

    Sartin, E. A.; Doran, S. E.; Riddell, M. G.; Herrera, G. A.; Tennyson, G. S.; D'Andrea, G.; Whitley, R. D.; Collins, F. S.

    1994-01-01

    Neurofibromatosis in cattle is typically a noncutaneous disease. A small group of cows in a Holstein dairy herd developed cutaneous neurofibromatosis. This unique condition was investigated and compared with neurofibromatosis type 1 (NF1) in humans. All cutaneous lesions but one were consistent with neurofibromas in noncutaneous sites in cattle and neurofibromas in patients with NF1. One bovine lesion was classified as a neurofibrosarcoma. Immunohistochemistry and electron microscopy supported Schwannian differentiation in benign and malignant lesions. Linkage analysis with a polymorphism in the bovine NF1 gene confirmed that two affected animals from the same sire inherited the same paternal NF1 allele. Bovine cutaneous neurofibromatosis is a naturally occurring disease in this group of animals, characterized by skin tumors morphologically identical to those of NF1. An informative polymorphism at the NF1 locus of two animals and their sire suggests this disorder may be caused by hereditary mutations at the bovine NF1 locus. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:7977647

  9. Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells

    PubMed Central

    Malik, Minnie; Webb, Joy; Catherino, William H

    2008-01-01

    Background Uterine leiomyomas are clinically significant tumours that may develop due to an altered differentiation pathway. We have previously identified a dysregulated retinoic acid (RA) pathway that reduced retinoic exposure in human leiomyoma surgical specimens, and have shown that the leiomyoma phenotype was characterized by excessive and disorganized extracellular matrix (ECM). Objective The goal of this study was to determine the impact of RA exposure on the disrupted ECM phenotype of leiomyomas. Design and methods Study of immortalized and molecularly confirmed cells generated from surgical specimens of spontaneous uterine leiomyoma and matched myometrium. Results Immortalized leiomyoma and myometrial cells retained the molecular characteristics of their progenitor tissue. Proliferation of leiomyoma cells was inhibited by all-trans retinoic acid (ATRA). Furthermore, there was a dose-dependent decrease in soluble extracellular collagen protein in ATRA-treated leiomyoma cells. Exposure of leiomyoma cells to ATRA resulted in a dose-dependent inhibition of templates for specific ECM protein production including collagen 1, collagen 4, fibronectin and versican. Notably, expression levels in treated leiomyoma cells approached those found in myometrial cells. These mRNA alterations translated into altered protein. Down-regulation was also observed among the RA pathway genes such as CYP26A1 with exposure to ATRA. Finally, ATRA down-regulated TGF-β3 mRNA expression and the TGF-β regulated genes in leiomyoma cells. Conclusion Exposure of leiomyomas to ATRA down-regulated cell proliferation, ECM formation, RA metabolism and TGF-β regulation, suggesting that RA exposure can alter the leiomyoma phenotype to one that more closely approximates normal myometrium. PMID:18248652

  10. Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer.

    PubMed

    Tang, J; Li, Y; Lyon, K; Camps, J; Dalton, S; Ried, T; Zhao, S

    2014-02-13

    Herein we report a proof-of-principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver-passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species, and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, although PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.

  11. Molecular subtyping by genome and plasmid analysis of Campylobacter jejuni serogroups O1 and O2 (Penner) from sporadic and outbreak cases of human diarrhoea.

    PubMed Central

    Fayos, A.; Owen, R. J.; Hernandez, J.; Jones, C.; Lastovica, A.

    1993-01-01

    Ribosomal RNA gene patterns, randomly amplified polymorphic genomic DNA (RAPD) profiles and plasmid profiles were used to discriminate between 28 strains of Campylobacter jejuni serogroups O1 and O2 (Penner). Most isolates were biotype I (Lior). The strains were representative isolates from a UK school outbreak of enteritis (7 cases) and from 21 sporadic human cases of enteritis in 4 countries. The molecular techniques discriminated to various degrees between strains in each of the serogroups. The outbreak strains were homogeneous in most molecular features but a variety of types was detected amongst the isolates from the sporadic cases. Five groups of two or more strains with identical ribopatterns were identified and within each, strains from different patients were homogenous with respect to serogroup. RAPD profile typing based on numerical analysis generally matched ribotyping. Plasmid profiling overall gave least discrimination but was useful in separating some strains similar in other features. We concluded that optimal discrimination of C. jejuni could best be achieved using a combination of phenotypic and genotypic properties. Hae III ribotyping was the single most discriminatory and reproducible technique investigated. Several strains of C. jejuni from sporadic infections had similar molecular profiles which have potential for general typing purposes. Images Fig. 1 Fig. 3 PMID:7505748

  12. Early events in xenograft development from the human embryonic stem cell line HS181--resemblance with an initial multiple epiblast formation.

    PubMed

    Gertow, Karin; Cedervall, Jessica; Jamil, Seema; Ali, Rouknuddin; Imreh, Marta P; Gulyas, Miklos; Sandstedt, Bengt; Ahrlund-Richter, Lars

    2011-01-01

    Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at day 5, and characterized by the appearance of multiple sites of engraftment, with structures of single or pseudostratified columnar epithelium surrounding small cavities. The striking histological resemblance to developing embryonic ectoderm, and the formation of epiblast-like structures was supported by the expression of the markers OCT4, NANOG, SSEA-4 and KLF4, but a lack of REX1. The early neural marker NESTIN was uniformly expressed, while markers linked to gastrulation, such as BMP-4, NODAL or BRACHYURY were not detected. Thus, observations on day 5 indicated differentiation comparable to the most early transient cell populations in human post implantation development. Confirming and expanding on previous findings from HS181 xenografts, these early events were followed by an increasingly chaotic development, incorporated in the formation of a benign teratoma with complex embryonic components. In the mature HS181 teratomas not all types of organs/tissues were detected, indicating a restricted differentiation, and a lack of adequate spatial developmental cues during the further teratoma formation. Uniquely, a kinetic alignment of rare complex structures was made to human embryos at diagnosed gestation stages, showing minor kinetic deviations between HS181 teratoma and the human counterpart.

  13. Human XCR1+ Dendritic Cells Derived In Vitro from CD34+ Progenitors Closely Resemble Blood Dendritic Cells, Including Their Adjuvant Responsiveness, Contrary to Monocyte-Derived Dendritic Cells

    PubMed Central

    Balan, Sreekumar; Ollion, Vincent; Colletti, Nicholas; Chelbi, Rabie; Montanana-Sanchis, Frédéric; Liu, Hong; Vu Manh, Thien-Phong; Sanchez, Cindy; Savoret, Juliette; Perrot, Ivan; Doffin, Anne-Claire; Fossum, Even; Bechlian, Didier; Chabannon, Christian; Bogen, Bjarne; Asselin-Paturel, Carine; Shaw, Michael; Soos, Timothy; Caux, Christophe; Valladeau-Guilemond, Jenny

    2014-01-01

    Human monocyte-derived dendritic cell (MoDC) have been used in the clinic with moderately encouraging results. Mouse XCR1+ DC excel at cross-presentation, can be targeted in vivo to induce protective immunity, and share characteristics with XCR1+ human DC. Assessment of the immunoactivation potential of XCR1+ human DC is hindered by their paucity in vivo and by their lack of a well-defined in vitro counterpart. We report in this study a protocol generating both XCR1+ and XCR1− human DC in CD34+ progenitor cultures (CD34-DC). Gene expression profiling, phenotypic characterization, and functional studies demonstrated that XCR1− CD34-DC are similar to canonical MoDC, whereas XCR1+ CD34-DC resemble XCR1+ blood DC (bDC). XCR1+ DC were strongly activated by polyinosinic-polycytidylic acid but not LPS, and conversely for MoDC. XCR1+ DC and MoDC expressed strikingly different patterns of molecules involved in inflammation and in cross-talk with NK or T cells. XCR1+ CD34-DC but not MoDC efficiently cross-presented a cell-associated Ag upon stimulation by polyinosinic-polycytidylic acid or R848, likewise to what was reported for XCR1+ bDC. Hence, it is feasible to generate high numbers of bona fide XCR1+ human DC in vitro as a model to decipher the functions of XCR1+ bDC and as a potential source of XCR1+ DC for clinical use. PMID:25009205

  14. MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD)-Novel and Unique Pathological Features

    PubMed Central

    Zhao, Yuhai; Pogue, Aileen I.; Lukiw, Walter J.

    2015-01-01

    Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS. PMID:26694372

  15. Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus.

    PubMed

    Wong-Baeza, Carlos; Tescucano, Alonso; Astudillo, Horacio; Reséndiz, Albany; Landa, Carla; España, Luis; Serafín-López, Jeanet; Estrada-García, Iris; Estrada-Parra, Sergio; Flores-Romo, Leopoldo; Wong, Carlos; Baeza, Isabel

    2015-01-01

    Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.

  16. Evolution of alpha 2-macroglobulin. The demonstration in a variety of vertebrate species of a protein resembling human alpha 2-macroglobulin.

    PubMed Central

    Starkey, P M; Barrett, A J

    1982-01-01

    Plasma or serum samples from a large number of vertebrate species were screened for the presence of a papain-binding protein resembling human alph a 2-macroglobulin (alpha 2M). The screening method depended on the unique property of alpha 2M of binding proteinases in such a way that the enzyme retains partial activity against low-molecular-weight substrates. A papain-binding protein was detected in serum from members of all the major vertebrate taxa. In mammals, birds, reptiles and amphibians the protein had an Mr similar to that of human alpha 2M (725 000), but in fish, including dipnoans, actinopterygians, elasmobranchs and cyclostomes, the papain-binding protein was of Mr about 360 000. Of the invertebrate species tested, all of which were arthropods, two were negative, but the horseshoe crab, an arachnid, did possess a papain-binding protein, although this was heterogeneous in electrophoresis and differed from alpha 2M in resisting inactivation by methylamine. From the results, and a detailed study of the properties of the fish papain-binding protein described in an accompanying paper [Starkey, Fletcher & Barrett (1982) Biochem. J. 205, 97-104], it seems that alpha 2M first appeared in an ancestor of all modern vertebrates as a protein of Mr 360 000 and that the larger macroglobulin (Mr 725 000) first appeared in an ancestor of the tetrapods. Images Fig. 1. PMID:6181778

  17. Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus

    PubMed Central

    Wong-Baeza, Carlos; Tescucano, Alonso; Astudillo, Horacio; Reséndiz, Albany; Landa, Carla; España, Luis; Serafín-López, Jeanet; Estrada-García, Iris; Estrada-Parra, Sergio; Flores-Romo, Leopoldo; Wong, Carlos; Baeza, Isabel

    2015-01-01

    Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice. PMID:26568960

  18. Simultaneous effects on parvalbumin-positive interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia

    PubMed Central

    Hamburg, Hannah; Trossbach, Svenja V.; Bader, Verian; Chwiesko, Caroline; Kipar, Anja; Sauvage, Magdalena; Crum, William R.; Vernon, Anthony C.; Bidmon, Hans J.; Korth, Carsten

    2016-01-01

    To date, unequivocal neuroanatomical features have been demonstrated neither for sporadic nor for familial schizophrenia. Here, we investigated the neuroanatomical changes in a transgenic rat model for a subset of sporadic chronic mental illness (CMI), which modestly overexpresses human full-length, non-mutant Disrupted-in-Schizophrenia 1 (DISC1), and for which aberrant dopamine homeostasis consistent with some schizophrenia phenotypes has previously been reported. Neuroanatomical analysis revealed a reduced density of dopaminergic neurons in the substantia nigra and reduced dopaminergic fibres in the striatum. Parvalbumin-positive interneuron occurrence in the somatosensory cortex was shifted from layers II/III to V/VI, and the number of calbindin-positive interneurons was slightly decreased. Reduced corpus callosum thickness confirmed trend-level observations from in vivo MRI and voxel-wise tensor based morphometry. These neuroanatomical changes help explain functional phenotypes of this animal model, some of which resemble changes observed in human schizophrenia post mortem brain tissues. Our findings also demonstrate how a single molecular factor, DISC1 overexpression or misassembly, can account for a variety of seemingly unrelated morphological phenotypes and thus provides a possible unifying explanation for similar findings observed in sporadic schizophrenia patients. Our anatomical investigation of a defined model for sporadic mental illness enables a clearer definition of neuroanatomical changes associated with subsets of human sporadic schizophrenia. PMID:27721451

  19. Lower urogenital tract anatomical and functional phenotype in lysyl oxidase like-1 knockout mice resembles female pelvic floor dysfunction in humans.

    PubMed

    Lee, Una J; Gustilo-Ashby, A Marcus; Daneshgari, Firouz; Kuang, Mei; Vurbic, Drina; Lin, Dan Li; Flask, Chris A; Li, Tiansen; Damaser, Margot S

    2008-08-01

    Female pelvic floor dysfunction (FPFD) is a complex group of conditions that include urinary incontinence and pelvic organ prolapse (POP). In humans, elastin homeostasis has been implicated in the pathophysiology of FPFD. Lysyl oxidase-like 1 knockout (LOXL1-KO) mice demonstrate abnormal elastic fiber homeostasis and develop FPFD after parturition. We compared the lower urogenital tract (LUT) anatomy and function in LOXL1-KO mice with and without POP. LUT anatomy was assessed in LOXL1-KO mice over 28 wk. Pelvic visceral anatomy in LOXL1-KO was evaluated with a 7-Tesla magnetic resonance imaging (MRI) scanner. LUT function was assessed using conscious cystometry and leak point pressure (LPP) testing. Quantitative histological analysis of elastic fibers was performed on external urethral sphincter (EUS) cross sections. By 25 wk of age, 50% of parous LOXL1-KO mice developed POP. LOXL1-KO mice with POP had greater variability in the size and location of the bladder on MRI compared with mice without POP. Parity and POP were associated with lower LPP. Elastin clusters were significantly increased in the EUS of LOXL1-KO mice with POP. Because parity triggers POP in LOXL1-KO mice, LOXL1-KO mice with POP have variable internal pelvic anatomy, and both parity and POP are associated with a decrease in LPP, we conclude that LOXL1 LUT anatomical and functional phenotype resembles FPFD in humans. The increase in elastin clusters in the urethra of LOXL1-KO mice with POP suggests that elastin disorganization may lead to functional abnormalities. We conclude that LOXL1 warrants further investigation in the pathphysiology of FPFD.

  20. Human bronchial epithelial cells exposed in vitro to cigarette smoke at the air-liquid interface resemble bronchial epithelium from human smokers.

    PubMed

    Mathis, Carole; Poussin, Carine; Weisensee, Dirk; Gebel, Stephan; Hengstermann, Arnd; Sewer, Alain; Belcastro, Vincenzo; Xiang, Yang; Ansari, Sam; Wagner, Sandra; Hoeng, Julia; Peitsch, Manuel C

    2013-04-01

    Organotypic culture of human primary bronchial epithelial cells is a useful in vitro system to study normal biological processes and lung disease mechanisms, to develop new therapies, and to assess the biological perturbations induced by environmental pollutants. Herein, we investigate whether the perturbations induced by cigarette smoke (CS) and observed in the epithelium of smokers' airways are reproducible in this in vitro system (AIR-100 tissue), which has been shown to recapitulate most of the characteristics of the human bronchial epithelium. Human AIR-100 tissues were exposed to mainstream CS for 7, 14, 21, or 28 min at the air-liquid interface, and we investigated various biological endpoints [e.g., gene expression and microRNA profiles, matrix metalloproteinase 1 (MMP-1) release] at multiple postexposure time points (0.5, 2, 4, 24, 48 h). By performing a Gene Set Enrichment Analysis, we observed a significant enrichment of human smokers' bronchial epithelium gene signatures derived from different public transcriptomics datasets in CS-exposed AIR-100 tissue. Comparison of in vitro microRNA profiles with microRNA data from healthy smokers highlighted various highly translatable microRNAs associated with inflammation or with cell cycle processes that are known to be perturbed by CS in lung tissue. We also found a dose-dependent increase of MMP-1 release by AIR-100 tissue 48 h after CS exposure in agreement with the known effect of CS on this collagenase expression in smokers' tissues. In conclusion, a similar biological perturbation than the one observed in vivo in smokers' airway epithelium could be induced after a single CS exposure of a human organotypic bronchial epithelium-like tissue culture.

  1. Familial Resemblance for Loneliness

    PubMed Central

    Rebollo-Mesa, Irene; Abdellaoui, Abdel; Derom, Catherine A.; Willemsen, Gonneke; Cacioppo, John T.; Boomsma, Dorret I.

    2010-01-01

    Social isolation and loneliness in humans have been associated with physical and psychological morbidity, as well as mortality. This study aimed to assess the etiology of individual differences in feelings of loneliness. The genetic architecture of loneliness was explored in an extended twin-family design including 8,683 twins, siblings and parents from 3,911 families. In addition, 917 spouses of twins participated. The presence of assortative mating, genetic non-additivity, vertical cultural transmission, genotype–environment (GE) correlation and interaction was modeled. GE interaction was considered for several demographic characteristics. Results showed non-random mating for loneliness. We confirmed that loneliness is moderately heritable, with a significant contribution of non-additive genetic variation. There were no effects of vertical cultural transmission. With respect to demographic characteristics, results indicated that marriage, having offspring, more years of education, and a higher number of siblings are associated with lower levels of loneliness. Interestingly, these effects tended to be stronger for men than women. There was little evidence of changes in genetic architecture as a function of these characteristics. We conclude that the genetic architecture of loneliness points to non-additive genetic influences, suggesting it may be a trait that was not neutral to selection in our evolutionary past. Sociodemographic factors that influence the prevalence of loneliness do not affect its genetic architecture. PMID:20145989

  2. Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease

    PubMed Central

    Mattoso-Barbosa, Armanda Moreira; Perdigão-de-Oliveira, Marcelo; Costa, Ronaldo Peres; Elói-Santos, Silvana Maria; Gomes, Matheus de Souza; do Amaral, Laurence Rodrigues; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Dick, Edward J.; Hubbard, Gene B.; VandeBerg, Jane F.; VandeBerg, John L.

    2016-01-01

    Background Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations. Methods and Findings Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications. Conclusions Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease. PMID:26808481

  3. Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease.

    PubMed

    Sathler-Avelar, Renato; Vitelli-Avelar, Danielle Marquete; Mattoso-Barbosa, Armanda Moreira; Perdigão-de-Oliveira, Marcelo; Costa, Ronaldo Peres; Elói-Santos, Silvana Maria; Gomes, Matheus de Souza; Amaral, Laurence Rodrigues do; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Dick, Edward J; Hubbard, Gene B; VandeBerg, Jane F; VandeBerg, John L

    2016-01-01

    Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations. Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications. Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease.

  4. Sporadic meteoroid complex: Modeling

    NASA Astrophysics Data System (ADS)

    Andreev, V.

    2014-07-01

    The distribution of the sporadic meteoroids flux density over the celestial sphere is the common form of representation of the meteoroids distribution in the vicinity of the Earth's orbit. The determination of the flux density of sporadic meteor bodies is Q(V,e,f) = Q_0 P_e(V) P(e,f) where V is the meteoroid velocity, e,f are the radiant coordinates, Q_0 is the meteoroid flux over whole celestial sphere, P_e(V) is the conditional velocity distributions and P(e,f) is the radiant distribution over the celestial sphere. The sporadic meteoroid complex model is analytical and based on heliocentric velocities and radiant distributions. The multi-mode character of the heliocentric velocity and radiant distributions follows from the analysis of meteor observational data. This fact points to a complicated structure of the sporadic meteoroid complex. It is the consequence of the plurality of the parent bodies and the origin mechanisms of the meteoroids. The meteoroid complex was divided into four groups for that reason and with a goal of more accurate modelling of velocities and radiant distributions. As the classifying parameter to determine the meteoroid membership in any group, we adopt the Tisserand invariant relative to Jupiter T_J = 1/a + 2 A_J^{-3/2} √{a (1 - e^2)} cos i and the meteoroid orbit inclination i. Two meteoroid groups relate to long-period and short-period comets. One meteoroid group is related to asteroids. The relationship to the last, fourth group is a problematic one. Then, we construct models of radiant and velocity distributions for each group. The analytical model for the whole sporadic meteoroid complex is the sum of the ones for each group.

  5. Children's Explanations of Family Resemblances.

    ERIC Educational Resources Information Center

    Horobin, Karen D.

    Four studies investigated children's explanations for family resemblance and species-typical characteristics, under different conditions of biological parentage and rearing environment. Participating were 226 children between 3 and 11 years. Children Children were presented with a number of different tasks, some involving people and some domestic…

  6. Detection and characterization of Human caliciviruses associated with sporadic acute diarrhea in adults in Djibouti (horn of Africa).

    PubMed

    Maslin, Jérôme; Nicand, Elisabeth; Ambert-Balay, Katia; Fouet, Christine; Kaplon, Jérôme; Haus, Rachel; Pothier, Pierre; Kohli, Evelyne

    2008-03-01

    Recent advances in molecular diagnostics have allowed us to recognize Human caliciviruses (HuCVs) as important agents of acute diarrhea in industrialized countries. Their prevalence and genetic diversity in developing countries remains unknown. We report on the characterization of HuCVs among adults presenting acute diarrheas in Djibouti; 108 stool samples collected were screened by EIA, RTPCR, or cell cultures for the group A Rotaviruses, Adenoviruses, Astroviruses, and HuCVs, which were further characterized by genotyping. Among stool samples screened for HuCVs, 25.3% were positive. The other enteric viruses were less prevalent. The 11 HuCV strains sequenced revealed a large diversity (3 sapoviruses and 8 noroviruses). GII strains noroviruses were predominant, five were newly described genotypes, and two were recombinant with a pol gene related to GGIIb strains with the particularity to associate a unique pol gene to different capsid genes. These results could help to the knowledge of HuCV infections in Tropical Africa.

  7. Sporadic (nonepidemic) puerperal mastitis.

    PubMed

    Niebyl, J R; Spence, M R; Parmley, T H

    1978-02-01

    Sporadic puerperal mastitis is an acute cellulitis, characterized by fever and segmental erythema in the breast. Staphylococcus aureus can be cultured in approximately one-half of the cases. With early antibiotic therapy, the infection can be cleared and abscess formation prevented. Breast engorgement may also contribute to abscess formation, and so nursing should not be discontinued. No ill effects are observed in infants who continue to nurse. Twenty women with acute puerperal mastitis had breast milk cultures, and Staphylococcus aureus was recovered in seven cases. All patients were treated with antibiotics and continued nursing. No abscesses developed, and no ill effects were observed in any infants.

  8. A murine model of K-ras and β-catenin induced renal tumors express high levels of E2F1 and resemble human Wilms Tumor

    PubMed Central

    Yi, Yajun; Polosukhina, Dina; Love, Harold D.; Hembd, Austin; Pickup, Michael; Moses, Harold L.; Lovvorn, Harold N.; Zent, Roy; Clark, Peter E.

    2016-01-01

    Background Wilms tumor (WT) is the most common renal neoplasm of childhood. We previously showed that restricted activation of the WNT/β-catenin pathway in renal epithelium late in kidney development is sufficient to induce small primitive neoplasms with features of epithelial WT. Metastatic disease progression required simultaneous addition of an activating mutation of the oncogene K-RAS. Here, we sought to define the molecular pathways activated in this process and their relationship to human renal malignancies. Methods Affymetrix expression microarray data from murine kidneys with activation of K-ras, Ctnnb1 (β-catenin), or both restricted to renal epithelium were analyzed and compared to publically available expression data from normal and neoplastic human renal tissue. Target genes were verified by immunoblot and immunohistochemistry. Results Mouse kidney tumors with activation of K-ras and Ctnnb1 and human renal malignancies have similar mRNA expression signatures and are associated with activation of networks centered on β-catenin and TP53. Up-regulation of WNT/β-catenin targets (MYC, Survivin, FOXA2, Axin2, Cyclin D1) was confirmed by immunoblotting. K-RAS/β-catenin murine kidney tumors were more similar to human WT than other renal malignancies and demonstrated activation of a TP53 dependent network of genes including the transcription factor E2F1. Up-regulation of E2F1 was confirmed in both murine and human WT samples. Conclusions Simultaneous activation of K-RAS and β-catenin in embryonic renal epithelium leads to neoplasms similar to human WT associated with activation of TP53 and up-regulation of E2F1. Further studies to evaluate the role of TP53 and E2F1 in human WT are warranted. PMID:25934441

  9. Cancer stem cells from human glioblastoma resemble but do not mimic original tumors after in vitro passaging in serum-free media

    PubMed Central

    Esteban-Rubio, Susana; Rackov, Gorjana; Rodríguez-Fanjul, Vanessa; Cruz, Jorge Oliver-De La; Prat-Acín, Ricardo; Peris-Celda, María; Blesa, David; Ramírez-Jiménez, Laura; Sánchez-Gómez, Pilar; Perona, Rosario; Escobedo-Lucea, Carmen; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel

    2016-01-01

    Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas. PMID:27589567

  10. Expression of catalytically active Matrix Metalloproteinase-1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin

    PubMed Central

    Xia, Wei; Hammerberg, Craig; Li, Yong; He, Tianyuan; Quan, Taihao; Voorhees, John J; Fisher, Gary J

    2013-01-01

    Summary Increased expression of matrix metalloproteinase-1 (MMP-1) and reduced production of type I collagen by dermal fibroblasts are prominent features of aged human skin. We have proposed that MMP-1-mediated collagen fibril fragmentation is a key driver of age-related decline of skin function. To investigate this hypothesis, we constructed, characterized, and expressed constitutively active MMP-1 mutant (MMP-1 V94G) in adult human skin in organ culture and fibroblasts in three dimensional collagen lattice cultures. Expression of MMP-1 V94G in young skin in organ culture caused fragmentation and ultrastructural alterations of collagen fibrils similar to those observed in aged human skin in vivo. Expression of MMP-1 V94G in dermal fibroblasts cultured in three-dimensional collagen lattices caused substantial collagen fragmentation, which was markedly reduced by MMP-1 siRNA-mediated knockdown or MMP inhibitor MMI270. Importantly, fibroblasts cultured in MMP-1 V94G-fragmented collagen lattices displayed many alterations observed in fibroblasts in aged human skin, including reduced cytoplasmic area, disassembled actin cytoskeleton, impaired TGF-β pathway, and reduced collagen production. These results support the concept that MMP-1-mediated fragmentation of dermal collagen fibrils alters the morphology and function of dermal fibroblasts, and provide a foundation for understanding specific mechanisms that link collagen fibril fragmentation to age-related decline of fibroblast function. PMID:23601157

  11. Cancer stem cells from human glioblastoma resemble but do not mimic original tumors after in vitro passaging in serum-free media.

    PubMed

    García-Romero, Noemí; González-Tejedo, Carmen; Carrión-Navarro, Josefa; Esteban-Rubio, Susana; Rackov, Gorjana; Rodríguez-Fanjul, Vanessa; Oliver-De La Cruz, Jorge; Prat-Acín, Ricardo; Peris-Celda, María; Blesa, David; Ramírez-Jiménez, Laura; Sánchez-Gómez, Pilar; Perona, Rosario; Escobedo-Lucea, Carmen; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel

    2016-10-04

    Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.

  12. Novel feline autoimmune blistering disease resembling bullous pemphigoid in humans: IgG autoantibodies target the NC16A ectodomain of type XVII collagen (BP180/BPAG2).

    PubMed

    Olivry, T; Chan, L S; Xu, L; Chace, P; Dunston, S M; Fahey, M; Marinkovich, M P

    1999-07-01

    In humans and dogs, bullous pemphigoid (BP) is an autoimmune blistering disease associated with the production of basement membrane autoantibodies that target the 180-kd type XVII collagen (BP180, BPAG2) and/or the 230-kd plakin epidermal isoform BPAG1e (BP230). In two adult cats, an acquired dermatosis and stomatitis was diagnosed as BP subsequent to the fulfillment of the following criteria: 1) presence of cutaneous vesicles, erosions, and ulcers; 2) histologic demonstration of subepidermal vesiculation with inflammatory cells, including eosinophils; 3) in vivo deposition of IgG autoantibodies at the epidermal basement membrane zone; and 4) serum IgG autoantibodies targeting a 180-kd epidermal protein identified as type XVII collagen. In both cats, the antigenic epitopes targeted by IgG autoantibodies were shown to be situated in the NC16A ectodomain of type XVII collagen, a situation similar to that of humans and dogs with BP. Feline BP therefore can be considered a clinical, histopathologic, and immunologic homologue of BP in humans and dogs.

  13. Genetic instability in inherited and sporadic leukemias.

    PubMed

    Popp, Henning D; Bohlander, Stefan K

    2010-12-01

    Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies. © 2010 Wiley-Liss, Inc.

  14. Detection and genetic characterization of porcine group A rotaviruses in asymptomatic pigs in smallholder farms in East Africa: predominance of P[8] genotype resembling human strains.

    PubMed

    Amimo, J O; Junga, J O; Ogara, W O; Vlasova, A N; Njahira, M N; Maina, S; Okoth, E A; Bishop, R P; Saif, L J; Djikeng, A

    2015-02-25

    Viral enteritis is a serious problem accounting for deaths in neonatal animals and humans worldwide. The absence of surveillance programs and diagnostic laboratory facilities have resulted in a lack of data on rotavirus associated diarrheas in pigs in East Africa. Here we describe the incidence of group A rotavirus (RVA) infections in asymptomatic young pigs in East Africa. Of the 446 samples examined, 26.2% (117/446) were positive for RVA. More nursing piglets (78.7%) shed RVA than weaned (32.9%) and grower (5.8%) pigs. RVA incidence was higher in pigs that were either housed_free-range (77.8%) or tethered_free-range (29.0%) than those that were free-range or housed or housed-tethered pigs. The farms with larger herd size (>10 pigs) had higher RVA prevalence (56.5%) than farms with smaller herd size (24.1-29.7%). This study revealed that age, management system and pig density significantly (p<0.01) influenced the incidence of RVA infections, with housed_free-range management system and larger herd size showing higher risks for RVA infection. Partial (811-1604nt region) sequence of the VP4 gene of selected positive samples revealed that different genotypes (P[6], P[8] and P[13]) are circulating in the study area with P[8] being predominant. The P[6] strain shared nucleotide (nt) and amino acid (aa) sequence identity of 84.4-91.3% and 95.1-96.9%, respectively, with known porcine and human P[6] strains. The P[8] strains shared high nt and aa sequence identity with known human P[8] strains ranging from 95.6-100% to 92-100%, respectively. The P[13] strains shared nt and aa sequence identity of 83.6-91.7% and 89.3-96.4%, respectively, only with known porcine P[13] strains. No P[8] strains yielded RNA of sufficient quality/quantity for full genome sequencing. However analysis of the full genome constellation of the P[6], two P[13] and one untypeable strains revealed that the P[6] strain (Ke-003-5) genome constellation was G26-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H1, P[13

  15. A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1).

    PubMed

    Wiedmer, Michaela; Oevermann, Anna; Borer-Germann, Stephanie E; Gorgas, Daniela; Shelton, G Diane; Drögemüller, Michaela; Jagannathan, Vidhya; Henke, Diana; Leeb, Tosso

    2015-11-23

    We observed a hereditary phenotype in Alaskan Huskies that was characterized by polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV). The affected dogs developed a progressive severe ataxia, which led to euthanasia between 8 and 16 months of age. The pedigrees were consistent with a monogenic autosomal recessive inheritance. We localized the causative genetic defect to a 4 Mb interval on chromosome 19 by a combined linkage and homozygosity mapping approach. Whole genome sequencing of one affected dog, an obligate carrier, and an unrelated control revealed a 218-bp SINE insertion into exon 7 of the RAB3GAP1 gene. The SINE insertion was perfectly associated with the disease phenotype in a cohort of 43 Alaskan Huskies, and it was absent from 541 control dogs of diverse other breeds. The SINE insertion induced aberrant splicing and led to a transcript with a greatly altered exon 7. RAB3GAP1 loss-of-function variants in humans cause Warburg Micro Syndrome 1 (WARBM1), which is characterized by additional developmental defects compared to canine POANV, whereas Rab3gap1-deficient mice have a much milder phenotype than either humans or dogs. Thus, the RAB3GAP1 mutant Alaskan Huskies provide an interesting intermediate phenotype that may help to better understand the function of RAB3GAP1 in development. Furthermore, the identification of the presumed causative genetic variant will enable genetic testing to avoid the nonintentional breeding of affected dogs. Copyright © 2016 Wiedmer et al.

  16. Mouse model of human RPE65 P25L hypomorph resembles wild type under normal light rearing but is fully resistant to acute light damage.

    PubMed

    Li, Yan; Yu, Shirley; Duncan, Todd; Li, Yichao; Liu, Pinghu; Gene, Erelda; Cortes-Pena, Yoel; Qian, Haohua; Dong, Lijin; Redmond, T Michael

    2015-08-01

    Human RPE65 mutations cause a spectrum of blinding retinal dystrophies from severe early-onset disease to milder manifestations. The RPE65 P25L missense mutation, though having <10% of wild-type (WT) activity, causes relatively mild retinal degeneration. To better understand these mild forms of RPE65-related retinal degeneration, and their effect on cone photoreceptor survival, we generated an Rpe65/P25L knock-in (KI/KI) mouse model. We found that, when subject to the low-light regime (∼100 lux) of regular mouse housing, homozygous Rpe65/P25L KI/KI mice are morphologically and functionally very similar to WT siblings. While mutant protein expression is decreased by over 80%, KI/KI mice retinae retain comparable 11-cis-retinal levels with WT. Consistently, the scotopic and photopic electroretinographic (ERG) responses to single-flash stimuli also show no difference between KI/KI and WT mice. However, the recovery of a-wave response following moderate visual pigment bleach is delayed in KI/KI mice. Importantly, KI/KI mice show significantly increased resistance to high-intensity (20 000 lux for 30 min) light-induced retinal damage (LIRD) as compared with WT, indicating impaired rhodopsin regeneration in KI/KI. Taken together, the Rpe65/P25L mutant produces sufficient chromophore under normal conditions to keep opsins replete and thus manifests a minimal phenotype. Only when exposed to intensive light is this hypomorphic mutation manifested physiologically, as its reduced expression and catalytic activity protects against the successive cycles of opsin regeneration underlying LIRD. These data also help define minimal requirements of chromophore for photoreceptor survival in vivo and may be useful in assessing a beneficial therapeutic dose for RPE65 gene therapy in humans. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  17. Mouse model of human RPE65 P25L hypomorph resembles wild type under normal light rearing but is fully resistant to acute light damage

    PubMed Central

    Li, Yan; Yu, Shirley; Duncan, Todd; Li, Yichao; Liu, Pinghu; Gene, Erelda; Cortes-Pena, Yoel; Qian, Haohua; Dong, Lijin; Redmond, T. Michael

    2015-01-01

    Human RPE65 mutations cause a spectrum of blinding retinal dystrophies from severe early-onset disease to milder manifestations. The RPE65 P25L missense mutation, though having <10% of wild-type (WT) activity, causes relatively mild retinal degeneration. To better understand these mild forms of RPE65-related retinal degeneration, and their effect on cone photoreceptor survival, we generated an Rpe65/P25L knock-in (KI/KI) mouse model. We found that, when subject to the low-light regime (∼100 lux) of regular mouse housing, homozygous Rpe65/P25L KI/KI mice are morphologically and functionally very similar to WT siblings. While mutant protein expression is decreased by over 80%, KI/KI mice retinae retain comparable 11-cis-retinal levels with WT. Consistently, the scotopic and photopic electroretinographic (ERG) responses to single-flash stimuli also show no difference between KI/KI and WT mice. However, the recovery of a-wave response following moderate visual pigment bleach is delayed in KI/KI mice. Importantly, KI/KI mice show significantly increased resistance to high-intensity (20 000 lux for 30 min) light-induced retinal damage (LIRD) as compared with WT, indicating impaired rhodopsin regeneration in KI/KI. Taken together, the Rpe65/P25L mutant produces sufficient chromophore under normal conditions to keep opsins replete and thus manifests a minimal phenotype. Only when exposed to intensive light is this hypomorphic mutation manifested physiologically, as its reduced expression and catalytic activity protects against the successive cycles of opsin regeneration underlying LIRD. These data also help define minimal requirements of chromophore for photoreceptor survival in vivo and may be useful in assessing a beneficial therapeutic dose for RPE65 gene therapy in humans. PMID:25972377

  18. In Vitro Development and Characterization of a Tissue-Engineered Conduit Resembling Esophageal Wall Using Human and Pig Skeletal Myoblast, Oral Epithelial Cells, and Biologic Scaffolds

    PubMed Central

    Poghosyan, Tigran; Gaujoux, Sebastien; Vanneaux, Valerie; Bruneval, Patrick; Domet, Thomas; Lecourt, Severine; Jarraya, Mohamed; Sfeir, Rony; Larghero, Jerome

    2013-01-01

    Introduction Tissue engineering represents a promising approach for esophageal replacement, considering the complexity and drawbacks of conventional techniques. Aim To create the components necessary to reconstruct in vitro or in vivo an esophageal wall, we analyzed the feasibility and the optimal conditions of human and pig skeletal myoblast (HSM and PSM) and porcine oral epithelial cell (OEC) culture on biologic scaffolds. Materials and Methods PSM and HSM were isolated from striated muscle and porcine OECs were extracted from oral mucosa biopsies. Myoblasts were seeded on an acellular scaffold issue from porcine small intestinal submucosa (SIS) and OEC on decellularized human amniotic membrane (HAM). Seeding conditions (cell concentrations [0.5×106 versus 106 cells/cm2] and culture periods [7, 14 and 21 days]), were analyzed using the methyl thiazoltetrazolium assay, quantitative PCR, flow cytometry, and immunohistochemistry. Results Phenotypic stability was observed after cellular expansion for PSM and HSM (85% and 97% CD56-positive cells, respectively), and OECs (90% AE1/AE3- positive cells). After PSM and HSM seeding, quantities of viable cells were similar whatever the initial cell concentration used and remained stable at all time points. During cell culture on SIS, a decrease of CD56-positive cells was observed (76% and 76% by D7, 56% and 70% by D14, 28% and 60% by D21, for PSM and HSM, respectively). Multilayered surface of α-actin smooth muscle and Desmine-positive cells organized in bundles was seen as soon as D7, with no evidence of cell within the SIS. Myoblasts fusion was observed at D21. Pax3 and Pax7 expression was downregulated and MyoD expression upregulated, at D14.OEC proliferation was observed on HAM with both cell concentrations from D7 to D21. The cell metabolism activity was more important on matrix seeded by 106 cells/cm2. With 0.5×106 OEC/cm2, a single layer of pancytokeratin-positive cells was seen at D7, which became pluristratified

  19. Archaic artifacts resembling celestial spheres

    NASA Astrophysics Data System (ADS)

    Dimitrakoudis, S.; Papaspyrou, P.; Petoussis, V.; Moussas, X.

    We present several bronze artifacts from the Archaic Age in Greece (750-480 BC) that resemble celestial spheres or forms of other astronomical significance. They are studied in the context of the Dark Age transition from Mycenaean Age astronomical themes to the philosophical and practical revival of astronomy in the Classical Age with its plethora of astronomical devices. These artifacts, mostly votive in nature are spherical in shape and appear in a variety of forms their most striking characteristic being the depiction of meridians and/or an equator. Most of those artifacts come from Thessaly, and more specifically from the temple of Itonia Athena at Philia, a religious center of pan-Hellenic significance. Celestial spheres, similar in form to the small artifacts presented in this study, could be used to measure latitudes, or estimate the time at a known place, and were thus very useful in navigation.

  20. Animal Model of Gestational Diabetes Mellitus with Pathophysiological Resemblance to the Human Condition Induced by Multiple Factors (Nutritional, Pharmacological, and Stress) in Rats

    PubMed Central

    Abdul Aziz, Siti Hajar; Nordin, Massita; Ramasamy, Rajesh; Adam, Aishah

    2016-01-01

    This study attempts to develop an experimental gestational diabetes mellitus (GDM) animal model in female Sprague-Dawley rats. Rats were fed with high fat sucrose diet, impregnated, and induced with Streptozotocin and Nicotinamide on gestational day 0 (D0). Sleeping patterns of the rats were also manipulated to induce stress, a lifestyle factor that contributes to GDM. Rats were tested for glycemic parameters (glucose, C-peptide, and insulin), lipid profiles (total cholesterol, triglycerides, HDL, and LDL), genes affecting insulin signaling (IRS-2, AKT-1, and PCK-1), glucose transporters (GLUT-2 and GLUT-4), proinflammatory cytokines (IL-6, TNF-α), and antioxidants (SOD, CAT, and GPX) on D6 and D21. GDM rats showed possible insulin resistance as evidenced by high expression of proinflammatory cytokines, PCK-1 and CRP. Furthermore, low levels of IRS-2 and AKT-1 genes and downregulation of GLUT-4 from the initial to final phases indicate possible defect of insulin signaling. GDM rats also showed an impairment of antioxidant status and a hyperlipidemic state. Additionally, GDM rats exhibited significantly higher body weight and blood glucose and lower plasma insulin level and C-peptide than control. Based on the findings outlined, the current GDM animal model closely replicates the disease state in human and can serve as a reference for future investigations. PMID:27379252

  1. Genetics Home Reference: sporadic hemiplegic migraine

    MedlinePlus

    ... Home Health Conditions sporadic hemiplegic migraine sporadic hemiplegic migraine Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Sporadic hemiplegic migraine is a rare form of migraine headache. Migraines ...

  2. A majority of Ig H chain cDNA of normal human adult blood lymphocytes resembles cDNA for fetal Ig and natural autoantibodies

    SciTech Connect

    Huang, C.; Stollar, B.D. )

    1993-11-15

    Certain Ig V[sub H] gene segments, with few or no mutations, recur frequently in natural autoantibodies, fetal antibodies, and products of B cell tumors. The goal of this study was to determine whether similar Ig gene segment usage occurs in normal human adult PBL. Extending previous analyses, 105 randomly picked H chain V region clones of representative cDNA libraries from PBL were sequenced. Clones were from: IgM and IgG libraries from one RNA sample of a normal adult; a second IgM library from the same subject 11 mo later; and one IgM library from a second subject. Although some clones had clear evidence of mutation, 48 of 77 IgM clones (62%) shared 99% or more identity with known germline V[sub H] segments, and most of these had no mutations in the CDR3 portion of the J[sub H] segment. Certain V[sub H] gene segments, expressed in autoantibodies and fetal antibodies, occurred at high frequency in these libraries. Fourteen of the clones with 99% identity to known V[sub H] segments had CDR3 segments identical to portions of known germline D[sub H] gene sequences; two such clones had no N nucleotides at the V[sub H] D[sub H] or D[sub H]J[sub H] junctions. IgG-encoding sequences had more mutations than IgM-encoding sequences. J[sub H] and D[sub H] usage was not random. The circulating B cell population may represent a distinct compartment, with a large proportion of cells similar to those of the fetal and natural autoantibody repertoire. Polyreactive Ig products of these circulating cells may serve a screening function, binding and delivering diverse Ag to secondary lymphoid tissues where more highly selective antibodies are formed to foreign or Self-Ag. 40 refs., 2 figs., 6 tabs.

  3. Soluble human leukocyte antigen -G during pregnancy and infancy in Benin: Mother/child resemblance and association with the risk of malaria infection and low birth weight

    PubMed Central

    Milet, Jacqueline; Cottrell, Gilles; Mondière, Amandine; Avokpaho, Euripide; Gineau, Laure; Sabbagh, Audrey; Massougbodji, Achille; Moutairou, Kabirou; Donadi, Eduardo A.; Favier, Benoit; Carosella, Edgardo; Moreau, Philippe; Rouas-Freiss, Nathalie; Courtin, David; Garcia, André

    2017-01-01

    Human leukocyte antigen (HLA) G is a tolerogenic molecule involved in the maternal-fetal immune tolerance phenomenon. Its expression during some infectious diseases leading to immune evasion has been established. A first study conducted in Benin has shown that the production of soluble HLA-G (sHLA-G) during the first months of life is strongly correlated with the maternal level at delivery and associated with low birth weight and malaria. However sHLA-G measurements during pregnancy were not available for mothers and furthermore, to date the evolution of sHLA-G in pregnancy is not documented in African populations. To extend these previous findings, between January 2010 and June 2013, 400 pregnant women of a malaria preventive trial and their newborns were followed up in Benin until the age of 2 years. Soluble HLA-G was measured 3 times during pregnancy and repeatedly during the 2 years follow-up to explore how sHLA-G evolved and the factors associated. During pregnancy, plasma levels of sHLA-G remained stable and increased significantly at delivery (p<0.001). Multigravid women seemed to have the highest levels (p = 0.039). In infants, the level was highest in cord blood and decreased before stabilizing after 18 months (p<0.001). For children, a high level of sHLA-G was associated with malaria infection during the follow-up (p = 0.02) and low birth weight (p = 0.06). The mean level of sHLA-G during infancy was strongly correlated with the mother’s level during pregnancy (<0.001), and not only at delivery. Moreover, mothers with placental malaria infection had a higher probability of giving birth to a child with a high level of sHLA-g (p = 0.006). High sHLA-G levels during pregnancy might be associated with immune tolerance related to placental malaria. Further studies are needed but this study provides a first insight concerning the potential role of sHLA-G as a biomarker of weakness for newborns and infants. PMID:28166246

  4. Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice.

    PubMed

    Jaumain, Emilie; Quadrio, Isabelle; Herzog, Laetitia; Reine, Fabienne; Rezaei, Human; Andréoletti, Olivier; Laude, Hubert; Perret-Liaudet, Armand; Haïk, Stéphane; Béringue, Vincent

    2016-12-01

    Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP(C)) and the infecting pathological PrP assemblies (PrP(Sc)) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP(C) and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP(Sc) signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. Since the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  5. DNA Methylation Identifies Loci Distinguishing Hereditary Nonpolyposis Colorectal Cancer Without Germ-Line MLH1/MSH2 Mutation from Sporadic Colorectal Cancer

    PubMed Central

    Chen, Chung-Hsing; Sheng Jiang, Shih; Hsieh, Ling-Ling; Tang, Reiping; Hsiung, Chao A; Tsai, Hui-Ju; Chang, I-Shou

    2016-01-01

    Objectives: Roughly half of hereditary nonpolyposis colorectal cancer (HNPCC) cases are Lynch syndrome and exhibit germ-line mutations in DNA mismatch repair (MMR) genes; the other half are familial colorectal cancer (CRC) type X (FCCTX) and are MMR proficient. About 70% of Lynch syndrome tumors have germ-line MLH1 or MSH2 mutations. The clinical presentation, histopathological features, and carcinogenesis of FCCTX resemble those of sporadic MMR-proficient colorectal tumors. It is of interest to obtain biomarkers that distinguish FCCTX from sporadic microsatellite stable (MSS) CRC, to develop preventive strategies. Methods: The tumors and adjacent normal tissues of 40 patients with HNPCC were assayed using the Illumina Infinium HumanMethylation27 (HM27) BeadChip to assess the DNA methylation level at about 27,000 loci. The germ-line mutation status of MLH1 and MSH2 and the microsatellite instability status in these patients were obtained. Genome-wide DNA methylation measurements of three groups of patients with general CRC were downloaded from public domain databases. Probes with DNA methylation levels that differed significantly between patients with sporadic MSS CRC and FCCTX were examined, to explore their potential as biomarkers. Results: We found that MSS HNPCC tumors were overwhelmingly hypomethylated compared with those from patient groups with other types of CRC, including germ-line MLH1/MSH2-mutated HNPCC and sporadic MSS CRC. Five gene-marker panels that exhibited a sensitivity of 100% and a specificity higher than 90% in both discovery and validation cohorts were proposed to distinguish MSS HNPCC tumors from sporadic MSS CRC. Conclusions: Our results warrant further investigation and validation. The loci identified here may become useful biomarkers for distinguishing between FCCTX and sporadic MSS CRC tumors. PMID:27977020

  6. Paternal Age and Sporadic Schizophrenia

    PubMed Central

    Malaspina, Dolores; Corcoran, Cheryl; Fahim, Cherine; Berman, Ariela; Harkavy-Friedman, Jill; Yale, Scott; Goetz, Deborah; Goetz, Raymond; Harlap, Susan; Gorman, Jack

    2010-01-01

    Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father’s age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia. PMID:11920852

  7. SAND FLY SPECIES COMPOSITION (DIPTERA: PSYCHODIDAE: PHLEBOTOMINAE) IN THE MUNICIPALITY OF CANTAGALO , AN AREA WITH SPORADIC CASES OF HUMAN CUTANEOUS LEISHMANIASIS IN RIO DE JANEIRO STATE, BRAZIL

    PubMed Central

    PERES-DIAS, Quezia Nunes; OLIVEIRA, Claudete Diniz; de SOUZA, Marcos Barbosa; MEIRA, Antônio de Medeiros; VILLANOVA, Ciro Benigno

    2016-01-01

    SUMMARY The municipality of Cantagalo is an area with sustained transmission of American Cutaneous Leishmaniasis (ACL). Monthly sand fly collections were performed for three years (June 2012 - May 2015) using a CDC light trap. A total of 3,310 specimens belonging to 12 species were trapped: Nyssomyia intermedia, Nyssomyia whitmani, Migonemyia migonei, Evandromyia lenti, Evandromyia cortelezzii, Micropygomyia quinquefer, Brumptomyia brumpti, Psathyromyia aragaoi, Micropygomyia schreiberi, Pintomyia fischeri, Sciopemyia sordellii, and Evandromyia edwardsi. The last seven species have not been previously recorded in this area. The highest abundance of species occurred between October and March. October was the month with the highest number of captured sand flies, one month before the peak in the summer rainfall. In October the highest number of Ny. intermedia, Ny. whitmani and Mg. migonei, were also collected, the three epidemiologically most important species. The high abundance of species with epidemiological importance for ACL transmission might explain the sporadic occurrence of the disease in the area. PMID:27410910

  8. Midlatitude sporadic-E layers

    NASA Technical Reports Server (NTRS)

    Miller, K. L.; Smith, L. G.

    1976-01-01

    The partially transparent echo from midlatitude sporadic E layers was recorded by ionosondes between the blanketing frequency and the maximum frequency. The theory that the midlatitude sporadic E layers are not uniform in the horizontal plane but contain localized regions of high electron density was evaluated using data obtained by incoherent scatter radar and found to provide a satisfactory explanation. The main features of midlatitude sporadic E layers are consistent with the convergence of metallic ions as described by the wind shear theory applied to gravity waves and tides. The interference of gravity waves with other gravity waves and tides can be recognized in the altitudes of occurrence and the structure of the layers. Small scale horizontal irregularities are attributed in some cases to critical level effects and in others to fluid instabilities. The convergence of a meteor trail can, under some circumstances, account for localized enhancement of the electron density in the layer.

  9. The monster sporadic group and a theory underlying superstring models

    SciTech Connect

    Chapline, G.

    1996-09-01

    The pattern of duality symmetries acting on the states of compactified superstring models reinforces an earlier suggestion that the Monster sporadic group is a hidden symmetry for superstring models. This in turn points to a supersymmetric theory of self-dual and anti-self-dual K3 manifolds joined by Dirac strings and evolving in a 13 dimensional spacetime as the fundamental theory. In addition to the usual graviton and dilaton this theory contains matter-like degrees of freedom resembling the massless states of the heterotic string, thus providing a completely geometric interpretation for ordinary matter. 25 refs.

  10. Positive selection at codon 38 of the human KCNE1 (= minK) gene and sporadic absence of 38Ser-coding mRNAs in Gly38Ser heterozygotes

    PubMed Central

    Herlyn, Holger; Zechner, Ulrich; Oswald, Franz; Pfeufer, Arne; Zischler, Hans; Haaf, Thomas

    2009-01-01

    Background KCNE1 represents the regulatory beta-subunit of the slowly activating delayed rectifier potassium channel (IKs). Variants of KCNE1 have repeatedly been linked to the long-QT syndrome (LQTS), a disorder which predisposes to deafness, ventricular tachyarrhythmia, syncope, and sudden cardiac death. Results We here analyze the evolution of the common Gly38Ser variant (rs1805127), using genomic DNAs, complementary DNAs, and HEK293-expressed variants of altogether 19 mammalian species. The between species comparison reveals that the human-specific Gly38Ser polymorphism evolved under strong positive Darwinian selection, probably in adaptation to specific challenges in the fine-tuning of IKs channels. The involved amino acid exchanges (Asp > Gly, Gly > Ser) are moderately radical and do not induce apparent changes in posttranslational modification. According to population genetic analyses (HapMap phase II) a heterozygote advantage accounts for the maintenance of the Gly38Ser polymorphism in humans. On the other hand, the expression of the 38Ser allele seems to be disadvantageous under certain conditions, as suggested by the sporadic deficiency of 38Ser-coding mRNAs in heterozygote Central Europeans and the depletion of homozygotes 38Ser in the Yoruban sample. Conclusion We speculate that individual differences in genomic imprinting or genomic recoding might have contributed to conflicting results of recent association studies between Gly38Ser polymorphism and QT phenotype. The findings thus highlight the relevance of mRNA data in future association studies of genotypes and clinical disorders. To the best of our knowledge, they moreover provide first time evidence for a unique pattern; i.e. coincidence of positive Darwinian selection and polymorphism with a sporadically suppressed expression of one allele. PMID:19660109

  11. New Variations in the Promoter Regions of Human DOCK4 and RAP1A Genes, and Coding Regions of RAP1A in Sporadic Breast Tumors

    PubMed Central

    Jalali, Akram; Ebrahimi, Hassan; Ohadi, Mina; Karimloo, Masood; Shemirani, Atena Irani; Mohajer, Behrokh; Khorshid, Hamid Reza Khorram

    2009-01-01

    Breast cancer is the most common cancer among women in developed countries. The prevalence of the disease is increasing in the world. Its annual incidence among Iranian women is about 7000 cases. RAP1A, a tumor suppressor gene, is located at 1p13.3 and plays an important role in the cellular adhesion pathway and is involved in the pathogenesis of breast cancer. The DOCK4 gene, which is located at 7q31.1, specifically activates RAP1A gene. In the present study, DNA samples from 64 cases of sporadic breast tumors (referred to Mehrad Hospital in Tehran) were screened using PCR-SSCP method and the number of observed variations compared with the control group (100 normal women). Mutation detection for coding exons of RAP1A gene and the 500 bp upstream of transcription initiation site as promoters of both DOCK4 and RAP1A were carried out and compared with the control group. The promoter region of DOCK4 showed a heterozygous mutation with G>A transition at nucleotide −303 in a fibroadenoma case. With regard to RAP1A we found a heterozygous mutation, G>A transition in an adenoid cystic carcinoma case, and another heterozygous mutation, G>T transversion in an intraductal papilloma case both at nucleotide +45. A homozygous variation, T>A transversion was also found at nucleotide +29 of a fibroadenoma case. The differences in the frequency of variations mentioned above were not statistically significant. However Fisher's exact showed significant difference for T>A transversion. Although, the higher frequency of these mutations and variations may be related to the disease, a larger sample size is needed for the confirmation of our findings. PMID:23407849

  12. New Variations in the Promoter Regions of Human DOCK4 and RAP1A Genes, and Coding Regions of RAP1A in Sporadic Breast Tumors.

    PubMed

    Jalali, Akram; Ebrahimi, Hassan; Ohadi, Mina; Karimloo, Masood; Shemirani, Atena Irani; Mohajer, Behrokh; Khorshid, Hamid Reza Khorram

    2009-07-01

    Breast cancer is the most common cancer among women in developed countries. The prevalence of the disease is increasing in the world. Its annual incidence among Iranian women is about 7000 cases. RAP1A, a tumor suppressor gene, is located at 1p13.3 and plays an important role in the cellular adhesion pathway and is involved in the pathogenesis of breast cancer. The DOCK4 gene, which is located at 7q31.1, specifically activates RAP1A gene. In the present study, DNA samples from 64 cases of sporadic breast tumors (referred to Mehrad Hospital in Tehran) were screened using PCR-SSCP method and the number of observed variations compared with the control group (100 normal women). Mutation detection for coding exons of RAP1A gene and the 500 bp upstream of transcription initiation site as promoters of both DOCK4 and RAP1A were carried out and compared with the control group. The promoter region of DOCK4 showed a heterozygous mutation with G>A transition at nucleotide -303 in a fibroadenoma case. With regard to RAP1A we found a heterozygous mutation, G>A transition in an adenoid cystic carcinoma case, and another heterozygous mutation, G>T transversion in an intraductal papilloma case both at nucleotide +45. A homozygous variation, T>A transversion was also found at nucleotide +29 of a fibroadenoma case. The differences in the frequency of variations mentioned above were not statistically significant. However Fisher's exact showed significant difference for T>A transversion. Although, the higher frequency of these mutations and variations may be related to the disease, a larger sample size is needed for the confirmation of our findings.

  13. CD68+ cells of monocyte/macrophage lineage in the environment of AIDS-associated and classic-sporadic Kaposi sarcoma are singly or doubly infected with human herpesviruses 7 and 6B

    PubMed Central

    Kempf, W.; Adams, V.; Wey, N.; Moos, R.; Schmid, M.; Avitabile, E.; Campadelli-Fiume, G.

    1997-01-01

    Earlier studies have shown that Kaposi sarcomas contain cells infected with human herpesvirus (HHV) 6B, and in current studies we report that both AIDS-associated and classic-sporadic Kaposi sarcoma contain HHV-7 genome sequences detectable by PCR. To determine the distribution of HHV-7-infected cells relative to those infected with HHV-6, sections from paraffin-embedded tissues were allowed to react with antibodies to HHV-7 virion tegument phosphoprotein pp85 and to HHV-6B protein p101. The antibodies are specific for HHV-7 and HHV-6B, respectively, and they retained reactivity for antigens contained in formalin-fixed, paraffin-embedded tissue samples. We report that (i) HHV-7 pp85 was present in 9 of 32 AIDS-associated Kaposi sarcomas, and in 1 of 7 classical-sporadic HIV-negative Kaposi sarcomas; (ii) HHV-7 pp85 was detected primarily in cells bearing the CD68 marker characteristic of the monocyte/macrophage lineage present in or surrounding the Kaposi sarcoma lesions; and (iii) in a number of Kaposi sarcoma specimens, tumor-associated CD68+ monocytes/macrophages expressed simultaneously antigens from both HHV-7 and HHV-6B, and therefore appeared to be doubly infected with the two viruses. CD68+ monocytes/macrophages infected with HHV-7 were readily detectable in Kaposi sarcoma, but virtually absent from other normal or pathological tissues that harbor macrophages. Because all of the available data indicate that HHV-7 infects CD4+ T lymphocytes, these results suggest that the environment of the Kaposi sarcoma (i) attracts circulating peripheral lymphocytes and monocytes, triggers the replication of latent viruses, and thereby increases the local concentration of viruses, (ii) renders CD68+ monocytes/macrophages susceptible to infection with HHV-7, and (iii) the combination of both events enables double infections of cells with both HHV-6B and HHV-7. PMID:9207138

  14. Sporadic ampullary hamartoma simulating cancer

    PubMed Central

    Moyana, Terence N.; Miller, Grant G.; Keith, Roger G.

    1997-01-01

    Ampullary tumours are uncommon. They may occur with familial polyposis syndromes or neurofibromatosis. It can be difficult to distinguish them from their periampullary counterparts on clinical, radiologic or histologic grounds. Because most ampullary and periampullary tumours are malignant, they tend to be treated by radical surgery. A 67-year-old man was seen with a sporadic ampullary hamartoma that simulated cancer. It was succesfully treated by local excision through a transverse duodenotomy. PMID:9194785

  15. Immune-privileged embryonic Swiss mouse STO and STO cell-derived progenitor cells: major histocompatibility complex and cell differentiation antigen expression patterns resemble those of human embryonic stem cell lines.

    PubMed

    Koch, Katherine S; Son, Kyung-Hwa; Maehr, Rene; Pellicciotta, Illenia; Ploegh, Hidde L; Zanetti, Maurizio; Sell, Stewart; Leffert, Hyam L

    2006-09-01

    Embryonic mouse STO (S, SIM; T, 6-thioguanine resistant; O, ouabain resistant) and 3(8)21-enhanced green fluorescent protein (EGFP) cell lines exhibit long-term survival and hepatic progenitor cell behaviour after xenogeneic engraftment in non-immunosuppressed inbred rats, and were previously designated major histocompatibility complex (MHC) class I- and class II-negative lines. To determine the molecular basis for undetectable MHC determinants, the expression and haplotype of H-2K, H-2D, H-2L and I-A proteins were reassessed by reverse transcriptase-polymerase chain reaction (RT-PCR), cDNA sequencing, RNA hybridization, immunoblotting, quantitative RT-PCR (QPCR), immunocytochemistry and flow cytometry. To detect cell differentiation (CD) surface antigens characteristic of stem cells, apoptotic regulation or adaptive immunity that might facilitate progenitor cell status or immune privilege, flow cytometry was also used to screen untreated and cytokine [interferon (IFN)-gamma]-treated cultures. Despite prior PCR genotyping analyses suggestive of H-2q haplotypes in STO, 3(8)21-EGFP and parental 3(8)21 cells, all three lines expressed H-2K cDNA sequences identical to those of d-haplotype BALB/c mice, as well as constitutive and cytokine-inducible H-2K(d) determinants. In contrast, apart from H-2L(d[LOW]) display in 3(8)21 cells, H-2Dd, H-2Ld and I-Ad determinants were undetectable. All three lines expressed constitutive and cytokine-inducible CD34; however, except for inducible CD117([LOW]) expression in 3(8)21 cells, no expression of CD45, CD117, CD62L, CD80, CD86, CD90.1 or CD95L/CD178 was observed. Constitutive and cytokine-inducible CD95([LOW]) expression was detected in STO and 3(8)21 cells, but not in 3(8)21-EGFP cells. MHC (class I(+[LOW])/class II-) and CD (CD34+/CD80-/CD86-/CD95L-) expression patterns in STO and STO cell-derived progenitor cells resemble patterns reported for human embryonic stem cell lines. Whether these patterns reflect associations with

  16. Sporadic medulloblastomas contain PTCH mutations.

    PubMed

    Raffel, C; Jenkins, R B; Frederick, L; Hebrink, D; Alderete, B; Fults, D W; James, C D

    1997-03-01

    Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syndrome, is an autosomal dominant disorder that predisposes to developmental defects and various forms of cancer. PTCH was recently proposed as a candidate gene for NBCCS due to its frequent mutation in basal cell carcinomas, the cancer most often associated with this syndrome. Another NBCCS-associated cancer is medulloblastoma, a common central nervous system tumor in children. Most medulloblastomas, however, occur without indication of an inherited predisposition. We have examined 24 sporadic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformational polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOH of PTCH in 5 of 24 tumors, and in three of these cases a mutation of the remaining allele was identified. Two of the mutations were duplication insertions, and the third consisted of a single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas.

  17. Relation of Resemblance in Information Retrieval.

    ERIC Educational Resources Information Center

    Pietilainen, Pirkko

    1982-01-01

    Presents a method for using the amount of semantic information in search-query terms as a weighting factor in constructing a fuzzy relation of resemblance between retrieved items in information retrieval online. Two tables, two figures, and a reference list accompany the text. (Author/JL)

  18. Sporadic Fatal Insomnia in an Adolescent

    PubMed Central

    Blase, Jennifer L.; Cracco, Laura; Schonberger, Lawrence B.; Maddox, Ryan A.; Cohen, Yvonne; Cali, Ignazio

    2014-01-01

    The occurrence of sporadic prion disease among adolescents is extremely rare. A prion disease was confirmed in an adolescent with disease onset at 13 years of age. Genetic, neuropathologic, and biochemical analyses of the patient’s autopsy brain tissue were consistent with sporadic fatal insomnia, a type of sporadic prion disease. There was no evidence of an environmental source of infection, and this patient represents the youngest documented case of sporadic prion disease. Although rare, a prion disease diagnosis should not be discounted in adolescents exhibiting neurologic signs. Brain tissue testing is necessary for disease confirmation and is particularly beneficial in cases with an unusual clinical presentation. PMID:24488737

  19. Hereditary or sporadic polyposis syndromes.

    PubMed

    Basso, Gianluca; Bianchi, Paolo; Malesci, Alberto; Laghi, Luigi

    2017-08-01

    Polyposis syndromes are encountered in endoscopy practice, and are considered rare entities, accounting for ≤1% of colorectal cancer. Polyposis can occur within inherited syndromes or as "sporadic" cases of unknown etiology. Their proper characterization is relevant for patient management, and should nowadays drive appropriate genetic tests which have a key role in clinical practice for driving surveillance and colorectal cancer prevention, enlarged to relatives. Polyposis classification is based upon polyp number and histology, familial and personal history. This review will explore the polyposis nosology and their genetic determinants in the emerging scenario of Next Generation Sequencing which allow testing multiples genes in parallel. This capability will likely continue to increase the range of polyposis predisposing genes, contributing to define new clinical entities. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Facial resemblances between heterosexual, gay, and lesbian couples.

    PubMed

    Abel, Ernest L; Kruger, Michael L

    2011-06-01

    Researchers have noted a physical resemblance (homophily) between human sex partners. To date, these studies and their related interpretations have been based on heterosexual couples. The present study compared physical resemblances between gay, lesbian, and heterosexual couples, using 40 photographs of each from national newspapers, which were rated by 34 men and 56 women (M age = 53 yr., SD = 12.1). Half the photographs were of actual couples and half were randomly mixed within each group. Actual couples were rated as significantly more similar in appearance than random pairings of people. Ratings of similarity were significantly higher (indicating greater perceived homophily) for gay couples than heterosexual couples, while there was no statistically significant difference in similarity ratings between lesbian couples versus gay and heterosexual couples. The results were interpreted in terms of evolutionary and parental imprinting hypotheses.

  1. Ig heavy chain third complementarity determining regions (H CDR3s) after stem cell transplantation do not resemble the developing human fetal H CDR3s in size distribution and Ig gene utilization.

    PubMed

    Gokmen, E; Raaphorst, F M; Boldt, D H; Teale, J M

    1998-10-15

    Previous studies have suggested that the B-cell repertoire after stem cell transplantation resembles the developing repertoire in the fetus. Fetal and adult repertoires differ strikingly at the molecular level in Ig heavy chain third complementarity determining region (H CDR3) size distribution and Ig gene utilization. Previously, the posttransplant repertoire has not been studied fully in this regard. In this study, we analyzed H CDR3s posttransplant using CDR3 fingerprinting, single-strand conformation polymorphism (SSCP), and random sequencing. Eleven adult patients who received either autologous (n = 6) or allogeneic adult sibling (n = 5) hematopoietic stem cell transplants were studied. IgM H CDR3 repertoires demonstrated limited clonal diversity within the first 6 to 10 weeks posttransplant. By 3 to 4 months, the IgM H CDR3 repertoires were as diverse as those in healthy adults. Reconstitution of the IgM diversity correlated with the expansion of the multimember VH3 family. By contrast, the contribution of the single-member VH6 family was limited in most patients up to 6 to 9 months. No evidence was seen for greater contribution of VH6 posttransplant. IgG repertoires remained clonally restricted at all times. In all patients, H CDR3 sizes fell within adult limits. Direct nucleotide sequencing of H CDR3s showed adult-type N-nucleotide insertions and Ig gene utilization. These results indicate that the emerging repertoire posttransplant does not resemble the developing fetal repertoire at the molecular level.

  2. A human antibody to the CD4 binding site of gp120 capable of highly potent but sporadic cross clade neutralization of primary HIV-1.

    PubMed

    Gach, Johannes S; Quendler, Heribert; Tong, Tommy; Narayan, Kristin M; Du, Sean X; Whalen, Robert G; Binley, James M; Forthal, Donald N; Poignard, Pascal; Zwick, Michael B

    2013-01-01

    Primary isolates of HIV-1 resist neutralization by most antibodies to the CD4 binding site (CD4bs) on gp120 due to occlusion of this site on the trimeric spike. We describe 1F7, a human CD4bs monoclonal antibody that was found to be exceptionally potent against the HIV-1 primary isolate JR-FL. However, 1F7 failed to neutralize a patient-matched primary isolate, JR-CSF even though the two isolates differ by <10% in gp120 at the protein level. In an HIV-1 cross clade panel (n = 157), 1F7 exhibited moderate breadth, but occasionally achieved considerable potency. In binding experiments using monomeric gp120s of select resistant isolates and domain-swap chimeras between JR-FL and JR-CSF, recognition by 1F7 was limited by sequence polymorphisms involving at least the C2 region of Env. Putative N-linked glycosylation site (PNGS) mutations, notably at position 197, allowed 1F7 to neutralize JR-CSF potently without improving binding to the cognate, monomeric gp120. In contrast, flow cytometry experiments using the same PNGS mutants revealed that 1F7 binding is enhanced on cognate trimeric Env. BN-PAGE mobility shift experiments revealed that 1F7 is sensitive to the diagnostic mutation D368R in the CD4 binding loop of gp120. Our data on 1F7 reinforce how exquisitely targeted CD4bs antibodies must be to achieve cross neutralization of two closely related primary isolates. High-resolution analyses of trimeric Env that show the orientation of glycans and polymorphic elements of the CD4bs that affect binding to antibodies like 1F7 are desirable to understand how to promote immunogenicity of more conserved elements of the CD4bs.

  3. Aloe vera Non-Decolorized Whole Leaf Extract-Induced Large Intestinal Tumors in F344 Rats Share Similar Molecular Pathways with Human Sporadic Colorectal Tumors

    PubMed Central

    Pandiri, Arun R.; Sills, Robert C.; Hoenerhoff, Mark J.; Peddada, Shyamal D.; Ton, Thai-Vu T.; Hong, Hue-Hua L.; Flake, Gordon P.; Malarkey, David E.; Olson, Greg R.; Pogribny, Igor P.; Walker, Nigel J.; Boudreau, Mary D.

    2016-01-01

    Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-β) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5–8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-β signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels. PMID:21937742

  4. Aloe vera non-decolorized whole leaf extract-induced large intestinal tumors in F344 rats share similar molecular pathways with human sporadic colorectal tumors.

    PubMed

    Pandiri, Arun R; Sills, Robert C; Hoenerhoff, Mark J; Peddada, Shyamal D; Ton, Thai-Vu T; Hong, Hue-Hua L; Flake, Gordon P; Malarkey, David E; Olson, Greg R; Pogribny, Igor P; Walker, Nigel J; Boudreau, Mary D

    2011-12-01

    Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-β) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-β signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels.

  5. Characterization of azoxymethane-induced colon tumor metastasis to lung in a mouse model relevant to human sporadic colorectal cancer and evaluation of grape seed extract efficacy.

    PubMed

    Derry, Molly M; Raina, Komal; Agarwal, Rajesh; Agarwal, Chapla

    2014-08-01

    The second leading cause of cancer-related deaths (both genders combined) in the United States is colorectal cancer (CRC). This emphasizes the need to develop both effective therapies for CRC patients and pre-clinical models mimicking human disease that carry translational potential in drug-development. Notably, at present there are no in situ models of CRC metastasis to lung. In our azoxymethane-induced colon tumorigenesis study in A/J mice assessing grape seed extract (GSE) efficacy, during necropsy we also found multiple lung nodules suggestive of colon tumor metastasis to lung that were significantly inhibited in GSE fed group. Both histopathological and molecular studies were performed to characterize and establish the origin of these lesions in lung. Histologically these nodules were determined as adenocarcinoma of mucin origin. Molecular analyses by immunohistochemistry (IHC) and RT-PCR revealed strong protein and transcript levels of colon specific markers CDX2 and CK20 in these lung nodules compared to uninvolved control lung tissue. Vis-à-vis, these nodules also showed minimally expressed lung specific biomarkers, specifically surfactant D and TTF-1, in IHC analysis. Additionally, 0.25% GSE supplementation in diet (w/w) decreased the incidence of these lung nodules by 53% and their total number by 66%. Together, the characterization of this unique in situ mouse model of CRC metastasis to lung provides translational opportunities in developing effective therapies to clinically manage and treat CRC at the advanced stage. Moreover, GSE efficacy in inhibiting CRC metastasis to lung in this model further supports its translational potential in controlling CRC growth, progression and metastasis in patients.

  6. High resolution human leukocyte antigen (HLA) class I and class II allele typing in Mexican mestizo women with sporadic breast cancer: case-control study.

    PubMed

    Cantú de León, David; Pérez-Montiel, Delia; Villavicencio, Verónica; García Carranca, Alejandro; Mohar Betancourt, Alejandro; Acuña-Alonzo, Victor; López-Tello, Alberto; Vargas-Alarcón, Gilberto; Barquera, Rodrigo; Yu, Neng; Yunis, Edmond J; Granados, Julio

    2009-02-05

    The development of breast cancer is multifactorial. Hormonal, environmental factors and genetic predisposition, among others, could interact in the presentation of breast carcinoma. Human leukocyte antigen (HLA) alleles play an important role in immunity (cellular immunity) and may be important genetic traits. HLAAllele-specific interaction has not been well established. Recently, several studies had been conducted in order to do so, but the results are controversial and in some instances contradictory. We designed a case-control study to quantify the association of HLA class I and II genes and breast cancer. HLA typing was performed by high resolution sequence-specific oligotyping after DNA amplification (PCR-SSOP) of 100 breast cancer Mexican mestizo patients and 99 matched healthy controls. HLA-A frequencies that we were able to observe that there was no difference between both groups from the statistical viewpoint. HLA-B*1501 was found three times more common in the case group (OR, 3.714; p = 0.031). HLA-Cw is not a marker neither for risk, nor protection for the disease, because we did not find significant statistical differences between the two groups. DRB1*1301, which is expressed in seven cases and in only one control, observing an risk increase of up to seven times and DRB1*1602, which behaves similarly in being present solely in the cases (OR, 16.701; 95% CI, 0.947 - 294.670). DQ*0301-allele expression, which is much more common in the control group and could be protective for the presentation of the disease (OR, 0.078; 95% CI, 0.027-0.223, p = 0.00001). Our results reveal the role of the MHC genes in the pathophysiology of breast cancer, suggesting that in the development of breast cancer exists a disorder of immune regulation. The triggering factor seems to be restricted to certain ethnic groups and certain geographical regions since the relevant MHC alleles are highly diverse. This is the first study in Mexican population where high resolutions HLA

  7. Molecular pathogenesis of sporadic prion diseases in man.

    PubMed

    Safar, Jiri G

    2012-01-01

    The yeast, fungal and mammalian prions determine heritable and infectious traits that are encoded in alternative conformations of proteins. They cause lethal sporadic, familial and infectious neurodegenerative conditions in man, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, sporadic fatal insomnia (SFI) and likely variable protease-sensitive prionopathy (VPSPr). The most prevalent of human prion diseases is sporadic (s)CJD. Recent advances in amplification and detection of prions led to considerable optimism that early and possibly preclinical diagnosis and therapy might become a reality. Although several drugs have already been tested in small numbers of sCJD patients, there is no clear evidence of any agent's efficacy. Therefore, it remains crucial to determine the full spectrum of sCJD prion strains and the conformational features in the pathogenic human prion protein governing replication of sCJD prions. Research in this direction is essential for the rational development of diagnostic as well as therapeutic strategies. Moreover, there is growing recognition that fundamental processes involved in human prion propagation - intercellular induction of protein misfolding and seeded aggregation of misfolded host proteins - are of far wider significance. This insight leads to new avenues of research in the ever-widening spectrum of age-related human neurodegenerative diseases that are caused by protein misfolding and that pose a major challenge for healthcare.

  8. Darwinian Behavior in a Cold, Sporadically Fed Pool of Ribonucleotides

    PubMed Central

    2012-01-01

    Abstract A testable, explicit origin for Darwinian behavior, feasible on a chaotic early Earth, would aid origins discussion. Here I show that a pool receiving unreliable supplies of unstable ribonucleotide precursors can recurrently fill this role. By using numerical integration, the differential equations governing a sporadically fed pool are solved, yielding quantitative constraints for the proliferation of molecules that also have a chemical phenotype. For example, templated triphosphate nucleotide joining is >104 too slow, suggesting that a group more reactive than pyrophosphate activated primordial nucleotides. However, measured literature rates are sufficient if the Initial Darwinian Ancestor (IDA) resembles a 5′-5′ cofactor-like dinucleotide RNA, synthesized via activation with a phosphorimidazolide-like group. A sporadically fed pool offers unforeseen advantages; for example, the pool hosts a novel replicator which is predominantly unpaired, even though it replicates. Such free template is optimized for effective selection during its replication. Pool nucleotides are also subject to a broadly based selection that impels the population toward replication, effective selection, and Darwinian behavior. Such a primordial pool may have left detectable modern traces. A sporadically fed ribonucleotide pool also fits a recognizable early Earth environment, has recognizable modern descendants, and suits the early shape of the phylogenetic tree of Earthly life. Finally, analysis points to particular data now needed to refine the hypothesis. Accordingly, a kinetically explicit chemical hypothesis for a terran IDA can be justified, and informative experiments seem readily accessible. Key Words: Cofactor—RNA—Origin of life—Replication—Initial Darwinian Ancestor (IDA). Astrobiology 12, 870–883. PMID:22946838

  9. Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer.

    PubMed

    Newmark, Harold L; Yang, Kan; Kurihara, Naoto; Fan, Kunhua; Augenlicht, Leonard H; Lipkin, Martin

    2009-01-01

    We reported previously that a new Western-style diet (NWD) for 18 months, consisting of elevated lipids and decreased calcium, vitamin D and methyl-donor nutrients, induced colonic tumors in normal C57Bl/6 mice [Newmark, H.L. et al. (2001) A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice. Carcinogenesis, 22, 1871-1875], suggesting a new mouse model for human sporadic colon cancer. Here, we have extended this study during a longer feeding period of 2 years wherein tumor formation, tumor inhibition by addition of dietary calcium and vitamin D and their effects on gene expression were determined. We also similarly tested individual supplements of methyl donor (transfer) nutrients (folic acid, choline, methionine and dietary fiber), but these had no significant effect on colonic tumor incidence or multiplicity, whereas supplementation with combined calcium and vitamin D produced significant decrease in both colon tumor incidence and multiplicity, during 2 years of feeding. No visible colonic tumors were found at 6 months, very few at 12 months, more at 18 months and significantly at 24 months. In a related study of gene changes of the mouse colonic mucosa at 6 months of feeding taken from this study, long before any tumors were visibly detectable, indicated altered profiles of gene expression linked to later risk of dietary initiation of colon tumor formation. This type of early genetic altered profile, an indication of increased risk of later colonic tumor development, may become a useful tool for prediction of colon tumor risk while the colon grossly still appears histologically and physiologically normal.

  10. Quantitative Expression Analysis of APP Pathway and Tau Phosphorylation-Related Genes in the ICV STZ-Induced Non-Human Primate Model of Sporadic Alzheimer’s Disease

    PubMed Central

    Park, Sang-Je; Kim, Young-Hyun; Nam, Gyu-Hwi; Choe, Se-Hee; Lee, Sang-Rae; Kim, Sun-Uk; Kim, Ji-Su; Sim, Bo-Woong; Song, Bong-Seok; Jeong, Kang-Jin; Lee, Youngjeon; Park, Young Il; Lee, Kyoung-Min; Huh, Jae-Won; Chang, Kyu-Tae

    2015-01-01

    The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (Aβ) and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer’s disease (AD). Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD) research using intracerebroventricular administration of streptozotocin (icv STZ). To date, no characterization of AD-related genes in different brain regions has been performed. Therefore, in the current study, the expression of seven amyloid precursor protein (APP) pathway-related and five tau phosphorylation-related genes was investigated by quantitative real-time PCR experiments, using two matched-pair brain samples from control and icv STZ-treated cynomolgus monkeys. The genes showed similar expression patterns within the control and icv STZ-treated groups; however, marked differences in gene expression patterns were observed between the control and icv STZ-treated groups. Remarkably, other than β-secretase (BACE1) and cyclin-dependent kinase 5 (CDK5), all the genes tested showed similar expression patterns in AD models compared to controls, with increased levels in the precuneus and occipital cortex. However, significant changes in gene expression patterns were not detected in the frontal cortex, hippocampus, or posterior cingulate. Based on these results, we conclude that APP may be cleaved via the general metabolic mechanisms of increased α- and γ-secretase levels, and that hyperphosphorylation of tau could be mediated by elevated levels of tau protein kinase, specifically in the precuneus and occipital cortex. PMID:25622254

  11. Sporadic case of warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome.

    PubMed

    Tarzi, Michael D; Jenner, Michael; Hattotuwa, Keith; Faruqi, Asma Z; Diaz, George A; Longhurst, Hilary J

    2005-11-01

    The term WHIM syndrome (WHIMS) is an acronym describing a rare primary immunodeficiency disorder characterized by warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis, the unusual association of neutropenia with bone marrow myeloid hypercellularity. WHIMS was recently associated with mutations in the gene encoding the chemokine receptor CXCR4 and as such is the first disease ascribed to abnormalities of chemokine signaling. We report a sporadic case of WHIMS in a woman presenting with recurrent infections and human papilloma virus-related genital dysplasia.

  12. Pseudohypoparathyroidism presenting with bony deformities resembling rickets.

    PubMed

    Bajpai, Anurag; Sharma, Jyoti; Hari, Pankaj; Bagga, Arvind

    2004-04-01

    Pseudohypoparathyroidism (PHP), characterized by hypocalcemia, hyperphosphatemia and elevated parathormone level, may rarely be associated with bony deformities resembling rickets. The authors report two siblings with clinical and radiological features suggestive of rickets unresponsive to treatment with vitamin D. Low serum calcium, elevated serum phosphate, normal renal functions, raised tubular maximum of phosphate and high serum parathormone were suggestive of PHP. Treatment with 1-hydroxyvitamin D and calcium carbonate led to decrease in bone pain, increase in height and weight and resolution of radiological features. PHP should be suspected in patients with bony deformities, hypocalcemia, elevated blood phosphate levels and normal renal functions.

  13. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.

    PubMed

    Depienne, Christel; Bouteiller, Delphine; Keren, Boris; Cheuret, Emmanuel; Poirier, Karine; Trouillard, Oriane; Benyahia, Baya; Quelin, Chloé; Carpentier, Wassila; Julia, Sophie; Afenjar, Alexandra; Gautier, Agnès; Rivier, François; Meyer, Sophie; Berquin, Patrick; Hélias, Marie; Py, Isabelle; Rivera, Serge; Bahi-Buisson, Nadia; Gourfinkel-An, Isabelle; Cazeneuve, Cécile; Ruberg, Merle; Brice, Alexis; Nabbout, Rima; Leguern, Eric

    2009-02-01

    Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.

  14. [Three sporadic cases of acute hepatitis E].

    PubMed

    Kim, Dong Han; Park, Hyeuk; Moon, Seung Won; Jeong, Jong Hyuk; Yang, Hyuk Seung; Kim, Do Hyun; Kim, Ho Dong

    2007-08-01

    Acute hepatitis E is an endemic disease, commonly reported in Indian subcontinent, China, Africa, Central America, and so forth. It is a self-limiting disease like other acute hepatitis except in pregnant patient. Although sporadic hepatitis E is noted all over the world, most of them are associated with travel history to HEV-endemic area. In Korea, Hepatitis E is rarely reported. Moreover, sporadic acute hepatitis E without travel history to HEV-endemic area is very rare. We experienced three sporadic cases of acute hepatitis E, without travel history. All of them presented acute hepatitis symptoms, elevated aminotransferase, and positive IgM HEV Ab. Symptoms and aminotransferase levels were normalized during hospitalization and IgM HEV Ab converted negative after 4-8 months. We report three sporadic cases of onset-acute hepatitis E without travel history to HEV-endemic area.

  15. Sporadic-E As Observed with Rockets

    NASA Technical Reports Server (NTRS)

    Seddon, J. Carl

    1961-01-01

    Data obtained with rockets flown over New Mexico, U.S.A. and Manitoba, Canada have always shown the sporadic-E layer to be a thin layer with a large electron density gradient. The vertical electron density profiles and the horizontal uniformity of the sporadic-E layer are discussed herein. These layers have a strong tendency to form at preferential altitudes separated by approximately 6 km, and a striking correlation exists with wind- shears and magnetic field variations. In two cases where comparisons with ionograms were possible, the minimum frequency of the F-region echoes was found approximately equal to the plasma frequency of the sporadic-E layer reduced by half the gyrofrequency. On the other hand, the maximum frequency of the sporadic-E echoes as noted on ionograms was sometimes as much as 1 to 2 Mc greater than the plasma frequency.

  16. Frequent alteration of the tumor suppressor gene APC in sporadic canine colorectal tumors.

    PubMed

    Youmans, Lydia; Taylor, Cynthia; Shin, Edwin; Harrell, Adrienne; Ellis, Angela E; Séguin, Bernard; Ji, Xinglai; Zhao, Shaying

    2012-01-01

    Sporadic canine colorectal cancers (CRCs) should make excellent models for studying the corresponding human cancers. To molecularly characterize canine CRC, we investigated exonic sequence mutations of adenomatous polyposis coli (APC), the best known tumor suppressor gene of human CRC, in 23 sporadic canine colorectal tumors, including 8 adenomas and 15 adenocarcinomas, via exon-resequencing analysis. As a comparison, we also performed the same sequencing analysis on 10 other genes, either located at human 5q22 (the same locus as APC) or 18q21 (also frequently altered in human CRC), or known to play a role in human carcinogenesis. We noted that APC was the most significantly mutated gene in both canine adenomas and adenocarcinomas among the 11 genes examined. Significantly, we detected large deletions of ≥ 10 bases, many clustered near the mutation cluster region, as well as single or two base deletions in ~70% canine tumors of both subtypes. These observations indicate that like in the human, APC is also frequently altered in sporadic colorectal tumors in the dog and its alteration is an early event in canine colorectal tumorigenesis. Our study provides further evidence demonstrating the molecular similarity in pathogenesis between sporadic human and canine CRCs. This work, along with our previous copy number abnormality study, supports that sporadic canine CRCs are valid models of human CRCs at the molecular level.

  17. Acute Sporadic Hepatitis in Sudanese Children

    DTIC Science & Technology

    1991-01-01

    potential risk factors of hepatitis transmission dur- hepatitis in children in this area, as well as a ing the 6 months prior to the onset of symptoms...1987aI. In the present study, the causes and risk Accepted for publication September 5. 1990. factors of acute sporadic hepatitis in Sudanese children ...ELEMENT NO. NO. NO. ACCESSION NO. N.A. 11. TITLE (include Security Cassification) Acute sporadic hepatitis in Sudanese children 12. PERSONAL AUTHOR(S

  18. MAJOR MOLECULAR GENETIC DRIVERS IN SPORADIC PRIMARY HYPERPARATHYROIDISM

    PubMed Central

    ARNOLD, ANDREW

    2016-01-01

    Primary hyperparathyroidism is primarily due to a solitary parathyroid adenoma but multi-gland disease, parathyroid carcinoma, and ectopic parathyroid hormone production can occur. Although primary hyperparathyroidism mostly presents sporadically, strong familial predispositions also exist. Much is known about heritable genetic mutations responsible for these syndromes, including multiple endocrine neoplasia types 1 and 2A, hyperparathyroidism-jaw tumor syndrome, and familial hypocalciuric hypercalcemia. Acquired mutations in common sporadic hyperparathyroidism have also been discovered. Here we focus on the most common and well-established genetic drivers: 1) involvement of the oncogene cyclin D1 in human neoplasia was first established in parathyroid adenomas, followed by recognition of its importance in other tumor types including breast cancer and B-lymphoid malignancy; and 2) somatic mutation of the MEN1 gene, first identified as the source of pathogenic germline mutations in patients with familial endocrinopathies, is found in a substantial fraction of non-familial parathyroid adenomas. PMID:28066056

  19. Neuroanatomy and pathology of sporadic Parkinson's disease.

    PubMed

    Braak, Heiko; Del Tredici, Kelly

    2009-01-01

    The proteinopathy sporadic Parkinson's disease (sPD) is the second most frequent degenerative disorder of the human nervous system after Alzheimer's disease. The alpha-synuclein inclusion body pathology (Lewy pathology) associated with sPD is distributed throughout the central, peripheral, and enteric nervous systems. The resulting nonrandom neuronal dysfunction and, in some regions, neuronal loss is reflected in a topographic distribution pattern of the Lewy pathology that, in the brain, can be staged. Except for olfactory structures and spinal cord constituents of the pain system, sensory components of the nervous system remain uninvolved or virtually intact. The most disease-related damage revolves around motor areas--particularly around superordinate centers of the limbic and visceromotor systems as well as portions of the somatomotor system. Vulnerable regions are interconnected anatomically and susceptible nerve cell types are not neurotransmitter-dependent. Not all clinical symptoms emerging in the course of sPD can be explained by a lack of dopamine in the nigrostriatal system. These include autonomic dysfunction, pain, hyposmia or anosmia, excessive daytime sleepiness, rapid eye movement (REM) sleep behavioral disorder, depression, anxiety, cognitive decline, and dementia. Against the background of the normal morphology and anatomy, the authors analyze the pathoanatomy of sPD in the nervous system at various neuropathological stages and summarize the potential functional consequences of the lesions.

  20. Spinal Tuberculosis Resembling Neoplastic Lesions on MRI

    PubMed Central

    Kumar, Anil

    2015-01-01

    Background Tuberculous spondylitis is one of the commonest forms of skeletal tuberculosis in developing countries like India causing significant morbidity due to compression of spinal cord and adjacent nerve roots. Diagnosis and intervention at early stage can prevent permanent damage such as spinal deformity and neurological deficits. Aim The purpose of this study was to demonstrate atypical MRI features in cases of tubercular spondylitis resembling neoplastic lesions and to stress that tuberculous spondylitis should be one of the differential diagnoses in any spinal pathology especially in developing countries. Materials and Methods This was a prospective study done in the patients diagnosed as tuberculous spondylitis on 0.2 T Siemens MRI between June 2011 and December 2014 in a tertiary care hospital in India. Total 529 cases of tubercular spinal lesions were diagnosed. Out of which only 59 patients showed atypical features on MR imaging which resembled neoplastic lesions were included in the study. The diagnosis was confirmed by cytology, histopathology, serology and corroborative findings. Results Lumbo-sacral region involvement (30.5%) is the commonest in our study followed by dorsal and cervical region. Multiple level lesions are seen in 14 cases (23.7%). All the 59 (100%) cases show no involvement of intervetebral disc. Posterior appendage involvement seen in 32 cases (54.2%). Soft tissue component seen in Intraspinal (37.2%) and paraspinal (45.7%) compartments. Cord compression seen in 19 cases (32.2%), out which only 7 cases (11.8%) shows cord oedema. Conclusion On MRI, tubercular spondylitis may have variable pictures on imaging. For any spinal and paraspinal lesions, we should also consider the possibility of tubercular aetiology along with other. Since early diagnosis avoids unnecessary delay in the treatment thereby reducing morbidity and possible complications. PMID:26675162

  1. The cybrid model of sporadic Parkinson's disease.

    PubMed

    Trimmer, Patricia A; Bennett, James P

    2009-08-01

    Parkinson's disease (PD) is the eponym attached to the most prevalent neurodegenerative movement disorder of adults, derived from observations of an early nineteenth century physician and paleontologist, James Parkinson, and is now recognized to encompass much more than a movement disorder clinically or dopamine neuron death pathologically. Most PD ( approximately 90%) is sporadic (sPD), is associated with mitochondrial deficiencies and has been studied in cell and animal models arising from the use of mitochondrial toxins that unfortunately have not predicted clinical efficacy to slow disease progression in humans. We have extensively studied the cytoplasmic hybrid ("cybrid") model of sPD in which donor mtDNAs are introduced into and expressed in neural tumor cells with identical nuclear genetic and environmental backgrounds. sPD cybrids demonstrate many abnormalities in which increased oxidative stress drives downstream antioxidant response and cell death activating signaling pathways. sPD cybrids regulate mitochondrial ETC genes and gene ontology families like sPD brain. sPD cybrids spontaneously form Lewy bodies and Lewy neurites, linking mtDNA expression to neuropathology, and demonstrate impaired organelle transport in processes and reduced mitochondrial respiration. Our recent studies show that near-infrared laser light therapy normalizes mitochondrial movement and can stimulate respiration in sPD cybrid neurons, and mitochondrial gene therapy can restore respiration and stimulate mitochondrial ETC gene and protein expression. sPD cybrids have provided multiple lines of circumstantial evidence linking mtDNA to sPD pathogenesis and can serve as platforms for therapy development. sPD cybrid models can be improved by the use of non-tumor human stem cell-derived neural precursor cells and by an introduction of postmortem brain mtDNA to test its causality directly.

  2. Body elimination attitude family resemblance in Kuwait.

    PubMed

    Al-Fayez, Ghenaim; Awadalla, Abdelwahid; Arikawa, Hiroko; Templer, Donald I; Hutton, Shane

    2009-12-01

    The purpose of the present study was to determine the family resemblance of attitude toward body elimination in Kuwaiti participants. This study was conceptualized in the context of the theories of moral development, importance of cleanliness in the Muslim religion, cross-cultural differences in personal hygiene practices, previous research reporting an association between family attitudes and body elimination attitude, and health implications. The 24-item Likert-type format Body Elimination Attitude Scale-Revised was administered to 277 Kuwaiti high school students and 437 of their parents. Females scored higher, indicating greater disgust, than the males. Moreover, sons' body elimination attitude correlated more strongly with fathers' attitude (r = .85) than with that of the mothers (r = .64). Daughters' attitude was similarly associated with the fathers' (r = .89) and the mothers' attitude (r = .86). The high correlations were discussed within the context of Kuwait having a collectivistic culture with authoritarian parenting style. The higher adolescent correlations, and in particular the boys' correlation with fathers than with mothers, was explained in terms of the more dominant role of the Muslim father in the family. Public health and future research implications were suggested. A theoretical formulation was advanced in which "ideal" body elimination attitude is relative rather than absolute, and is a function of one's life circumstances, one's occupation, one's culture and subculture, and the society that one lives in.

  3. Giant sublingual epidermoid cyst resembling plunging ranula

    PubMed Central

    Verma, Sandeep; Kushwaha, Jitendra Kumar; Sonkar, A A; Kumar, Rahul; Gupta, Rajni

    2012-01-01

    Epidermoid and dermoid cysts represent less than 0.01% of all oral cavity cysts. We describe a rare case of large epidermoid cyst in floor of mouth, with an oral as well as submental component resembling plunging ranula reported in the literature from India. We present a case of a 16-year-old girl with complaints of a mass in sublingual region, difficulty chewing, and dysphagia for about 5 months. Fine-needle aspiration cytology showed keratin flakes and proteinaceous material. Contrast-enhanced CT oral cavity was done and showed 7.0 × 5 × 4.5 cm well-circumscribed non-enhancing cystic mass extending into the floor of the mouth. On examination, a firm swelling was noticed in the submental area, extending down to the thyroid notch. The patient underwent surgical removal of the mass. On histopathology, acidophilic stratum corneum and basophilic dot like staining of stratum granulosum, which is the hallmark of an epidermoid cyst, were seen. PMID:23833501

  4. Disseminated cutaneous leishmaniasis resembling post-kala-azar dermal leishmaniasis caused by Leishmania donovani in three patients co-infected with visceral leishmaniasis and human immunodeficiency virus/acquired immunodeficiency syndrome in Ethiopia.

    PubMed

    Gelanew, Tesfaye; Hurissa, Zewdu; Diro, Ermias; Kassahun, Aysheshm; Kuhls, Katrin; Schönian, Gabriele; Hailu, Asrat

    2011-06-01

    We report paired strains of Leishmania parasites, one from the viscera and the other from skin lesions that were isolated from three patients with visceral leishmaniasis and disseminated cutaneous leishmaniasis that were co-infected with human immunodeficiency virus. The causative parasites were characterized by polymerase chain reaction-restriction length polymorphism of the ribosomal DNA internal transcribed spacer 1 and by a panel of multilocus microsatellite markers. We demonstrated that the causative agent was Leishmania donovani in all cases, irrespective of the phenotype of the disease. The paired strains from viscera and skin lesions of the same patients showed genetic identity across the 14 microsatellite markers investigated. These findings demonstrate that the skin lesions in these human immunodeficiency virus-positive patients with visceral leishmaniasis were caused by dissemination of viscerotropic L. donovani parasites as a consequence of severe immunosuppression. However, in all three patients, rapid clearance of the skin lesions was observed after antimonial therapy.

  5. Sporadically Emitting Pulsars at Low Frequencies

    NASA Astrophysics Data System (ADS)

    Meyers, B. W.; Tremblay, S. E.; Bhat, N. D. R.; Shannon, R. M.

    2017-01-01

    Sporadic emission from pulsars has long been observed, however, the mechanism which causes the intermittency is still a mystery. The proposed observations of three nulling pulsars (J0659+1414, J2048-1616 and J1456-6843), two Rotating Radio Transients (J0410-31 and J1423-56) and one intermittent pulsar (J1107-5907) will provide information on pulsar emission over a variety of time scales. Studying these objects at low frequencies allows us to explore the links between the different populations and how the sporadic emission evolves with frequency. Ultimately, studying these extraordinary pulsars gives us new insight into the dynamic nature of the emission processes and pulsar magnetosphere. This information is imperative for linking models and theories regarding pulsar radio emission physics to the myriad sporadic emission phenomena we observe.

  6. Functional properties of human nicotinic AChRs expressed by IMR-32 neuroblastoma cells resemble those of alpha3beta4 AChRs expressed in permanently transfected HEK cells.

    PubMed

    Nelson, M E; Wang, F; Kuryatov, A; Choi, C H; Gerzanich, V; Lindstrom, J

    2001-11-01

    We characterized the functional and molecular properties of nicotinic acetylcholine receptors (AChRs) expressed by IMR-32, a human neuroblastoma cell line, and compared them to human alpha3 AChRs expressed in stably transfected human embryonic kidney (HEK) cells. IMR-32 cells, like neurons of autonomic ganglia, have been shown to express alpha3, alpha5, alpha7, beta2, and beta4 AChR subunits. From these subunits, several types of alpha3 AChRs as well as homomeric alpha7 AChRs could be formed. However, as we show, the properties of functional AChRs in these cells overwhelmingly reflect alpha3beta4 AChRs. alpha7 AChR function was not detected, yet we estimate that there are 70% as many surface alpha7 AChRs in IMR-32 when compared with alpha3 AChRs. Agonist potencies (EC(50) values) followed the rank order of 1,1-dimethyl-4-phenylpiperazinium (DMPP; 16+/-1 microM) > nicotine (Nic; 48 +/- 7 microM) > or = cytisine (Cyt; 57 +/- 3 microM) = acetylcholine (ACh; 59 +/- 6 microM). All agonists exhibited efficacies of at least 80% relative to ACh. The currents showed strong inward rectification and desensitized at a rate of 3 s(-1) (300 microM ACh; -60 mV). Assays that used mAbs confirmed the predominance of alpha3- and beta4-containing AChRs in IMR-32 cells. Although 18% of total alpha3 AChRs contained beta2 subunits, no beta2 subunit was detected on the cell surface. Chronic Nic incubation increased the amount of total, but not surface alpha3beta2 AChRs in IMR-32 cells. Nic incubation and reduced culture temperature increased total and surface AChRs in alpha3beta2 transfected HEK cells. Characterization of various alpha3 AChRs expressed in HEK cell lines revealed that the functional properties of the alpha3beta4 cell line best matched those found for IMR-32 cells. The rank order of agonist potencies (EC(50) values) for this line was DMPP (14 +/- 1 microM) = Cyt (18 +/- 1 microM) > Nic (56 +/- 15 microM > ACh (79 +/- 8 microM). The efficacies of both Cyt and DMPP were

  7. The prion protein preference of sporadic Creutzfeldt-Jakob disease subtypes.

    PubMed

    Klemm, Helen M J; Welton, Jeremy M; Masters, Colin L; Klug, Genevieve M; Boyd, Alison; Hill, Andrew F; Collins, Steven J; Lawson, Victoria A

    2012-10-19

    Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes.

  8. Models of sporadic meteor body distributions

    NASA Technical Reports Server (NTRS)

    Andreev, V. V.; Belkovich, O. I.

    1987-01-01

    The distribution of orbital elements and flux density over the celestial sphere are the most common forms of representation of the meteor body distribution in the vicinity of the Earth's orbit. The determination of flux density distribution of sporadic meteor bodies was worked out. The method and its results are discussed.

  9. On the variability of sporadic E

    SciTech Connect

    Paul, A.K. )

    1990-02-01

    The analysis of digital ionograms taken in short-time intervals shows rapid changes of sporadic E parameters. This is directly visible in the variation of the top frequency or maximum electron density of such layers. Angle of arrival data which were available with those ionograms also showed fast changes of the apparent direction and often large deviations from vertical propagation. 5 refs.

  10. Genetic Insights into Sporadic Parkinson's Disease Pathogenesis

    PubMed Central

    Chai, Chou; Lim, Kah-Leong

    2013-01-01

    Intensive research over the last 15 years has led to the identification of several autosomal recessive and dominant genes that cause familial Parkinson’s disease (PD). Importantly, the functional characterization of these genes has shed considerable insights into the molecular mechanisms underlying the etiology and pathogenesis of PD. Collectively; these studies implicate aberrant protein and mitochondrial homeostasis as key contributors to the development of PD, with oxidative stress likely acting as an important nexus between the two pathogenic events. Interestingly, recent genome-wide association studies (GWAS) have revealed variations in at least two of the identified familial PD genes (i.e. α-synuclein and LRRK2) as significant risk factors for the development of sporadic PD. At the same time, the studies also uncovered variability in novel alleles that is associated with increased risk for the disease. Additionally, in-silico meta-analyses of GWAS data have allowed major steps into the investigation of the roles of gene-gene and gene-environment interactions in sporadic PD. The emergent picture from the progress made thus far is that the etiology of sporadic PD is multi-factorial and presumably involves a complex interplay between a multitude of gene networks and the environment. Nonetheless, the biochemical pathways underlying familial and sporadic forms of PD are likely to be shared. PMID:24532982

  11. Application of quantitative DTI metrics in sporadic CJD.

    PubMed

    Caverzasi, E; Henry, R G; Vitali, P; Lobach, I V; Kornak, J; Bastianello, S; Dearmond, S J; Miller, B L; Rosen, H J; Mandelli, M L; Geschwind, M D

    2014-01-01

    Diffusion Weighted Imaging is extremely important for the diagnosis of probable sporadic Jakob-Creutzfeldt disease, the most common human prion disease. Although visual assessment of DWI MRI is critical diagnostically, a more objective, quantifiable approach might more precisely identify the precise pattern of brain involvement. Furthermore, a quantitative, systematic tracking of MRI changes occurring over time might provide insights regarding the underlying histopathological mechanisms of human prion disease and provide information useful for clinical trials. The purposes of this study were: 1) to describe quantitatively the average cross-sectional pattern of reduced mean diffusivity, fractional anisotropy, atrophy and T1 relaxation in the gray matter (GM) in sporadic Jakob-Creutzfeldt disease, 2) to study changes in mean diffusivity and atrophy over time and 3) to explore their relationship with clinical scales. Twenty-six sporadic Jakob-Creutzfeldt disease and nine control subjects had MRIs on the same scanner; seven sCJD subjects had a second scan after approximately two months. Cortical and subcortical gray matter regions were parcellated with Freesurfer. Average cortical thickness (or subcortical volume), T1-relaxiation and mean diffusivity from co-registered diffusion maps were calculated in each region for each subject. Quantitatively on cross-sectional analysis, certain brain regions were preferentially affected by reduced mean diffusivity (parietal, temporal lobes, posterior cingulate, thalamus and deep nuclei), but with relative sparing of the frontal and occipital lobes. Serial imaging, surprisingly showed that mean diffusivity did not have a linear or unidirectional reduction over time, but tended to decrease initially and then reverse and increase towards normalization. Furthermore, there was a strong correlation between worsening of patient clinical function (based on modified Barthel score) and increasing mean diffusivity.

  12. Application of quantitative DTI metrics in sporadic CJD☆

    PubMed Central

    Caverzasi, E.; Henry, R.G.; Vitali, P.; Lobach, I.V.; Kornak, J.; Bastianello, S.; DeArmond, S.J.; Miller, B.L.; Rosen, H.J.; Mandelli, M.L.; Geschwind, M.D.

    2014-01-01

    Diffusion Weighted Imaging is extremely important for the diagnosis of probable sporadic Jakob–Creutzfeldt disease, the most common human prion disease. Although visual assessment of DWI MRI is critical diagnostically, a more objective, quantifiable approach might more precisely identify the precise pattern of brain involvement. Furthermore, a quantitative, systematic tracking of MRI changes occurring over time might provide insights regarding the underlying histopathological mechanisms of human prion disease and provide information useful for clinical trials. The purposes of this study were: 1) to describe quantitatively the average cross-sectional pattern of reduced mean diffusivity, fractional anisotropy, atrophy and T1 relaxation in the gray matter (GM) in sporadic Jakob–Creutzfeldt disease, 2) to study changes in mean diffusivity and atrophy over time and 3) to explore their relationship with clinical scales. Twenty-six sporadic Jakob–Creutzfeldt disease and nine control subjects had MRIs on the same scanner; seven sCJD subjects had a second scan after approximately two months. Cortical and subcortical gray matter regions were parcellated with Freesurfer. Average cortical thickness (or subcortical volume), T1-relaxiation and mean diffusivity from co-registered diffusion maps were calculated in each region for each subject. Quantitatively on cross-sectional analysis, certain brain regions were preferentially affected by reduced mean diffusivity (parietal, temporal lobes, posterior cingulate, thalamus and deep nuclei), but with relative sparing of the frontal and occipital lobes. Serial imaging, surprisingly showed that mean diffusivity did not have a linear or unidirectional reduction over time, but tended to decrease initially and then reverse and increase towards normalization. Furthermore, there was a strong correlation between worsening of patient clinical function (based on modified Barthel score) and increasing mean diffusivity. PMID:24624328

  13. Neurofibromatosis type 1 and sporadic optic gliomas

    PubMed Central

    Singhal, S; Birch, J; Kerr, B; Lashford, L; Evans, D

    2002-01-01

    Aims: To compare the natural history of sporadic optic glioma with those associated with neurofibromatosis type 1 (NF1). Methods: Optic glioma cases were identified using both the Manchester Children's Tumour Registry (CTR) and the North West Regional NF1 Database (NF1DB), with detailed information on natural history available from the former (in 34 of 36 cases identified). Results: A total of 52 cases over a period of 41 years were identified. From the 34 whose natural history was known, almost all (n = 31) were symptomatic, with mean ages of presentation of 4.5 and 5.1 years for NF1 and sporadic cases respectively. The majority (n = 22) presented with visual impairment, seven of whom were blind in at least one eye. Sporadic cases were over twice as likely as NF1 to have visual impairment. Recurrence occurred in 12 patients. Fewer NF1 patients died as a direct result of their optic glioma, but overall mortality and 5 and 10 year survival rates between the two groups were similar. All five primary (non-metastatic) second central nervous system (CNS) tumours occurred in NF1 cases, two of these following radiotherapy. Conclusions: Symptomatic sporadic optic gliomas presented with impaired vision more frequently and were more aggressive than NF1 optic gliomas. Only optic glioma cases with NF1 were at risk of developing a second CNS tumour. Aggressive treatment of sporadic optic gliomas and early surveillance of NF1 optic gliomas may be required. The use of radiotherapy in these children requires further clarification. PMID:12089128

  14. Sporadic Cryptosporidiosis Decline after Membrane Filtration of Public Water Supplies, England, 1996–2002

    PubMed Central

    Goh, Stella; Casemore, David P.; Verlander, Neville Q.; Charlett, André; Chalmers, Rachel M.; Knowles, Margaret; Pennington, Anthony; Williams, Joy; Osborn, Keith; Richards, Sarah

    2005-01-01

    The incidence of sporadic cryptosporidiosis among 106,000 residents of 2 local government districts in northwest England before and after installation of membrane filtration of public water supplies was compared to that of 59,700 residents whose public water supplies remained unchanged. A national outbreak of foot and mouth disease in livestock during 2001 was associated with a decline in sporadic human cryptosporidiosis in all regions of the United Kingdom. In a Poisson regression model, membrane filtration was associated with an estimated 79% reduction (incidence ratio 0.207, 95% confidence intervals 0.099–0.431, p < 0.0001) after adjustment for the interval of the foot and mouth disease epidemic and the water source. Despite the confounding effect of that epidemic, membrane filtration of the public water supply was effective in reducing the risk for sporadic human Cryptosporidium infection in this population. PMID:15752443

  15. On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease

    PubMed Central

    McShane, Lisa M.; Zanusso, Gianluigi; Detwiler, Linda

    2006-01-01

    Strategies to investigate the possible existence of sporadic bovine spongiform encephalopathy (BSE) require systematic testing programs to identify cases in countries considered to have little or no risk of orally acquired disease or to detect a stable occurrence of atypical cases in countries in which orally acquired disease is disappearing. To achieve 95% statistical confidence that the prevalence for sporadic BSE is no greater than 1 per million (i.e., the annual incidence of sporadic Creutzfeldt-Jakob disease [CJD] in humans) would require negative tests in 3 million randomly selected older cattle. A link between BSE and sporadic CJD has been suggested on the basis of laboratory studies but is unsupported by epidemiologic observation. Such a link might yet be established by the discovery of a specific molecular marker or of particular combinations of trends over time of typical and atypical BSE and various subtypes of sporadic CJD, as their numbers are influenced by a continuation of current public health measures that exclude high-risk bovine tissues from the animal and human food chains. PMID:17326930

  16. BIN1 Is Decreased in Sporadic but Not Familial Alzheimer’s Disease or in Aging

    PubMed Central

    Glennon, Elizabeth B. C.; Whitehouse, Isobel J.; Miners, J. Scott; Kehoe, Patrick G.; Love, Seth; Kellett, Katherine A. B.; Hooper, Nigel M.

    2013-01-01

    Bridging integrator 1 (BIN1) has been implicated in sporadic Alzheimer’s disease (AD) by a number of genome wide association studies (GWAS) in a variety of populations. Here we measured BIN1 in frontal cortex samples from 24 sporadic AD and 24 age-matched non-dementia brains and correlated the expression of this protein with markers of AD. BIN1 was reduced by 87% (p=0.007) in sporadic AD compared to non-dementia controls, but BIN1 in sporadic AD did not correlate with soluble Aβ (rs=-0.084, p=0.698), insoluble Aβ (rs=0.237, p=0.269), Aβ plaque load (rs=0.063, p=0.771) or phospho-tau load (rs=-0.160, p=0.489). In contrast to our findings in sporadic AD, BIN1 was unchanged in the hippocampus from 6 cases of familial AD compared to 6 age-matched controls (p=0.488). BIN1 declined with age in a cohort of non-dementia control cases between 25 and 88 years but the correlation was not significant (rs=-0.449, p=0.081). Although BIN1 is known to have a role in endocytosis, and the processing of the amyloid precursor protein (APP) to form amyloid-β (Aβ) peptides is dependent on endocytosis, knockdown of BIN1 by targeted siRNA or the overexpression of BIN1 in a human neuroblastoma cell line (SH-SY5Y) had no effect on APP processing. These data suggest that the alteration in BIN1 is involved in the pathogenesis of sporadic, but not familial AD and is not a consequence of AD neurodegeneration or the ageing process, a finding in keeping with the numerous GWAS that implicate BIN1 in sporadic AD. However, the mechanism of its contribution remains to be established. PMID:24205320

  17. Comparison Between Sporadic and Misdiagnosed Sporadic Creutzfeldt-Jakob Disease: A Report of Two Cases.

    PubMed

    Zhao, Xiongfei; Yu, Yingxin; Zhao, Zhiru; Xu, Jiaping

    2015-06-01

    Definite accurate diagnosis for Creutzfeldt-Jakob disease (CJD) depends on neuropathologic examination of brain biopsy or autopsy. However, transmissible nature makes the invasive examination dangerous. This study was set to determine that the clinical features are for the diagnosis of CJD through a comparison study. We compared clinical features of two cases with initial diagnosis of sporadic CJD. One case was finally diagnosed as definite sporadic CJD. According to World Health Organization diagnosis criteria, the other one, which had been diagnosed as probable sporadic CJD, was confirmed as limbic encephalitis after long-term follow-up. Compared with the case of definite sporadic CJD, the misdiagnosed case did not present typical electroencephalogram (EEG) and diffusion-weighted in magnetic resonance images (DWI) of CJD. However, cerebrospinal fluid in the misdiagnosed patient showed 14-3-3 protein positivity. The patient conditions improved after treatment. Through this case comparison, we conclude that EEG and DWI are necessary for accurate diagnosis of sporadic CJD. Further, long-term follow-up is crucial to diagnosis and treatment of CJD.

  18. Infectivity in bone marrow from sporadic CJD patients.

    PubMed

    Huor, Alvina; Douet, Jean Yves; Lacroux, Caroline; Lugan, Séverine; Tillier, Cécile; Aron, Naima; Cassard, Hervé; Arnold, Mark; Torres, Juan Maria; Ironside, James W; Andréoletti, Olivier

    2017-08-09

    Prion infectivity was recently identified in the blood of both sporadic and variant Creutzfeldt-Jakob disease (CJD) patients. In variant CJD (vCJD), the widespread distribution of prions in peripheral tissues of both asymptomatic and symptomatic patients is likely to explain the occurrence of the observed prionaemia. However, in sporadic CJD (sCJD), prion infectivity is described to be located principally in the central nervous system. In this study, we investigated the presence of prion infectivity in bone marrow collected after death in patients affected with different sCJD agents. Bioassays in transgenic mice expressing the human prion protein revealed the presence of unexpectedly high levels of infectivity in the bone marrow from seven out of eight sCJD cases. These findings may explain the presence of blood-borne infectivity in sCJD patients. They also suggest that the distribution of prion infectivity in peripheral tissues in sCJD patients could be wider than currently believed, with potential implications for the iatrogenic transmission risk of this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  19. The NF1 gene: a frequent mutational target in sporadic pheochromocytomas and beyond.

    PubMed

    Welander, Jenny; Söderkvist, Peter; Gimm, Oliver

    2013-08-01

    Patients suffering from the neurofibromatosis type 1 syndrome, which is caused by germline mutations in the NF1 gene, have a tiny but not negligible risk of developing pheochromocytomas. It is, therefore, of interest that the NF1 gene has recently been revealed to carry somatic, inactivating mutations in a total of 35 (21.7%) of 161 sporadic pheochromocytomas in two independent tumor series. A majority of the tumors in both studies displayed loss of heterozygosity at the NF1 locus and a low NF1 mRNA expression. In view of previous findings that many sporadic pheochromocytomas cluster with neurofibromatosis type 1 syndrome-associated pheochromocytomas instead of forming clusters of their own, NF1 inactivation appears to be an important step in the pathogenesis of a large number of sporadic pheochromocytomas. A literature and public mutation database review has revealed that pheochromocytomas are among those human neoplasms in which somatic NF1 alterations are most frequent.

  20. Effect of Partnership Status on Preferences for Facial Self-Resemblance

    PubMed Central

    Lindová, Jitka; Little, Anthony C.; Havlíček, Jan; Roberts, S. Craig; Rubešová, Anna; Flegr, Jaroslav

    2016-01-01

    Self-resemblance has been found to have a context-dependent effect when expressing preferences for faces. Whereas dissimilarity preference during mate choice in animals is often explained as an evolutionary adaptation to increase heterozygosity of offspring, self-resemblance can be also favored in humans, reflecting, e.g., preference for kinship cues. We performed two studies, using transformations of facial photographs to manipulate levels of resemblance with the rater, to examine the influence of self-resemblance in single vs. coupled individuals. Raters assessed facial attractiveness of other-sex and same-sex photographs according to both short-term and long-term relationship contexts. We found a preference for dissimilarity of other-sex and same-sex faces in single individuals, but no effect of self-resemblance in coupled raters. No effect of sex of participant or short-term vs. long-term attractiveness rating was observed. The results support the evolutionary interpretation that dissimilarity of other-sex faces is preferred by uncoupled individuals as an adaptive mechanism to avoid inbreeding. In contrast, lower dissimilarity preference of other-sex faces in coupled individuals may reflect suppressed attention to attractiveness cues in potential alternative partners as a relationship maintenance mechanism, and its substitution by attention to cues of kinship and psychological similarity connected with greater likelihood of prosocial behavior acquisition from such persons. PMID:27378970

  1. Dynamical model for the toroidal sporadic meteors

    SciTech Connect

    Pokorný, Petr; Vokrouhlický, David; Nesvorný, David; Campbell-Brown, Margaret; Brown, Peter E-mail: vokrouhl@cesnet.cz E-mail: margaret.campbell@uwo.ca

    2014-07-01

    More than a decade of radar operations by the Canadian Meteor Orbit Radar have allowed both young and moderately old streams to be distinguished from the dispersed sporadic background component. The latter has been categorized according to broad radiant regions visible to Earth-based observers into three broad classes: the helion and anti-helion source, the north and south apex sources, and the north and south toroidal sources (and a related arc structure). The first two are populated mainly by dust released from Jupiter-family comets and new comets. Proper modeling of the toroidal sources has not to date been accomplished. Here, we develop a steady-state model for the toroidal source of the sporadic meteoroid complex, compare our model with the available radar measurements, and investigate a contribution of dust particles from our model to the whole population of sporadic meteoroids. We find that the long-term stable part of the toroidal particles is mainly fed by dust released by Halley type (long period) comets (HTCs). Our synthetic model reproduces most of the observed features of the toroidal particles, including the most troublesome low-eccentricity component, which is due to a combination of two effects: particles' ability to decouple from Jupiter and circularize by the Poynting-Robertson effect, and large collision probability for orbits similar to that of the Earth. Our calibrated model also allows us to estimate the total mass of the HTC-released dust in space and check the flux necessary to maintain the cloud in a steady state.

  2. Sporadic Layer es and Siesmic Activity

    NASA Astrophysics Data System (ADS)

    Alimov, Obid; Blokhin, Alexandr; Kalashnikova, Tatyana

    2016-07-01

    To determine the influence of seismogenic disturbances on the calm state of the iono-sphere and assess the impact of turbulence development in sporadic-E during earthquake prepa-ration period we calculated the variation in the range of semitransparency ∆fES = f0ES - fbES. The study was based primarily on the ionograms obtained by vertical sounding of the ionosphere at Dushanbe at nighttime station from 15 to 29 August 1986. In this time period four successive earthquakes took place, which serves the purpose of this study of the impact of seis-mogenic processes on the intensity of the continuous generation of ionospheric turbulence. Analysis of the results obtained for seismic-ionospheric effects of 1986 earthquakes at station Dushanbe has shown that disturbance of ionospheric parameters during earthquake prepa-ration period displays a pronounced maximum with a duration of t = 1-6 hours. Ionospheric effects associated with the processes of earthquake preparation emerge quite predictably, which verifies seismogenic disturbances in the ionosphere. During the preparation of strong earthquakes, ionograms of vertical sounding produced at station Dushanbe - near the epicenter area - often shown the phenomenon of spreading traces of sporadic Es. It is assumed that the duration of manifestation of seismic ionospheric precursors in Du-shanbe τ = 1 - 6 hours may be associated with deformation processes in the Earth's crust and var-ious faults, as well as dissimilar properties of the environment of the epicentral area. It has been shown that for earthquakes with 4.5 ≤ M ≤ 5.5 1-2 days prior to the event iono-spheric perturbations in the parameters of the sporadic layer Es and an increase in the value of the range of semitransparency Es - ΔfEs were observed, which could lead to turbulence at altitudes of 100-130 km.

  3. Dynamical Model for the Toroidal Sporadic Meteors

    NASA Astrophysics Data System (ADS)

    Pokorný, Petr; Vokrouhlický, David; Nesvorný, David; Campbell-Brown, Margaret; Brown, Peter

    2014-07-01

    More than a decade of radar operations by the Canadian Meteor Orbit Radar have allowed both young and moderately old streams to be distinguished from the dispersed sporadic background component. The latter has been categorized according to broad radiant regions visible to Earth-based observers into three broad classes: the helion and anti-helion source, the north and south apex sources, and the north and south toroidal sources (and a related arc structure). The first two are populated mainly by dust released from Jupiter-family comets and new comets. Proper modeling of the toroidal sources has not to date been accomplished. Here, we develop a steady-state model for the toroidal source of the sporadic meteoroid complex, compare our model with the available radar measurements, and investigate a contribution of dust particles from our model to the whole population of sporadic meteoroids. We find that the long-term stable part of the toroidal particles is mainly fed by dust released by Halley type (long period) comets (HTCs). Our synthetic model reproduces most of the observed features of the toroidal particles, including the most troublesome low-eccentricity component, which is due to a combination of two effects: particles' ability to decouple from Jupiter and circularize by the Poynting-Robertson effect, and large collision probability for orbits similar to that of the Earth. Our calibrated model also allows us to estimate the total mass of the HTC-released dust in space and check the flux necessary to maintain the cloud in a steady state.

  4. Genomic aspects of sporadic Parkinson's disease.

    PubMed

    Riederer, P; Youdim, M B H; Mandel, S; Gerlach, M; Grünblatt, E

    2008-01-01

    Parkinson's disease (PD) is thought to be associated with oxidative stress mechanisms, as well as with glutamate receptor abnormalities, ubiquitin-proteasome dysfunction, inflammatory and cytokine activation, dysfunction in neurotrophic factors, damage to mitochondria, cytoskeletal abnormalities, synaptic dysfunction and activation of apoptotic pathways. To investigate these hypotheses, many researchers have applied molecular biology techniques to the study of neuronal cell death in these conditions. In this article, we discuss recent findings of gene expression in PD that may elucidate the usage of specific new biomarkers for sporadic PD and point to novel drug developments.

  5. Early Detection of Sporadic Pancreatic Cancer

    PubMed Central

    Chari, Suresh T.; Kelly, Kimberly; Hollingsworth, Michael A.; Thayer, Sarah P.; Ahlquist, David A.; Andersen, Dana K.; Batra, Surinder K.; Brentnall, Teresa A.; Canto, Marcia; Cleeter, Deborah F.; Firpo, Matthew A.; Gambhir, Sanjiv Sam; Go, Vay Liang W.; Hines, O. Joe; Kenner, Barbara J.; Klimstra, David S.; Lerch, Markus M.; Levy, Michael J.; Maitra, Anirban; Mulvihill, Sean J.; Petersen, Gloria M.; Rhim, Andrew D.; Simeone, Diane M.; Srivastava, Sudhir; Tanaka, Masao; Vinik, Aaron I.; Wong, David

    2015-01-01

    Abstract Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC. PMID:25931254

  6. Sporadic formation of slope streaks on Mars

    NASA Astrophysics Data System (ADS)

    Schorghofer, Norbert; King, Christina M.

    2011-11-01

    Slope streaks are a form of gravity-driven mass-movements that frequently occur on Mars today. The cause of slope streak formation remains unclear; both, dry and wet processes have been suggested. Here, we observationally constrain the time of the year during which slope streaks form. Imagery from four Mars-orbiting cameras is mined to identify locations that have been imaged repeatedly, and the overlapping images are surveyed for streak activity. A search algorithm automatically finds the locations on the surface that have been imaged most often based on a graph representation. Dark slope streaks are found to form sporadically throughout the Mars year. At one study site in the Olympus Mons Aureole, observations constrain slope streak formation to at least five distinct time intervals within a single Mars year. New slope streaks form spatially isolated or in small groups within a few kilometers of one another. The observations suggest that slope streak triggering is unrelated to season and not caused by any large regional events. Most slope streaks are caused by sporadic events of small spatial extent.

  7. Genetic associations with sporadic neuroendocrine tumor risk.

    PubMed

    Ter-Minassian, Monica; Wang, Zhaoxi; Asomaning, Kofi; Wu, Michael C; Liu, Chen-Yu; Paulus, Jessica K; Liu, Geoffrey; Bradbury, Penelope A; Zhai, Rihong; Su, Li; Frauenhoffer, Christine S; Hooshmand, Susanne M; De Vivo, Immaculata; Lin, Xihong; Christiani, David C; Kulke, Matthew H

    2011-08-01

    Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value ≤0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET.

  8. Genetic associations with sporadic neuroendocrine tumor risk

    PubMed Central

    Ter-Minassian, Monica; Wang, Zhaoxi; Asomaning, Kofi; Wu, Michael C.; Liu, Chen-Yu; Paulus, Jessica K.; Liu, Geoffrey; Bradbury, Penelope A.; Zhai, Rihong; Su, Li; Frauenhoffer, Christine S.; Hooshmand, Susanne M.; De Vivo, Immaculata; Lin, Xihong; Christiani, David C.; Kulke, Matthew H.

    2011-01-01

    Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value ≤0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET. PMID:21606320

  9. Early Detection of Sporadic Pancreatic Cancer

    PubMed Central

    Kenner, Barbara J.; Chari, Suresh T.; Cleeter, Deborah F.; Go, Vay Liang W.

    2015-01-01

    Abstract Innovation leading to significant advances in research and subsequent translation to clinical practice is urgently necessary in early detection of sporadic pancreatic cancer. Addressing this need, the Early Detection of Sporadic Pancreatic Cancer Summit Conference was conducted by Kenner Family Research Fund in conjunction with the 2014 American Pancreatic Association and Japan Pancreas Society Meeting. International interdisciplinary scientific representatives engaged in strategic facilitated conversations based on distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. Ideas generated from the summit have led to the development of a Strategic Map for Innovation built upon 3 components: formation of an international collaborative effort, design of an actionable strategic plan, and implementation of operational standards, research priorities, and first-phase initiatives. Through invested and committed efforts of leading researchers and institutions, philanthropic partners, government agencies, and supportive business entities, this endeavor will change the future of the field and consequently the survival rate of those diagnosed with pancreatic cancer. PMID:25938853

  10. An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis

    PubMed Central

    Rotunno, Melissa S.; Bosco, Daryl A.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that targets motor neurons, leading to paralysis and death within a few years of disease onset. While several genes have been linked to the inheritable, or familial, form of ALS, much less is known about the cause(s) of sporadic ALS, which accounts for ~90% of ALS cases. Due to the clinical similarities between familial and sporadic ALS, it is plausible that both forms of the disease converge on a common pathway and, therefore, involve common factors. Recent evidence suggests the Cu,Zn-superoxide dismutase (SOD1) protein to be one such factor that is common to both sporadic and familial ALS. In 1993, mutations were uncovered in SOD1 that represent the first known genetic cause of familial ALS. While the exact mechanism of mutant-SOD1 toxicity is still not known today, most evidence points to a gain of toxic function that stems, at least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, non-genetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a “toxic conformation” that is similar to familial ALS-linked SOD1 variants. These observations, together with the detection of misfolded wild-type SOD1 within human post-mortem sporadic ALS samples, have been used to support the controversial hypothesis that misfolded forms of wild-type SOD1 contribute to sporadic ALS pathogenesis. In this review, we present data from the literature that both support and contradict this hypothesis. We also discuss SOD1 as a potential therapeutic target for both familial and sporadic ALS. PMID:24379756

  11. Neuropathological and biochemical criteria to identify acquired Creutzfeldt-Jakob disease among presumed sporadic cases.

    PubMed

    Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-06-01

    As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP(Sc) ). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP(Sc) in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP(Sc) , represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.

  12. Two sisters resembling Gorlin-Chaudhry-Moss syndrome.

    PubMed

    Aravena, Teresa; Passalacqua, Cristóbal; Pizarro, Oscar; Aracena, Mariana

    2011-10-01

    The Gorlin-Chaudhry-Moss syndrome (GCMS), was describe initially by Gorlin et al. [Gorlin et al. (1960)] in two sisters with craniosynostosis, hypertrichosis, hypoplastic labia majora, dental defects, eye anomalies, patent ductus arteriosus, and normal intelligence. Two other sporadic instances have been documented. Here, we report on two sisters with a condition with some similarities to GCMS as well as some differences, which could represent either previously unreported variability in GCMS, or it may represent a novel disorder.

  13. Gait analysis in a mouse model resembling Leigh disease.

    PubMed

    de Haas, Ria; Russel, Frans G; Smeitink, Jan A

    2016-01-01

    Leigh disease (LD) is one of the clinical phenotypes of mitochondrial OXPHOS disorders and also known as sub-acute necrotizing encephalomyelopathy. The disease has an incidence of 1 in 77,000 live births. Symptoms typically begin early in life and prognosis for LD patients is poor. Currently, no clinically effective treatments are available. Suitable animal and cellular models are necessary for the understanding of the neuropathology and the development of successful new therapeutic strategies. In this study we used the Ndufs4 knockout (Ndufs4(-/-)) mouse, a model of mitochondrial complex I deficiency. Ndusf4(-/-) mice exhibit progressive neurodegeneration, which closely resemble the human LD phenotype. When dissecting behavioral abnormalities in animal models it is of great importance to apply translational tools that are clinically relevant. To distinguish gait abnormalities in patients, simple walking tests can be assessed, but in animals this is not easy. This study is the first to demonstrate automated CatWalk gait analysis in the Ndufs4(-/-) mouse model. Marked differences were noted between Ndufs4(-/-) and control mice in dynamic, static, coordination and support parameters. Variation of walking speed was significantly increased in Ndufs4(-/-) mice, suggesting hampered and uncoordinated gait. Furthermore, decreased regularity index, increased base of support and changes in support were noted in the Ndufs4(-/-) mice. Here, we report the ability of the CatWalk system to sensitively assess gait abnormalities in Ndufs4(-/-) mice. This objective gait analysis can be of great value for intervention and drug efficacy studies in animal models for mitochondrial disease.

  14. Intentions vs. resemblance: understanding pictures in typical development and autism.

    PubMed

    Hartley, Calum; Allen, Melissa L

    2014-04-01

    Research has debated whether children reflect on artists' intentions when comprehending pictures, or instead derive meaning entirely from resemblance. We explore these hypotheses by comparing how typically developing toddlers and low-functioning children with autism (a population impaired in intentional reasoning) interpret abstract pictures. In Experiment 1, both groups mapped familiar object names onto abstract pictures, however, they related the same representations to different 3-D referents. Toddlers linked abstract pictures with intended referents they did not resemble, while children with autism mapped picture-referent relations based on resemblance. Experiment 2 showed that toddlers do not rely upon linguistic cues to determine intended referential relations. Experiment 3 confirmed that the responding of children with autism was not due to perseveration or associative word learning, and also provided independent evidence of their intention-reading difficulties. We argue that typically developing children derive meaning from the social-communicative intentions underlying pictures when resemblance is an inadequate cue to meaning. By contrast, children with autism do not reflect on artists' intentions and simply relate pictures to whatever they happen to resemble. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Sporadic wind wave horse-shoe patterns

    NASA Astrophysics Data System (ADS)

    Annenkov, S. Yu.; Shrira, V. I.

    The work considers three-dimensional crescent-shaped patterns often seen on water surface in natural basins and observed in wave tank experiments. The most common of these 'horse-shoe-like' patterns appear to be sporadic, i.e., emerging and disappearing spontaneously even under steady wind conditions. The paper suggests a qualitative model of these structures aimed at explaining their sporadic nature, physical mechanisms of their selection and their specific asymmetric form. First, the phenomenon of sporadic horse-shoe patterns is studied numerically using the novel algorithm of water waves simulation recently developed by the authors (Annenkov and Shrira, 1999). The simulations show that a steep gravity wave embedded into widespectrum primordial noise and subjected to small nonconservative effects typically follows the simple evolution scenario: most of the time the system can be considered as consisting of a basic wave and a single pair of oblique satellites, although the choice of this pair tends to be different at different instants. Despite the effective low-dimensionality of the multimodal system dynamics at relatively sho ' rt time spans, the role of small satellites is important: in particular, they enlarge the maxima of the developed satellites. The presence of Benjamin-Feir satellites appears to be of no qualitative importance at the timescales under consideration. The selection mechanism has been linked to the quartic resonant interactions among the oblique satellites lying in the domain of five-wave (McLean's class II) instability of the basic wave: the satellites tend to push each other out of the resonance zone due to the frequency shifts caused by the quartic interactions. Since the instability domain is narrow (of order of cube of the basic wave steepness), eventually in a generic situation only a single pair survives and attains considerable amplitude. The specific front asymmetry is found to result from the interplay of quartic and quintet

  16. [Treatability of sporadic late onset nemaline myopathy].

    PubMed

    Hanisch, F; Schneider, I; Müller, T; Romeike, B F; Stoltenburg, G; Holzhausen, H J; Zierz, S

    2013-08-01

    Sporadic late onset nemaline myopathy (SLONM) is an extremely rare disorder which can be associated with monoclonal gammopathy of unclear significance (MGUS). Clinically SLONM appears mostly after the fourth decade of life as rapidly progressing tetraparesis, respiratory insufficiency and features, such as dropped head syndrome, facial and bulbar involvement. Diagnosis is confirmed by muscle biopsy with detection of nemaline bodies and also frequently lobulated fibres. Immunosuppressant and immunomodulating therapies have been shown to be ineffective but clinical improvement accompanied by disappearance of monoclonal gammopathy and even nemaline bodies was reported following autologous stem cell transplantation and chemotherapy with melphalan. This article presents the case of a 53-year-old man with a 4-year history of SLOMN with MGUS in which administration of intravenous immunoglobulin therapy (IVIG) was not successful in reversing gammopathy, histopathological changes or clinical symptoms.

  17. Ongoing developments in sporadic inclusion body myositis.

    PubMed

    Machado, Pedro M; Ahmed, Mhoriam; Brady, Stefen; Gang, Qiang; Healy, Estelle; Morrow, Jasper M; Wallace, Amanda C; Dewar, Liz; Ramdharry, Gita; Parton, Matthew; Holton, Janice L; Houlden, Henry; Greensmith, Linda; Hanna, Michael G

    2014-12-01

    Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM.

  18. Proteasomal dysfunction in sporadic Parkinson's disease.

    PubMed

    McNaught, Kevin St P; Jackson, Tehone; JnoBaptiste, Ruth; Kapustin, Alexander; Olanow, C Warren

    2006-05-23

    The cause and mechanism of neuronal death in sporadic Parkinson's disease (PD) continue to elude investigators. Recently, alterations in proteasomal function have been detected in the brain of patients with the illness. The biochemical basis of the defect and its relevance to the disease process are now being studied. The available results suggest that proteasomal dysfunction could underlie protein accumulation, Lewy body formation, and neuron death in PD. The cause of proteasomal dysfunction is unknown at present, but this could relate to gene mutations, oxidative damage, ATP depletion, or the actions of environmental toxins. It remains to be established if proteasomal dysfunction plays a primary or a secondary role in the initiation or progression of the neurodegenerative process in PD.

  19. Introduction to sporadic groups for physicists

    NASA Astrophysics Data System (ADS)

    Boya, Luis J.

    2013-04-01

    We describe the collection of finite simple groups, with a view to physical applications. We recall first the prime cyclic groups Zp and the alternating groups Altn > 4. After a quick revision of finite fields {F}_q, q = pf, with p prime, we consider the 16 families of finite simple groups of Lie type. There are also 26 extra ‘sporadic’ groups, which gather in three interconnected ‘generations’ (with 5+7+8 groups) plus the pariah groups (6). We point out a couple of physical applications, including constructing the biggest sporadic group, the ‘Monster’ group, with close to 1054 elements from arguments of physics, and also the relation of some Mathieu groups with compactification in string and M-theory. This article is dedicated to the memory of Juan Sancho Guimerá.

  20. A hypothesis to explain accuracy of wasp resemblances.

    PubMed

    Boppré, Michael; Vane-Wright, Richard I; Wickler, Wolfgang

    2017-01-01

    Mimicry is one of the oldest concepts in biology, but it still presents many puzzles and continues to be widely debated. Simulation of wasps with a yellow-black abdominal pattern by other insects (commonly called "wasp mimicry") is traditionally considered a case of resemblance of unprofitable by profitable prey causing educated predators to avoid models and mimics to the advantage of both (Figure 1a). However, as wasps themselves are predators of insects, wasp mimicry can also be seen as a case of resemblance to one's own potential antagonist. We here propose an additional hypothesis to Batesian and Müllerian mimicry (both typically involving selection by learning vertebrate predators; cf. Table 1) that reflects another possible scenario for the evolution of multifold and in particular very accurate resemblances to wasps: an innate, visual inhibition of aggression among look-alike wasps, based on their social organization and high abundance. We argue that wasp species resembling each other need not only be Müllerian mutualists and that other insects resembling wasps need not only be Batesian mimics, but an innate ability of wasps to recognize each other during hunting is the driver in the evolution of a distinct kind of masquerade, in which model, mimic, and selecting agent belong to one or several species (Figure  1b). Wasp mimics resemble wasps not (only) to be mistaken by educated predators but rather, or in addition, to escape attack from their wasp models. Within a given ecosystem, there will be selection pressures leading to masquerade driven by wasps and/or to mimicry driven by other predators that have to learn to avoid them. Different pressures by guilds of these two types of selective agents could explain the widely differing fidelity with respect to the models in assemblages of yellow jackets and yellow jacket look-alikes.

  1. Ext-mutation analysis in Italian sporadic and hereditary osteochondromas.

    PubMed

    Gigante, M; Matera, M G; Seripa, D; Izzo, A M; Venanzi, R; Giannotti, A; Digilio, M C; Gravina, C; Lazzari, M; Monteleone, G; Monteleone, M; Dallapiccola, B; Fazio, V M

    2001-11-20

    Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes. Copyright 2001 Wiley-Liss, Inc.

  2. Investigations on the Plasma Irregularities Associated with Midlatitude Sporadic-E Layers

    NASA Astrophysics Data System (ADS)

    Riggin, Dennis Marshall

    The Cornell University Portable Radar Interferometer (CUPRI), a 50 MHz Doppler radar system, was operated during May and August/September, 1983, on the island of St. Croix (17.7(DEGREES)N, 64.8(DEGREES)W) to study the plasma instabilities associated with nighttime sporadic-E layers. The CURPI beam was directed over Arecibo, Puerto Rico, during these experiments and on several nights concurrent F region plasma drifts and electron density profiles were measured by the Arecibo Observatory's 430 MHz radar. CUPRI was stationed at Ft. Macon, North Carolina, in August 1984 for another collaborative experiment involving the launch of a sounding rocket from Wallops Island, Virginia. The usual E region linear plasma fluid theory is adequate to explain many features of the 3-m waves probed by the radar. Measurements at St. Croix determined that the 3-m sporadic-E irregularities are highly field-aligned (to within 0.3(DEGREES)) as the theory predicts. Some of the radar spectra obtained from St. Croix are narrow, similar to equatorial type 1. We find from linear theory that the type 1 3-m waves could be generated at midlatitudes with drift velocities well below the sound speed because of the very sharp gradients associated with metallic ion sporadic-E layers. Two events during the St. Croix campaign show evidence of large scale plasma waves, with horizontal wavelengths of 6-10 km and periods of 2-5 minutes. These waves were large in amplitude with mean Doppler velocities at times exceeding 250 m/s, and the power spectra closely resemble those obtained at the magnetic equator during type 1 conditions. The rocket measurements also revealed large scale plasma irregularities in a low density region above a sporadic-E layer. The large scale structure had an apparent wavelength of about 2 km and modulated the ambient density (10('4) cm('-3)) by almost 100%. We attribute the large scale waves seen during these experiments to the same gradient drift instability mechanism responsible

  3. Reflection of radio waves by sporadic-E layers

    NASA Technical Reports Server (NTRS)

    Miller, K. L.; Smith, L. G.

    1977-01-01

    A full-wave analysis of the reflection coefficient is developed and applied to electron-density profiles of midlatitude sporadic-E layers observed by rocket-borne probes. It is shown that partial reflection from the large electron-density gradients at the upper and lower boundaries of sporadic-E layers does not account for the partial transparency observed by ionosondes.

  4. Reflection of radio waves by sporadic-E layers

    NASA Technical Reports Server (NTRS)

    Miller, K. L.; Smith, L. G.

    1977-01-01

    A full-wave analysis of the reflection coefficient is developed and applied to electron-density profiles of midlatitude sporadic-E layers observed by rocket-borne probes. It is shown that partial reflection from the large electron-density gradients at the upper and lower boundaries of sporadic-E layers does not account for the partial transparency observed by ionosondes.

  5. Family resemblance in fat intake in The Netherlands.

    PubMed

    Feunekes, G I; Stafleu, A; de Graaf, C; van Staveren, W A

    1997-12-01

    To assess family resemblance in fat intake in a representative sample of Dutch families. Households (n = 1077) with children between 1 and 30 y old were selected from the data set of the Dutch National Food Consumption Survey 1992. Two-day diet records were available for all household members. Pearson correlation coefficients for fat and fatty acid intakes (En%) ranged from r = 0.51 to r = 0.61 between parents, and from r = 0.52 to r = 0.72 between siblings. The mean associations in fat and fatty acid intake (En%) between mothers or fathers and children ranged from r = 0.37 to r = 0.50, and they were surprisingly similar for children from 1-3 y of age up to children above 21 y of age. Associations were consistently high for foods eaten at home, and weak for foods eaten outside of the home. Similar within-family associations were found in a set of 1052 households of the Dutch National Food Consumption Survey of 1987. Reported adherence to a therapeutic diet by one of the parents did not erase within-family intake correlations, suggesting that family resemblance is a dynamic phenomenon. Dutch parents and children living together resemble each other in short term intake of fats and fatty acids. This study was supported by the Ministry of Agriculture, Nature Management and Fisheries. Fat intake; dietary intake; social environment; family resemblance.

  6. ASL Nominal Constructions Involving Signs That Resemble Pronouns

    ERIC Educational Resources Information Center

    Sloan, Vivion Smith

    2013-01-01

    This dissertation examines six different types of noun phrases that commonly occur in American Sign Language. These noun phrases all include at least a head noun and one of four signs resembling a pronoun. Videos of natural ASL discourses are gathered, multiple instances of the six types of noun phrases are identified, and their meanings are…

  7. Differential grandparental investment - the impact of phenotypic resemblance.

    PubMed

    Schlee, Juliane; Kirchengast, Sylvia

    2015-01-01

    Differential grandparental investment is mainly explained as a result of paternity uncertainty. Phenotypic resemblance may be interpreted as an indicator of genetically relatedness. Consequently the present study focused on the impact of phenotypic resemblance on grandparental investment, i.e. solicitude, contact frequency and quality of relationship. 213 adults persons between the age 19 and 32 years (x = 25.5; SD = 3.4) were enrolled in the study. Data concerning grandparental investment during childhood were collected retrospectively using a 30 item questionnaire. Grandparental investment patterns differed significantly according grandparent category. In detail maternal grandmothers showed the highest contact frequency and the highest solicitude while - as to be expected - the paternal grandfather exhibited the lowest degree of investment. Grandparental investment was independent of grandparent category mainly influenced by residential distance. Phenotypic resemblance had an impact on grandparental investment independent of residential distance. This was first of all true of paternal grandfathers. An impact of phenotypic resemblance on grandparental investment patters can be assumed.

  8. Studies of sporadic E (Es) associated with the main ionospheric trough

    SciTech Connect

    Rodger, A.S.; Morrell, C.; Dudeney, J.R.

    1983-11-01

    Sporadic E, or E(s) events under the main F region trough have been confirmed on the basis of ionograms from a vertical incidence ionosonde at Halley Bay, Antarctica. Analyses indicate that E(s) is frequently observable under both the equatorward and the poleward edges of the trough, as well as poleward of it. Before magnetic midnight, E(s) layers whose semithickness resembles those of the normal E layer are common, in contrast to layers seen after magnetic midnight which show the characteristics of thin E(s) layers. A possible explanation of the observed change in the E(s) layer characteristics at magnetic midnight is related to differences in the type and spectra of the precipitating particles. It is shown that the redistribution of ionization by the convection electric field may be important. 40 references.

  9. Viruses detected among sporadic cases of parotitis, United States, 2009-2011.

    PubMed

    Barskey, Albert E; Juieng, Phalasy; Whitaker, Brett L; Erdman, Dean D; Oberste, M Steven; Chern, Shur-Wern Wang; Schmid, D Scott; Radford, Kay W; McNall, Rebecca J; Rota, Paul A; Hickman, Carole J; Bellini, William J; Wallace, Gregory S

    2013-12-15

    Sporadic cases of parotitis are generally assumed to be mumps, which often requires a resource-intensive public health response. This project surveyed the frequency of viruses detected among such cases. During 2009-2011, 8 jurisdictions throughout the United States investigated sporadic cases of parotitis. Epidemiologic information, serum, and buccal and oropharyngeal swabs were collected. Polymerase chain reaction methods were used to detect a panel of viruses. Anti-mumps virus immunoglobulin M (IgM) antibodies were detected using a variety of methods. Of 101 specimens, 38 were positive for a single virus: Epstein-Barr virus (23), human herpesvirus (HHV)-6B (10), human parainfluenza virus (HPIV)-2 (3), HPIV-3 (1), and human bocavirus (1). Mumps virus, enteroviruses (including human parechovirus), HHV-6A, HPIV-1, and adenoviruses were not detected. Early specimen collection did not improve viral detection rate. Mumps IgM was detected in 17% of available specimens. Patients in whom a virus was detected were younger, but no difference was seen by sex or vaccination profile. No seasonal patterns were identified. Considering the timing of specimen collection, serology results, patient vaccination status, and time of year may be helpful in assessing the likelihood that a sporadic case of parotitis without laboratory confirmation is mumps.

  10. Congenital symmetrical weakness of the upper limbs resembling brachial plexus palsy: a possible sequel of drug toxicity in first trimester of pregnancy?

    PubMed

    Philpot, J; Muntoni, F; Skellett, S; Dubowitz, V

    1995-01-01

    We report a 14-month-old girl with a symmetrical paralysis from birth, limited to the upper limbs and resembling a severe, complete bilateral brachial plexus palsy. The presence of dimples over the wrists, shoulders and scapulae and abnormal palmar dermatoglyphics suggested an early prenatal onset. Previous reports and the course of the disease in our case suggest this sporadic condition is not progressive. Although no definitive causative factor has been identified in previously reported cases, the affection in our case is possibly related to Debendox (Bendectin) and nitrofurantoin taken in early pregnancy for nausea and renal tract infection, respectively.

  11. Sporadic nocturnal frontal lobe epilepsy: A consecutive series of 8 cases

    PubMed Central

    Yeh, Shih-Bin; Schenck, Carlos H.

    2014-01-01

    Objective To present findings on a series of cases of sporadic nocturnal frontal lobe epilepsy (NFLE), a form of NFLE that is infrequently reported, in contrast to familial (autosomal dominant) NFLE. Both forms of NFLE need to be distinguished from parasomnias, nocturnal temporal lobe epilepsy, and other nocturnal disorders. Methods Eight consecutive cases of sporadic NFLE were evaluated at a sleep clinic in Taiwan. All patients had clinical evaluations, daytime waking and sleeping EEGs, brain MRIs, and overnight video-polysomnography (vPSG) with seizure montage. Results Gender was equal (four males, four females); mean age was 18.4 yrs (range, 7–41 yrs). Age of NFLE onset was by puberty. Premorbid history was negative for any neurologic, medical or psychiatric disorder. NFLE subtypes: nocturnal paroxysmal dystonia, n=6; paroxysmal arousals, n=2. MRI brain scan abnormalities with clinical correlates were found in one patient. Daytime awake EEGs were negative for ictal/interictal activity in all patients, but two patients had daytime sleep EEGs with interictal epileptiform EEG activity. During vPSG studies, three of eight patients with NFLE seizure events had concurrent epileptiform EEG activity, and two patients had interictal epileptiform EEG activity during their vPSG studies. No case had a spontaneous remission. Anticonvulsant therapy was highly effective in all eight cases (>75% reduction in seizure frequency). Discussion These cases confirm that sporadic NFLE closely resembles familial NFLE, and comprises a set of distinct clinical manifestations, with variable intensity, and variable scalp EEG epileptiform abnormalities across sleep and wakefulness, which have previously been identified in Caucasian patients from Europe and North America. PMID:26483923

  12. Sporadic aurorae observed in East Asia

    NASA Astrophysics Data System (ADS)

    Willis, D. M.; Stephenson, F. R.; Fang, Huiping

    2007-03-01

    All the accessible auroral observations recorded in Chinese and Japanese histories during the interval AD 1840-1911 are investigated in detail. Most of these auroral records have never been translated into a Western language before. The East Asian auroral reports provide information on the date and approximate location of each auroral observation, together with limited scientific information on the characteristics of the auroral luminosity such as colour, duration, extent, position in the sky and approximate time of occurrence. The full translations of the original Chinese and Japanese auroral records are presented in an appendix, which contains bibliographic details of the various historical sources. (There are no known reliable Korean observations during this interval.) A second appendix discusses a few implausible "auroral" records, which have been rejected. The salient scientific properties of all exactly dated and reliable East Asian auroral observations in the interval AD 1840-1911 are summarised succinctly. By comparing the relevant scientific information on exactly dated auroral observations with the lists of great geomagnetic storms compiled by the Royal Greenwich Observatory, and also the tabulated values of the Ak (Helsinki) and aa (Greenwich and Melbourne) magnetic indices, it is found that 5 of the great geomagnetic storms (aa>150 or Ak>50) during either the second half of the nineteenth century or the first decade of the twentieth century are clearly identified by extensive auroral displays observed in China or Japan. Indeed, two of these great storms produced auroral displays observed in both countries on the same night. Conversely, at least 29 (69%) of the 42 Chinese and Japanese auroral observations occurred at times of weak-to-moderate geomagnetic activity (aa or Ak≤50). It is shown that these latter auroral displays are very similar to the more numerous (about 50) examples of sporadic aurorae observed in the United States during the interval AD

  13. Radar studies of long-wavelength waves associated with mid-latitude sporadic E layers

    NASA Astrophysics Data System (ADS)

    Riggin, D.; Swartz, W. E.; Providakes, J.; Farley, D. T.

    1986-07-01

    The Cornell University Portable Radar Interferometer (CUPRI), a 50-MHz Doppler radar system, was operated during May and August/September 1983 on the island of St. Croix (17.7 deg N, 64.8 deg W) to study the plasma instabilities associated with nighttime sporadic E layers. Two events, on May 7 and August 22, show evidence of large-amplitude waves, with apparent horizontal wavelengths of 10-12 km and periods of 2-6 min. These apparent wavelengths are upper limits for the true wavelengths. The CUPRI beam was directed over Arecibo, PR, and on May 7, concurrent electron density profiles within the CUPRI scattering volume were measured by the Arecibo Observatory's 430-MHz radar. During the stronger event of August 22, radar echoes were received from several altitudes up to 130 km. Large mean Doppler velocities (at times exceeding 250 m/s) were observed during this event, and the power spectra closely resemble those obtained at the magnetic equator during type 1 conditions. It is believed (1) that the midlatitude large-scale waves are generated by the same gradient drift instability mechanism responsible for equatorial large-scale waves, and (2) that the type 1 3-m waves can be generated at midlatitudes with drift velocities well below the sound speed because of the very sharp plasma density gradients associated with metallic ion sporadic E layers.

  14. Kuru prions and sporadic Creutzfeldt-Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice.

    PubMed

    Wadsworth, Jonathan D F; Joiner, Susan; Linehan, Jacqueline M; Desbruslais, Melanie; Fox, Katie; Cooper, Sharon; Cronier, Sabrina; Asante, Emmanuel A; Mead, Simon; Brandner, Sebastian; Hill, Andrew F; Collinge, John

    2008-03-11

    Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt-Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD.

  15. Kuru prions and sporadic Creutzfeldt–Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice

    PubMed Central

    Wadsworth, Jonathan D. F.; Joiner, Susan; Linehan, Jacqueline M.; Desbruslais, Melanie; Fox, Katie; Cooper, Sharon; Cronier, Sabrina; Asante, Emmanuel A.; Mead, Simon; Brandner, Sebastian; Hill, Andrew F.; Collinge, John

    2008-01-01

    Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt–Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD. PMID:18316717

  16. [The Nomenclature and Classification of Sporadic Spinocerebellar Degeneration].

    PubMed

    Koga, Shunsuke

    2016-12-01

    Spinocerebellar degeneration (SCD) is a neurodegenerative disease characterized by progressive cerebellar ataxia. SCD has a wide range of clinical, pathological, and genetic features, including whether the disease is sporadic or hereditary, and whether it manifests as purely cerebellar or affects multiple systems. Therefore, the classification of SCD has been complicated and has changed over time. Recent advances in genetic testing have shed light on the classification of hereditary SCD. In contrast, the classification of sporadic SCD remains chaotic and there exist nomenclature discrepancies in sporadic SCD between Japanese and English literature. Sporadic SCD is usually divided into multiple system atrophy and cortical cerebellar atrophy in Japanese literature, but the latter nomenclature seems to be uncommon in English literature. The aim of this review is to reconsider the nomenclature and classification of sporadic SCD. At this time, sporadic adult-onset ataxia of unknown etiology is an acceptable term to describe a case of sporadic SCD that does not fit the multiple system atrophy classification.

  17. Synchrony in Metapopulations with Sporadic Dispersal

    NASA Astrophysics Data System (ADS)

    Jeter, Russell; Belykh, Igor

    2015-06-01

    We study synchronization in ecological networks under the realistic assumption that the coupling among the patches is sporadic/stochastic and due to rare and short-term meteorological conditions. Each patch is described by a tritrophic food chain model, representing the producer, consumer, and predator. If all three species can migrate, we rigorously prove that the network can synchronize as long as the migration occurs frequently, i.e. fast compared to the period of the ecological cycle, even though the network is disconnected most of the time. In the case where only the top trophic level (i.e. the predator) can migrate, we reveal an unexpected range of intermediate switching frequencies where synchronization becomes stable in a network which switches between two nonsynchronous dynamics. As spatial synchrony increases the danger of extinction, this counterintuitive effect of synchrony emerging from slower switching dispersal can be destructive for overall metapopulation persistence, presumably expected from switching between two dynamics which are unfavorable to extinction.

  18. Microsatellite instability in early sporadic breast cancer.

    PubMed Central

    Shaw, J. A.; Walsh, T.; Chappell, S. A.; Carey, N.; Johnson, K.; Walker, R. A.

    1996-01-01

    We have studied the incidence of microsatellite instability at three trinucleotide repeats and seven dinucleotide repeats from five chromosomal regions, in a group of 30 mammographically detected 'early' invasive breast cancers and correlated its occurrence with clinicopathological parameters. The myotonic dystrophy (DM-1) trinucleotide repeat was analysed in 48 additional cases. In 4 out of 78 (5%) paired tumour-normal DNA samples we found evidence of somatic microsatellite instability at DM-1: a novel allele of a different size was seen in the tumour DNA which was not present in the normal DNA sample. All four tumours that showed evidence of instability were from the core group of 30 cases (13%) and were well or moderately differentiated, oestrogen receptor-positive, infiltrating ductal carcinomas. Two of these tumours were unstable at nine of ten loci studied, both trinucleotide and dinucleotide repeats. DNA prepared from different normal tissues showed no evidence of instability, for all four instability cases. These data indicate that microsatellite instability is specific to the tumour DNA and is an early event in the genesis of some sporadic breast cancers. Images Figure 1 PMID:8645585

  19. [Swinepox--skin disease with sporadic occurrence].

    PubMed

    Moorkamp, L; Beineke, A; Kaim, U; Diesterbeck, U; Urstadt, S; Czerny, C P; Rüberg, H; Grosse Beilage, E

    2008-04-01

    Swinepox virus infection results in an acute, mild or subclinical course and is characterised by typical poxvirus skin lesions in affected pigs. Additionally, sporadic vertical swinepox virus transmission leads to congenital generalised infection and subsequent abortion or stillbirth. The present report describes the occurrence of epidermal efflorescences in two piglets after intrauterine natural suipoxvirus infection. No clinical abnormalities of the gilt and littermates as well as in other pigs from this herd were present. One of the affected piglets was stillborn and submitted for necropsy, the other animal was alive at birth, but died 3 days later. Histologically, a proliferative to ulcerative dermatitis with epithelial ballooning degeneration and characteristic intracytoplasmatic inclusion bodies was observed. The pathomorphological and histopathological suspected diagnosis of a poxvirus infection was confirmed by electron microscopy. Furthermore, the agent was identified as suipoxvirus by polymerase chain reaction. As demonstrated here, obvious skin lesions in suipoxvirus infection leads to a suspected diagnosis in newborn piglets on macroscopic examination. However, further post mortem examinations, including electron microscopy as well as molecular techniques are essential for the identification of the aetiology and the exclusion of differential diagnoses. Because the disease only affected two pigs there was only a small economic loss. A valid diagnostic plays an important role in advising farmers and for herd health monitoring.

  20. Sporadic and hereditary amyotrophic lateral sclerosis (ALS).

    PubMed

    Ajroud-Driss, Senda; Siddique, Teepu

    2015-04-01

    Genetic discoveries in ALS have a significant impact on deciphering molecular mechanisms of motor neuron degeneration. The identification of SOD1 as the first genetic cause of ALS led to the engineering of the SOD1 mouse, the backbone of ALS research, and set the stage for future genetic breakthroughs. In addition, careful analysis of ALS pathology added valuable pieces to the ALS puzzle. From this joint effort, major pathogenic pathways emerged. Whereas the study of TDP43, FUS and C9ORF72 pointed to the possible involvement of RNA biology in motor neuron survival, recent work on P62 and UBQLN2 refocused research on protein degradation pathways. Despite all these efforts, the etiology of most cases of sporadic ALS remains elusive. Newly acquired genomic tools now allow the identification of genetic and epigenetic factors that can either increase ALS risk or modulate disease phenotype. These developments will certainly allow for better disease modeling to identify novel therapeutic targets for ALS. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

  1. Anterior cervical hypertrichosis: a sporadic case

    PubMed Central

    Bostan, Sezen; Yaşar, Şirin; Serdar, Zehra Aşiran; Gizlenti, Sevda

    2016-01-01

    Anterior cervical hypertrichosis is a very rare form of primary localized hypertrichosis. It consists of a tuft of terminal hair on the anterior neck just above the laryngeal prominence. The etiology is still unknown. In this article, we reported a 15-year-old female patient who presented to our clinic with a complaint of hypertrichosis on the anterior aspect of the neck for the last five years. Her past medical history revealed no pathology except for vesicoureteral reflux. On the basis of clinical presentation, our patient was diagnosed with anterior cervical hypertrichosis and she was considered to be a sporadic case due to lack of other similar cases in familial history. To date, 33 patients with anterior cervical hypertrichosis have been reported. Anterior cervical hypertrichosis can be associated with other abnormalities, but it frequently presents as an isolated defect (70%). The association of vesicoureteral reflux and anterior cervical hypertrichosis which was observed in our patient might be coincidental. So far, no case of anterior cervical hypertrichosis associated with vesicoureteral reflux has been reported in the literature. PMID:27103865

  2. Aneurysm in a Large Sporadic Renal Angiomyolipoma

    PubMed Central

    Al Omran, Bedoor; Ansari, Naseem

    2016-01-01

    Angiomyolipomas (AMLs) are the most common mesenchymal renal neoplasms and are classified as neoplasms of perivascular epithelioid cells (PEComa). AML is usually a benign neoplasm arising most often in the kidney although it has been described in a wide variety of sites. Most patients are adults, and one-third suffer from tuberous sclerosis. We describe a case of renal AML in a 54-year-old Bahraini woman who presented to the Bahrain Defence Force Hospital with right flank pain and hematuria, and who was known to have rheumatoid arthritis but had no cutaneous or other stigmata of tuberous sclerosis. It is the largest AML reported in Bahrain and is also striking for the fact that it contained an intratumoral aneurysm that ruptured causing symptoms leading to the radiological diagnosis of renal mass. Furthermore, the occurrence of an aneurysm in sporadic AML, as in our case, is rare since the large majority tend to be seen in association with tuberous sclerosis. PMID:27162594

  3. Anterior cervical hypertrichosis: a sporadic case.

    PubMed

    Bostan, Sezen; Yaşar, Şirin; Serdar, Zehra Aşiran; Gizlenti, Sevda

    2016-03-01

    Anterior cervical hypertrichosis is a very rare form of primary localized hypertrichosis. It consists of a tuft of terminal hair on the anterior neck just above the laryngeal prominence. The etiology is still unknown. In this article, we reported a 15-year-old female patient who presented to our clinic with a complaint of hypertrichosis on the anterior aspect of the neck for the last five years. Her past medical history revealed no pathology except for vesicoureteral reflux. On the basis of clinical presentation, our patient was diagnosed with anterior cervical hypertrichosis and she was considered to be a sporadic case due to lack of other similar cases in familial history. To date, 33 patients with anterior cervical hypertrichosis have been reported. Anterior cervical hypertrichosis can be associated with other abnormalities, but it frequently presents as an isolated defect (70%). The association of vesicoureteral reflux and anterior cervical hypertrichosis which was observed in our patient might be coincidental. So far, no case of anterior cervical hypertrichosis associated with vesicoureteral reflux has been reported in the literature.

  4. Sporadic, severe bronchointerstitial pneumonia of foals

    PubMed Central

    Prescott, John F.; Wilcock, Brian P.; Carman, P. Suzanne; Hoffman, Andrew M.

    1991-01-01

    Bronchointerstitial pneumonia was diagnosed postmortem in 19 foals in a 10 year retrospective study of submissions to a diagnostic center in Ontario. Mean age at death was 2.0 ± 0.05 (SEM) mo (range five days to four months). Fourteen of 19 were aged from 1.5 to 2.5 mo. Clinically, the disease was generally characterized by sudden onset of fever and increasingly severe dyspnea which developed into respiratory distress before death. Mean length of illness was 7.0 ± 0.33 days (range 1-21 days). The disease appeared to affect only individual foals on 19 different farms. At postmortem, lungs were typically diffusely red, wet, firm, and failed to collapse. The major lesion recognized histologically was epithelial necrosis of alveoli and terminal bronchioles. Alveolar lumens contained large epithelioid cells, which were probably macrophages, and multinucleated syncytial cells were present in 16 of the 19 lungs. Inflammatory cells were sparse. Intraalveolar fibrin was prominent in all lungs. Bacteriological examination revealed no significant pathogen in 12 animals, but Rhodococcus equi was isolated from seven foals, associated in two animals with extensive abscesses. Viruses were not recovered from eight foals examined. On the basis of the similarity and severity of lesions, the sporadic nature of the disease, and the similar age at onset which appears to coincide with declining maternally-derived immunoglobulins, we speculate that this disease may be the result of a viral infection. ImagesFigure 1.Figure 2.Figure 3. PMID:17423819

  5. Sensorineural hearing loss in sporadic congenital hypothyroidism.

    PubMed Central

    Vanderschueren-Lodeweyckx, M; Debruyne, F; Dooms, L; Eggermont, E; Eeckels, R

    1983-01-01

    Hearing acuity was assessed in 45 children with sporadic congenital hypothyroidism during adequate long-term treatment. Otoscopy was performed in each and additional tympanometry in some of them. Secretory otitis media was found in 6 and was treated medically or by inserting grommets in the eardrum. In these children, hearing acuity was assessed after the otitis had been cured. Hearing acuity was measured either by conventional monoaural pure-tone audiometry (125-8000 Hz) or by binaural free field testing depending on the child's age (above and below 4 years respectively). Hearing was normal in 36 (80%) children. In the remaining 9, sensorineural hearing loss to some degree was detected affecting the higher frequencies in particular. Perceptive deafness required the use of a hearing aid in 4 children. No relationship could be found between hearing acuity and chronological age or bone age at diagnosis of congenital hypothyroidism or type of hypothyroidism. Sensorineural hearing loss is common in children with congenital hypothyroidism and should be searched for carefully and systematically to avoid difficulties related to speech and language development. PMID:6859932

  6. Lifestyle and Sporadic Colorectal Cancer in India.

    PubMed

    Sinha, Rupal; Doval, Dinesh Chandra; Hussain, Showket; Kumar, Kapil; Singh, Shivendra; Basir, Seemi Farhat; Bharadwaj, Mausumi

    2015-01-01

    The study evaluated the patient, lifestyle and tumor profile in patients undergoing upfront surgery for sporadic colorectal cancer (CRC) in Indian population. One hundred consecutive patients were included. Details related to their demographic profile, habits, signs and symptoms, tumor profile, further treatment and follow up were recorded. The majority of the patients had colonic cancer (68%), advanced tumor stage 3 and 4 (46%), moderately differentiated tumors (70%) with absence of lymphatic invasion (60%) and metastasis (90%). Correlations between tumor location and abdominal pain (p-value 0.002), bleeding per rectum (p-value <0.001), difficulty in micturition (p-value 0.012) and constipation (p-value 0.007) were found to be statistically significant. Abdominal pain was more frequently reported in patients with metastasis (p-value 0.031). Loss of weight statistically correlated with absence of lymphatic invasion (p-value 0.047). Associations between tumor stage and alcohol intake (p-value 0.050) and non vegetarian diet (p-value 0.006); lymphatic invasion and intake of spicy food (p-value 0.040) and non vegetarian diet (p-value 0.001) and metastasis and alcohol intake (p-value 0.041) were also observed. Age and tumor grade were also correlated (p-value 0.020). Minimizing the adverse lifestyle factors can help in reducing the overall incidence of CRC in the Indian population.

  7. Angiogenesis and lymphangiogenesis in sporadic hepatic angiomyolipoma.

    PubMed

    Xian, Zhi-Hong; Cong, Wen-Ming; Lu, Xin-Yuan; Yu, Hua; Wu, Meng-Chao

    2011-07-15

    Angiogenesis and lymphangiogenesis are critical processes for tumor growth, invasion, and metastasis. The present study aimed to investigate the distribution and clinical significance of angiogenesis and lymphangiogenesis in hepatic angiomyolipoma (AML). We performed immunohistochemical staining for endothelial cell markers (CD34 and podoplanin) on 80 cases of sporadic hepatic AMLs. Microvessel density (MVD) and lymphatic vessel density (LVD) were determined in intratumoral and peritumoral regions and adjacent non-tumorous liver tissues. All hepatic AMLs showed positive staining for CD34 and podoplanin. Intratumoral and peritumoral MVDs and LVDs were significantly higher than those in adjacent liver tissues (P<0.001). No statistical difference in both MVD and LVD was found between intratumoral and peritumoral areas. Large tumors (>5cm) had a significantly increased MVD and LVD as compared with smaller tumors. A significant positive correlation was found between average LVDs and MVDs (r=0.567, P<0.001), and LVDs were a relatively lower event as compared with MVDs. Double immunostaining revealed that no neoplastic cells positive for HMB-45, an antibody reacting with melanosome-associated antigen, were concurrently immunoreactive for endothelial cell markers. In conclusion, intratumoral and peritumoral angiogenesis and lymphangiogenesis commonly occur in hepatic AMLs, thus representing potential therapeutic targets for this disease.

  8. Finger flexion resembling focal dystonia in Isaacs' syndrome.

    PubMed

    Jamora, Roland Dominic G; Umapathi, T; Tan, Louis C S

    2006-01-01

    We describe a patient with a 5-month history of gradually progressive painless flexion of the left ring finger associated with cramps in both thighs. She has severe chronic obstructive pulmonary disease and was on salbutamol. Serum anti-voltage-gated potassium channel antibodies was positive. Electromyography showed generalized neuromyotonia and myokymic discharges. The cramps were partially relieved by phenytoin. We would like to highlight that finger flexion resembling dystonia can be a presenting sign of Isaacs' syndrome.

  9. Arteriovenous shunts resembling patent ductus arteriosus in dogs: 3 cases.

    PubMed

    Fujii, Yoko; Aoki, Takuma; Takano, Hiroshi; Ishikawa, Ryokichi; Wakao, Yoshito

    2009-12-01

    Three dogs presented for the evaluation of cardiac murmurs were diagnosed with aberrant arteriovenous shunts. All cases demonstrated the following findings: 1) relatively soft continuous murmur loudest at the left heart base resembling patent ductus arteriosus (PDA); 2) shunt flow signals in the pulmonary artery on echocardiography; and 3) no PDA on selective angiography, but evidence of anomalous shunting vessels from thoracic aorta to pulmonary vasculature. An aberrant arteriovenous shunt should be considered when a continuous murmur of relatively small intensity is heard.

  10. Allergic Contact Dermatitis to Benzoyl Peroxide Resembling Impetigo.

    PubMed

    Kim, Changhyun; Craiglow, Brittany G; Watsky, Kalman L; Antaya, Richard J

    2015-01-01

    A 17-year-old boy presented with recurring severe dermatitis of the face of 5-months duration that resembled impetigo. He had been treated with several courses of antibiotics without improvement. Biopsy showed changes consistent with allergic contact dermatitis and patch testing later revealed sensitization to benzoyl peroxide, which the patient had been using for the treatment of acne vulgaris. © 2015 Wiley Periodicals, Inc.

  11. Sporadic hypercalcitoninemia: clinical and therapeutic consequences.

    PubMed

    Scheuba, C; Kaserer, K; Moritz, A; Drosten, R; Vierhapper, H; Bieglmayer, C; Haas, O A; Niederle, B

    2009-03-01

    'Calcitonin screening' is not accepted as the standard of care in daily practice. The clinical and surgical consequences of 'calcitonin screening' in a series of patients with mildly elevated basal calcitonin and pentagastrin stimulated calcitonin levels are presented. 260 patients with elevated basal (>10 pg/ml) and stimulated calcitonin levels (>100 pg/ml) were enrolled in this prospective study. None of the patients was member of a known medullary thyroid carcinoma family. Thyroidectomy and bilateral central and lateral neck dissections were performed. Testing for the presence of germ-line mutations was performed in all patients. Histological and immunohistochemical findings were compared with basal and stimulated calcitonin levels. All patients were subsequently followed biochemically. C-cell hyperplasia (CCH) was found in 126 (49%) and medullary thyroid cancer was found in 134 (51%) patients. RET proto-oncogen mutations were documented in 22 (8%) patients (medullary thyroid cancer:18, CCH:4). In 56 (46%) of 122 patients, sporadic CCH was classified neoplastic ('carcinoma in situ'). Of 97 (72%; 10 with hereditary medullary thyroid cancer) had pT1 (International Union against Cancer recommendations 2002) and 33 (25%) had pT2 or pT3 and 4 (3%) pT4 tumors. Of 39 (29.1%) had lymph node metastases. 106 (79.1%; 15 (38.5%) with lymph node metastases) patients were cured. Evaluation of basal and stimulated calcitonin levels enables the prediction of medullary thyroid cancer. All patients with basal calcitonin >64 pg/ml and stimulated calcitonin >560 pg/ml have medullary thyroid cancer. Medullary thyroid cancer was documented in 20% of patients with basal calcitonin >10 pg/ml but <64 pg/ml and stimulated calcitonin >100 pg/ml but <560 pg/ml.

  12. Sporadic phaeochromocytoma in childhood: clinical and molecular variability.

    PubMed

    Pozo, Jesús; Muñoz, Maria Teresa; Martos, Gabriel; Argente, Jesús

    2005-06-01

    Sporadic phaeochromocytoma is an infrequent tumour during paediatric age and may or may not be associated with specific autosomal dominant inherited cancer syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (VHL) type 2 or neurofibromatosis (NF) type 1. We report two cases of benign, adrenal, and unilateral phaeochromocytoma that clearly demonstrate the clinical and molecular heterogeneity of this disease during the paediatric period. The first patient presented a characteristic symptomatic form of sporadic phaeochromocytoma. The second patient, an incidental finding, was practically asymptomatic and had a de novo germline point mutation in the VHL gene (Arg167Trp). The frequency of de novo mutations in susceptible genes (especially the VHL gene) in paediatric patients with sporadic phaeochromocytoma and the elevated mortality of these cancer syndromes suggest that screening for mutations should be performed even in cases of non-familial sporadic phaeochromocytoma.

  13. Near Earth space sporadic radio emission busts occurring during sunrise

    NASA Technical Reports Server (NTRS)

    Dudnik, A. V.; Zaljubovsky, I. I.; Kartashev, V. M.; Lasarev, A. V.; Shmatko, E. S.

    1985-01-01

    During the period of low solar activity at sunrise the effect of sporadic high frequency near Earth space radio emission was experimentally discovered at middle latitudes. The possible mechanism of its origin is discussed.

  14. Sporadic pseudohypoparathyroidism type-1b with asymptomatic hypocalcemia.

    PubMed

    Goto, Motohide; Yamamoto, Yukiyo; Ishii, Masahiro; Nakamura, Akie; Sano, Shinichiro; Kagami, Masayo; Fukami, Maki; Saito, Reiko; Araki, Shunsuke; Kubo, Kazuyasu; Kawagoe, Rinko; Kawada, Yasusada; Kusuhara, Koichi

    2016-11-01

    Pseudohypoparathyroidism type 1b (PHP-1b) is usually diagnosed on various symptoms of hypocalcemia. Previous studies reported a few cases of autosomal dominant pattern PHP-1b identified on familial analysis with asymptomatic hypocalcemia. Herein we report the case of a 6-year-old male patient with sporadic PHP-1b incidentally detected on preoperative examination. He had neither characteristic findings of Albright hereditary osteodystrophy nor evidence of tetany. Sporadic PHP-1b was diagnosed on the basis of clinical observation and laboratory examination. In addition, genetic testing using methylation-specific multiplex ligation-dependent probe amplification indicated broad methylation abnormalities and confirmed the sporadic form of PHP-1b. Sporadic PHP-1b might often be overlooked when diagnosis is done simply on definitive clinical features. To avoid this, DNA sequencing and methylation analysis should be performed even in the absence of definitive clinical features. © 2016 Japan Pediatric Society.

  15. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kallenberg, K.; Summers, D. M.; Romero, C.; Taratuto, A.; Heinemann, U.; Breithaupt, M.; Varges, D.; Meissner, B.; Ladogana, A.; Schuur, M.; Haik, S.; Collins, S. J.; Jansen, Gerard H.; Stokin, G. B.; Pimentel, J.; Hewer, E.; Collie, D.; Smith, P.; Roberts, H.; Brandel, J. P.; van Duijn, C.; Pocchiari, M.; Begue, C.; Cras, P.; Will, R. G.; Sanchez-Juan, P.

    2009-01-01

    Several molecular subtypes of sporadic Creutzfeldt–Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt–Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt–Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt–Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Patients with sporadic Creutzfeldt–Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt–Jakob disease’ but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt–Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt–Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic

  16. Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Takatsuki, Hanae; Fuse, Takayuki; Nakagaki, Takehiro; Mori, Tsuyoshi; Mihara, Ban; Takao, Masaki; Iwasaki, Yasushi; Yoshida, Mari; Murayama, Shigeo; Atarashi, Ryuichiro; Nishida, Noriyuki; Satoh, Katsuya

    2016-10-01

    Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creutzfeldt-Jakob disease patients at autopsy. Although infectivity of the sporadic form is thought to be restricted within the central nervous system, results showed that prion-seeding activities reach 10(6)/g from a 50% seeding dose in non-neuronal tissues, suggesting that prion-seeding activity exists in non-neural organs, and we suggested that non-neural tissues of 10(6)/g SD50 did not exist the infectivity.

  17. Tumor LOH analysis provides reliable linkage information for prenatal genetic testing of sporadic NF1 patients.

    PubMed

    Serra, Eduard; Pros, Eva; García, Carles; López, Eva; Gili, M Lluïsa; Gómez, Carolina; Ravella, Anna; Capellá, Gabriel; Blanco, Ignacio; Lázaro, Conxi

    2007-09-01

    The neurofibromatosis type 1 gene has one of the highest mutation rates in humans: about 50% of NF1 patients are de novo cases. Although direct mutation characterization has greatly improved over the past decade, in the context of clinical genetics services worldwide, there is still a significant number of patients for which, while fulfilling NF1 clinical criteria, no constitutive mutation is found at a desired time. This is particularly critical for prenatal genetic testing of sporadic cases. Here we describe the use of loss of heterozygosity information in neurofibromas to obtain linkage information on the affected NF1 haplotype, which may be applied for prenatal testing in sporadic patients. However, proper genetic counseling should be provided regarding the possibility of somatic mosaicism.

  18. Personalised pathway analysis reveals association between DNA repair pathway dysregulation and chromosomal instability in sporadic breast cancer.

    PubMed

    Liu, Chao; Srihari, Sriganesh; Lal, Samir; Gautier, Benoît; Simpson, Peter T; Khanna, Kum Kum; Ragan, Mark A; Lê Cao, Kim-Anh

    2016-01-01

    The Homologous Recombination (HR) pathway is crucial for the repair of DNA double-strand breaks (DSBs) generated during DNA replication. Defects in HR repair have been linked to the initiation and development of a wide variety of human malignancies, and exploited in chemical, radiological and targeted therapies. In this study, we performed a personalised pathway analysis independently for four large sporadic breast cancer cohorts to investigate the status of HR pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics. Specifically, we first manually curated a list of HR genes according to our recent review on this pathway (Liu et al., 2014), and then applied a personalised pathway analysis method named Pathifier (Drier et al., 2013) on the expression levels of the curated genes to obtain an HR score quantifying HR pathway dysregulation in individual tumours. Based on the score, we observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes, and by using two published HR-defect signatures, we found HR pathway dysregulation reflects HR repair deficiency. Furthermore, we identified a novel association between HR pathway dysregulation and chromosomal instability (CIN) in sporadic breast cancer. Although CIN has long been considered as a hallmark of most solid tumours, with recent extensive studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in sporadic cancers remains poorly understood. Our results imply that HR pathway dysregulation might contribute to CIN in sporadic breast cancer.

  19. SN 2013fs now resembles a SN IIP

    NASA Astrophysics Data System (ADS)

    Childress, M.; Scalzo, R.; Yuan, F.; Schmidt, B.; Tucker, B.

    2013-10-01

    Further to ATel #5455, we obtained another 40-minutes spectrum of SN 2013fs (was PSN J23194467+1011045) with WiFeS on 2013 Oct 24. The spectrum now strongly resembles an SN IIP, with clear P-Cygni H-alpha, with no evidence of broadened emission. SNID gives a best match to SN 1999em at phase +7. The previously observed emission from the Oct 08 spectrum which prompted a possible IIn classification was most likely due to the host, however we cannot rule out SN-related emission which has faded since the first epoch.

  20. Sequence of retrovirus provirus resembles that of bacterial transposable elements

    NASA Astrophysics Data System (ADS)

    Shimotohno, Kunitada; Mizutani, Satoshi; Temin, Howard M.

    1980-06-01

    The nucleotide sequences of the terminal regions of an infectious integrated retrovirus cloned in the modified λ phage cloning vector Charon 4A have been elucidated. There is a 569-base pair direct repeat at both ends of the viral DNA. The cell-virus junctions at each end consist of a 5-base pair direct repeat of cell DNA next to a 3-base pair inverted repeat of viral DNA. This structure resembles that of a transposable element and is consistent with the protovirus hypothesis that retroviruses evolved from the cell genome.

  1. Emission spectrum of a sporadic fireball afterglow

    NASA Astrophysics Data System (ADS)

    Madiedo, J.; Trigo-Rodríguez, J.

    2014-07-01

    A mag. -11 fireball was imaged over southern Spain on April 14, 2013 at 22:35:49.8 ± 0.1s UTC. Its emission spectrum was also obtained. This event was assigned the SPMN code 140413 after the recording date. By the end of its atmospheric path, it exhibited a very bright flare which resulted in a persistent train whose spectrum was recorded. Here we present a preliminary analysis of this event and focus special attention on the evolution of the main emission lines in the spectrum of the afterglow. An array of low-lux CCD video devices (models 902H and 902H Ultimate from Watec Co.) operating from our stations at Sevilla and El Arenosillo was employed to record the SPMN140413 fireball. The operation of these systems is explained in [1,2]. Some of these are configured as spectrographs by attaching holographic diffraction gratings (1000 lines/mm) to the objective lens [3]. To calculate the atmospheric trajectory, radiant, and orbit we have employed our AMALTHEA software, which follows the planes intersection method [4]. The spectrum was analyzed with our CHIMET application [5]. The parent meteoroid impacted the atmosphere with an initial velocity of 28.9 ± 0.3 km/s and the fireball began at a height of 104.4 ± 0.5 km. The event ended at 80.7 ± 0.5 km above the ground level, with the main flare taking place at 83 ± 0.5 km. The calculated radiant and orbital parameters confirm the sporadic nature of the bolide. The calibrated emission spectrum shows that the most important contributions correspond to the Na I-1 (588.9 nm) and Mg I-2 (517.2 nm) multiplets. In the ultraviolet, the contribution from the H and K lines from Ca was also identified. As usual in meteor spectra, most of the lines correspond to Fe I. The train spectrum was recorded during about 0.12 seconds. This provided the evolution with time of the intensity of the emission lines in this signal. The contributions from Mg I, Na I, Ca I, Fe I, Ca II, and O I were identified in the afterglow, with the Na I-1

  2. Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis.

    PubMed

    Mumm, Steven; Wenkert, Deborah; Zhang, Xiafang; McAlister, William H; Mier, Richard J; Whyte, Michael P

    2007-02-01

    Autosomal dominant OPK and BOS feature widespread foci of osteosclerotic trabeculae without or with skin lesions, respectively. Occasionally, a larger area of dense bone in OPK or BOS resembles MEL, a sporadic sclerosing disorder primarily involving cortical bone. Others, finding deactivating germline LEMD3 mutations in OPK or BOS, concluded such defects explain all three conditions. We found germline LEMD3 mutations in OPK and BOS but not in sporadic MEL. In 2004, others discovered that heterozygous, loss-of-function, germline mutations in the LEMD3 gene (LEMD3 or MAN1) cause both osteopoikilosis (OPK) and Buschke-Ollendorff syndrome (BOS). OPK is an autosomal dominant, usually benign, skeletal dysplasia featuring multiple, small, especially metaphyseal, oval or round, dense trabecular foci distributed symmetrically throughout the skeleton. BOS combines OPK with connective tissue nevi comprised of collagen and elastin. In some OPK and BOS families, an individual may have relatively large, asymmetric areas of dense cortical bone interpreted as melorheostosis (MEL). MEL, however, classically refers to a sporadic, troublesome skeletal dysostosis featuring large, asymmetric, "flowing hyperostosis" of long bone cortices often with overlying, constricting soft tissue abnormalities. However, a heterozygous germline mutation in LEMD3 was offered to explain MEL. We studied 11 unrelated individuals with sclerosing bone disorders where LEMD3 mutation was a potential etiology: familial OPK (1), familial BOS (2), previously reported familial OPK with MEL (1), sporadic MEL (3), sporadic MEL with mixed-sclerosing-bone dystrophy (1), and patients with other unusual sclerosing bone disorders (3). All coding exons and adjacent mRNA splice sites for LEMD3 were amplified by PCR and sequenced using genomic DNA from leukocytes. We did not study lesional tissue from bone or skin. In the OPK family, a heterozygous nonsense mutation (c.1433T>A, p.L478X) was discovered in exon 1. In the

  3. Ritodrine-induced pustular eruptions distinctly resembling impetigo herpetiformis.

    PubMed

    Kuwabara, Yoshimitsu; Sato, Atsuki; Abe, Hiroko; Abe, Sumino; Kawai, Naoki; Takeshita, Toshiyuki

    2011-01-01

    A 27-year-old nulligravida woman without a history of dermatosis was hospitalized for threatened preterm labor at 29 weeks' gestation; therefore, continuous infusion of ritodrine hydrochloride was started. At 31 weeks' gestation, erythematous plaques appeared and spread over the body surface; therefore, a topical steroid preparation was applied. At 32 weeks' gestation, the eruptions developed into irregular annular areas of erythema with multiple pustules accompanied by severe itching, and oral prednisolone treatment was started. Bacterial cultures of the pustules were negative, and a crural cutaneous biopsy revealed Kogoj's spongiform pustules. Based on the clinicopathological findings, the most likely diagnosis was impetigo herpetiformis, which causes cutaneous symptoms closely resembling pustular psoriasis in pregnant females without a history of psoriasis. To rule out ritodrine-induced pustular eruptions, the ritodrine infusion was stopped and treatment with an MgSO(4) preparation was started at 33 weeks' 3 days' gestation; however, the uterine contractions could not be suppressed. Because of the patient's highly edematous, severely painful feet, a cesarean section was performed the same day. Within several days of delivery, the eruptions began to resolve, and no recurrence was observed after treatment with oral prednisolone was stopped 31 days after delivery. On the basis of a positive patch test for ritodrine, we diagnosed pustular drug eruptions caused by ritodrine hydrochloride. Although ritodrine-induced pathognomonic cutaneous eruptions are rare, we would like to emphasize that ritodrine can cause drug-induced pustular eruptions distinctly resembling life-threatening impetigo herpetiformis.

  4. Extending disorder: essentialism, family resemblance and secondary sense.

    PubMed

    Pickering, Neil

    2013-05-01

    It is commonly thought that mental disorder is a valid concept only in so far as it is an extension of or continuous with the concept of physical disorder. A valid extension has to meet two criteria: determination and coherence. Essentialists meet these criteria through necessary and sufficient conditions for being a disorder. Two Wittgensteinian alternatives to essentialism are considered and assessed against the two criteria. These are the family resemblance approach and the secondary sense approach. Where the focus is solely on the characteristics or attributes of things, both these approaches seem to fail to meet the criteria for valid extension. However, this focus on attributes is mistaken. The criteria for valid extension are met in the case of family resemblance by the pattern of characteristics associated with a concept, and by the limits of intelligibility of applying a concept. Secondary sense, though it may have some claims to be a good account of the relation between physical and mental disorder, cannot claim to meet the two criteria of valid extension.

  5. Erosive rhinitis resembling granulomatosis with polyangiitis (Wegener's granulomatosis) in an Anatolian shepherd dog.

    PubMed

    Böhm, Marlies; Basson, Sandra

    2015-04-21

    Granulomatosis with polyangiitis (Wegener's granulomatosis) is one of the idiopathicimmune-mediated small-vessel vasculitides described in humans which are characterised by the presence of circulating antineutrophil cytoplasmic antibodies. It most commonly involves capillaries, venules and arterioles of the ear, nose and throat, lungs and glomeruli. A case of destructive haemopurulent rhinitis associated with relapsing periods of pyrexia, lethargy and stiffness as well as generalised pulmonary infiltrates in a young Anatolian shepherd dog is presented that closely resembles granulomatosis with polyangiitis (GPA) as reported in humans. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) were detected in the dog's serum. Signs resolved promptly and completely once immunosuppressive doses of prednisone were administered, and have not recurred. This is the first report onthe use of pANCA to investigate rhinitis in dogs. It is also, to the authors' knowledge, the first description of a relapsing haemopurulent lytic rhinitis in this species. The concurrent manifestations of erosive haemopurulent rhinitis, ground-glass opacities on pulmonary computed tomography, pyrexia and listlessness resemble GPA as described in humans.

  6. High-throughput screen detects calcium signaling dysfunction in typical sporadic autism spectrum disorder

    PubMed Central

    Schmunk, Galina; Nguyen, Rachel L.; Ferguson, David L.; Kumar, Kenny; Parker, Ian; Gargus, J. Jay

    2017-01-01

    Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca2+ signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP3)-mediated Ca2+ release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism – fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca2+ signals in human primary skin fibroblasts. Our results indicate that IP3 -mediated Ca2+ release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP3-mediated Ca2+ signaling represent a convergent hub function shared across the spectrum of autistic disorders – whether caused by rare highly penetrant mutations or sporadic forms – and holds promise as a biomarker for diagnosis and novel drug discovery. PMID:28145469

  7. Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type

    PubMed Central

    Cracco, Laura; Notari, Silvio; Cali, Ignazio; Sy, Man-Sun; Chen, Shu G.; Cohen, Mark L.; Ghetti, Bernardino; Appleby, Brian S.; Zou, Wen-Quan; Caughey, Byron; Safar, Jiri G.; Gambetti, Pierluigi

    2017-01-01

    In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrPSc) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrPSc type 2 but are associated with quite distinct phenotypes. Our detailed comparative study of the PrPSc conformers has revealed major differences between the two diseases, which preferentially involve the PrPSc component that is sensitive to digestion with proteases (senPrPSc) and to a lesser extent the resistant component (resPrPSc). We conclude that these variations are consistent with two distinct strains in sFI and sCJDMM2, and that the rarer sFI is the result of a variant strain selection pathway that might be favoured by a different brain site of initial PrPSc formation in the two diseases. PMID:28091514

  8. Aggregation of Copper–Zinc Superoxide Dismutase in Familial and Sporadic ALS

    PubMed Central

    Chattopadhyay, Madhuri

    2009-01-01

    Abstract Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by the selective death of motor neurons. While the most common form of ALS is sporadic and has no known cause, a small subset of cases is familial because of underlying genetic mutations. The best-studies example of familial ALS is that caused by mutations in the protein copper–zinc superoxide dismutase. The formation of SOD1-rich inclusions in the spinal cord is an early and prominent feature of SOD1-linked familial ALS in human patients and animal models of this disease. These inclusions have been shown to consist of SOD1-rich fibrils, suggesting that the conversion of soluble SOD1 into amyloid fibrils may play an important role in the etiology of familial ALS. SOD1 is also present in inclusions found in spinal cords of sporadic ALS patients, allowing speculations to arise regarding a possible involvement of SOD1 in the sporadic form of this disease. We here review the recent research on the significance, causes, and mechanisms of SOD1 fibril formation from a biophysical perspective. Antioxid. Redox Signal. 11, 1603–1614. PMID:19271992

  9. PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease

    PubMed Central

    Martín-Maestro, Patricia; Gargini, Ricardo; Perry, George; Avila, Jesús; García-Escudero, Vega

    2016-01-01

    Mitochondrial anomalies have been previously reported in patients′ brain and peripheral tissue, suggesting their relevance in sporadic Alzheimer's disease (AD). The present work evaluates mitochondrial function and recycling in human fibroblasts and brain biopsies. Functional studies using patients′ skin fibroblasts showed slower mitochondrial membrane potential recovery after a mitochondrial insult together with alterations in lysosomes and autophagy, accompanied by an increase of oxidized and ubiquitinated proteins. Impairment in mitophagy has been proven in these cells due to diminished PARK2 and insufficient vesicle induction, accumulating depolarized mitochondria and PINK1. Augmented Δ1 PINK1 fragment levels suggest an inhibitory effect over PARK2 translocation to the mitochondria, causing the accumulation of activated PINK1. Moreover, the overexpression of PARK2 diminished ubiquitinated proteins accumulation, improves its targeting to mitochondria and potentiates autophagic vesicle synthesis. This allows the reversion of mitophagy failure reflected in the recovery of membrane potential and the decrease of PINK1 and mitochondria accumulation. Sporadic AD fibroblasts exhibited alterations similar to what it could be found in patients’ hippocampal samples at early stages of the disease, where there was an accumulation of PINK1 and Δ1 PINK1 together with abnormally increased mitochondrial content. Our findings indicate that mitophagy alterations can be considered a new hallmark of sporadic AD and validate the use of fibroblasts for modelling this pathology. PMID:26721933

  10. ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.

    PubMed

    Halim, Danny; Hofstra, Robert M W; Signorile, Luca; Verdijk, Rob M; van der Werf, Christine S; Sribudiani, Yunia; Brouwer, Rutger W W; van IJcken, Wilfred F J; Dahl, Niklas; Verheij, Joke B G M; Baumann, Clarisse; Kerner, John; van Bever, Yolande; Galjart, Niels; Wijnen, Rene M H; Tibboel, Dick; Burns, Alan J; Muller, Françoise; Brooks, Alice S; Alves, Maria M

    2016-02-01

    Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin γ-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.

  11. High-throughput screen detects calcium signaling dysfunction in typical sporadic autism spectrum disorder.

    PubMed

    Schmunk, Galina; Nguyen, Rachel L; Ferguson, David L; Kumar, Kenny; Parker, Ian; Gargus, J Jay

    2017-02-01

    Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca(2+) signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP3)-mediated Ca(2+) release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism - fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca(2+) signals in human primary skin fibroblasts. Our results indicate that IP3 -mediated Ca(2+) release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP3-mediated Ca(2+) signaling represent a convergent hub function shared across the spectrum of autistic disorders - whether caused by rare highly penetrant mutations or sporadic forms - and holds promise as a biomarker for diagnosis and novel drug discovery.

  12. Novel multiple endocrine neoplasia type 1 variations in patients with sporadic primary hyperparathyroidism

    PubMed Central

    Birla, S; Malik, E; Jyotsna, VP; Sharma, A

    2016-01-01

    Background and Objectives: Primary hyperparathyroidism (PHPT) can occur either as a sporadic case or in association with syndromes such as multiple endocrine neoplasia. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal-dominant disease resulting from mutations in MEN1 gene encoding a 621 amino acid long tumor suppressor protein “menin.” We report here the results of MEN1 screening in 31 patients diagnosed with sporadic PHPT. Materials and Methods: Diagnosis of sporadic PHPT was made when blood urea and serum creatinine were normal, serum parathyroid hormone was high, and parathyroid enlargement could be localized on ultrasound and/or parathyroid scan. A total of 31 patients and 50 healthy volunteers were recruited for molecular analysis after taking informed consent. Results: Major symptoms at presentation were bone pain, fatigue, muscle weakness, and renal stones. Molecular genetic analysis revealed the presence of two novel intronic variations, c. 913-79T>A and c. 784-129T>A which by human splicing finder are predicted to cause potential alteration of splicing by either activating an intronic cryptic acceptor site or converting a conserved exonic splicing silencer sequence to an exonic splicing enhancer site. Apart from these, two reported polymorphisms rs144677807 and rs669976 were seen only in patients and none of the controls. Other reported polymorphisms rs2071313 and rs654440 were identified both in controls and patients. Conclusions: This is the first study of MEN1 gene screening in sporadic PHPT in India reporting on the clinical and genetic findings, wherein two novel intronic variations c. 913-79T>A and c. 784-129T>A were identified showing their possible role in disease causation. PMID:27366707

  13. Consolation in the aftermath of robberies resembles post-aggression consolation in chimpanzees.

    PubMed

    Lindegaard, Marie Rosenkrantz; Liebst, Lasse Suonperä; Bernasco, Wim; Heinskou, Marie Bruvik; Philpot, Richard; Levine, Mark; Verbeek, Peter

    2017-01-01

    Post-aggression consolation is assumed to occur in humans as well as in chimpanzees. While consolation following peer aggression has been observed in children, systematic evidence of consolation in human adults is rare. We used surveillance camera footage of the immediate aftermath of nonfatal robberies to observe the behaviors and characteristics of victims and bystanders. Consistent with empathy explanations, we found that consolation was linked to social closeness rather than physical closeness. While females were more likely to console than males, males and females were equally likely to be consoled. Furthermore, we show that high levels of threat during the robbery increased the likelihood of receiving consolation afterwards. These patterns resemble post-aggression consolation in chimpanzees and suggest that emotions of empathic concern are involved in consolation across humans and chimpanzees.

  14. Consolation in the aftermath of robberies resembles post-aggression consolation in chimpanzees

    PubMed Central

    Heinskou, Marie Bruvik; Philpot, Richard; Levine, Mark; Verbeek, Peter

    2017-01-01

    Post-aggression consolation is assumed to occur in humans as well as in chimpanzees. While consolation following peer aggression has been observed in children, systematic evidence of consolation in human adults is rare. We used surveillance camera footage of the immediate aftermath of nonfatal robberies to observe the behaviors and characteristics of victims and bystanders. Consistent with empathy explanations, we found that consolation was linked to social closeness rather than physical closeness. While females were more likely to console than males, males and females were equally likely to be consoled. Furthermore, we show that high levels of threat during the robbery increased the likelihood of receiving consolation afterwards. These patterns resemble post-aggression consolation in chimpanzees and suggest that emotions of empathic concern are involved in consolation across humans and chimpanzees. PMID:28562686

  15. Genetic overlap between apparently sporadic motor neuron diseases.

    PubMed

    van Blitterswijk, Marka; Vlam, Lotte; van Es, Michael A; van der Pol, W-Ludo; Hennekam, Eric A M; Dooijes, Dennis; Schelhaas, Helenius J; van der Kooi, Anneke J; de Visser, Marianne; Veldink, Jan H; van den Berg, Leonard H

    2012-01-01

    Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS.

  16. Genetic Overlap between Apparently Sporadic Motor Neuron Diseases

    PubMed Central

    van Blitterswijk, Marka; Vlam, Lotte; van Es, Michael A.; van der Pol, W-Ludo; Hennekam, Eric A. M.; Dooijes, Dennis; Schelhaas, Helenius J.; van der Kooi, Anneke J.; de Visser, Marianne

    2012-01-01

    Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS. PMID:23155438

  17. Resembling a viper: implications of mimicry for conservation of the endangered smooth snake.

    PubMed

    Valkonen, Janne K; Mappes, Johanna

    2014-12-01

    The phenomenon of Batesian mimicry, where a palatable animal gains protection against predation by resembling an unpalatable model, has been a core interest of evolutionary biologists for 150 years. An extensive range of studies has focused on revealing mechanistic aspects of mimicry (shared education and generalization of predators) and the evolutionary dynamics of mimicry systems (co-operation vs. conflict) and revealed that protective mimicry is widespread and is important for individual fitness. However, according to our knowledge, there are no case studies where mimicry theories have been applied to conservation of mimetic species. Theoretically, mimicry affects, for example, frequency dependency of predator avoidance learning and human induced mortality. We examined the case of the protected, endangered, nonvenomous smooth snake (Coronella austriaca) that mimics the nonprotected venomous adder (Vipera berus), both of which occur in the Åland archipelago, Finland. To quantify the added predation risk on smooth snakes caused by the rarity of vipers, we calculated risk estimates from experimental data. Resemblance of vipers enhances survival of smooth snakes against bird predation because many predators avoid touching venomous vipers. Mimetic resemblance is however disadvantageous against human predators, who kill venomous vipers and accidentally kill endangered, protected smooth snakes. We found that the effective population size of the adders in Åland is very low relative to its smooth snake mimic (28.93 and 41.35, respectively).Because Batesian mimicry is advantageous for the mimic only if model species exist in sufficiently high numbers, it is likely that the conservation program for smooth snakes will fail if adders continue to be destroyed. Understanding the population consequences of mimetic species may be crucial to the success of endangered species conservation. We suggest that when a Batesian mimic requires protection, conservation planners should

  18. Uterine Tumour Resembling Ovarian Sex Cord Tumour- A Rare Entity

    PubMed Central

    Ilhan, Tolgay Tuyan; Gül, Ayhan; Ugurluoglu, Ceyhan; Çelik, Çetin

    2016-01-01

    Uterine Tumour Resembling Ovarian Sex-Cord Tumours (UTROSCTs) are an extremely rare type of uterine body tumours arising from the endometrial stroma. Epidemiology, aetiology, pathogenesis, management and natural history of UTROSCTs are still a question of debate, as there is little available data in the literature. Although rare, the possibility of UTROSCTs should be kept in mind, when a patient presents with abnormal bleeding and an enlarged uterus. UTROSCTs appear dirty white/cream-coloured, gelatinous, well-circumscribed mass with smooth surface on macroscopic examination. We present a rare case of endometrial stromal tumour with sex-cord-like differentiation which was successfully treated by hysterectomy with bilateral salpingo-oophorectomy. The clinical manifestations, pathologic characteristics, diagnosis and management of these tumours are reviewed here. PMID:28208949

  19. Adenomyomatosis of the gallbladder resembling honeycomb in a child.

    PubMed

    Akçam, Mustafa; Buyukyavuz, Ilker; Ciriş, Metin; Eriş, Naim

    2008-09-01

    Adenomyomatosis of the gallbladder is believed to be an uncommon pathologic condition of the gallbladder in childhood. Only three pediatric cases have been described in the literature up to now. Honeycomb gallbladder has been described in two adult patients; no patients have been reported in childhood until now. To the best of our knowledge, we report here the first case of adenomyomatosis of the gallbladder which resembled honeycomb, in a 9-year-old girl presented with recurrent abdominal pain. The diagnosis was made by ultrasound, and confirmed by magnetic resonance cholangiopancreatography and finally cholecystectomy. In conclusion, ultrasound scanning performed more generally in children presenting with recurrent abdominal pain might lead to accurate diagnosis of adenomyomotosis of the gallbladder during childhood.

  20. Imperfect Batesian mimicry and the conspicuousness costs of mimetic resemblance.

    PubMed

    Speed, Michael P; Ruxton, Graeme D

    2010-07-01

    We apply signal detection methodology to make predictions about the evolution of Batesian mimicry. Our approach is novel in three ways. First, we applied a deterministic evolutionary modeling system that allows a large number of alternative mimetic morphs to coexist and compete. Second, we considered that there may be natural boundaries to phenotypic expression. Finally, we allowed increasing conspicuousness to impose an increasing detection cost on mimics. In some instances, the model predicts widespread variation in mimetic forms at evolutionary stability. In other situations, rather than a polymorphism the model predicts dimorphisms in which some prey were maximally cryptic and had minimal resemblance to the model, whereas many others were more conspicuous than the model. The biological implications of these results, particularly for our understanding of imperfect mimicry, are discussed.

  1. PTCH mutations are not mainly involved in the pathogenesis of sporadic trichoblastomas.

    PubMed

    Hafner, Christian; Schmiemann, Viola; Ruetten, Arno; Coras, Brigitte; Landthaler, Michael; Reifenberger, Julia; Vogt, Thomas

    2007-10-01

    Trichoblastomas are rare, benign tumors of the appendix in human skin. The histopathology comprises elements of basal cell carcinoma and trichoepithelioma with a variable degree of follicular differentiation. Both basal cell carcinoma and trichoepithelioma reveal alterations of PTCH, the human homolog of the Drosophila segment polarity patched gene. Furthermore, heterozygous PTCH knockout mice develop trichoblastoma-like tumors. This suggests an involvement of the PTCH gene in the pathogenesis of human trichoblastomas. However, trichoblastomas arising in nevus sebaceus did not show loss of heterozygosity at the PTCH locus (9q22.3) in a previous study. Sequencing of the PTCH gene and analysis of sporadic human trichoblastomas have not been performed yet. We therefore screened 10 sporadic trichoblastomas and 1 trichoblastoma arising within a nevus sebaceus for PTCH mutations. After microdissection of the tumors, single-strand conformational polymorphism (SSCP)/heteroduplex analysis of exons 2 to 23 of PTCH was performed, and polymerase chain reaction products with aberrant band patterns were sequenced. One trichoblastoma revealed a silent mutation at codon 562 in exon 12. Another trichoblastoma showed a somatic C > T single nucleotide substitution at codon 1,315 (exon 23), which was not present in corresponding normal epidermis. This mutation at codon 1,315 represents an already described PTCH germline polymorphism and results in a heterozygous Pro to Leu substitution in the tumor. The Pro/Leu polymorphism in germline is associated with a higher risk for breast cancer, but a potential contribution to the tumorigenesis of trichoblastoma is unknown. We detected no classical PTCH mutations in the investigated trichoblastomas. Our results indicate that PTCH mutations are not mainly involved in the pathogenesis of sporadic trichoblastomas, in contrast to basal cell carcinomas and trichoepitheliomas. The genetic basis of this rare appendageal tumor remains elusive.

  2. Parameters of Sporadic E Layers and Transparency For Radio Waves

    NASA Astrophysics Data System (ADS)

    Bencze, P.

    Two frequency parameters of sporadic E layers are included into the scaling of verti- cal incidence ionograms, foEs and fbEs. They are called critical and blanketing fre- quency, respectively. On the basis of results of incoherent scatter measurements at mid-latitudes referring to the structure of sporadic E layers, the critical frequency is considered representing the mean electron density of patches imbedded in the back- ground electron density. The blanketing frequency would correspond to the back- ground electron density. Thus, the difference between critical and blanketing frequen- cies foEs-fbEs could indicate the transparency of sporadic E layers. Comparison of temporal and spatial variations of the transparency with corresponding variations of the vertical shear of the horizontal wind shows that the transparancy can be due to the wind-shear and patches would indicate eddies in the layer.

  3. Parkin Plays a Role in Sporadic Parkinson’s Disease

    PubMed Central

    Dawson, Ted M.; Dawson, Valina L.

    2014-01-01

    Background Parkinson’s Disease (PD) is a chronic progressive neurologic disorder, which affects approximately one million men and women in the U.S. alone. PD represents a heterogeneous disorder with common clinical manifestations and for the most part common neuropathological findings. Objective This short article reviews the role of the ubiquitin E3 ligase in sporadic PD. Methods The role of parkin in sporadic PD was reviewed by querying PubMed Results Parkin is inactivated in sporadic PD via S-nitrosylation, oxidative and dopaminergic stress, and phosphorylation by the stress activated kinase, c-Abl leading to the accumulation of AIMP2 and PARIS (ZNF746). Conclusion Strategies aimed at maintaining parkin in a catalytically active state or interfering with toxicity of AIMP2 and PARIS (ZNF746) offer new therapeutic opportunities. PMID:24029689

  4. Valosin-containing protein mutations in sporadic amyotrophic lateral sclerosis

    PubMed Central

    Abramzon, Yevgeniya; Johnson, Janel O.; Scholz, Sonja W.; Taylor, J. Paul; Brunetti, Maura; Calvo, Andrea; Mandrioli, Jessica; Benatar, Michael; Mora, Gabriele; Restagno, Gabriella; Chiò, Adriano; Traynor, Bryan J.

    2012-01-01

    We recently reported that mutations in the VCP gene are a cause of 1–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three US cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS, but account for less than 1% of this form of disease. PMID:22572540

  5. Sporadic Corticobasal Syndrome due to FTLD-TDP

    PubMed Central

    Tartaglia, Maria Carmela; Sidhu, Manu; Laluz, Victor; Racine, Caroline; Rabinovici, Gil D; Creighton, Kelly; Karydas, Anna; Rademakers, Rosa; Huang, Eric J; Miller, Bruce L; DeArmond, Stephen J; Seeley, William W

    2010-01-01

    Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau (MAPT) or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS. PMID:19876635

  6. Cervical dystonia: about familial and sporadic cases in 88 patients.

    PubMed

    Camargo, Carlos Henrique F; Camargos, Sarah Teixeira; Becker, Nilson; Munhoz, Renato Puppi; Raskin, Salmo; Cardoso, Francisco Eduardo C; Teive, Hélio Afonso G

    2014-02-01

    Cervical dystonia (CD) affects the musculature of the neck in a focal way or associated to other parts of the body. The aim of this study was to identify clinical differences between patients with dystonia patients without family history and with family history (sporadic). Eighty-eight patients with CD were recruited in a Movement Disorders Clinic between June of 2008 and June of 2009. Only patients with no etiological diagnosis were accepted for analysis. The age of onset of symptoms was later in patients with focal and segmental dystonia than in patients with generalized dystonia (p<0.001). The severity of symptoms was higher in patients with sporadic dystonia than in familial patients (p<0.01). Generalized cases were more severe in patients with a family history (p<0.01). Sporadic patients had higher levels of pain than familial cases (p<0.05). We expect soon to present the results of genetic analyzes of these patients.

  7. Microsatellite instability is rare in sporadic ovarian cancer

    SciTech Connect

    Chen, S.S.; Han, H.; Schwartz, P.E.

    1994-09-01

    Microsatellite instability was first demonstrated to be a common underlying mechanism in hereditary nonpolyposis colorectal cancer (HNPCC) and has recently been implicated in the development of several other human cancers. Although numerous genetic changes have been documented in ovarian cancer, their molecular bases are poorly understood. In investigating the molecular genetics of ovarian cancer, we analyzed twelve short tandem repeats that were amplified by PCR from DNA of 48 tumors and their corresponding lymphocyte samples. All of the 48 cases studied have no noticeable family history and, of them, 42 are epithelial (benign/borderline, 5; grade I, 4; GII, 4; GIII, 29) and 6 are nonepithelial. A microsatellite instability has been shown to be inversely correlated with the occurrence of allelic losses, half of those cases chosen have a fractional allele loss of {le}15 (median = .18 of 50 tumors tested for 86 loci from every chromosomal arm). The loci examined included eight dinucleotide repeats (D2S123, D9S104, D10S197, D11S904, D16S408, D16S421, D17S250, and D17S579), two trinucleotide repeats (DM and AR) and two tetranucleotide repeats (DXS981 and VWF). Despite the fact that HNPCC phenotype includes ovarian cancer and that microsatellite instability has been shown in one ovarian cancer from an HNPCC family, the allele sizes of 12 loci were found to be identical in all paired tumor and normal samples we studied except for one tumor at a single locus. The band shift displayed on polyacrylamide gel representing an additional allele of VWF was only observed in one grade III tumor. Our results are thus a strong indication that the alteration of microsatellite repeats may not play a major role in the development of sporadic ovarian cancer.

  8. Sporadic Creutzfeldt-Jakob disease--a review.

    PubMed

    Sharma, Stuti; Mukherjee, Madhurima; Kedage, Vivekananda; Muttigi, Manjunatha S; Rao, Anjali; Rao, Suryanarayana

    2009-01-01

    The objective is to study a patient with sporadic Creutzfeldt-Jakob disease (CJD). The patient, a 70-year-old woman with a history spanning over 1 month, with acute onset, progressive abnormal behavior, and cognitive decline with generalized asymmetrical myoclonic jerking, startle phenomenon, and cortical blindness, was referred to the hospital. On observation of clinical symptoms, metabolic and hematological investigations, MRI (magnetic resonance imaging), and EEG (electroencephalogram) were done. The clinical symptoms, MRI, and diagnostic EEG were suggestive of sporadic CJD. Other metabolic encephalopathies were ruled out. With sodium valproate and clonezepam, her myoclonic jerks improved slightly. As CJD is an incurable disease, no definitive treatment could be given.

  9. Arterial surgery for sporadic hemiplegic migraine: preliminary results.

    PubMed

    Shevel, Elliot

    2014-05-01

    My aim was to report for the first time (to my knowledge) the successful treatment of 3 patients with sporadic hemiplegic migraine by surgical cautery of terminal branches of the external carotid artery under conscious sedation. Since the operations (between 1 and 2 years) none of the patients have had further attacks of migraine or hemiplegia. This preliminary report suggests that for patients with sporadic hemiplegic migraine with a confirmed arterial component, surgical cautery of selected terminal branches of the external carotid artery may be effective treatment. Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  10. Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia

    PubMed Central

    Johnson, David Y.; Dunkelberger, Diana L.; Henry, Maya; Haman, Aissatou; Greicius, Michael D.; Wong, Katherine; DeArmond, Stephen J.; Miller, Bruce L.; Gorno-Tempini, Maria Luisa; Geschwind, Michael D.

    2015-01-01

    Objective To report the clinical, neuropsychological, linguistic, imaging, and neuropathological features of a unique case of sporadic Jakob-Creutzfeldt disease in which the patient presented with a logopenic variant of primary progressive aphasia. Design Case report. Setting Large referral center for atypical memory and aging disorders, particularly Jakob-Creutzfeldt disease. Patient Patient presenting with logopenic variant primary progressive aphasia initially thought to be due to Alzheimer disease. Results Despite the long, slow 3.5-year course, the patient was shown to have pathology-proven sporadic Jakob-Creutzfeldt disease. Conclusions These findings expand the differential of primary progressive aphasia to include prion disease. PMID:23400721

  11. Necroptosis drives motor neuron death in models of both sporadic and familial ALS

    PubMed Central

    Re, Diane B.; Verche, Virginia Le; Yu, Changhao; Amoroso, Mackenzie W.; Politi, Kristin A.; Phani, Sudarshan; Ikiz, Burcin; Hoffmann, Lucas; Koolen, Martijn; Nagata, Tetsuya; Papadimitriou, Dimitra; Nagy, Peter; Mitsumoto, Hiroshi; Kariya, Shingo; Wichterle, Hynek; Henderson, Christopher E.; Przedborski, Serge

    2014-01-01

    SUMMARY Most cases of neurodegenerative disease are sporadic, hindering the use of genetic mouse models to analyze disease mechanisms. Focusing on the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS) we therefore devised a fully humanized co-culture model composed of human adult primary sporadic ALS (sALS) astrocytes and human embryonic stem cell-derived MNs. The model reproduces the cardinal features of human ALS: sALS astrocytes, but not those from control patients, trigger selective death of MNs. The mechanisms underlying this non-cell-autonomous toxicity were investigated in both astrocytes and MNs. Although causal in familial ALS (fALS), SOD1 does not contribute to the toxicity of sALS astrocytes. Death of MNs triggered by either sALS or fALS astrocytes occurs through necroptosis, a form of programmed necrosis involving receptor-interacting protein 1 and the mixed lineage kinase domain-like protein. The necroptotic pathway therefore constitutes a novel potential therapeutic target for this incurable disease. PMID:24508385

  12. [Crohn's disease with the onset resembling systemic lupus erythematosus].

    PubMed

    Shimizu, T; Nishinarita, S; Son, K; Tomita, Y; Yoshihiro; Matsukawa; Kitamura, N; Horie, T; Baba, M; Hiranuma, M

    1999-06-01

    We described a 37-year-old man with Crohn's disease (CD) resembling systemic lupus erythematosus (SLE) at his disease onset. He was admitted to the municiple Akiru Hospital in October 1986 by fever, aphtous oral ulcerations, sore throat and polyarthralgia. Hematologic examination showed leukocytopenia, lymphocytopenia, positive tests for antinuclear antibody, anti-DNA antibody and LE cell phenomenon. He has had episodes of convulsion and conciousness loss of unknown etiology when he was 17 years old. The diagnosis of SLE was made, and oral medication of prednisolone was started. Several weeks later, most of symptoms and autoantibodies disappeared, although the oral aphtous ulcerations and leukocytopenia remained. In May 1987, he admitted to the other hospital because of bloody vomiting. Endoscopic examination showed the esophagial ulceration, and histology of biopsied-specimen was nonspecific esophagitis. The combination of prednisolone and oral cyclophosphamide or methotrexate was employed thereafter. However, the leukocytopenia, oral aphtous ulceration and esophagial ulceration continued in spite of these treatments. All the immunosuppressive treatment was stopped at March 1992. In October 1995, he admitted to our hospital because of body weight loss and continuous diarrhea with occasional bloody stool. Barium enema and endoscopic examination of the colon revealed the findings compatible with CD. The patient responded favorably to methylprednisolone pulse therapy followed by oral sulphasalazine. This case indicated that cases with inflammatory bowel diseases like CD could show similar clinical signs and symptoms to SLE, and in some cases of CD might satisfied the classification of criteria for SLE.

  13. A neural network dynamics that resembles protein evolution

    NASA Astrophysics Data System (ADS)

    Ferrán, Edgardo A.; Ferrara, Pascual

    1992-06-01

    We use neutral networks to classify proteins according to their sequence similarities. A network composed by 7 × 7 neurons, was trained with the Kohonen unsupervised learning algorithm using, as inputs, matrix patterns derived from the bipeptide composition of cytochrome c proteins belonging to 76 different species. As a result of the training, the network self-organized the activation of its neurons into topologically ordered maps, wherein phylogenetically related sequences were positioned close to each other. The evolution of the topological map during learning, in a representative computational experiment, roughly resembles the way in which one species evolves into several others. For instance, sequences corresponding to vertebrates, initially grouped together into one neuron, were placed in a contiguous zone of the final neural map, with sequences of fishes, amphibia, reptiles, birds and mammals associated to different neurons. Some apparent wrong classifications are due to the fact that some proteins have a greater degree of sequence identity than the one expected by phylogenetics. In the final neural map, each synaptic vector may be considered as the pattern corresponding to the ancestor of all the proteins that are attached to that neuron. Although it may be also tempting to link real time with learning epochs and to use this relationship to calibrate the molecular evolutionary clock, this is not correct because the evolutionary time schedule obtained with the neural network depends highly on the discrete way in which the winner neighborhood is decreased during learning.

  14. On the resemblance of synapse formation and CNS myelination.

    PubMed

    Almeida, R G; Lyons, D A

    2014-09-12

    The myelination of axons in the central nervous system (CNS) is essential for nervous system formation, function and health. CNS myelination continues well into adulthood, but not all axons become myelinated. Unlike the peripheral nervous system, where we know of numerous axon-glial signals required for myelination, we have a poor understanding of the nature or identity of such molecules that regulate which axons are myelinated in the CNS. Recent studies have started to elucidate cell behavior during myelination in vivo and indicate that the choice of which axons are myelinated is made prior to myelin sheath generation. Here we propose that interactions between axons and the exploratory processes of oligodendrocyte precursor cells (OPCs) lead to myelination and may be similar to those between dendrites and axons that prefigure and lead to synapse formation. Indeed axons and OPCs form synapses with striking resemblance to those of neurons, suggesting a similar mode of formation. We discuss families of molecules with specific functions at different stages of synapse formation and address studies that implicate the same factors during axon-OPC synapse formation and myelination. We also address the possibility that the function of such synapses might directly regulate the myelinating behavior of oligodendrocyte processes in vivo. In the future it may be of benefit to consider these similarities when taking a candidate-based approach to dissect mechanisms of CNS myelination. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. 40 MHz Ionospheric Scintillation and the Sporadic E Layer.

    DTIC Science & Technology

    high scintillation indices and a height spreading of the sporadic E trace. These observations, carried out at Athens (37 degrees 58 minutes N, 23...degrees 43 minutes E ) over a period of 18 months lead to the conclusion that the existence of spreading is usually associated with strong scintillation. (Author)

  16. LR11/SorLA Expression Is Reduced in Sporadic Alzheimer Disease but not in Familial Alzheimer Disease

    PubMed Central

    Dodson, Sara E.; Gearing, Marla; Lippa, Carol F.; Montine, Thomas J.; Levey, Allan I.; Lah, James J.

    2009-01-01

    LR11 is an ApoE receptor that is enriched in the brain. We have shown that LR11 is markedly downregulated in patients with sporadic Alzheimer disease (AD). This finding led us to explore whether reduced LR11 expression reflects a primary mechanism of disease or merely a secondary consequence of other AD-associated changes. Therefore, LR11 expression was assessed in a transgenic mouse model of AD and familial AD (FAD) brains. Immunohistochemistry and immunoblotting of LR11 in PS1/APP transgenic and wild-type mice indicated that LR11 levels are not affected by genotype or accumulation of amyloid pathology. LR11 expression was also evaluated based on immunoblotting and LR11 immunostaining intensity in human frontal cortex in controls, sporadic AD, and FAD, including cases with presenilin-1 (PS1) and presenilin-2 (PS2) mutations. Although LR11 was reduced in sporadic AD, there was no difference in protein level or staining intensity between control and FAD cases. The finding that LR11 expression is unaffected in both a mouse model of AD and autosomal-dominant forms of AD suggests that LR11 is not regulated by amyloid accumulation or other AD neuropathologic changes. We hypothesize that LR11 loss may be specific to sporadic AD and influence amyloid pathology through mechanisms independent of substrate–enzyme interactions regulated by FAD mutations. PMID:16957580

  17. Identification of preneoplastic lesions as mucin-depleted foci in patients with sporadic colorectal cancer.

    PubMed

    Sakai, Eiji; Morioka, Takamitsu; Yamada, Eiji; Ohkubo, Hidenori; Higurashi, Takuma; Hosono, Kunihiro; Endo, Hiroki; Takahashi, Hirokazu; Takamatsu, Reika; Cui, Changxu; Shiozawa, Manabu; Akaike, Makoto; Samura, Hironori; Nishimaki, Tadashi; Nakajima, Atsushi; Yoshimi, Naoki

    2012-01-01

    In experimental models, mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucin production have been recognized to be correlated with colorectal carcinogenesis and to serve as preneoplastic lesions of colorectal cancer (CRC). In humans, there is only one report of identification of MDF in patients with familial adenomatous polyposis and CRC; however, the histological characteristics of human MDF are not discussed extensively in the report. In the present study, colonic samples from 53 patients with sporadic CRC were stained with Alcian blue and examined for the presence of MDF. Subsequently, the samples were examined for the presence of aberrant crypt foci (ACF) by methylene blue staining. We classified MDF into two categories: flat-MDF and protruded-MDF (having the characteristics of both ACF and MDF). We found a total of 354, 41 and 19 colonic mucosal lesions with a mean multiplicity of 44, 38.9 and 66.9 crypts (ACF, flat-MDF and protruded-MDF, respectively). The density of MDF was 0.0082 lesions/cm(2) . The ACF identified in sporadic CRC patients corresponded to hyperplastic or non-dysplasic lesions. However, MDF identified in these patients corresponded to low-grade dysplasia. In addition, we found that Paneth cell metaplasia and inflammatory cell infiltration were specific histological features of MDF. These histological characteristics are reported to be associated with the development of CRC. Therefore, our results indicate that MDF might represent preneoplastic lesions in human colorectal carcinogenesis.

  18. White matter involvement in sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Mandelli, Maria Luisa; DeArmond, Stephen J.; Hess, Christopher P.; Vitali, Paolo; Papinutto, Nico; Oehler, Abby; Miller, Bruce L.; Lobach, Irina V.; Bastianello, Stefano; Geschwind, Michael D.; Henry, Roland G.

    2014-01-01

    Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white

  19. White matter involvement in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Caverzasi, Eduardo; Mandelli, Maria Luisa; DeArmond, Stephen J; Hess, Christopher P; Vitali, Paolo; Papinutto, Nico; Oehler, Abby; Miller, Bruce L; Lobach, Irina V; Bastianello, Stefano; Geschwind, Michael D; Henry, Roland G

    2014-12-01

    Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P=0.002), axial (P=0.0003) and radial (P=0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P<0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P=0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter

  20. Self-inflicted burns: a sporadic phenomenon.

    PubMed

    Rashid, Abid; Gowar, John P

    2004-12-01

    Self-inflicted burns are a regular cause of admission to burn units. Historically, a full moon has been associated with mental instability. Circadian rhythms and seasonal changes are known to influence human affect. Such cosmic effects, however, have not yet been studied for self-inflicted burns. In this regard, the results of a retrospective analysis of 184 self-inflicted burns admitted during a 20-year period to the Birmingham Burns Centre are presented. The analysis fails to show a connection between the timing of self-inflicted burns and cosmic events. Such incidents are random, not influenced by the day of the week, first or second half of the month, seasonal variation or phase of the lunar cycle.

  1. Positive 14-3-3 and tau proteins in a sporadic Creutzfeldt-Jakob disease case and a brief perspective of prion diseases in Colombia.

    PubMed

    Escandón-Vargas, Kevin; Zorrilla-Vaca, Andrés; Corral-Prado, Raúl Heli

    2016-02-24

    Prion diseases are rare neurodegenerative disorders occurring worldwide and affecting both humans and animals. Herein, we present the case of a patient diagnosed with definite sporadic Creutzfeldt-Jakob disease in Cali, Colombia. Besides neurological examination, 14-3-3 and tau proteins were valuable tools supporting the diagnosis. We also present a brief perspective of the prion diseases reported in Colombia to date. Although the incidence of prion diseases is unknown in Colombia, our literature review revealed that one case of scrapie in 1981 and 29 human sporadic cases of Creutzfeldt-Jakob disease have been documented and published in our country.

  2. Familial resemblance for body composition measures: the HERITAGE Family Study.

    PubMed

    Rice, T; Daw, E W; Gagnon, J; Bouchard, C; Leon, A S; Skinner, J S; Wilmore, J H; Rao, D C

    1997-11-01

    A sex-specific familial correlation model was used to assess the heritable contributions to several measures of body composition in 86 sedentary white families participating in the HERITAGE Family Study. For this study, sedentary families were recruited, tested for a battery of measures, endurance exercise trained for 20 weeks, and remeasured. This sample is unique in that activity level was controlled for in these families at baseline measurement. In this report, three body composition variables measured at baseline were analyzed, two indexing adiposity (total subcutaneous fat based on eight skinfold measurements [SF8] and percent body fat measured by underwater weighing techniques [%BF]) and one assessing fat free mass ([FFM] derived from underwater weighing). The maximal heritabilities for SF8 (34%) and %BF (62%) were consistent with those reported in previous studies. There were no sex nor generation differences in the familial correlations, and the spouse correlation was significant, consistent with the hypothesis that the familial aggregation reflects genetic and familial environmental factors. However, the results for FFM were very different. The most parsimonious pattern of familial resemblance was consistent with mitochondrial inheritance (i.e., mother-offspring and sibling correlations were equal and were larger than those for spouse and father-offspring pairs). Under the mitochondrial hypothesis, 39% of the variance was accounted for by familial/genetic effects. However, under a nonmitochondrial hypothesis, which could not be ruled out, 65% of the FFM phenotypic variance was accounted for by familial/genetic factors. This high heritability level, as compared with results from previous studies, is consistent with the hypothesis that activity may constitute an important environmental determinant of FFM. These alternative hypotheses for FFM warrant further investigation using complex multilocus-multitrait segregation models, which allow for major genetic

  3. Ventricular Tachycardia and Resembling Acute Coronary Syndrome During Pheochromocytoma Crisis

    PubMed Central

    Li, Shi-jun; Wang, Tao; Wang, Lin; Pang, Zhan-qi; Ma, Ben; Li, Ya-wen; Yang, Jian; Dong, He

    2016-01-01

    Abstract Pheochromocytomas are neuroendocrine tumors, and its cardiac involvement may include transient myocardial dysfunction, acute coronary syndrome (ACS), and even ventricular arrhythmias. A patient was referred for evaluation of stuttering chest pain, and his electrocardiogram showed T-wave inversion over leads V1 to V4. Coronary angiography showed 90% stenosis in the mid-left anterior descending coronary artery (LAD), which was stented. Five days later, the patient had ventricular tachycardia, and severe hypertension, remarkable blood pressure fluctuation between 224/76 and 70/50 mm Hg. The patient felt abdominal pain and his abdominal ultrasound showed suspicious right adrenal gland tumor. Enhanced computed tomography of adrenal gland conformed that there was a tumor in right adrenal gland accompanied by an upset level of aldosterone. The tumor was removed by laparoscope, and the pathological examination showed pheochromocytoma. After the surgery, the blood pressure turned normal gradually. There was no T-wave inversion in lead V1-V4. Our case illustrates a rare pheochromocytoma presentation with a VT and resembling ACS. In our case, the serious stenosis in the mid of LAD could be explained by worsen the clinical course of myocardial ischemia or severe coronary vasospasm by the excessive amounts of catecholamines released from the tumor. Coronary vasospasm was possible because he had no classic coronary risk factors (e.g. family history and smoking habit, essential hypertension, hyperglycemia and abnormal serum lipoprotein, high body mass index). Thus, pheochromocytoma was missed until he revealed the association of his symptoms with abdominalgia. As phaeochromocytomas that present with cardiovascular complications can be fatal, it is necessary to screen for the disease when patients present with symptoms indicating catecholamine excess. PMID:27057898

  4. Role of Poultry Meat in Sporadic Campylobacter Infections in Bosnia and Herzegovina: Laboratory-based Study

    PubMed Central

    Uzunović-Kamberović, Selma; Zorman, Tina; Heyndrickx, Marc; Smole Možina, Sonja

    2007-01-01

    Aim To investigate genetic diversity and specificity of Campylobacter jejuni and Campylobacter coli strains isolated from humans, retail poultry meat, and live farm chickens in Zenica-Doboj Canton, Bosnia and Herzegovina, and identify the role of poultry meat in sporadic Campylobacter infections. Methods We determined the type of Campylobacter species using standard microbiological methods and multiplex polymerase chain reaction (PCR), and performed pulsed field gel-electrophoresis (PFGE) and restriction fragment length polymorphism (RFLP) typing of the flaA gene to investigate genetic diversity among the isolates. Results We isolated C jejuni and C coli from 75 (5.2%) of 1453 samples of consecutive outpatients with sporadic diarrhea; from 51 (34.7%) of 147 samples of poultry meat; and from 15 out of 23 farm chicken samples. The proportion of C coli found among human (30.1%), poultry meat (56.9%), and farm chicken isolates (53.3%), was greater than the proportion of C jejuni. Fourteen and 24 PFGE genotypes were identified among 20 C coli and 37 C jejuni isolates, respectively. Identical PFGE genotypes were found in two cases of human and poultry meat isolates and two cases of poultry meat and farm chicken isolates. Conclusion Only a minority of human Campylobacter isolates shared identical PFGE type with poultry meat isolates. Although poultry is the source of a certain number of human infections, there may be other more important sources. Further research is required to identify the environmental reservoir of Campylobacter spp responsible for causing human disease and the reason for the high prevalence of C coli human infections in this region. PMID:18074419

  5. Intestinal differentiated mucinous adenocarcinoma of the endometrium with sporadic MSI high status: a case report.

    PubMed

    Trippel, Mafalda; Imboden, Sara; Papadia, Andrea; Mueller, Michael D; Mertineit, Nando; Härmä, Kirsi; Nicolae, Alina; Vassella, Erik; Rau, Tilman T

    2017-05-12

    Intestinal differentiation of primary mucinous adenocarcinoma of the uterine corpus is exceedingly rare in comparison to the approximately 25% rate in endocervical and ovarian mucinous carcinoma. Additionally, little is known about the related genetic and epigenetic alterations, even though large-scale molecular characterisation of the different types of endometrial cancer took place in the TCGA project along the entities defined by the recent WHO classification. We present a 62-year-old patient harbouring a primary mucinous carcinoma of the uterine corpus with a morphological resemblance to mucinous colorectal adenocarcinoma. The intestinal differentiation was substantiated by CDX2 and CK20 positivity in the absence of PAX8, p16, WT1, p53, ER, PgR, AFP, SALL4 and Glypican3. A high MSI status with MLH1 hypermethylation was revealed by molecular testing. Intestinal differentiation of mucinous adenocarcinoma of the endometrium is a unique observation. Besides morphology, it obviously can share molecular features of sporadic MSI colorectal cancers. It can be speculated that either CDX2 positive morula formation or intestinal metaplasia of the endometrium as rare conditions might be the origin of carcinogenesis for this type II endometrial cancer. Both conditions were not detectable in this case. Of note, categorising endometrial cancers in genetic subgroups like MSI high cancers alone might lead to the integration of likewise morphologically different tumours like the case presented here with intestinal differentiation. Hence, careful genotype-phenotype correlations are warranted for studies of mucinous adenocarcinoma of the endometrium.

  6. Facial resemblance to emotions: group differences, impression effects, and race stereotypes.

    PubMed

    Zebrowitz, Leslie A; Kikuchi, Masako; Fellous, Jean-Marc

    2010-02-01

    The authors used connectionist modeling to extend previous research on emotion overgeneralization effects. Study 1 demonstrated that neutral expression male faces objectively resemble angry expressions more than female faces do, female faces objectively resemble surprise expressions more than male faces do, White faces objectively resemble angry expressions more than Black or Korean faces do, and Black faces objectively resemble happy and surprise expressions more than White faces do. Study 2 demonstrated that objective resemblance to emotion expressions influences trait impressions even when statistically controlling possible confounding influences of attractiveness and babyfaceness. It further demonstrated that emotion overgeneralization is moderated by face race and that racial differences in emotion resemblance contribute to White perceivers' stereotypes of Blacks and Asians. These results suggest that intergroup relations may be strained not only by cultural stereotypes but also by adaptive responses to emotion expressions that are overgeneralized to groups whose faces subtly resemble particular emotions. Copyright 2009 APA, all rights reserved

  7. Facial Resemblance to Emotions: Group Differences, Impression Effects, and Race Stereotypes

    PubMed Central

    Zebrowitz, Leslie A.; Kikuchi, Masako; Fellous, Jean-Marc

    2013-01-01

    The authors used connectionist modeling to extend previous research on emotion overgeneralization effects. Study 1 demonstrated that neutral expression male faces objectively resemble angry expressions more than female faces do, female faces objectively resemble surprise expressions more than male faces do, White faces objectively resemble angry expressions more than Black or Korean faces do, and Black faces objectively resemble happy and surprise expressions more than White faces do. Study 2 demonstrated that objective resemblance to emotion expressions influences trait impressions even when statistically controlling possible confounding influences of attractiveness and babyfaceness. It further demonstrated that emotion overgeneralization is moderated by face race and that racial differences in emotion resemblance contribute to White perceivers’ stereotypes of Blacks and Asians. These results suggest that intergroup relations may be strained not only by cultural stereotypes but also by adaptive responses to emotion expressions that are overgeneralized to groups whose faces subtly resemble particular emotions. PMID:20085393

  8. Progressive hereditary hearing impairment caused by a MYO6 mutation resembles presbyacusis.

    PubMed

    Oonk, A M M; Leijendeckers, J M; Lammers, E M; Weegerink, N J D; Oostrik, J; Beynon, A J; Huygen, P L M; Kunst, H P M; Kremer, H; Snik, A F M; Pennings, R J E

    2013-05-01

    Since deafness is the most common sensorineural disorder in humans, better understanding of the underlying causes is necessary to improve counseling and rehabilitation. A Dutch family with autosomal dominantly inherited sensorineural hearing loss was clinically and genetically assessed. The MYO6 gene was selected to be sequenced because of similarities with other, previously described DFNA22 phenotypes and a pathogenic c.3610C > T (p.R1204W) mutation was found to co-segregate with the disease. This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life. The age-related typical audiograms (ARTA) constructed for this family resemble presbyacusis. Speech audiometry and results of loudness scaling support the hypothesis that the phenotype of this specific MYO6 mutation mimics presbyacusis.

  9. Static and space-time visual saliency detection by self-resemblance.

    PubMed

    Seo, Hae Jong; Milanfar, Peyman

    2009-11-20

    We present a novel unified framework for both static and space-time saliency detection. Our method is a bottom-up approach and computes so-called local regression kernels (i.e., local descriptors) from the given image (or a video), which measure the likeness of a pixel (or voxel) to its surroundings. Visual saliency is then computed using the said "self-resemblance" measure. The framework results in a saliency map where each pixel (or voxel) indicates the statistical likelihood of saliency of a feature matrix given its surrounding feature matrices. As a similarity measure, matrix cosine similarity (a generalization of cosine similarity) is employed. State of the art performance is demonstrated on commonly used human eye fixation data (static scenes (N. Bruce & J. Tsotsos, 2006) and dynamic scenes (L. Itti & P. Baldi, 2006)) and some psychological patterns.

  10. Extraocular muscle dysinnervation disorder resembling Duane retraction syndrome in a 9-month-old French Bulldog.

    PubMed

    Mari, Lorenzo; Blacklock, Benjamin T; Stavinohova, Renata; De Risio, Luisa

    2016-06-18

    A 9-month-old French Bulldog was presented with a chronic history of lateral strabismus and intermittent third eyelid protrusion in the left eye. The neuro-ophthalmological examination revealed mild ptosis of the left upper eyelid, mild lateral strabismus, and external ophthalmoparesis of the left eye. Retraction and ventral deviation of the left eye globe with protrusion of the third eyelid and elevation of the upper eyelid were elicited on attempted voluntary adduction of the left eye. Hematology, serum biochemistry, serology for infectious diseases, magnetic resonance of the head, and cerebrospinal fluid analysis did not reveal significant abnormalities. Forced duction test did not show signs of mechanical restriction in ocular motility. A suspected congenital cranial dysinnervation disorder resembling Duane retraction syndrome in humans was diagnosed based on the typical clinical signs and exclusion of structural abnormalities. The clinical signs remained stable for 9 months until the time of writing this report.

  11. Frequent activation of the β-catenin gene in sporadic colorectal carcinomas: A mutational & expression analysis.

    PubMed

    Anwar, Mumtaz; Kochhar, Rakesh; Singh, Rajinder; Bhatia, Alka; Vaiphei, Kim; Mahmood, Akhtar; Mahmood, Safrun

    2016-11-01

    β-catenin (CTNNB1), an oncogene/onco-protein and an adhesion molecule is a key effector in colorectal cancer (CRC). Its activation, and subsequent up-regulation of Wnt-signaling, is an important event in the development of certain human cancers including CRC. Mutations in the β-catenin gene in the region of serine-threonine glycogen kinase (GSK)-3β phosphorylation target sites have been identified in colorectal cancer in humans. In the current study, we investigated 60 sporadic colorectal adenocarcinomas along with adjoining and normal mucosa cases in humans for β-catenin mutations. Thirteen of sixty colorectal tumors from humans had point mutations with a frequency of 21.66% at codons 24, 26, 27, 32, 34, 35, 41, 42,43, 46, 49, 54, 55, or 67 sites which are mutated in colorectal cancer and some of these sites in other cancers. Thus, there appears to be a key involvement of β-catenin activation in human colorectal carcinogenesis. mRNA expression analysis using q-Real Time PCR showed 21.5-fold up-regulation of β-catenin mRNA in tumor tissue compared to normal and adjoining mucosa. Protein expression analysis using immunohistochemistry, confocal microscopy, and Western blot confirmed aberrant accumulation of β-catenin protein along the nucleus and cytoplasm following mutation. The observed mutations and up-regulation of mRNA in tumors, and the increased expression of β-catenin protein in CRC suggest that these alterations are early and prognostic events in sporadic colorectal carcinogenesis in humans. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  12. Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

    PubMed Central

    Tashiro, Jun; Rubio, Gustavo A.; Limper, Andrew H.; Williams, Kurt; Elliot, Sharon J.; Ninou, Ioanna; Aidinis, Vassilis; Tzouvelekis, Argyrios; Glassberg, Marilyn K.

    2017-01-01

    Large multicenter clinical trials have led to two recently approved drugs for patients with idiopathic pulmonary fibrosis (IPF); yet, both of these therapies only slow disease progression and do not provide a definitive cure. Traditionally, preclinical trials have utilized mouse models of bleomycin (BLM)-induced pulmonary fibrosis—though several limitations prevent direct translation to human IPF. Spontaneous pulmonary fibrosis occurs in other animal species, including dogs, horses, donkeys, and cats. While the fibrotic lungs of these animals share many characteristics with lungs of patients with IPF, current veterinary classifications of fibrotic lung disease are not entirely equivalent. Additional studies that profile these examples of spontaneous fibroses in animals for similarities to human IPF should prove useful for both human and animal investigators. In the meantime, studies of BLM-induced fibrosis in aged male mice remain the most clinically relevant model for preclinical study for human IPF. Addressing issues such as time course of treatment, animal size and characteristics, clinically irrelevant treatment endpoints, and reproducibility of therapeutic outcomes will improve the current status of preclinical studies. Elucidating the mechanisms responsible for the development of fibrosis and disrepair associated with aging through a collaborative approach between researchers will promote the development of models that more accurately represent the realm of interstitial lung diseases in humans. PMID:28804709

  13. On permanent and sporadic pulsations of the magnetosphere

    NASA Astrophysics Data System (ADS)

    Guglielmi, A. V.

    2015-05-01

    A question concerning the influence of permanent Pc3-band pulsations (periods from 10 to 45 s) on the excitation of sporadic Pi2-band pulsations (40 to 150 s) is raised. It is hypothesized that, being generated ahead of the front of the Earth's magnetosphere, the Pc3 penetrate into the geomagnetic tail where they cause local depression in the electric current in the neutral sheet and, under favorable conditions, initiate tearing instability. This leads to the reconnection of the magnetic field lines and explosion-like release of the magnetic energy stored in the tail. As a result, a substorm arises with the sporadic Pi2 pulsations being its important element. Ways are suggested to theoretically substantiate and experimentally validate this hypothesis.

  14. Sporadic endolymphatic sac tumor – a diagnostic and therapeutic challenge

    PubMed Central

    Künzel, Julian; Agaimy, Abbas; Hornung, Joachim; Lell, Michael; Ganslandt, Oliver; Semrau, Sabine; Zenk, Johannes

    2014-01-01

    Endolymphatic sac tumor (ELST) is a rare low-grade locally aggressive neoplasm of the inner ear that may occur sporadically or in the setting of von Hippel-Lindau syndrome. We herein present a case of sporadic ELST in a 39-year-old man, treated using an interdisciplinary approach (surgery + radiotherapy), with a 10-year follow-up. The patient presented with hearing loss of sudden onset. The treatment of choice for ELST is radical tumor resection, which is associated with a good long-term prognosis. Remission may last for years, but there may be local recurrences, probably as a result of incomplete resection. Adjuvant radiotherapy is an option in case of recurrence and could be discussed after incomplete resection. The purpose of this report is to call attention to ELSTs, which are difficult to diagnose due to their rarity and variety of presentations. PMID:24966979

  15. Systematic comparison of sporadic and syndromic pancreatic islet cell tumors.

    PubMed

    Erlic, Zoran; Ploeckinger, Ursula; Cascon, Alberto; Hoffmann, Michael M; von Duecker, Laura; Winter, Aurelia; Kammel, Gerit; Bacher, Janina; Sullivan, Maren; Isermann, Berend; Fischer, Lars; Raffel, Andreas; Knoefel, Wolfram Trudo; Schott, Matthias; Baumann, Tobias; Schaefer, Oliver; Keck, Tobias; Baum, Richard P; Milos, Ioana; Muresan, Mihaela; Peczkowska, Mariola; Januszewicz, Andrzej; Cupisti, Kenko; Tönjes, Anke; Fasshauer, Mathias; Langrehr, Jan; von Wussow, Peter; Agaimy, Abbas; Schlimok, Günter; Lamberts, Regina; Wiech, Thorsten; Schmid, Kurt Werner; Weber, Alexander; Nunez, Mercedes; Robledo, Mercedes; Eng, Charis; Neumann, Hartmut P H

    2010-12-01

    Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (P<0.001) in VHL-ICTs compared to sporadic cases. VHL was prevalent in <0.5% of NETs, while NETs occur in ∼10% of VHL, virtually exclusively as ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

  16. Application of dopplionograms to an understanding of sporadic E

    SciTech Connect

    Wright, J.W.

    1982-03-01

    The dopplionogram can be used to infer the vertical motion of plasma contours under some circumstances. In a sporadic E sequence, motions downward from above, and upward from below, are observed as the layer peak plasma density increases: this is interpreted as consistent with plasma convergence resulting from an east-west wind shear. When divergent motions occur, the layer is observed to dissipate and recede rapidly.

  17. Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer

    PubMed Central

    Carethers, John M.; Jung, Barbara H.

    2015-01-01

    Sporadic colorectal cancer (CRC) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient’s genetic background. Consolidating the knowledge of genetic and epigenetic events that occur with initiation, progression, and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging, and inform treatment approaches. Modern next generation sequencing of sporadic CRCs has confirmed prior identified genetic alterations, and has classified new alterations. Each patient’s CRC is genetically unique, propelled by 2 to 8 driver gene alterations that have accumulated within the CRC since initiation. Commonly observed alterations across sporadic CRCs have allowed classification into a: (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability (MSI) and POLE mutations in ~15%, containing multiple frameshifted genes and BRAFV600E; (2) non-hypermutated group with multiple somatic copy number alterations and aneuploidy in ~85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes such as APC and TP53; (3) CpG Island Methylator Phenotype CRCs in ~20% that overlap greatly with MSI CRCs and some non-hypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in ~60% that associates with metastatic behavior in both hypermutated and non-hypermutated groups. Components from these classifications are now used as diagnostic, prognostic and treatment biomarkers. Additional common biomarkers may come from genome-wide association studies and microRNAs among other sources, as well as from the unique alteration profile of an individual CRC to apply a precision medicine approach to care. PMID:26216840

  18. Exact solutions for sporadic acceleration of cosmic rays

    NASA Technical Reports Server (NTRS)

    Cowsik, R.

    1985-01-01

    The steady state spectra of cosmic rays which are subject to a sporadic acceleration process, wherein the gain in energy in each encounter is a finite fraction of the particle energy are discussed. They are derived from a mathematical model which includes the possibility of energy dependent leakage of cosmic rays from the galaxy. Comparison with observations allows limits to be placed on the frequency and efficiency of such encounters.

  19. Acute sporadic hepatitis E virus infection in southern China.

    PubMed

    Tan, D; Im, S W; Yao, J L; Ng, M H

    1995-09-01

    The hepatitis E virus is responsible for epidemic and sporadic hepatitis in northwestern China, but its role as a cause of acute sporadic hepatitis in southern China has not been reported. We applied the most practical current methods for diagnosis of hepatitis E virus infection, IgM and IgG anti-HEV detection by enzyme linked immunosorbent assay, to investigate the prevalence of hepatitis E virus infection among acute sporadic hepatitis. Anti-HEV IgM was found in 1 of 26 (3.8%), 4 of 20 (20.0%), 4 of 19 (21.1%), and 51 of 142 (35.9%), with acute hepatitis A, B, C and non-ABC, respectively. Anti-HEV IgM was not detectable in healthy subjects, while IgG anti-HEV was found in 14 of 77 healthy subjects (18.2%) and was long-lasting. Ninety-one cases without any evidence of hepatitis A, B or C infections and anti-HEV IgM were tentatively classified as non-A, B, C, D, E (non-ABCDE) hepatitis. By comparison with non-ABCDE, cases with hepatitis E were more frequently icteric and exhibited higher alanine aminotransferase levels (92.2% vs. 45.1%, 770 iu/l vs 377 iu/l, respectively, p < 0.005). Chronic cases were not observed in hepatitis E virus infections. However, 14 of 91 (15.4%) cases with non-ABCDE developed to chronicity (p < 0.005). Hepatitis E virus infection is sporadic as well as endemic in southern China. Only IgM anti-HEV but not IgG anti-HEV can be used as an appropriate marker of acute hepatitis E virus infection. Superinfection of hepatitis E virus with other types of hepatitis viruses is frequent in this area. While the disease was associated with more severe clinical manifestations, patients usually recovered completely.

  20. Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis

    PubMed Central

    Cronkhite, Jennifer T.; Xing, Chao; Raghu, Ganesh; Chin, Kelly M.; Torres, Fernando; Rosenblatt, Randall L.; Garcia, Christine Kim

    2008-01-01

    Rationale: Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres. Objectives: To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC. Methods: Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis. Measurements and Main Results: All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 × 10−8). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 × 10−11). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile. Conclusions: A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease. PMID:18635888

  1. Lightning-induced intensification of the ionospheric sporadic E layer.

    PubMed

    Davis, C J; Johnson, C G

    2005-06-09

    A connection between thunderstorms and the ionosphere has been hypothesized since the mid-1920s. Several mechanisms have been proposed to explain this connection, and evidence from modelling as well as various types of measurements demonstrate that lightning can interact with the lower ionosphere. It has been proposed, on the basis of a few observed events, that the ionospheric 'sporadic E' layer--transient, localized patches of relatively high electron density in the mid-ionosphere E layer, which significantly affect radio-wave propagation--can be modulated by thunderstorms, but a more formal statistical analysis is still needed. Here we identify a statistically significant intensification and descent in altitude of the mid-latitude sporadic E layer directly above thunderstorms. Because no ionospheric response to low-pressure systems without lightning is detected, we conclude that this localized intensification of the sporadic E layer can be attributed to lightning. We suggest that the co-location of lightning and ionospheric enhancement can be explained by either vertically propagating gravity waves that transfer energy from the site of lightning into the ionosphere, or vertical electrical discharge, or by a combination of these two mechanisms.

  2. Formation of ionospheric sporadic E by atmospheric gravity waves

    NASA Astrophysics Data System (ADS)

    Didebulidze, Goderdzi; Dalakishvili, Giorgi; Matiashvili, Giorgi

    2016-07-01

    The atmospheric gravity waves (AGWs) significantly influence the behavior of the thermosphere ions/electrons. It is shown, that in the lower thermosphere when the background wind present, the AGWs evolving in this wind affect the heavy metallic ions vertical motions and can lead to their convergence into horizontal thin layers and consequently form ionosphere sporadic E (Es). For certain values of the velocity of horizontal back-ground wind, occurring in this region, the declined propagation of the AGWs in the mid-latitude lower thermosphere can cause formation multilayered sporadic E. The distances between such Es layers i.e. distance between locations of maximal ions/electrons densities occur is about one AGWs vertical wavelength. The observed phenomena like of sporadic E multilayered structures and Es layers downward motions are demonstrated by using 3-D numerical simulations describing Es formation by AGWs. The formation of quasi-periodic echoes like structures by AGWs evolving in the horizontal inhomogeneous wind and possibility of its ions/electrons density oscillations by smaller periods (smaller than Bunt-Väisälä period), which also is observed phenomena, is shown. Acknowledgements: This work has been supported by Shota Rustaveli National Science Foundation grant No 31/81.

  3. Stable and sporadic symbiotic communities of coral and algal holobionts

    PubMed Central

    Hester, Eric R; Barott, Katie L; Nulton, Jim; Vermeij, Mark JA; Rohwer, Forest L

    2016-01-01

    Coral and algal holobionts are assemblages of macroorganisms and microorganisms, including viruses, Bacteria, Archaea, protists and fungi. Despite a decade of research, it remains unclear whether these associations are spatial–temporally stable or species-specific. We hypothesized that conflicting interpretations of the data arise from high noise associated with sporadic microbial symbionts overwhelming signatures of stable holobiont members. To test this hypothesis, the bacterial communities associated with three coral species (Acropora rosaria, Acropora hyacinthus and Porites lutea) and two algal guilds (crustose coralline algae and turf algae) from 131 samples were analyzed using a novel statistical approach termed the Abundance-Ubiquity (AU) test. The AU test determines whether a given bacterial species would be present given additional sampling effort (that is, stable) versus those species that are sporadically associated with a sample. Using the AU test, we show that coral and algal holobionts have a high-diversity group of stable symbionts. Stable symbionts are not exclusive to one species of coral or algae. No single bacterial species was ubiquitously associated with one host, showing that there is not strict heredity of the microbiome. In addition to the stable symbionts, there was a low-diversity community of sporadic symbionts whose abundance varied widely across individual holobionts of the same species. Identification of these two symbiont communities supports the holobiont model and calls into question the hologenome theory of evolution. PMID:26555246

  4. Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism.

    PubMed

    Amitrano, Sara; Marozza, Annabella; Somma, Serena; Imperatore, Valentina; Hadjistilianou, Theodora; De Francesco, Sonia; Toti, Paolo; Galimberti, Daniela; Meloni, Ilaria; Cetta, Francesco; Piu, Pietro; Di Marco, Chiara; Dosa, Laura; Lo Rizzo, Caterina; Carignani, Giulia; Mencarelli, Maria Antonietta; Mari, Francesca; Renieri, Alessandra; Ariani, Francesca

    2015-11-01

    In about 50% of sporadic cases of retinoblastoma, no constitutive RB1 mutations are detected by conventional methods. However, recent research suggests that, at least in some of these cases, there is somatic mosaicism with respect to RB1 normal and mutant alleles. The increased availability of next generation sequencing improves our ability to detect the exact percentage of patients with mosaicism. Using this technology, we re-tested a series of 40 patients with sporadic retinoblastoma: 10 of them had been previously classified as constitutional heterozygotes, whereas in 30 no RB1 mutations had been found in lymphocytes. In 3 of these 30 patients, we have now identified low-level mosaic variants, varying in frequency between 8 and 24%. In 7 out of the 10 cases previously classified as heterozygous from testing blood cells, we were able to test additional tissues (ocular tissues, urine and/or oral mucosa): in three of them, next generation sequencing has revealed mosaicism. Present results thus confirm that a significant fraction (6/40; 15%) of sporadic retinoblastoma cases are due to postzygotic events and that deep sequencing is an efficient method to unambiguously distinguish mosaics. Re-testing of retinoblastoma patients through next generation sequencing can thus provide new information that may have important implications with respect to genetic counseling and family care.

  5. A novel splice site associated polymorphism in the tuberous sclerosis 2 (TSC2) gene may predispose to the development of sporadic gangliogliomas.

    PubMed

    Platten, M; Meyer-Puttlitz, B; Blümcke, I; Waha, A; Wolf, H K; Nöthen, M M; Louis, D N; Sampson, J R; von Deimling, A

    1997-07-01

    The tuberous sclerosis 2 (TSC2) gene is thought to function as a growth suppressor in sporadic and TSC-associated hamartomas and tumors. Clusters of dysplastic glial cells are a common feature of cortical tubers and subependymal nodules in tuberous sclerosis patients. In an effort to identify TSC2 gene alterations in sporadic gliomas, we detected a novel polymorphism adjacent to the 3'splice site of intron 4. We evaluated the distribution of this variant allele in a series of 244 patients with glial tumors, including 55 gangliogliomas, 31 pilocytic astrocytomas (WHO grade I), 50 astrocytomas (WHO grades II and III), and 108 glioblastomas (WHO grade IV). The allelic distribution in the general population was estimated by examining 381 healthy blood donors. This rare allele appeared in the control population and in the patients with astrocytic gliomas with a virtually identical frequency (8.14%, and 8.20%, respectively). The frequency of the rare allele in gangliogliomas, however, was significantly higher (15.5%; p = 0.024). The fact that both gangliogliomas and cortical tubers in tuberous sclerosis contain neuronal and astrocytic elements and may resemble each other histologically suggests that the TSC2 gene may be involved in the development of these tumors. The rare allele of the TSC2 gene emerges as a candidate for a predisposing factor for the formation of sporadic gangliogliomas.

  6. Sporadic colon cancer murine models demonstrate the value of autoantibody detection for preclinical cancer diagnosis.

    PubMed

    Barderas, Rodrigo; Villar-Vázquez, Roi; Fernández-Aceñero, María Jesús; Babel, Ingrid; Peláez-García, Alberto; Torres, Sofía; Casal, J Ignacio

    2013-10-15

    Although autoantibody detection has been proposed for diagnosis of colorectal cancer, little is known about their initial production and development correlation with cancer progression. Azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice developed colon adenocarcinoma in the distal colon similar to human sporadic colon cancer. We assessed this model together with AOM and DSS-only models for their applicability to early detection of cancer. All AOM/DSS-treated mice produced autoantibodies to tumor-associated antigens analogous to those observed in human colon cancer patients. Autoantibody response was related to tumor antigen overexpression. Cancer autoantibodies were detected 21 days after starting treatment, when no malignant histopathological features were detectable, and they increased according to tumor progression. When carcinogenesis was induced separately by AOM or DSS, only those mice that developed malignant lesions produced significant levels of autoantibodies. These findings demonstrate that autoantibody development is an early event in tumorigenesis and validates its use for preclinical colon cancer diagnosis.

  7. Hereditary and Sporadic Forms of Aβ-Cerebrovascular Amyloidosis and Relevant Transgenic Mouse Models

    PubMed Central

    Kumar-Singh, Samir

    2009-01-01

    Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the leptomeningeal and cerebral blood vessel walls, often causing secondary vascular degenerative changes. Although many kinds of peptides are known to be deposited as vascular amyloid, amyloid-β (Aβ)-CAA is the most common type associated with normal aging, sporadic CAA, Alzheimer’s disease (AD) and Down’s syndrome. Moreover, Aβ-CAA is also associated with rare hereditary cerebrovascular amyloidosis due to mutations within the Aβ domain of the amyloid precursor protein (APP) such as Dutch and Flemish APP mutations. Genetics and clinicopathological studies on these familial diseases as well as sporadic conditions have already shown that CAA not only causes haemorrhagic and ischemic strokes, but also leads to progressive dementia. Transgenic mouse models based on familial AD mutations have also successfully reproduced many of the features found in human disease, providing us with important insights into the pathogenesis of CAA. Importantly, such studies have pointed out that specific vastopic Aβ variants or an unaltered Aβ42/Aβ40 ratio favor vascular Aβ deposition over parenchymal plaques, but higher than critical levels of Aβ40 are also observed to be anti-amyloidogenic. These data would be important in the development of therapies targeting amyloid in vessels. PMID:19468344

  8. Unconsidered sporadic sources of carbon dioxide emission from soils in taiga forests.

    PubMed

    Karelin, D V; Zamolodchikov, D G; Isaev, A S

    2017-07-01

    Long-term monitoring in the Russian taiga zone has shown that all known extreme destructive effects resulting in the weakening and death of tree stands (windfalls, pest attacks, drought events, etc.) can be sporadic, but significant sources of CO2 soil emission. Among them are (i) a recently found effect of the multiyear CO2 emission from soil at the bottom of deadwood of spruce trees that died due to climate warming and subsequent pest outbreaks, (ii) increased soil CO2 emissions due to to the fall of tree trunks during massive windfalls, and (iii) pulse CO2 emission as a result of the so-called Birch effect after drought events in the taiga zone. According to the modeling, while depending on the spatial and temporal scales of their manifestation, the impact of these sporadic effects on the regional and global soil respiration fluxes could be significant and should be taken into consideration. This is due to continuing Climate Change, and further increase of local, regional and Global human impacts on the atmospheric greenhouse gases balance, and land use, as well.

  9. Global Phylogenomic Analysis of Nonencapsulated Streptococcus pneumoniae Reveals a Deep-Branching Classic Lineage That Is Distinct from Multiple Sporadic Lineages

    PubMed Central

    Hilty, Markus; Wüthrich, Daniel; Salter, Susannah J.; Engel, Hansjürg; Campbell, Samuel; Sá-Leão, Raquel; de Lencastre, Hermínia; Hermans, Peter; Sadowy, Ewa; Turner, Paul; Chewapreecha, Claire; Diggle, Mathew; Pluschke, Gerd; McGee, Lesley; Köseoğlu Eser, Özgen; Low, Donald E.; Smith-Vaughan, Heidi; Endimiani, Andrea; Küffer, Marianne; Dupasquier, Mélanie; Beaudoing, Emmanuel; Weber, Johann; Bruggmann, Rémy; Hanage, William P.; Parkhill, Julian; Hathaway, Lucy J.; Mühlemann, Kathrin; Bentley, Stephen D.

    2014-01-01

    The surrounding capsule of Streptococcus pneumoniae has been identified as a major virulence factor and is targeted by pneumococcal conjugate vaccines (PCV). However, nonencapsulated S. pneumoniae (non-Ec-Sp) have also been isolated globally, mainly in carriage studies. It is unknown if non-Ec-Sp evolve sporadically, if they have high antibiotic nonsusceptiblity rates and a unique, specific gene content. Here, whole-genome sequencing of 131 non-Ec-Sp isolates sourced from 17 different locations around the world was performed. Results revealed a deep-branching classic lineage that is distinct from multiple sporadic lineages. The sporadic lineages clustered with a previously sequenced, global collection of encapsulated S. pneumoniae (Ec-Sp) isolates while the classic lineage is comprised mainly of the frequently identified multilocus sequences types (STs) ST344 (n = 39) and ST448 (n = 40). All ST344 and nine ST448 isolates had high nonsusceptiblity rates to β-lactams and other antimicrobials. Analysis of the accessory genome reveals that the classic non-Ec-Sp contained an increased number of mobile elements, than Ec-Sp and sporadic non-Ec-Sp. Performing adherence assays to human epithelial cells for selected classic and sporadic non-Ec-Sp revealed that the presence of a integrative conjugative element (ICE) results in increased adherence to human epithelial cells (P = 0.005). In contrast, sporadic non-Ec-Sp lacking the ICE had greater growth in vitro possibly resulting in improved fitness. In conclusion, non-Ec-Sp isolates from the classic lineage have evolved separately. They have spread globally, are well adapted to nasopharyngeal carriage and are able to coexist with Ec-Sp. Due to continued use of PCV, non-Ec-Sp may become more prevalent. PMID:25480686

  10. Resemblance and divergence: the "new" members of the genus Bordetella.

    PubMed

    Gross, Roy; Keidel, Kristina; Schmitt, Karin

    2010-08-01

    Bordetella pertussis, the etiological agent of whooping cough, belongs to the bacterial pathogens first described in the so-called golden era of microbiology more than 100 years ago. In the course of the following decades, several other closely related pathogens were described which are nowadays classified in the genus Bordetella together with B. pertussis. These are the human and animal pathogens B. parapertussis, B. bronchiseptica and B. avium which are of high medical or veterinary interest, and which, together with B. pertussis, are referred to as the "classical" Bordetella species. Only in the past 15 years, several additional species were classified in the genus, frequently isolated from patients with underlying disease, animals or from the environment. Very little is known about most of these bacteria. In the present review, the current knowledge about these "new" Bordetella species is briefly summarized.

  11. Early-onset colorectal cancer: a sporadic or inherited disease?

    PubMed

    Stigliano, Vittoria; Sanchez-Mete, Lupe; Martayan, Aline; Anti, Marcello

    2014-09-21

    Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a "sporadic" subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the "sporadic" subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this "sporadic" early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.

  12. Sungrazing dust particles against the sporadic meteor background

    NASA Astrophysics Data System (ADS)

    Golubaev, A. V.

    2015-07-01

    From the results of the statistical study, the genetic relation between some meteors (from -5 m to +5 m ) of the sporadic background and the comets of the Kreutz, Marsden, and Kracht families has been revealed. The radiants of sporadic meteors are concentrated at the geocentric ecliptic latitudes 7°-10° northward and southward of the ecliptic. The radiants of the sungrazing meteoroids, that were detected on their heliocentric orbits "before" and "after" the perihelion passage, are concentrated in the elongation intervals of approximately 120°-165° and 20°-60° from the Sun, respectively. Each of the specified radiant regions, in its turn, breaks up into two groups. The group of radiants with elongations of about 30° and 155° from the Sun belongs to the Marsden and Kracht cometary families, while the group with 50° and 135°, to the Kreutz cometary family. In the distribution by perihelion distance, a sharp decrease of the number of observed dust particles with q < 0.08 AU was found. This corresponds to the heliocentric distances (20-30 R ⊙), where the production of microscopic dust due to sublimation of cometary nuclei, while approaching the Sun, terminates. The number of sporadic sungrazing meteoroids detected after their passage in the vicinity of the Sun is approximately 20 times smaller than the number of similar particles in the preperihelion part of the trajectory. This result is of special importance for studying the thermodesorption effect of meteoroids (i.e., the change in the content of chemical elements in meteoroids as a function of the perihelion distance).

  13. New results on sporadic ionization observed with the API technique

    NASA Astrophysics Data System (ADS)

    Bakhmetieva, N. V.; Belikovich, V. V.; Kagan, L. M.

    We present new results of our studies of sporadic E-layers E s by means of the artificial periodic irregularities API technique Artificial periodic irregularities were generated in antinodes of the standing electromagnetic wave formed due to interference of HF radio waves transmitted vertically and reflected from the ionosphere The API are horizontally aligned with a vertical scale of one-half of the wavelength lambda of the transmitted wave for more details on the API method and its applications see Belikovich et al Ionospheric Research by Means of Artificial Periodic Irregularities - Katlenburg-Lindau Germany 2002 Copernicus GmbH ISBN 3-936586-03-9 160 pp Recently we have presented and experimentally realized a method to determine the sporadic E-layer ion composition the molecular masses of the predominant metallic ions and the total ion densities on the basis of the measurements of the amplitude and the decay time of the API signals To study the structure of sporadic ionization layers in the E region as well as a possibility and effectiveness of Es modification by high-power radiowave transmissions we designed and carried out another experiment at the SURA facility 56 1 r N 44 1 r E in August 10-15 2004 The ionosphere modification was done by O-mode waves using two SURA transmitters at the frequency 4 3 MHz with effective radiated power ERP of about 60 MW at the transmitting schedule of the 1-min on 2-min off so-called additional heating The third transmitter was used for API formation and

  14. Notch1 hallmarks fibrillary depositions in sporadic Alzheimer's disease.

    PubMed

    Brai, Emanuele; Alina Raio, Noemi; Alberi, Lavinia

    2016-07-01

    Notch1 signaling is a cellular cascade with a fundamental role from brain development to adult brain function. Reduction in Notch1 affects synaptic plasticity, memory and olfaction. On the other hand, Notch1 overactivation after brain injury is detrimental for neuronal survival. Some familial Alzheimer's disease (FAD) mutations in Presenilins can affect Notch1 processing/activation. Others report that Notch1 is overexpressed in sporadic Alzheimer's disease (AD). These works indicate that imbalances in Notch1 may be implicated in AD pathophysiology. In this study, we addressed whether Notch1 alteration can be considered a hallmark of AD. Immunohistochemical analysis of Notch1 on cortical and hippocampal tissue from post-mortem patients indicates an accumulation of Notch1 in plaque-like structures in the brain parenchyma of subjects with sporadic AD. Further analysis shows that displaced Notch1 is associated with fibrillary tangles/plaques. Biochemical validation confirms an accumulation of Notch1 in cytosolic brain fractions. This increase in protein is not accompanied with a raise in the Notch1 targets Hes1 and Hey1. Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma. Our research indicates that Notch1 is significantly displaced and accumulated in fibrillary structures in the susceptible hippocampal and cortical regions of sporadic AD patients. The dominant deposition of Notch1 in the brain parenchyma and its general signal reduction in neurons is consistent in all the AD patients analyzed and suggests that Notch1 may potentially be considered a novel hallmark of AD.

  15. ATM gene mutations in sporadic breast cancer patients from Brazil.

    PubMed

    Mangone, Flavia Rotea; Miracca, Elisabete C; Feilotter, Harriet E; Mulligan, Lois M; Nagai, Maria Aparecida

    2015-01-01

    The Ataxia-telangiectasia mutated (ATM) gene encodes a multifunctional kinase, which is linked to important cellular functions. Women heterozygous for ATM mutations have an estimated relative risk of developing breast cancer of 3.8. However, the pattern of ATM mutations and their role in breast cancer etiology has been controversial and remains unclear. In the present study, we investigated the frequency and spectrum of ATM mutations in a series of sporadic breast cancers and controls from the Brazilian population. Using PCR-Single Strand Conformation Polymorphism (SSCP) analysis and direct DNA sequencing, we screened a panel of 100 consecutive, unselected sporadic breast tumors and 100 matched controls for all 62 coding exons and flanking introns of the ATM gene. Several polymorphisms were detected in 12 of the 62 coding exons of the ATM gene. These polymorphisms were observed in both breast cancer patients and the control population. In addition, evidence of potential ATM mutations was observed in 7 of the 100 breast cancer cases analyzed. These potential mutations included six missense variants found in exon 13 (p.L546V), exon 14 (p.P604S), exon 20 (p.T935R), exon 42 (p.G2023R), exon 49 (p.L2307F), and exon 50 (p.L2332P) and one nonsense mutation in exon 39 (p.R1882X), which was predicted to generate a truncated protein. Our results corroborate the hypothesis that sporadic breast tumors may occur in carriers of low penetrance ATM mutant alleles and these mutations confer different levels of breast cancer risk.

  16. Mutations in the RET proto-oncogene in sporadic pheochromocytomas

    SciTech Connect

    Thibodeau, S.N.; Lindor, N.M.; Honchel, R.

    1994-09-01

    Mutations in the RET proto-oncogene have recently been demonstrated in kindreds with Multiple Endocrine Neoplasia (MEN) types 2A and 2B. Both of these autosomal dominant disorders are characterized by the development of neoplasia in cell lines of neural crest origin, such as medullary throid carcinomas and pheochromocytomas. Individuals with MEN 2B have, in addition, ganglioneuromas of the lips, tongue and colon, a marfanoid habitus, and corneal nerve thickening. Approximately 90% of patients with MEN 2A have a germline mutation in exons 10 or 11, while 95% of patients with MEN 2B have a T{yields}C transition in codon 918 of exon 16. In this study, pheochromocytomas from 29 individuals who had no clinical evidence of MEN 2A or 2B (sporadic) were examined for the presence of either germline or somatic mutations in exons 10, 11, and 16 of the RET proto-oncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in one of the three exons. One tumor had a G{yields}A transition in codon 609 (exon 10), another had a 6 bp deletion encompassing codons 632 & 633 (exon 11), and the final tumor had a T{yields}C transition in codon 918 (exon 16). These mutations were not found in the corresponding normal DNA from these individuals, indicating that the mutation were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET proto-oncogene, our data suggests that: (1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN 2A or 2B; and (2) somatic mutations in the RET proto-oncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas.

  17. Emotional Family Resemblances? Darwin's Contributions to a Theory of Emotions and Emotional Development.

    ERIC Educational Resources Information Center

    Hesse, Petra

    A family resemblance model of emotions is proposed which uses Darwin's discussion of emotions and Eleanor Rosch's and the philosopher Ludwig Wittgenstein's work on family resemblances. In Darwin's discussion of emotions, certain core features are thought to be widely shared by the members of the respective families of emotions, and more marginal…

  18. Sporadic and familial hemiplegic migraine: diagnosis and treatment.

    PubMed

    Black, David F

    2006-04-01

    Hemiplegic migraine is a rare subtype of migraine with aura associated with transient hemiplegia. The weakness is caused by motor aura. Hemiplegic migraine is the only headache syndrome associated with known genetic mutations and serves as a model for understanding more common varieties of migraine. Because the phenotype includes striking yet transient neurological signs and symptoms, it is imperative that clinicians know the differential diagnosis to rule out possible secondary etiologies when treating patients with hemiplegic spells. Hemiplegic migraine occurs with equal prevalence in either a sporadic or familial form differentiated only by family history. Thus far, treatment trials are anecdotal, although verapamil and acetazolamide have shown promise.

  19. Most common 'sporadic' cancers have a significant germline genetic component.

    PubMed

    Lu, Yi; Ek, Weronica E; Whiteman, David; Vaughan, Thomas L; Spurdle, Amanda B; Easton, Douglas F; Pharoah, Paul D; Thompson, Deborah J; Dunning, Alison M; Hayward, Nicholas K; Chenevix-Trench, Georgia; Macgregor, Stuart

    2014-11-15

    Common cancers have been demarcated into 'hereditary' or 'sporadic' ('non-hereditary') types historically. Such distinctions initially arose from work identifying rare, highly penetrant germline mutations causing 'hereditary' cancer. While rare mutations are important in particular families, most cases in the general population are 'sporadic'. Twin studies have suggested that many 'sporadic' cancers show little or no heritability. To quantify the role of germline mutations in cancer susceptibility, we applied a method for estimating the importance of common genetic variants (array heritability, h(2)g) to twelve cancer types. The following cancers showed a significant (P < 0.05) array heritability: melanoma USA set h(2)g = 0.19 (95% CI = 0.01-0.37) and Australian set h(2)g = 0.30 (0.10-0.50); pancreatic h(2)g = 0.18 (0.06-0.30); prostate h(2)g = 0.81 (0.32-1); kidney h(2)g = 0.18 (0.04-0.32); ovarian h(2)g = 0.30 (0.18-0.42); esophageal adenocarcinoma h(2)g = 0.24 (0.14-0.34); esophageal squamous cell carcinoma h(2)g = 0.19 (0.07-0.31); endometrial UK set h(2)g = 0.23 (0.01-0.45) and Australian set h(2)g = 0.39 (0.02-0.76). Three cancers showed a positive but non-significant effect: breast h(2) g = 0.13 (0-0.56); gastric h(2)g = 0.11 (0-0.27); lung h(2)g = 0.10 (0-0.24). One cancer showed a small effect: bladder h(2)g = 0.01 (0-0.11). Among these cancers, previous twin studies were only able to show heritability for prostate and breast cancer, but we can now make much stronger statements for several common cancers which emphasize the important role of genetic variants in cancer susceptibility. We have demonstrated that several 'sporadic' cancers have a significant inherited component. Larger genome-wide association studies in these cancers will continue to find more loci, which explain part of the remaining polygenic component.

  20. Reprogramming A375 cells to induced-resembled neuronal cells by structured overexpression of specific transcription genes

    PubMed Central

    Zhang, Hengzhu; Wei, Min; Jiang, Yangyang; Wang, Xiaodong; She, Lei; Yan, Zhengcun; Dong, Lun; Pang, Lujun; Wang, Xingdong

    2016-01-01

    Induced-resembled neuronal cells (irNCs) are generated by reprogramming human melanoma cells through the introduction of key transcription factors, providing novel concepts in the treatment of malignant tumor cells and making it possible to supply neural cells for laboratory use. In the present study, irNCs were derived from A375 cells by inducing the 'forced' overexpression of specific genes, including achaete-scute homolog 1 (Ascl1), neuronal differentiation factor 1 (Neurod1), myelin transcription factor 1 (Myt1), brain protein 2 (Brn2, also termed POU3F2) and human brain-derived neurotrophic factor (h-BDNF). irNCs induced from A375 cells express multiple neuronal markers and fire action potentials, exhibiting properties similar to those of motor neurons. The reprogramming procedure comprised reverse transcription-polymerase chain reaction and immunofluorescence staining; furthermore, electrophysiological profiling demonstrated the characteristics of the induced-resembled neurons. The present study obtained a novel type of human irNC from human melanoma, which secreted BDNF continuously, providing a model for neuron-like cells. Thus, irNCs offer promise in investigating various neural diseases by using neural-like cells derived directly from the patient of interest. PMID:27510459

  1. High-resolution analysis of DNA copy number alterations in patients with isolated sporadic keratoconus

    PubMed Central

    Hellani, Ali M.; Al Mansouri, Sameer M.; Kalantan, Hatem; Al-Muammar, Abdulrahman M.

    2011-01-01

    Purpose To determine whether patients with sporadic, non-familial keratoconus and no pathogenic mutations in the visual system homeobox 1 (VSX1) gene have evidence of chromosomal copy number alterations. Methods Twenty Saudi Arabian patients with isolated keratoconus, no family history of the disease and no mutations in VSX1 were recruited. Additionally, 10 ethnically-matched healthy controls were also recruited for this study. We screened patients for chromosomal copy number aberrations using the Agilent Human Genome CGH 244A Oligo Microarray Chip. Results None of the keratoconus patients screened had evidence of chromosomal copy number alterations when compared to normal ethnically matched controls. Conclusions Chromosomal deletions and/or duplications were not detected in any of the patients tested here. Other chromosomal imbalances such as translocations, inversions, and some ploidies cannot be detected by current array CGH technology and other nuclear genetic or epigenetic factors cannot be excluded as a possible contributing factor to keratoconus pathogenesis. PMID:21528002

  2. High-resolution analysis of DNA copy number alterations in patients with isolated sporadic keratoconus.

    PubMed

    Abu-Amero, Khaled K; Hellani, Ali M; Al Mansouri, Sameer M; Kalantan, Hatem; Al-Muammar, Abdulrahman M

    2011-03-30

    To determine whether patients with sporadic, non-familial keratoconus and no pathogenic mutations in the visual system homeobox 1 (VSX1) gene have evidence of chromosomal copy number alterations. Twenty Saudi Arabian patients with isolated keratoconus, no family history of the disease and no mutations in VSX1 were recruited. Additionally, 10 ethnically-matched healthy controls were also recruited for this study. We screened patients for chromosomal copy number aberrations using the Agilent Human Genome CGH 244A Oligo Microarray Chip. None of the keratoconus patients screened had evidence of chromosomal copy number alterations when compared to normal ethnically matched controls. Chromosomal deletions and/or duplications were not detected in any of the patients tested here. Other chromosomal imbalances such as translocations, inversions, and some ploidies cannot be detected by current array CGH technology and other nuclear genetic or epigenetic factors cannot be excluded as a possible contributing factor to keratoconus pathogenesis.

  3. Comparing Characteristics of Sporadic and Outbreak-Associated Foodborne Illnesses, United States, 2004–2011

    PubMed Central

    Ebel, Eric D.; Cole, Dana; Travis, Curtis C.; Klontz, Karl C.; Golden, Neal J.; Hoekstra, Robert M.

    2016-01-01

    Outbreak data have been used to estimate the proportion of illnesses attributable to different foods. Applying outbreak-based attribution estimates to nonoutbreak foodborne illnesses requires an assumption of similar exposure pathways for outbreak and sporadic illnesses. This assumption cannot be tested, but other comparisons can assess its veracity. Our study compares demographic, clinical, temporal, and geographic characteristics of outbreak and sporadic illnesses from Campylobacter, Escherichia coli O157, Listeria, and Salmonella bacteria ascertained by the Foodborne Diseases Active Surveillance Network (FoodNet). Differences among FoodNet sites in outbreak and sporadic illnesses might reflect differences in surveillance practices. For Campylobacter, Listeria, and Escherichia coli O157, outbreak and sporadic illnesses are similar for severity, sex, and age. For Salmonella, outbreak and sporadic illnesses are similar for severity and sex. Nevertheless, the percentage of outbreak illnesses in the youngest age category was lower. Therefore, we do not reject the assumption that outbreak and sporadic illnesses are similar. PMID:27314510

  4. Disease onset in familial and sporadic multiple sclerosis in Argentina.

    PubMed

    Rojas, J I; Patrucco, L; MIguez, J; Sinay, V; Cassara, F Pagani; Cáceres, F; Liguori, N Fernandez; Saladino, M L; Deri, N; Jaacks, G; Marcilla, M Parada; Arrigoni, M I; Correale, J; Fiol, M; Ysrraelit, M C; Carrá, A; Curbelo, M C; Martinez, A; Steinberg, J; Bestoso, S; Hryb, J P; Di Pace, J L; Perassolo, M B; Contentti, E Carnero; Caride, A; Lopez, P A; Martinez, C; Reich, E; Cristiano, E

    2016-03-01

    The present study was carried out to assess if there is an anticipation of age at onset in younger generations of familial multiple sclerosis (FMS) vs. sporadic MS (SMS) in Argentina. multicenter study that included patients from 14 MS Centers of Argentina. Patients were considered as FMS if they had in their family at least one relative of first or second degree diagnosed with MS; otherwise, patients were considered to have SMS. We compared the age at onset between familial and sporadic cases as well as the age at onset between relatives from different generations in FMS vs. SMS. 1333 patients were included, 97 of them were FMS (7.3%). A lower age at onset in the younger generations of FMS cases was found compared with older generations of FMS as well as. SMS cases (24.1±3.7 years vs. 30.3±5.7 years, and 32.4±9.4 respectively; p<0.001). No differences were observed between older generations of FMS vs. SMS cases (p=0.12). we observed an anticipation of age at onset of MS in younger generations of patients with FMS vs. older generations of FMS and SMS. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.

    PubMed

    Capurso, Gabriele; Archibugi, Livia; Delle Fave, Gianfranco

    2015-08-01

    Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.

  6. Cognitive disorders after sporadic ecstasy use? A case report.

    PubMed

    Ruis, Carla; Postma, Albert; Bouvy, Willem; van der Ham, Ineke

    2015-01-01

    Memory problems and changes in hippocampal structures after chronic ecstasy use are well described in the literature. Cognitive problems after incidental ecstasy use are rare, and the few patients described in case reports returned to their normal cognitive level after a relative short period. FV is a 39-year-old man who used an ecstasy tablet in 2005. This resulted in severe confusion for a few days. The confusion was followed by persistent memory complaints and difficulties orientating in new surroundings. An extensive neuropsychological examination 7 years after the ecstasy use revealed a severe memory disorder. Furthermore, his performance on a virtual reality test of navigation showed serious problems navigating in new surroundings. In comparison with matched control subjects (Bayesian approach for single case studies) his scores were significantly impaired on several subtasks of the navigation test. On a magnetic resonance imaging (MRI) scan of the brain bilateral hippocampal atrophy and sclerosis were visible, comparable to previous MRI studies describing hippocampal damage following ecstasy ingestion. This case report describes persistent memory and navigation disorders after sporadic ecstasy use, supported by structural brain abnormalities seen on the MRI scan. These findings revive the debate on whether sporadic ecstasy use can cause persistent cognitive deficits.

  7. Permanent changes in sporadic E layers over fortaleza, Brazil

    NASA Astrophysics Data System (ADS)

    Abdu, M. A.; Batista, I. S.; MacDougall, J.; Sobral, J. H. A.; Muralikrishna, P.

    1997-01-01

    Data available on sporadic E layers in ionograms, from 1975 to 1995 over Fortaleza (38 deg W, 4 deg S) in Brazil are analysed as an extension of a previous study to examine permanent changes in the occurrence characteristics of the different types of E_s layers. The so called q type E_s produced by plasma instability (type II) process of the equatorial electrojet and the other types of E_s produced by wind/wind shear mechanism are studied separately. The results show that while the occurrence of the former variety steadily decreased during the period of analysis, the latter type showed marked increases. These characteristics are shown to be associated mainly with the steady drift of the magnetic equator to northward of Fortaleza at a rate of ~ 0.2 degree per year. The long term trends are, however, modulated by solar activity cycle in F_10.7 flux. Also there is a suggestion of a possible effect from the June 1991 Pinatubo volcanic eruption. The competing roles of the neutral winds and electric fields in the formation of the low latitude sporadic E layer is demonstrated.

  8. Is familial papillary thyroid microcarcinoma more aggressive than sporadic form?

    PubMed Central

    Lee, Cho Rok; Park, Seulkee; Kang, Sang-Wook; Lee, Jandee; Jeong, Jong Ju; Chung, Woong Youn; Park, Cheong Soo

    2017-01-01

    Purpose With the increasing incidence of papillary thyroid microcarcinoma (PTMC), familial papillary thyroid microcarcinoma (FPTMC) is now recognized more frequently. However, the biological behavior of FPTMC is poorly understood. The aim of this study was to investigate the prevalence of FPTMC and its biological aggressiveness. Methods Between March 2006 and July 2010, 2,414 patients underwent primary surgical therapy for PTMC and 149 (6.2%) were further classified as FPTMC. To determine the biological aggressiveness of FPTMC, we compared the clinicopathological features and prognosis between FPTMC and sporadic PTMC (SPTMC). Results The male-to-female ratio was higher in FPTMC than in sporadic papillary thyroid microcarcinoma (SPTMC: 1:4.5 vs. 1:7.2, P = 0.041). The central lymph node (LN) metastasis rate was significantly higher in FPTMC than in SPTMC (36.2% vs. 24.2%, P = 0.002). The local recurrence rate was also higher in FPTMC than in SPTMC (4.5% vs. 0.6%, P < 0.001). We identified familial occurrence in 6.2% of cases of PTMC. FPTMC is associated with a high rate of central LN metastasis and local recurrence. Conclusion These findings suggest that close follow-up can be beneficial in FPTMC patients to detect local recurrence. PMID:28289666

  9. A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

    PubMed Central

    Yu, Haiyang; Artomov, Mykyta; Brähler, Sebastian; Stander, M. Christine; Shamsan, Ghaidan; Sampson, Matthew G.; White, J. Michael; Kretzler, Matthias; Jain, Sanjay; Winkler, Cheryl A.; Mitra, Robi D.; Daly, Mark J.; Shaw, Andrey S.

    2016-01-01

    Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes. PMID:26901816

  10. Sporadic Multifocal Venous Malformations of the Head and Neck

    PubMed Central

    Amato, Michael V.; Patel, Neha A.; Hu, Shirley; Pantelides, Harry

    2015-01-01

    Objective. To report a case of unusually widespread sporadic venous malformations of the head and neck associated with normal D-dimer levels and, due to the protean clinical manifestations and increased risk of coagulopathy of these lesions, to review their diagnosis and clinical management. Case Report. A 25-year-old man presented with a one-year history of intermittent right-sided neck swelling and tongue swelling. Physical exam revealed additional lesions present throughout the head and neck. There was no family history suggestive of heritable vascular malformations. Radiographic imaging demonstrated 15 lesions located in various tissue layers consistent with venous malformations. A coagulation screen showed a normal prothrombin time, activated partial thromboplastin time, international normalized ratio, D-dimer level, and fibrinogen level. It was determined that the patient was not at increased risk for intraoperative coagulopathy and preoperative heparin administration would not be necessary. The patient's buccal and tongue lesions were subsequently excised with no complications. The patient also underwent sclerotherapy evaluation for his neck mass. Conclusion. This case describes a unique presentation of sporadic multifocal venous malformations. It also emphasizes the importance of prompt diagnosis and workup when multiple venous malformations are present to prevent morbidity during surgical excision secondary to intravascular coagulopathy. PMID:26483982

  11. Early detection of sporadic pancreatic cancer: summative review.

    PubMed

    Chari, Suresh T; Kelly, Kimberly; Hollingsworth, Michael A; Thayer, Sarah P; Ahlquist, David A; Andersen, Dana K; Batra, Surinder K; Brentnall, Teresa A; Canto, Marcia; Cleeter, Deborah F; Firpo, Matthew A; Gambhir, Sanjiv Sam; Go, Vay Liang W; Hines, O Joe; Kenner, Barbara J; Klimstra, David S; Lerch, Markus M; Levy, Michael J; Maitra, Anirban; Mulvihill, Sean J; Petersen, Gloria M; Rhim, Andrew D; Simeone, Diane M; Srivastava, Sudhir; Tanaka, Masao; Vinik, Aaron I; Wong, David

    2015-07-01

    Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

  12. Risk factors for sporadic shigellosis, FoodNet 2005.

    PubMed

    Haley, Clinton C; Ong, Kanyin L; Hedberg, Katrina; Cieslak, Paul R; Scallan, Elaine; Marcus, Ruthanne; Shin, Sanghyuk; Cronquist, Alicia; Gillespie, Jennifer; Jones, Timothy F; Shiferaw, Beletshachew; Fuller, Candace; Edge, Karen; Zansky, Shelley M; Ryan, Patricia A; Hoekstra, Robert M; Mintz, Eric

    2010-07-01

    An estimated 450,000 cases of shigellosis occur annually in the United States. Outbreaks have been associated with food, water, child daycare centers, and men who have sex with men. However, for sporadic infections, which account for the majority of cases, risk exposures are poorly characterized. Foodborne Diseases Active Surveillance Network (FoodNet) conducts active, laboratory-based shigellosis surveillance in 10 US sites. We interviewed cases with illness onset during 2005 about exposures during the week before symptom onset using a standardized questionnaire. The proportion of patients who denied nonfood risks was used to estimate the burden attributable to foodborne transmission. Overall, 1494 cases were identified. The approximate incidence was 3.9/100,000, with the highest rates among children aged 1-4 years (16.4) and Hispanics (8.4). Of the 929 cases interviewed, 223 (24%) reported international travel in the week before symptom onset. Of the 626 nontraveling cases with complete risk factor information, 298 (48%) reported exposure to daycare or a household member with diarrhea; 99 (16%) reported drinking untreated water or recreational exposure to water; and 16 (3%) reported sexual contact with a person with diarrhea. Two hundred and fifty-nine (41%) denied all nonfood exposures examined. Sporadic shigellosis is most common among young children and Hispanics. Common exposures include international travel and contact with ill persons or daycare. However, more than one-third of US shigellosis cases annually might be due to food consumed in the United States.

  13. BRCA1 dysfunction in sporadic basal-like breast cancer.

    PubMed

    Turner, N C; Reis-Filho, J S; Russell, A M; Springall, R J; Ryder, K; Steele, D; Savage, K; Gillett, C E; Schmitt, F C; Ashworth, A; Tutt, A N

    2007-03-29

    Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells. Breast cancers arising in carriers of germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers. We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age- and grade-matched controls, for downregulation of BRCA1. Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P=0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P=0.008). ID4, a negative regulator of BRCA1, was expressed at 9.1-fold higher levels in basal-like breast cancer (P<0.0001), suggesting a potential mechanism of BRCA1 downregulation. BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype. Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls (P<0.0001). The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer.

  14. Seroepidemiology and risk factors for sporadic norovirus/Mexico strain.

    PubMed

    Peasey, Anne E; Ruiz-Palacios, Guillermo M; Quigley, Maria; Newsholme, William; Martinez, Julia; Rosales, Gustavo; Jiang, Xi; Blumenthal, Ursula J

    2004-06-01

    Risk factors associated with transmission of sporadic norovirus (NV; formerly Norwalk-like virus)/Mexico strain were identified in a seroepidemiological study conducted in rural Mexico. Acquisition of Mexico strain IgA antibodies was age-related; 34% of 1-4-year-olds were seropositive, compared with 81% of adults (P<.001). After 12 months, 42% of 1-4-year-olds showed a seroresponse to Mexico strain, compared with 27% of adults (P<.01). Personal and domestic hygiene measures, such as hand washing, general cleanliness of the mother's clothing, and the type of room assigned for cooking were significantly associated with odds of a seroresponse. For infants, having a dog in or near the home was a risk factor for seroresponse (P<.01), whereas, for older children, the mother's involvement in agricultural activities was a risk factor (P<.001). This study provides initial evidence of risk factors associated with sporadic NV infection. Data indicate some similarities to risk factors associated with outbreaks of NV infection.

  15. Trace amounts of sporadically reappearing HCV RNA can cause infection

    PubMed Central

    Veerapu, Naga Suresh; Park, Su-Hyung; Tully, Damien C.; Allen, Todd M.; Rehermann, Barbara

    2014-01-01

    Successful hepatitis C virus (HCV) treatment is defined as the absence of viremia 6 months after therapy cessation. We previously reported that trace amounts of HCV RNA, below the sensitivity of the standard clinical assay, can reappear sporadically in treatment responders. Here, we assessed the infectivity of this RNA and infused 3 chimpanzees sequentially at 9-week intervals with plasma or PBMCs from patients who tested positive for trace amounts of HCV RNA more than 6 months after completing pegylated IFN-α/ribavirin therapy. A fourth chimpanzee received HCV RNA–negative plasma and PBMCs from healthy blood donors. The 3 experimental chimpanzees, but not the control chimpanzee, generated HCV-specific T cell responses against nonstructural and structural HCV sequences 6–10 weeks after the first infusion of patient plasma and during subsequent infusions. In 1 chimpanzee, T cell responses declined, and this animal developed high-level viremia at week 27. Deep sequencing of HCV demonstrated transmission of a minor HCV variant from the first infusion donor that persisted in the chimpanzee for more than 6 months despite undetectable systemic viremia. Collectively, these results demonstrate that trace amounts of HCV RNA, which appear sporadically in successfully treated patients, can be infectious; furthermore, transmission can be masked in the recipient by an extended eclipse phase prior to establishing high-level viremia. PMID:25003189

  16. ERKed by LRRK2: A cell biological perspective on hereditary and sporadic Parkinson’s disease

    PubMed Central

    Verma, Manish; Steer, Erin K.; Chu, Charleen T.

    2014-01-01

    The leucine rich repeat kinase 2 (LRRK2/dardarin) is implicated in autosomal dominant familial and sporadic Parkinson’s disease (PD); mutations in LRRK2 account for up to 40% of PD cases in some populations. LRRK2 is a large protein with a kinase domain, a GTPase domain, and multiple potential protein interaction domains. As such, delineating the functional pathways for LRRK2 and mechanisms by which PD-linked variants contribute to age-related neurodegeneration could result in pharmaceutically tractable therapies. A growing number of recent studies implicate dysregulation of mitogen activated protein kinases 3 and 1 (also known as ERK1/2) as possible downstream mediators of mutant LRRK2 effects. As these master regulators of growth, differentiation, neuronal plasticity and cell survival have also been implicated in other PD models, a set of common cell biological pathways may contribute to neuronal susceptibility in PD. Here, we review the literature on several major cellular pathways impacted by LRRK2 mutations – autophagy, microtubule/cytoskeletal dynamics, and protein synthesis – in context of potential signaling crosstalk involving the ERK1/2 and Wnt signaling pathways. Emerging implications for calcium homeostasis, mitochondrial biology and synaptic dysregulation are discussed in relation to LRRK2 interactions with other PD gene products. It has been shown that substantia nigra neurons in human PD and Lewy body dementia patients exhibit cytoplasmic accumulations of ERK1/2 in mitochondria, autophagosomes and bundles of intracellular fibrils. Both experimental and human tissue data implicate pathogenic changes in ERK1/2 signaling in sporadic, toxin-based and mutant LRRK2 settings, suggesting engagement of common cell biological pathways by divergent PD etiologies. PMID:24225420

  17. Conspicuousness, color resemblance, and toxicity in geographically diverging mimicry: The pan-Amazonian frog Allobates femoralis.

    PubMed

    Amézquita, Adolfo; Ramos, Óscar; González, Mabel Cristina; Rodríguez, Camilo; Medina, Iliana; Simões, Pedro Ivo; Lima, Albertina Pimentel

    2017-04-01

    Predation risk is allegedly reduced in Batesian and Müllerian mimics, because their coloration resembles the conspicuous coloration of unpalatable prey. The efficacy of mimicry is thought to be affected by variation in the unpalatability of prey, the conspicuousness of the signals, and the visual system of predators that see them. Many frog species exhibit small colorful patches contrasting against an otherwise dark body. By measuring toxicity and color reflectance in a geographically variable frog species and the syntopic toxic species, we tested whether unpalatability was correlated with between-species color resemblance and whether resemblance was highest for the most conspicuous components of coloration pattern. Heterospecific resemblance in colorful patches was highest between species at the same locality, but unrelated to concomitant variation in toxicity. Surprisingly, resemblance was lower for the conspicuous femoral patches compared to the inconspicuous dorsum. By building visual models, we further tested whether resemblance was affected by the visual system of model predators. As predicted, mimic-model resemblance was higher under the visual system of simulated predators compared to no visual system at all. Our results indicate that femoral patches are aposematic signals and support a role of mimicry in driving phenotypic divergence or mimetic radiation between localities. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

  18. Multisystemic Eosinophilia Resembling Hypereosinophilic Syndrome in a Colony-Bred Owl Monkey (Aotus vociferans)

    PubMed Central

    Gozalo, Alfonso S; Rosenberg, Helene F; Elkins, William R; Montoya, Enrique J; Weller, Richard E

    2009-01-01

    In animals, multisystemic eosinophilic disease is a rare condition characterized by eosinophilic and lymphoplasmacytic infiltrates in various organs. This disorder resembles the human disease known as hypereosinophilic syndrome, a condition defined by prolonged peripheral eosinophilia in the absence of recognizable etiology and associated with end-organ damage. In this report we describe a research-naïve, colony-born, juvenile female owl monkey (Aotus vociferans) who presented clinically with severe respiratory distress and histologically with multiple end-organ infiltration with phenotypically mature eosinophils, plasma cells, and lymphocytes. No tumors or infectious agents were noted either macroscopically or microscopically. Cultures from lung samples revealed no bacteria or fungi. Histologic examination of lung, heart, thymus, liver, spleen, kidney, adrenal, pancreas, stomach, small intestine, and colon revealed no migrating nematode larvae, other parasites, or foreign material that might trigger eosinophilia, nor was there any evidence of or history consistent with an allergic etiology. Given that we ruled out most exogenous and endogenous triggers of eosinophilia, the signs, symptoms, and pathologic findings support the diagnosis of multisystemic eosinophilic disease. To our knowledge, this report is the first description of presumptive hypereosinophilic syndrome in a nonhuman primate. PMID:19476722

  19. Loss of epidermal Evi/Wls results in a phenotype resembling psoriasiform dermatitis.

    PubMed

    Augustin, Iris; Gross, Julia; Baumann, Daniel; Korn, Claudia; Kerr, Grainne; Grigoryan, Tamara; Mauch, Cornelia; Birchmeier, Walter; Boutros, Michael

    2013-08-26

    Cells of the epidermis renew constantly from germinal layer stem cells. Although epithelial cell differentiation has been studied in great detail and the role of Wnt signaling in this process is well described, the contribution of epidermal Wnt secretion in epithelial cell homeostasis remains poorly understood. To analyze the role of Wnt proteins in this process, we created a conditional knockout allele of the Wnt cargo receptor Evi/Gpr177/Wntless and studied mice that lacked Evi expression in the epidermis. We found that K14-Cre, Evi-LOF mice lost their hair during the first hair cycle, showing a reddish skin with impaired skin barrier function. Expression profiling of mutant and wild-type skin revealed up-regulation of inflammation-associated genes. Furthermore, we found that Evi expression in psoriatic skin biopsies is down-regulated, suggesting that Evi-deficient mice developed skin lesions that resemble human psoriasis. Immune cell infiltration was detected in Evi-LOF skin. Interestingly, an age-dependent depletion of dendritic epidermal T cells (DETCs) and an infiltration of γδ(low) T cells in Evi mutant epidermis was observed. Collectively, the described inflammatory skin phenotype in Evi-deficient mice revealed an essential role of Wnt secretion in maintaining normal skin homeostasis by enabling a balanced epidermal-dermal cross talk, which affects immune cell recruitment and DETC survival.

  20. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.

    PubMed Central

    Lyon, M F; Peters, J; Glenister, P H; Ball, S; Wright, E

    1990-01-01

    The X chromosome-linked scurfy (sf) mutant of the mouse is recognized by the scaliness of the skin from which the name is derived and results in death of affected males at about 3-4 weeks of age. Consideration of known man-mouse homologies of the X chromosome prompted hematological studies, which have shown that the blood is highly abnormal. The platelet and erythrocyte counts are both reduced and become progressively lower relative to normal as the disease progresses. There is gastrointestinal bleeding, and most animals appear to die of severe anemia. By contrast, the leukocyte count is consistently raised. Some animals showed signs of infection but it is not yet clear whether there is immunodeficiency. Other features include the scaly skin and apparently reduced lateral growth of the skin, conjunctivitis, and diarrhea in some animals. The mutant resembles Wiskott-Aldrich syndrome in man, which is characterized by thrombocytopenia, eczema, diarrhea, and immunodeficiency. The loci of the human and mouse genes lie in homologous segments of the X chromosome, although apparently in somewhat different positions relative to other gene loci. Scurfy differs from Wiskott-Aldrich syndrome in that scurfy males are consistently hypogonadal. Images PMID:2320565

  1. Alzheimer's disease modeling: ups, downs, and perspectives for human induced pluripotent stem cells.

    PubMed

    Wojda, Urszula; Kuznicki, Jacek

    2013-01-01

    Major breakthroughs are required to win the war against the increasing threat of Alzheimer's disease. Until now, however, despite enormous efforts and funds, effective therapies are lacking, and adequate models for drug validation are still unavailable. In this article, we review the available animal and cellular models of different features of human Alzheimer's disease and critically evaluate their usefulness for understanding the mechanisms of the disease. The majority of the presently used models are based on the amyloid-β and hyperphosphorylated tau hypothesis, which resembles features of familial Alzheimer's disease. Unfortunately, these models offer limited help for understanding the pathomechanisms of the early stages of sporadic Alzheimer's disease. Thus, new models are needed to discover ways to treat or delay the onset of Alzheimer's disease, and we discuss the prospects for such desperately needed models, including human induced pluripotent stem cells and in silico brain models.

  2. Sporadic impact flashes on the Moon and their implications

    NASA Astrophysics Data System (ADS)

    Trigo-Rodriguez, J. M.; Ortiz, J. L.; Llorca, J.; Santos-Sanz, P.

    The systematic impact flash survey that we carried out between 2001 and 2004 resulted in the first unambiguous detection of lunar sporadic impact flashes (Ortiz et al., 2006) and already allowed us to estimate the impact rate of objects on Earth as a function of their incoming energy under the assumption of a certain range of luminous efficiencies of the impact processes. Some present unknown parameters can be constrained in the future by monitoring impact flashes associated with meteoroid streams exhibiting a wide range of impact angles and energies. Here we further investigate some implications of the sporadic impact flashes detected so far and in particular we focus on whether the SMART-1 impact flash can give additional constraints on the luminous efficiency applicable to sporadic impacts, in order to derive more accurate impact rates on Earth. We have compared our derived impact fluxes with those obtained by Ceplecha (2001) and Brown et al. (2002) and we conclude that the present flux in the observed energy range would be underestimated. Finally, we conclude that the large lunar surface coverage and increasing sensitivity of modern video cameras makes this a powerful method to estimate terrestrial impact rates of large bodies that are statistically difficult to be detected from more limited atmospheric coverages characteristic of terrestrial networks. REFERENCES Brown, P., Spalding, R. E., Revelle, D. O., Tagliaferri, E., Worden, S. P. 2002. The flux of small near-Earth objects colliding with the Earth. Nature 420, 294-296. Ceplecha Z. (2001) in Collisional processes in the solar system, eds. Mikhail Ya. Marov and Hans Rickman, Astrophysics and Space Science library, Vol. 261, Dordrecht, Kluwer Academic Publishers, 35 - 50. Ortiz J.L., F.J. Aceituno, J.A. Quesada, J. Aceituno, M. Fernández, P. Santos-Sanz, J.M. Trigo-Rodríguez, J. Llorca, F.J. Martín-Torres, P. Montañés-Rodríguez, E. Pallé (2006) Icarus, in press.

  3. Staphylococcus pseudintermedius expresses surface proteins that closely resemble those from Staphylococcus aureus.

    PubMed

    Geoghegan, Joan A; Smith, Emma J; Speziale, Pietro; Foster, Timothy J

    2009-09-18

    Staphylococcus pseudintermedius is a commensal of dogs that is implicated in the pathogenesis of canine pyoderma. This study aimed to determine if S. pseudintermedius expresses surface proteins resembling those from Staphylococcus aureus and to characterise them. S. pseudintermedius strain 326 was shown to adhere strongly to purified fibrinogen, fibronectin and cytokeratin 10. It adhered to the alpha-chain of fibrinogen which, along with binding to cytokeratin 10, is the hallmark of clumping factor B of S. aureus, a surface protein that is in part responsible for colonisation of the human nares. Ligand-affinity blotting with cell-wall extracts demonstrated that S. pseudintermedius 326 expressed a cell-wall anchored fibronectin binding protein which recognised the N-terminal 29kDa fragment. The ability to bind fibronectin is an important attribute of pathogenic S. aureus and is associated with the ability of S. aureus to colonise skin of human atopic dermatitis patients. S. pseudintermedius genomic DNA was probed with labelled DNA amplified from the serine-aspartate repeat encoding region of clfA of S. aureus. This probe hybridised to a single SpeI fragment of S. pseudintermedius DNA. In the cell-wall extract of S. pseudintermedius 326, a 180kDa protein was discovered which bound to fibrinogen by ligand-affinity blotting and reacted in a Western blot with antibodies raised against the serine-aspartate repeat region of ClfA and the B-repeats of SdrD of S. aureus. It is proposed that this is an Sdr protein with B-repeats that has an A domain that binds to fibrinogen. Whether it is the same protein that binds cytokeratin 10 is not clear.

  4. Assembling polycyclic bisguanidine motifs resembling batzelladine alkaloids by double tethered Biginelli condensations.

    PubMed

    Cohen, Frederick; Collins, Shawn K; Overman, Larry E

    2003-11-13

    [reaction: see text] Double tethered Biginelli condensations furnish linked polycyclic bisguanidines or bisureas. Alteration of the bis-beta-ketoester component allows bispolycyclic guanidine motifs to be constructed that resemble natural batzelladine alkaloids or have novel linkages.

  5. RESEMBLANCES BETWEEN THE ELECTROMOTOR VARIATIONS OF RHYTHMICALLY REACTING LIVING AND NON-LIVING SYSTEMS.

    PubMed

    Lillie, R S

    1929-09-20

    1. The electromotor variations of pure iron wires, arranged to react rhythmically with nitric acid, are recorded and described. 2. Resemblances between these variations and those of rhythmically reacting living tissues (especially the heart) are pointed out and discussed.

  6. Double sporadic metal layers as observed by colocated Fe and Na lidars at Wuhan, China

    NASA Astrophysics Data System (ADS)

    Wang, Xiaodong; Yi, Fan; Huang, Kaiming

    2017-02-01

    In this paper, we report a set of double sporadic layer events observed by Fe and Na lidars over Wuhan, China. The two sporadic metal layers above normal layer were named as upper and middle sporadic metal layers, respectively. In these events, the upper, middle, and normal Fe layers presented altitude separately. There were nine double sporadic Fe events observed in 163 nights during 2010-2013. Eight of the nine events were observed in summer. The maximum ratios of peak density for upper and middle sporadic Fe layers to normal Fe layer were up to 375% and 225%, respectively. The peak altitudes of upper (middle) sporadic Fe layers were in the range of 102-107 km (95-98.5 km). The double sporadic Fe layers lasted more than 2 h. Interestingly, we found that density enhancement occurred simultaneously in upper, middle, and normal Fe layers on two events. On the nine Fe events, there existed five nights of colocated Na lidar observations. We found that double sporadic Na and Fe layers simultaneously appeared. They presented similar structures, altitudes, and temporal variations in all five compared events. A little different from Fe, the middle sporadic Na layer was not separated from Na main layer maybe for the wide altitude range of Na main layer. The ratios of upper (middle) sporadic Fe and Na peak values were in the range of 6.6-52 (0.57-6.58). While the exact formation mechanism responsible for double sporadic metal layers is still unclear, some possible explanations and corresponding observations are discussed.

  7. [Sporadic Late-Onset Nemaline Myopathy Associated with MGUS].

    PubMed

    Nagai, Taiji; Sunada, Yoshihide

    2015-12-01

    Sporadic late-onset nemaline myopathy is an uncommon disease. Clinically, it is characterized by progressive muscle weakness that can develop in limbs or axial muscles. Asymmetrical distal weakness, facial weakness, dropped head, and dysphagia can also occur. Since the serum creatine kinase level usually remains within the normal range, patients can be misdiagnosed with motor neuron disease. Recognition of nemaline rods on muscle biopsy is crucial for accurate diagnosis. If it is associated with monoclonal gammopathy of undetermined significance, the outcome is known to be unfavorable. In spite of various immunotherapies such as corticosteroids, immunosuppressants, and plasmapheresis, most patients die of respiratory failure within 5 years. Since the efficacy of autologous stem cell transplantation following high-dose melphalan was first reported in 2008, there have been accumulating reports that showed the positive effect of this therapy for the disease.

  8. Sporadic late onset nemaline myopathy and immunoglobulin deposition disease.

    PubMed

    Doppler, Kathrin; Knop, Stefan; Einsele, Hermann; Sommer, Claudia; Wessig, Carsten

    2013-12-01

    In monoclonal gammopathy, organ dysfunction can occur due to deposition of immunoglobulin fragments. A rare form of acquired myopathy often associated with monoclonal gammopathy is sporadic late onset nemaline myopathy (SLONM), which is characterized by nemaline rods in myofibers. The pathogenetic link between monoclonal gammopathy and SLONM has not yet been elucidated. Case report of a patient with monoclonal gammopathy who developed a progressive myopathy, finally diagnosed as SLONM. A muscle biopsy showed mild myopathic changes. A second biopsy 1 year after clinical onset demonstrated deposition of immunoglobulin light and heavy chains and the presence of nemaline rods. The patient experienced marked improvement of muscle strength after autologous stem cell transplantation and treatment with bortezomib, a therapy that is known to be effective in light chain deposition disease. We speculate that deposition of light and heavy chains, rather than nemaline bodies, has myotoxic effects on skeletal muscle. Copyright © 2013 Wiley Periodicals, Inc.

  9. A sporadic third layer in the ionosphere of Mars.

    PubMed

    Pätzold, M; Tellmann, S; Häusler, B; Hinson, D; Schaa, R; Tyler, G L

    2005-11-04

    The daytime martian ionosphere has been observed as a two-layer structure with electron densities that peak at altitudes between about 110 and 130 kilometers. The Mars Express Orbiter Radio Science Experiment on the European Mars Express spacecraft observed, in 10 out of 120 electron density profiles, a third ionospheric layer at altitude ranges of 65 to 110 kilometers, where electron densities, on average, peaked at 0.8 x 10(10) per cubic meter. Such a layer has been predicted to be permanent and continuous. Its origin has been attributed to ablation of meteors and charge exchange of magnesium and iron. Our observations imply that this layer is present sporadically and locally.

  10. [Virological and clinical features of patients with sporadic hepatitis C].

    PubMed

    Tang, Z; Wang, Y; Yu, Z; Yang, D; Hao, L

    1997-06-01

    In this study, the transmission route in 16 sporadic hepatitis C (SHC) patients was investigated. Three of them were surgeons who had often had occupational needlestick accidents, another 3 had close household contact with their spouses who had been diagnosed as chronic posttransfusion viral hepatitis C (PTHC), and the remaining 5 had potential parenteral exposure such as tooth extraction, injection or inoculation and so on. Five patients with SHC didn't have such history, their transmission route was not determined. Our result showed a lower viremia level in patients with SHC when compared to PTHC patients (the serum dilutions for HCV RNA detection was 10-100 times in the former and 100-10000 times in the latter. P<0.01). Only 1 patient with SHC was anti-HCV positive. Comparing to PTHC, the patients with SHC in our study had milder liver demage and lower ALT levels, and most of them (10/16) were symptomless.

  11. Ion Mass Spectrometer for Sporadic-E Rocket Experiments

    NASA Technical Reports Server (NTRS)

    Heelis, R. A.; Earle, G. D.; Pfaff, Robert

    2000-01-01

    NASA grant NAG5-5086 provided funding for the William B. Hanson Center for Space Sciences at the University of Texas at Dallas (UTD) to design, fabricate, calibrate, and ultimately fly two ion mass spectrometer instruments on a pair of sounding rocket payloads. Drs. R.A. Heelis and G.D. Earle from UTD were co-investigators on the project. The principal investigator for both rocket experiments was Dr. Robert Pfaff of the Goddard Space Flight Center. The overall project title was "Rocket/Radar Investigation of Lower Ionospheric Electrodynamics Associated with Intense Mid-Latitude Sporadic-E Layers". This report describes the overall objectives of the project, summarizes the instrument design and flight experiment details, and presents representative data obtained during the flights.

  12. Apoptosis signals in sporadic amyotrophic lateral sclerosis: an immunocytochemical study.

    PubMed

    Embacher, N; Kaufmann, W A; Beer, R; Maier, H; Jellinger, K A; Poewe, W; Ransmayr, G

    2001-11-01

    Sporadic amyotrophic lateral sclerosis (sALS) is a neurodegenerative disorder of unknown cause characterized by selective loss of both upper and lower motor neurons. Whether neuronal death in sALS is due to apoptosis has so far not been clarified. In this study, the expression and distribution patterns of pro- and anti-apoptotic bcl-2 family members as well as the executioner caspase-3 were investigated in post-mortem CNS tissue of eight sALS patients and seven age-matched controls. Sparse motor neurons were immunoreactive for bcl-2, bax, bak, and CM1 on serial sections through the spinal cord and motor cortex of individual sALS patients and controls. However, there was no obvious difference in the numbers of immunoreactive (IR) neurons between the two groups. The study did not find evidence for apoptosis as a major mechanism of motor neuronal cell death in sALS.

  13. Sporadic Insulinoma Presenting as Early Morning Night Terrors.

    PubMed

    Beisang, Daniel; Forlenza, Gregory P; Luquette, Mark; Sarafoglou, Kyriakie

    2017-06-01

    A 16-year-old boy with a recent diagnosis of night terrors was evaluated for recurrent early morning hypoglycemia after an early morning seizure. Evaluation in clinic with critical laboratories identified hyperinsulinemic hypoglycemia. Additional investigation revealed a sporadic insulinoma as the etiology of his hypoglycemia and all symptoms were resolved after pancreaticoduodenectomy. The importance of obtaining critical laboratory samples is highlighted and appropriate radiologic, medical, and pathologic testing is discussed. We additionally review the medical and surgical management of hyperinsulinemic hypoglycemia. A discussion of multiple endocrine neoplasia type 1 associated insulinomas is included as well. This case highlights the importance of considering hypoglycemia in the evaluation of night terrors and new-onset seizures. Copyright © 2017 by the American Academy of Pediatrics.

  14. Sporadic radio emission of the Sun in the decametre range

    NASA Astrophysics Data System (ADS)

    Melnik, Valentin N.; Konovalenko, Alexander A.; Rucker, Helmut O.; Lecacheux, Alain

    2007-08-01

    Results of the last observations of solar sporadic radio emission at the UTR-2 radio telescope (Kharkov, Ukraine) at the frequencies 10 - 30 MHz are presented. The use of new backend facilities, the DSP and 60-channel spectrometer, allows us to obtain data with time resolution up to 2 ms and frequency resolution of 12 kHz in the continuous frequency band 12 MHz. Usual Type III bursts, Type IIIb bursts, U- and J-bursts in the decameter range are discussed. Special attention is paid to detection and analysis of Type II bursts and their properties, newly discovered fine time structures of Type III bursts, Type III-like bursts, s-bursts, new observational features of drift pair bursts, and ‘absorption’ bursts.

  15. Sporadic Radio Emission of the Sun in the Decameter Range

    NASA Astrophysics Data System (ADS)

    Mel'Nik, V. N.; Konovalenko, A. A.; Rucker, H. O.; Lecacheux, A.

    2006-08-01

    Results of the last observations of solar sporadic radio emission on the UTR-2 radio telescope (Kharkov, Ukraine) at the frequencies 10-30MHz are presented. Using of new back-end facilities, the DSP and 60-channel spectrometer, allows obtaining data with time resolution up to 2 ms and frequency resolution 12 kHz in the continuous frequency band 12MHz. Usual Type III bursts, type III-b bursts, U- and J- bursts in the decameter range are discussed. Especial attention is paid to detection and analysis of Type II bursts and their properties, first found fine time structures of Type III bursts, Type III-like bursts, s-bursts, new observational features of drift pair bursts, "absorption" burst.

  16. Whole-Exome Sequencing Studies of Nonhereditary (Sporadic) Parathyroid Adenomas

    PubMed Central

    Newey, Paul J.; Nesbit, M. Andrew; Rimmer, Andrew J.; Attar, Moustafa; Head, Rosie T.; Christie, Paul T.; Gorvin, Caroline M.; Stechman, Michael; Gregory, Lorna; Mihai, Radu; Sadler, Greg; McVean, Gil; Buck, David

    2012-01-01

    Context: Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in <50% of nonhereditary (sporadic) parathyroid adenomas. Objective: To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis. Design: Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas. Results: Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2–110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (∼35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor. Conclusions: Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations. PMID:22855342

  17. Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease.

    PubMed Central

    Mathews, P. M.; Cataldo, A. M.; Kao, B. H.; Rudnicki, A. G.; Qin, X.; Yang, J. L.; Jiang, Y.; Picciano, M.; Hulette, C.; Lippa, C. F.; Bird, T. D.; Nochlin, D.; Walter, J.; Haass, C.; Lévesque, L.; Fraser, P. E.; Andreadis, A.; Nixon, R. A.

    2000-01-01

    BACKGROUND: Mutations in the presenilin proteins cause early-onset, familial Alzheimer's disease (FAD). MATERIALS AND METHODS: We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer's disease (AD). RESULTS: Amino-terminal antibodies to both presenilins predominantly decorated large neurons. Regional differences between the broad distributions of the two presenilins were greatest in the cerebellum, where most Purkinje cells showed high levels of only PS2 immunoreactivity. PS2 endoproteolysis in brain yielded multiple amino-terminal fragments similar in size to the PS1 amino-terminal fragments detected in brain. In addition, two different PS2 amino-terminal antibodies also detected a prominent 42 kDa band that may represent a novel PS2 form in human brain. Similar to PS1 findings, neither amino-terminal nor antiloop PS2 antibodies revealed substantial full-length PS2 in brain. Immunocytochemical examination of brains from individuals with the N141I PS2 mutation or eight different PS1 mutations, spanning the molecule from the second transmembrane domain to the large cytoplasmic loop domain, revealed immunodecoration of no senile plaques and only neurofibrillary tangles in the M139I PS1 mutation stained with PS1 antibodies. CONCLUSIONS: Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenilin FAD cases were similar to control cases and sporadic AD cases. Thus, accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined. PMID:11126202

  18. Mitochondrial haplogroups and polymorphisms reveal no association with sporadic prostate cancer in a southern European population.

    PubMed

    Álvarez-Cubero, María Jesús; Saiz Guinaldo, María; Martínez-González, Luís Javier; Álvarez Merino, Juan Carlos; Cózar Olmo, José Manuel; Acosta, José Antonio Lorente

    2012-01-01

    It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer. Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage. Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results.

  19. Mitochondrial Haplogroups and Polymorphisms Reveal No Association with Sporadic Prostate Cancer in a Southern European Population

    PubMed Central

    Álvarez-Cubero, María Jesús; Saiz Guinaldo, María; Martínez-González, Luís Javier; Álvarez Merino, Juan Carlos; Cózar Olmo, José Manuel; Acosta, José Antonio Lorente

    2012-01-01

    Background It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer. Methodology and Principal Findings Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage. Conclusions and Significance Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results. PMID:22815971

  20. Risk factors associated with sporadic salmonellosis in adults: a case-control study.

    PubMed

    Ziehm, D; Dreesman, J; Campe, A; Kreienbrock, L; Pulz, M

    2013-02-01

    In order to identify and assess recent risk factors for sporadic human infections with Salmonella enterica, we conducted a case-control study in Lower Saxony, Germany. The data collection was based on standardized telephone interviews with 1017 cases and 346 controls aged >14 years. Odds ratios were calculated in single-factor and multi-factor analyses for Salmonella cases and two different control groups, i.e. population controls and controls with rotavirus infection. Multi-factor analysis revealed associations between sporadic Salmonella infections for two exposures by both sets of controls: consumption of raw ground pork [adjusted odds ratio (aOR) 2·38, 95% confidence interval (CI) 1·27-4·44] and foreign travel (aOR 2·12, 95% CI 1·00-4·52). Other exposures included consumption of food items containing eggs (aOR 1·43, 95% CI 0·80-2·54), consumption of chicken meat (aOR 1·77, 95% CI 1·26-2·50), outdoor meals/barbecues (aOR 3·96, 95% CI 1·41-11·12) and taking gastric acidity inhibitors (aOR 2·42, 95% CI 1·19-4·92), all were significantly associated with respect to one of the two control groups. The impact of consuming food items containing eggs or chicken meat was lower than expected from the literature. This might be a consequence of Salmonella control programmes as well as increased public awareness of eggs and chicken products being a risk factor for salmonellosis. Efforts to reduce Salmonella infections due to raw pork products should be intensified.

  1. Who Resembles Whom? Mimetic and Coincidental Look-Alikes among Tropical Reef Fishes

    PubMed Central

    Robertson, D. Ross

    2013-01-01

    Studies of mimicry among tropical reef-fishes usually give little or no consideration to alternative explanations for behavioral associations between unrelated, look-alike species that benefit the supposed mimic. I propose and assess such an alternative explanation. With mimicry the mimic resembles its model, evolved to do so in response to selection by the mimicry target, and gains evolved benefits from that resemblance. In the alternative, the social-trap hypothesis, a coincidental resemblance of the model to the “mimic” inadvertently attracts the latter to it, and reinforcement of this social trapping by learned benefits leads to the “mimic” regularly associating with the model. I examine three well known cases of supposed aggressive mimicry among reef-fishes in relation to nine predictions from these hypotheses, and assess which hypothesis offers a better explanation for each. One case, involving precise and complex morphological and behavioral resemblance, is strongly consistent with mimicry, one is inconclusive, and one is more consistent with a social-trap based on coincidental, imprecise resemblance. Few cases of supposed interspecific mimicry among tropical reef fishes have been examined in depth, and many such associations may involve social traps arising from generalized, coincidental resemblance. Mimicry may be much less common among these fishes than is generally thought. PMID:23372795

  2. Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors.

    PubMed

    Hagel, Christian; Zils, Ulrich; Peiper, Matthias; Kluwe, Lan; Gotthard, Stefan; Friedrich, Reinhard E; Zurakowski, David; von Deimling, Andreas; Mautner, Victor Felix

    2007-04-01

    The differences in the clinical course and histopathology of sporadic and neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) were investigated retrospectively. The collective comprised 38 NF1 patients and 14 sporadic patients. NF1 patients were significantly younger at diagnosis (p<0.001) and had a significantly shorter survival time than sporadic patients (median survival 17 months vs. 42 months, Breslow p<0.05). The time interval to local recurrence and metastatic spread was also significantly shorter in NF1 patients (9.4 months vs. 30.0 months, p<0.01; 9.1 months vs. 33.2 months, p<0.001, respectively). In patients with the original histopathological data available (22 NF1 patients, 14 sporadic cases), NF1-associated MPNST showed a significantly higher cellularity compared to sporadic tumors (p<0.001) whereas sporadic MPNST featured a significantly higher pleomorphism (p<0.01). Most importantly, while histopathological variables correlated with French Fédération Nationale des Centres de Lutte Contre le Cancer grading in sporadic MPNST, this was not the case for NF1-associated tumors. The differences between NF1-associated and sporadic MPNST in regard to the clinical course and histopathology may reflect some fundamental differences in biology and pathomechanism of the two tumor groups. Our findings indicate the necessity for a separate grading scheme which takes into account the genetic background in NF1 patients.

  3. Alzheimer disease: from inherited to sporadic AD-crossing the biomarker bridge.

    PubMed

    Hampel, Harald; Lista, Simone

    2012-11-05

    Whether dominantly inherited variants of Alzheimer disease (AD) and 'sporadic' forms exhibit similar pathophysiological and biomarker signatures remains unresolved. A landmark study has proposed a biomarker progression model of dominantly inherited AD, but a complex systems biology and physiology approach is required to translate these findings to sporadic disease.

  4. [Molecular and metabolic changes in human clear cell liver foci].

    PubMed

    Ribback, S; Calvisi, D F; Cigliano, A; Rausch, J; Heidecke, C-D; Birth, M; Dombrowski, F

    2015-11-01

    Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype are evident both in human hepatocellular carcinoma and in the rat model of insulin-induced hepatocarcinogenesis in the earliest preneoplastic lesions, i.e. clear cell foci (CCF) of altered hepatocytes. These CCFs have also been described in the human liver but characterization of molecular and metabolic changes are still pending. In this study, human sporadic CCFs were investigated in a collection of human non-cirrhotic liver specimens using histology, histochemistry, immunohistochemistry, electron microscopy and molecular pathological analysis. Human CCFs occurred in approximately 33 % of non-cirrhotic livers and stored masses of glycogen in the cytoplasm, largely due to reduced activity of glucose-6-phosphatase. Hepatocytes revealed an upregulation of the AKT/mTOR and the Ras/MAPK pathways, the insulin receptor, glucose transporters and enzymes of glycolysis and de novo lipogenesis. Proliferative activity was 2-fold higher than in extrafocal tissue. The CCFs of altered hepatocytes are metabolically and proliferatively active lesions even in humans. They resemble the well-known preneoplastic lesions from experimental models in terms of morphology, glycogen storage, overexpression of protooncogenic signaling pathways and activation of the lipogenic phenotype, which are also known in human hepatocellular carcinoma. This suggests that hepatic CCFs also represent very early lesions of hepatocarcinogenesis in humans.

  5. Estrogen receptor β-deficient female mice develop a bladder phenotype resembling human interstitial cystitis

    PubMed Central

    Imamov, Otabek; Yakimchuk, Konstantin; Morani, Andrea; Schwend, Thomas; Wada-Hiraike, Osamu; Razumov, Sergei; Warner, Margaret; Gustafsson, Jan-Åke

    2007-01-01

    Interstitial cystitis/painful bladder syndrome is a disease seen mostly in women, and symptoms tend to be worse premenopausally or during ovulation. The four cardinal symptoms of interstitial cystitis/painful bladder syndrome are bladder pain, urgency, frequency, and nocturia. Estrogen has been implicated in the etiology of this disease, but the role of the two estrogen receptors (ER), ERα and ERβ, has not been investigated. We found that, in the bladders of WT mice, ERβ is expressed in the basal cell layer of the urothelium. Bladders of male ERβ−/− mice were intact and morphologically indistinguishable from those of their WT littermates. However, in female ERβ−/− mice, there was ulceration and atrophy of bladder urothelium concomitant with infiltration of γδ T cells concentrated in the areas of atrophy and shedding of urothelium. The data support the idea that activated γδ T cells are causing the damage to the urothelium. The hyperactivity of T cells may be because of an imbalance between ERα and ERβ signaling in female ERβ−/− mice. Our data suggest that reduced ERβ signaling might have a role in the pathogenesis of interstitial cystitis, and ERβ could be a candidate for a target of medical therapy. PMID:17522255

  6. Dwarfism in Alaskan malamutes: a disease resembling metaphyseal dysplasia in human beings.

    PubMed Central

    Sande, R. D.; Alexander, J. E.; Spencer, G. R.; Padgett, G. A.; Davis, W. C.

    1982-01-01

    In a study of 300 Alaskan Malamutes, dwarfism was shown to be an autosomal recessive inherited disease with complete penetrance that resulted in disturbed endochondral bone formation. Osseous growth disturbance was manifest at the metaphyses of tubular bones. Clinical and radiographic changes were very similar to those of rickets, although appositional bone formation rates were normal. Serum calcium, phosphorus, and alkaline phosphatase were within normal limits. Urinary excretion of calcium, phosphate, and amino acids were normal. Excess matrix was formed in the zone of cartilage cell proliferation, and the matrix persisted in the growth plate. Normal stresses resulted in microfractures in the metaphyses with subsequent interference of vascular penetration into the zone of degenerated cartilage cells. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:7065114

  7. Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas

    PubMed Central

    Ikegaki, Naohiko; Shimada, Hiroyuki; Fox, Autumn M.; Regan, Paul L.; Jacobs, Joshua R.; Hicks, Sakeenah L.; Rappaport, Eric F.; Tang, Xao X.

    2013-01-01

    Cancer stem cells (CSCs) are plastic in nature, a characteristic that hampers cancer therapeutics. Neuroblastoma (NB) is a pediatric tumor of neural crest origin, and half of the cases are highly aggressive. By treating NB cell lines [SKNAS, SKNBE(2)C, CHP134, and SY5Y] with epigenetic modifiers for a short time, followed by sphere-forming culture conditions, we have established stem cell–like NB cells that are phenotypically stable for more than a year. These cells are characterized by their high expression of stemness factors, stem cell markers, and open chromatin structure. We referred to these cells as induced CSCs (iCSCs). SKNAS iCSC and SKNBE(2)C iCSC clones (as few as 100 cells) injected s.c. into SCID/Beige mice formed tumors, and in one case, SKNBE(2)C iCSCs metastasized to the adrenal gland, suggesting their increased metastatic potential. SKNAS iCSC xenografts showed the histologic appearance of totally undifferentiated large-cell NBs (LCNs), the most aggressive and deadly form of NB in humans. Immunohistochemical analyses showed that SKNAS iCSC xenografts expressed high levels of the stem cell marker CXCR4, whereas the SKNAS monolayer cell xenografts did not. The patterns of CXCR4 and MYC expression in SKNAS iCSC xenografts resembled those in the LCNs. The xenografts established from the NB iCSCs shared two common features: the LCN phenotype and high-level MYC/MYCN expression. These observations suggest both that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell–like tumor cells and that epigenetic changes may have contributed to the development of these most malignant NB cells. PMID:23479628

  8. Proximal Neuropathy and Associated Skeletal Muscle Changes Resembling Denervation Atrophy in Hindlimbs of Chronic Hypoglycaemic Rats.

    PubMed

    Jensen, Vivi F H; Molck, Anne-Marie; Soeborg, Henrik; Nowak, Jette; Chapman, Melissa; Lykkesfeldt, Jens; Bogh, Ingrid B

    2017-08-16

    Peripheral neuropathy is one of the most common complications of diabetic hyperglycaemia. Insulin-induced hypoglycaemia (IIH) might potentially exacerbate or contribute to neuropathy as hypoglycaemia also causes peripheral neuropathy. In rats, IIH induces neuropathy associated with skeletal muscle changes. Aims of this study were to investigate the progression and sequence of histopathologic changes caused by chronic IIH in rat peripheral nerves and skeletal muscle, and whether such changes were reversible. Chronic IIH was induced by infusion of human insulin, followed by an infusion-free recovery period in some of the animals. Sciatic, plantar nerves and thigh muscle were examined histopathologically after four or eight weeks of infusion and after the recovery period. IIH resulted in high incidence of axonal degeneration in sciatic nerves and low incidence in plantar nerves indicating proximo-distal progression of the neuropathy. The neuropathy progressed in severity (sciatic nerve) and incidence (sciatic and plantar nerve) with the duration of IIH. The myopathy consisted of groups of angular atrophic myofibres which resembled histopathologic changes classically seen after denervation of skeletal muscle, and severity of the myofibre atrophy correlated with severity of axonal degeneration in sciatic nerve. Both neuropathy and myopathy were still present after four weeks of recovery, although the neuropathy was less severe. In conclusion, the results suggest that peripheral neuropathy induced by IIH progresses proximo-distally, that severity and incidence increase with duration of the hypoglycaemia and that these changes are partially reversible within four weeks. Furthermore, IIH-induced myopathy is most likely secondary to the neuropathy. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  9. Establishment of an oral infection model resembling the periodontal pocket in a perfusion bioreactor system

    PubMed Central

    Bao, Kai; Papadimitropoulos, Adam; Akgül, Baki; Belibasakis, Georgios N; Bostanci, Nagihan

    2015-01-01

    Periodontal infection involves a complex interplay between oral biofilms, gingival tissues and cells of the immune system in a dynamic microenvironment. A humanized in vitro model that reduces the need for experimental animal models, while recapitulating key biological events in a periodontal pocket, would constitute a technical advancement in the study of periodontal disease. The aim of this study was to use a dynamic perfusion bioreactor in order to develop a gingival epithelial-fibroblast-monocyte organotypic co-culture on collagen sponges. An 11 species subgingival biofilm was used to challenge the generated tissue in the bioreactor for a period of 24 h. The histological and scanning electron microscopy analysis displayed an epithelial-like layer on the surface of the collagen sponge, supported by the underlying ingrowth of gingival fibroblasts, while monocytic cells were also found within the sponge mass. Bacterial quantification of the biofilm showed that in the presence of the organotypic tissue, the growth of selected biofilm species, especially Campylobacter rectus, Actinomyces oris, Streptococcus anginosus, Veillonella dispar, and Porphyromonas gingivalis, was suppressed, indicating a potential antimicrobial effect by the tissue. Multiplex immunoassay analysis of cytokine secretion showed that interleukin (IL)-1 β, IL-2, IL-4, and tumor necrosis factor (TNF)-α levels in cell culture supernatants were significantly up-regulated in presence of the biofilm, indicating a positive inflammatory response of the organotypic tissue to the biofilm challenge. In conclusion, this novel host-biofilm interaction organotypic model might resemble the periodontal pocket and have an important impact on the study of periodontal infections, by minimizing the need for the use of experimental animal models. PMID:25587671

  10. Establishment of an oral infection model resembling the periodontal pocket in a perfusion bioreactor system.

    PubMed

    Bao, Kai; Papadimitropoulos, Adam; Akgül, Baki; Belibasakis, Georgios N; Bostanci, Nagihan

    2015-01-01

    Periodontal infection involves a complex interplay between oral biofilms, gingival tissues and cells of the immune system in a dynamic microenvironment. A humanized in vitro model that reduces the need for experimental animal models, while recapitulating key biological events in a periodontal pocket, would constitute a technical advancement in the study of periodontal disease. The aim of this study was to use a dynamic perfusion bioreactor in order to develop a gingival epithelial-fibroblast-monocyte organotypic co-culture on collagen sponges. An 11 species subgingival biofilm was used to challenge the generated tissue in the bioreactor for a period of 24 h. The histological and scanning electron microscopy analysis displayed an epithelial-like layer on the surface of the collagen sponge, supported by the underlying ingrowth of gingival fibroblasts, while monocytic cells were also found within the sponge mass. Bacterial quantification of the biofilm showed that in the presence of the organotypic tissue, the growth of selected biofilm species, especially Campylobacter rectus, Actinomyces oris, Streptococcus anginosus, Veillonella dispar, and Porphyromonas gingivalis, was suppressed, indicating a potential antimicrobial effect by the tissue. Multiplex immunoassay analysis of cytokine secretion showed that interleukin (IL)-1 β, IL-2, IL-4, and tumor necrosis factor (TNF)-α levels in cell culture supernatants were significantly up-regulated in presence of the biofilm, indicating a positive inflammatory response of the organotypic tissue to the biofilm challenge. In conclusion, this novel host-biofilm interaction organotypic model might resemble the periodontal pocket and have an important impact on the study of periodontal infections, by minimizing the need for the use of experimental animal models.

  11. Sporadic cases of adult measles: a research article.

    PubMed

    Premaratna, Ranjan; Luke, Nathasha; Perera, Harsha; Gunathilake, Mahesh; Amarasena, Pubudu; Chandrasena, T G A Nilmini

    2017-01-10

    Measles caused by a paramyxovirus, characterized by fever, malaise, cough, coryza conjunctivitis, a maculopapular rash is known to result in pneumonia, encephalitis and death. Fatal cases of measles in Sri Lanka are rare after implementation of the National Immunization Programme in 1984. Thereafter 0.1% case fatality rate was observed during October 1999-June 2000 which is a very low figure compared to other regional countries. Immunization guidelines were further revised in 2001, 2011 and in 2012 when additional immunization was recommended to age group 4-21 years; who are likely to have inadequate immunization, in order to achieve elimination of Measles by 2020. However, in 2013-2014, 4690 cases were reported and the majority were children less than 1 year of age. The occurrence in adults is hard to retrieve in published epidemiological reports, however had been 38% (out of 1008 patients) in the 3rd quarter of 2013. During this outbreak 73/101 (72%) reported from the North Central Province of Sri Lanka had been more than 12 years of age with 50% being more than 29 years. 14 Sri lankan adult patients [median age 32 years (range 25-48)] who presented sporadically from June 2014 to March 2016, with confirmed measles infection were enrolled retrospectively after informed consent. Details with regards to their clinical presentation, immunization and other relevant areas were collected using an interviewer administered questionnaire or using patient management records. The patients presented with high fever, headache, severe body aches, sore throat, dry cough, intense tearing, red eyes and posterior cervical lymphadenopathy over 3-5 days duration. Later they developed discrete maculopapular rash helping the diagnosis. They had a variable degree of leucopenia, lymphocytosis, thrombocytopenia and derangements in the liver functions mimicking any other acute febrile illnesses such as dengue, chikungunya, leptospirosis or Zika virus infection. At least a 3-5

  12. Association studies in late onset sporadic Alzheimer`s disease

    SciTech Connect

    Goate, A.M.; Lendon, C.; Talbot, C.

    1994-09-01

    Alzheimer`s disease (AD) is characterized by an adult onset progressive dementia and the presence of numerous plaques and tangles within the brain at autopsy. The senile plaques are composed of a proteinaceous core surrounded by dystrophic neurites. The major protein component of the core is {beta}-amyloid but antibodies to many other proteins bind to senile plaques, e.g., antibodies to apolioprotein E (ApoE) and to {alpha}1-antichymotrypsin (AACT). Genetic studies have implicated mutations within the {beta}-amyloid precursor protein gene as the cause of AD in a small number of early onset AD families. More recently, assocition studies in late onset AD have demonstrated a positive association between ApoE-{epsilon}4 and AD. We report evidence for a negative association between ApoE-{epsilon}2 and AD in a large sample of sporadic late onset AD cases and matched controls supporting the role of ApoE in the etiology of AD. Ninety-three patients with sporadic AD (average age = 75 years, s.d. 8 yrs.) and 67 normal controls from the same ethnic background (age = 77 yrs., s.d. 10 yrs.) were recruited through the patient registry of the Washington University Alzheimer`s Disease Research Center. We found a statistically significant increase in ApoE-{epsilon}4 allele frequency in patients compared with controls ({chi}{sup 2}=7.75, 1 d.f., one tailed p=0.0027) and a significant decrease in {epsilon}2 allele frequency (Fisher`s exact test, one tailed p=0.0048), whereas the decreased frequency of {epsilon}3 in the patient groups was not statistically significant. Allele {epsilon}2 conferred a strong protective effect in our sample, with the odds ratio for AD for subjects possessing this allele being 0.08 (85% confidence interval 0.01-0.69). Similar studies using a polymorphism within the AACT gene showed no association with alleles at this locus in the entire AD sample or in AD cases homozygous for ApoE-{epsilon}3.

  13. Familial resemblance for hostility: the National Heart, Lung, and Blood Institute Family Heart Study.

    PubMed

    Weidner, G; Rice, T; Knox, S S; Ellison, R C; Province, M A; Rao, D C; Higgins, M W

    2000-01-01

    The purpose of this study was to examine whether several aspects of hostility as measured by the Cook-Medley Hostility Scale (ie, aggressive responding, hostile affect, cynicism, and overall hostility score) were determined in part by family factors (ie, genes and/or familial environments). Analyses were based on 680 European-American families (2525 individuals) from the NHLBI Family Heart Study (FHS), a population-based study of genetic and nongenetic determinants of CHD, atherosclerosis, and cardiovascular risk factors. The influence of family relationships, age, and education on the variation in each of the four hostility scores were estimated. Significant familial resemblance in all hostility scores was found, accounting for 42% of the variance in total hostility, 30% in cynicism, 38% in aggressive responding, and 18% in hostile affect. Very little of this resemblance could be explained by similarities in education. Familial resemblance for cynicism was solely due to significant parent-offspring and sibling correlations (ie, no spouse resemblance), suggesting the possibility of genetic influences. Gender and generation differences were also evident in the familial correlations. Hostility aggregates in families. Both family environmental and genetic sources of resemblance are suggested for hostility.

  14. Older Adults' Trait Impressions of Faces Are Sensitive to Subtle Resemblance to Emotions

    PubMed Central

    Zebrowitz, Leslie A.

    2013-01-01

    Younger adults (YA) attribute emotion-related traits to people whose neutral facial structure resembles an emotion (emotion overgeneralization). The fact that older adults (OA) show deficits in accurately labeling basic emotions suggests that they may be relatively insensitive to variations in the emotion resemblance of neutral expression faces that underlie emotion overgeneralization effects. On the other hand, the fact that OA, like YA, show a ‘pop-out’ effect for anger, more quickly locating an angry than a happy face in a neutral array, suggests that both age groups may be equally sensitive to emotion resemblance. We used computer modeling to assess the degree to which neutral faces objectively resembled emotions and assessed whether that resemblance predicted trait impressions. We found that both OA and YA showed anger and surprise overgeneralization in ratings of danger and naiveté, respectively, with no significant differences in the strength of the effects for the two age groups. These findings suggest that well-documented OA deficits on emotion recognition tasks may be more due to processing demands than to an insensitivity to the social affordances of emotion expressions. PMID:24058225

  15. Fathers see stronger family resemblances than non-fathers in unrelated children's faces.

    PubMed

    Bressan, Paola; Dal Pos, Stefania

    2012-12-01

    Even after they have taken all reasonable measures to decrease the probability that their spouses cheat on them, men still face paternal uncertainty. Such uncertainty can lead to paternal disinvestment, which reduces the children's probability to survive and reproduce, and thus the reproductive success of the fathers themselves. A theoretical model shows that, other things being equal, men who feel confident that they have fathered their spouses' offspring tend to enjoy greater fitness (i.e., leave a larger number of surviving progeny) than men who do not. This implies that fathers should benefit from exaggerating paternal resemblance. We argue that the self-deceiving component of this bias could be concealed by generalizing this resemblance estimation boost to (1) family pairs other than father-child and (2) strangers. Here, we tested the prediction that fathers may see, in unrelated children's faces, stronger family resemblances than non-fathers. In Study 1, 70 men and 70 women estimated facial resemblances between children paired, at three different ages (as infants, children, and adolescents), either to themselves or to their parents. In Study 2, 70 men and 70 women guessed the true parents of the same children among a set of adults. Men who were fathers reported stronger similarities between faces than non-fathers, mothers, and non-mothers did, but were no better at identifying childrens' real parents. We suggest that, in fathers, processing of facial resemblances is biased in a manner that reflects their (adaptive) wishful thinking that fathers and children are related.

  16. A gain-of-function mutation in TNFRSF13B is a candidate for predisposition to familial or sporadic immune thrombocytopenia.

    PubMed

    Peng, H-L; Zhang, Y; Sun, N-N; Yin, Y-F; Wang, Y-W; Cheng, Z; Yan, W-Z; Liu, S-F; Xu, Y-X; Xiao, X; Zhang, G-S

    2017-08-20

    Essentials Positive family histories suggest the existence of hereditary immune thrombocytopenia (ITP). The predisposing gene for familial ITP was screened in two familial ITP patients. The G76S mutation on TNFRSF13B led to immune dysfunction and induced megakaryocyte apoptosis. The G76S mutation on TNFRSF13B is a gain-of-function mutation and a predisposing variant for ITP. Background Most immune thrombocytopenia (ITP) is sporadic but a positive family history of ITP in some patients suggests that hereditary forms exist. Because of the rarity of familial ITP families available for study and the heterogeneity of sporadic ITP, family linkage analysis or genome-wide association studies are limited. Objectives Based on one ITP pedigree, we try to identify the predisposing gene in familial or sporadic ITP and reveal the way in which it causes thrombocytopenia. Methods Gene expression profiling analysis and whole-exome sequencing were performed on samples from family members with ITP, sporadic ITP cases and healthy individuals. We also evaluated the influence of potential pathogenic mutation on immune function and megakaryocyte apoptosis. Results Whole-exome sequencing identified a potential pathologic p.G76S heterozygous mutation on the TNFRSF13B gene in familial ITP patients. ITP patients harboring the G76S mutation displayed an upregulated 'cytokine-cytokine receptor interaction' signal, increased serum TNFα, IL-17α, IFNγ and BAFF levels, and enhanced binding capacity of APRIL ligand to B cells. Additionally, Epstein-Barr virus (EBV)-transformed B cells with the G76S mutation could induce human megakaryocyte line (Meg-01) apoptosis significantly. Conclusion p.G76S mutation on the TNFRSF13B gene is responsible for ITP, and is a genetic predisposing factor for familial or sporadic ITP. © 2017 International Society on Thrombosis and Haemostasis.

  17. HER2 Analysis in Sporadic Thyroid Cancer of Follicular Cell Origin

    PubMed Central

    Ruggeri, Rosaria M.; Campennì, Alfredo; Giuffrè, Giuseppe; Giovanella, Luca; Siracusa, Massimiliano; Simone, Angela; Branca, Giovanni; Scarfì, Rosa; Trimarchi, Francesco; Ieni, Antonio; Tuccari, Giovanni

    2016-01-01

    The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The present study was aimed to investigate HER2 status in sporadic cancers of follicular cell origin to better clarify the role of this receptor in the stratification of thyroid cancer. By immunohistochemistry and fluorescence in-situ hybridization, HER2 expression was investigated in formalin-fixed paraffin-embedded surgical specimens from 90 DTC patients, 45 follicular (FTC) and 45 papillary (PTC) histotypes. No HER2 immunostaining was recorded in background thyroid tissue. By contrast, overall HER2 overexpression was found in 20/45 (44%) FTC and 8/45 (18%) PTC, with a significant difference between the two histotypes (p = 0.046). Five of the six patients who developed metastatic disease during a median nine-year follow-up had a HER2-positive tumor. Therefore, we suggest that HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy. PMID:27929428

  18. Impact of sporadic reporting of poultry Salmonella serovars from selected developing countries.

    PubMed

    Barbour, Elie K; Ayyash, Danielle B; Alturkistni, Wafa; Alyahiby, Areej; Yaghmoor, Soonham; Iyer, Archana; Yousef, Jehad; Kumosani, Taha; Harakeh, Steve

    2015-01-15

    This review documents the sporadic reporting of poultry Salmonella serovars in South Africa, Egypt, Indonesia, India, and Romania, five countries selected based on the importance of their distribution in different regions of the world and their cumulative significant population size of 1.6 billion. South Africa reported contamination of its poultry carcasses by S. Hadar, S. Blockley, S. Irumu, and S. Anatum. Results from Egypt showed that S. Enteritidis and S. Typhimurium were predominant in poultry along with other non-typhoid strains, namely S. Infantis, S. Kentucky, S. Tsevie, S. Chiredzi, and S. Heidelberg. In Indonesia, the isolation of Salmonella Typhi was the main focus, while other serovars included S. Kentucky, S. Typhimurium, and S. Paratyhi C. In India, S. Bareilly was predominant compared to S. Enteritidis, S. Typhimurium, S. Paratyphi B, S. Cerro, S. Mbandaka, S. Molade, S. Kottbus, and S. Gallinarum. Romania reported two Salmonella serovars in poultry that affect humans, namely S. Enteritidis and S. Typhimurium, and other non-typhoid strains including S. Infantis, S. Derby, S. Colindale, S. Rissen, S. Ruzizi, S. Virchow, S. Brandenburg, S. Bredeney, S. Muenchen, S. Kortrijk, and S. Calabar. The results showed the spread of different serovars of Salmonella in those five developing countries, which is alarming and emphasizes the urgent need for the World Health Organization Global Foodborne Infections Network (WHO-GFN) to expand its activities to include more strategic participation and partnership with most developing countries in order to protect poultry and humans from the serious health impact of salmonellosis.

  19. Brain sterol dys-regulation in sporadic AD and MCI: Relationship to heme oxygenase-1

    PubMed Central

    Hascalovici, Jacob R.; Vaya, Jacob; Khatib, Soliman; Holcroft, Christina A.; Zukor, Hillel; Song, Wei; Arvanitakis, Zoe; Bennett, David A.; Schipper, Hyman M.

    2009-01-01

    The objective of this study was to ascertain the impact of aging and Alzheimer disease (AD) on brain cholesterol (CH), CH precursors and oxysterol homeostasis. Altered CH metabolism and up-regulation of heme oxygenase-1 (HO-1) are characteristic of AD-affected neural tissues. We recently determined that HO-1 over-expression suppresses total CH levels by augmenting liver X receptor-mediated CH efflux and enhances oxysterol formation in cultured astroglia. Lipids and proteins were extracted from post-mortem human frontal cortex derived from subjects with sporadic AD, mild cognitive impairment (MCI) and no cognitive impairment (NCI; n=17 per group) enrolled in the Religious Orders Study, an ongoing clinical-pathologic study of aging and AD. ELISA was used to quantify human HO-1 protein expression from brain tissue and GC-MS to quantify total CH, CH precursors and relevant oxysterols. The relationships of sterol/oxysterol levels to HO-1 protein expression and clinical/demographic variables were determined by multivariable regression and non-parametric statistical analyses. Decreased CH, increased oxysterol and increased CH precursors concentrations in the cortex correlated significantly with HO-1 levels in MCI and AD, but not NCI. Specific oxysterols correlated with disease state, increasing neuropathological burden, neuropsychological impairment and age. A model featuring compensated and de-compensated states of altered sterol homeostasis in MCI and AD are presented based on the current data set and our earlier in vitro work. PMID:19522732

  20. Sporadic colon cancer murine models demonstrate the value of autoantibody detection for preclinical cancer diagnosis

    PubMed Central

    Barderas, Rodrigo; Villar-Vázquez, Roi; Fernández-Aceñero, María Jesús; Babel, Ingrid; Peláez-García, Alberto; Torres, Sofía; Casal, J. Ignacio

    2013-01-01

    Although autoantibody detection has been proposed for diagnosis of colorectal cancer, little is known about their initial production and development correlation with cancer progression. Azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice developed colon adenocarcinoma in the distal colon similar to human sporadic colon cancer. We assessed this model together with AOM and DSS-only models for their applicability to early detection of cancer. All AOM/DSS-treated mice produced autoantibodies to tumor-associated antigens analogous to those observed in human colon cancer patients. Autoantibody response was related to tumor antigen overexpression. Cancer autoantibodies were detected 21 days after starting treatment, when no malignant histopathological features were detectable, and they increased according to tumor progression. When carcinogenesis was induced separately by AOM or DSS, only those mice that developed malignant lesions produced significant levels of autoantibodies. These findings demonstrate that autoantibody development is an early event in tumorigenesis and validates its use for preclinical colon cancer diagnosis. PMID:24126910

  1. From similitude to success: The effects of facial resemblance on perceptions of team effectiveness.

    PubMed

    Wang, Ze; He, Xin; Liu, Fan

    2016-03-01

    Scant empirical research has focused on how impressions of teams are formed based on members' collective appearance, even though team photos are omnipresent in visual communications and teamwork is a common theme to elicit positive responses. Across 4 studies, we show that a subtle increase in the facial resemblance among team members enhances observers' evaluations of team effectiveness. This resemblance effect is mediated by perceived cooperative intent among team players. Furthermore, we demonstrate a reversal of the resemblance effect through the moderating role of information valence and extend the finding from team perception to behavioral intention. These results hold across different manipulations, contexts, stimuli, and sample characteristics. Collectively, this research presents the first empirical evidence that inferences based on facial morphology persist well beyond evaluations of individuals to influence the way a team, as a whole, is perceived.

  2. Sporadic pediatric meningiomas: a neuroradiological and neuropathological study of 15 cases.

    PubMed

    Huntoon, Kristin; Pluto, Charles P; Ruess, Lynne; Boué, Daniel R; Pierson, Christopher R; Rusin, Jerome A; Leonard, Jeffrey

    2017-08-01

    OBJECTIVE Sporadic meningiomas have been classified in many different ways. Radiographically, these lesions can be described as occurring in either typical or atypical locations. The purpose of this study was to determine if there are any histopathological differences between sporadic meningiomas that arise in these varying locations in children. METHODS The neuroimaging, histopathological findings, and clinical records in patients with sporadic pediatric meningiomas not associated with neurofibromatosis Type 2 or prior radiation therapy were retrospectively reviewed. Tumors were classified by radiological findings as either typical or atypical, and they were categorized histopathologically by using the latest WHO nomenclature and grading criteria. RESULTS Fifteen sporadic meningiomas in pediatric patients were biopsied or resected at the authors' institution between 1989 and 2013. Five (33%) were typical in radiographic appearance and/or location and 10 (67%) were atypical. Four (80%) typical meningiomas were WHO Grade I tumors. Most (60%) of the atypical meningiomas were WHO Grade II or III. CONCLUSIONS This study is the largest series of sporadic pediatric meningiomas in atypical locations to date. Although sporadic meningiomas are relatively infrequent in children, those with atypical imaging, specifically those with apparently intraparenchymal and intraosseous locations, may be more common than previously recognized. In this study, pediatric sporadic meningiomas arising in atypical locations, in particular intraparenchymal meningiomas, may be of higher histopathological grade. The authors' findings should alert clinicians to the potential for more aggressive clinical behavior in these tumors.

  3. Minor physical anomalies in familial and sporadic schizophrenia: the Maudsley family study

    PubMed Central

    Griffiths, T; Sigmundsson, T; Takei, N; Frangou, S; Birkett, P; Sharma, T; Reveley, A; Murray, R

    1998-01-01

    OBJECTIVES—(1) To test the hypothesis that minor physical anomalies are increased in patients with schizophrenia and (2) to investigate differences in the prevalence of minor physical anomalies in patients with familial and sporadic schizophrenia and their first degree relatives.
METHODS—A weighted Waldrop assessment was carried out on 214 subjects in five groups: schizophrenic patients from multiply affected families; first degree relatives of these familial schizophrenic patients; sporadic schizophrenic patients; first degree relatives of these sporadic schizophrenic patients, and normal controls. Broad and narrow criteria for abnormality were defined based on the distribution of minor physical anomalies in the control group.
RESULTS—(1) The total schizophrenic group did not have a significant increase in minor physical anomalies using a narrow criterion of abnormality, but did when a broader criterion was used. (2) A significant increase in the proportion of subjects with an abnormally high number of minor physical abnormalities was shown in the group of sporadic schizophrenic patients (uncorrected p<0.01). Separate analyses for males and females showed a significant increase in the male sporadic group (uncorrected p<0.05), and a smaller non-significant increase in the female sporadic group. Neither the familial schizophrenic group nor either group of first degree relatives showed any significant increases in the proportion of patients with high abnormality scores.
CONCLUSION—This work supports prenatal developmental abnormality as a mechanism for sporadic, but not familial, schizophrenia.

 PMID:9436728

  4. Vitamin D receptor gene polymorphisms, smoking, and risk of sporadic Parkinson's disease in Japan.

    PubMed

    Tanaka, Keiko; Miyake, Yoshihiro; Fukushima, Wakaba; Kiyohara, Chikako; Sasaki, Satoshi; Tsuboi, Yoshio; Oeda, Tomoko; Shimada, Hiroyuki; Kawamura, Nobutoshi; Sakae, Nobutaka; Fukuyama, Hidenao; Hirota, Yoshio; Nagai, Masaki; Nakamura, Yoshikazu

    2017-03-16

    Epidemiological evidence on the relationships between the vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI), and rs2228570 (FokI) and Parkinson's disease (PD) is inconsistent. We investigated these relationships in 229 sporadic PD patients within six years of onset in Japan. Controls were 357 patients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. A significant inverse association was found between SNP rs2228570 and the risk of sporadic PD under the additive but not the co-dominant or dominant model (P=0.048); however, this fell below significance after adjustment for multiple comparisons (adjusted P=0.46). No significant relationships were found between SNPs rs731236, rs7975232, or rs1544410 and the risk of sporadic PD in any genetic model. VDR haplotypes inferred in the current study were not associated with sporadic PD. Compared with subjects with the GA or AA genotype of SNP rs2228570 who had ever smoked, those with the GG genotype who had never smoked had a 3.78-fold increased risk of sporadic PD; however, no significant interaction was observed. VDR SNP rs2228570 may be associated with sporadic PD in Japan. Smoking did not significantly modify the relationship between SNP rs2228570 and sporadic PD.

  5. Keratocystic odontogenic tumor associated with nevoid basal cell carcinoma syndrome: similar behavior to sporadic type?

    PubMed

    Figueroa, Adriana; Correnti, Maria; Avila, Maira; Andea, Aleodor; DeVilliers, Patricia; Rivera, Helen

    2010-02-01

    The objective of this study was to analyze the expression of proliferative markers and p53 in keratocystic odontogenic tumor (KCOT) sporadic type and KCOT associated with nevoid basal cell carcinoma syndrome (NBCCS). We performed a cross-sectional study. A total of 19 patients with KCOT were selected from the Oral Pathology Laboratory archives, Central University of Venezuela, from 1995 to 2005. Twelve cases corresponded to sporadic KCOT, and seven cases were associated with NBCCS. Immunohistochemical analysis for p53, proliferating cell nuclear antigen (PCNA), and Ki-67 was performed in all 19 cases. Of the seven cases associated with NBCCS, six (86%) were positive for PCNA. From the 12 sporadic cases, nine (75%) were positive for PCNA. Only one case of sporadic KCOT showed Ki-67 positivity. Five of 12 (42%) cases of sporadic KCOT were positive for p53, and only one (14%) case associated with NBCCS was positive for p53. On the basis of the analysis of the expression of PCNA, Ki-67, and p53, there appears to be no evidence to indicate higher aggressiveness in growth and infiltrative behavior in syndromic KCOT compared with the sporadic type. Therefore, surgical treatment may be approached in the same manner in KCOT sporadic and syndromic with the goal of minimizing recurrence. Copyright 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.

  6. Mid-latitude lidar observations of large sporadic sodium layers

    SciTech Connect

    Senft, D.C.; Collins, R.L.; Gardner, C.S. )

    1989-07-01

    During the early morning of October 31, 1988 two large sporadic Na (Na{sub s}) layers were observed near the mesopause above Urbana, IL (40{degree}N, 88{degree}W) with a Na lidar system. The layers began forming near 102 km at 0026 LST and 0110 LST and moved downward with vertical velocities as high as 4 ms{sup {minus}1} before dissipating between 94 and 96 km. The duration of each layer was approximately 80 min. The layers were narrow ({approximately} 1 km FWHM) and dense with maximum densities approaching 7,800 cm{sup {minus}3}. The characteristics of these two Na{sub s} layers are very similar to those of similar phenomena observed recently at Andoya, Norway and Mauna Kea, Hawaii. Lidar observations of the mesospheric Na layer have been conducted routinely by several groups at mid-latitudes for almost 20 years. Although large Na{sub s} layers now appear to be relatively common at low- and high-latitudes, to our knowledge the two layers described in this letter are only the second observation of this puzzling phenomenon at mid-latitudes.

  7. Sporadic Inclusion Body Myositis: new insights and potential therapy

    PubMed Central

    Machado, Pedro; Dimachkie, Mazen M.; Barohn, Richard J.

    2014-01-01

    Purpose of the review To describe new insights and developments in the pathogenesis, diagnosis and treatment of sporadic inclusion body myositis (IBM). Recent findings Various hypothesis about the pathogenesis of IBM continue to be investigated, including autoimmune factors, mitochondrial dysfunction, protein dyshomeostasis, altered nucleic acid metabolism, myonuclear degeneration and the role of the myostatin pathway. Serum autoantibodies against cytosolic 5′ nucleotidase 1A have been identified in IBM showing moderate diagnostic performance. The differential diagnostic value of histopathological features, including different protein aggregates, continues to be evaluated. MRI may also be of monitoring value in IBM. New therapeutic strategies are being tested in IBM patients, namely the up-regulation of the heat shock response and the antagonism of myostatin. Summary Recent important advances have occurred in IBM. These advances, including recent and ongoing clinical trials, may lead to earlier diagnosis and improved understanding and treatment of the disease. Despite improved knowledge, IBM continues to be a puzzling disease and the pathogenesis remains to be clarified. An interdisciplinary, bench to bedside translational research approach is crucial for the successful identification of novel treatments for this debilitating, currently untreatable disorder. PMID:25159931

  8. Targeting Protein Homeostasis in Sporadic Inclusion Body Myositis

    PubMed Central

    Ahmed, Mhoriam; Machado, Pedro M.; Miller, Adrian; Spicer, Charlotte; Herbelin, Laura; He, Jianghua; Noel, Janelle; Wang, Yunxia; McVey, April L.; Pasnoor, Mamatha; Gallagher, Philip; Statland, Jeffrey; Lu, Ching-Hua; Kalmar, Bernadett; Brady, Stefen; Sethi, Huma; Samandouras, George; Parton, Matt; Holton, Janice L.; Weston, Anne; Collinson, Lucy; Taylor, J. Paul; Schiavo, Giampietro; Hanna, Michael G.; Barohn, Richard J.; Dimachkie, Mazen M.; Greensmith, Linda

    2016-01-01

    Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with Arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein VCP mice, which develop an inclusion body myopathy (IBM), treatment with Arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated the safety and tolerability of Arimoclomol in an investigator-lead, randomised, double-blind, placebo-controlled, proof-of-concept patient trial and gathered exploratory efficacy data which showed that Arimoclomol was safe and well tolerated. Although Arimoclomol improved some IBM-like pathology in vitro and in vivo in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in this proof of concept patient trial. PMID:27009270

  9. EFEMP1 is not associated with sporadic early onset drusen.

    PubMed

    Sauer, C G; White, K; Kellner, U; Rudolph, G; Jurklies, B; Pauleikhoff, D; Weber, B H

    2001-03-01

    The early onset of multiple drusen in the posterior pole of the retina is characteristic of a group of macular dystrophies often referred to as dominant or radial drusen. At least two forms, Doyne honeycomb retinal dystrophy (DHRD) and Malattia Leventinese (MLVT), are associated with a single missense mutation (R345W) in the gene encoding the EGF-containing fibulin-like extracellular matrix protein-1 (EFEMP1) and are now thought to represent a single entity. Here, we present a further evaluation of the role of EFEMP1 in the pathogenesis of sporadic forms of early onset drusen. We analyzed all coding exons of the EFEMP1 gene by SSCP analysis in 14 unrelated individuals with early onset of multiple drusen and no apparent family history of the disease. In this patient group, we did not detect the R345W mutation or any other disease-associated mutation. Three different polymorphisms and two intragenic polymorphic repeats were present in similar frequencies in the patients and control individuals. We conclude that EFEMP1 is unlikely to be involved in the disease in this patient group. This suggests that mutations in a different as yet unknown gene or genes may lead to the early onset drusen phenotype.

  10. CAMS newly detected meteor showers and the sporadic background

    NASA Astrophysics Data System (ADS)

    Jenniskens, P.; Nénon, Q.; Gural, P. S.; Albers, J.; Haberman, B.; Johnson, B.; Morales, R.; Grigsby, B. J.; Samuels, D.; Johannink, C.

    2016-03-01

    The Cameras for Allsky Meteor Surveillance (CAMS) video-based meteoroid orbit survey adds 60 newly identified showers to the IAU Working List of Meteor Showers (numbers 427, 445-446, 506-507, and part of 643-750). 28 of these are also detected in the independent SonotaCo survey. In total, 230 meteor showers and shower components are identified in CAMS data, 177 of which are detected in at least two independent surveys. From the power-law size frequency distribution of detected showers, we extrapolate that 36% of all CAMS-observed meteors originated from ∼700 showers above the N = 1 per 110,000 shower limit. 71% of mass falling to Earth from streams arrives on Jupiter-family type orbits. The transient Geminids account for another 15%. All meteoroids not assigned to streams form a sporadic background with highest detected numbers from the apex source, but with 98% of mass falling in from the antihelion source. Even at large ∼7-mm sizes, a Poynting-Robertson drag evolved population is detected, which implies that the Grün et al. collisional lifetimes at these sizes are underestimated by about a factor of 10. While these large grains survive collisions, many fade on a 104-y timescale, possibly because they disintegrate into smaller particles by processes other than collisions, leaving a more resilient population to evolve.

  11. FUS GENE MUTATIONS IN FAMILIAL AND SPORADIC AMYOTROPHIC LATERAL SCLEROSIS

    PubMed Central

    Rademakers, Rosa; Stewart, Heather; DeJesus-Hernandez, Mariely; Krieger, Charles; Graff-Radford, Neill; Fabros, Marife; Briemberg, Hannah; Cashman, Neil; Eisen, Andrew; Mackenzie, Ian R. A.

    2010-01-01

    Introduction Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). Methods We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. Results In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. Discussion This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS. It suggests there are specific clinicogenetic correlations and provides the first detailed neuropathological description. PMID:20544928

  12. 20 March 2015 solar eclipse influence on sporadic E layer

    NASA Astrophysics Data System (ADS)

    Pezzopane, M.; Pietrella, M.; Pignalberi, A.; Tozzi, R.

    2015-11-01

    This paper shows how the solar eclipse occurred on 20 March 2015 influenced the sporadic E (Es) layer as recorded by the Advanced Ionospheric Sounder by Istituto Nazionale di Geofisica e Vulcanologia (AIS-INGV) ionosondes installed at Rome (41.8°N, 12.5°E) and Gibilmanna (37.9°N, 14.0°E), Italy. In these locations, the solar eclipse was only partial, with the maximum area of the solar disk obscured by the Moon equal to ∼54% at Rome and ∼45% at Gibilmanna. Nevertheless, it is shown that the strong thermal gradients that usually accompany a solar eclipse, have significantly influenced the Es phenomenology. Specifically, the solar eclipse did not affect the Es layer in terms of its maximum intensity, which is comparable with that of the previous and next day, but rather in terms of its persistence. In fact, both at Rome and Gibilmanna, contrary to what typically happens in March, the Es layer around the solar eclipse time is always present. On the other hand, this persistence is also confirmed by the application of the height-time-intensity (HTI) technique. A detailed analysis of isoheight ionogram plots suggests that traveling ionospheric disturbances (TIDs) likely caused by gravity wave (GW) propagation have played a significant role in causing the persistence of the Es layer.

  13. Analysis of GLRA 1 in familial and sporadic hyperekplexia

    SciTech Connect

    Elmslie, F.V.; Rees, M.; Covanis, A.

    1994-09-01

    Hyperekplexia or familial startle syndrome is an autosomal dominant condition, causing an exaggerated startle response to unexpected stimuli. Infants have variable hypertonia in the neonatal period, with a startle response causing sustained muscular contraction. The gene was localized to chromosome 5q in 1992 and subsequently mutations were detected in the alpha{sub 1} subunit of the glycine receptor in four large pedigrees with hyperekplexia. Eight probands with hyperekplexia have been ascertained, including three sporadic and four familial cases. In one pedigree, hyperekplexia appears to be associated with spastic paraparesis, and the hyperekplexia/spastic paraparesis is linked to marker loci on chromosome 5q. Genomic DNA was extracted from white cells. GLRA1 exons were amplified from genomic DNA by PCR using specific oligonucleotide primers. Amplified exon 6 fragments are being screened for the previously described mutations by restriction enzyme analysis using Bfa1 and Xho1. In addition, all exons have been screened by single-stranded conformational polymorphism (SSCP) and are currently being screened by heteroduplex analysis. No sequence changes have been detected to date. Products displaying aberrant bands on screening will be analyzed further by di-deoxy sequencing.

  14. A unified genetic theory for sporadic and inherited autism

    PubMed Central

    Zhao, Xiaoyue; Leotta, Anthony; Kustanovich, Vlad; Lajonchere, Clara; Geschwind, Daniel H.; Law, Kiely; Law, Paul; Qiu, Shanping; Lord, Catherine; Sebat, Jonathan; Ye, Kenny; Wigler, Michael

    2007-01-01

    Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring. PMID:17652511

  15. Is sporadic Alzheimer's disease associated with diphtheria toxin?

    PubMed

    Merril, Carl R

    2013-01-01

    The two major aspects of Alzheimer's disease (AD) that must be considered in a search for causative agents are its association with aging and its widespread epidemiology. While a number of agents have been identified, additional factors may play a role. An association with diphtheria toxin was suggested by observations that vaccinations may provide protective effects, and the observation that decreased proteins synthesis in cortical regions from AD patients is associated with modification of elongation factor 2, the target of diphtheria toxin. While protection against diphtheria toxin is provided by vaccination, the known decline in the immune system associated with aging would result in a renewed sensitivity to the toxin. An association with diphtheria toxin would be consistent with the observations that the bacteria associated with the toxin, Corynebacterium diphtheria, is often found in the nasopharynx and an early symptom of AD is the loss of smell with a disease progression from the entorhinal cortex to the hippocampus and the neocortical areas. If diphtheria toxin is involved in sporadic AD, booster vaccinations given to elderly individuals might result in a decreased incidence of this disease. As booster DPT vaccinations are already recommended for individuals over 65, cognitive testing at the time of the booster and 5 years later, along with similar cognitive testing in age-matched individuals who decline vaccination, might provide an inexpensive method to investigate whether diphtheria toxin plays a role in AD and the efficacy of DPT booster vaccines for AD.

  16. Facing and managing natural disasters in the Sporades Islands, Greece

    NASA Astrophysics Data System (ADS)

    Karanikola, P.; Panagopoulos, T.; Tampakis, S.; Karantoni, M. I.; Tsantopoulos, G.

    2013-11-01

    The region of the Sporades Islands located in central Greece is at the mercy of many natural phenomena, such as earthquakes, due to the marine volcano "Psathoura", and the rift of Anatolia, forest fires, floods, landslides, storms, hail, snowfall and frost. The present work aims at studying the perceptions and attitudes of the residents regarding how they face and manage natural disasters. A positive public response during a hazard crisis depends not only upon the availability and good management of a civil defence plan but also on the knowledge and perception of the possible hazards by the local population. It is important for the stakeholders to know what the citizens expect from each of the separate stakeholders so that the necessary structures can be developed in the phase of preparation and organization. The residents were asked about their opinion about what they think should be done by the stakeholders after a catastrophic natural disaster, particularly the immediate response of stakeholders and their involvement and responsibilities at different, subsequent intervals of time following the disaster. The residents were also asked about the most common disasters that happen in their region and about the preparation activities of the stakeholders.

  17. Facing and managing natural disasters in the Sporades islands, Greece

    NASA Astrophysics Data System (ADS)

    Karanikola, P.; Panagopoulos, T.; Tampakis, S.; Karantoni, M. I.; Tsantopoulos, G.

    2014-04-01

    The region of the Sporades islands located in central Greece is at the mercy of many natural phenomena, such as earthquakes due to the marine volcano Psathoura and the rift of Anatolia, forest fires, floods, landslides, storms, hail, snowfall and frost. The present work aims at studying the perceptions and attitudes of the residents regarding how they face and manage natural disasters. A positive public response during a hazard crisis depends not only upon the availability and good management of a civil defense plan but also on the knowledge and perception of the possible hazards by the local population. It is important for the stakeholders to know what the citizens expect so that the necessary structures can be developed in the phase of preparation and organization. The residents were asked their opinion about what they think should be done by the stakeholders after a catastrophic natural disaster, particularly about the immediate response of stakeholders and their involvement and responsibilities at different, subsequent intervals of time following the disaster. The residents were also asked about the most common disasters that happen in their region and about the preparation activities of the stakeholders.

  18. Mutations modifying sporadic Alzheimer's disease age of onset.

    PubMed

    Vélez, Jorge I; Lopera, Francisco; Patel, Hardip R; Johar, Angad S; Cai, Yeping; Rivera, Dora; Tobón, Carlos; Villegas, Andrés; Sepulveda-Falla, Diego; Lehmann, Shaun G; Easteal, Simon; Mastronardi, Claudio A; Arcos-Burgos, Mauricio

    2016-12-01

    The identification of mutations modifying the age of onset (AOO) in Alzheimer's disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole-exome genotyped. Single- and multi-locus linear mixed-effects models were used to identify functional variants modifying AOO. A posteriori enrichment and bioinformatic analyses were applied to evaluate the non-random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome-wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. This set of new genes harboring these mutations could be of importance for prediction, follow-up and eventually as therapeutical targets of AD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis

    PubMed Central

    2013-01-01

    Background Potential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophic Lateral Sclerosis, a progressive motor neuronal degenerative disorder. The present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (SALS; ALS-CSF), and could be associated with the pathogenesis of this disease. Results Quantitative mass spectrometry of ALS-CSF and control-CSF (from orthopaedic surgical patients undergoing spinal anaesthesia) samples showed upregulation of 31 proteins in the ALS-CSF, amongst which a ten-fold increase in the levels of chitotriosidase-1 (CHIT-1) was seen compared to the controls. A seventeen-fold increase in the CHIT-1 levels was detected by ELISA, while a ten-fold elevated enzyme activity was also observed. Both these results confirmed the finding of LC-MS/MS. CHIT-1 was found to be expressed by the Iba-1 immunopositive microglia. Conclusion Elevated CHIT-1 levels in the ALS-CSF suggest a definitive role for the enzyme in the disease pathogenesis. Its synthesis and release from microglia into the CSF may be an aligned event of neurodegeneration. Thus, high levels of CHIT-1 signify enhanced microglial activity which may exacerbate the process of neurodegeneration. In view of the multifold increase observed in ALS-CSF, it can serve as a potential CSF biomarker for the diagnosis of SALS. PMID:24295388

  20. Spousal resemblance in psychopathology: A comparison of parents of children with and without psychopathology.

    PubMed

    Wesseldijk, L W; Dieleman, G C; Lindauer, R J L; Bartels, M; Willemsen, G; Hudziak, J J; Boomsma, D I; Middeldorp, C M

    2016-04-01

    Spouses resemble each other for psychopathology, but data regarding spousal resemblance in externalizing psychopathology, and data regarding spousal resemblance across different syndromes (e.g. anxiety in wives and attention deficit/hyperactivity disorder [ADHD] in husbands) are limited. Moreover, knowledge is lacking regarding spousal resemblance in parents of children with psychiatric disorders. We investigated and compared spousal resemblance within and across internalizing and externalizing symptom domains in parents of children with and without psychopathology. Symptoms of depression, anxiety, avoidant personality, ADHD, and antisocial personality were assessed with the Adult Self Report in 728 mothers and 544 fathers of 778 children seen in child and adolescent psychiatric outpatient clinics and in 2075 mothers and 1623 fathers of 2784 children from a population-based sample. Differences in symptom scores and spousal correlations between the samples were tested. Parents in the clinical sample had higher symptom scores than in the population-based sample. In both samples, correlations within and across internalizing and externalizing domains of psychopathology were significant. Importantly, correlations were significantly higher in the clinical sample (P=0.03). Correlations, within and across symptoms, ranged from 0.14 to 0.30 in the clinical sample and from 0.05 to 0.23 in the population-based sample. This large study shows that spousal resemblance is not only present within but also across symptom domains. Especially in the clinical sample, ADHD symptoms in fathers and antisocial personality symptoms in mothers were correlated with a range of psychiatric symptoms in their spouses. Clinicians need to be alert of these multiple affected families. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Inferior Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation in Purebred Eurasier Dogs with Familial Non-Progressive Ataxia: A Retrospective and Prospective Clinical Cohort Study

    PubMed Central

    Bernardino, Filipa; Rentmeister, Kai; Schmidt, Martin J.; Bruehschwein, Andreas; Matiasek, Kaspar; Matiasek, Lara A.; Lauda, Alexander; Schoon, Heinz A.; Fischer, Andrea

    2015-01-01

    Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5 – 6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance. PMID:25668516

  2. Daytime Observations of Mid-latitude Sporadic-E and QP Radar Echoes

    NASA Astrophysics Data System (ADS)

    Pfaff, R. F.; Liebrecht, C.; Urbina, J.; Kudeki, E.

    2007-12-01

    Although sporadic-E layers and quasi-periodic (QP) radars are typically detected during nighttime conditions at mid-latitudes, they also may exist in the daytime lower ionosphere as well. We present observations of ionosonde observations of daytime sporadic-E layers gathered at the Wallops Flight Facility, Virginia, in the late morning to noon local times. The data reveal sporadic-E characteristics similar to nighttime observations including considerable variations in frequency and altitude. For one event, observed on 23 July 1999 near 14 U.T. (10 L.T.), we present coincident strong Wallops ionosonde sporadic-E observations and 50MHz backscatter radar observations of quasi-periodic echoes gathered with the University of Illinois radar situated at Ft. Macon, N.C., whose beam was perpendicular to the magnetic field in the lower E-region over Wallops. The radar data show daytime QP structuring that is very similar to the nighttime observations, suggesting a similar driving mechanism. A statistical survey of the daytime ionogram data at Wallops shows a preponderance of daytime sporadic-E events occurring during the local summer months, a seasonal dependence that is well-established for nighttime sporadic-E conditions in the northern hemisphere. No clear correlation is observed between the daytime sporadic-E events and magnetic storms, suggesting that the daytime sporadic-E events are not necessarily driven by the disturbance dynamo. Rather, we speculate that the same large wind shears that are believed to be the main engine for the nighttime sporadic-E and QP echoes, may also be at work during the daytime. The existence of enhanced plasma density layers during the daytime and their role in generating QP- echoes during the day remain open questions.

  3. Coincident extremely large sporadic sodium and sporadic E layers observed in the lower thermosphere over Colorado and Utah

    NASA Astrophysics Data System (ADS)

    Williams, B. P.; Berkey, F. T.; Sherman, J.; She, C. Y.

    2007-02-01

    On the night of 2 June 2002, the sodium lidar in Fort Collins, CO (40.6 N, 105 W) measured an extremely strong sporadic sodium layer lasting from 03:30 to 05:00 UT with several weaker layers later in the night at 06:00 and 09:00 UT. There is a double layer structure with peaks at 101 and 104 km. The peak sodium density was 21 000 atoms/cm3 with a column abundance of up to twice that of the normal sodium layer. The peak density was 500 times greater than the typical density at that altitude. The sporadic layer abundance and strength factor were higher than any reported in the literature. The two lidar beams, separated by 70 km at this altitude, both measured 0.6 h periodicities in the abundance, but out of phase with each other by 0.3 h. There is also evidence for strong wave activity in the lidar temperatures and winds. The NOAA ionosonde in Boulder, CO (40.0 N, 105 W) measured a critical frequency (foEs) of 14.3 MHz at 03:00 UT on this night, the highest value anytime during 2002. The high values of total ion density inferred means that Na+ fraction must have been only a few percent to explain the neutral Na layer abundances. The Bear Lake, Utah (41.9 N, 111.4 W) dynasonde also measured intense Es between 02:00 and 05:00 UT and again from 06:00 to 08:00 UT about 700 km west of the lidar, with most of the ionograms during these intervals measuring Es up to 12 MHz, the limit of the ionosonde sweep. Other ionosondes around North America on the NGDC database measured normal foEs values that night, so it was a localized event within North America. The peak of Es activity observed in Europe during the summer of 2002 occurred on 4 June. The observations are consistent with the current theories where a combination of wind shears and long period waves form and push downward a concentrated layer of ions, which then chemically react and form a narrow layer of sodium atoms.

  4. No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia.

    PubMed

    Schumacher, Axel; Friedrich, Patricia; Diehl-Schmid, Janine; Ibach, Bernd; Eisele, Tamara; Laws, Simon M; Förstl, Hans; Kurz, Alexander; Riemenschneider, Matthias

    2007-11-01

    Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.

  5. Tetraparesis resembling acute transverse myelitis in a captive chimpanzee (Pan troglodytes): long-term care and recovery.

    PubMed

    Miyabe-Nishiwaki, T; Kaneko, A; Nishiwaki, K; Watanabe, A; Watanabe, S; Maeda, N; Kumazaki, K; Morimoto, M; Hirokawa, R; Suzuki, J; Ito, Y; Hayashi, M; Tanaka, M; Tomonaga, M; Matsuzawa, T

    2010-10-01

    A 24-year-old, male chimpanzee (Pan troglodytes) developed acute tetraparesis. Magnetic resonance imaging showed a diffuse T2-weighted hyperintensive lesion, indicating inflammation at the C1-2 level. All infective, autoimmune, and vascular investigations were unremarkable. The chimpanzee's condition most resembled acute transverse myelitis (ATM) in humans. The chimpanzee was in severe incapacitated neurological condition with bedridden status and required 24-hour attention for 2 months followed by special care for over a year. Initially, corticosteroid therapy was performed, and his neurological symptoms improved to some extent; however, the general condition of the chimpanzee deteriorated in the first 6 months after onset. Pressure ulcers had developed at various areas on the animal's body, as the bedridden status was protracted. Supportive therapy was continued, and the general condition, appetite, mobility, and pressure ulcers have slowly but synergistically recovered over the course of 2 years. © 2010 John Wiley & Sons A/S.

  6. Classification of sporadic Creutzfeldt-Jakob disease revisited.

    PubMed

    Cali, Ignazio; Castellani, Rudolph; Yuan, Jue; Al-Shekhlee, Amer; Cohen, Mark L; Xiao, Xiangzhu; Moleres, Francisco J; Parchi, Piero; Zou, Wen-Quan; Gambetti, Pierluigi

    2006-09-01

    The sporadic form of Creutzfeldt-Jakob disease (sCJD) has been classified on the basis of the molecular mass of the protease-resistant scrapie prion protein (PrP(Sc)), which can be type 1 or type 2, and the genotype at the methionine (M)/valine (V) polymorphic codon 129, which can be MM, MV or VV. In one classification proposed by Parchi et al., [Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I , Budka H , Kopp N , Piccardo P , Poser S , Rojiani A , Streichemberger N , Julien J , Vital C , Ghetti B , Gambetti P , Kretzschmar H . Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-33.] the most common subtype of sCJD, designated sCJDMM1, is viewed as a single entity. Two other classifications proposed by Collinge et al. [Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 1996; 383: 685-90.] and Zanusso et al., [Zanusso G, Farinazzo A, Fiorini M, Gelati M, Castagna A, Righetti PG, Rizzuto N, Monaco S . pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 2001; 276: 40377-80.] respectively, subdivide sCJDMM1 into two subtypes on the basis of the different molecular mass and phenotypic characteristics, primarily disease duration. To resolve this discrepancy, we divided a group of 22 subjects with confirmed sCJDMM1 according to Parchi et al. into two sub-populations according to whether the disease duration was <5 months (short-duration subjects) or >7 months (long-duration subjects). We then examined the PrP(Sc) molecular mass under the conditions that allowed wide variability of the pH of the PrP(Sc) preparations as well as under stringent pH conditions, using high-resolution gel electrophoresis. We also compared the characteristics of the PrP(Sc) associated with the short- and long-duration subjects using two

  7. Familial or Sporadic Idiopathic Scoliosis - classification based on artificial neural network and GAPDH and ACTB transcription profile.

    PubMed

    Waller, Tomasz; Nowak, Roman; Tkacz, Magdalena; Zapart, Damian; Mazurek, Urszula

    2013-01-04

    Importance of hereditary factors in the etiology of Idiopathic Scoliosis is widely accepted. In clinical practice some of the IS patients present with positive familial history of the deformity and some do not. Traditionally about 90% of patients have been considered as sporadic cases without familial recurrence. However the exact proportion of Familial and Sporadic Idiopathic Scoliosis is still unknown. Housekeeping genes encode proteins that are usually essential for the maintenance of basic cellular functions. ACTB and GAPDH are two housekeeping genes encoding respectively a cytoskeletal protein β-actin, and glyceraldehyde-3-phosphate dehydrogenase, an enzyme of glycolysis. Although their expression levels can fluctuate between different tissues and persons, human housekeeping genes seem to exhibit a preserved tissue-wide expression ranking order. It was hypothesized that expression ranking order of two representative housekeeping genes ACTB and GAPDH might be disturbed in the tissues of patients with Familial Idiopathic Scoliosis (with positive family history of idiopathic scoliosis) opposed to the patients with no family members affected (Sporadic Idiopathic Scoliosis). An artificial neural network (ANN) was developed that could serve to differentiate between familial and sporadic cases of idiopathic scoliosis based on the expression levels of ACTB and GAPDH in different tissues of scoliotic patients. The aim of the study was to investigate whether the expression levels of ACTB and GAPDH in different tissues of idiopathic scoliosis patients could be used as a source of data for specially developed artificial neural network in order to predict the positive family history of index patient. The comparison of developed models showed, that the most satisfactory classification accuracy was achieved for ANN model with 18 nodes in the first hidden layer and 16 nodes in the second hidden layer. The classification accuracy for positive Idiopathic Scoliosis anamnesis

  8. Children and Adolescents' Understandings of Family Resemblance: A Study of Naive Inheritance Concepts

    ERIC Educational Resources Information Center

    Williams, Joanne M.

    2012-01-01

    This paper aims to provide developmental data on two connected naive inheritance concepts and to explore the coherence of children's naive biology knowledge. Two tasks examined children and adolescents' (4, 7, 10, and 14 years) conceptions of phenotypic resemblance across kin (in physical characteristics, disabilities, and personality traits). The…

  9. LINGAM AS A SACRED OBJECT AND THE HEAD-DRESS OF SUFI RESEMBLING IT

    PubMed Central

    Mahdihassan, S.

    1990-01-01

    This study scans into past of ancient man and discusses meticulously how the reproductive organ Lingam became sacred object to Hindus and why a sufi wore a phallus shaped head-dress resembling to it. In this manner the author demystifies here the procreation, the law of nature. PMID:22557692

  10. Schwannoma of the biliary tract resembling cholangiocarcinoma: A case report and review

    PubMed Central

    Garcia Sanz, I; Muñoz de Nova, JL; Valdés de Anca, A; Martín Pérez, ME

    2016-01-01

    Schwannomas are benign tumours derived from Schwann cells and are extremely rare in the biliary tract. We present the case of a 62-year-old patient with a common bile duct schwannoma that resembled a cholangiocarcinoma. We also review all 17 previously published cases of schwannoma of the biliary tract and discuss the challenges of preoperative diagnosis. PMID:27269434

  11. Effects of parenting quality on adolescents' personality resemblance to their parents. The TRAILS study.

    PubMed

    Langenhof, M Rohaa; Komdeur, Jan; Oldehinkel, Albertine J

    2016-08-01

    This study considers the development of resemblance between 741 adolescents and their biological parents, across six NEO-PI-R personality traits known to be important in psychological problems: anger-hostility, impulsiveness, vulnerability, assertiveness, excitement-seeking, and self-discipline. We modelled the association between perceived parental warmth and rejection at age eleven and personality resemblance to parents at about age sixteen. Parenting experienced during early adolescence was related to the degree and direction in which adolescents resembled their parents five years later in life. Rejection, especially from fathers, significantly predicted a smaller resemblance to both the parents. Girls were more strongly affected by parental quality than boys, and there was some indication that adolescents responded in opposite ways to parenting from mothers and fathers. This study is a first step in uncovering the complex interplay between parenting, gender, and the current generation's ability to develop personality traits independent from the previous generation. Copyright © 2016 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

  12. Children and Adolescents' Understandings of Family Resemblance: A Study of Naive Inheritance Concepts

    ERIC Educational Resources Information Center

    Williams, Joanne M.

    2012-01-01

    This paper aims to provide developmental data on two connected naive inheritance concepts and to explore the coherence of children's naive biology knowledge. Two tasks examined children and adolescents' (4, 7, 10, and 14 years) conceptions of phenotypic resemblance across kin (in physical characteristics, disabilities, and personality traits). The…

  13. Molecular interactions between prions as seeds and recombinant prion proteins as substrates resemble the biological interspecies barrier in vitro.

    PubMed

    Panza, Giannantonio; Luers, Lars; Stöhr, Jan; Nagel-Steger, Luitgard; Weiss, Jürgen; Riesner, Detlev; Willbold, Dieter; Birkmann, Eva

    2010-12-09

    Prion diseases like Creutzfeldt-Jakob disease in humans, Scrapie in sheep or bovine spongiform encephalopathy are fatal neurodegenerative diseases, which can be of sporadic, genetic, or infectious origin. Prion diseases are transmissible between different species, however, with a variable species barrier. The key event of prion amplification is the conversion of the cellular isoform of the prion protein (PrP(C)) into the pathogenic isoform (PrP(Sc)). We developed a sodiumdodecylsulfate-based PrP conversion system that induces amyloid fibril formation from soluble α-helical structured recombinant PrP (recPrP). This approach was extended applying pre-purified PrP(Sc) as seeds which accelerate fibrillization of recPrP. In the present study we investigated the interspecies coherence of prion disease. Therefore we used PrP(Sc) from different species like Syrian hamster, cattle, mouse and sheep and seeded fibrillization of recPrP from the same or other species to mimic in vitro the natural species barrier. We could show that the in vitro system of seeded fibrillization is in accordance with what is known from the naturally occurring species barriers.

  14. Axonal TDP-43 aggregates in sporadic amyotrophic lateral sclerosis.

    PubMed

    Onozato, T; Nakahara, A; Suzuki-Kouyama, E; Hineno, A; Yasude, T; Nakamura, T; Yahikozawa, H; Watanabe, M; Kayanuma, K; Makishita, H; Ohara, S; Hashimoto, T; Higuchi, K; Sakai, T; Asano, K; Hashimoto, T; Kanno, H; Nakayama, J; Oyanagi, K

    2016-10-01

    Axonal aggregates of phosphorylated (p-) transactive response DNA-binding protein 43 kDa (TDP-43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system. Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin-fixed paraffin-embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course. (i) Aggregates of p-TDP-43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p-TDP-43 in the axons showed two characteristic microscopic features - dash-like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p-neurofilaments, but p-neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p- and p-independent (i)-TDP-43, and almost all neurones had lost their nuclear TDP-43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP-43-immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p-TDP-43 deposition was evident. There are two types of axonal p-TDP-43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p-i-TDP-43 in the nuclei of postsynaptic neurones. © 2016 British Neuropathological Society.

  15. Multiple sporadic colorectal cancers display a unique methylation phenotype.

    PubMed

    Gonzalo, Victoria; Lozano, Juan Jose; Alonso-Espinaco, Virginia; Moreira, Leticia; Muñoz, Jenifer; Pellisé, Maria; Castellví-Bel, Sergi; Bessa, Xavier; Andreu, Montserrat; Xicola, Rosa M; Llor, Xavier; Ruiz-Ponte, Clara; Carracedo, Angel; Jover, Rodrigo; Castells, Antoni; Balaguer, Francesc

    2014-01-01

    Epigenetics are thought to play a major role in the carcinogenesis of multiple sporadic colorectal cancers (CRC). Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the epigenetic signature of multiple CRC using a genome-scale DNA methylation profiling. We analyzed 12 patients with synchronous CRC and 29 age-, sex-, and tumor location-paired patients with solitary tumors from the EPICOLON II cohort. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significant results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP); KRAS and BRAF mutations and mismatch repair deficiency status. Functional annotation clustering was performed. We identified 102 CpG sites that showed significant DNA hypermethylation in multiple tumors with respect to the solitary counterparts (difference in β value ≥0.1). Methylight assays validated the results for 4 selected genes (p = 0.0002). Eight out of 12(66.6%) multiple tumors were classified as CIMP-high, as compared to 5 out of 29(17.2%) solitary tumors (p = 0.004). Interestingly, 76 out of the 102 (74.5%) hypermethylated CpG sites found in multiple tumors were also seen in CIMP-high tumors. Functional analysis of hypermethylated genes found in multiple tumors showed enrichment of genes involved in different tumorigenic functions. In conclusion, multiple CRC are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity.

  16. Functional relevance of mitochondrial abnormalities in sporadic inclusion body myositis.

    PubMed

    Joshi, Pushpa Raj; Vetterke, Mirjam; Hauburger, Anja; Tacik, Pawel; Stoltenburg, Gisela; Hanisch, Frank

    2014-11-01

    Cytochrome c oxidase (COX)-deficient fibers and multiple mitochondrial DNA (mtDNA) deletions are frequent findings in sporadic inclusion body myositis (s-IBM). However, the functional impact of these defects is not known. We investigated oxygen desaturation during exercise using the forearm exercise test, accumulation of lactate during exercise using a cycle ergometry test and mitochondrial changes (COX-deficient fibers, biochemical activities of respiratory chain complexes, multiple mtDNA deletions by long-range polymerase chain reaction) in 10 patients with s-IBM and compared the findings with age and sex-matched normal and diseased controls (without mitochondrial disorders) as well as patients with mitochondrial disorder due to nuclear gene defects resulting in multiple mtDNA deletions (MITO group). The mean age of the s-IBM patients was 68.2 ± 5.7 years (range: 56-75). Patients with s-IBM had statistically significantly reduced oxygen desaturation (ΔsO2) during the handgrip exercise (p<0.05) and elevated peak serum lactate levels during cycle ergometry compared to normal controls (p<0.05). The percentage of COX-deficient fibers in s-IBM and MITO patients was significantly increased compared to normal controls (p<0.01). Five out of nine s-IBM patients had multiple mtDNA deletions. Thirty-three percent of s-IBM patients showed an increased citrate synthase content and decreased activities of complex IV (COX). The biochemical pattern of respiratory chain complexes in patients with s-IBM and MITO was similar. Histopathological analysis showed similar changes in s-IBM and MITO due to nuclear gene defects. Functional tests reflecting mitochondrial impairment suggest a contribution of mitochondrial defects to disease-related symptoms such as fatigue and exertion-induced symptoms. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Genotype and phenotype analysis of patients with sporadic periodic paralysis.

    PubMed

    Sung, Chih-Chien; Cheng, Chih-Jen; Lo, Yi-Fen; Lin, Mei-Shan; Yang, Sung-Sen; Hsu, Yu-Chuan; Lin, Shih-Hua

    2012-04-01

    Sporadic periodic paralysis (SPP), the second leading cause of hypokalemic periodic paralysis (HPP) in Asia, has a presentation similar to that of familial periodic paralysis (FPP) and is caused by gene mutations in the calcium (Ca(2+)) (CACNA1S) and sodium (Na(+)) (SCN4A) channels of skeletal muscle. The authors determined whether SPP shares similar genotype and phenotype with FPP. Sixty SPP patients who did not have a family history of paralysis, abnormal thyroid function tests and other identifiable causes of HPP, and 8 FPP patients were enrolled. Genomic DNA was isolated from blood leukocytes of all SPP and FPP patients. Genetic analysis of whole S4 segment in CACNA1S and SCN4A was performed. Phenotypic analysis included clinical presentations, laboratory data and precipitating events. All FPP patients had mutations in either CACNA1S or SCN4A, but only 4 SPP patients had de novo mutations in CACNA1S (R1239H) and SCN4A (R669×2, R1135H). SPP patients with de novo mutations manifested a phenotype indistinguishable from that of FPP patients except a later age of onset. SPP patients without mutations also had a later age of onset, significantly fewer attacks of paralysis than FPP patients, and unidentifiable precipitating factors. A minority of SPP patients had de novo CACNA1S or SCN4A mutations and may have a variant of FPP. The majority of SPP patients, those without mutations in CACNA1S and SCN4A, represent a unique subgroup of HPP patients, and this form of SPP usually manifests at a later age, is associated with fewer attacks and lacks apparent triggering factors.

  18. Treatment of sporadic inclusion body myositis with bimagrumab.

    PubMed

    Amato, Anthony A; Sivakumar, Kumaraswamy; Goyal, Namita; David, William S; Salajegheh, Mohammad; Praestgaard, Jens; Lach-Trifilieff, Estelle; Trendelenburg, Anne-Ulrike; Laurent, Didier; Glass, David J; Roubenoff, Ronenn; Tseng, Brian S; Greenberg, Steven A

    2014-12-09

    To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. Transforming growth factor β superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks. © 2014 American Academy of Neurology.

  19. Chlamydia pecorum: fetal and placental lesions in sporadic caprine abortion.

    PubMed

    Giannitti, Federico; Anderson, Mark; Miller, Myrna; Rowe, Joan; Sverlow, Karen; Vasquez, Marce; Cantón, Germán

    2016-03-01

    Chlamydial abortion in small ruminants is usually associated with Chlamydia abortus infection. Although Chlamydia pecorum has been detected in aborted ruminants and epidemiological data suggests that C. pecorum is abortigenic in these species, published descriptions of lesions in fetuses are lacking. This work describes fetoplacental lesions in a caprine abortion with C. pecorum infection, and further supports the abortigenic role of C. pecorum in ruminants. A 16-month-old Boer goat aborted twin fetuses at ~130 days of gestation. Both fetuses (A and B) and the placenta of fetus A were submitted for postmortem examination and diagnostic workup. At autopsy, the fetuses had moderate anasarca, intermuscular edema in the hindquarters (A), and brachygnathia and palatoschisis (B). In the placenta, the cotyledons were covered by yellow fibrinosuppurative exudate that extended into the adjacent intercotyledonary areas. Histologically, there was severe suppurative and necrotizing placentitis with vasculitis (arteriolitis) and thrombosis, multifocal lymphohistiocytic and neutrophilic hepatitis (A), and fibrinosuppurative enteritis in both fetuses. Chlamydia antigen was detected in the placenta by the direct fluorescent antibody test and in fetal intestines by immunohistochemistry. Nested polymerase chain reaction of DNA extracted from formalin-fixed, paraffin-embedded sections of placenta and intestine amplified 400 bp of the Chlamydia 16S rRNA gene that was sequenced and found to be 99% identical to C. pecorum by BLAST analysis. Other known abortigenic infectious agents were ruled out by specific testing. It is concluded that C. pecorum infection is associated with fetoplacental lesions and sporadic abortion in goats. © 2015 The Author(s).

  20. Dietary factors and truncating APC mutations in sporadic colorectal adenomas.

    PubMed

    Diergaarde, Brenda; Tiemersma, Edine W; Braam, Hanneke; van Muijen, Goos N P; Nagengast, Fokko M; Kok, Frans J; Kampman, Ellen

    2005-01-01

    Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control study of sporadic colorectal adenomas (278 cases; 414 polyp-free controls). Direct-sequencing was used to screen adenomas for mutations in the mutation cluster region of APC; truncating mutations were detected in 161 (58%) of the adenomas. Red meat consumption was significantly differently related to polyps with truncating APC mutation (APC(+) polyps) compared to polyps without truncating APC mutation (APC(-) polyps) (highest vs. lowest tertile, odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.3-1.0). High intake of red meat and fat seemed to increase the risk of APC(-) polyps only (APC(+) vs. controls: red meat, OR = 1.0, 95% CI = 0.6-1.6; fat, OR = 1.1, 95% CI = 0.6-1.9; APC(-) vs. controls: red meat, OR = 1.8, 95% CI = 1.0-3.1; fat, OR = 1.9, 95% CI = 1.0-3.7). Intake of carbohydrates was inversely associated with both polyp groups, most noticeably with APC(-) polyps. Most other evaluated dietary factors were not distinctively associated with a specific APC status. None of the dietary factors was specifically associated with a particular type of truncating APC mutation. Our data suggest that red meat and fat may increase the risk of APC(-) polyps in particular, whereas carbohydrates may especially decrease the risk of APC(-) polyps. However, most examined dietary factors do not appear to be specifically associated with the occurrence of truncating APC mutations in colorectal adenomas but seem to affect both pathways equally.

  1. Identification of Epigenetically Altered Genes in Sporadic Amyotrophic Lateral Sclerosis

    PubMed Central

    Bender, Diane E.; Delaney, Colin E.; Cataldo, Michael D.; Smith, Andrea L.; Yung, Raymond; Ruden, Douglas M.; Callaghan, Brian C.; Feldman, Eva L.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS) with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC) and hydroxymethylation (5 HmC) in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression), was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets. PMID:23300739

  2. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kuo, Amy L.; Wong, Katherine S.; Haman, Aissa; Devereux, Gillian; Raudabaugh, Benjamin J.; Johnson, David Y.; Torres-Chae, Charles C.; Finley, Ron; Garcia, Paul; Thai, Julie N.; Cheng, Hugo Q.; Neuhaus, John M.; Forner, Sven A.; Duncan, Jacque L.; Possin, Katherine L.; DeArmond, Stephen J.; Prusiner, Stanley B.; Miller, Bruce L.

    2013-01-01

    Objective: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD). Methods: This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2. Results: Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months. Conclusion: This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials. Classification of evidence: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months. PMID:24122181

  3. Clinical Perspective of Oxidative Stress in Sporadic ALS

    PubMed Central

    D’Amico, Emanuele; Factor-Litvak, Pam; Santella, Regina M.; Mitsumoto, Hiroshi

    2013-01-01

    Sporadic amyotrophic lateral sclerosis (sALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/anti-oxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine, are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly support the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis. PMID:23797033

  4. Multiple Sporadic Colorectal Cancers Display a Unique Methylation Phenotype

    PubMed Central

    Gonzalo, Victoria; Lozano, Juan Jose; Alonso-Espinaco, Virginia; Moreira, Leticia; Muñoz, Jenifer; Pellisé, Maria; Castellví-Bel, Sergi; Bessa, Xavier; Andreu, Montserrat; Xicola, Rosa M.; Llor, Xavier; Ruiz-Ponte, Clara; Carracedo, Angel; Jover, Rodrigo; Castells, Antoni; Balaguer, Francesc

    2014-01-01

    Epigenetics are thought to play a major role in the carcinogenesis of multiple sporadic colorectal cancers (CRC). Previous studies have suggested concordant DNA hypermethylation between tumor pairs. However, only a few methylation markers have been analyzed. This study was aimed at describing the epigenetic signature of multiple CRC using a genome-scale DNA methylation profiling. We analyzed 12 patients with synchronous CRC and 29 age-, sex-, and tumor location-paired patients with solitary tumors from the EPICOLON II cohort. DNA methylation profiling was performed using the Illumina Infinium HM27 DNA methylation assay. The most significant results were validated by Methylight. Tumors samples were also analyzed for the CpG Island Methylator Phenotype (CIMP); KRAS and BRAF mutations and mismatch repair deficiency status. Functional annotation clustering was performed. We identified 102 CpG sites that showed significant DNA hypermethylation in multiple tumors with respect to the solitary counterparts (difference in β value ≥0.1). Methylight assays validated the results for 4 selected genes (p = 0.0002). Eight out of 12(66.6%) multiple tumors were classified as CIMP-high, as compared to 5 out of 29(17.2%) solitary tumors (p = 0.004). Interestingly, 76 out of the 102 (74.5%) hypermethylated CpG sites found in multiple tumors were also seen in CIMP-high tumors. Functional analysis of hypermethylated genes found in multiple tumors showed enrichment of genes involved in different tumorigenic functions. In conclusion, multiple CRC are associated with a distinct methylation phenotype, with a close association between tumor multiplicity and CIMP-high. Our results may be important to unravel the underlying mechanism of tumor multiplicity. PMID:24643221

  5. Visual art therapy in sporadic Creutzfeldt-Jakob disease: a case study.

    PubMed

    Shrestha, Rajeet; Trauger-Querry, Barbara; Loughrin, Athena; Appleby, Brian S

    2016-01-01

    This paper describes the diagnostic and treatment utility of visual art therapy in a case of sporadic Creutzfeldt-Jakob disease. Visual art therapy was compared longitudinally with clinical and neuroimaging data over five-month period in an autopsy-confirmed case of sporadic Creutzfeldt-Jakob disease of MM2-cortical subtype. Art therapy sessions and content were useful in ascertaining neuropsychiatric symptoms during the course of her illness. Art therapy offered a unique emotional and cognitive outlet as illness progressed. Patients and families affected by sporadic Creutzfeldt-Jakob disease may benefit from art therapy despite the rapidly progressive nature of the illness. Art therapy can also be useful for assessment of patients with sporadic Creutzfeldt-Jakob disease by healthcare professionals.

  6. Re-Assessment of PrPSc Distribution in Sporadic and Variant CJD

    PubMed Central

    Rubenstein, Richard; Chang, Binggong

    2013-01-01

    Human prion diseases are fatal neurodegenerative disorders associated with an accumulation of PrPSc in the central nervous system (CNS). Of the human prion diseases, sporadic Creutzfeldt-Jakob disease (sCJD), which has no known origin, is the most common form while variant CJD (vCJD) is an acquired human prion disease reported to differ from other human prion diseases in its neurological, neuropathological, and biochemical phenotype. Peripheral tissue involvement in prion disease, as judged by PrPSc accumulation in the tonsil, spleen, and lymph node has been reported in vCJD as well as several animal models of prion diseases. However, this distribution of PrPSc has not been consistently reported for sCJD. We reexamined CNS and non-CNS tissue distribution and levels of PrPSc in both sCJD and vCJD. Using a sensitive immunoassay, termed SOFIA, we also assessed PrPSc levels in human body fluids from sCJD as well as in vCJD-infected humanized transgenic mice (Tg666). Unexpectedly, the levels of PrPSc in non-CNS human tissues (spleens, lymph nodes, tonsils) from both sCJD and vCJD did not differ significantly and, as expected, were several logs lower than in the brain. Using protein misfolding cyclic amplification (PMCA) followed by SOFIA, PrPSc was detected in cerebrospinal fluid (CSF), but not in urine or blood, in sCJD patients. In addition, using PMCA and SOFIA, we demonstrated that blood from vCJD-infected Tg666 mice showing clinical disease contained prion disease-associated seeding activity although the data was not statistically significant likely due to the limited number of samples examined. These studies provide a comparison of PrPSc in sCJD vs. vCJD as well as analysis of body fluids. Further, these studies also provide circumstantial evidence that in human prion diseases, as in the animal prion diseases, a direct comparison and intraspecies correlation cannot be made between the levels of PrPSc and infectivity. PMID:23843953

  7. Comparison of nonampullary duodenal adenomas in patients with familial adenomatous polyposis versus patients with sporadic adenomas.

    PubMed

    Cassani, Lisa S; Lanke, Gandhi; Chen, Hsiang-Chun; Wang, Xuemei; Lynch, Patrick; Lee, Jeffrey H

    2017-04-01

    Nonampullary duodenal adenomas are either sporadic or associated with a hereditary syndrome such as familial adenomatous polyposis (FAP). The aim of this study is to compare characteristics and outcomes of sporadic and FAP-associated duodenal adenomas. We retrospectively collected clinical, endoscopic, and pathologic data in patients diagnosed with duodenal adenomas at our institution and included all available follow-up. Two hundred thirteen subjects were identified; 118 had FAP and 95 had sporadic adenomas. FAP subjects were more likely to have multifocal disease. Initial size was not significantly associated with dysplasia. Fourteen (12%) with FAP and 33 (35%) with sporadic adenomas underwent EMR. Among those subjects who did not undergo EMR or surgery, there was no difference between the FAP and sporadic groups with progression to new dysplasia or cancer. However, the FAP group was significantly more likely to have dysplasia at follow-up (P = .05). There was a significant difference in overall survival between the FAP and sporadic groups (log-rank test, P < .001). In the subgroup of patients aged 40 years old and older who did not undergo intervention, the FAP group had a shorter time to pathology progression compared with the similar sporadic subgroup. Range of time to progression to cancer was 3 to 161 months. FAP subjects were more likely to be younger and have multifocal disease. Progression of pathology was more likely in the older FAP group compared with the sporadic group. Time to progression to cancer was widely variable and, therefore, unpredictable. Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

  8. Familial Adenomatous Polyposis-Associated Desmoids Display Significantly More Genetic Changes than Sporadic Desmoids

    PubMed Central

    Robanus-Maandag, Els; Bosch, Cathy; Amini-Nik, Saeid; Knijnenburg, Jeroen; Szuhai, Karoly; Cervera, Pascale; Poon, Raymond; Eccles, Diana; Radice, Paolo; Giovannini, Marco; Alman, Benjamin A.; Tejpar, Sabine; Devilee, Peter; Fodde, Riccardo

    2011-01-01

    Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression. PMID:21931686

  9. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

    PubMed Central

    Beilina, Alexandria; Rudenko, Iakov N.; Kaganovich, Alice; Civiero, Laura; Chau, Hien; Kalia, Suneil K.; Kalia, Lorraine V.; Lobbestael, Evy; Chia, Ruth; Ndukwe, Kelechi; Ding, Jinhui; Nalls, Mike A.; Olszewski, Maciej; Hauser, David N.; Kumaran, Ravindran; Lozano, Andres M.; Baekelandt, Veerle; Greene, Lois E.; Taymans, Jean-Marc; Greggio, Elisa; Cookson, Mark R.; Nalls, Mike A.; Plagnol, Vincent; Martinez, Maria; Hernandez, Dena G; Sharma, Manu; Sheerin, Una-Marie; Saad, Mohamad; Simón-Sánchez, Javier; Schulte, Claudia; Lesage, Suzanne; Sveinbjörnsdóttir, Sigurlaug; Arepalli, Sampath; Barker, Roger; Ben-Shlomo, Yoav; Berendse, Henk W; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M A; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Bras, Jose M; Brockmann, Kathrin; Brooks, Janet; Burn, David J; Charlesworth, Gavin; Chen, Honglei; Chong, Sean; Clarke, Carl E; Cookson, Mark R; Cooper, J Mark; Corvol, Jean Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean-François; Deloukas, Panos; Deuschl, Günther; Dexter, David T; van Dijk, Karin D; Dillman, Allissa; Durif, Frank; Dürr, Alexandra; Edkins, Sarah; Evans, Jonathan R; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Gibbs, J Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Gústafsson, Ómar; Harris, Clare; van Hilten, Jacobus J; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E; Huttenlocher, Johanna; Illig, Thomas; München, Helmholtz Zentrum; Jónsson, Pálmi V; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; München, Helmholtz Zentrum; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw R; Morrison, Karen E; Mudanohwo, Ese; O’Sullivan, Sean S; Pearson, Justin; Perlmutter, Joel S; Pétursson, Hjörvar; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Shoulson, Ira; Sidransky, Ellen; Smith, Colin; Spencer, Chris C A; Stefánsson, Hreinn; Steinberg, Stacy; Stockton, Joanna D; Strange, Amy; Talbot, Kevin; Tanner, Carlie M; Tashakkori-Ghanbaria, Avazeh; Tison, François; Trabzuni, Daniah; Traynor, Bryan J; Uitterlinden, André G; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H; Winder-Rhodes, Sophie; Stefánsson, Kári; Hardy, John; Heutink, Peter; Brice, Alexis; Gasser, Thomas; Singleton, Andrew B; Wood, Nicholas W; Chinnery, Patrick F; Arepalli, Sampath; Cookson, Mark R; Dillman, Allissa; Ferrucci, Luigi; Gibbs, J Raphael; Hernandez, Dena G; Johnson, Robert; Longo, Dan L; Majounie, Elisa; Nalls, Michael A; O’Brien, Richard; Singleton, Andrew B; Traynor, Bryan J; Troncoso, Juan; van der Brug, Marcel; Zielke, H Ronald; Zonderman, Alan B

    2014-01-01

    Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein–protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G–associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy–lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanisms. PMID:24510904

  10. Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers

    PubMed Central

    Detours, V; Delys, L; Libert, F; Weiss Solís, D; Bogdanova, T; Dumont, J E; Franc, B; Thomas, G; Maenhaut, C

    2007-01-01

    Papillary thyroid cancers (PTCs) incidence dramatically increased in the vicinity of Chernobyl. The cancer-initiating role of radiation elsewhere is debated. Therefore, we searched for a signature distinguishing radio-induced from sporadic cancers. Using microarrays, we compared the expression profiles of PTCs from the Chernobyl Tissue Bank (CTB, n=12) and from French patients with no history of exposure to ionising radiations (n=14). We also compared the transcriptional responses of human lymphocytes to the presumed aetiological agents initiating these tumours, γ-radiation and H2O2. On a global scale, the transcriptomes of CTB and French tumours are indistinguishable, and the transcriptional responses to γ-radiation and H2O2 are similar. On a finer scale, a 118 genes signature discriminated the γ-radiation and H2O2 responses. This signature could be used to classify the tumours as CTB or French with an error of 15–27%. Similar results were obtained with an independent signature of 13 genes involved in homologous recombination. Although sporadic and radio-induced PTCs represent the same disease, they are distinguishable with molecular signatures reflecting specific responses to γ-radiation and H2O2. These signatures in PTCs could reflect the susceptibility profiles of the patients, suggesting the feasibility of a radiation susceptibility test. PMID:17712314

  11. HEREDITARY, SPORADIC AND METASTATIC COLORECTAL CANCER ARE COMMONLY DRIVEN BY SPECIFIC SPECTRUMS OF DEFECTIVE DNA MISMATCH REPAIR COMPONENTS

    PubMed Central

    CARETHERS, JOHN M.

    2016-01-01

    DNA mismatch repair (MMR) is one of several human cell mechanisms utilized to repair mutable mistakes within DNA, particularly after DNA is replicated. MMR function is dependent upon heterodimerization of specific MMR proteins that can recognize base-base mispairs as well as frameshifts at microsatellite sequences, followed by the triggering of other complementary proteins that execute excision and repair or initiate cell demise if repair is futile. MMR function is compromised in specific disease states, all of which can be biochemically recognized by faulty repair of microsatellite sequences, causing microsatellite instability. Germline mutation of an MMR gene causes Lynch syndrome, the most common inherited form of colorectal cancer (CRC), and biallelic germline mutations cause the rare constitutional mismatch repair deficiency syndrome. Somatic inactivation of MMR through epigenetic mechanisms is observed in 15% of sporadic CRC, and a smaller portion of CRCs possess biallelic somatic mutations. A novel inflammation-driven nuclear-to-cytoplasmic shift of the specific MMR protein hMSH3 is seen in up to 60% of sporadic CRCs that associates with metastasis and poor patient prognosis, unlike improved outcome when MMR is genetically inactivated. The mechanism for MMR inactication as well as the component affected dictates the clinical spectrum and clinical response for patients. PMID:28066040

  12. [Clinical significance and distribution of BRCA genes mutation in sporadic high grade serous ovarian cancer].

    PubMed

    Liu, W L; Wang, Z Z; Zhao, J Z; Hou, Y Y; Wu, X X; Li, W; Dong, B; Tong, T T; Guo, Y J

    2017-01-25

    Objective: To investigate the mutations of BRCA genes in sporadic high grade serous ovarian cancer (HGSOC) and study its clinical significance. Methods: Sixty-eight patients between January 2015 and January 2016 from the Affiliated Cancer Hospital of Zhengzhou University were collected who were based on pathological diagnosis of ovarian cancer and had no reported family history, and all patients firstly hospitalized were untreated in other hospitals before. (1) The BRCA genes were detected by next-generation sequencing (NGS) method. (2) The serum tumor markers included carcinoembryonic antigen (CEA), CA(125), CA(199), and human epididymis protein 4 (HE4) were detected by the chemiluminescence methods, and their correlation was analyzed by Pearson linear correlation. Descriptive statistics and comparisons were performed using two-tailed t-tests, Pearson's chi square test, Fisher's exact tests or logistic regression analysis as appropriate to research the clinicopathologic features associated with BRCA mutations, including age, International Federation of Gynecology and Obstetrics (FIGO) stage, platinum-based chemotherapy sensitivity, distant metastases, serum tumor markers (STM) . Results: (1) Fifteen cases (22%, 15/68) BRCA mutations were identified (BRCA1: 11 cases; BRCA2: 4 cases), and four novel mutations were observed. (2) The levels of CEA, CA(199), and HE4 were lower in BRCA mutations compared to that in control group, while no significant differences were found (P>0.05), but the level of CA(125) was much higher in BRCA mutation group than that in controls (t=-3.536, P=0.003). Further linear regression analysis found that there was a significant linear correlation between CA(125) and HE4 group (r=0.494, P<0.01), and the same correlation as CEA and CA(199) group (r=0.897, P<0.01). (3) Single factor analysis showed that no significant differences were observed in onset age, FIGO stage, distant metastasis, and STM between BRCA(+) and BRCA(-) group (P>0

  13. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells.

    PubMed

    Israel, Mason A; Yuan, Shauna H; Bardy, Cedric; Reyna, Sol M; Mu, Yangling; Herrera, Cheryl; Hefferan, Michael P; Van Gorp, Sebastiaan; Nazor, Kristopher L; Boscolo, Francesca S; Carson, Christian T; Laurent, Louise C; Marsala, Martin; Gage, Fred H; Remes, Anne M; Koo, Edward H; Goldstein, Lawrence S B

    2012-01-25

    Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt

  14. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells

    PubMed Central

    Israel, Mason A.; Yuan, Shauna H.; Bardy, Cedric; Reyna, Sol M.; Mu, Yangling; Herrera, Cheryl; Hefferan, Michael P.; Van Gorp, Sebastiaan; Nazor, Kristopher L.; Boscolo, Francesca S.; Carson, Christian T.; Laurent, Louise C.; Marsala, Martin; Gage, Fred H.; Remes, Anne M.; Koo, Edward H.; Goldstein, Lawrence S. B.

    2012-01-01

    Our understanding of Alzheimer’s disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer’s disease, both caused by a duplication of the amyloid-β precursor protein gene1 (APP; termed APPDp), two with sporadic Alzheimer’s disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1–40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APPDp and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer’s disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer’s disease, even though it can take decades for overt

  15. Seasonal correlation of sporadic schizophrenia to Ixodes ticks and Lyme borreliosis

    PubMed Central

    Fritzsche, Markus

    2002-01-01

    Background Being born in winter and spring is considered one of the most robust epidemiological risk factors for schizophrenia. The aetiology and exact timing of this birth excess, however, has remained elusive so far. Since during phylogeny, Borrelia DNA has led to multiple germ-line mutations within the CB1 candidate gene for schizophrenia, a meta analysis has been performed of all papers on schizophrenic birth excesses with no less than 3000 cases each. All published numerical data were then plotted against the seasonal distributions of Ixodes ticks worldwide. Results In the United States, Europe and Japan the birth excesses of those individuals who later in life develop schizophrenia mirror the seasonal distribution of Ixodes ticks nine months earlier at the time of conception. South of the Wallace Line, which limits the spread of Ixodes ticks and Borrelia burgdorferi into Australia, seasonal trends are less significant, and in Singapore, being non-endemic for Ixodes ticks and Lyme disease, schizophrenic birth excesses are absent. Conclusion At present, it cannot be excluded that prenatal infection by B. burgdorferi is harmful to the implanting human blastocyst. The epidemiological clustering of sporadic schizophrenia by season and locality rather emphasises the risk to the unborn of developing a congenital, yet preventable brain disorder later in life. PMID:12453316

  16. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia

    PubMed Central

    Vinh, Donald C.; Patel, Smita Y.; Uzel, Gulbu; Anderson, Victoria L.; Freeman, Alexandra F.; Olivier, Kenneth N.; Spalding, Christine; Hughes, Stephen; Pittaluga, Stefania; Raffeld, Mark; Sorbara, Lynn R.; Elloumi, Houda Z.; Kuhns, Douglas B.; Turner, Maria L.; Cowen, Edward W.; Fink, Danielle; Long-Priel, Debra; Hsu, Amy P.; Ding, Li; Paulson, Michelle L.; Whitney, Adeline R.; Sampaio, Elizabeth P.; Frucht, David M.; DeLeo, Frank R.

    2010-01-01

    We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/μL; median, 14.5 cells/μL), B lymphocytopenia (mean, 9.4 cells/μL; median, 4 cells/μL), and NK lymphocytopenia (mean, 16 cells/μL; median, 5.5 cells/μL). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus+ leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti–granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern. PMID:20040766

  17. Sporadic Hirschsprung`s disease due to a novel nonsense mutation in the RET protooncogene

    SciTech Connect

    Carlson, K.M.; Donis-Keller, H.; Langer, J.C.

    1994-09-01

    Hirschsprung`s disease (HSCR, aganglionic megacolon) is characterized by a lack of ganglion cells along variable lengths of the hindgut. This is most likely due to a failure of the progenitor cells (that are destined to become the ganglion cells of the submucosal and myenteric plexuses) to complete their distal migration in the colon. Recently, mutations in the RET protoocogene have been reported in association with HSCR. We report a novel nonsense mutation resulting in a severely truncated protein. Germline DNA from a panel of 6 HSCR patients was analyzed by SSCP for 20 exons of RET. Eight exons were also directly sequenced. We identified a novel mutation within RET exon 2. The mutation (TAC{sub 36}{yields}TAG{sub 36}), which occurs at nucleotide position 108, involves the replacement of tyrosine with a stop codon and results in a truncated 35 amino acid protein. This mutation is the most 5{prime} nonsense mutation reported thus far. Interestingly, the patient has no prior family history of HSCR and was also diagnosed with multiple developmental anomalies including dysplastic kidney. Recent gene targeting studies with mouse models have shown that RET is essential for normal renal development. However, a parallel phenotype has not been seen in other reported HSCR patients with RET mutations. The observations reported here provide evidence that RET plays a role in human renal development. Ongoing studies will determine the extent of RET involvement in sporadic cases of HSCR.

  18. Subtype and Regional-Specific Neuroinflammation in Sporadic Creutzfeldt–Jakob Disease

    PubMed Central

    Llorens, Franc; López-González, Irene; Thüne, Katrin; Carmona, Margarita; Zafar, Saima; Andréoletti, Olivier; Zerr, Inga; Ferrer, Isidre

    2014-01-01

    The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sporadic Creutzfeldt–Jakob disease (sCJD) MM1 and VV2 subtypes compared to age-matched controls. Deregulated genes include pro- and anti-inflammatory cytokines, toll-like receptors, colony stimulating factors, cathepsins, members of the complement system, and members of the integrin and CTL/CTLD family with particular regional and sCJD subtype patterns. Analysis of cytokines and mediators at protein level shows expression of selected molecules and receptors in neurons, in astrocytes, and/or in microglia, thus suggesting interactions between neurons and glial cells, mainly microglia, in the neuroinflammatory response in sCJD. Similar inflammatory responses have been shown in the tg340 sCJD MM1 mice, revealing a progressive deregulation of inflammatory mediators with disease progression. Yet, inflammatory molecules involved are subjected to species differences in humans and mice. Moreover, inflammatory-related cell signaling pathways NFκB/IKK and JAK/STAT are activated in sCJD and sCJD MM1 mice. Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD. Considering this scenario, measures tailored to modulate (activate or inhibit) specific molecules could be therapeutic options in CJD. PMID:25136317

  19. The TP53 Codon 72 Polymorphism and Risk of Sporadic Prostate Cancer among Iranian Patients

    PubMed Central

    BABAEI, Farhad; AHMADI, Seyed Ali; ABIRI, Ramin; REZAEI, Farhad; NASERI, Maryam; MAHMOUDI, Mahmoud; NATEGH, Rakhshande; MOKHTARI AZAD, Talat

    2014-01-01

    Abstract Background The TP53 gene is one of the most frequently mutated genes amongst human malignancies, particularly TP53 codon 72 polymorphism. Furthermore, an association between the TP53 codon 72 variants and prostate cancer has been reported in several studies. Although some studies have indicated an association between the TP53 Arg/Arg variant and an increased risk for prostate cancer, other studies have shown a positive correlation between the TP53 Pro/Pro genotype instead. Therefore, to clarify if this polymorphism is associated with an increased risk of prostate cancer in Iranian men, we conducted a case-control study of 40 sporadic prostate cancer patients and 80 benign prostate hyperplasia cases. Methods The TP53 codon 72 was genotyped using an allele specific PCR. Results A significant association between the TP53 codon 72 genotype and prostate cancer risk was found (OR = 6.8, 95% CI = [1.8-25.1], P = 0.005). However, the results of this study did not support an association between age, the Gleason score nor TP53 genotype at codon 72 in prostate cancer patients. Conclusions TP53 codon 72 polymorphism may have a great impact in the development of prostate cancer. PMID:26005655

  20. A Common BACE1 Polymorphism Is a Risk Factor for Sporadic Creutzfeldt-Jakob Disease

    PubMed Central

    Calero, Olga; Bullido, María J.; Clarimón, Jordi; Frank-García, Ana; Martínez-Martín, Pablo; Lleó, Alberto; Rey, María Jesús; Sastre, Isabel; Rábano, Alberto; de Pedro-Cuesta, Jesús; Ferrer, Isidro; Calero, Miguel

    2012-01-01

    The β site APP cleaving enzyme 1 (BACE1) is the rate-limiting β-secretase enzyme in the amyloidogenic processing of APP and Aβ formation, and therefore it has a prominent role in Alzheimer’s disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its β-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aβ oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer’s and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aβ oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players. PMID:22952813

  1. Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis.

    PubMed

    Larman, H Benjamin; Salajegheh, Mohammad; Nazareno, Remedios; Lam, Theresa; Sauld, John; Steen, Hanno; Kong, Sek Won; Pinkus, Jack L; Amato, Anthony A; Elledge, Stephen J; Greenberg, Steven A

    2013-03-01

    We previously identified a circulating autoantibody against a 43 kDa muscle autoantigen in sporadic inclusion body myositis (IBM) and demonstrated the feasibility of an IBM diagnostic blood test. Here, we sought to identify the molecular target of this IBM autoantibody, understand the relationship between IBM autoimmunity and muscle degeneration, and develop an IBM blood test with high diagnostic accuracy. IBM blood samples were screened using mass spectrometry and a synthetic human peptidome. Plasma and serum samples (N=200 patients) underwent immunoblotting assays, and results were correlated to clinical features. Muscle biopsy samples (n=30) were examined by immunohistochemistry and immunoblotting. Exome or whole genome sequencing was performed on DNA from 19 patients. Both mass spectrometry and screening of a 413,611 human peptide library spanning the entire human proteome identified cytosolic 5'-nucleotidase 1A (cN1A; NT5C1A) as the likely 43 kDa IBM autoantigen, which was then confirmed in dot blot and Western blot assays using recombinant cN1A protein. Moderate reactivity of anti-cN1A autoantibodies was 70% sensitive and 92% specific, and high reactivity was 34% sensitive and 98% specific for the diagnosis of IBM. One to 3 major cN1A immunodominant epitopes were identified. cN1A reactivity by immunohistochemistry accumulated in perinuclear regions and rimmed vacuoles in IBM muscle, localizing to areas of myonuclear degeneration. Autoantibodies against cN1A are common in and highly specific to IBM among muscle diseases, and may provide a link between IBM's dual processes of autoimmunity and myodegeneration. Blood diagnostic testing is feasible and should improve early and reliable diagnosis of IBM. Copyright © 2013 American Neurological Association.

  2. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients

    PubMed Central

    Moore, Roger A.; Head, Mark W.; Ironside, James W.; Ritchie, Diane L.; Zanusso, Gianluigi; Pyo Choi, Young; Priola, Suzette A.

    2016-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrPSc). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrPC) into infectious PrPSc. By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrPSc. In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrPC allotype to PrPSc in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrPSc with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrPC containing an M or V at residue 129 having a similar propensity to misfold into PrPSc thus causing sCJD. By contrast, PrPSc with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrPSc containing V at residue 129. In both types of CJD, the PrPSc allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrPSc allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD. PMID:26840342

  3. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Moore, Roger A; Head, Mark W; Ironside, James W; Ritchie, Diane L; Zanusso, Gianluigi; Choi, Young Pyo; Pyo Choi, Young; Priola, Suzette A

    2016-02-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc). By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrP(Sc). In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrP(C) allotype to PrP(Sc) in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrP(Sc) with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrP(C) containing an M or V at residue 129 having a similar propensity to misfold into PrP(Sc) thus causing sCJD. By contrast, PrP(Sc) with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrP(Sc) containing V at residue 129. In both types of CJD, the PrP(Sc) allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrP(Sc) allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD.

  4. Differential diagnosis of sporadic adult-onset ataxia: The role of REM sleep behavior disorder.

    PubMed

    Teive, Hélio A G; Arruda, Walter O; Moro, Adriana; Moscovich, Mariana; Munhoz, Renato P

    2015-06-01

    Sporadic adult-onset ataxia encompasses a group of degenerative, non-hereditary disorders, including idiopathic adult-onset ataxia and the cerebellar form of multiple system atrophy. Our objective was to analyze the diagnosis at follow-up of 50 sporadic adult-onset ataxia patients. Clinical and laboratory findings of 50 adult patients with sporadic adult-onset ataxia were analyzed. Diagnosis of probable REM sleep behavior disorder was based predominantly on clinically accepted criteria. Multiple system atrophy was diagnosed in 48% of cases, the remaining 52% received a diagnosis of sporadic adult-onset ataxia. REM sleep behavior disorder was diagnosed in 46% of the patients. However, among patients with probable multiple system atrophy, the corresponding figure was 83.34% versus 11.53% among those with sporadic ataxia (p < 0.001). REM sleep behavior disorder is an important aid to the differentiation of multiple system atrophy from sporadic adult-onset ataxia and its use for this purpose should be encouraged. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Sporadic mortality in chronic toxicity tests using Pimephales promelas (Rafinesque): Cases of characterization and control

    SciTech Connect

    Downey, P.J.; Fleming, K.; Guinn, R.; Chapman, N.; Varner, P.; Cooney, J.D.

    2000-01-01

    In whole effluent toxicity tests, organisms are exposed to various effluent concentrations for a specific time period to estimate the potential effects of an effluent on a receiving stream. Laboratories typically have good success performing valid chronic toxicity tests. However, some difficulty in conducting valid chronic whole effluent toxicity tests with Pimephales promelas (fathead minnow) has been encountered as a result of sporadic control mortality. Some investigators report an interference that causes anomalous patterns of survival in chronic fathead minnow tests. This interference has been termed sporadic mortality phenomenon. Characteristics of sporadic mortality phenomenon include high variability among replicates, nonmonotonic dose responses, mortality beginning on or about day 4 of the test, and fungal growths often observed on the larvae. Histopathologic examinations often indicate bacterial and/or fungal infections on fish exhibiting symptoms of sporadic mortality phenomenon. The most plausible explanation of sporadic mortality phenomenon is a naturally occurring pathogen or pathogens that interfere with the test method. This interference may invalidate tests or falsely indicate toxicity. Sporadic mortality phenomenon can be reduced or eliminated by sample treatments intended to inactivate (heating, antibiotics, or ultraviolet light) or remove (filtration) pathogenic microorganisms. These methods must be used with forethought because of their potential to alter the toxicity of a sample.

  6. The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinson's Disease.

    PubMed

    Santos, Daniel; Esteves, A Raquel; Silva, Diana F; Januário, Cristina; Cardoso, Sandra M

    2015-08-01

    Accumulating data suggests that mitochondrial deficits may underline both sporadic and familial Parkinson's disease (PD) neurodegenerative process. Impairment of mitochondrial dynamics results in reactive oxygen species (ROS) production, decreases mitochondrial membrane potential, and could potentiate the accumulation of dysfunctional mitochondria. Excessive mitochondrial fragmentation is associated with the pathology of sporadic PD. Therefore, we modulated mitochondria fusion and fission in different sporadic PD cellular models. We found alterations in two proteins known to regulate mitochondrial fusion and fission events (OPA1 and Drp1, respectively). OPA1 long isoform cleavage seems to be, at least in part, responsible for mitochondrial fragmented pattern observed in sporadic PD cellular models. Moreover, mitochondrial fragmentation can also occur due to an increase in Drp1 that is translocated into the mitochondria by phosphorylation. To disclose the relevance of these alterations to the fragmentation of the mitochondrial network, we overexpressed OPA1 and knock down Drp1. OPA1 overexpression did not rescue MPP(+)-induced increase in ROS. Nevertheless, Drp1 knockdown due to an increase in mitochondrial elongation and interconnectivity rescued mitochondrial membrane potential and decreased ROS production in sporadic PD cells. Overall, our findings suggest that Drp1-dependent mitochondrial fragmentation plays a crucial role in mediating mitochondrial DNA induced mitochondria abnormalities and cellular dysfunction in sporadic PD.

  7. Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease.

    PubMed

    Spataro, Nino; Calafell, Francesc; Cervera-Carles, Laura; Casals, Ferran; Pagonabarraga, Javier; Pascual-Sedano, Berta; Campolongo, Antònia; Kulisevsky, Jaime; Lleó, Alberto; Navarro, Arcadi; Clarimón, Jordi; Bosch, Elena

    2015-04-01

    Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.

  8. Structure and sources of the sporadic meteor background from video observations

    NASA Astrophysics Data System (ADS)

    Jakšová, Ivana; Porubčan, Vladimír; Klačka, Jozef

    2015-10-01

    We investigate and discuss the structure of the sporadic meteor background population in the near-Earth space based on video meteor orbits from the SonotaCo database (SonotaCo 2009, WGN, 37, 55). The selection of the shower meteors was done by the Southworth-Hawkins streams-search criterion (Southworth & Hawkins 1963, Smithson. Contr. Astrophys., 7, 261). Of a total of 117786 orbits, 69.34% were assigned to sporadic background meteors. Our analysis revealed all the known sporadic sources, such as the dominant apex source which is splitting into the northern and southern branch. Part of a denser ring structure about the apex source connecting the antihelion and north toroidal sources is also evident. We showed that the annual activity of the apex source is similar to the annual variation in activity of the whole sporadic background. The antihelion source exhibits a very broad maximum from July until January and the north toroidal source shows three maxima similar to the radar observations by the Canadian Meteor Orbit Radar (CMOR). Potential parent bodies of the sporadic population were searched for by comparison of the distributions of the orbital elements of sporadic meteors, minor planets and comets.

  9. Coincident extremely large sporadic sodium and sporadic E layers observed in the lower thermosphere over Colorado and Utah

    NASA Astrophysics Data System (ADS)

    Milikh, G. M.; Guzdar, P. N.; Sharma, S. A.; Williams, B. P.; Sherman, J.; She, C. Y.; Wright, J. W.; Zabotin, N. A.; Berkey, F. T.

    2004-05-01

    On the night of June 2, 2002, the CSU sodium lidar measured an extremely strong sporadic sodium layer lasting from 3.5 to 5 UT with several weaker layers later in the night at 6 and 9 UT. There is a double layer stucture with peaks at 101 and 104 km. The peak sodium density was 21,000 atoms/cm3 with a column abundance up to twice the normal sodium layer. The peak density was 500 times greater than the typical density at that altitude. The abundance and strength factor were higher than any reported in the literature. The two lidar beams, separated by 80km at this altitude, both measured 1 hour periodicities in the abundance, but directly out-of-phase. There is also evidence for strong wave activity in the lidar temperatures and winds. The NOAA Boulder ionosonde measured an foEs of 14.3 MHz at 3 UT on this night, the highest value during 2002. The Bear Lake, Utah dynasonde also measured intense Es between 2-5 UT and again from 6-8 UT about 700 km west of the lidar, with most of the ionograms during these intervals measuring Es up to 12 MHz, the limit of the ionosonde sweep. Other ionosondes around North America on the NGDC database measured normal foEs values that night, so it was a localized event. Using the sodium density, wind and temperature from the lidar and the ionospheric data from the ionosondes, we will investigate the formation mechanism for this extreme event.

  10. Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas.

    PubMed

    Costa-Guda, Jessica; Soong, Chen-Pang; Parekh, Vaishali I; Agarwal, Sunita K; Arnold, Andrew

    2013-10-01

    The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood. The possible role of cyclin-dependent kinase inhibitor (CDKI) genes was raised by recognition of cyclin D1 as a parathyroid oncogene, identification of rare germline mutations in CDKI genes in patients with multiple endocrine neoplasia type 1; that in rodents, mutation in Cdkn1b caused parathyroid tumors; and subsequently through identification of rare predisposing germline sequence variants and somatic mutation of CDKN1B, encoding p27(kip1), in sporadic human parathyroid adenoma. We therefore sought to determine whether mutations/variants in the other six CDKI genes CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and CDKN2D, encoding p21, p57, p14(ARF)/p16, p15, p18, and p19, respectively, contribute to the development of typical parathyroid adenomas. In a series of 85 sporadic parathyroid adenomas, direct DNA sequencing identified alterations in five adenomas (6 %): Two contained distinct heterozygous changes in CDKN1A, one germline and one of undetermined germline status; one had a CDKN2B germline alteration, accompanied by loss of the normal allele in the tumor (LOH); two had variants of CDKN2C, one somatic and one germline with LOH. Abnormalities of three of the mutant proteins were readily demonstrable in vitro. Thus, germline mutations/rare variants in CDKN1A, CDKN2B, and CDKN2C likely contribute to the development of a significant subgroup of common sporadic parathyroid adenomas, and somatic mutation in CDKN2C further suggests a direct role for CDKI alteration in conferring a selective growth advantage to parathyroid cells, providing novel support for the concept that multiple CDKIs can play primary roles in human neoplasia.

  11. Endoscopic treatment of sporadic small duodenal and ampullary neuroendocrine tumors.

    PubMed

    Gincul, Rodica; Ponchon, Thierry; Napoleon, Bertrand; Scoazec, Jean-Yves; Guillaud, Olivier; Saurin, Jean-Christophe; Ciocirlan, Mihai; Lepilliez, Vincent; Pioche, Mathieu; Lefort, Christine; Adham, Mustapha; Pialat, Jean; Chayvialle, Jean-Alain; Walter, Thomas

    2016-11-01

    Background and study aim: As duodenal neuroendocrine tumors (NETs) are rare, their optimal management has not been clearly established. The aim of this study was to evaluate the feasibility and outcome of endoscopic treatment of duodenal NETs. Patients and methods: We reviewed the files of all patients who underwent endoscopic resection of a sporadic duodenal or ampullary NET between 1996 and 2014 at two centers. Results: A total of 29 patients with 32 uT1N0M0 NETs < 20 mm were included. Treatment consisted of endoscopic mucosal resection in 19 cases, and cap aspiration in 13 cases. Prior submucosal saline injection was used in 15 cases. Mortality was 3 % (one severe bleeding). Morbidity was 38 % (11/29). At post-resection analysis, mean tumor size was 8.9 mm (range 3 - 17 mm), 29 lesions were stage pT1, one was pT2, and 2 were pTx because of piecemeal resection. All NETs were well differentiated. A total of 27 lesions were classified as grade 1 and 5 were grade 2. The resection was R0, R1, and Rx for 16, 14, and 2 lesions, respectively. Three R1 patients underwent additional surgical treatment, with no residual tumor on the surgical specimen but with positive metastatic lymph nodes in two cases. One patient was lost to follow-up. Finally, 24 patients were included in the follow-up analysis. The median follow-up period was 56 months (range 6 - 175 months). Two patients presented a tumor recurrence during the follow-up period. Conclusions: Endoscopic treatment of small duodenal NETs was associated with significant morbidity, a difficulty in obtaining an R0 specimen, and the risk of lymph node metastasis. Nevertheless, it represents an interesting alternative in small grade 1 duodenal lesions and in patients at high surgical risk. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Sporadic E Morphology from GPS-CHAMP Radio Occultation

    NASA Technical Reports Server (NTRS)

    Wu, Dong L.; Ao, Chi O.; Hajj, George A.; de la Torre Juarez, Manuel; Mannucci, Anthony J.

    2005-01-01

    The scintillations of phase and amplitude in terms of signal-to-noise ratio (SNR) of the GPS radio occultation signal are caused by thin ionization layers. These thin irregular electron density layers in the E region ionosphere are often called sporadic E (Es). For a monthly retrieval of Es morphology we use the variances of the phase and SNR fluctuations of worldwide 6000 GPS/CHAMP occultations in the E region. The Es climatology is studied globally with the SNR and phase variances in terms of monthly zonal means, seasonal maps, and diurnal and long-term variations. The zonal mean variances reveal strong, extended Es activities at summertime midlatitudes but weak, confined activities in wintertime high latitudes, peaking at 105 km. Global maps at 105-km altitude show clear dependence of Es activities on the geomagnetic dip angle, where the summertime midlatitude Es occurs mostly at dip angles of 30 deg. - 60 deg. and the wintertime high-latitude enhancement occurs mostly at dip angles greater than 80 deg. The midlatitude Es variances exhibit a strong semidiurnal variation with peak hours near 0800 1000 and 2000 local solar time, respectively. The peak hours are delayed slightly with decreasing height, suggesting influences from the semidiurnal tide. To provide more insights on the observed SNR and phase variances, we model radio wave propagation for the CHAMP observing geometry under several perturbed cases in the E region ionosphere. The model simulations indicate that the SNR variance has the maximum response to Es perturbations at vertical wavelengths of 1.2 km, whereas the phase response maximizes at 2 km (for the 1-s variance analysis). The characteristic scale depends little on the truncation time used in the SNR variance analysis, but it increases with the truncation time for the phase variances. Initial studies show that reasonable global Es morphology can be produced on a monthly and seasonal basis with the CHAMP one-antenna occultations. Better results

  13. Sporadic Medullary Thyroid Carcinoma: Clinical Data From A University Hospital

    PubMed Central

    Correia-Deur, Joya Emilie M.; Toledo, Rodrigo A.; Imazawa, Alice T.; Lourenço, Delmar M.; Ezabella, Marilza C. L.; Tavares, Marcos R.; Toledo, Sergio P. A.

    2009-01-01

    INTRODUCTION: Medullary thyroid carcinoma may occur in a sporadic (s-medullary thyroid carcinoma, 75%) or in a multiple endocrine neoplasia type 2 form (MEN2, 25%). These clinical forms differ in many ways, as s-medullary thyroid carcinoma cases are RET-negative in the germline and are typically diagnosed later than medullary thyroid carcinoma in MEN2 patients. In this study, a set of cases with s-medullary thyroid carcinoma are documented and explored. PURPOSE: To document the phenotypes observed in s-medullary thyroid carcinoma cases from a university group and to attempt to improve earlier diagnosis of s-medullary thyroid carcinoma. Some procedures for diagnostics are also recommended. METHOD: Patients (n=26) with apparent s-medullary thyroid carcinoma were studied. Their clinical data were reviewed and peripheral blood was collected and screened for RET germline mutations. RESULTS: The average age at diagnosis was 43.9 years (± 10.82 SD) and did not differ between males and females. Calcitonin levels were increased in all cases. Three patients presented values that were 100-fold greater than the normal upper limit. Most (61.54%) had values that were 20-fold below this limit. Carcinoembryonic antigen levels were high in 70.6% of cases. There was no significant association between age at diagnosis, basal calcitonin levels or time of disease onset with thyroid tumor size (0.6–15 cm). Routine thyroid cytology yielded disappointing diagnostic accuracy (46.7%) in this set of cases. After total thyroidectomy associated with extensive cervical lymph node resection, calcitonin values remained lower than 5 pg/mL for at least 12 months in eight of the cases (30.8%). Immunocyto- and histochemistry for calcitonin were positive in all analyzed cases. None of the 26 cases presented germline mutations in the classical hotspots of the RET proto-oncogene. CONCLUSION: Our cases were identified late. The basal calcitonin measurements and immunostaining for calcitonin were

  14. Sporadic colorectal cancer: Studying ways to an end

    PubMed Central

    Fidalgo, Paulo; Filipe, Bruno; Albuquerque, Cristina; Fonseca, Ricardo; Chaves, Paula; Pereira, António D

    2015-01-01

    Introduction Although colorectal cancer (CRC) has often been regarded as a single entity, different pathways may lead to macroscopically similar cancers. These pathways may evolve into a patchy colonic field defect that we aimed to study in consecutive CRC patients. Methods In a single-center, observational, prospective study, consecutive CRC patients were included if surgery and a perioperative colonoscopy were planned. Personal and familial history data were collected. Tumors were studied for microsatellite instability (MSI) status, DNA repair protein expression (DRPE) and presence of BRAF and/or APC mutations. Macroscopically normal mucosa samples were tested for APC mutations. Presence and location of synchronous and metachronous adenomas and patient follow-up were analyzed. The association of two categorical variables was tested through the Fisher’s exact test (SPSS 19). Results Twenty-four patients (12 male, mean age 69 years) were studied. High-grade MSI (MSI-H) was found in eight tumors—these were significantly more common in the right colon (p = 0.047) and more likely to have an altered DRPE (p = 0.007). BRAF mutation was found in two of six tested MSI-H tumors. APC gene mutations were found in nine of 16 non-MSI-H tumors and absent in normal mucosa samples. There was a nonsignificant co-localization of CRC and synchronous adenomas and a significant co-localization (p = 0.05) of synchronous and metachronous adenomas. Discussion Sporadic CRCs evolve through distinct pathways, evidenced only by pathological and molecular analysis, but clinically relevant both for patients and their families. In non-MSI-H tumors, the expected APC gene mutations were not detected by the most commonly used techniques in a high number of cases. More studies are needed to fully characterize these tumors and to search for common early events in normal mucosa patches, which might explain the indirect evidence found here for a field defect in the colon. PMID:27087959

  15. Sporadic E Morphology from GPS-CHAMP Radio Occultation

    NASA Technical Reports Server (NTRS)

    Wu, Dong L.; Ao, Chi O.; Hajj, George A.; de la Torre Juarez, Manuel; Mannucci, Anthony J.

    2005-01-01

    The scintillations of phase and amplitude in terms of signal-to-noise ratio (SNR) of the GPS radio occultation signal are caused by thin ionization layers. These thin irregular electron density layers in the E region ionosphere are often called sporadic E (Es). For a monthly retrieval of Es morphology we use the variances of the phase and SNR fluctuations of worldwide 6000 GPS/CHAMP occultations in the E region. The Es climatology is studied globally with the SNR and phase variances in terms of monthly zonal means, seasonal maps, and diurnal and long-term variations. The zonal mean variances reveal strong, extended Es activities at summertime midlatitudes but weak, confined activities in wintertime high latitudes, peaking at 105 km. Global maps at 105-km altitude show clear dependence of Es activities on the geomagnetic dip angle, where the summertime midlatitude Es occurs mostly at dip angles of 30 deg. - 60 deg. and the wintertime high-latitude enhancement occurs mostly at dip angles greater than 80 deg. The midlatitude Es variances exhibit a strong semidiurnal variation with peak hours near 0800 1000 and 2000 local solar time, respectively. The peak hours are delayed slightly with decreasing height, suggesting influences from the semidiurnal tide. To provide more insights on the observed SNR and phase variances, we model radio wave propagation for the CHAMP observing geometry under several perturbed cases in the E region ionosphere. The model simulations indicate that the SNR variance has the maximum response to Es perturbations at vertical wavelengths of 1.2 km, whereas the phase response maximizes at 2 km (for the 1-s variance analysis). The characteristic scale depends little on the truncation time used in the SNR variance analysis, but it increases with the truncation time for the phase variances. Initial studies show that reasonable global Es morphology can be produced on a monthly and seasonal basis with the CHAMP one-antenna occultations. Better results

  16. Forensic facial approximation assessment: can application of different average facial tissue depth data facilitate recognition and establish acceptable level of resemblance?

    PubMed

    Herrera, Lara Maria; Strapasson, Raíssa Ananda Paim; da Silva, Jorge Vicente Lopes; Melani, Rodolfo Francisco Haltenhoff

    2016-09-01

    Facial soft tissue thicknesses (FSTT) are important guidelines for modeling faces from skull. Amid so many FSTT data, Forensic artists have to make a subjective choice of a dataset that best meets their needs. This study investigated the performance of four FSTT datasets in the recognition and resemblance of Brazilian living individuals and the performance of assessors in recognizing people, according to sex and knowledge on Human Anatomy and Forensic Dentistry. Sixteen manual facial approximations (FAs) were constructed using three-dimensional (3D) prototypes of skulls (targets). The American method was chosen for the construction of the faces. One hundred and twenty participants evaluated all FAs by means of recognition and resemblance tests. This study showed higher proportions of recognition by FAs conducted with FSTT data from cadavers compared with those conducted with medical imaging data. Targets were also considered more similar to FAs conducted with FSTT data from cadavers. Nose and face shape, respectively, were considered the most similar regions to targets. The sex of assessors (male and female) and the knowledge on Human Anatomy and Forensic Dentistry did not play a determinant role to reach greater recognition rates. It was possible to conclude that FSTT data obtained from imaging may not facilitate recognition and establish acceptable level of resemblance. Grouping FSTT data by regions of the face, as proposed in this paper, may contribute to more accurate FAs.

  17. Necrotizing meningoencephalitis of Pug dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis.

    PubMed

    Greer, K A; Wong, A K; Liu, H; Famula, T R; Pedersen, N C; Ruhe, A; Wallace, M; Neff, M W

    2010-08-01

    Necrotizing meningoencephalitis (NME) is a disorder of Pug Dogs that appears to have an immune etiology and high heritability based on population studies. The present study was undertaken to identify a genetic basis for the disease. A genome-wide association scan with single tandem repeat (STR) markers showed a single strong association near the dog leukocyte antigen (DLA) complex on CFA12. Fine resolution mapping with 27 STR markers on CFA12 further narrowed association to the region containing DLA-DRB1, -DQA1 and, -DQB1 genes. Sequencing confirmed that affected dogs were more likely to be homozygous for specific alleles at each locus and that these alleles were linked, forming a single high risk haplotype. The strong DLA class II association of NME in Pug Dogs resembles that of human multiple sclerosis (MS). Like MS, NME appears to have an autoimmune basis, involves genetic and nongenetic factors, has a relatively low incidence, is more frequent in females than males, and is associated with a vascularly orientated nonsuppurative inflammation. However, NME of Pug Dogs is more aggressive in disease course than classical human MS, appears to be relatively earlier in onset, and involves necrosis rather than demyelination as the central pathobiologic feature. Thus, Pug Dog encephalitis (PDE) shares clinical features with the less common acute variant forms of MS. Accordingly, NME of Pug Dogs may represent a naturally occurring canine model of certain idiopathic inflammatory disorders of the human central nervous system.

  18. A Family Resemblance Approach to the Nature of Science for Science Education

    NASA Astrophysics Data System (ADS)

    Irzik, Gürol; Nola, Robert

    2011-07-01

    Although there is universal consensus both in the science education literature and in the science standards documents to the effect that students should learn not only the content of science but also its nature, there is little agreement about what that nature is. This led many science educators to adopt what is sometimes called "the consensus view" about the nature of science (NOS), whose goal is to teach students only those characteristics of science on which there is wide consensus. This is an attractive view, but it has some shortcomings and weaknesses. In this article we present and defend an alternative approach based on the notion of family resemblance. We argue that the family resemblance approach is superior to the consensus view in several ways, which we discuss in some detail.

  19. Gastrointestinal symptoms resembling ulcerative proctitis caused by larvae of the drone fly Eristalis tenax

    PubMed Central

    Desoubeaux, Guillaume; Gaillard, Julien; Borée-Moreau, Diane; Bailly, Éric; Andres, Christian R; Chandenier, Jacques

    2014-01-01

    We report a case of facultative intestinal myiasis due to larvae of the drone fly Eristalis tenax, also named the rat-tailed maggots. The development of larvae in the lower bowel was responsible for non-specific gastrointestinal symptoms that resembled ulcerative proctitis. The diagnosis was established upon the observation of four spontaneously excreted mobile larvae. The definite identification of the E. tenax species was made possible by scanning electron microscopy. The clinical outcome was satisfactory. PMID:24766340

  20. Identification of Anthrax Toxin Genes in a Bacillus cereus Associated With An Illness Resembling Inhalation Anthrax

    DTIC Science & Technology

    2004-01-01

    Identification of anthrax toxin genes in a Bacillus cereus associated with an illness resembling inhalation anthrax Alex R. Hoffmaster*†, Jacques... Bacillus anthracis is the etiologic agent of anthrax, an acute fatal disease among mammals. It was thought to differ from Bacillus cereus , an...correlation of phenotypic characteristics and their genetic basis. Bacillus cereus and Bacillus anthracis are members of a closelyrelated phylogenetic

  1. Gastrointestinal symptoms resembling ulcerative proctitis caused by larvae of the drone fly Eristalis tenax.

    PubMed

    Desoubeaux, Guillaume; Gaillard, Julien; Borée-Moreau, Diane; Bailly, Éric; Andres, Christian R; Chandenier, Jacques

    2014-04-01

    We report a case of facultative intestinal myiasis due to larvae of the drone fly Eristalis tenax, also named the rat-tailed maggots. The development of larvae in the lower bowel was responsible for non-specific gastrointestinal symptoms that resembled ulcerative proctitis. The diagnosis was established upon the observation of four spontaneously excreted mobile larvae. The definite identification of the E. tenax species was made possible by scanning electron microscopy. The clinical outcome was satisfactory.

  2. Parent-Child Resemblance in Weight Status and Its Correlates in the United States

    PubMed Central

    Liang, Lan; Wang, Youfa

    2013-01-01

    Background Few studies have examined parent-child resemblance in body weight status using nationally representative data for the US. Design We analyzed Body Mass Index (BMI), weight status, and related correlates for 4,846 boys, 4,725 girls, and their parents based on US nationally representative data from the 2006 and 2007 Medical Expenditure Panel Survey (MEPS). Pearson partial correlation coefficients, percent agreement, weighted kappa coefficients, and binary and multinomial logistic regression were used to examine parent-child resemblance, adjusted for complex sampling design. Results Pearson partial correlation coefficients between parent and child’s BMI measures were 0.15 for father-son pairs, 0.17 for father-daughter pairs, 0.20 for mother-son pairs, and 0.23 for mother-daughter pairs. The weighted kappa coefficients between BMI quintiles of parent and child ranged from −0.02 to 0.25. Odds ratio analyses found children were 2.1 (95% confidence interval (CI): 1.6, 2.8) times more likely to be obese if only their father was obese, 1.9 (95% CI: 1.5, 2.4) times more likely if only their mother was obese, and 3.2 (95% CI: 2.5, 4.2) times more likely if both parents were obese. Conclusions Parent-child resemblance in BMI appears weak and may vary across parent-child dyad types in the US population. However, parental obesity status is associated with children’s obesity status. Use of different measures of parent-child resemblance in body weight status can lead to different conclusions. PMID:23762352

  3. Plague in China 2014-All sporadic case report of pneumonic plague.

    PubMed

    Li, Yun-Fang; Li, De-Biao; Shao, Hong-Sheng; Li, Hong-Jun; Han, Yue-Dong

    2016-02-19

    Yersinia pestis is the pathogen of the plague and caused three pandemics worldwide. Pneumonic plague is rarer than bubonic and septicemic plague. We report detailed clinical and pathogenic data for all the three sporadic cases of pneumonic plagues in China in 2014. All the three patients are herders in Gansu province of China. They were all infected by Yersinia pestis and displayed in the form of pneumonic plague respectively without related. We tested patient specimens from the upper (nasopharyngeal swabs) or the lower (sputum) respiratory tract and whole blood, plasma, and serum specimens for Yersinia pestis. All patients had fever, cough and dyspnea, and for patient 2 and 3, unconscious. Respiratory symptoms were predominant with acute respiratory failure. The chest X-ray showed signs consistent with necrotizing inflammation with multiple lobar involvements. Despite emergency treatment, all patients died of refractory multiple organ failure within 24 h after admission to hospital. All the contacts were quarantined immediately and there were no secondary cases. Nowadays, the plague is epidemic in animals and can infect people who contact with the infected animals which may cause an epidemic in human. We think dogs maybe an intermediate vector for plague and as a source of risk for humans who are exposed to pet animals or who work professionally with canines. If a patient has been exposed to a risk factor and has fever and dyspnea, plague should be considered. People who had contact with a confirmed case should be isolated and investigated for F1 antigen analysis and receive post-exposure preventive treatment. A vaccination strategy might be useful for individuals who are occupationally exposed in areas where endemically infected reservoirs of plague-infected small mammals co-exist.

  4. Altered Ca(2+) homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Llorens, Franc; Thüne, Katrin; Sikorska, Beata; Schmitz, Matthias; Tahir, Waqas; Fernández-Borges, Natalia; Cramm, Maria; Gotzmann, Nadine; Carmona, Margarita; Streichenberger, Nathalie; Michel, Uwe; Zafar, Saima; Schuetz, Anna-Lena; Rajput, Ashish; Andréoletti, Olivier; Bonn, Stefan; Fischer, Andre; Liberski, Pawel P; Torres, Juan Maria; Ferrer, Isidre; Zerr, Inga

    2017-04-27

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrP(Sc)). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca(2+)) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca(2+) responsive genes in sCJD brain tissue, accompanied by two Ca(2+)-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrP(Sc) in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca(2+) homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.

  5. Familial resemblance for VO2max in the sedentary state: the HERITAGE family study.

    PubMed

    Bouchard, C; Daw, E W; Rice, T; Pérusse, L; Gagnon, J; Province, M A; Leon, A S; Rao, D C; Skinner, J S; Wilmore, J H

    1998-02-01

    This study investigates the familial resemblance of maximal oxygen uptake (VO2max) based on data from 86 nuclear families of Caucasian descent participating in the HERITAGE Family Study. In the current study, VO2max was measured twice on a cycle ergometer in 429 sedentary individuals (170 parents and 259 of their offspring), aged between 16 and 65 yr. The VO2max was adjusted by regression procedures for the effects of 1) age and sex; 2) age, sex, and body mass; and 3) age, sex, body mass, fat mass, and fat-free mass, as determined by underwater weighing. Evidence for significant familial resemblance was observed for each of the three VO2max phenotypes. Spouse, sibling, and parent-offspring correlations were significant, suggesting that both genetic and environmental factors contribute to the familial resemblance for VO2max. Maximal heritability estimates were at least 50%, a value inflated to an undetermined degree by nongenetic factors. The hypothesis of maternal inheritance, with the father's contribution being environmental, was also found to fit the data with estimates of maternal heritability, potentially associated in part with mitochondrial inheritance, reaching about 30%. These results suggest that genetic and nongenetic factors as well as maternal influences contribute to the familial aggregation of VO2max in sedentary individuals.

  6. Reduced Fhit expression in sporadic and BRCA2-linked breast carcinomas.

    PubMed

    Ingvarsson, S; Agnarsson, B A; Sigbjornsdottir, B I; Kononen, J; Kallioniemi, O P; Barkardottir, R B; Kovatich, A J; Schwarting, R; Hauck, W W; Huebner, K; McCue, P A

    1999-06-01

    Evidence for alteration of the FHIT gene in a significant fraction of breast carcinomas has been reported, in apparent concordance with loss of heterozygosity (LOH) at chromosome region 3p14.2 in breast cancer and benign proliferative breast disease. A significantly higher frequency of LOH at the FHIT locus was reported for BRCA2-/- tumors, possibly due to misrepaired double-strand breaks at this common fragile region. To determine whether such genomic alterations lead to Fhit inactivation, we have assessed the level of Fhit expression by immunohistochemical detection in sporadic tumors and cancers occurring in BRCA2 999del5 carriers. To determine whether Fhit inactivation may have prognostic significance, we have also assessed expression of breast cancer markers and clinical features in sporadic tumors relative to Fhit expression. Of 40 consecutive sporadic breast carcinomas studied for tumor markers, 50% showed reduced Fhit expression. In these sporadic cancers, loss of Fhit expression was not correlated significantly with the presence or absence of other tumor markers. In a study of 58 sporadic and 34 BRCA2 999del5 Icelandic invasive cancers, there was a significant association of LOH at 3p14.2 with reduced expression of Fhit (P = 0.001); also the lower expression of Fhit and higher LOH at 3p14.2 in BRCA2 999del5 tumors relative to sporadic cancers was significant (P = 0.002). Thus, genetic alteration at the fragile site within the FHIT gene leads to loss of Fhit protein in a significant fraction of sporadic breast cancers and a much larger fraction of familial breast cancers with an inherited BRCA2 mutation, consistent with the idea that loss of BRCA2 function affects stability of the FHIT/FRA3B locus.

  7. MSI phenotype and MMR alterations in familial and sporadic gastric cancer.

    PubMed

    Leite, Marina; Corso, Giovanni; Sousa, Sónia; Milanezi, Fernanda; Afonso, Luís P; Henrique, Rui; Soares, José Manuel; Castedo, Sérgio; Carneiro, Fátima; Roviello, Franco; Oliveira, Carla; Seruca, Raquel

    2011-04-01

    Microsatellite instability (MSI) is a major pathway involved in gastric carcinogenesis occurring in 20% of gastric cancer (GC). However, it is not clear whether MSI phenotype preferentially occurs in the sporadic or familial GC, when stringent inclusion criteria are used. The aim of this study was to compare the frequency of MSI and hypermethylation of MLH1 promoter in a large series of familial GC patients (non-HNPCC and non-CDH1-related) and sporadic cases. Additionally, we analysed the immunoexpression of MMR proteins in a fraction of cases. Overall, the frequency of familial GC was 7.1%, and the frequency of hereditary tumours was 4.6%. MSI phenotype and MLH1 hypermethylation frequencies were not statistical different between familial and sporadic GC settings. Further, the MSI phenotype was not associated with any clinico-pathological features studied in the familial GC setting, whereas in the sporadic setting, it was associated with older age, female gender and intestinal histotype. Using our stringent Amsterdam-based clinical criteria to select familial GC (number of cases, age of onset), we verified that sporadic and familial cases differed in gender but shared histopathological features. We verified that the frequency of MSI was similar in familial and sporadic GC settings, demonstrating that this molecular phenotype is not a hallmark of familial GC in contrast to what is verified in HNPCC. Moreover, we observed that the frequency of MLH1 hypermethylation is similar in sporadic and familial cases suggesting that in both settings MSI is not associated to MMR genetic alterations but in contrast to epigenetic deregulation. Copyright © 2010 UICC.

  8. Early Detection of Epidemic GII-4 Norovirus Strains in UK and Malawi: Role of Surveillance of Sporadic Acute Gastroenteritis in Anticipating Global Epidemics

    PubMed Central

    Callaghan, Anna; O’Brien, Sarah J.; Cunliffe, Nigel A.; Iturriza-Gómara, Miren

    2016-01-01

    Noroviruses are endemic in the human population, and are recognised as a leading cause of acute gastroenteritis worldwide. Although they are a highly diverse group of viruses, genogroup-II genotype-4 (GII-4) noroviruses are the most frequently identified strains worldwide. The predominance of GII-4 norovirus strains is driven by the periodic emergence of antigenic variants capable of evading herd protection. The global molecular epidemiology of emerging GII-4 strains is largely based on data from outbreak surveillance programmes, but the epidemiology of GII-4 strains among sporadic or community cases is far less well studied. To understand the distribution of GII-4 norovirus strains associated with gastroenteritis in the wider population, we characterised the GII-4 norovirus strains detected during studies of sporadic cases of infectious gastroenteritis collected in the UK and Malawi between 1993 and 2009. Our data shows that GII-4 norovirus strains that have emerged as strains of global epidemic importance have circulated in the community up to 18 years before their recognition as pandemic strains associated with increases in outbreaks. These data may suggest that more comprehensive surveillance programmes that incorporate strains associated with sporadic cases may provide a way for early detection of emerging strains with pandemic potential. This may be of particular relevance as vaccines become available. PMID:27115152

  9. Sporadic Visual Acuity Loss in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)

    PubMed Central

    Kim, Benjamin J.; Ying, Gui-Shuang; Huang, Jiayan; Levy, Nicole E.; Maguire, Maureen G.

    2014-01-01

    Purpose To evaluate transient, large visual acuity (VA) decreases, termed sporadic vision loss, during anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration (AMD). Design Cohort within a randomized clinical trial. Methods Setting Comparison of AMD Treatments Trials (CATT). Study Population 1185 CATT patients. Main Outcome Measures incidence of sporadic vision loss and odds ratio (OR) for association with patient and ocular factors. Sporadic vision loss was a decline of ≥ 15 letters from the previous visit, followed by a return at the next visit to no more than 5 letters worse than the visit before the VA loss. Results There were 143 sporadic vision loss events in 122/1185 (10.3%) patients. Mean VA at two years for those with and without sporadic vision loss was 58.5 (~20/63) and 68.4 (~20/40) letters, respectively (P < 0.001). Among patients treated pro re nata, no injection was given for 27.6% (27/98) of sporadic vision loss events. Multivariate analysis demonstrated that baseline predictors for sporadic vision loss included worse baseline VA (OR 2.92, 95%CI:1.65–5.17 for ≤ 20/200 compared with ≥ 20/40), scar (OR 2.21, 95%CI:1.22–4.01), intraretinal foveal fluid on optical coherence tomography (OR 1.80, 95%CI:1.11–2.91), and medical history of anxiety (OR 1.90, 95%CI:1.12–3.24) and syncope (OR 2.75, 95%CI:1.45–5.22). Refraction decreased the likelihood of sporadic vision loss (OR 0.62, 95%CI:0.42–0.91). Conclusions Approximately 10% of CATT patients had sporadic vision loss. Baseline predictors included AMD-related factors and factors independent of AMD. These data are relevant for clinicians in practice and those involved in clinical trials. PMID:24727261

  10. Sporadic visual acuity loss in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).

    PubMed

    Kim, Benjamin J; Ying, Gui-Shuang; Huang, Jiayan; Levy, Nicole E; Maguire, Maureen G

    2014-07-01

    To evaluate transient, large visual acuity (VA) decreases, termed sporadic vision loss, during anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration (AMD). Cohort within a randomized clinical trial. setting: Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). study population: Total of 1185 CATT patients. main outcome measures: Incidence of sporadic vision loss and odds ratio (OR) for association with patient and ocular factors. Sporadic vision loss was a decline of ≥15 letters from the previous visit, followed by a return at the next visit to no more than 5 letters worse than the visit before the VA loss. There were 143 sporadic vision loss events in 122 of 1185 patients (10.3%). Mean VA at 2 years for those with and without sporadic vision loss was 58.5 (∼20/63) and 68.4 (∼20/40) letters, respectively (P < .001). Among patients treated pro re nata, no injection was given for 27.6% (27/98) of sporadic vision loss events. Multivariate analysis demonstrated that baseline predictors for sporadic vision loss included worse baseline VA (OR 2.92, 95% confidence interval [CI]:1.65-5.17 for ≤20/200 compared with ≥20/40), scar (OR 2.21, 95% CI:1.22-4.01), intraretinal foveal fluid on optical coherence tomography (OR 1.80, 95% CI:1.11-2.91), and medical history of anxiety (OR 1.90, 95% CI:1.12-3.24) and syncope (OR 2.75, 95% CI:1.45-5.22). Refraction decreased the likelihood of sporadic vision loss (OR 0.62, 95%CI: 0.42-0.91). Approximately 10% of CATT patients had sporadic vision loss. Baseline predictors included AMD-related factors and factors independent of AMD. These data are relevant for clinicians in practice and those involved in clinical trials. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

    PubMed

    Carmona-Iragui, María; Balasa, Mircea; Benejam, Bessy; Alcolea, Daniel; Fernández, Susana; Videla, Laura; Sala, Isabel; Sánchez-Saudinós, María Belén; Morenas-Rodriguez, Estrella; Ribosa-Nogué, Roser; Illán-Gala, Ignacio; Gonzalez-Ortiz, Sofía; Clarimón, Jordi; Schmitt, Frederick; Powell, David K; Bosch, Beatriz; Lladó, Albert; Rafii, Michael S; Head, Elizabeth; Molinuevo, José Luis; Blesa, Rafael; Videla, Sebastián; Lleó, Alberto; Sánchez-Valle, Raquel; Fortea, Juan

    2017-04-29

    We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  12. Current Status of Molecular Markers for Early Detection of Sporadic Pancreatic Cancer

    PubMed Central

    Chakraborty, Subhankar; Baine, Michael J.; Sasson, Aaron R.; Batra, Surinder K.

    2010-01-01

    Pancreatic cancer (PC) is a highly lethal malignancy with near 100% mortality. This is in part due to the fact that most patients present with metastatic or locally advanced disease at the time of diagnosis. Significantly, in nearly 95% of PC patients there is neither an associated family history of PC nor of diseases known to be associated with an increased risk of PC. These groups of patients who comprise the bulk of PC cases are termed as “sporadic PC” in contrast to the familial PC cases that comprise only about 5% of all PCs. Given the insidious onset of the malignancy and its extreme resistance to chemo and radiotherapy, an abundance of research in recent years has focused on identifying biomarkers for the early detection of PC, specifically aiming at the sporadic PC cohort. However, while several studies have established that asymptomatic individuals with a positive family history of PC and those with certain heritable syndromes are candidates for PC screening, the role of screening in identifying sporadic PC is still an unsettled question. The present review attempts to assess this critical question by investigating the recent advances made in molecular markers with potential use in the early diagnosis of sporadic PC- the largest cohort of PC cases worldwide. It also outlines a novel yet simple risk-factor based stratification system that could be potentially employed by clinicians to identify those individuals who at an elevated-risk for the development of sporadic PC and therefore candidates for screening. PMID:20888394

  13. Intrinsic Brain Activity of Cognitively Normal Older Persons Resembles More That of Patients Both with and at Risk for Alzheimer's Disease Than That of Healthy Younger Persons

    PubMed Central

    Pasquini, Lorenzo; Tonch, Annika; Plant, Claudia; Zherdin, Andrew; Ortner, Marion; Kurz, Alexander; Förstl, Hans; Zimmer, Claus; Grimmer, Timo; Wohlschäger, Afra; Riedl, Valentin

    2014-01-01

    Abstract In Alzheimer's disease (AD), recent findings suggest that amyloid-β (Aβ)-pathology might start 20–30 years before first cognitive symptoms arise. To account for age as most relevant risk factor for sporadic AD, it has been hypothesized that lifespan intrinsic (i.e., ongoing) activity of hetero-modal brain areas with highest levels of functional connectivity triggers Aβ-pathology. This model induces the simple question whether in older persons without any cognitive symptoms intrinsic activity of hetero-modal areas is more similar to that of symptomatic patients with AD or to that of younger healthy persons. We hypothesize that due to advanced age and therefore potential impact of pre-clinical AD, intrinsic activity of older persons resembles more that of patients than that of younger controls. We tested this hypothesis in younger (ca. 25 years) and older healthy persons (ca. 70 years) and patients with mild cognitive impairment and AD-dementia (ca. 70 years) by the use of resting-state functional magnetic resonance imaging, distinct measures of intrinsic brain activity, and different hierarchical clustering approaches. Independently of applied methods and involved areas, healthy older persons' intrinsic brain activity was consistently more alike that of patients than that of younger controls. Our result provides evidence for larger similarity in intrinsic brain activity between healthy older persons and patients with or at-risk for AD than between older and younger ones, suggesting a significant proportion of pre-clinical AD cases in the group of cognitively normal older people. The observed link of aging and AD with intrinsic brain activity supports the view that lifespan intrinsic activity may contribute critically to the pathogenesis of AD. PMID:24689864

  14. [FGFR2 gene mutation in a family with Crouzon syndrome and a sporadic Crouzon syndrome patient].

    PubMed

    Guo, Lu; Lai, Yan-ni; Li, Lian-xi

    2008-04-01

    To detect the gene mutation of fibroblast growth factor receptor (FGFR2)in a Crouzon syndrome family and a sporadic patient. The genomic DNA from 10 members in the Crouzon syndrome family, as well as a sporadic patient, was extracted. Then exons 8 and 10 of FGFR2 gene and their flanking sequences were amplified by polymerase chain reaction. Some of the family members were studied by only amplifying exon 8. Finally, the PCR products were purified and sequenced. The G to T transversion mutation (heterozygote) at nucleotide 833 in exon 8 of FGFR2 (C278F), was found both in the patients of the family and the sporadic patient. FGFR2 gene mutation is responsible for the pathogenesis of Crouzon syndrome in these patients.

  15. Case-control studies of sporadic cryptosporidiosis in Melbourne and Adelaide, Australia.

    PubMed Central

    Robertson, B.; Sinclair, M. I.; Forbes, A. B.; Veitch, M.; Kirk, M.; Cunliffe, D.; Willis, J.; Fairley, C. K.

    2002-01-01

    Few studies have assessed risk factors for sporadic cryptosporidiosis in industrialized countries, even though it may be numerically more common than outbreaks of disease. We carried out case-control studies assessing risk factors for sporadic disease in Melbourne and Adelaide, which have water supplies from different ends of the raw water spectrum. In addition to examining drinking water, we assessed several other exposures. 201 cases and 795 controls were recruited for Melbourne and 134 cases and 536 controls were recruited for Adelaide. Risk factors were similar for the two cities, with swimming in public pools and contact with a person with diarrhoea being most important. The consumption of plain tap water was not found to be associated with disease. This study emphasizes the need for regular public health messages to the public and swimming pool managers in an attempt to prevent sporadic cryptosporidiosis, as well as outbreaks of disease. PMID:12113486

  16. De novo TBR1 mutations in sporadic autism disrupt protein functions

    PubMed Central

    Deriziotis, Pelagia; O’Roak, Brian J.; Graham, Sarah A.; Estruch, Sara B.; Dimitropoulou, Danai; Bernier, Raphael A.; Gerdts, Jennifer; Shendure, Jay; Eichler, Evan E.; Fisher, Simon E.

    2014-01-01

    Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits. PMID:25232744

  17. Structures in sporadic-E observed with an impedance probe during the SEEK Campaign: Comparisons with neutral-wind and radar-echo observations

    NASA Astrophysics Data System (ADS)

    Yamamoto, Masayuki; Ono, Takayuki; Oya, Hiroshi; Tsunoda, Roland T.; Larsen, Miguel F.; Fukao, Shoichiro; Yamamoto, Mamoru

    In order to clarify the origin of the so-called quasi periodic echoes (QPE) that have been often detected by radar observations in the presence of sporadic-E (Es) layers in the nighttime midlatitude ionosphere, two sounding rockets were launched during the SEEK (Sporadic-E Experiment over Kyushu) campaign. Each rocket carried a swept-frequency impedance probe to measure the E-region electron-density (Ne) profile. Using the four Ne profiles obtained during the two rocket flights together with a neutral-wind profile obtained from a trimethyl aluminum (TMA) chemical release experiment on one of the rockets and QPE obtained with a ground-based radar, we consider the role of wind shear in the formation of the observed Es layers, and the question of whether QPE are associated with Es layers that are modulated in altitude. The Ne profiles of Es structures that were obtained in the presence of QPE were characterized by the highly concentrated thin layers. The formation of such a thin layer by a neutral-wind shear process was confirmed in comparison with the TMA measurements. The peak Ne values of the Es layers ranged from 2.2 to 9.3 × 104 el/cm³ near 100-km altitude. These primary Es layers were accompanied by significant secondary structures that were located about 12 to 20 km above the main Es layers and had peak Ne that ranged from 5.2 × 10³ to 1.3×104 el/cm³. The average altitude profiles of QPE approximately covered the range where the Es-layer peaks appeared. Our principal finding is that the observed Es structures tended to resemble horizontally stratified layers rather than structures with deep altitude modulation like previous QPE model, although the rocket measurements were separated from those by radar by 90 to 145 km.

  18. UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort.

    PubMed

    Vidal-Taboada, Jose Manuel; Lopez-Lopez, Alan; Salvado, Maria; Lorenzo, Laura; Garcia, Cecilia; Mahy, Nicole; Rodríguez, Manuel J; Gamez, Josep

    2015-10-01

    To investigate the association of functional variants of the human UNC13A gene with the risk of ALS, survival and the disease progression rate in a Spanish ALS cohort. 136 sporadic ALS (sALS) patients and 487 healthy controls were genotyped for the UNC13A rs12608932 variant. Clinical characterization of ALS patients included gender, age at first symptom, initial topography, disease progression rate, and survival. Genetic association was analyzed under five inheritance models. The sALS patients with the rs12608932(CC) genotype had an increased risk of ALS under a recessive genetic model [OR 2.16; 95 % CI (1.23, 3.8), p = 0.009; corrected p = 0.028]. Genotypes with a C allele are also associated with increased risk [OR 1.47; 95 % CI (1.11, 1.95); p = 0.008; corrected p = 0.023] under an additive model. sALS patients with a C/C genotype had a shorter survival than patients with A/A and A/C genotypes [HR 1.44; 95 % CI (1.11, 1.873); p = 0.007] under a recessive model. In an overdominant model, heterozygous patients had a longer survival than homozygous patients [HR 0.36; 95 % CI (0.22, 0.59); p = 0.001]. The rs12608932 genotypes modify the progression of symptoms measured using the ALSFRS-R. No association with age of onset, initial topography or rate of decline in FVC was found. Our results show that rs12608932 is a risk factor for ALS in the Spanish population and replicate the findings described in other populations. The rs12608932 is a modifying factor for survival and disease progression rate in our series. Our results also corroborated that it did not influence the age of onset.

  19. A genome-wide association study of sporadic ALS in a homogenous Irish population.

    PubMed

    Cronin, Simon; Berger, Stephen; Ding, Jinhui; Schymick, Jennifer C; Washecka, Nicole; Hernandez, Dena G; Greenway, Matthew J; Bradley, Daniel G; Traynor, Bryan J; Hardiman, Orla

    2008-03-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive limb or bulbar weakness. Efforts to elucidate the disease-associated loci have to date produced conflicting results. One strategy to improve power in genome-wide studies is to genotype a genetically homogenous population. Such a population exhibits extended linkage disequilibrium (LD) and lower allelic heterogeneity to facilitate disease gene mapping. We sought to identify associated variants for ALS in the Irish, a stable population of relatively homogenous genetic background, and to replicate these findings in larger genetically out-bred populations. We conducted a genome-wide association study in 432 Irish individuals using Illumina HumanHap 550K single nucleotide polymorphism chips. We demonstrated extended LD and increased homogeneity in the Irish sample when compared to an out-bred population of mixed European ancestry. The Irish scan identified 35 loci associated with P-values below 0.0001. For replication, we identified seven chromosomal regions commonly associated in a joint analysis of genome-wide data on 958 ALS cases and 932 controls from Ireland and the previously published datasets from the US and The Netherlands. When pooled, the strongest association was a variant in the gene encoding DPP6, a component of type A neuronal transmembrane potassium channels. Further confirmation of the candidate loci is warranted in additional genome-wide datasets. We have made our individual genotyping data publicly available, contributing to a powerful world-wide resource to refine our understanding of the genetics of sporadic ALS.

  20. Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases

    PubMed Central

    Calero, Olga; Bullido, María J.; Clarimón, Jordi; Frank-García, Ana; Martínez-Martín, Pablo; Lleó, Alberto; Rey, María Jesús; Rábano, Alberto; Blesa, Rafael; Gómez-Isla, Teresa; Valdivieso, Fernando; de Pedro-Cuesta, Jesús; Ferrer, Isidro; Calero, Miguel

    2011-01-01

    Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD. PMID:21799773