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Sample records for adult-onset neuronal ceroid

  1. Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD

    PubMed Central

    van der Zee, Julie; Mariën, Peter; Crols, Roeland; Van Mossevelde, Sara; Dillen, Lubina; Perrone, Federica; Engelborghs, Sebastiaan; Verhoeven, Jo; D'aes, Tine; Ceuterick-De Groote, Chantal; Sieben, Anne; Versijpt, Jan; Cras, Patrick; Martin, Jean-Jacques

    2016-01-01

    Objective: To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD). Methods: Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing. Results: We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype. Conclusions: A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms. PMID:27668283

  2. Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Donnelier, Julien; Braun, Samuel T.; Dolzhanskaya, Natalia; Ahrendt, Eva; Braun, Andrew P.; Velinov, Milen; Braun, Janice E. A.

    2015-01-01

    Cysteine string protein (CSPα) is a presynaptic J protein co-chaperone that opposes neurodegeneration. Mutations in CSPα (i.e., Leu115 to Arg substitution or deletion (Δ) of Leu116) cause adult neuronal ceroid lipofuscinosis (ANCL), a dominantly inherited neurodegenerative disease. We have previously demonstrated that CSPα limits the expression of large conductance, calcium-activated K+ (BK) channels in neurons, which may impact synaptic excitability and neurotransmission. Here we show by western blot analysis that expression of the pore-forming BKα subunit is elevated ~2.5 fold in the post-mortem cortex of a 36-year-old patient with the Leu116∆ CSPα mutation. Moreover, we find that the increase in BKα subunit level is selective for ANCL and not a general feature of neurodegenerative conditions. While reduced levels of CSPα are found in some postmortem cortex specimens from Alzheimer’s disease patients, we find no concomitant increase in BKα subunit expression in Alzheimer’s specimens. Both CSPα monomer and oligomer expression are reduced in synaptosomes prepared from ANCL cortex compared with control. In a cultured neuronal cell model, CSPα oligomers are short lived. The results of this study indicate that the Leu116∆ mutation leads to elevated BKα subunit levels in human cortex and extend our initial work in rodent models demonstrating the modulation of BKα subunit levels by the same CSPα mutation. While the precise sequence of pathogenic events still remains to be elucidated, our findings suggest that dysregulation of BK channels may contribute to neurodegeneration in ANCL. PMID:25905915

  3. Equine neuronal ceroid lipofuscinosis.

    PubMed

    Url, A; Bauder, B; Thalhammer, J; Nowotny, N; Kolodziejek, J; Herout, N; Fürst, S; Weissenböck, H

    2001-04-01

    Neuronal ceroid lipofuscinosis (NCL) is an inherited, neurodegenerative disorder with fatal outcome in humans. It has also been described in some animal species; this is the first report of NCL in equines. Three horses showed developmental retardation, slow movements and loss of appetite at the age of six months. Neurological symptoms, as well as visual failure in one case, were noticed at the age of 1 year. Due to slowly progressing deterioration, euthanasia was indicated 1.5 years after onset of conspicuous behavior. At necropsy, slight flattening of the gyri and discoloring of the brain was noticed. Histopathology revealed eosinophilic, autofluorescent material in the perikarya of neurons throughout the brain and spinal cord. Identical material was found in neurons of retina, submucous and myenteric ganglia, as well as in glial cells. Immunohistochemistry, using antiserum against subunit c of mitochondrial ATP synthase, showed positive signals in neurons and glial cells. Electron microscopical studies revealed fingerprint profiles mixed with rectilinear structures in markedly enlarged lysosomes of neurons and renal tubules, and rectilinear structures mixed with curvilinear bodies in macrophages and lymphocytes of lymph nodes. Thus, our study presents the first occurrence of lysosomal storage disease in horses, further characterized by immunohistochemical and electron microscopical investigations as NCL.

  4. The Neuronal Ceroid-Lipofuscinoses

    ERIC Educational Resources Information Center

    Bennett, Michael J.; Rakheja, Dinesh

    2013-01-01

    The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in…

  5. Altered elemental profiles in neuronal ceroid lipofuscinosis.

    PubMed

    Johansson, E; Lindh, U; Westermarck, T; Heiskala, H; Santavuori, P

    1990-09-01

    The elemental profiles of thrombocytes and mononuclear cells were investigated in five patients with Infantile and eight with Juvenile Neuronal Ceroid Lipofuscinosis. The patients with the infantile form had suffered from the disease for a year and those with the juvenile form for some six years. The thrombocytes exhibited increased concentrations of calcium and magnesium, but the same concentrations of iron and zinc as found in healthy subjects. The mononuclear cells exhibited an increased concentration of iron and a reduced concentration of zinc. The elevated concentrations of magnesium, calcium and iron in the thrombocytes and mononuclear cells may represent the end products of ceroid pigmentation. Five patients with Juvenile and one with Infantile Neuronal Ceroid Lipofuscinosis were treated with antioxidants along with vitamins E, B2 and B6, but this treatment did not affect significantly the concentration of iron in the mononuclear cells. However, selenium was detected in some mononuclear cells in all the patients so treated. This was unexpected since iron (III), being antagonistic to selenium in the form of selenite--which was the antioxidant given--forms a stable complex which cannot be broken down biologically.

  6. Clinicopathological features of adult-onset neuronal intranuclear inclusion disease

    PubMed Central

    Sone, Jun; Mori, Keiko; Inagaki, Tomonori; Katsumata, Ryu; Takagi, Shinnosuke; Yokoi, Satoshi; Araki, Kunihiko; Kato, Toshiyasu; Nakamura, Tomohiko; Koike, Haruki; Takashima, Hiroshi; Hashiguchi, Akihiro; Kohno, Yutaka; Kurashige, Takashi; Kuriyama, Masaru; Takiyama, Yoshihisa; Tsuchiya, Mai; Kitagawa, Naoyuki; Kawamoto, Michi; Yoshimura, Hajime; Suto, Yutaka; Nakayasu, Hiroyuki; Uehara, Naoko; Sugiyama, Hiroshi; Takahashi, Makoto; Kokubun, Norito; Konno, Takuya; Katsuno, Masahisa; Tanaka, Fumiaki; Iwasaki, Yasushi; Yoshida, Mari

    2016-01-01

    Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs. NIID has been considered to be a heterogeneous disease because of the highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. However, since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID. In this study, we studied 57 cases of adult-onset NIID and described their clinical and pathological features. We analysed both NIID cases diagnosed by post-mortem dissection and by ante-mortem skin biopsy based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion: 38 sporadic cases and 19 familial cases, from six families. In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated ‘dementia dominant group’, followed by miosis, ataxia and unconsciousness. Muscle weakness and sensory disturbance were also observed. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated ‘limb weakness group’, followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent (100%). Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging. Both sporadic and

  7. Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

    PubMed Central

    Choi, Won Jun; Oh, Ki-Wook; Nahm, Minyeop; Xue, Yuanchao; Choi, Jae Hyeok; Choi, Ji Young; Kim, Young-Eun; Chung, Ki Wha; Fu, Xiang-Dong; Ki, Chang-Seok; Kim, Seung Hyun

    2016-01-01

    Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by defective β-galactosylceramidase (GALC), a lysosomal enzyme responsible for cleavage of several key substrates including psychosine. Accumulation of psychosine to the cytotoxic levels in KD patients is thought to cause dysfunctions in myelinating glial cells based on a comprehensive study of demyelination in KD. However, recent evidence suggests myelin-independent neuronal death in the murine model of KD, thus indicating defective GALC in neurons as an autonomous mechanism for neuronal cell death in KD. These observations prompted us to generate induced neurons (iNeurons) from two adult-onset KD patients carrying compound heterozygous mutations (p.[K563*];[L634S]) and (p.[N228_S232delinsTP];[G286D]) to determine the direct contribution of autonomous neuronal toxicity to KD. Here we report that directly converted KD iNeurons showed not only diminished GALC activity and increased psychosine levels, as expected, but also neurite fragmentation and abnormal neuritic branching. The lysosomal-associated membrane proteins 1 (LAMP1) was expressed at higher levels than controls, LAMP1-positive vesicles were significantly enlarged and fragmented, and mitochondrial morphology and its function were altered in KD iNeurons. Strikingly, we demonstrated that psychosine was sufficient to induce neurite defects, mitochondrial fragmentation, and lysosomal alterations in iNeurons derived in healthy individuals, thus establishing the causal effect of the cytotoxic GALC substrate in KD and the autonomous neuronal toxicity in KD pathology. PMID:27780934

  8. Neuronal ceroid-lipofuscinosis and hydrocephalus in a chihuahua.

    PubMed

    Kuwamura, M; Hattori, R; Yamate, J; Kotani, T; Sasai, K

    2003-05-01

    A two-year-old, female chihuahua presented with a six-month history of visual dysfunction. Computed tomography revealed dilation of the lateral ventricles in the central nervous system (CNS). The dog was tentatively diagnosed as having hydrocephalus and a month later was euthanased at the owner's request. The skull was expanded and dome-like in shape and an open fontanelle was observed on postmortem examination. Histologically, swollen neurons possessing yellowish pigment granules in the cytoplasm were observed throughout the CNS. These storage materials stained positively with periodic acid Schiff, Schmorl method for lipofuscin and oil red O for lipid, and showed autofluorescence under fluorescence microscopy. Ultrastructurally, the storage materials consisted of dense lamellar structures. This case was unique in having ceroid-lipofuscinosis in association with hydrocephalus.

  9. Perioperative care of a patient with neuronal ceroid lipofuscinoses

    PubMed Central

    Kako, Hiromi; Martin, David P.; Tobias, Joseph D.

    2013-01-01

    The neuronal ceroid lipofuscinoses (NCL) are a group of inherited, autosomal recessive, and progressive neurodegenerative diseases, which result from an enzymatic defect or the deficiency of a transmembrane protein, leading to the accumulation of lipopigments (lipofuscin) in various tissues. NCL results in the impairment of function in several end-organs including the central nervous system with loss of cognitive and motor function, myoclonus, and intractable seizures. Additional involvement includes the cardiovascular system with arrhythmias and bradycardia as well as impairment of thermoregulation leading to perioperative hypothermia. Given the complexity of the end-organ involvement and the progressive nature of the disorder, the anesthetic care of such patients can be challenging. Till date, there are a limited number of reports regarding the anesthetic management of patients with NCL. We present an 18-year-old patient with NCL who required anesthetic care during replacement of a vagal nerve stimulator. Previous reports of anesthetic care for these patients are reviewed, the end-organ involvement of NCL discussed, and options for anesthetic care presented. PMID:24015141

  10. Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease)

    PubMed Central

    Staropoli, John F.; Carpenter, Stirling; Oliver, Karen L.; Kmoch, Stanislav; Anderson, Glenn W.; Damiano, John A.; Hildebrand, Michael S.; Sims, Katherine B.; Cotman, Susan L.; Bahlo, Melanie; Smith, Katherine R.; Cadieux-Dion, Maxime; Cossette, Patrick; Jedličková, Ivana; Přistoupilová, Anna; Mole, Sara E.

    2016-01-01

    Objective: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. Methods: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. Results: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. Conclusions: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes. PMID:27412140

  11. Linkage analysis of late-infantile neuronal ceroid-lipofuscinosis

    SciTech Connect

    Sharp, J.; Wheeler, R.B.; Jaervelae, I.

    1995-06-05

    The neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative disorders with an autosomal-recessive pattern of inheritance. There are 3 main categories of childhood NCL, namely, infantile, late-infantile, and juvenile NCL. These can be distinguished on the basis of age of onset, clinical course, and histopathology. A number of variant forms of NCL have also been mapped to chromosome areas 1p32 and 16p12, respectively. The gene for late-infantile NCL (LINCL), CLN2, has been excluded from both these loci, but its location is as yet unknown. Recently, CLN5, the gene for the Finnish variant form of LINCL, was mapped to 13q21.1-32. Using the 3 microsatellite markers which were most tightly linked to CLN5, we have excluded CLN2 from this region using a subset of 17 families. Thus, CLN2 represents a fourth distinct genetic locus involved in the pathogenesis of NCL. 6 refs., 1 fig., 1 tab.

  12. Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations

    PubMed Central

    Gilioli, Isabella; Invernizzi, Federica; Sofia, Vito; Fugnanesi, Valeria; Morbin, Michela; Chiapparini, Luisa; Granata, Tiziana; Binelli, Simona; Scaioli, Vidmer; Garavaglia, Barbara; Nardocci, Nardo; Berkovic, Samuel F.; Franceschetti, Silvana

    2015-01-01

    Objectives: To describe the clinical and neurophysiologic patterns of patients with neuronal ceroid lipofuscinoses associated with CLN6 mutations. Methods: We reviewed the features of 11 patients with different ages at onset. Results: Clinical disease onset occurred within the first decade of life in 8 patients and in the second and third decades in 3. All children presented with progressive cognitive regression associated with ataxia and pyramidal and extrapyramidal signs. Recurrent seizures, visual loss, and myoclonus were mostly reported after a delay from onset; 7 children were chairbound and had severe dementia less than 4 years from onset. One child, with onset at 8 years, had a milder course. Three patients with a teenage/adult onset presented with a classic progressive myoclonic epilepsy phenotype that was preceded by learning disability in one. The EEG background was slow close to disease onset in 7 children, and later showed severe attenuation; a photoparoxysmal response (PPR) was present in all. The 3 teenage/adult patients had normal EEG background and an intense PPR. Early attenuation of the electroretinogram was seen only in children with onset younger than 5.5 years. Somatosensory evoked potentials were extremely enlarged in all patients. Conclusions: In all patients, multifocal myoclonic jerks and seizures were a key feature, but myoclonic seizures were an early and prominent sign in the teenage/adult form only. Conversely, the childhood-onset form was characterized by initial and severe cognitive impairment coupled with electroretinogram and EEG attenuation. Cortical hyperexcitability, shown by the PPR and enlarged somatosensory evoked potentials, was a universal feature. PMID:26115733

  13. Late onset juvenile neuronal ceroid-lipofuscinosis with granular osmiophilic deposits (GROD)

    SciTech Connect

    Hofman, I.L.; Taschner, P.E.M.

    1995-06-05

    The juvenile-onset subtype of the neuronal ceroid lipofuscinoses (JNCL) is well known and ultra-structurally characterized by fingerprints and/or curvilinear bodies in many cell types. Linkage studies indicated a most likely location for CLN3, the gene involved in JNCL, in the interval between loci D16S297 and D16S57, within close proximity of the loci D16S298 and D16S299. We present two sibs with a late onset progressive disease of mental deterioration, progressive macular degeneration, motor disturbances, and epilepsy. Histological symptoms of neuronal ceroid lipofuscinosis and ultrastructural granular osmiophilic deposits (GROD) in lymphocytes and neurons are found. Individual haplotypes at polymorphic marker loci on chromosome 16 were constructed to determine whether JNCL with GROD is linked to the CLN3 locus. 8 refs., 3 figs.

  14. Apparent loss and hypertrophy of interneurons in a mouse model of neuronal ceroid lipofuscinosis: evidence for partial response to insulin-like growth factor-1 treatment.

    PubMed

    Cooper, J D; Messer, A; Feng, A K; Chua-Couzens, J; Mobley, W C

    1999-04-01

    The neuronal ceroid lipofuscinoses (NCL) are progressive neurodegenerative disorders with onset from infancy to adulthood that are manifested by blindness, seizures, and dementia. In NCL, lysosomes accumulate autofluorescent proteolipid in the brain and other tissues. The mnd/mnd mutant mouse was first characterized as exhibiting adult-onset upper and lower motor neuron degeneration, but closer examination revealed early, widespread pathology similar to that seen in NCL. We used the autofluorescent properties of accumulated storage material to map which CNS neuronal populations in the mnd/mnd mouse show NCL-like pathological changes. Pronounced, early accumulation of autofluorescent lipopigment was found in subpopulations of GABAergic neurons, including interneurons in the cortex and hippocampus. Staining for phenotypic markers normally present in these neurons revealed progressive loss of staining in the cortex and hippocampus of mnd/mnd mice, with pronounced hypertrophy of remaining detectable interneurons. In contrast, even in aged mutant mice, many hippocampal interneurons retained staining for glutamic acid decarboxylase. Treatment with insulin-like growth factor-1 partially restored interneuronal number and reduced hypertrophy in some subregions. These results provide the first evidence for the involvement of interneurons in a mouse model of NCL. Moreover, our findings suggest that at least some populations of these neurons persist in a growth factor-responsive state.

  15. Progress in the Development of Small Molecule Therapeutics for the Treatment of Neuronal Ceroid Lipofuscinoses (NCLs).

    PubMed

    Kinarivala, Nihar; Trippier, Paul C

    2016-05-26

    The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited and incurable neurodegenerative disorders primarily afflicting the pediatric population. Current treatment regimens offer only symptomatic relief and do not target the underlying cause of the disease. Although the underlying pathophysiology that drives disease progression is unknown, several small molecules have been identified with diverse mechanisms of action that provide promise for the treatment of this devastating disease. This review aims to summarize the current cellular and animal models available for the identification of potential therapeutics and presents the current state of knowledge on small molecule compounds that demonstrate in vitro and/or in vivo efficacy across the NCLs with an emphasis on targets of action.

  16. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders.

    PubMed

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary "myopathic" changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.

  17. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders

    PubMed Central

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary “myopathic” changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions. PMID:26999347

  18. A new simple enzyme assay for pre- and postnatal diagnosis of infantile neuronal ceroid lipofuscinosis (INCL) and its variants

    PubMed Central

    Voznyi, Y; Keulemans, J; Mancini, G; Catsman-Berrevoet..., C; Young, E; Winchester, B; Kleijer, W; van Diggelen, O P

    1999-01-01

    Palmitoyl-protein thioesterase (PPT) deficiency was recently shown to be the primary defect in infantile neuronal ceroid lipofuscinosis (INCL). The available enzyme assay is complicated and impractical for diagnostic use and is, in practice, unavailable. We have developed a new fluorimetric assay for PPT based on the sensitive fluorochrome 4-methylumbelliferone. This PPT assay is simple, sensitive, and robust and will facilitate the definition of the full clinical spectrum associated with a deficiency of PPT. PPT activity was readily detectable in fibroblasts, leucocytes, lymphoblasts, amniotic fluid cells, and chorionic villi, but was profoundly deficient in these tissues from INCL patients. Similarly, a deficiency of PPT was shown in patients with the variant juvenile NCL with GROD. These results show that rapid pre- and postnatal diagnosis can be performed with this new enzyme assay for PPT.


Keywords: infantile neuronal ceroid lipofuscinosis; CLN1; palmitoyl-protein thioesterase; enzyme analysis PMID:10874636

  19. Neuronal ceroid lipofuscinosis in a 31-year-old woman presenting as biventricular heart failure with restrictive features.

    PubMed

    Fealey, Michael E; Edwards, William D; Grogan, Martha; Orszulak, Thomas A

    2009-01-01

    A 31-year-old woman presented with dyspnea and left-sided chest discomfort and was found to have biventricular heart failure with impaired ventricular filling. Clinically, she was thought to have restrictive cardiomyopathy or constrictive pericarditis. Transmission electron microscopy of myocardial tissue unexpectedly revealed crosshatched, curvilinear, and fingerprint depositions, which were characteristic for neuronal ceroid lipofuscinosis. Cardiac involvement by this inherited disorder is discussed in light of the findings in this patient and in 15 other reported cases.

  20. Adult onset motor neuron disease: worldwide mortality, incidence and distribution since 1950.

    PubMed Central

    Chancellor, A M; Warlow, C P

    1992-01-01

    This review examines the commonly held premise that, apart from the Western Pacific forms, motor neuron disease (MND), has a uniform worldwide distribution in space and time; the methodological problems in studies of MND incidence; and directions for future epidemiological research. MND is more common in men at all ages. Age-specific incidence rises steeply into the seventh decade but the incidence in the very elderly is uncertain. A rise in mortality from MND over recent decades has been demonstrated wherever this has been examined and may be real rather than due to improved case ascertainment. Comparison of incidence studies in different places is complicated by non-standardised methods of case ascertainment and diagnosis but there appear to be differences between well studied populations. In developed countries in the northern hemisphere there is a weak positive correlation between standardised, age-specific incidence and distance from the equator. There is now strong evidence for an environmental factor as the cause of the Western Pacific forms of MND. A number of clusters of sporadic MND have been reported from developed countries, but no single agent identified as responsible. Images PMID:1479386

  1. [18F]fluorodopa PET shows striatal dopaminergic dysfunction in juvenile neuronal ceroid lipofuscinosis.

    PubMed Central

    Ruottinen, H M; Rinne, J O; Haaparanta, M; Solin, O; Bergman, J; Oikonen, V J; Järvelä, I; Santavuori, P

    1997-01-01

    OBJECTIVES: To investigate whether nigrostriatal dopaminergic hypofunction is related to the extrapyramidal symptoms in patients with juvenile neuronal ceroid lipofuscinosis (JNCL). METHODS: Nine patients with JNCL and seven healthy controls were studied using [18F]fluorodopa PET. RESULTS: In the patients with JNCL [18F]fluorodopa uptake (K[i][occ]) in the putamen was 60% of the control mean and the corresponding figure in the caudate nucleus was 79%. There was a weak correlation between putamen K(i)(occ) values and extrapyramidal symptoms of the patients evaluated by the motor part of the unified Parkinson's disease rating scale (r = -0.57, P < 0.05). The overall severity of the disease also displayed a negative correlation with the K(i)(occ) values in the putamen (r = -0.71, P < 0.05). CONCLUSION: In patients with JNCL there was reduced striatal [18F]fluorodopa uptake, which had a modest correlation with extrapyramidal symptoms. Dysfunction of nigrostriatal dopaminergic neurons is therefore not the only cause of the patients' extrapyramidal symptoms, but degenerative changes in other brain areas are also contributory. Images PMID:9219750

  2. The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

    PubMed

    Faller, Kiterie M E; Bras, Jose; Sharpe, Samuel J; Anderson, Glenn W; Darwent, Lee; Kun-Rodrigues, Celia; Alroy, Joseph; Penderis, Jacques; Mole, Sara E; Gutierrez-Quintana, Rodrigo; Guerreiro, Rita J

    2016-04-01

    Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease.

  3. Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis.

    PubMed

    Pike, L S; Tannous, B A; Deliolanis, N C; Hsich, G; Morse, D; Tung, C-H; Sena-Esteves, M; Breakefield, X O

    2011-12-01

    Adeno-associated virus (AAV)-mediated gene replacement for lysosomal disorders have been spurred by the ability of some serotypes to efficiently transduce neurons in the brain and by the ability of lysosomal enzymes to cross-correct among cells. Here, we explored enzyme replacement therapy in a knock-out mouse model of congenital neuronal ceroid lipofuscinosis (NCL), the most severe of the NCLs in humans. The missing protease in this disorder, cathepsin D (CathD) has high levels in the central nervous system. This enzyme has the potential advantage for assessing experimental therapy in that it can be imaged using a near-infrared fluorescence (NIRF) probe activated by CathD. Injections of an AAV2/rh8 vector-encoding mouse CathD (mCathD) into both cerebral ventricles and peritoneum of newborn knock-out mice resulted in a significant increase in lifespan. Successful delivery of active CathD by the AAV2/rh8-mCathD vector was verified by NIRF imaging of mouse embryonic fibroblasts from knock-out mice in culture, as well as by ex vivo NIRF imaging of the brain and liver after gene transfer. These studies support the potential effectiveness and imaging evaluation of enzyme replacement therapy to the brain and other organs in CathD null mice via AAV-mediated gene delivery in neonatal animals.

  4. Granulin Knock Out Zebrafish Lack Frontotemporal Lobar Degeneration and Neuronal Ceroid Lipofuscinosis Pathology

    PubMed Central

    Solchenberger, Barbara; Russell, Claire; Kremmer, Elisabeth; Haass, Christian; Schmid, Bettina

    2015-01-01

    Loss of function mutations in granulin (GRN) are linked to two distinct neurological disorders, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). It is so far unknown how a complete loss of GRN in NCL and partial loss of GRN in FTLD can result in such distinct diseases. In zebrafish, there are two GRN homologues, Granulin A (Grna) and Granulin B (Grnb). We have generated stable Grna and Grnb loss of function zebrafish mutants by zinc finger nuclease mediated genome editing. Surprisingly, the grna and grnb single and double mutants display neither spinal motor neuron axonopathies nor a reduced number of myogenic progenitor cells as previously reported for Grna and Grnb knock down embryos. Additionally, grna−/−;grnb−/− double mutants have no obvious FTLD- and NCL-related biochemical and neuropathological phenotypes. Taken together, the Grna and Grnb single and double knock out zebrafish lack any obvious morphological, pathological and biochemical phenotypes. Loss of zebrafish Grna and Grnb might therefore either be fully compensated or only become symptomatic upon additional challenge. PMID:25785851

  5. Evidence for aberrant astrocyte hemichannel activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL).

    PubMed

    Burkovetskaya, Maria; Karpuk, Nikolay; Xiong, Juan; Bosch, Megan; Boska, Michael D; Takeuchi, Hideyuki; Suzumura, Akio; Kielian, Tammy

    2014-01-01

    Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in

  6. Neuronal ceroid lipofuscinosis: late infantile or Jansky Bielschowsky type--re-revisited.

    PubMed

    Wheeler, R B; Schlie, M; Kominami, E; Gerhard, L; Goebel, H H

    2001-11-01

    Among the now eight genetic types of neuronal ceroid-lipofuscinoses (NCL), CLN1 to CLN8, CLN2 is considered classic late-infantile NCL. It was originally described by Jansky in a family of eight children with four of them affected [Jansky J (1908) Sborn Lék 13:165-196] and, subsequently, by Bielschowsky in a family of three children each of whom was affected, and, hence, termed Jansky-Bielschowsky type of NCL. Earlier, archival studies of Bielschowsky's original post-mortem tissue blocks had documented accumulation of autofluorescent lipopigments with a curvilinear ultrastructure. In a subsequent study, described here, immunohistochemical absence of the CLN2-related lysosomal enzyme tripeptidyl peptidase-I and two heterozygous mutations in the CLN2 gene could be demonstrated in these archival tissues, further corroborating the identity of Bielschowsky's familial disorder and CLN2 described by M. Bielschowsky at the beginning of the last century. Furthermore, these immunohistochemical and mutational investigations underscore the value of archival tissue studies.

  7. Localization of juvenile, but not late-infantile, neuronal ceroid lipofuscinosis on chromosome 16

    SciTech Connect

    Wenliang Yan; Ozelius, L.; Breakefield, X.O.; Gusella, J.F. Harvard Medical School, Boston, MA ); Boustany, R.M.N. ); Konradi, C.; Lerner, T.; Trofatter, J.A.; Haines, J.L. ); Julier, C. )

    1993-01-01

    The neuronal ceroid lipofuscinoses (NCL) are a group of progressive neurodegenerative disorders characterized by the deposition of autofluorescent proteinaceous fingerprint or curvilinear bodies. The authors have found that CLN3, the gene underlying the juvenile form of NCL, is very tightly linked to the dinucleotide repeat marker D16S285 on chromosome 16. Integration of D16S285 into the genetic map of chromosome 16 by using the Centre d'Etude du Polymorphisme Humain panel of reference pedigrees yielded a favored marker order in the CLN3 region of qtel-D16S150-.08-D16S285-.04-D16S148-.02-D16S67-ptel. The most likely location of the disease gene, near D16S285 in the D16S150-D16S148 interval, was favored by odds of greater than 10[sup 4]:1 over the adjacent D16S148-D16S67 interval, which was recently reported as the minimum candidate region. Analysis of D16S285 in pedigrees with late-infantile NCL virtually excluded the CLN3 region, suggesting that these two forms of NCL are genetically distinct. 23 refs., 3 figs., 2 tabs.

  8. A Case-controlled Investigation of Pain Experience and Sensory Function in Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Barney, Chantel C.; Hoch, John; Byiers, Breanne; Dimian, Adele; Symons, Frank J.

    2014-01-01

    Objectives This case-control study explored pain experience and expression among individuals with Neuronal Ceroid Lipofuscinosis (NCL) through parental report, tactile-sensory testing, and infrared thermography (IRT). Methods Individuals with NCL (n=8; M age= 14.8 years) and their unaffected siblings (n=8;M age 23.5 years) were characterized in terms of pain response to a brief tactile sensory test (light touch, Von Frey monofilament). During sensory testing, behavioral expression was measured using the Battens Observational Pain Scale (BOPS) and infrared thermography (IRT) was used to quantify changes in skin/eye temperature. Results Individuals with NCL experienced pain frequently and from multiple sources that negatively impacted their lives. Individuals with NCL were reactive to the sensory testing as indexed by significant increased IRT temperature change (p<.001). Across combined sensory conditions, individuals with NCL were significantly more reactive (BOPS total score) to sensory testing compared to siblings (p< .05). Similarly, IRT difference scores between sensory conditions revealed a significant increase in temperature for individuals with NCL compared to siblings (p<.001). Discussion Ongoing reported pain was a problem for the individuals with NCL in this sample. Increased pain expression during the repeated Von Frey filament suggests that the pathophysiology of the ongoing pain may be centrally mediated. PMID:25569218

  9. Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis.

    PubMed

    Teixeira, Carla A; Espinola, Janice; Huo, Liang; Kohlschütter, Johannes; Persaud Sawin, Dixie-Ann; Minassian, Berge; Bessa, Carlos J P; Guimarães, A; Stephan, Dietrich A; Sá Miranda, Maria Clara; MacDonald, Marcy E; Ribeiro, Maria Gil; Boustany, Rose-Mary N

    2003-05-01

    The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of autosomal recessive neurodegenerative diseases comprising Batten and other related diseases plus numerous variants. They are characterized by progressive neuronal cell death. The CLN6 gene was recently identified, mutations in which cause one of the variant late infantile forms of NCL (vLINCL). We describe four novel mutations in the CLN6 gene. This brings the total number of CLN6 mutations known to 11 in 38 families. This suggests that the CLN6 gene may be highly mutable. An American patient of Irish/French/Native American origin was heterozygous for a 4-bp insertion (c.267_268insAACG) in exon 3. The other allele had a point mutation (c.898T>C) in exon 7 resulting in a W300R amino acid change. Two Trinidadian siblings of Indian origin were homozygous for a mutation at the 5' donor splice site of exon 4 (IVS4+1G>T), affecting the first base of the invariant GT at the beginning of intron 4. The fourth novel mutation, a double deletion of 4 bp and 1 bp in exon 7 (c.829_832delGTCG;c.837delG), was identified in a Portuguese patient heterozygous for the I154del Portuguese CLN6 mutation. Four of the 11 mutations identified are in exon 4. Three Portuguese patients with clinical profiles similar to CLN6 patients without defects in CLN6 or other known NCL genes are described. We conclude the following: 1) the CLN6 gene may be a highly mutable gene; 2) exon 4 must code for a segment of the protein crucial for function; 3) vLINCL disease in Portugal is genetically heterogeneous; 4) the I154del accounts for 81.25% of affected CLN6 Portuguese alleles; and 5) three vLINCL Portuguese patients may have defects in a new NCL gene.

  10. A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System

    PubMed Central

    Staropoli, John F.; Karaa, Amel; Lim, Elaine T.; Kirby, Andrew; Elbalalesy, Naser; Romansky, Stephen G.; Leydiker, Karen B.; Coppel, Scott H.; Barone, Rosemary; Xin, Winnie; MacDonald, Marcy E.; Abdenur, Jose E.; Daly, Mark J.; Sims, Katherine B.; Cotman, Susan L.

    2012-01-01

    Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14. PMID:22748208

  11. The novel Cln1R151X mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy

    PubMed Central

    Miller, Jake N.; Kovács, Attila D.; Pearce, David A.

    2015-01-01

    The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive neurodegenerative disorders in children characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. Patients with mutations in CLN1 primarily manifest with infantile NCL (INCL or Haltia-Santavuori disease), which is second only to congenital NCL for its age of onset and devastating progression. CLN1 encodes a lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1). Nonsense mutations in CLN1 account for 52.3% of all disease causing alleles in infantile NCL, the most common of which worldwide is the p.R151X mutation. Previously, we have shown how nonsense-mediated decay is involved in the degradation of CLN1 mRNA transcripts containing the p.R151X mutation in human lymphoblast cell lines. We have also shown how the read-through drugs gentamicin and ataluren (PTC124) increase CLN1 (PPT1) enzyme activity. Here, we provide the initial characterization of the novel Cln1R151X mouse model of infantile neuronal ceroid lipofuscinosis that we have generated. This nonsense mutation model recapitulates the molecular, histological and behavioral phenotypes of the human disease. Cln1R151X mice showed a significant decrease in Cln1 mRNA level and PPT1 enzyme activity, accumulation of autofluorescent storage material, astrocytosis and microglial activation in the brain. Behavioral characterization of Cln1R151X mice at 3 and 5 months of age revealed significant motor deficits as measured by the vertical pole and rotarod tests. We also show how the read-through compound ataluren (PTC124) increases PPT1 enzyme activity and protein level in Cln1R151X mice in a proof-of-principle study. PMID:25205113

  12. Tandem Mass Spectrometry Assays of Palmitoyl Protein Thioesterase 1 and Tripeptidyl Peptidase Activity in Dried Blood Spots for the Detection of Neuronal Ceroid Lipofuscinoses in Newborns

    PubMed Central

    2015-01-01

    We report new substrates for quantitative enzyme activity measurements of human palmitoyl protein thioesterase (PPT1) and tripeptidyl peptidase (TPP1) in dried blood spots from newborns using tandem mass spectrometry. Deficiencies in these enzyme activities due to inborn errors of metabolism cause neuronal ceroid lipofuscinoses. The assays use synthetic compounds that were designed to mimic the natural substrates. Incubation produces nanomole quantities of enzymatic products per a blood spot that are quantified by tandem mass spectrometry using synthetic internal standards and selected reaction monitoring. The assays utilize a minimum steps for sample workup and can be run in a duplex format for the detection of neuronal ceroid lipofuscinoses or potentially multiplexed with other mass spectrometry-based assays for newborn screening of lysosomal storage disorders. PMID:25019629

  13. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.

    PubMed

    Arnold, Eveline S; Ling, Shuo-Chien; Huelga, Stephanie C; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B; McAlonis-Downes, Melissa; Platoshyn, Oleksandr; Parone, Philippe A; Da Cruz, Sandrine; Clutario, Kevin M; Swing, Debbie; Tessarollo, Lino; Marsala, Martin; Shaw, Christopher E; Yeo, Gene W; Cleveland, Don W

    2013-02-19

    Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.

  14. A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis.

    PubMed

    Abitbol, Marie; Thibaud, Jean-Laurent; Olby, Natasha J; Hitte, Christophe; Puech, Jean-Philippe; Maurer, Marie; Pilot-Storck, Fanny; Hédan, Benoit; Dréano, Stéphane; Brahimi, Sandra; Delattre, Delphine; André, Catherine; Gray, Françoise; Delisle, Françoise; Caillaud, Catherine; Bernex, Florence; Panthier, Jean-Jacques; Aubin-Houzelstein, Geneviève; Blot, Stéphane; Tiret, Laurent

    2010-08-17

    Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.

  15. Adult onset retinoblastoma

    PubMed Central

    Sengupta, Sabyasachi; Pan, Utsab; Khetan, Vikas

    2016-01-01

    Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes. PMID:27609158

  16. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

    PubMed Central

    Arnold, Eveline S.; Ling, Shuo-Chien; Huelga, Stephanie C.; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B.; McAlonis-Downes, Melissa; Platoshyn, Oleksandr; Parone, Philippe A.; Da Cruz, Sandrine; Clutario, Kevin M.; Swing, Debbie; Tessarollo, Lino; Marsala, Martin; Shaw, Christopher E.; Yeo, Gene W.; Cleveland, Don W.

    2013-01-01

    Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43Q331K and TDP-43M337V), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43–dependent alternative splicing events conferred by both human wild-type and mutant TDP-43Q331K, but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43Q331K enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage. PMID:23382207

  17. Refined assignment of the infantile neuronal ceroid lipofuscinosis (INCL, CLN1) locus at 1p32: Incorporation of linkage disequilibrium in multipoint analysis

    SciTech Connect

    Hellsten, E.; Vesa, J.; Peltonen, L.; Jaervela, I. ); Speer, M.C.; Ott, J. New York State Psychiatric Institute, New York ); Maekelae, T.P.; Alitalo, K. )

    1993-06-01

    Infantile neuronal ceroid lipofuscinosis, INCL, CLN1, is an autosomally inherited progressive neuro-generative disorder. The disease results in the massive death of cortical neurons, suggesting an essential role for the CLN1 gene product in the normal neuronal maturation during the first years of life. Identification of new multiallelic markers has now made possible the construction of a refined genetic map encompassing the CLN1 locus at 1p32. Strong allelic association was detected with a new, highly polymorphic HY-TM1 marker. The authors incorporated this observed linkage disequilibrium into multipoint linkage analysis, which significantly increased the informativeness of the limited family material and facilitated refined assignment of the CLN1 locus. 23 refs., 2 figs., 4 tabs.

  18. The neuronal ceroid lipofuscinosis Cln8 gene expression is developmentally regulated in mouse brain and up-regulated in the hippocampal kindling model of epilepsy

    PubMed Central

    Lonka, Liina; Aalto, Antti; Kopra, Outi; Kuronen, Mervi; Kokaia, Zaal; Saarma, Mart; Lehesjoki, Anna-Elina

    2005-01-01

    Background The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by accumulation of autofluorescent material in many tissues, especially in neurons. Mutations in the CLN8 gene, encoding an endoplasmic reticulum (ER) transmembrane protein of unknown function, underlie NCL phenotypes in humans and mice. The human phenotype is characterized by epilepsy, progressive psychomotor deterioration and visual loss, while motor neuron degeneration (mnd) mice with a Cln8 mutation show progressive motor neuron dysfunction and retinal degeneration. Results We investigated spatial and temporal expression of Cln8 messenger ribonucleic acid (mRNA) using in situ hybridization, reverse transcriptase polymerase chain reaction (RT-PCR) and northern blotting. Cln8 is ubiquitously expressed at low levels in embryonic and adult tissues. In prenatal embryos Cln8 is most prominently expressed in the developing gastrointestinal tract, dorsal root ganglia (DRG) and brain. In postnatal brain the highest expression is in the cortex and hippocampus. Expression of Cln8 mRNA in the central nervous system (CNS) was also analyzed in the hippocampal electrical kindling model of epilepsy, in which Cln8 expression was rapidly up-regulated in hippocampal pyramidal and granular neurons. Conclusion Expression of Cln8 in the developing and mature brain suggests roles for Cln8 in maturation, differentiation and supporting the survival of different neuronal populations. The relevance of Cln8 up-regulation in hippocampal neurons of kindled mice should be further explored. PMID:15826318

  19. Novel rapid genotyping assays for neuronal ceroid lipofuscinosis in Border Collie dogs and high frequency of the mutant allele in Japan.

    PubMed

    Mizukami, Keijiro; Chang, Hye-Sook; Yabuki, Akira; Kawamichi, Takuji; Kawahara, Natsuko; Hayashi, Daisuke; Hossain, Mohammad A; Rahman, Mohammad M; Uddin, Mohammad M; Yamato, Osamu

    2011-11-01

    Neuronal ceroid lipofuscinosis (NCL) constitutes a group of recessively inherited lysosomal storage diseases that primarily affect neuronal cells. Such diseases share certain clinical and pathologic features in human beings and animals. Neuronal ceroid lipofuscinosis in Border Collie dogs was first detected in Australia in the 1980s, and the pathogenic mutation was shown to be a nonsense mutation (c.619C>T) in exon 4 in canine CLN5 gene. In the present study, novel rapid genotyping assays including polymerase chain reaction (PCR)-restriction fragment length polymorphism, PCR primer-induced restriction analysis, mutagenically separated PCR, and real-time PCR with TaqMan minor groove binder probes, were developed. The utility of microchip electrophoresis was also evaluated. Furthermore, a genotyping survey was carried out in a population of Border Collies in Japan using these assays to determine the current allele frequency in Japan, providing information to control and prevent this disease in the next stage. All assays developed in the current study are available to discriminate these genotypes, and microchip electrophoresis showed a timesaving advantage over agarose gel electrophoresis. Of all assays, real-time PCR was the most suitable for large-scale examination because of its high throughput. The genotyping survey demonstrated that the carrier frequency was 8.1%. This finding suggested that the mutant allele frequency of NCL in Border Collies is high enough in Japan that measures to control and prevent the disease would be warranted. The genotyping assays developed in the present study could contribute to the prevention of NCL in Border Collies.

  20. Adult-onset Atopic Dermatitis

    PubMed Central

    Kanwar, Amrinder Jit

    2016-01-01

    Adult-onset atopic dermatitis is still an under recognized condition as there are only few studies regarding this entity. As compared to childhood onset atopic dermatitis, clinical features of adult onset atopic dermatitis are still not categorized. Adult atopic dermatitis can present for the first time in adult age with atypical morphology or may progress from childhood onset. This article reviews the characteristic clinical features of adult atopic dermatitis, associated risk factors and management. PMID:27904186

  1. The Scottish Motor Neuron Disease Register: a prospective study of adult onset motor neuron disease in Scotland. Methodology, demography and clinical features of incident cases in 1989.

    PubMed Central

    1992-01-01

    The Scottish Motor Neuron Disease Register (SMNDR) is a prospective, collaborative, population based study of motor neuron disease (MND) in Scotland. The register started in January 1989 with the aim of studying the clinical and epidemiological features of MND by prospectively identifying incident patients. It is based on a system of registration by recruitment from multiple sources, followed by the collection of complete clinical data and follow up, mainly through general practitioners. In this report the register's methodology and the demography and incidence data for the first year of study are presented. One hundred and fourteen newly diagnosed patients were identified in 1989 giving a crude incidence for Scotland of 2.24/100,000/year. Standardised incidence ratios showed a non-significant trend towards lower rates in north eastern regions and island areas. PMID:1640227

  2. Neuronal ceroid lipofuscinoses (NCL)

    MedlinePlus

    ... blindness (with the early-onset forms of the disease) Mental impairment, ranging from severe developmental delays at birth to dementia later in life Rigid muscles (due to severe problems with ... totally dependent on others for help with daily activities.

  3. Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.

    PubMed

    Katz, M L; Johnson, G C; Leach, S B; Williamson, B G; Coates, J R; Whiting, R E H; Vansteenkiste, D P; Whitney, M S

    2017-02-02

    CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.Gene Therapy advance online publication, 2 February 2017; doi:10.1038/gt.2017.4.

  4. Neuronal ceroid lipofuscinosis in Devon cattle is caused by a single base duplication (c.662dupG) in the bovine CLN5 gene.

    PubMed

    Houweling, Peter J; Cavanagh, Julie A L; Palmer, David N; Frugier, Tony; Mitchell, Nadia L; Windsor, Peter A; Raadsma, Herman W; Tammen, Imke

    2006-10-01

    The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are recessively inherited neurodegenerative disorders that affect humans and other animals, characterised by brain atrophy and the accumulation of lysosome derived fluorescent storage bodies in neurons and most other cells. Common clinical signs include blindness, ataxia, dementia, seizures and premature death. The associated genes for six different human forms have been identified (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8), and three other human forms suggested (CLNs 4, 7 and 9). A form of NCL in Australian Devon cattle is caused by a single base duplication (c.662dupG) in bovine CLN5. This mutation causes a frame-shift and premature termination (p.Arg221GlyfsX6) which is predicted to result in a severely truncated protein, analogous to disease causing mutations in human Finnish late infantile variant NCL (CLN5), and a simple genetic diagnostic test has been developed. The symptoms and disease course in cattle also matches CLN5. Only one initiation site was found in the bovine gene, equivalent to the third of four possible initiation sites in the human gene. As cattle are anatomically and physiologically similar to humans with a human-like central nervous system and easy to maintain and breed, they provide a valuable alternative model for CLN5 studies.

  5. Adult-onset deficiency in growth hormone and insulin-like growth factor-I decreases survival of dentate granule neurons: insights into the regulation of adult hippocampal neurogenesis.

    PubMed

    Lichtenwalner, Robin J; Forbes, M Elizabeth; Sonntag, William E; Riddle, David R

    2006-02-01

    Insulin-like growth factor-I (IGF-I), long thought to provide critical trophic support during development, also has emerged as a candidate for regulating ongoing neuronal production in adulthood. Whether and how IGF-I influences each phase of neurogenesis, however, remains unclear. In the current study, we used a selective model of growth hormone (GH) and plasma IGF-I deficiency to evaluate the role of GH and IGF-I in regulating cell proliferation, survival, and neuronal differentiation in the adult dentate gyrus. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete throughout development via twice daily injections of GH, and then GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Bromodeoxyuridine (BrdU) labeling revealed no effect of GH/IGF-I deficiency on cell proliferation, but adult-onset depletion of GH and plasma IGF-I significantly reduced the survival of newly generated cells in the dentate gyrus. Colabeling for BrdU and markers of immature and mature neurons revealed a selective effect of GH/IGF-I deficiency on the survival of more mature new neurons. The number of BrdU-labeled cells expressing the immature neuronal marker TUC-4 did not differ between GH/IGF-I-deficient and -replete animals, but the number expressing only the marker of maturity NeuN was lower in depleted animals. Taken together, results from the present study suggest that, under conditions of short-term GH/IGF-I deficiency during adulthood, dentate granule cells continue to be produced, to commit to a neuronal fate, and to begin the process of neuronal maturation, whereas survival of the new neurons is impaired.

  6. Adult-onset food allergy.

    PubMed

    Kivity, Shmuel

    2012-01-01

    The prevalence of food allergy is increasing in both the pediatric and adult populations. While symptom onset occurs mostly during childhood, there are a considerable number of patients whose symptoms first begin to appear after the age of 18 years. The majority of patients with adult-onset food allergy suffer from the pollen-plant allergy syndromes. Many of them manifest their allergy after exercise and consuming food to which they are allergic. Eosinophilic esophagitis, an eosinophilic inflammation of the esophagus affecting individuals of all ages, recently emerged as another allergic manifestation, with both immediate and late response to the ingested food. This review provides a condensed update of the current data in the literature on adult-onset allergy.

  7. Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis but is not a component of the storage material

    PubMed Central

    XU, Su; SLEAT, David E.; JADOT, Michel; LOBEL, Peter

    2010-01-01

    Classical late neuronal ceroid lipofuscinosis (LINCL) is a fatal neurodegenerative disease of children caused by mutations in TPP1, the gene encoding the lysosomal protease tripeptidyl peptidase 1. LINCL is characterized by lysosomal accumulation of storage material of which only a single protein component, subunit c of mitochondrial ATP synthase, has been well established to date. Identification of other protein constituents of the storage material could provide useful insights into the pathophysiology of disease and the natural substrates for TPP1. We have therefore initiated a proteomic analysis of storage material in brain from a LINCL mouse model. One protein, glial fibrillary acidic protein (GFAP), was found to be elevated in the LINCL mice compared to normal controls in both isolated storage bodies and a lysosome-enriched subcellular fraction that contains storage material. To determine whether GFAP accumulates within the lysosome in LINCL, we examined its intracellular distribution using subcellular fractionation and morphological methods. These experiments demonstrate that GFAP is not a component of the storage material in LINCL, suggesting that reports of GFAP storage in other NCLs may need to be reexamined. A number of other proteins were elevated in the storage material and/or lysosome-enriched fraction from the LINCL mice but it remains unclear whether these proteins are true constituents of the storage material or, like GFAP, if they associate with this material upon purification. PMID:20370715

  8. Partial genetic suppression of a loss-of-function mutant of the neuronal ceroid lipofuscinosis-associated protease TPP1 in Dictyostelium discoideum.

    PubMed

    Phillips, Jonathan E; Gomer, Richard H

    2015-02-01

    Neuronal ceroid lipofuscinosis (NCL) is the most common childhood-onset neurodegenerative disease. NCL is inevitably fatal, and there is currently no treatment available. Children with NCL show a progressive decline in movement, vision and mental abilities, and an accumulation of autofluorescent deposits in neurons and other cell types. Late-infantile NCL is caused by mutations in the lysosomal protease tripeptidyl peptidase 1 (TPP1). TPP1 cleaves tripeptides from the N-terminus of proteins in vitro, but little is known about the physiological function of TPP1. TPP1 shows wide conservation in vertebrates but it is not found in Drosophila, Caenorhabditis elegans or Saccharomyces cerevisiae. Here, we characterize ddTpp1, a TPP1 ortholog present in the social amoeba Dictyostelium discoideum. Lysates from cells lacking ddTpp1 show a reduced but not abolished ability to cleave a TPP1 substrate, suggesting that other Dictyostelium enzymes can perform this cleavage. ddTpp1 and human TPP1 localize to the lysosome in Dictyostelium, indicating conserved function and trafficking. Cells that lack ddTpp1 show precocious multicellular development and a reduced ability to form spores during development. When cultured in autophagy-stimulating conditions, cells lacking ddTpp1 rapidly decrease in size and are less viable than wild-type cells, suggesting that one function of ddTpp1 could be to limit autophagy. Cells that lack ddTpp1 exhibit strongly impaired development in the presence of the lysosome-perturbing drug chloroquine, and this phenotype can be suppressed through a secondary mutation in the gene that we name suppressor of tpp1(-) A (stpA), which encodes a protein with some similarity to mammalian oxysterol-binding proteins (OSBPs). Taken together, these results suggest that targeting specific proteins could be a viable way to suppress the effects of loss of TPP1 function.

  9. Adult-onset mitochondrial myopathy.

    PubMed Central

    Fernandez-Sola, J.; Casademont, J.; Grau, J. M.; Graus, F.; Cardellach, F.; Pedrol, E.; Urbano-Marquez, A.

    1992-01-01

    Mitochondrial diseases are polymorphic entities which may affect many organs and systems. Skeletal muscle involvement is frequent in the context of systemic mitochondrial disease, but adult-onset pure mitochondrial myopathy appears to be rare. We report 3 patients with progressive skeletal mitochondrial myopathy starting in adult age. In all cases, the proximal myopathy was the only clinical feature. Mitochondrial pathology was confirmed by evidence of ragged-red fibres in muscle histochemistry, an abnormal mitochondrial morphology in electron microscopy and by exclusion of other underlying diseases. No deletions of mitochondrial DNA were found. We emphasize the need to look for a mitochondrial disorder in some non-specific myopathies starting in adult life. Images Figure 1 Figure 2 PMID:1589382

  10. Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of Cln3Δex1-6 mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)

    PubMed Central

    Wavre-Shapton, Silène T.; Calvi, Alessandra A.; Turmaine, Mark; Seabra, Miguel C.; Cutler, Daniel F.; Futter, Clare E.; Mitchison, Hannah M.

    2015-01-01

    Retinal degeneration and visual impairment are the first signs of juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations, followed by inevitable progression to blindness. We investigated retinal degeneration in Cln3Δex1-6 null mice, revealing classic ‘fingerprint’ lysosomal storage in the retinal pigment epithelium (RPE), replicating the human disease. The lysosomes contain mitochondrial F0-ATP synthase subunit c along with undigested membranes, indicating a reduced degradative capacity. Mature autophagosomes and basal phagolysosomes, the terminal degradative compartments of autophagy and phagocytosis, are also increased in Cln3Δex1-6 RPE, reflecting disruption to these key pathways that underpin the daily phagocytic turnover of photoreceptor outer segments (POS) required for maintenance of vision. The accumulated autophagosomes have post-lysosome fusion morphology, with undigested internal contents visible, while accumulated phagosomes are frequently docked to cathepsin D-positive lysosomes, without mixing of phagosomal and lysosomal contents. This suggests lysosome-processing defects affect both autophagy and phagocytosis, supported by evidence that phagosomes induced in Cln3Δex1-6-derived mouse embryonic fibroblasts have visibly disorganized membranes, unprocessed internal vesicles and membrane contents, in addition to reduced LAMP1 membrane recruitment. We propose that defective lysosomes in Cln3Δex1-6 RPE have a reduced degradative capacity that impairs the final steps of the intimately connected autophagic and phagocytic pathways that are responsible for degradation of POS. A build-up of degradative organellar by-products and decreased recycling of cellular materials is likely to disrupt processes vital to maintenance of vision by the RPE. PMID:26450516

  11. Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America

    PubMed Central

    Kohan, Romina; Noelia Carabelos, María; Xin, Winnie; Sims, Katherine; Guelbert, Norberto; Adriana Cismondi, Inés; Pons, Patricia; Alonso, Graciela Irene; Troncoso, Mónica; Witting, Scarlet; Pearce, David A.; de Kremer, Raquel Dodelson; Oller-Ramírez, Ana María; de Halac, Inés Noher

    2013-01-01

    Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60–15.85 nmol/h/mg (nr 110–476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887-10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at nonconserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity. PMID:23266810

  12. Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis

    PubMed Central

    Fossale, Elisa; Wolf, Pavlina; Espinola, Janice A; Lubicz-Nawrocka, Tanya; Teed, Allison M; Gao, Hanlin; Rigamonti, Dorotea; Cattaneo, Elena; MacDonald, Marcy E; Cotman, Susan L

    2004-01-01

    Background JNCL is a recessively inherited, childhood-onset neurodegenerative disease most-commonly caused by a ~1 kb CLN3 mutation. The resulting loss of battenin activity leads to deposition of mitochondrial ATP synthase, subunit c and a specific loss of CNS neurons. We previously generated Cln3Δex7/8 knock-in mice, which replicate the common JNCL mutation, express mutant battenin and display JNCL-like pathology. Results To elucidate the consequences of the common JNCL mutation in neuronal cells, we used P4 knock-in mouse cerebella to establish conditionally immortalized CbCln3 wild-type, heterozygous, and homozygous neuronal precursor cell lines, which can be differentiated into MAP-2 and NeuN-positive, neuron-like cells. Homozygous CbCln3Δex7/8 precursor cells express low levels of mutant battenin and, when aged at confluency, accumulate ATPase subunit c. Recessive phenotypes are also observed at sub-confluent growth; cathepsin D transport and processing are altered, although enzyme activity is not significantly affected, lysosomal size and distribution are altered, and endocytosis is reduced. In addition, mitochondria are abnormally elongated, cellular ATP levels are decreased, and survival following oxidative stress is reduced. Conclusions These findings reveal that battenin is required for intracellular membrane trafficking and mitochondrial function. Moreover, these deficiencies are likely to be early events in the JNCL disease process and may particularly impact neuronal survival. PMID:15588329

  13. A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry.

    PubMed

    Guo, Juyuan; Johnson, Gary S; Brown, Holly A; Provencher, Michele L; da Costa, Ronaldo C; Mhlanga-Mutangadura, Tendai; Taylor, Jeremy F; Schnabel, Robert D; O'Brien, Dennis P; Katz, Martin L

    2014-08-01

    The neuronal ceroid lipofuscinoses (NCLs) are hereditary neurodegenerative diseases characterized by seizures and progressive cognitive decline, motor impairment, and vision loss accompanied by accumulation of autofluorescent lysosomal storage bodies in the central nervous system and elsewhere in the body. Mutations in at least 14 genes underlie the various forms of NCL. One of these genes, CLN8, encodes an intrinsic membrane protein of unknown function that appears to be localized primarily to the endoplasmic reticulum. Most CLN8 mutations in people result in a form of NCL with a late infantile onset and relatively rapid progression. A mixed breed dog with Australian Shepherd and Blue Heeler ancestry developed neurological signs characteristic of NCL starting at about 8months of age. The signs became progressively worse and the dog was euthanized at 21months of age due to seizures of increasing frequency and severity. Postmortem examination of the brain and retinas identified massive accumulations of intracellular autofluorescent inclusions characteristic of the NCLs. Whole genome sequencing of DNA from this dog identified a CLN8:c.585G>A transition that predicts a CLN8:p.Trp195* nonsense mutation. This mutation appears to be rare in both ancestral breeds. All of our 133 archived DNA samples from Blue Heelers, and 1481 of our 1488 archived Australian Shepherd DNA samples tested homozygous for the reference CLN8:c.585G allele. Four of the Australian Shepherd samples tested heterozygous and 3 tested homozygous for the mutant CLN8:c.585A allele. All 3 dogs homozygous for the A allele exhibited clinical signs of NCL and in 2 of them NCL was confirmed by postmortem evaluation of brain tissue. The occurrence of confirmed NCL in 3 of 4 CLN8:c.585A homozygous dogs, plus the occurrence of clinical signs consistent with NCL in the fourth homozygote strongly suggests that this rare truncating mutation causes NCL. Identification of this NCL-causing mutation provides the

  14. Association between CLN3 (Neuronal Ceroid Lipofuscinosis, CLN3 Type) Gene Expression and Clinical Characteristics of Breast Cancer Patients.

    PubMed

    Makoukji, Joelle; Raad, Mohamad; Genadry, Katia; El-Sitt, Sally; Makhoul, Nadine J; Saad Aldin, Ehab; Nohra, Eden; Jabbour, Mark; Sangaralingam, Ajanthah; Chelala, Claude; Habib, Robert H; Boulos, Fouad; Tfayli, Arafat; Boustany, Rose-Mary

    2015-01-01

    Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines. Here, we determine CLN3 expression in non-tumor vs. tumor samples from fresh and formalin-fixed/paraffin-embedded (FFPE) breast tissue and analyze the association between CLN3 overexpression and different clinicopathological characteristics of breast cancer patients. Additionally, gene expression of 28 enzymes involved in sphingolipid metabolism was determined. CLN3 mRNA is overexpressed in tumor vs. non-tumor breast tissue from FFPE and fresh samples, as well as in mouse MCF7 breast cancer compared to MCF10A normal cells. Of the clinicopathological characteristics of tumor grade, age, menopause status, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), only absence of HER2 expression correlated with CLN3 overexpression. Sphingolipid genes for ceramide synthases 2 and 6 (CerS2; CerS6), delta(4)-desaturase sphingolipid 2 (DEGS2), and acidic sphingomyelinase (SMPD1) displayed higher expression levels in breast cancer vs. control tissue, whereas ceramide galactosyltransferase (UGT8) was underexpressed in breast cancer samples. CLN3 may be a novel molecular target for cancer drug discovery with the goal of modulation of ceramide pathways.

  15. Association between CLN3 (Neuronal Ceroid Lipofuscinosis, CLN3 Type) Gene Expression and Clinical Characteristics of Breast Cancer Patients

    PubMed Central

    Makoukji, Joelle; Raad, Mohamad; Genadry, Katia; El-Sitt, Sally; Makhoul, Nadine J.; Saad Aldin, Ehab; Nohra, Eden; Jabbour, Mark; Sangaralingam, Ajanthah; Chelala, Claude; Habib, Robert H.; Boulos, Fouad; Tfayli, Arafat; Boustany, Rose-Mary

    2015-01-01

    Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines. Here, we determine CLN3 expression in non-tumor vs. tumor samples from fresh and formalin-fixed/paraffin-embedded (FFPE) breast tissue and analyze the association between CLN3 overexpression and different clinicopathological characteristics of breast cancer patients. Additionally, gene expression of 28 enzymes involved in sphingolipid metabolism was determined. CLN3 mRNA is overexpressed in tumor vs. non-tumor breast tissue from FFPE and fresh samples, as well as in mouse MCF7 breast cancer compared to MCF10A normal cells. Of the clinicopathological characteristics of tumor grade, age, menopause status, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), only absence of HER2 expression correlated with CLN3 overexpression. Sphingolipid genes for ceramide synthases 2 and 6 (CerS2; CerS6), delta(4)-desaturase sphingolipid 2 (DEGS2), and acidic sphingomyelinase (SMPD1) displayed higher expression levels in breast cancer vs. control tissue, whereas ceramide galactosyltransferase (UGT8) was underexpressed in breast cancer samples. CLN3 may be a novel molecular target for cancer drug discovery with the goal of modulation of ceramide pathways. PMID:26528430

  16. Ceroid in fish

    USGS Publications Warehouse

    Wood, E.M.; Yasutake, W.T.

    1956-01-01

    Since the original description of ceroid in rats, many papers have appeared on the etiology and characteristics of this pigment. It was first seen as a yellow, granular pigment in hematoxylin and eosin sections of the cirrhotic livers of choline deficient rats. The pigment was more fully characterized by Endicott and Lillie, and additional stainging reactions were summarized recently by Lillie. The pigment is sudanophilic in paraffin sections, acid-fast, basophilic, isotropic, iron negative, and highly resistant to solution in water, alcohol, fat solvents, and dilute aqueous acids and alkalis. It is stained by Mallory's hemofuscin stain and Weigert's myelin stain. It reduces osmium tetraoxide and diamine silver carbonate but not ferric ferricyanide. The Gmelin reactions for bile pigments is negative. It has a greenish yellow fluorescence at 3650-3660 Å. It is Schiff positive with or without antecedent diastase digestion after performic or periodic acid oxidation.

  17. Adult-onset opsoclonus-myoclonus syndrome.

    PubMed

    Klaas, James P; Ahlskog, J Eric; Pittock, Sean J; Matsumoto, Joseph Y; Aksamit, Allen J; Bartleson, J D; Kumar, Rajeev; McEvoy, Kathleen F; McKeon, Andrew

    2012-12-01

    BACKGROUND Little is known about adult-onset opsoclonus-myoclonus syndrome (OMS) outside of individual case reports. OBJECTIVE To describe adult-onset OMS. DESIGN Review of medical records (January 1, 1990, through December 31, 2011), prospective telephone surveillance, and literature review (January 1, 1967, through December 31, 2011). SETTING Department of Neurology, Mayo Clinic, Rochester, Minnesota. PATIENTS Twenty-one Mayo Clinic patients and 116 previously reported patients with adult-onset OMS. MAIN OUTCOME MEASURES Clinical course and longitudinal outcomes. RESULTS The median age at onset of the 21 OMS patients at the Mayo Clinic was 47 years (range, 27-78 years); 11 were women. Symptoms reported at the first visit included dizziness, 14 patients; balance difficulties, 14; nausea and/or vomiting, 10; vision abnormalities, 6; tremor/tremulousness, 4; and altered speech, 2. Myoclonus distribution was extremities, 15 patients; craniocervical, 8; and trunk, 4. Cancer was detected in 3 patients (breast adenocarcinoma, 2; and small cell lung carcinoma, 1); a parainfectious cause was assumed in the remainder of the patients. Follow-up of 1 month or more was available for 19 patients (median, 43 months; range, 1-187 months). Treatment (median, 6 weeks) consisted of immunotherapy and symptomatic therapy in 16 patients, immunotherapy alone for 2, and clonazepam alone for 1. Of these 19 patients, OMS remitted in 13 and improved in 3; 3 patients died (neurologic decline, 1; cancer, 1; and myocardial infarction, 1). The cause of death was of paraneoplastic origin in 60 of 116 literature review patients, with the most common carcinomas being lung (33 patients) and breast (7); the most common antibody was antineuronal nuclear antibody type 2 (anti-Ri, 15). Other causes were idiopathic in origin, 38 patients; parainfectious, 15 (human immunodeficiency virus, 7); toxic/metabolic, 2; and other autoimmune, 1. Both patients with N -methyl-D-aspartate receptor antibody had

  18. Partial correction of the CNS lysosomal storage defect in a mouse model of juvenile neuronal ceroid lipofuscinosis by neonatal CNS administration of an adeno-associated virus serotype rh.10 vector expressing the human CLN3 gene.

    PubMed

    Sondhi, Dolan; Scott, Emma C; Chen, Alvin; Hackett, Neil R; Wong, Andrew M S; Kubiak, Agnieszka; Nelvagal, Hemanth R; Pearse, Yewande; Cotman, Susan L; Cooper, Jonathan D; Crystal, Ronald G

    2014-03-01

    Juvenile neuronal ceroid lipofuscinosis (JNCL or CLN3 disease) is an autosomal recessive lysosomal storage disease resulting from mutations in the CLN3 gene that encodes a lysosomal membrane protein. The disease primarily affects the brain with widespread intralysosomal accumulation of autofluorescent material and fibrillary gliosis, as well as the loss of specific neuronal populations. As an experimental treatment for the CNS manifestations of JNCL, we have developed a serotype rh.10 adeno-associated virus vector expressing the human CLN3 cDNA (AAVrh.10hCLN3). We hypothesized that administration of AAVrh.10hCLN3 to the Cln3(Δex7/8) knock-in mouse model of JNCL would reverse the lysosomal storage defect, as well as have a therapeutic effect on gliosis and neuron loss. Newborn Cln3(Δex7/8) mice were administered 3 × 10(10) genome copies of AAVrh.10hCLN3 to the brain, with control groups including untreated Cln3(Δex7/8) mice and wild-type littermate mice. After 18 months, CLN3 transgene expression was detected in various locations throughout the brain, particularly in the hippocampus and deep anterior cortical regions. Changes in the CNS neuronal lysosomal accumulation of storage material were assessed by immunodetection of subunit C of ATP synthase, luxol fast blue staining, and periodic acid-Schiff staining. For all parameters, Cln3(Δex7/8) mice exhibited abnormal lysosomal accumulation, but AAVrh.10hCLN3 administration resulted in significant reductions in storage material burden. There was also a significant decrease in gliosis in AAVrh.10hCLN3-treated Cln3(Δex7/8) mice, and a trend toward improved neuron counts, compared with their untreated counterparts. These data demonstrate that AAVrh.10 delivery of a wild-type cDNA to the CNS is not harmful and instead provides a partial correction of the neurological lysosomal storage defect of a disease caused by a lysosomal membrane protein, indicating that this may be an effective therapeutic strategy for JNCL and

  19. Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates

    PubMed Central

    de Blieck, Elisabeth A.; Augustine, Erika F.; Marshall, Frederick J.; Adams, Heather; Cialone, Jennifer; Dure, Leon; Kwon, Jennifer M.; Newhouse, Nicole; Rose, Katherine; Rothberg, Paul G.; Vierhile, Amy; Mink, Jonathan W.

    2013-01-01

    Introduction Juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) is a rare, inherited, fatal lysosomal storage childhood disorder. True for many rare diseases, there are no treatments that impact the course of JNCL. The University of Rochester Batten Center’s (URBC) mission is to find treatments to slow, halt, or prevent JNCL. Objectives Our initial objective was to develop clinical research infrastructure preparatory to clinical trials, establish a JNCL research cohort, construct a disease-specific clinical outcome measure, and validate a non-invasive diagnostic sampling method. The long-term objective is to design and implement JNCL clinical trials. Methods The Unified Batten Disease Rating Scale (UBDRS) was developed. The Batten Disease Support and Research Association (BDSRA) referred participants; annual BDSRA meetings provided a mobile research setting for registry enrollment and UBDRS piloting. Neuropsychological examinations were performed, enabling external validation of the UBDRS. Buccal epithelial cell collection for genotyping was introduced. Telemedicine for remote UBDRS assessment was piloted. Results The registry enrolled 198 families representing 237 children with NCL. The UBDRS was piloted, validated and has been used to collect natural history data from 120 subjects. Funding and regulatory approval were obtained for a recently launched phase II clinical trial. Several additional lines of inquiry were reported. Conclusion The registry and BDSRA collaboration have enabled development of a clinical rating scale, natural history and neuropsychological studies, and genetic studies for disease confirmation. This work highlights an approach for preparatory natural history research and infrastructure development needed to facilitate efficient implementation of clinical trials in rare diseases. PMID:23628560

  20. Phenotypes, Risk Factors, and Mechanisms of Adult-Onset Asthma

    PubMed Central

    Ilmarinen, Pinja; Tuomisto, Leena E.; Kankaanranta, Hannu

    2015-01-01

    Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Genetic factors, atopy, and early respiratory tract infections are well-recognized factors predisposing to childhood-onset asthma. Adult-onset asthma is more often associated with obesity, smoking, depression, or other life-style or environmental factors, even though genetic factors and respiratory tract infections may also play a role in adult-onset disease. Adult-onset asthma is characterized by absence of atopy and is often severe requiring treatment with high dose of inhaled and/or oral steroids. Variety of risk factors and nonatopic nature of adult-onset disease suggest that variety of mechanisms is involved in the disease pathogenesis and that these mechanisms differ from the pathobiology of childhood-onset asthma with prevailing Th2 airway inflammation. Recognition of the mechanisms and mediators that drive the adult-onset disease helps to develop novel strategies for the treatment. The aim of this review was to summarize the current knowledge on the pathogenesis of adult-onset asthma and to concentrate on the mechanisms and mediators involved in establishing adult-onset asthma in response to specific risk factors. We also discuss the involvement of these mechanisms in the currently recognized phenotypes of adult-onset asthma. PMID:26538828

  1. Refractory Coats’ Disease of Adult Onset

    PubMed Central

    Beselga, D.; Campos, A.; Mendes, S.; Carvalheira, F.; Castro, M.; Castanheira, D.

    2012-01-01

    Purpose We present the case of an 18-year-old Caucasian male with a unilateral macular star and retinal vascular anomalies compatible with adult onset Coats’ disease. Methods Diagnosis was based on fundoscopic, fluorescein angiography and optical coherence tomography findings. Results The patient presented to our emergency department with complaints of low vision in his left eye (LE) detected 10 days before. The best-corrected visual acuity in the LE was 20/50. Fundoscopy of the LE evidenced a complete macular star. Optical coherence tomography showed increased retinal thickness, infiltration of the retinal wall, and detachment of the neuroepithelium. Angiography revealed no appreciable diffusion in the macula. Above the superior temporal (ST) arcade, anomalies in the retinal vasculature were found, with interruption of the peripheral vessels and vessels which were ‘sausage’-like. After 1 month, the LE vision evolved to hand movements. Laser photocoagulation was performed in the ST quadrant. Intravitreal injection of bevacizumab 1.25 mg/0.05 ml and photodynamic therapy were performed without any significant changes, progression of ST serous detachment of the neuroepithelium, and finally progression to macular fibrosis. Discussion Coats’ disease is usually diagnosed in childhood, but rare cases may occur in adults. Those cases usually have a more indolent course which was not observed in our patient. When there is macular involvement, prognosis is more guarded, despite treatment. PMID:22548045

  2. Adult-onset amenorrhea: a study of 262 patients.

    PubMed

    Reindollar, R H; Novak, M; Tho, S P; McDonough, P G

    1986-09-01

    A series of 262 patients with amenorrhea of adult onset are reported. Hypothalamic suppression followed by inappropriate positive feedback, and then hyperprolactinemia and ovarian failure are the most frequently encountered etiologies. Other etiologies are diverse and numerically less frequent. Amenorrhea after use of oral contraceptives, or postpill amenorrhea, occurred in 77 (29%) of all patients. The average age of presentation, prior menstrual history, associated morbidity, and subsequent reproductive potential of each diagnostic group are reported. Adult-onset amenorrhea has a less significant impact on future wellbeing than was reported for a similar-sized group of patients whose amenorrhea developed as a result of pubertal aberrancy.

  3. Clinical profile of patients with adult-onset eosinophilic asthma

    PubMed Central

    Storm, Huib; Amelink, Marijke; de Nijs, Selma B.; Eichhorn, Edwin; Reitsma, Bennie H.; Bel, Elisabeth H.D.; ten Brinke, Anneke

    2016-01-01

    Adult-onset eosinophilic asthma is increasingly recognised as a severe and difficult-to-treat subtype of asthma. In clinical practice, early recognition of patients with this asthma subtype is important because it may have treatment implications. Therefore, physicians need to know the distinct characteristics of this asthma phenotype. The objective of the present study was to determine the characteristic profile of patients with adult-onset eosinophilic asthma. 130 patients with adult-onset (>18 years of age) asthma and high blood eosinophil counts (≥0.3×109 L−1) were compared with 361 adult-onset asthma patients with low (<0.3×109 L−1) blood eosinophils. Measurements included a series of clinical, functional and imaging parameters. Patients with high blood eosinophils were more often male, had less well controlled asthma and higher exacerbation rates, despite the use of higher doses of inhaled corticosteroids. They had higher levels of total IgE without more sensitisation to common inhaled allergens. In addition, these patients had worse lung function, and more often showed fixed airflow limitation, air trapping, nasal polyposis and abnormalities on sinus computed tomography scanning. Chronic rhinosinusitis, air trapping and male sex were three independent factors associated with blood eosinophilia (adjusted OR 3.8 (95% CI 1.7–8.1), 3.0 (95% CI 1.1–8.1) and 2.4 (95% CI 1.3–4.4), respectively). Patients with adult-onset asthma with elevated blood eosinophils exhibit a distinct profile, which can readily be recognised in clinical practice. PMID:27730197

  4. Clinical profile of patients with adult-onset eosinophilic asthma.

    PubMed

    de Groot, Jantina C; Storm, Huib; Amelink, Marijke; de Nijs, Selma B; Eichhorn, Edwin; Reitsma, Bennie H; Bel, Elisabeth H D; Ten Brinke, Anneke

    2016-04-01

    Adult-onset eosinophilic asthma is increasingly recognised as a severe and difficult-to-treat subtype of asthma. In clinical practice, early recognition of patients with this asthma subtype is important because it may have treatment implications. Therefore, physicians need to know the distinct characteristics of this asthma phenotype. The objective of the present study was to determine the characteristic profile of patients with adult-onset eosinophilic asthma. 130 patients with adult-onset (>18 years of age) asthma and high blood eosinophil counts (≥0.3×10(9) L(-1)) were compared with 361 adult-onset asthma patients with low (<0.3×10(9) L(-1)) blood eosinophils. Measurements included a series of clinical, functional and imaging parameters. Patients with high blood eosinophils were more often male, had less well controlled asthma and higher exacerbation rates, despite the use of higher doses of inhaled corticosteroids. They had higher levels of total IgE without more sensitisation to common inhaled allergens. In addition, these patients had worse lung function, and more often showed fixed airflow limitation, air trapping, nasal polyposis and abnormalities on sinus computed tomography scanning. Chronic rhinosinusitis, air trapping and male sex were three independent factors associated with blood eosinophilia (adjusted OR 3.8 (95% CI 1.7-8.1), 3.0 (95% CI 1.1-8.1) and 2.4 (95% CI 1.3-4.4), respectively). Patients with adult-onset asthma with elevated blood eosinophils exhibit a distinct profile, which can readily be recognised in clinical practice.

  5. Quantification of Ceroid and Lipofuscin in Skeletal Muscle

    PubMed Central

    Tohma, Hatice; Hepworth, Anna R.; Shavlakadze, Thea; Grounds, Miranda D.; Arthur, Peter G.

    2011-01-01

    Ceroid and lipofuscin are autofluorescent granules thought to be generated as a consequence of chronic oxidative stress. Because ceroid and lipofuscin are persistent in tissue, their measurement can provide a lifetime history of exposure to chronic oxidative stress. Although ceroid and lipofuscin can be measured by quantification of autofluorescent granules, current methods rely on subjective assessment. Furthermore, there has not been any evaluation of variables affecting quantitative measurements. The article describes a simple statistical approach that can be readily applied to quantitate ceroid and lipofuscin. Furthermore, it is shown that several factors, including magnification tissue thickness and tissue level, can affect precision and sensitivity. After optimizing for these factors, the authors show that ceroid and lipofuscin can be measured reproducibly in the skeletal muscle of dystrophic mice (ceroid) and aged mice (lipofuscin). PMID:21804079

  6. Adult Onset Still's Disease and Rocky Mountain Spotted Fever.

    PubMed

    Persad, Paul; Patel, Rajendrakumar; Patel, Niki

    2010-01-01

    Adult Still's Disease was first described in 1971 by Bywaters in fourteen adult female patients who presented with symptoms indistinguishable from that of classic childhood Still's Disease (Bywaters, 1971). George Still in 1896 first recognized this triad of quotidian (daily) fevers, evanescent rash, and arthritis in children with what later became known as juvenile inflammatory arthritis (Still, 1990). Adult Onset Still's Disease (AOSD) is an inflammatory condition of unknown etiology characterized by an evanescent rash, quotidian fevers, and arthralgias. Numerous infectious agents have been associated with its presentation. This case is to our knowledge the first presentation of AOSD in the setting of Rocky Mountain Spotted Fever. Although numerous infectious agents have been suggested, the etiology of this disorder remains elusive. Nevertheless, infection may in fact play a role in triggering the onset of symptoms in those with this disorder. Our case presentation is, to our knowledge, the first case of Adult Onset Still's Disease associated with Rocky Mountain spotted fever (RMSF).

  7. Adult onset pigmentary orthochromatic leukodystrophy with ovarian dysgenesis.

    PubMed

    Verghese, J; Weidenheim, K; Malik, S; Rapin, I

    2002-11-01

    Pigmentary type of orthochromatic leukodystrophy (POLD) is an adult-onset leukodystrophy, characterized pathologically by the presence of glial and microglial cytoplasmic pigment inclusions. The complete phenotype, genotype and pathogenetic mechanisms in POLD have not been elucidated. We followed for 18 years a woman with autopsy-proven POLD, who presented with 'frontal' dementia and spasticity. Her further course was marked by progressive mutism, apraxia and seizures. Her sister had died of the same disease after a much more rapidly progressing course. These sisters had primary infertility with pathologic evidence of streak ovaries. Diagnosis was confirmed in both cases by post-mortem examination. POLD is a rare cause of adult-onset leukodystrophy presenting with dementia. Ovarian dysgenesis is extremely rare in the absence of demonstrable chromosomal abnormalities and extends the clinical spectrum of POLD.

  8. Etiopathogenesis and Therapeutic Approach to Adult Onset Acne

    PubMed Central

    Kaur, Sarabjit; Verma, Poonam; Sangwan, Ankita; Dayal, Surabhi; Jain, Vijay Kumar

    2016-01-01

    Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14–17 years in females and 16–19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID:27512185

  9. Hepatitis A infection mimicking adult onset Still's disease.

    PubMed

    Sridharan, S; Mossad, S; Hoffman, G

    2000-07-01

    Fever, rash, and arthritis may be components of the prodrome of viral hepatitis. In the absence of jaundice and abnormal liver function tests, this form of polyarthritis is easily confused with primary autoimmune diseases. Whereas the association of systemic illness with musculoskeletal symptoms and numerous viral infections is well known, such an association with hepatitis A has only been rarely reported. We describe a case of hepatitis A infection mimicking adult onset Still's disease, and review the pathogenesis and differential diagnosis of Still's disease and the extraarticular manifestations of hepatitis.

  10. Adult-onset idiopathic chondrolysis of the hip.

    PubMed

    Yapp, Liam Z; McClymont, Liusaidh; Beggs, Ian; Gaston, Paul; Salter, Donald M

    2017-05-01

    We report the case of a 23-year-old man diagnosed with adult-onset idiopathic chondrolysis of the hip. Chondrolysis of the hip is a disorder most frequently seen in children who have suffered with slipped capital femoral epiphyses. Idiopathic chondrolysis of the hip is extremely rare and to our knowledge, its onset has never been documented in adults aged over 20. With reference to the available medical literature, we summarise the current clinical management of this unusual but important cause of young adult hip pain.

  11. Season of Birth and Risk for Adult Onset Glioma

    PubMed Central

    Efird, Jimmy T.

    2010-01-01

    Adult onset glioma is a rare cancer which occurs more frequently in Caucasians than African Americans, and in men than women. The etiology of this disease is largely unknown. Exposure to ionizing radiation is the only well established environmental risk factor, and this factor explains only a small percentage of cases. Several recent studies have reported an association between season of birth and glioma risk. This paper reviews the plausibility of evidence focusing on the seasonal interrelation of farming, allergies, viruses, vitamin D, diet, birth weight, and handedness. To date, a convincing explanation for the occurrence of adult gliomas decades after a seasonal exposure at birth remains elusive. PMID:20623001

  12. Refractory Genital HPV Infection and Adult-Onset Still Disease

    PubMed Central

    Yu, Xin; Zheng, Heyi

    2016-01-01

    Abstract Adult-onset Still disease (AOSD) is a systemic autoimmune disease (AIID) that can develop after exposure to infectious agents. Genital human papillomavirus (HPV) infection has been reported to induce or exacerbate AIIDs, such as systemic lupus erythematosus (SLE). No guidelines are available for the management of genital warts in AOSD. Case report and literature review. We report a patient who was diagnosed AOSD in the setting of refractory and recurrent genital HPV infection, demonstrating a possible link between HPV infection and AOSD. In addition, we also discuss the management of genital warts in patients with AOSD. To the best of our knowledge, no previous cases of AOSD with genital HPV infection have been reported in literature. We then conclude that the patient AOSD may be triggered by primary HPV infection. Larger number of patient samples is needed to confirm whether HPV could trigger AOSD. PMID:27082556

  13. A novel mouse model that recapitulates adult-onset glycogenosis type 4

    PubMed Central

    Orhan Akman, H.; Emmanuele, Valentina; Kurt, Yasemin Gülcan; Kurt, Bülent; Sheiko, Tatiana; DiMauro, Salvatore; Craigen, William J.

    2015-01-01

    Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen-branching enzyme (GBE). The diagnostic hallmark of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variable tissue involvement and age at onset. Complete loss of enzyme activity is lethal in utero or in infancy and affects primarily the muscle and the liver. However, residual enzyme activity as low as 5–20% leads to juvenile or adult onset of a disorder that primarily affects the central and peripheral nervous system and muscles and in the latter is termed adult polyglucosan body disease (APBD). Here, we describe a mouse model of GSD IV that reflects this spectrum of disease. Homologous recombination was used to knock in the most common GBE1 mutation p.Y329S c.986A > C found in APBD patients of Ashkenazi Jewish decent. Mice homozygous for this allele (Gbe1ys/ys) exhibit a phenotype similar to APBD, with widespread accumulation of PG. Adult mice exhibit progressive neuromuscular dysfunction and die prematurely. While the onset of symptoms is limited to adult mice, PG accumulates in tissues of newborn mice but is initially absent from the cerebral cortex and heart muscle. Thus, PG is well tolerated in most tissues, but the eventual accumulation in neurons and their axons causes neuropathy that leads to hind limb spasticity and premature death. This mouse model mimics the pathology and pathophysiologic features of human adult-onset branching enzyme deficiency. PMID:26385640

  14. Hematopoietic cell transplantation in fetal lambs with ceroid-lipofuscinosis.

    PubMed

    Westlake, V J; Jolly, R D; Jones, B R; Mellor, D J; Machon, R; Zanjani, E D; Krivit, W

    1995-06-05

    Hematopoietic cells from the liver of normal 45-48-day-old fetal lambs (Hb type AA) were transplanted intraperitoneally into 58-60-day-old recipient fetuses (Hb type BB). The recipient fetuses resulted from mating homozygous ceroid-lipofuscinosis affected males with heterozygous, phenotypically normal, females. The sex of the donor fetus was also recorded. At age 2 1/2 months the recipient lambs with ceroid-lipofuscinosis were diagnosed by histopathology of brain biopsies. Monitoring of blood and bone marrow cells showed that an average of 9% of blood cells in ceroid-lipofuscinosis affected recipients were of donor origin. No differences were evident in the clinical course of disease, brain weight, or histopathology of organs between transplanted and non-transplanted lambs with ceroid-lipofuscinosis. Under the conditions of this experiment, transplantation of fetal hematopoietic cells was not beneficial.

  15. Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

    ERIC Educational Resources Information Center

    de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

    2007-01-01

    This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

  16. Periocular xanthogranulomas associated with severe adult-onset asthma.

    PubMed Central

    Jakobiec, F A; Mills, M D; Hidayat, A A; Dallow, R L; Townsend, D J; Brinker, E A; Charles, N C

    1993-01-01

    This article describes six patients who presented, usually bilaterally, with yellow-orange, elevated, indurated, and nonulcerated xanthomatous eyelid lesions, typically extending into the anterior orbital fat, and sometimes involving the extraocular muscles and the lacrimal gland. Because the eyelids remained intact and because the process did not reach the deep orbital and perioptic connective tissues, visual acuity was well preserved. There is cosmetic morbidity and occasionally motility restriction with advancing involvement of the extraocular muscles. All patients had variably severe adult-onset asthma that required treatment with systemic prednisone and inhalants. No evidence of Erdheim-Chester disease was found in any patient, but the appearance in one patient, after 25 years of follow-up, of a separate subcutaneous necrobiotic xanthogranulomatous lesion in the mandibular region with an associated paraproteinemia, suggests that at least some of our cases might be a mild form of necrobiotic xanthogranuloma. For this reason, we would suggest repeated periodic serum protein immunoelectrophoretic studies as well as evaluation for lymphoma. Therapy probably should consist of low doses of periorbital radiotherapy coupled with high doses of corticosteroids. Should this not be successful, then systemic administration of corticosteroids with chemotherapeutic agents might be efficacious, as in necrobiotic xanthogranuloma. Images FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 FIGURE 11 FIGURE 12 FIGURE 13 FIGURE 14 FIGURE 15 FIGURE 16 FIGURE 17 FIGURE 18 FIGURE 19 PMID:8140711

  17. Adult onset Still’s disease with dermatopathic lymphadenopathy

    PubMed Central

    Qureshi, Ahmad Z.; AlSheef, Mohammad; Qureshi, Waqas T.; Amjad, Waseem

    2016-01-01

    Adult onset Still’s disease (AOSD) is a chronic inflammatory disorder involving multiple systems. The symptoms mimic those of lymphomas, therefore, the diagnosis of lymphoma needs to be excluded prior to establishing the diagnosis of AOSD. Another similar condition is dermatopathic lymphadenopathy (DL). In DL, the histopathological appearance of lymph node biopsy may also mimic AOSD. The DL is associated with several systemic pathologies, such as malignant lymphomas, and rarely AOSD. We present a case of a 43-year-old male presented with 3 months history of fatigue, fever, and lymphadenopathy. Initial work-up satisfactorily met the criteria for diagnosis of AOSD. But considering the well-known association of DL with hematological malignancies, detailed pathological studies were considered, including tumor markers to rule out the possibility of malignancy. The patient was started on steroids and showed remarkable recovery within 2 weeks. Evaluation of malignant lymphomas in a patient with DL is important, in order to diagnose AOSD and rule out hematological malignancy. PMID:27761568

  18. Adult-onset hypophosphatemic osteomalacia associated with Sjogren syndrome

    PubMed Central

    Shen, Guohua; Zhang, Yuwei; Hu, Shuang; Liu, Bin; Kuang, Anren

    2017-01-01

    Abstract Rationale: Hypophosphatemic osteomalacia (HO) is a metabolic bone disease, exhibiting different etiologies such as genetic mutation, tumor induction, dysimmunity, or renal disease. Sjogren's syndrome (SS) is a connective tissue disorder commonly involving exocrine glands; however kidney involvement is also encountered, leading to abnormal phosphorus metabolism, even HO. Patient concerns: A 47-year-old female patient presented progressively worsening pain in the chest wall, back and bilateral lower extremities as well as muscle weakness was referred to our department. Diagnoses, interventions and outcomes: Due to the laboratory test results, radiographic findings and pathologic results, she was diagnosed with adult-onset HO associated with SS. She was then treated with alkalinization, steroids, neutral phosphate, calcium supplements together with activated vitamin D. So far, she recovered uneventfully with relieved pain and increased serum phosphorus level. Lessons: HO may be secondary to renal tubular acidosis of SS patients, and it might be a diagnostic challenge when the kidney involvement in SS is latent and precede the typical sicca symptoms. PMID:28353596

  19. Efficacy of Anakinra in Refractory Adult-Onset Still's Disease

    PubMed Central

    Ortiz-Sanjuán, Francisco; Blanco, Ricardo; Riancho-Zarrabeitia, Leyre; Castañeda, Santos; Olivé, Alejandro; Riveros, Anne; Velloso-Feijoo, María.L.; Narváez, Javier; Jiménez-Moleón, Inmaculada; Maiz-Alonso, Olga; Ordóñez, Carmen; Bernal, José A.; Hernández, María V.; Sifuentes-Giraldo, Walter A.; Gómez-Arango, Catalina; Galíndez-Agirregoikoa, Eva; Blanco-Madrigal, Juan; Ortiz-Santamaria, Vera; del Blanco-Barnusell, Jordi; De Dios, Juan R.; Moreno, Mireia; Fiter, Jordi; Riscos, Marina de los; Carreira, Patricia; Rodriguez-Valls, María J.; González-Vela, M. Carmen; Calvo-Río, Vanesa; Loricera, Javier; Palmou-Fontana, Natalia; Pina, Trinitario; Llorca, Javier; González-Gay, Miguel A.

    2015-01-01

    Abstract Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2–6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3–47.5] mg/day at ANK onset to 5 [0–10] at 12 months. After a median [IQR] follow-up of 16 [5–50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations. PMID:26426623

  20. Parenchymal lung involvement in adult-onset Still disease

    PubMed Central

    Gerfaud-Valentin, Mathieu; Cottin, Vincent; Jamilloux, Yvan; Hot, Arnaud; Gaillard-Coadon, Agathe; Durieu, Isabelle; Broussolle, Christiane; Iwaz, Jean; Sève, Pascal

    2016-01-01

    Abstract Parenchymal lung involvement (PLI) in adult-onset Still's disease (AOSD) has seldom, if ever, been studied. We examine here retrospective cohort AOSD cases and present a review of the literature (1971–2014) on AOSD-related PLI cases. Patients with PLI were identified in 57 AOSD cases. For inclusion, the patients had to fulfill Yamaguchi or Fautrel classification criteria, show respiratory symptoms, and have imaging evidence of pulmonary involvement, and data allowing exclusion of infectious, cardiogenic, toxic, or iatrogenic cause of PLI should be available. This AOSD + PLI group was compared with a control group (non–PLI-complicated AOSD cases from the same cohort). AOSD + PLI was found in 3 out of the 57 patients with AOSD (5.3%) and the literature mentioned 27 patients. Among these 30 AOSD + PLI cases, 12 presented an acute respiratory distress syndrome (ARDS) and the remaining 18 another PLI. In the latter, a nonspecific interstitial pneumonia computed tomography pattern prevailed in the lower lobes, pulmonary function tests showed a restrictive lung function, the alveolar differential cell count was neutrophilic in half of the cases, and the histological findings were consistent with bronchiolitis and nonspecific interstitial pneumonia. Corticosteroids were fully efficient in all but 3 patients. Ten out of 12 ARDS cases occurred during the first year of the disease course. All ARDS-complicated AOSD cases received corticosteroids with favorable outcomes in 10 (2 deceased). Most PLIs occurred during the systemic onset of AOSD. PLI may occur in 5% of AOSDs, of which ARDS is the most severe. Very often, corticosteroids are efficient in controlling this complication. PMID:27472698

  1. Interleukin 6 SNP rs1800797 associates with the risk of adult-onset asthma.

    PubMed

    Lajunen, T K; Jaakkola, J J K; Jaakkola, M S

    2016-04-01

    Interleukin 6 (IL6) is an inflammatory cytokine that has been suggested to have an important role in the pathogenesis of asthma. IL6 single-nucleotide polymorphisms (SNPs) have been associated with levels of IL6, and with childhood and prevalent adult asthma. A recent study also suggested that IL6 SNPs associate especially with atopic asthma. However, association of IL6 SNPs with adult-onset asthma has not been studied. In a population-based study of 467 incident adult-onset asthma cases and 613 disease-free controls from South Finland, we analyzed association of 6 tagging SNPs of the IL6 locus with the risk of adult-onset asthma and with atopy. Asthma was clinically diagnosed, and atopy was defined based on Phadiatop test. IL6 SNP rs1800797 associated with the risk of adult-onset asthma in a log additive model, with adjusted odds ratio (aOR) 1.31 (95% confidence interval 1.09-1.57), and especially with the risk of atopic adult-onset asthma when compared with non-atopic controls, aOR 1.46 (95% CI 1.12-1.90). This is the first study to show an association of IL6 with adult-onset asthma, and especially with atopic adult-onset asthma.

  2. Adult-onset Still's disease with atypical cutaneous manifestations

    PubMed Central

    Narváez Garcia, Francisco Javier; Pascual, María; López de Recalde, Mercè; Juarez, Pablo; Morales-Ivorra, Isabel; Notario, Jaime; Jucglà, Anna; Nolla, Joan M.

    2017-01-01

    Abstract The diagnosis of adult-onset Still's disease (AOSD) can be very difficult. There are no specific tests available, and diagnosis is usually based on a symptom complex and the well-described typical evanescent rash seen in the majority of patients. However, in recent years, other atypical cutaneous manifestations of AOSD have been reported. These atypical skin eruptions often present in addition to the typical evanescent rash but may also be the only skin manifestation, resulting in delayed diagnosis because of under-recognition. In this study, we present 3 new cases of AOSD with atypical cutaneous manifestations diagnosed during a 30-year period in our department and review 78 additional cases previously reported (PubMed 1990–2016). These 81 patients form the basis of the present analysis. The overall prevalence of atypical cutaneous manifestations in our AOSD population was 14%. These manifestations may appear at any time over the course of the disease, and usually occur in patients who have persistent and severe disease, with a considerable frequency of clinical complications (23%), including serositis, myopericarditis, lung involvement, abdominal pain, neurologic involvement, and reactive hemophagocytic syndrome. The most representative and frequent lesion among the nonclassical skin rashes is the development of persistent pruritic papules and/or plaques. Interestingly, these lesions show a distinctive histological pattern. Other, less frequently observed lesions include urticaria and urticaria-like eruptions, generalized or widespread non-pruritic persistent erythema, vesiculopustular eruptions, a widespread peau d’orange appearance of the skin, and edema of the eyelids mimicking dermatomyositis without any accompanying skin lesion. The great majority of these patients required medium or high doses of glucocorticoids (including intravenous methylprednisolone pulse therapy in some cases) and, in nearly 40%, a more potent or maintenance immunotherapy

  3. Genetics Home Reference: adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

    MedlinePlus

    ... it causes a severe decline in thinking and reasoning abilities (dementia). Over time, motor skills are affected, ... Schmahmann JD. Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations. Brain Pathol. 2009 Jan; ...

  4. [Kimura's disease: an unrecognized cause of adult-onset nephrotic syndrome with minimal change disease].

    PubMed

    Shehwaro, N; Langlois, A-L; Gueutin, V; Debchi, L; Charlotte, F; Rouvier, P; Rottembourg, J; Izzedine, H

    2014-02-01

    Kimura's disease (KD) is an angiolymphoid proliferative disorder of soft tissue with eosinophilia, with a predilection for head and neck regions in young Oriental men. Kidney disease is thought to be rare in KD. About a case of adult-onset nephrotic syndrome with minimal change disease, we comment Kimura's disease and its associated kidney damage. Kimura disease should be suspected and included in the diagnosis of adult-onset nephrotic syndrome with minimal change disease.

  5. Adult Onset Vitiligo: Multivariate Analysis Suggests the Need for a Thyroid Screening

    PubMed Central

    Lazzeri, L.; Cammi, A.; Dragoni, F.

    2016-01-01

    Background. There are limited epidemiological studies evaluating the effect of age at onset on disease features in vitiligo. Objectives. To identify factors associated with adult onset vitiligo in comparison with childhood onset vitiligo. Patients and Methods. We retrospectively collected medical records of 191 patients. Such records included clinical examination, personal and familial medical history, laboratory evaluations, concomitant vitiligo treatment and drug assumption. Results. 123 patients with a disease onset after the age of 40 (adult onset vitiligo) were compared with 68 patients who developed vitiligo before the age of 12 (childhood onset vitiligo). Multivariate analysis revealed that personal history of thyroid diseases (P = 0.04; OR 0.4), stress at onset (P = 0.002; OR = 0.34), personal history of autoimmune thyroid disease (ATD) (P = 0.003; OR = 0.23), and thyroid nodules (P = 0.001; OR 0.90) were independently associated with adult onset vitiligo, whereas family history of dermatological diseases (P = 0.003; OR = 2.87) and Koebner phenomenon (P < 0.001; OR = 4.73) with childhood onset vitiligo. Moreover, in the adult onset group, concomitant thyroid disease preceded vitiligo in a statistically significant number of patients (P = 0.014). Conclusions. Childhood onset and adult onset vitiligo have different clinical features. In particular, ATD and thyroid nodules were significantly associated with adult onset vitiligo, suggesting that a thyroid screening should be recommended in this group of patients. PMID:27747240

  6. Adult Onset Vitiligo: Multivariate Analysis Suggests the Need for a Thyroid Screening.

    PubMed

    Lazzeri, L; Colucci, R; Cammi, A; Dragoni, F; Moretti, S

    2016-01-01

    Background. There are limited epidemiological studies evaluating the effect of age at onset on disease features in vitiligo. Objectives. To identify factors associated with adult onset vitiligo in comparison with childhood onset vitiligo. Patients and Methods. We retrospectively collected medical records of 191 patients. Such records included clinical examination, personal and familial medical history, laboratory evaluations, concomitant vitiligo treatment and drug assumption. Results. 123 patients with a disease onset after the age of 40 (adult onset vitiligo) were compared with 68 patients who developed vitiligo before the age of 12 (childhood onset vitiligo). Multivariate analysis revealed that personal history of thyroid diseases (P = 0.04; OR 0.4), stress at onset (P = 0.002; OR = 0.34), personal history of autoimmune thyroid disease (ATD) (P = 0.003; OR = 0.23), and thyroid nodules (P = 0.001; OR 0.90) were independently associated with adult onset vitiligo, whereas family history of dermatological diseases (P = 0.003; OR = 2.87) and Koebner phenomenon (P < 0.001; OR = 4.73) with childhood onset vitiligo. Moreover, in the adult onset group, concomitant thyroid disease preceded vitiligo in a statistically significant number of patients (P = 0.014). Conclusions. Childhood onset and adult onset vitiligo have different clinical features. In particular, ATD and thyroid nodules were significantly associated with adult onset vitiligo, suggesting that a thyroid screening should be recommended in this group of patients.

  7. [Adult-onset ataxia-telangiectasia. A clinical and therapeutic observation].

    PubMed

    Gazulla, J; Benavente, I; Sarasa Barrio, M

    2006-10-01

    A case of adult-onset ataxia-telangiectasia (AT) is presented, with debut at the age of 18 years and survival into the fourth decade. The clinical picture included cerebellar ataxia, distal weakness and hypopalesthesia in the lower limbs, oculomotor apraxia, dysarthria, and conjunctival telangiectasiae. Carcinoembrionic antigen was raised in plasma. MR imaging showed atrophy of the cerebellar vermis and thinning of the spinal cord. Deficiencies of gamma-aminobutyric acid and glutamate have been found in the cerebellar cortex in a case of AT. These were attributed to the loss of Purkinje cells and granule cells. In spite of some ataxias having improved with the gabaergic drugs gabapentin and tiagabine, the administration of gabapentin, acetazolamide and a placebo, did not benefit this patient. Pregabalin, 225 mg/day, ameliorated the ataxia unexpectedly, with further improvement after the addition of tiagabine. The authors suggest that the beneficial effect observed might have been due, either to the higher affinity of pregabalin towards alpha2-delta, a subtype of the alpha2-delta subunit which forms part of the voltage-gated calcium channel; either to the profusion of this subtype in the Purkinje cell layer, or to its larger capacity to let calcium into the neuron; or to the combination of these. These differences with gabapentin could explain the higher power of pregabalin in the stimulation of the cerebellar structures, thus justifying the improvement of ataxia in this case of AT. A synergistic effect with pregabalin is proposed as the cause of the improvement obtained with the addition of tiagabine.

  8. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q.

    PubMed Central

    Wirtz, M K; Samples, J R; Kramer, P L; Rust, K; Topinka, J R; Yount, J; Koler, R D; Acott, T S

    1997-01-01

    Glaucoma is the third-leading cause of blindness in the world, affecting >13.5 million people. Adult-onset primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States. We present a family in which adult-onset POAG is inherited as an autosomal dominant trait. Twelve affected family members were identified from 44 at-risk individuals. The disease-causing gene was mapped to chromosome 3q21-24, with analysis of recombinant haplotypes suggesting a total inclusion region of 11.1 cM between markers D3S3637 and D3S1744. This is the first report of mapping of an adult-onset POAG gene to chromosome 3q, gene symbol GLC1C. PMID:9012402

  9. Adult-onset Still's disease and cardiac tamponade: a rare association.

    PubMed

    Carrilho-Ferreira, Pedro; Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-06-01

    Adult-onset Still's disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy. The authors describe a case of adult-onset Still's disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity.

  10. Adult-Onset Still's Disease and Cardiac Tamponade: A Rare Association

    PubMed Central

    Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-01-01

    Adult-onset Still's disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy. The authors describe a case of adult-onset Still's disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity. PMID:26175648

  11. [Adult onset Still's disease as a diagnostics challenge in case of fever of unknown origin].

    PubMed

    Debski, Marcin; Stepniewski, Piotr; Wróbel, Michał

    2013-01-01

    Fever of unknown origin is often a diagnostic challenge. Here we present a case of 55-year-old woman with a history of a few months fever, progressing weakness and salmon-coloured, macular skin rash. The differential diagnosis included neoplasmatic conditions, infections and connective tissue disorders. Finally adult onset Still's disease was suspected. Glucocorticosteroid treatment was induced. During the therapy a central nervous system infection occurred, which was fatal for the patient. The presented clinical case shows that among many causes of fever of unknown origin, adult onset Still's disease should be taken into account.

  12. Is Adolescent-Onset First-Episode Psychosis Different from Adult Onset?

    ERIC Educational Resources Information Center

    Ballageer, Trevor; Malla, Ashok; Manchanda, Rahul; Takhar, Jatinder; Haricharan, Raj

    2005-01-01

    Objective: To examine whether first-episode psychosis patients with onset during adolescence (ages 15-18) differ significantly from those with young-adult onset (ages 19-30). Method: Consecutive patients presenting with first-episode psychosis (N = 242) were assessed for demographic and illness characteristics such as duration of untreated…

  13. Epidemiology and outcome of articular complications in adult onset Still's disease.

    PubMed

    Mahfoudhi, Madiha; Shimi, Rafik; Turki, Sami; Kheder, Adel

    2015-01-01

    The adult onset Still's disease is a rare inflammatory pathology of unknown pathogeny. The clinical features are variable. The diagnosis is difficult since exclusion of infectious, systemic and tumoral pathologies should be done. The articular complications are frequent and can be revelatory of this pathology. The articular prognosis depends on the diagnosis delay and the treatment efficiency. Our study aims to analyze different aspects of articular manifestations complicating adult onset Still disease to define epidemiological, clinical and evolving characteristics of these complications. It was a cross-sectional study concerning 18 cases of adult onset Still disease diagnosed from 1990 to 2014 in the internal medicine A department of Charles Nicolle Hospital in Tunis, meeting Yamaguchi criteria. We identified clinical, radiological, evolving and therapeutic profile of the articular manifestations occurred in these patients. There were 11 women and 7 men. The average age was 27 years. The arthralgias were reported in all cases; while, the arthritis interested thirteen patients. A hand deformation was found in four patients. A wrist ankylosis was noted in one case and a flexion elbow in one patient. The Standard articular radiographs were normal in ten cases. The treatment associated essentially non-steroidal anti-inflammatory and/or corticosteroids and/or methotrexate. Concerning the evolving profile, the monocyclic form was present in 25% of the cases, the intermittent form in 40% and the chronic articular form in 35% of our patients. The adult onset Still's disease is rare and heterogeneous. The articular disturbances are frequent and have various outcomes.

  14. Adult-Onset Antisocial Behavior Trajectories: Associations with Adolescent Family Processes and Emerging Adulthood Functioning

    ERIC Educational Resources Information Center

    Mata, Andrea D.; van Dulmen, Manfred H. M.

    2012-01-01

    Guided by conceptual and empirical work on emerging adulthood, this study investigated the role of closeness to mother and father and behavioral autonomy during adolescence on the development of adult-onset antisocial behavior. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we identified four aggressive…

  15. Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease

    PubMed Central

    Killick, Richard; Augustin, Hrvoje; Gandy, Carina; Allen, Marcus J.; Hardy, John; Lovestone, Simon; Partridge, Linda

    2010-01-01

    Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD. PMID:20824130

  16. [Pathophysiology, subtypes, and treatments of adult-onset Still's disease: An update].

    PubMed

    Gerfaud-Valentin, M; Sève, P; Hot, A; Broussolle, C; Jamilloux, Y

    2015-05-01

    Adult-onset Still's disease is a rare and difficult to diagnose multisystemic disorder considered as a multigenic autoinflammatory syndrome. Its immunopathogenesis seems to be at the crossroads between inflammasomopathies and hemophagocytic lymphohistiocytosis, the most severe manifestation of the disease. According to recent insights in the pathophysiology and thanks to cohort studies and therapeutic trials, two phenotypes of adult-onset Still's disease may be distinguished: a systemic pattern, initially highly symptomatic and with a higher risk to exhibit life-threatening complications such as reactive hemophagocytic lymphohistiocytosis, where interleukin-1 blockade seems to be very effective, a chronic articular pattern, more indolent with arthritis in the foreground and less severe systemic manifestations, which would threat functional outcome and where interleukin-6 blockade seems to be more effective. This review focuses on these data.

  17. Adult-onset Still's disease as a mask of Hodgkin lymphoma

    PubMed Central

    Pawlak-Buś, Katarzyna; Leszczyński, Piotr

    2015-01-01

    Adult-onset Still's disease is a rare disorder, which creates difficulties in making a proper diagnosis. Ambiguous symptoms and results of auxiliary tests, lack of unequivocal diagnostic tests and the need to exclude other causes of the disease are major problems in clinical practice. A case of a 22-year-old woman with dominated recurrent fever, significantly elevated inflammation markers and arthritis is presented. Based on clinical signs after exclusion of infection, hematological and other reasons, the patient was diagnosed with adult-onset Still's disease. Standard treatment, with high doses of glucocorticoids and a disease-modifying drug, was applied, without the anticipated effects. The diagnostic tests were conducted again due to the lack of clinical improvement, increase of inflammatory markers and unusual response to treatment. A new symptom of significance, i.e. mediastinal lymphadenopathy, was found. After the histopathological examination of lymph nodes, Hodgkin's disease was diagnosed and targeted therapy for hematological malignancy was applied. PMID:27407236

  18. Adult-onset Still's disease as a mask of Hodgkin lymphoma.

    PubMed

    Dudziec, Ewa; Pawlak-Buś, Katarzyna; Leszczyński, Piotr

    2015-01-01

    Adult-onset Still's disease is a rare disorder, which creates difficulties in making a proper diagnosis. Ambiguous symptoms and results of auxiliary tests, lack of unequivocal diagnostic tests and the need to exclude other causes of the disease are major problems in clinical practice. A case of a 22-year-old woman with dominated recurrent fever, significantly elevated inflammation markers and arthritis is presented. Based on clinical signs after exclusion of infection, hematological and other reasons, the patient was diagnosed with adult-onset Still's disease. Standard treatment, with high doses of glucocorticoids and a disease-modifying drug, was applied, without the anticipated effects. The diagnostic tests were conducted again due to the lack of clinical improvement, increase of inflammatory markers and unusual response to treatment. A new symptom of significance, i.e. mediastinal lymphadenopathy, was found. After the histopathological examination of lymph nodes, Hodgkin's disease was diagnosed and targeted therapy for hematological malignancy was applied.

  19. Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes.

    PubMed

    Levin, M E; Boisseau, V C; Avioli, L V

    1976-01-29

    To assess the influence of diabetes mellitus on bone metabolism, we measured skeletal mass in the forearms of 35 patients with juvenile diabetes on insulin and 101 stable patients with adult-onset diabetes, on diet alone, insulin, or oral hypoglycemic agents. There was a significant loss of bone mass in both juvenile and adult-onset diabetes (P less than 0.01) as compared to controls matched for age and sex. The decrease was already present in patients with diabetes of less than five years' duration. Bone loss and duration of the diabetes did not correlate; the greatest decrease in bone mass was observed in the patients receiving oral agents. These data are consistent with the hypothesis that the loss of skeletal tissue in diabetes reflects the underlying disease since it occurs early and is not related to severity as evidenced by the need for insulin, to duration, or to treatment with insulin or diet alone.

  20. Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers.

    PubMed

    Guerrero-Bosagna, Carlos; Covert, Trevor R; Haque, Md M; Settles, Matthew; Nilsson, Eric E; Anway, Matthew D; Skinner, Michael K

    2012-12-01

    The endocrine disruptor vinclozolin has previously been shown to promote epigenetic transgenerational inheritance of adult onset disease in the rat. The current study was designed to investigate the transgenerational actions of vinclozolin on the mouse. Transient exposure of the F0 generation gestating female during gonadal sex determination promoted transgenerational adult onset disease in F3 generation male and female mice, including spermatogenic cell defects, testicular abnormalities, prostate abnormalities, kidney abnormalities and polycystic ovarian disease. Pathology analysis demonstrated 75% of the vinclozolin lineage animals developed disease with 34% having two or more different disease states. Interestingly, the vinclozolin induced transgenerational disease was observed in the outbred CD-1 strain, but not the inbred 129 mouse strain. Analysis of the F3 generation sperm epigenome identified differential DNA methylation regions that can potentially be utilized as epigenetic biomarkers for transgenerational exposure and disease.

  1. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q

    SciTech Connect

    Wirtz, M.K.; Samples, J.R.; Kramer, P.L.

    1997-02-01

    Glaucoma is the third-leading cause of blindness in the world, affecting >13.5 million people. Adult-on-set primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States. We present a family in which adult-onset POAG is inherited as an autosomal dominant trait. Twelve affected family members were identified from 44 at-risk individuals. The disease-causing gene was mapped to chromosome 3q21-24, with analysis of recombinant haplotypes suggesting a total inclusion region of 11.1 cM between markers D3S3637 and D3S1744. This is the first report of mapping of an adult-onset POAG gene to chromosome 3q, gene symbol GLC1C. 57 refs., 3 figs., 3 tabs.

  2. Update on differences between childhood-onset and adult-onset systemic lupus erythematosus

    PubMed Central

    2013-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease and occurs worldwide in both children and adults. The estimated annual incidence among children is 2.22/100,000 and among adults is 23.2/100,000 in the United States. There is increasing understanding about differences in disease manifestations, medication use, and disease severity between those with childhood-onset SLE as compared with adult-onset SLE. Children have a more fulminant disease onset and course than adults with SLE, resulting in two to three times higher mortality. In future years, we anticipate more insight into the genetics between childhood-onset SLE and adult-onset SLE to help delineate the best therapies for both subsets of patients. PMID:23998441

  3. Adult-onset Still's disease revealed by perimyocarditis and a concomitant reactivation of an EBV infection

    PubMed Central

    Meckenstock, Roderich; Therby, Audrey; Gibault-Genty, Geraldine; Khau, David; Monnier, Sebastien; Greder-Belan, Alix

    2012-01-01

    We describe a 17-year-old patient presenting perimyocarditis as the initial manifestation of the adult-onset Still's disease. Corticotherapy was rapidly successful but induced major acute hepatitis in relation with Epstein-Barr virus reactivation. After 1 year, even if the global outcome is favourable, a slightly lowered ejection fraction still persists. Former case reports and differential diagnosis with reactive haemophagocytic syndrome would be discussed. PMID:23166163

  4. Epidemiology of adult-onset hydrocephalus: institutional experience with 2001 patients.

    PubMed

    Bir, Shyamal C; Patra, Devi Prasad; Maiti, Tanmoy K; Sun, Hai; Guthikonda, Bharat; Notarianni, Christina; Nanda, Anil

    2016-09-01

    OBJECTIVE Adult-onset hydrocephalus is not commonly discussed in the literature, especially regarding its demographic distribution. In contrast to pediatric hydrocephalus, which is related to a primary CSF pathway defect, its development in adults is often secondary to other pathologies. In this study, the authors investigated the epidemiology of adult-onset hydrocephalus as it pertains to different etiologies and in reference to age, sex, and race distributions. METHODS The authors retrospectively reviewed the clinical notes of 2001 patients with adult-onset hydrocephalus who presented to Louisiana State University Health Sciences Center within a 25-year span. Significant differences between the groups were analyzed by a chi-square test; p < 0.05 was considered significant. RESULTS The overall mean (± SEM) incidence of adult hydrocephalus in this population was 77 ± 30 per year, with a significant increase in incidence in the past decade (55 ± 3 [1990-2003] vs 102 ± 6 [2004-2015]; p < 0.0001). Hydrocephalus in a majority of the patients had a vascular etiology (45.5%) or was a result of a tumor (30.2%). The incidence of hydrocephalus in different age groups varied according to various pathologies. The incidence was significantly higher in males with normal-pressure hydrocephalus (p = 0.03) or head injury (p = 0.01) and higher in females with pseudotumor cerebri (p < 0.0001). In addition, the overall incidence of hydrocephalus was significantly higher in Caucasian patients (p = 0.0002) than in those of any other race. CONCLUSIONS Knowledge of the demographic variations in adult-onset hydrocephalus is helpful in achieving better risk stratification and better managing the disease in patients. For general applicability, these results should be validated in a large-scale meta-analysis based on a national population database.

  5. Guinea worm cause of adult onset asthmatic attack, a radiological diagnosis.

    PubMed

    Marchie, T T

    1999-01-01

    A case report of a fifty years old Hausa male from Sokoto town, Nigeria an endemic region of guinea worm infestation, who presented with sudden adult onset of asthmatic attack and was evaluated radiologically and the diagnosis of acute obstructive airway disease was confirmed. It was noted, that there were associated calcified chain of guinea worms in the lung parenchyma. A rare association of acute asthmatic attack. Patient responded there-after to an anti-asthmatic regime of management.

  6. Niemann-Pick type C: focus on the adolescent/adult onset form.

    PubMed

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment.

  7. Clinical Characteristics of Pediatric-Onset and Adult-Onset Multiple Sclerosis in Hispanic Americans.

    PubMed

    Langille, Megan M; Islam, Talat; Burnett, Margaret; Amezcua, Lilyana

    2016-07-01

    Multiple sclerosis can affect pediatric patients. Our aim was to compare characteristics between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanic Americans. This was a cross-sectional analysis of 363 Hispanic American multiple scleroses cases; demographic and clinical characteristics were analyzed. A total of 110 Hispanic patients presented with multiple sclerosis before age 18 and 253 as adult multiple sclerosis. The most common presenting symptoms for both was optic neuritis. Polyfocal symptoms, seizures, and cognitive symptoms at presentation were more prevalent in pediatric-onset multiple sclerosis (P ≤ .001). Transverse myelitis was more frequent in adult-onset multiple sclerosis (P ≤ .001). Using multivariable analysis, pediatric-onset multiple sclerosis (adjusted odds ratio, 0.3OR 95% confidence interval 0.16-0.71, P = .004) and being US born (adjusted odds ratio, 0.553, 95% confidence interval 0.3-1.03, P = .006) were less likely to have severe ambulatory disability. Results suggest that pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanics have differences that could be important for treatment and prognosis.

  8. Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.

    PubMed

    Manikkam, Mohan; Tracey, Rebecca; Guerrero-Bosagna, Carlos; Skinner, Michael K

    2012-01-01

    Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.

  9. Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population

    PubMed Central

    Ostrowski, Jerzy; Paziewska, Agnieszka; Lazowska, Izabella; Ambrozkiewicz, Filip; Goryca, Krzysztof; Kulecka, Maria; Rawa, Tomasz; Karczmarski, Jakub; Dabrowska, Michalina; Zeber-Lubecka, Natalia; Tomecki, Roman; Kluska, Anna; Balabas, Aneta; Piatkowska, Magdalena; Paczkowska, Katarzyna; Kierkus, Jaroslaw; Socha, Piotr; Lodyga, Michal; Rydzewska, Grazyna; Klopocka, Maria; Mierzwa, Grazyna; Iwanczak, Barbara; Krzesiek, Elzbieta; Bak-Drabik, Katarzyna; Walkowiak, Jaroslaw; Klincewicz, Beata; Radwan, Piotr; Grzybowska-Chlebowczyk, Urszula; Landowski, Piotr; Jankowska, Agnieszka; Korczowski, Bartosz; Starzynska, Teresa; Albrecht, Piotr; Mikula, Michal

    2016-01-01

    Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn’s disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Altogether, out of 88 selected SNPs, 31 SNPs were replicated for association with IBD. A novel BRD2 (rs1049526) association reached significance of P = 5.2 × 10−11 and odds ratio (OR) = 2.43. Twenty SNPs were shared between pediatric and adult patients; 1 and 7 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare and potentially deleterious variants in IBD-associated or innate immunity-associated genes. Deleterious alleles in both groups were over-represented among rare variants in affected children. Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare and deleterious variants in affected children suggests a contribution by yet unexplained genetic components. PMID:28008999

  10. Lifetime Increased Risk of Adult Onset Atopic Dermatitis in Adolescent and Adult Patients with Food Allergy

    PubMed Central

    Yu, Hsu-Sheng; Tu, Hung-Pin; Hong, Chien-Hui; Lee, Chih-Hung

    2016-01-01

    Food allergy can result in life-threatening anaphylaxis. Atopic dermatitis (AD) causes intense itching and impaired quality of life. Previous studies have shown that patients with classical early-onset AD tend to develop food allergy and that 10% of adults with food allergies have concomitant AD. However, it is not known whether late-onset food allergy leads to adult-onset AD, a recently recognized disease entity. Using an initial cohort of one-million subjects, this study retrospectively followed-up 2851 patients with food allergy (age > 12 years) for 14 years and compared them with 11,404 matched controls. While 2.8% (81) of the 2851 food allergy patients developed AD, only 2.0% (227) of the 11,404 controls developed AD. Multivariate regression analysis showed that food allergy patients were more likely to develop AD (adjusted hazard ratio = 2.49, p < 0.0001). Controls had a 1.99% risk of developing AD, while food allergy patients had a significantly higher risk (7.18% and 3.46% for patients with ≥3 and <3 food allergy claims, respectively) of developing adult-onset AD. This is the first study to describe the chronological and dose-dependent associations between food allergy in adolescence and the development of adult-onset AD. PMID:28035995

  11. Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.

    PubMed

    Manikkam, Mohan; Haque, M Muksitul; Guerrero-Bosagna, Carlos; Nilsson, Eric E; Skinner, Michael K

    2014-01-01

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.

  12. Adult Onset Still's Disease: A Review on Diagnostic Workup and Treatment Options

    PubMed Central

    Gopalarathinam, Rajesh; Orlowsky, Eric; Kesavalu, Ramesh; Yelaminchili, Sreeteja

    2016-01-01

    Adult onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology and pathogenesis that presents in 5 to 10% of patients as fever of unknown origin (FUO) accompanied by systemic manifestations. We report an interesting case of a 33-year-old African-American male who presented with one-month duration of FUO along with skin rash, sore throat, and arthralgia. After extensive workup, potential differential diagnoses were ruled out and the patient was diagnosed with AOSD based on the Yamaguchi criteria. The case history, incidence, pathogenesis, clinical manifestations, differential diagnoses, diagnostic workup, treatment modalities, and prognosis of AOSD are discussed in this case report. PMID:27042373

  13. Piriform sinus carcinoma with a paraneoplastic syndrome misdiagnosed as adult onset Still's disease: a case report.

    PubMed

    Yang, Liu; Li, Wen; Du, Jintao

    2015-01-01

    Paraneoplastic syndromes (PS) occur less commonly in association with otolaryngologic neoplasms than other carcinomas such as those of lung or breast. Piriform sinus carcinoma with PS is extremely rare. We here report a case of piriform sinus carcinoma accompanied by PS that was initially misdiagnosed as adult onset Still's disease and describe our diagnosis and treatment. One lesson we have drawn from the experience of this misdiagnosis is that PS symptoms may manifest before the primary tumor is evident and complicate the diagnostic process.

  14. Familial Adult-onset Alexander Disease: Clinical and Neuroradiological Findings of Three Cases

    PubMed Central

    ELMALI, Ayşe Deniz; ÇETİNÇELİK, Ümran; IŞLAK, Civan; UZUN ADATEPE, Nurten; KARAALİ SAVRUN, Feray; YALÇINKAYA, Cengiz

    2016-01-01

    The adult-onset Alexander disease (AOAD) dramatically differs from the early onset AD with respect to clinical and neuroradiological findings. Herein we report the detailed clinical and neuroradiological findings of a Turkish family with AOAD. In all three cases, magnetic resonance imaging revealed marked atrophy of the mesencephalon, bulbus, and cervical spinal cord accompanied with signal abnormalities in the same regions along with supratentorial white matter. Basal ganglia were affected in two cases. Molecular genetic analysis revealed heterozygous mutation in the 8th exon of the glial fibrillary acidic protein gene M451I (c.1245G>A), leading to the diagnosis of AOAD in all cases. PMID:28360791

  15. [Adult-onset Still's disease with liver failure requiring liver transplantation].

    PubMed

    Terán, Alvaro; Casafont, Fernando; Fábrega, Emilio; Martínez-Taboada, Víctor Manuel; Rodríguez-Valverde, Vicente; Pons-Romero, Fernando

    2009-12-01

    We present the case of a 23-year-old man with fever of unknown origin, who developed acute liver failure 2 months after symptom onset, requiring an urgent liver transplantation. The diagnosis of adult-onset Still's disease was established after the reappearance of symptoms after transplantation, and high doses of corticosteroids were used to control disease activity. Subsequently, given the impossibility of tapering the steroid dose, interleukin-1 receptor blocking treatment was started with satisfactory outcome. We also review the published literature.

  16. Non-motor symptoms in patients with adult-onset focal dystonia: Sensory and psychiatric disturbances.

    PubMed

    Conte, Antonella; Berardelli, Isabella; Ferrazzano, Gina; Pasquini, Massimo; Berardelli, Alfredo; Fabbrini, Giovanni

    2016-01-01

    Dystonia is characterized by the presence of involuntary muscle contractions that cause abnormal movements and posture. Adult onset focal dystonia include cervical dystonia, blepharospasm, arm dystonia and laryngeal dystonia. Besides motor manifestations, patients with focal dystonia frequently also display non-motor signs and symptoms. In this paper, we review the evidence of sensory and psychiatric disturbances in adult patients with focal dystonia. Clinical studies and neurophysiological investigations consistently show that the sensory system is involved in dystonia. Several studies have also demonstrated that neuropsychiatric disorders, particularly depression and anxiety, are more frequent in patients with focal dystonia, whereas data on obsessive compulsive disorders are more contrasting.

  17. Adult onset primary focal dystonia of the foot: an orthopaedic intervention.

    PubMed

    Logan, Loretta; Resseque, Barbara; Dontamsetti, Monica Sakshi

    2016-03-30

    A 54-year-old woman presented to a foot centre with a chief symptom of cramping in her toes, which, she believed, was of a secondary cause originating from a bunion. She was treated conservatively; however, she returned a month later as the symptoms had progressed to painful cramping of toes, toe-curling and instability while walking, due to involuntary movement of her toes. It was believed that the patient presented with a rare case of primary adult onset focal foot dystonia. This case report explains dystonia further in detail and delves into the different treatment and management options available today, including the unique orthopaedic intervention provided for this patient.

  18. Adult-onset opsoclonus-myoclonus syndrome due to West Nile Virus treated with intravenous immunoglobulin.

    PubMed

    Hébert, Julien; Armstrong, David; Daneman, Nick; Jain, Jennifer Deborah; Perry, James

    2017-02-01

    A 63-year-old female with no significant past medical history was presented with a 5-day history of progressive opsoclonus-myoclonus, headaches, and fevers. Her workup was significant only for positive West-Nile Virus serum serologies. She received a 2-day course of intravenous immunoglobulin (IvIG). At an 8-week follow up, she had a complete neurological remission. Adult-onset opsoclonus-myoclonus syndrome is a rare condition for which paraneoplastic and infectious causes have been attributed. To our knowledge, this is the first case reported of opsoclonus-myoclonus secondary to West-Nile Virus treated with intravenous immunoglobulin monotherapy.

  19. Herpes Zoster Meningitis Complicating Combined Tocilizumab and Cyclosporine Therapy for Adult-Onset Still's Disease

    PubMed Central

    Tsurukawa, Shinichiro; Iwanaga, Nozomi; Izumi, Yasumori; Shirakawa, Atsunori; Kawahara, Chieko; Shukuwa, Tetsuo; Inamoto, Miwako; Kawakami, Atsushi; Migita, Kiyoshi

    2016-01-01

    A 56-year-old female with refractory adult-onset Still's disease presented with ocular herpes zoster infection during TCZ treatment. After three days of acyclovir treatment (5 mg/kg), she developed a severe headache and high fever. Viral DNA isolation and cerebral spinal fluid abnormalities led to a herpes zoster meningitis diagnosis. Her meningitis was cured by high doses of intravenous acyclovir (10 mg/kg for 14 days). To our knowledge, this is the first report of meningeal herpes zoster infection in rheumatic diseases under TCZ treatment. PMID:27092286

  20. Adult-onset Still disease with peculiar persistent plaques and papules.

    PubMed

    Yoshifuku, A; Kawai, K; Kanekura, T

    2014-06-01

    Adult-onset Still disease (AOSD) is a systemic inflammatory disorder characterized clinically by high spiking fever, polyarthralgia/arthritis, a salmon-pink evanescent rash, predominantly neutrophilic leucocytosis, lymphadenopathy, liver dysfunction, and splenomegaly. Recently, a nonclassic, nonevanescent skin rash has been reported. We report a 27-year-old woman with AOSD showing persistent pruritic papular lesions. Histologically, dyskeratotic keratinocytes were seen in the upper epidermis. We describe this case in detail and review the previous literature. Nonclassic pruritic eruptions with characteristic dyskeratotic keratinocytes might provide an important clue for the diagnosis of AOSD.

  1. Adult onset leukodystrophy with neuroaxonal spheroids and demyelinating plaque-like lesions.

    PubMed

    Martinez-Saez, Elena; Shah, Sachit; Costa, Carme; Fleminger, Simon; Connor, Stephen; Bodi, Istvan

    2012-06-01

    Adult onset leukodystrophy with neuroaxonal spheroids is an uncommon cause of dementia. Both hereditary (autosomal dominant) and sporadic cases have been described. A 41-year-old African woman presented with inappropriate behavior and personality change consistent with frontal lobe dysfunction. MRI demonstrated diffuse frontoparietal white matter signal abnormality and volume loss, as well as focal enhancing white matter lesions, while CT scan showed white matter calcifications. She had been gradually deteriorating over the last 5 years, diagnosed as having progressive demyelinating illness. She died of recurrent chest infections. There was no familial history. The brain showed prominent symmetrical white matter changes with greyish discolorization mainly affecting the frontal and parietal lobes, with less involvement of the temporal lobe and only mildly affecting the occipital white matter. Histology revealed deep white matter atrophy with many neuroaxonal spheroids labelled by neurofilament and β-amyloid precursor protein. In addition, scattered inactive demyelinating plaque-like lesions were found in the periventricular areas, brainstem and the cervical spinal cord. This case had typical features of an adult onset leukodystrophy with neuroaxonal spheroids. However, we also demonstrated demyelinating plaque-like lesions, which has not been previously described. The possibility of a demyelinating origin contributing to the changes may be considered in the pathogenesis of this condition.

  2. Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis

    PubMed Central

    Yang, Yi; Lynch, David R.; Lukas, Thomas; Ahmeti, Kreshnik; Sleiman, Patrick M.A.; Ryan, Eanna; Schadt, Kimberly A.; Newman, Jordan H.; Deng, Han-Xiang; Siddique, Nailah

    2016-01-01

    Objective: To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients. Methods: Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer. Results: Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced. Conclusions: Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial. PMID:27123479

  3. Chinese new immigrant mothers' perception about adult-onset non-communicable diseases prevention during childhood.

    PubMed

    Wang, Linda Dong Ling; Lam, Wendy Wing Tak; Wu, Joseph Tsz Kei; Fielding, Richard

    2015-12-01

    Many non-communicable diseases (NCDs) are largely preventable via behaviour change and healthy lifestyle, which may be best established during childhood. This study sought insights into Chinese new immigrant mothers' perceptions about adult-onset NCDs prevention during childhood. Twenty-three semi-structured interviews were carried out with new immigrant mothers from mainland China who had at least one child aged 14 years or younger living in Hong Kong. Interviews were audio taped, transcribed and analysed using a Grounded Theory approach. The present study identified three major themes: perceived causes of adult NCDs, beliefs about NCDs prevention and everyday health information practices. Unhealthy lifestyle, contaminated food and environment pollution were perceived as the primary causes of adult NCDs. Less than half of the participants recognized that parents had responsibility for helping children establish healthy behaviours from an early age to prevent diseases in later life. Most participants expressed helplessness about chronic diseases prevention due to lack of knowledge of prevention, being perceived as beyond individual control. Many participants experienced barriers to seeking health information, the most common sources of health information being interpersonal conversation and television. Participants' everyday information practice was passive and generally lacked awareness regarding early prevention of adult-onset NCDs. Updated understanding of this issue has notable implications for future health promotion interventions.

  4. Distinguishing adult-onset asthma from COPD: a review and a new approach

    PubMed Central

    Abramson, Michael J; Perret, Jennifer L; Dharmage, Shyamali C; McDonald, Vanessa M; McDonald, Christine F

    2014-01-01

    Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are major public health burdens. This review presents a comprehensive synopsis of their epidemiology, pathophysiology, and clinical presentations; describes how they can be distinguished; and considers both established and proposed new approaches to their management. Both adult-onset asthma and COPD are complex diseases arising from gene–environment interactions. Early life exposures such as childhood infections, smoke, obesity, and allergy influence adult-onset asthma. While the established environmental risk factors for COPD are adult tobacco and biomass smoke, there is emerging evidence that some childhood exposures such as maternal smoking and infections may cause COPD. Asthma has been characterized predominantly by Type 2 helper T cell (Th2) cytokine-mediated eosinophilic airway inflammation associated with airway hyperresponsiveness. In established COPD, the inflammatory cell infiltrate in small airways comprises predominantly neutrophils and cytotoxic T cells (CD8 positive lymphocytes). Parenchymal destruction (emphysema) in COPD is associated with loss of lung tissue elasticity, and small airways collapse during exhalation. The precise definition of chronic airflow limitation is affected by age; a fixed cut-off of forced expiratory volume in 1 second/forced vital capacity leads to overdiagnosis of COPD in the elderly. Traditional approaches to distinguishing between asthma and COPD have highlighted age of onset, variability of symptoms, reversibility of airflow limitation, and atopy. Each of these is associated with error due to overlap and convergence of clinical characteristics. The management of chronic stable asthma and COPD is similarly convergent. New approaches to the management of obstructive airway diseases in adults have been proposed based on inflammometry and also multidimensional assessment, which focuses on the four domains of the airways, comorbidity, self-management, and

  5. The ocular motor features of adult-onset alexander disease: a case and review of the literature.

    PubMed

    Pfeffer, Gerald; Abegg, Mathias; Vertinsky, A Talia; Ceccherini, Isabella; Caroli, Francesco; Barton, Jason J S

    2011-06-01

    A 51-year-old Chinese man presented with gaze-evoked nystagmus, impaired smooth pursuit and vestibular ocular reflex cancellation, and saccadic dysmetria, along with a family history suggestive of late-onset autosomal dominant parkinsonism. MRI revealed abnormalities of the medulla and cervical spinal cord typical of adult-onset Alexander disease, and genetic testing showed homozygosity for the p.D295N polymorphic allele in the gene encoding the glial fibrillary acidic protein. A review of the literature shows that ocular signs are frequent in adult-onset Alexander disease, most commonly gaze-evoked nystagmus, pendular nystagmus, and/or oculopalatal myoclonus, and less commonly ptosis, miosis, and saccadic dysmetria. These signs are consistent with the propensity of adult-onset Alexander disease to cause medullary abnormalities on neuroimaging.

  6. Limited diagnostic value of procalcitonin in early diagnosis of adult onset Still’s disease

    PubMed Central

    Wysocki, Jacek

    2016-01-01

    A 17-year-old female patient was referred to the Infectious Diseases Ward because of fever lasting for 14 days. On admission to the hospital the patient was in a generally good state, without any abnormalities on physical examination. Laboratory investigation revealed elevated inflammatory markers. Diagnostic imaging comprising chest X-ray, abdominal ultrasonography, and echocardiography showed no abnormalities. During the hospitalization, there occurred episodes of fever with skin rash and musculoskeletal pain of the lower limbs. Procalcitonin concentrations continued to increase. C-reactive protein concentrations decreased during therapy, starting from 191 mg/l. On the 23rd day of the disease, edema of the feet, ankles, and knees appeared. On the basis of the clinical picture and after excluding other possible causes of fever, the patient was diagnosed with adult onset Still’s disease. The procalcitonin concentration was normalized after 5 days of steroid therapy. The patient was discharged under ambulatory rheumatologic supervision. PMID:27826176

  7. Limited diagnostic value of procalcitonin in early diagnosis of adult onset Still's disease.

    PubMed

    Gowin, Ewelina; Wysocki, Jacek

    2016-01-01

    A 17-year-old female patient was referred to the Infectious Diseases Ward because of fever lasting for 14 days. On admission to the hospital the patient was in a generally good state, without any abnormalities on physical examination. Laboratory investigation revealed elevated inflammatory markers. Diagnostic imaging comprising chest X-ray, abdominal ultrasonography, and echocardiography showed no abnormalities. During the hospitalization, there occurred episodes of fever with skin rash and musculoskeletal pain of the lower limbs. Procalcitonin concentrations continued to increase. C-reactive protein concentrations decreased during therapy, starting from 191 mg/l. On the 23(rd) day of the disease, edema of the feet, ankles, and knees appeared. On the basis of the clinical picture and after excluding other possible causes of fever, the patient was diagnosed with adult onset Still's disease. The procalcitonin concentration was normalized after 5 days of steroid therapy. The patient was discharged under ambulatory rheumatologic supervision.

  8. [A case of adult-onset type II citrullinemia in an elderly patient].

    PubMed

    Kitaoka, Mayuko; Sakaeda, Hiroshi; Suzuki, Mika; Miki, Toshifumi; Saito, Junko; Chikamori, Masayasu; Tomita, Hideharu; Ichikawa, Hiromoto; Yoshimoto, Kaori; Takamatsu, Masahiro; Okada, Mitsuo; Aono, Rei; Enzan, Hideaki; Miyamoto, Takako

    2013-03-01

    A 72-year-old man presented with consciousness disturbance. The results of brain magnetic resonance imaging and cerebrospinal fluid examination were normal, but triphasic waves were noted on electroencephalography. His plasma ammonia level was elevated due to which encephalopathy secondary to hyperammonemia was suspected. However, his liver function was normal, and no evidence of cirrhosis or portal-systemic shunt was noted. The patient's medical history revealed that he had a tendency to excessively consume pulse products since childhood, and an amino acid analysis showed elevation of citrulline and arginine levels. Thus, we diagnosed the patient with an extremely rare case of adult-onset type II citrullinemia, which was triggered by cessation of the intake of pulse foods (soybeans and peanuts) due to dental problems.

  9. Adult-onset nemaline myopathy in a dog presenting with persistent atrial standstill and primary hypothyroidism.

    PubMed

    Nakamura, R K; Russell, N J; Shelton, G D

    2012-06-01

    A nine-year-old neutered female mixed breed dog presented for evaluation following a five-day history of lethargy, inappetence, weakness, abdominal distension and generalised muscle atrophy. Persistent vatrial standstill with a junctional rhythm was identified on electrocardiogram. Echocardiogram identified moderate dilation of all cardiac chambers and mild thickening of the mitral and tricuspid valves. Serology was negative for Neospora caninum and Toxoplasma gondii. Permanent pacemaker implantation was performed in addition to endomyocardial and skeletal muscle biopsies. Cryosections from the biceps femoris muscle showed numerous nemaline rod bodies while endomyocardial biopsies were possibly consistent with end-stage myocarditis. Rod bodies have rarely been reported in the veterinary literature. To the authors' knowledge, this is the first report of adult-onset nemaline rod myopathy and hypothyroidism with concurrent cardiac disease in a dog.

  10. Adult-onset Still’s disease: current challenges and future prospects

    PubMed Central

    Siddiqui, Mariam; Putman, Michael S; Dua, Anisha B

    2016-01-01

    Adult-onset Still’s disease (AOSD) – a multi-systemic inflammatory condition characterized by high fevers, polyarthritis, an evanescent rash, and pharyngitis – has been a challenging condition to diagnose expediently and treat effectively. Questions remain regarding the underlying pathophysiology and etiology of AOSD. Pathognomonic diagnostic tests and reliable biomarkers remain undiscovered. Over the past decade, important progress has been made. Diagnostic criteria employing glycosylated ferritin have improved specificity. More important, novel biologic therapies have offered important clues to AOSD’s underlying pathophysiology. Cytokine-specific biologic therapies have been instrumental in providing more effective treatment for disease refractory to conventional treatment. While IL-1 therapy has demonstrated efficacy in refractory disease, novel therapies targeting IL-6 and IL-18 show great promise and are currently under investigation. PMID:27843366

  11. Adult-onset intradural spinal teratoma in the lumbar spine: A case report.

    PubMed

    Arai, Yasuhisa; Takahashi, Masaki; Takeda, Koutarou; Shitoto, Katsuo

    2000-12-01

    Intradural spinal teratoma is a very rare tumour that can be associated with dysraphic defects. We report a case of adult-onset intradural spinal teratoma in the lumbar spine. The patient was a 54-year-old female who had chief complaints of a gait disturbance. X-rays showed an enlargement of the interpedicular distance at L3/L4 and spina bifida distal to L4. MRI showed a spindle-shaped tumour between L2 and L5. We performed laminotomy using an ultrasonic surgical knife. Pathological diagnosis of the resected tumour was matured teratoma. The diagnosis of matured teratoma was made because the tumour had no epithelium and a layered structure including prostate tissue, matured fat, cartilage and sweat gland.

  12. Hidden in plain sight: macrophage activation syndrome complicating Adult Onset Still's Disease.

    PubMed

    Benitez, Lourdes; Vila, Salvador; Mellado, Robert Hunter

    2010-01-01

    Hemophagocytic Lymphystiocytosis is a rare and fatal complication of rheumatic diseases, particularly Adult Onset Still's Disease (AOSD). It may be precipitated with immunosuppressive drugs and with viral and bacterial infections. A diagnosis depends on a high index of suspicion associated to certain clinical manifestations (fever, rash, Splemomegaly, any cytology blood dyscrasia, hipertrigliceridemia, hiperfibrinogenemia, and others), as well as pathologic evidence of hemophagocitosis from bone marrow biopsy or tissue samples of affected organs. Therapy consists of high dose corticosteroids and immunosuppressive drugs. We present a 42 year old woman with AOSD in remission who developed HLH in spite of receiving therapy with high dose steroids and immunosuppressive drugs. She had 2 negative bone marrow aspirates. Evidence of Hemophagocytosis was detected in both bone marrow biopsies. Timely evaluation and recognition of the signs and symptoms of HLH is crucial for the prompt management and a decrease in the mortality associated with this disease.

  13. Predictive Medicine: Recombinant DNA Technology and Adult-Onset Genetic Disorders

    PubMed Central

    Hayden, Michael

    1988-01-01

    Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID:21253100

  14. Adult-onset Still's disease and chronic recurrent multifocal osteomyelitis: a hitherto undescribed manifestation of autoinflammation.

    PubMed

    Rech, J; Manger, B; Lang, B; Schett, G; Wilhelm, M; Birkmann, J

    2012-06-01

    Still's disease and chronic recurrent multifocal osteomyelitis (CRMO) are febrile rheumatic diseases of unknown etiology, which predominantly affect children but can also have their initial manifestation in adults. Both can present as intermittent, relapsing episodes and are considered potential candidates within the expanding spectrum of autoinflammatory disorders, although no genetic abnormalities have been described for either of them. Here, we describe a man with an initial manifestation of abacterial multifocal osteitis at the age of 41. During a relapsing-remitting course of his illness, he increasingly developed symptoms of adult-onset Still's disease (AOSD), and the diagnosis was established according to the Yamaguchi criteria. When treated with anakinra, not only the acute symptoms disappeared promptly, but also the osteitis went into complete remission. This is to our knowledge the first description of a simultaneous occurrence of these two manifestations of autoinflammation in adulthood.

  15. Case report: An adult-onset type II citrin deficiency patient in the emergency department

    PubMed Central

    TANG, LUJIA; CHEN, LIANG; WANG, HAIRONG; DAI, LIHUA; PAN, SHUMING

    2016-01-01

    Mutations in the solute carrier family 25 (SLC25A13) gene may result in neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia. These conditions are inherited in an autosomal recessive manner. The current case report describes a 43-year-old man who presented with sudden delirium and upper limb weakness. Upon admission, the patient was fully conscious and alert but later lost consciousness subsequent to a sudden convulsive seizure. Hyperammonemia was detected and analysis of the SLC25A13 gene identified an 851del4 mutation. Thus, the possibility of genetic disease should be considered as a potential cause of the symptoms of patients with altered states of consciousness, such as delirium and loss of consciousness, in cases where the cause of the disturbance is unknown. PMID:27347070

  16. Occupational exposures and uncontrolled adult-onset asthma in the European Community Respiratory Health Survey II.

    PubMed

    Le Moual, Nicole; Carsin, Anne-Elie; Siroux, Valérie; Radon, Katja; Norback, Dan; Torén, Kjell; Olivieri, Mario; Urrutia, Isabel; Cazzoletti, Lucia; Jacquemin, Bénédicte; Benke, Geza; Kromhout, Hans; Mirabelli, Maria C; Mehta, Amar J; Schlünssen, Vivi; Sigsgaard, Torben; Blanc, Paul D; Kogevinas, Manolis; Antó, Josep M; Zock, Jan-Paul

    2014-02-01

    Occupational exposure is a well-recognised modifiable risk factor for asthma, but the relationship between occupational exposure and asthma control has not been studied. We aimed to study this association among working-age adults from the European Community Respiratory Health Survey (ECRHS). Data were available for 7077 participants (mean age 43 years, 45% never-smokers, 5867 without asthma and 1210 with current asthma). Associations between occupational exposure to specific asthmagens and asthma control status (33% with uncontrolled asthma, based on the Global Initiative for Asthma guidelines) were evaluated using logistic and multinomial regressions, adjusted for age, sex and smoking status, with study areas included as a random effect. Statistically significant positive associations were observed between uncontrolled adult-onset asthma and both past 12-month and 10-year exposure to any occupational asthmagens (OR (95% CI) 1.6 (1.0-2.40) and 1.7 (1.2-2.5), respectively); high (1.7 (1.0-2.8) and 1.9 (1.3-2.9), respectively) and low (1.6 (1.0-2.7) and 1.8 (1.2-2.7), respectively) molecular weight agents; and cleaning agents (2.0 (1.1-3.6) and 2.3 (1.4-3.6), respectively), with stronger associations for long-term exposures. These associations were mainly explained by the exacerbation domain of asthma control and no associations were observed between asthmagens and partly controlled asthma. These findings suggest that occupational exposure to asthmagens is associated with uncontrolled adult-onset asthma. Occupational risk factors should be quickly identified to prevent uncontrolled asthma.

  17. Wolman's Disease: A Microscopic and Biochemical Study Showing Accumulation of Ceroid and Esterified Cholesterol

    PubMed Central

    Lowden, J. A.; Barson, A. J.; Wentworth, P.

    1970-01-01

    A case of Wolman's disease is described in a female infant who died at 7 weeks of age. This rare familial disorder is characterized by bilateral adrenal calcification and the accumulation of esterified cholesterol in many tissues. For the first time large quantities of ceroid have been demonstrated in the liver, spleen, adrenals, lymph nodes and particularly within the lamina propria of the small intestine. It is postulated that there exists in these patients a decreased activity of cholesterol esterases. The accumulated cholesterol esters may then be oxidized to form ceroid. Since ceroid is quite impermeable, intestinal absorption is progressively impaired, leading ultimately to death. ImagesFIG. 1FIG. 2FIG. 3 PMID:5414926

  18. Adult-onset Still's disease presenting as fever of unknown origin in a patient with HIV infection.

    PubMed

    DelVecchio, Sally; Skidmore, Peter

    2008-02-15

    A 43-year-old African American man with known human immunodeficiency virus (HIV) infection was found to have adult-onset Still's disease manifesting as fever of unknown origin. In the era of highly active antiretroviral therapy, HIV-infected patients are preserving their immune status and, thus, must be evaluated in a manner similar to that for the general population.

  19. Occasional detection of thymic epithelial tumor 4 years after diagnosis of adult onset Still disease

    PubMed Central

    Lococo, Filippo; Bajocchi, Gianluigi; Caruso, Andrea; Valli, Riccardo; Ricchetti, Tommaso; Sgarbi, Giorgio; Salvarani, Carlo

    2016-01-01

    Abstract Background: Thymoma is a T cell neoplasm arising from the thymic epithelium that due to its immunological role, frequently undercover derangements of immunity such a tumors and autoimmune diseases. Methods: Herein, we report, to the best of our knowledge, the first description of an association between thymoma and adult onset Still disease (AOSD) in a 47-year-old man. The first one was occasionally detected 4 years later the diagnosis of AOSD, and surgically removed via right lateral thoracotomy. Histology confirmed an encapsulated thymic tumor (type AB sec. WHO-classification). Results: The AOSD was particularly resistant to the therapy, requiring a combination of immunosuppressant followed by anti-IL1R, that was the only steroids-sparing treatment capable to induce and maintain the remission. The differential diagnosis was particularly challenging because of the severe myasthenic-like symptoms that, with normal laboratory tests, were initially misinterpreted as fibromyalgia. The pathogenic link of this association could be a thymus escape of autoreactive T lymphocytes causing autoimmunity. Conclusion: Clinicians should be always include the possibility of a thymoma in the differential diagnosis of an unusual new onset of weakness and normal laboratories data, in particular once autoimmune disease is present in the medical history. PMID:27603335

  20. A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy

    PubMed Central

    Bee, Leonardo; Nasca, Alessia; Zanolini, Alice; Cendron, Filippo; d'Adamo, Pio; Costa, Rodolfo; Lamperti, Costanza; Celotti, Lucia; Ghezzi, Daniele; Zeviani, Massimo

    2015-01-01

    We studied two monozygotic twins, born to first cousins, affected by a multisystem disease. At birth, they both presented with bilateral cryptorchidism and malformations. Since early adulthood, they developed a slowly progressive neurological syndrome, with cerebellar and pyramidal signs, cognitive impairment, and depression. Dilating cardiomyopathy is also present in both. By whole-exome sequencing, we found a homozygous nucleotide change in XRCC4 (c.673C>T), predicted to introduce a premature stop codon (p.R225*). XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts. XRCC4 plays an important role in non-homologous end joining of DNA double-strand breaks (DSB), a system that is involved in repairing DNA damage from, for example, ionizing radiations. Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair. In contrast with embryonic lethality of the Xrcc4 KO mouse, nonsense mutations in human XRCC4 have recently been associated with primordial dwarfism and, in our cases, with adult-onset neurological impairment, suggesting an important role for DNA repair in the brain. Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients. PMID:25872942

  1. Adult-onset hypogonadism: evaluation and role of testosterone replacement therapy

    PubMed Central

    Davidiuk, Andrew J.

    2016-01-01

    Testosterone deficiency (TD) has become a growing concern in the field of men’s sexual health, with an increasing number of men presenting for evaluation of this condition. Given the increasing demand for testosterone replacement therapy (TRT), a panel of experts met in August of 2015 to discuss the treatment of men who present for evaluation in the setting of low or normal gonadotropin levels and the associated signs and symptoms of hypogonadism. This constellation of factors can be associated with elements of both primary and secondary hypogonadism. Because this syndrome commonly occurs in men who are middle-aged and older, it was termed adult-onset hypogonadism (AOH). AOH can be defined by the following elements: low levels of testosterone, associated signs and symptoms of hypogonadism, and low or normal gonadotropin levels. Although there are significant benefits of TRT for patients with AOH, candidates also need to understand the potential risks. Patients undergoing TRT will need to be monitored regularly because there are potential complications that can develop with long-term use. This review is aimed at providing a deeper understanding of AOH, discussing the benefits and risks of TRT, and outlining each modality of TRT in use for AOH. PMID:28078213

  2. Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability

    PubMed Central

    Ahmed, Naghia; Ronchi, Dario; Comi, Giacomo Pietro

    2015-01-01

    Replication and maintenance of mtDNA entirely relies on a set of proteins encoded by the nuclear genome, which include members of the core replicative machinery, proteins involved in the homeostasis of mitochondrial dNTPs pools or deputed to the control of mitochondrial dynamics and morphology. Mutations in their coding genes have been observed in familial and sporadic forms of pediatric and adult-onset clinical phenotypes featuring mtDNA instability. The list of defects involved in these disorders has recently expanded, including mutations in the exo-/endo-nuclease flap-processing proteins MGME1 and DNA2, supporting the notion that an enzymatic DNA repair system actively takes place in mitochondria. The results obtained in the last few years acknowledge the contribution of next-generation sequencing methods in the identification of new disease loci in small groups of patients and even single probands. Although heterogeneous, these genes can be conveniently classified according to the pathway to which they belong. The definition of the molecular and biochemical features of these pathways might be helpful for fundamental knowledge of these disorders, to accelerate genetic diagnosis of patients and the development of rational therapies. In this review, we discuss the molecular findings disclosed in adult patients with muscle pathology hallmarked by mtDNA instability. PMID:26251896

  3. A new structural approach to genomic discovery of disease: example of adult-onset diabetes.

    PubMed

    Sirovich, Lawrence

    2016-12-01

    This paper reports on an investigation of disease discovery from genomic data, by methods which depart substantially from customary practices found in the investigation of genome-wide association studies. Such data in general are composed of the genomic content from two contrasting phenotypes, e.g., disease versus control populations, and the analysis proceeds under the hypothesis that populational dissimilarities might reveal disease risk alleles. The proposed suite of new methods is in part based on information theory (Shannon in Bell Syst Tech J 27:379-423, 1948a; Bell Syst Tech J 27:623-656, 1948b; Jaynes in Phys Rev 106:620-630, 1957), and strong evidence will be given of the effectiveness of this new approach. The methodology extends naturally and successfully to predicting genomic disposition to disease arising from large collections of weakly contributing genomic loci. Evidence will be advanced that the example of adult-onset diabetes ("type 2 diabetes") is such a candidate disease, and in this case, probably for the first time, it can be demonstrated that disease prediction is possible. Another novel element of this study is the search and identification of potential beneficial genomic loci that may counter a disease. The generality of the methodology suggests that it might extend to other diseases.

  4. Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease Successfully Treated with Anakinra

    PubMed Central

    Kato, Hiroshi

    2016-01-01

    Macrophage activation syndrome (MAS) is a potentially fatal complication of Adult-Onset Still's disease (Still's disease). Whereas an increasing body of evidence supports interleukin-1 (IL-1) blockade as a promising treatment for Still's disease, whether it is therapeutic for MAS associated with Still's disease remains unclear. We report a 34-year-old Caucasian man with one-decade history of TNF-blockade-responsive seronegative arthritis who presented with abrupt onset of fever, serositis, bicytopenia, splenomegaly, hepatitis, and disseminated intravascular coagulation. Striking hyperferritinemia was noted without evidence of infection, malignancy, or hemophagocytosis on bone marrow biopsy. NK cells were undetectable in the peripheral blood, whereas soluble IL-2 receptor was elevated. His multiorgan disease resolved in association with methylprednisolone pulse therapy, Anakinra, and a tapering course of prednisone. This case reinforces the notion that Still's disease is inherently poised to manifest MAS as one of the clinical phenotypes by shedding light on the role of IL-1 underlying both Still's disease and related MAS. PMID:27818826

  5. Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis.

    PubMed

    Santín, Sheila; García-Maset, Rafael; Ruíz, Patricia; Giménez, Isabel; Zamora, Isabel; Peña, Antonia; Madrid, Alvaro; Camacho, Juan A; Fraga, Gloria; Sánchez-Moreno, Ana; Cobo, Maria Angeles; Bernis, Carmen; Ortiz, Alberto; de Pablos, Augusto Luque; Pintos, Guillem; Justa, Maria Luisa; Hidalgo-Barquero, Emilia; Fernández-Llama, Patricia; Ballarín, José; Ars, Elisabet; Torra, Roser

    2009-12-01

    Mutations in the NPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3 months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistant nephrotic syndrome and milder courses of disease, but their role in adults with focal segmental glomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate the pathogenicity of amino-acid substitutions using the biophysical and biochemical difference between wild-type and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs, and defined domains, with the addition of contextual information. Mutation analysis was performed in 97 patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndrome after 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in five familial and seven sporadic cases, including one patient 27 years old at onset of the disease. Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest an earlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one 'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosis indicates that NPHS1 analysis could be considered in patients with later onset of the disease.

  6. The distinction between juvenile and adult-onset primary open-angle glaucoma

    SciTech Connect

    Wiggs, J.L.; Haines, J.L.; Damji, K.F.

    1996-01-01

    Because of the significant differences between the juvenile and adult forms of open-angle glaucoma, especially with regard to inheritance, prevalence, severity, and age of onset, we read with interest the recent publication by Morissette et al., describing a pedigree with a phenotype that overlaps the distinctive features of juvenile-onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (usually abbreviated as POAG or COAG). These authors conclude that a gene mapped to human chromosome 1q21-q31 (GLC1A) can be responsible for both juvenile and adult forms of open-angle glaucoma. The implications of such a result could be extremely important, in light of the high prevalence of the adult form of the disease. However, while the data presented in this report suggest that variable expressivity of the GLC1A gene may lead to a broader range of onset for this form of juvenile glaucoma, these data do not identify the GLC1A gene as an important cause of POAG. To prevent misleading interpretations of this and similar studies, we wish to clarify the distinction between the juvenile and adult forms of open-angle glaucoma. 8 refs.

  7. Clinical and histopathological features of cutaneous manifestations of adult-onset Still disease.

    PubMed

    Santa, Erin; McFalls, Jeanne M; Sahu, Joya; Lee, Jason B

    2017-03-25

    Adult-onset Still disease (AOSD) is a rare autoinflammatory syndrome characterized by recurring fevers, arthralgia, and consistent laboratory abnormalities that include leukocytosis and hyperferritinemia. Skin findings accompany the disease in nearly 90% of the cases. Early reports described evanescent, pruritic, salmon-pink or urticarial lesions, referred to as the typical eruption of AOSD. Histopathologic findings consist of superficial perivascular dermatitis with varying number of interstitial neutrophils. Later reports described a more persistent rash that tended to be photodistributed, hyperpigmented, often in a linear configuration, sometimes in a rippled pattern, referred to as the atypical eruption of AOSD. The presence of individual necrotic keratinocytes in the upper spinous layer has been the consistent histopathologic finding. The persistent rash may not represent an atypical presentation of AOSD as recent reports indicate a high prevalence of the rash. Emerging data also suggest that patients with persistent eruption have a worse prognosis. The recognition of the clinical and histopathological findings of skin eruptions of AOSD may facilitate an earlier diagnosis, potentially improving disease outcome. Herein, clinical and histopathological features of cutaneous manifestation of AOSD in two Asian women are highlighted accompanied by relevant review of the disease.

  8. Updates in adult-onset Still disease: Atypical cutaneous manifestations and associations with delayed malignancy.

    PubMed

    Sun, Natalie Z; Brezinski, Elizabeth A; Berliner, Jacqueline; Haemel, Anna; Connolly, M Kari; Gensler, Lianne; McCalmont, Timothy H; Shinkai, Kanade

    2015-08-01

    Adult-onset Still disease (AOSD) is a systemic inflammatory disorder that is clinically characterized by a heterogeneous constellation of symptoms and signs. Though an evanescent eruption is the classic cutaneous finding, recent literature has highlighted atypical rashes associated with Still disease. A second emerging concept in presentations of AOSD is its association with malignancy. This review focuses on these concepts: the clinical spectrum of atypical skin manifestations and AOSD as a paraneoplastic phenomenon. PubMed-MEDLINE was screened for peer-reviewed articles describing atypical presentations of AOSD and cases associated with malignancy. Erythematous, brown or violaceous, persistent papules and plaques were the most common cutaneous finding (28/30 [93%]). Linear configurations were also rarely described. Of these patients, 81% concurrently had the typical evanescent skin eruption. There were 31 patients with associated malignancies, most commonly breast cancer and lymphoma. The diagnosis of malignancy did not precede or immediately follow a clinical presentation otherwise consistent with AOSD in a considerable subset of patients (42%). Understanding the cutaneous spectrum of AOSD and heightened awareness for its delayed association with malignancy may lead to improved recognition of cutaneous variants and reinforce the need for diagnostic evaluation and long-term follow-up for malignancy in patients with this clinical presentation.

  9. Effects of Aging and Adult-Onset Hearing Loss on Cortical Auditory Regions

    PubMed Central

    Cardin, Velia

    2016-01-01

    Hearing loss is a common feature in human aging. It has been argued that dysfunctions in central processing are important contributing factors to hearing loss during older age. Aging also has well documented consequences for neural structure and function, but it is not clear how these effects interact with those that arise as a consequence of hearing loss. This paper reviews the effects of aging and adult-onset hearing loss in the structure and function of cortical auditory regions. The evidence reviewed suggests that aging and hearing loss result in atrophy of cortical auditory regions and stronger engagement of networks involved in the detection of salient events, adaptive control and re-allocation of attention. These cortical mechanisms are engaged during listening in effortful conditions in normal hearing individuals. Therefore, as a consequence of aging and hearing loss, all listening becomes effortful and cognitive load is constantly high, reducing the amount of available cognitive resources. This constant effortful listening and reduced cognitive spare capacity could be what accelerates cognitive decline in older adults with hearing loss. PMID:27242405

  10. A search for the primary abnormality in adult-onset type II citrullinemia

    SciTech Connect

    Kobayashi, Keiko; Shaheen, Nazma; Saheki, Takeyori ); Kumashiro, Ryukichi; Tanikawa, Kyuichi ); O'Brien, W.E.; Beaudet, A.L. )

    1993-11-01

    Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, the authors show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. The authors also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus. 29 refs., 1 fig., 3 tabs.

  11. Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability.

    PubMed

    Ahmed, Naghia; Ronchi, Dario; Comi, Giacomo Pietro

    2015-08-05

    Replication and maintenance of mtDNA entirely relies on a set of proteins encoded by the nuclear genome, which include members of the core replicative machinery, proteins involved in the homeostasis of mitochondrial dNTPs pools or deputed to the control of mitochondrial dynamics and morphology. Mutations in their coding genes have been observed in familial and sporadic forms of pediatric and adult-onset clinical phenotypes featuring mtDNA instability. The list of defects involved in these disorders has recently expanded, including mutations in the exo-/endo-nuclease flap-processing proteins MGME1 and DNA2, supporting the notion that an enzymatic DNA repair system actively takes place in mitochondria. The results obtained in the last few years acknowledge the contribution of next-generation sequencing methods in the identification of new disease loci in small groups of patients and even single probands. Although heterogeneous, these genes can be conveniently classified according to the pathway to which they belong. The definition of the molecular and biochemical features of these pathways might be helpful for fundamental knowledge of these disorders, to accelerate genetic diagnosis of patients and the development of rational therapies. In this review, we discuss the molecular findings disclosed in adult patients with muscle pathology hallmarked by mtDNA instability.

  12. Juvenile versus adult-onset ankylosing spondylitis -- clinical, radiographic, and social outcomes. a systematic review.

    PubMed

    Jadon, Deepak R; Ramanan, Athimalaipet V; Sengupta, Raj

    2013-11-01

    Ankylosing spondylitis (AS) has 2 main modes of onset: juvenile-onset AS (JoAS) and adult-onset AS (AoAS). It is not known whether JoAS is a subtype of AS, or AS modulated by early age of onset and longer disease duration. We performed a systematic review of the literature, identifying 12 articles and 1 abstract directly comparing JoAS and AoAS cohorts, with observational study design. Patients with JoAS appear to have more peripheral joint involvement both clinically and radiographically (especially knees and ankles) and more root joint involvement (hips and shoulders); they are more likely to proceed to hip arthroplasty and often initially present with peripheral rather than axial symptoms. Patients with AoAS appear to have more axial symptoms and radiographic disease, particularly in the lumbar spine, and worse axial metrology. In terms of other characteristics, more evidence is needed to confidently state whether JoAS and AoAS are different.

  13. Unique histopathologic findings in a patient with adult-onset Still disease.

    PubMed

    Wolgamot, Greg; Yoo, Jane; Hurst, Stan; Gardner, Greg; Olerud, John; Argenyi, Zsolt

    2007-04-01

    Adult-onset Still disease (AOSD) is an uncommon disorder characterized by fever, polyarthralgia, elevated white blood cell count, and a maculopapular rash, the histologic features of which have not been well-known. A 55-year-old Asian woman presented initially with a "burning" and severely pruritic eruption on her face, hands, and arms, thought clinically to be urticaria. Within 1 month, she began spiking high fevers, developed diffuse joint pain, and had marked elevations of ferritin, C-reactive protein, and erythrocyte sedimentation rate, characteristic of AOSD. The cutaneous eruption became more widespread, involving the trunk, scalp, and remainder of the extremities, with diffuse thickening of the skin with papular and linear hyperpigmentation and accentuation. Biopsies from several locations showed focal hyperkeratosis associated with dyskeratotic keratinocytes with a peculiar, distinctive distribution in the upper epidermis and cornified layers. In addition, increased dermal mucin was present, with minimal fibroblast proliferation and inflammation. This unusual combination of diffuse dermal mucinosis and a unique pattern of dyskeratosis can present a challenge in generating an accurate differential diagnosis, and may represent an unusual response to chronic scratching or be a distinctive histologic manifestation of AOSD.

  14. Adult-onset NREM parasomnia with hypnopompic hallucinatory pain: a case report.

    PubMed

    Mantoan, Laura; Eriksson, Sofia H; Nisbet, Angus P; Walker, Matthew C

    2013-02-01

    We report the case of a 43-year-old woman presenting with nocturnal episodes of pain and screaming during sleep starting at age 30. There was no childhood or family history of parasomnia. The events had gradually become more frequent over the years, occurring in the first half of the night within 2 h of sleep onset. There were no triggers, and she had partial amnesia for the events. A diagnosis of adult-onset sleep terrors was made on clinical grounds and supported polysomnographically. Seizures and periodic limb movements were excluded as triggering factors. There was some mild sleep disordered breathing (predominantly non-desaturating hypopnea with a propensity for REM sleep of debatable significance). Imaging of the brain and spine and neurophysiological investigations ruled out lesions, entrapments, or neuropathies as possible causes of pain. Treatment (clonazepam, paroxetine, or gabapentin) was poorly tolerated and made no difference to the nocturnal episodes, while trazodone worsened them. This is the first report of hypnopompic psychic pain in association with a NREM parasomnia. We hypothesize that the pain may represent a sensory hallucination analogous to the more commonly recognized visual NREM parasomnia-associated hypnopompic visual hallucinations and that, as such, it may arise during arousal of the sensory neocortex as confabulatory response.

  15. B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

    PubMed Central

    Schwarz, Alexander; Balint, Bettina; Korporal-Kuhnke, Mirjam; Jarius, Sven; von Engelhardt, Kathrin; Fürwentsches, Alexandra; Bussmann, Cornelia; Ebinger, Friedrich; Haas, Jürgen

    2016-01-01

    Objective: To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS). Methods: In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA. Results: Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M. Conclusions: We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS. PMID:28053999

  16. Novel case of Trevor’s disease: Adult onset and later recurrence

    PubMed Central

    Khalsa, Amrit S; Kumar, Neil S; Chin, Matthew A; Lackman, Richard D

    2017-01-01

    Dysplasia epiphysealis hemimelica (DEH), or Trevor’s disease, is an osteocartilaginous epiphyseal overgrowth typically occurring in children. The literature reports 6 adult cases and none describe recurrence requiring additional procedures. We present a new-onset proximal tibial DEH in an adult recurring approximately 3 years after open excision. A 39-year-old female presented with a history of right knee pain, swelling, and instability. Physical examination revealed a firm proximal tibial mass. Computed tomography (CT) imaging showed an exophytic, lobulated, sclerotic mass involving the anterolateral margin of the lateral tibial plateau. Magnetic resonance imaging was suggestive of an osteochondroma. The patient underwent curettage of the lesion due to its periarticular location. Histology revealed benign and reactive bone and cartilage consistent with periosteal chondroma. Two and a half years later, the patient presented with a firm, palpable mass larger than the initial lesion. CT revealed a lateral tibial plateau sclerotic mass consistent with recurrent intra-articular DEH. A complete excision was performed and histology showed sclerotic bone with overlying cartilage consistent with exostosis. DEH is a rare epiphyseal osteocartilaginous outgrowth frequently occurring in the long bones of children less than 8 years old. DEH resembles an osteochondroma due to its pediatric presentation and similar histologic appearance. Adult-onset cases comprise less than 1% of reported cases. Recurrence rate after surgical intervention is unknown. Only 1 such case, occurring in a child, has been described. Clinicians contemplating operative treatment for DEH should note the potential for recurrence and consider complete excision. A follow-up period of several years may be warranted to identify recurrent lesions. PMID:28144583

  17. Parental smoking in pregnancy and the risks of adult-onset hypertension.

    PubMed

    de Jonge, Layla L; Harris, Holly R; Rich-Edwards, Janet W; Willett, Walter C; Forman, Michele R; Jaddoe, Vincent W V; Michels, Karin B

    2013-02-01

    Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33086 participants of the Nurses' Health Study II and the Nurses' Mothers' Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8575 (25.9%) mothers and 18874 (57.0%) fathers smoked during pregnancy. During follow-up, 7825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥ 15 cigarettes/d during pregnancy were associated with increased risks of hypertension (rate ratio, 1.19; 95% CI, 1.09-1.29; and rate ratio, 1.18; 95% CI, 1.12-1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, whereas additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (rate ratio, 1.07; 95% CI, 0.98-1.16; and rate ratio, 1.06; 95% CI, 1.01-1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms.

  18. Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium

    PubMed Central

    Postma, D. S.; Moffatt, M. F.; Jarvis, D.; Ramasamy, A.; Wjst, M.; Omenaas, E. R.; Bouzigon, E.; Demenais, F.; Nadif, R.; Siroux, V.; Polonikov, A. V.; Solodilova, M.; Ivanov, V. P.; Curjuric, I.; Imboden, M.; Kumar, A.; Probst-Hensch, N.; Ogorodova, L. M.; Puzyrev, V. P.; Bragina, E. Yu; Freidin, M. B.; Nolte, I. M.; Farrall, A. M.; Cookson, W. O. C. M.; Strachan, D. P.; Koppelman, G. H.; Boezen, H. M.

    2017-01-01

    Background Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. Methods We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. Results First approach: 50 SNPs were selected based on an overall interaction effect at p<10−4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10−5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10−4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10−4; replication: ORint = 1.40, p = 0.03). Conclusions Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma. PMID:28253294

  19. Muscle MRI Findings in Childhood/Adult Onset Pompe Disease Correlate with Muscle Function

    PubMed Central

    Figueroa-Bonaparte, Sebastián; Segovia, Sonia; Llauger, Jaume; Belmonte, Izaskun; Pedrosa, Irene; Alejaldre, Aída; Mayos, Mercè; Suárez-Cuartín, Guillermo; Gallardo, Eduard; Illa, Isabel; Díaz-Manera, Jordi

    2016-01-01

    Objectives Enzyme replacement therapy has shown to be effective for childhood/adult onset Pompe disease (AOPD). The discovery of biomarkers useful for monitoring disease progression is one of the priority research topics in Pompe disease. Muscle MRI could be one possible test but the correlation between muscle MRI and muscle strength and function has been only partially addressed so far. Methods We studied 34 AOPD patients using functional scales (Manual Research Council scale, hand held myometry, 6 minutes walking test, timed to up and go test, time to climb up and down 4 steps, time to walk 10 meters and Motor Function Measure 20 Scale), respiratory tests (Forced Vital Capacity seated and lying, Maximun Inspiratory Pressure and Maximum Expiratory Pressure), daily live activities scales (Activlim) and quality of life scales (Short Form-36 and Individualized Neuromuscular Quality of Life questionnaire). We performed a whole body muscle MRI using T1w and 3-point Dixon imaging centered on thighs and lower trunk region. Results T1w whole body muscle MRI showed a homogeneous pattern of muscle involvement that could also be found in pre-symptomatic individuals. We found a strong correlation between muscle strength, muscle functional scales and the degree of muscle fatty replacement in muscle MRI analyzed using T1w and 3-point Dixon imaging studies. Moreover, muscle MRI detected mild degree of fatty replacement in paraspinal muscles in pre-symptomatic patients. Conclusion Based on our findings, we consider that muscle MRI correlates with muscle function in patients with AOPD and could be useful for diagnosis and follow-up in pre-symptomatic and symptomatic patients under treatment. Take home message Muscle MRI correlates with muscle function in patients with AOPD and could be useful to follow-up patients in daily clinic. PMID:27711114

  20. Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

    PubMed Central

    Santín, Sheila; Tazón-Vega, Bárbara; Silva, Irene; Cobo, María Ángeles; Giménez, Isabel; Ruíz, Patricia; García-Maset, Rafael; Ballarín, José

    2011-01-01

    Summary Background and objectives To date, very few cases with adult-onset focal segmental glomerulosclerosis (FSGS) carrying NPHS2 variants have been described, all of them being compound heterozygous for the p.R229Q variant and one pathogenic mutation. Design, setting, participants, & measurements Mutation analysis was performed in 148 unrelated Spanish patients, of whom 50 presented with FSGS after 18 years of age. Pathogenicity of amino acid substitutions was evaluated through an in silico scoring system. Haplotype analysis was carried out using NPHS2 single nucleotide polymorphism and microsatellite markers. Results Compound heterozygous or homozygous NPHS2 pathogenic mutations were identified in seven childhood-onset steroid-resistant nephrotic syndrome (SRNS) cases. Six additional cases with late childhood- and adult-onset SRNS were compound heterozygotes for p.R229Q and one pathogenic mutation, mostly p.A284V. p.R229Q was more frequent among SRNS cases relative to controls (odds ratio = 2.65; P = 0.02). Significantly higher age at onset of the disease and slower progression to ESRD were found in patients with one pathogenic mutation plus the p.R229Q variant in respect to patients with two NPHS2 pathogenic mutations. Conclusions NPHS2 analysis has a clinical value in both childhood- and adult-onset SRNS patients. For adult-onset patients, the first step should be screening for p.R229Q and, if positive, for p.A284V. These alleles are present in conserved haplotypes, suggesting a common origin for these substitutions. Patients carrying this specific NPHS2 allele combination did not respond to corticoids or immunosuppressors and showed FSGS, average 8-year progression to ESRD, and low risk for recurrence of FSGS after kidney transplant. PMID:20947785

  1. Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series

    PubMed Central

    Jaunmuktane, Zane; Sheerin, Una-Marie; Phadke, Rahul; Brandner, Sebastian; Milonas, Ionnis; Dean, Andrew; Bajaj, Nin; McNicholas, Nuala; Costello, Daniel; Cronin, Simon; McGuigan, Chris; Rossor, Martin; Fox, Nick; Murphy, Elaine; Chataway, Jeremy; Houlden, Henry

    2016-01-01

    Background Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia. PMID:25935893

  2. Mechanism of ceroid formation in atherosclerotic plaque: in situ studies using a combination of Raman and fluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    Haka, Abigail S.; Kramer, John R.; Dasari, Ramachandra R.; Fitzmaurice, Maryann

    2011-01-01

    Accumulation of the lipid-protein complex ceroid is a characteristic of atherosclerotic plaque. The mechanism of ceroid formation has been extensively studied, because the complex is postulated to contribute to plaque irreversibility. Despite intensive research, ceroid deposits are defined through their fluorescence and histochemical staining properties, while their composition remains unknown. Using Raman and fluorescence spectral microscopy, we examine the composition of ceroid in situ in aorta and coronary artery plaque. The synergy of these two types of spectroscopy allows for identification of ceroid via its fluorescence signature and elucidation of its chemical composition through the acquisition of a Raman spectrum. In accordance with in vitro predictions, low density lipoprotein (LDL) appears within the deposits primarily in its peroxidized form. The main forms of modified LDL detected in both coronary artery and aortic plaques are peroxidation products from the Fenton reaction and myeloperoxidase-hypochlorite pathway. These two peroxidation products occur in similar concentrations within the deposits and represent ~40 and 30% of the total LDL (native and peroxidized) in the aorta and coronary artery deposits, respectively. To our knowledge, this study is the first to successfully employ Raman spectroscopy to unravel a metabolic pathway involved in disease pathogenesis: the formation of ceroid in atherosclerotic plaque.

  3. Serum calprotectin--a promising diagnostic marker for adult-onset Still's disease.

    PubMed

    Guo, Qian; Zha, Xicao; Li, Chun; Jia, Yuan; Zhu, Lei; Guo, Jianping; Su, Yin

    2016-01-01

    Calprotectin is a calcium-binding cytosolic protein, mainly expressed in immune cells, such as neutrophils, monocytes, and macrophages. Our study aimed to evaluate the diagnostic value of calprotectin for adult-onset Still's disease (AOSD), by comparing serum calprotectin concentrations in patients with AOSD (n = 46), rheumatoid arthritis (RA, n = 34), primary Sjögren syndrome (pSS, n = 40), systemic lupus erythematosus (SLE, n = 39), osteoarthritis (OA, n = 20), and healthy controls (HCs, n = 49). Calprotectin concentrations were significantly higher in patients with AOSD (55.26 ± 18.00 ng/ml), compared to patients with RA (39.17 ± 18.90 ng/ml), pSS (35.31 ± 19.47 ng/ml), SLE (32.21 ± 25.01 ng/ml), OA (19.24 ± 10.67 ng/ml), and HCs (8.46 ± 5.17 ng/ml). All the differences were highly significant (p < 0.001). Using receiver-operating characteristic curve, the cut-off value of calprotectin was defined as 45.488 ng/ml, and its sensitivity and specificity for AOSD diagnosis were 63.0 and 80.1%, respectively. The positive rate of calprotectin was significantly higher in AOSD cases compared to patients with other diseases and healthy controls (p < 0.001). Serum calprotectin was positively correlated with ferritin (r = 0.294, p < 0.05), and concentration of hemoglobin was significantly lower in calprotectin-positive patients compared to negative patients in AOSD (103.49 ± 20.21 g/l vs 115.71 ± 15.59 g/l, t = -2.142, p = 0.038). These findings suggest that serum calprotectin may serve as a promising marker for the diagnosis of AOSD and monitor disease activity to a certain extent.

  4. Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature.

    PubMed

    Pareyson, Davide; Fancellu, Roberto; Mariotti, Caterina; Romano, Silvia; Salmaggi, Andrea; Carella, Francesco; Girotti, Floriano; Gattellaro, Grazietta; Carriero, Maria Rita; Farina, Laura; Ceccherini, Isabella; Savoiardo, Mario

    2008-09-01

    Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibre accumulation. Following the identification of glial fibrillary acidic protein (GFAP) gene as the causative gene, cases of adult-onset AD (AOAD) are being described with increasing frequency. AOAD has a different clinical and neuroradiological presentation with respect to early-onset AD, as abnormalities are mainly concentrated in the brainstem-spinal cord junction. We report detailed clinical and genetic data of 11 cases of AOAD, observed over a 4-year period, and a review of the previously reported 25 cases of genetically confirmed AOAD. In our series, onset occurred as late as age 62, and up to 71 in an affected deceased relative. Most cases appeared sporadic, but family history may be misleading. The most frequent symptoms were related to bulbar dysfunction-with dysarthria, dysphagia, dysphonia (seven patients)-, pyramidal involvement (seven patients) and cerebellar ataxia (seven patients). Four patients had palatal myoclonus. Sleep disorders were also observed (four cases). Bulbar symptoms, however, were infrequent at onset and two symptomatic patients had an almost pure pyramidal involvement. Two subjects were asymptomatic. Misdiagnosis at presentation was frequent and MRI was instrumental in suggesting the correct diagnosis by showing, in all cases, mild to severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord. In ten patients, molecular studies revealed six novel missense mutations and three previously reported changes in GFAP. The last typical patient carried no definitely pathogenic mutation, but a missense variant (p.D157N), supposedly a rare polymorphism. Revision of the literature and the present series indicate that the clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive

  5. Stroke prevention by direct revascularization for patients with adult-onset moyamoya disease presenting with ischemia.

    PubMed

    Kim, Tackeun; Oh, Chang Wan; Kwon, O-Ki; Hwang, Gyojun; Kim, Jeong Eun; Kang, Hyun-Seung; Cho, Won-Sang; Bang, Jae Seung

    2016-06-01

    . CONCLUSIONS Direct or combined revascularization for patients with adult-onset moyamoya disease presenting with ischemia can prevent further stroke.

  6. Early Pathogenesis in the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis

    PubMed Central

    van Zundert, Brigitte; Izaurieta, Pamela; Fritz, Elsa; Alvarez, Francisco J.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motor neurons starting in adulthood. Most of our knowledge about the pathophysiological mechanisms of ALS comes from transgenic mice models that emulate a subgroup of familial ALS cases (FALS), with mutations in the gene encoding superoxide dismutase (SOD1). In the more than 15 years since these mice were generated, a large number of abnormal cellular mechanisms underlying motor neuron degeneration have been identified, but to date this effort has led to few improvements in therapy, and no cure. Here, we consider that this surfeit of mechanisms is best interpreted by current insights that suggest a very early initiation of pathology in motor neurons, followed by a diversity of secondary cascades and compensatory mechanisms that mask symptoms for decades, until trauma and/or aging overloads their protective function. This view thus posits that adultonset ALS is the consequence of processes initiated during early development. In fact, motor neurons in neonatal mutant SOD mice display important alterations in their intrinsic electrical properties, synaptic inputs and morphology that are accompanied by subtle behavioral abnormalities. We consider evidence that human mutant SOD1 protein in neonatal hSOD1G93A mice instigates motor neuron degeneration by increasing persistent sodium currents and excitability, in turn altering synaptic circuits that control excessive motor neuron firing and leads to excitotoxicity. We also discuss how therapies that are aimed at suppressing abnormal neuronal activity might effectively mitigate or prevent the onset of irreversible neuronal damage in adulthood. PMID:22740507

  7. Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis.

    PubMed

    Pohl, Daniela; Rostasy, Kevin; Jacobi, Christian; Lange, Peter; Nau, Roland; Krone, Bernd; Hanefeld, Folker

    2010-02-01

    Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS). Recent reports proposed an increased EBV-targeted humoral immune response in MS, which appears to be more pronounced in pediatric patients. However, little is known about the CNS-derived antibody production against EBV in patients with MS. The objective of this study was to assess the frequency and intensity of intrathecal antibody production against EBV as compared to other neurotropic viruses in pediatric and adult onset MS. In cohorts of 43 childhood, 50 adult onset MS patients, 20 children and 12 adults with other CNS disorders, paired CSF and serum samples were studied. Frequency and intensity of intrathecal antibody production against EBV as compared to measles, rubella, varicella zoster (VZV) and herpes simplex virus (HSV) were analyzed by determination of virus-specific CSF-to-serum Antibody Indices (AI). Intrathecally synthesized EBV antibodies were detectable in 26% pediatric and 10% adult onset MS patients, compared to frequencies ranging in both groups from 10 to 60% for the other viruses. Median AIs for EBV were lower than those for all other viruses, with more than twofold higher median AI for measles, rubella and VZV. The EBV-targeted humoral immune response in the CNS is only part of the intrathecal polyspecific antibody production in MS, directed against various neurotropic viruses. Our results do not rule out the possibility that EBV is involved in the pathogenesis of MS by triggering diverse cellular immune mechanisms, but they argue against a direct pathogenic role of EBV-targeted humoral immune response within the CNS.

  8. Young-onset parkinsonism in a Hong Kong Chinese man with adult-onset Hallervorden-Spatz syndrome.

    PubMed

    Mak, Chloe Miu; Sheng, Bun; Lee, Hencher Han-chih; Lau, Kwok-kwong; Chan, Wing-tak; Lam, Ching-wan; Chan, Yan-wo

    2011-04-01

    Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of disorders varied in genetic etiologies, clinical presentations, and radiological features. NBIA is an iron homeostasis disorder with progressive iron accumulation in the central nervous systems and is clinically characterized by extrapyramidal movement abnormalities, retinal pigmentary changes, and cognitive impairment. Panthothenate kinase-associated neurodegeneration (Hallervorden-Spatz disease) is the commonest disorder of NBIA with a prevalence of one-three per million. Clinically, it is classified into early-onset childhood, atypical late-onset, and adult-onset type. Adult-onset type is rarer. We report the first case of adult-onset panthothenate kinase-associated neurodegeneration in Hong Kong in a 28-year-old Chinese man who presented with pure young-onset parkinsonism. Magnetic resonance imaging (MRI) of the brain showed the presence of eye-of-the-tiger sign. Two compound heterozygous mutations PANK2 NM_153638.2: c.445G > T; NP_705902.2: p.E149X and PANK2 NM_153638.2: c.1133A > G; NP_705902.2: p.D378G were detected. Parkinsonism per se is a very heterogeneous phenotypic group. In view of the readily available genetic analysis of PANK2, panthothenate kinase-associated neurodegeneration should be considered in adult patients with young-onset parkinsonism with or without the eye-of-the-tiger sign. The exact diagnosis offers a different management approach and genetic counseling. NBIA is likely under- or misdiagnosed in Hong Kong Chinese.

  9. Variation in genes related to cochlear biology is strongly associated with adult-onset deafness in border collies.

    PubMed

    Yokoyama, Jennifer S; Lam, Ernest T; Ruhe, Alison L; Erdman, Carolyn A; Robertson, Kathryn R; Webb, Aubrey A; Williams, D Colette; Chang, Melanie L; Hytönen, Marjo K; Lohi, Hannes; Hamilton, Steven P; Neff, Mark W

    2012-09-01

    Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years) than typically expected for aging dogs (8-10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09 × 10(-13)). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS-guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.

  10. Obesity-related abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D.

    PubMed

    Nguyen, K Hoa; Ande, Sudharsana R; Mishra, Suresh

    2016-01-29

    The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D.

  11. Adult-onset nemaline rods in a patient treated for suspected dermatomyositis: study with two-dimensional electrophoresis

    SciTech Connect

    Danon, M.J.; Giometti, C.S.; Manaligod, J.R.; Perurena, O.H.; Skosey, J.L.

    1981-12-01

    A 65-year-old woman with progressive muscle weakness and a diffuse rash of three years' duration was examined. Muscle tissue was studied with histochemical techniques, phase-contrast microscopy, electron microscopy, and two-dimensional electrophoresis. Histochemical studies showed numerous nemaline rods, with a normal ratio of types I and II fibers. Two-dimensional electrophoresis revealed abnormalities in the myosin light chain and tropomyosin protein patterns when compared with normal and diseased muscle biopsy samples, including those from two patients with adult-onset dermatomyositis.

  12. Solitary, adult-onset, intraosseous myofibroma of the finger: report of a case and review of literature.

    PubMed

    Ma, Yihong; Siegal, Gene P; Wei, Shi

    2015-09-01

    Myofibroma is a rare benign neoplasm of myofibroblastic origin. It typically occurs in the skin and subcutaneous tissues of the head and neck in infants and young children as multicentric lesions known as infantile myofibromatosis. Intraosseous myofibromas are very rare and are typically destructive lesions that predominantly affect craniofacial bones in the setting of myofibromatosis. Solitary, intraosseous myofibromas in adults are exceedingly rare. Herein, we report a myofibroma involving the middle phalanx of the right index finger in a 58-year-old man who presented with a pathologic fracture. Twelve other cases of adult-onset, intraosseous myofibroma were compiled from the English language literature and integrated with this report.

  13. Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease.

    PubMed Central

    Huggins, M; Bloch, M; Kanani, S; Quarrell, O W; Theilman, J; Hedrick, A; Dickens, B; Lynch, A; Hayden, M

    1990-01-01

    The goal of predictive testing is to modify the risk for currently healthy individuals to develop a genetic disease in the future. Such testing using polymorphic DNA markers has had major application in Huntington disease. The Canadian Collaborative Study of Predictive Testing for Huntington Disease has been guided by major principles of medical ethics, including autonomy, beneficence, confidentiality, and justice. Numerous ethical and legal dilemmas have arisen in this program, challenging these principles and occasionally casting them into conflict. The present report describes these dilemmas and offers our approach to resolving them. These issues will have relevance to predictive-testing programs for other adult-onset disorders. PMID:1971997

  14. [Recurrent effusive pericarditis in the course of adult-onset Still's disease--case reports of two patients].

    PubMed

    Bilska, Anna; Wilińska, Ewelina; Szturmowicz, Monika; Wawrzyńska, Liliana; Fijałkowska, Anna; Oniszh, Karina; Swiatowiec, Andrzej; Wsół, Agnieszka; Torbicki, Adam

    2011-01-01

    Pericardial effusion is caused by various pathological agents. In differential diagnosis infectious as well as non-infectious factors have to be considered. Adult-onset Still disease (AOSD)--relatively uncommon systemic inflammatory disorder of unknown etiology--is among possible diagnosis. The disease typically affects patients in the age between 16-35 years and is characterized by spiking fever, arthralgia, evanescent salmon rash with other abnormalities including pharingitis, serositis (especially pleuritis and pericarditis) and leucocytosis as well as increased serum levels of inflammatory indicators. We present two patients with recurrent pericardial effusion in the course of AOSD.

  15. Inadvertent Skipping of Steroids in Septic Shock Leads to a Diagnosis of Adult Onset Still’s Disease

    PubMed Central

    Sethuraman, Vinoth K; Balasubramanian, Kavitha; Aghoram, Rajeswari

    2017-01-01

    Adult onset Still’s disease is uncommon in middle-aged and elderly individuals and can rarely present with shock; shock is usually associated with disseminated intravascular coagulation, multiorgan dysfunction syndrome or acute respiratory distress syndrome. We report a post-menopausal woman with arthritis, fever, pneumonitis and hypotension which was managed as septic shock. Steroids were inadvertently missed during the second day of hospitalization in the intensive care unit. Persistence of hypotension on inotropes, with normal renal, hepatic and neurological function and recurrence of fever when steroids were skipped, led to suspicion of an inflammatory disorder. A diagnosis of Still’s disease may be entertained in postmenopausal women with polyarthritis, rash, and fever with leukocytosis. Sepsis is mimicked, and multiple antibiotics use is common before the diagnosis of such an entity is made. Shock is rare in adult onset Still’s disease and is not necessarily associated with disseminated intravascular coagulation, acute respiratory distress syndrome, or multiorgan dysfunction. PMID:28191382

  16. GC-MS metabolomic analysis reveals significant alterations in cerebellar metabolic physiology in a mouse model of adult onset hypothyroidism.

    PubMed

    Constantinou, Caterina; Chrysanthopoulos, Panagiotis K; Margarity, Marigoula; Klapa, Maria I

    2011-02-04

    Although adult-onset hypothyroidism (AOH) has been connected to neural activity alterations, including movement, behavioral, and mental dysfunctions, the underlying changes in brain metabolic physiology have not been investigated in a systemic and systematic way. The current knowledge remains fragmented, referring to different experimental setups and recovered from various brain regions. In this study, we developed and applied a gas chromatography-mass spectrometry (GC-MS) metabolomics protocol to obtain a holistic view of the cerebellar metabolic physiology in a Balb/cJ mouse model of prolonged adult-onset hypothyroidism induced by a 64-day treatment with 1% potassium perchlorate in the drinking water of the animals. The high-throughput analysis enabled the correlation between multiple parallel-occurring metabolic phenomena; some have been previously related to AOH, while others implicated new pathways, designating new directions for further research. Specifically, an overall decline in the metabolic activity of the hypothyroid compared to the euthyroid cerebellum was observed, characteristically manifested in energy metabolism, glutamate/glutamine metabolism, osmolytic/antioxidant capacity, and protein/lipid synthesis. These alterations provide strong evidence that the mammalian cerebellum is metabolically responsive to AOH. In light of the cerebellum core functions and its increasingly recognized role in neurocognition, these findings further support the known phenotypic manifestations of AOH into movement and cognitive dysfunctions.

  17. Adult-Onset Still’s Disease: Still a Serious Health Problem (a Case Report and Literature Review)

    PubMed Central

    Agha-Abbaslou, Mojgan; Bensaci, Ana Maria; Dike, Oluchi; Poznansky, Mark C.; Hyat, Arooj

    2017-01-01

    Patient: Female, 53 Final Diagnosis: Adult-onset Still’s Disease Symptoms: Abdominal pain • fever Medication: — Clinical Procedure: — Specialty: Rheumatology Objective: Rare disease Background: Adult-onset Still’s Disease (AOSD) is a rare systemic inflammatory disease accompanied by a triad of spiking fever, maculopapular exanthema, and arthralgia. To date, there is no definite laboratory or imaging test available for diagnosing AOSD, and the diagnosis is one of exclusion, which can be very challenging. Case Report: We report on the case of a 53-year-old female who presented with fever, arthralgia, and abdominal pain. Her initial laboratory tests showed elevated AST and ALT, and normal leukocytes with bandemia. During her hospitalization, we evaluated the patient for other potential differential diagnoses. After an extensive workup, the patient was diagnosed with AOSD based on Yamaguchi criteria. Her serum ferritin levels were measured and found to be markedly elevated, which is a non-specific finding in AOSD patients. Conclusions: This case highlights the important role of a detailed history and physical examination for timely diagnosis of AOSD to prevent complications and improve patient’s prognosis. PMID:28154368

  18. Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP)

    PubMed Central

    Chitu, Violeta; Gokhan, Solen; Gulinello, Maria; Branch, Craig A.; Patil, Madhuvati; Basu, Ranu; Stoddart, Corrina; Mehler, Mark F.; Stanley, E. Richard

    2014-01-01

    Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/− and control Csf1r+/+ mice. Six to 8-month old Csf1r+/− mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/− mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/− mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches

  19. A Case of Adult-Onset Acute Rheumatic Fever With Long-Lasting Atrioventricular Block Requiring Permanent Pacemaker Implantation.

    PubMed

    Oba, Yusuke; Watanabe, Hiroaki; Nishimura, Yoshioki; Ueno, Shuichi; Nagashima, Takao; Imai, Yasushi; Shimpo, Masahisa; Kario, Kazuomi

    2015-01-01

    A 45-year-old hypertensive Japanese woman presented with epigastric pain on inspiration, fever, complete atrioventricular block and polyarthritis. Her antistreptolysin O levels were markedly elevated. A diagnosis of rheumatic fever was made according to the modified Jones criteria. She was prescribed loxoprofen sodium, which was partially effective for her extracardiac clinical symptoms. However, she had syncope due to complete atrioventricular block with asystole longer than 10 seconds. Consequently, we implanted a permanent pacemaker. Although we prescribed prednisolone, the efficacy of which was limited for the patient's conduction disturbance, the complete atrioventricular block persisted. In our systematic review of 12 similar cases, the duration of complete heart block was always transient and there was no case requiring a permanent pacemaker. We thus encountered a very rare case of adult-onset acute rheumatic fever with persistent complete atrioventricular block necessitating permanent pacemaker implantation.

  20. Acute pneumonitis in a patient with adult-onset disease after toclizumab treatment with good response to anakinra.

    PubMed

    Sangüesa Gómez, Clara; Flores Robles, Bryan Josué; Jara Chinarro, Beatriz; Espinosa Malpartida, María; Barbadillo Mateos, Carmen

    Pulmonary involvement in the form of acute pneumonitis in adult-onset Still's disease (AOSD) is an uncommon manifestation, with few cases reported in the literature. We report the case of a 61-year-old male with 3 years of AOSD evolution, treated with methotrexate (MTX) and half-dose corticosteroids, which debuted with symptoms of fever, dyspnea and dry cough after 3 weeks of receiving the first dose of tocilizumab (TCZ). In the follow-up study showed leukocytosis with left shift, elevated serum ferritin and C-reactive protein standard. The chest CT scan showed ground-glass pattern predominantly in central and upper lobes and the BAL shows an increase in the percentage of lymphocyte with normal subpopulations and negative cultures. MTX and TCM were suspended, prednisone was increased to 30mg/day and within a week Anakinra 100mg/day SC was iniciated, noting in a few days a progressive clinical, analytical and radiological improvement.

  1. Adult-onset focal expression of mutated human tau in the hippocampus impairs spatial working memory of rats.

    PubMed

    Mustroph, Martina L; King, Michael A; Klein, Ronald L; Ramirez, Julio J

    2012-07-15

    Tauopathy in the hippocampus is one of the earliest cardinal features of Alzheimer's disease (AD), a condition characterized by progressive memory impairments. In fact, density of tau neurofibrillary tangles (NFTs) in the hippocampus strongly correlates with severity of cognitive impairments in AD. In the present study, we employed a somatic cell gene transfer technique to create a rodent model of tauopathy by injecting a recombinant adeno-associated viral vector with a mutated human tau gene (P301L) into the hippocampus of adult rats. The P301L mutation is causal for frontotemporal dementia with parkinsonism-17 (FTDP-17), but it has been used for studying memory effects characteristic of AD in transgenic mice. To ascertain if P301L-induced mnemonic deficits are persistent, animals were tested for 6 months. It was hypothesized that adult-onset, spatially restricted tau expression in the hippocampus would produce progressive spatial working memory deficits on a learned alternation task. Rats injected with the tau vector exhibited persistent impairments on the hippocampal-dependent task beginning at about 6 weeks post-transduction compared to rats injected with a green fluorescent protein vector. Histological analysis of brains for expression of human tau revealed hyperphosphorylated human tau and NFTs in the hippocampus in experimental animals only. Thus, adult-onset, vector-induced tauopathy spatially restricted to the hippocampus progressively impaired spatial working memory in rats. We conclude that the model faithfully reproduces histological and behavioral findings characteristic of dementing tauopathies. The rapid onset of sustained memory impairment establishes a preclinical model particularly suited to the development of potential tauopathy therapeutics.

  2. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation.

    PubMed

    Kleinfeld, Kirk; Mobley, Bret; Hedera, Peter; Wegner, Adam; Sriram, Subramaniam; Pawate, Siddharama

    2013-02-01

    The objective of this work is to report on a series of five patients with adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia (ALSP). ALSP is a rare adult-onset leukodystrophy, which encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmentary orthochromatic leukodystrophy. This was a retrospective chart review and literature review. Five previously healthy women presented with a rapidly progressive neurological disorder at ages 39, 37, 40, 30, and 47, respectively. All five individuals were initially diagnosed as suffering from multiple sclerosis. The clinical courses of the five patients were dominated by progressive spastic quadriparesis (patient 5, newly diagnosed, has paraparesis at this time) and dementia. Brain magnetic resonance imaging (MRI) showed diffuse cerebral atrophy, corpus callosal atrophy, and diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions. Three patients showed involvement of pyramidal tracts from motor cortex to the brainstem. Cerebrospinal fluid was normal in all cases. Diagnosis of ALSP was established by biopsy (two cases) and autopsy (two cases). Histopathology showed the presence of neuroaxonal spheroids in all four cases and pigmented glia in three. In the fifth case, diagnosis was established by genetic analysis alone that showed a disease-causing mutation in the colony-stimulating factor 1 receptor (CSF1R) gene. Genetic analysis was done in three patients with available DNA, and identified the disease-causing mutation in all three, including a novel mutation F828S. ALSP may be suspected in adults with rapid to subacute progression of neurological disease when (1) MRI shows corpus callosal atrophy on a background of generalized brain atrophy and diffuse white matter disease without postcontrast enhancement, (2) CSF studies are normal, and (3) studies for systemic inflammatory diseases and specific leukodystrophies are

  3. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells

    PubMed Central

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington’s disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions. PMID:26863614

  4. Adult-onset type 1 diabetes patients display decreased IGRP-specific Tr1 cells in blood.

    PubMed

    Chujo, Daisuke; Nguyen, Thien-Son; Foucat, Emile; Blankenship, Derek; Banchereau, Jacques; Nepom, Gerald T; Chaussabel, Damien; Ueno, Hideki

    2015-12-01

    The breakdown of immune tolerance against islet antigens causes type 1 diabetes (T1D). The antigens associated with adult-onset T1D (AT1D) remain largely undefined. It is possible that AT1D patients display a unique type of CD4(+) T cells specific for a certain islet antigen. Here we analyzed the cytokine production profiles of CD4(+) helper T (Th) cells that are specific for three islet antigens; GAD65, preproinsulin, and IGRP in patients with AT1D, juvenile-onset T1D (JT1D), and age-, gender- and human leukocyte antigen (HLA)-matched control adults. While IGRP-specific Th cells in AT1D patients were dominantly Th1 cells, IGRP-specific Th cells in control adults and JT1D patients were dominantly Th2 and T regulatory type 1 (Tr1) cells. Notably, the frequency of IGRP-specific Tr1 cells was significantly lower in AT1D patients than in control adults and JT1D patients. In conclusion, our study suggests that IGRP-specific Th cells play a unique pathogenic role in AT1D.

  5. The Phospholipase D2 Knock Out Mouse Has Ectopic Purkinje Cells and Suffers from Early Adult-Onset Anosmia

    PubMed Central

    Zhang, Qifeng; Smethurst, Elizabeth; Segonds-Pichon, Anne; Schrewe, Heinrich; Wakelam, Michael J. O.

    2016-01-01

    Phospholipase D2 (PLD2) is an enzyme that produces phosphatidic acid (PA), a lipid messenger molecule involved in a number of cellular events including, through its membrane curvature properties, endocytosis. The PLD2 knock out (PLD2KO) mouse has been previously reported to be protected from insult in a model of Alzheimer's disease. We have further analysed a PLD2KO mouse using mass spectrophotometry of its lipids and found significant differences in PA species throughout its brain. We have examined the expression pattern of PLD2 which allowed us to define which region of the brain to analyse for defect, notably PLD2 was not detected in glial-rich regions. The expression pattern lead us to specifically examine the mitral cells of olfactory bulbs, the Cornus Amonis (CA) regions of the hippocampus and the Purkinje cells of the cerebellum. We find that the change to longer PA species correlates with subtle architectural defect in the cerebellum, exemplified by ectopic Purkinje cells and an adult-onset deficit of olfaction. These observations draw parallels to defects in the reelin heterozygote as well as the effect of high fat diet on olfaction. PMID:27658289

  6. Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications.

    PubMed

    Tezcan, Kamer; Louie, Kristal T; Qu, Yong; Velasquez, Jorge; Zaldivar, Frank; Rioseco-Camacho, Natalia; Camacho, José Angel

    2012-01-01

    The Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter, ORNT1 (SLC25A15). In general, the majority of patients with HHH syndrome come to medical attention during infancy or early school years with symptoms such as learning disabilities, changes in cognitive development, spasticity, or liver dysfunction. In this report, we describe a 35-year-old male of Indian descent who was diagnosed with HHH syndrome after he presented to the emergency room with gastroenteritis, disorientation, and slurred speech. Molecular analysis revealed that this patient was heterozygous for two ORNT1 mutations, p.[Gly220Arg(+)Arg275X] (c.[658G>A(+)823C>T]) that had been previously reported in homozygous probands who presented during the first year of life. Cellular studies revealed that the ORNT1 p.Gly220Arg mutation was nonfunctional but targeted to the mitochondria. Given that this patient was a successful college graduate on a vegetarian diet without a prior history of learning or neurological impairment, additional factors such as gene redundancy, environmental, and epigenetic factors may have contributed to the delay in onset of presentation and lack of any previous symptoms. To the best of our knowledge, this is the first reported case of an adult-onset HHH syndrome presentation without a prior history of neurological or cognitive deficiency.

  7. Combination Immunosuppressive Therapy Including Rituximab for Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease

    PubMed Central

    Schäfer, Eva Johanna; Jung, Wolfram

    2016-01-01

    Hemophagocytic lymphopcytosis (HLH) is a life-threatening condition. It can occur either as primary form with genetic defects or secondary to other conditions, such as hematological or autoimmune diseases. Certain triggering factors can predispose individuals to the development of HLH. We report the case of a 25-year-old male patient who was diagnosed with HLH in the context of adult-onset Still's disease (AOSD) during a primary infection with Epstein-Barr virus (EBV). During therapy with anakinra and dexamethasone, he was still symptomatic with high-spiking fevers, arthralgia, and sore throat. His laboratory values showed high levels of ferritin and C-reactive protein. His condition improved after the addition of rituximab and cyclosporine to his immunosuppressive regimen with prednisolone and anakinra. This combination therapy led to a sustained clinical and serological remission of his condition. While rituximab has been used successfully for HLH in the context of EBV-associated lymphoma, its use in autoimmune diseases is uncommon. We hypothesize that the development of HLH was triggered by a primary EBV infection and that rituximab led to elimination of EBV-infected B-cells, while cyclosporine ameliorated the cytokine excess. We therefore propose that this combination immunosuppressive therapy might be successfully used in HLH occurring in the context of autoimmune diseases. PMID:28018698

  8. Rituximab Treatment for PR3-ANCA-Positive Membranoproliferative Glomerulonephritis Associated with Adult-Onset Periodic Fever Syndrome

    PubMed Central

    Hamano, Yoshitomo; Yoshizawa, Hiromichi; Sugase, Taro; Miki, Takuya; Ohtani, Naoko; Hanawa, Shiho; Takeshima, Eri; Morishita, Yoshiyuki; Saito, Osamu; Takemoto, Fumi; Muto, Shigeaki; Yumura, Wako; Kusano, Eiji

    2012-01-01

    We report the case of a 36-year-old Japanese woman with nephrotic syndrome due to membranoproliferative glomerulonephritis (MPGN) Type I diagnosed after a 5-year history of periodic fever syndrome (PFS). Hypocomplementemia and elevation of anti-proteinase 3 anti-neutrophil cytoplasmic autoantibody (PR3-ANCA) were observed. HIV, and hepatitis B and C serology were negative. Nephrotic syndrome and periodic fever did not respond to oral steroid and intravenous steroid pulse therapies combined with cyclosporine, dipyridamole, warfarin and losartan. We tried immunotherapy using rituximab, a human-mouse chimeric monoclonal antibody directed against the CD20 antigen on mature B cells. This therapeutic approach led to improvement of renal function and remission of nephrotic syndrome and hypocomplementemia. However, it did not have a beneficial effect on periodic fever. Suspecting adult-onset hereditary PFS, we analyzed her genetic alteration of MEFV and TNFRSF1A genes. A rare genotype in intron 6 of TNFRSF1A was revealed. The etiological relationship between periodic fever and MPGN is discussed. Rituximab is a hopeful choice of induction therapy for refractory MPGN. PMID:23197963

  9. Clinical characteristics and follow-up analysis of adult-onset Still's disease complicated by hemophagocytic lymphohistiocytosis.

    PubMed

    Zhang, Yun; Yang, Yingyun; Bai, Yujia; Yang, Dan; Xiong, Yangyang; Zeng, Xuejun

    2016-05-01

    We evaluated clinical characteristics and prognosis for adult-onset Still's disease (AOSD) complicated by hemophagocytic lymphohistiocytosis (HLH). We retrospectively identified cases of AOSD with (n = 10) and without (n = 305) HLH complications. We reviewed their medical records, completed follow-up through outpatient clinic and telephone interviews, and analyzed their clinical symptoms, signs, laboratory test results, treatments, and prognosis. More AOSD patients with HLH developed hepatomegaly, bleeding, serositis, and neurologic symptoms than those without HLH, and they more commonly presented with leukopenia, thrombocytopenia, severe anemia, severe liver function abnormalities, decreased fibrinogen, elevated immunoglobulin, and bone marrow hemophagocytosis. The ten patients with AOSD complicated by HLH were treated with high-dose steroids or pulse steroid therapy, and eight of them also received cytotoxic drugs, while biological agents showed poor response. Follow-up results indicated that AOSD patients overall had good prognosis, while those with HLH showed worse prognosis, including higher relapse and readmission rates and increased mortality. In patients with AOSD, unexplained decreased blood cells, severe liver dysfunction, and/or hemophagocytosis in the bone marrow should be considered as signs of HLH complication. Patients with AOSD complicated by HLH have worse prognosis and higher relapse rates compared to AOSD patients without HLH complications. Thus, these patients should undergo frequent and careful follow-up.

  10. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: Report of four Korean cases.

    PubMed

    Kim, Eun-Joo; Shin, Jin-Hong; Lee, Jeong Hee; Kim, Jong Hun; Na, Duk L; Suh, Yeon-Lim; Hwang, Sun Jae; Lee, Jae-Hyeok; Lee, Young Min; Shin, Myung-Jun; Lee, Myung Jun; Kim, Seong-Jang; Yoon, Uicheul; Park, Do Youn; Jung, Dae Soo; Ahn, Jae Woo; Sung, Suk; Huh, Gi Yeong

    2015-02-15

    We describe detailed clinical, biochemical, neuroimaging and neuropathological features in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), linked to colony-stimulating factor 1 receptor (CSF1R) mutations in four Korean cases. Clinical, biochemical, neuroimaging and neuropathological findings were obtained by direct evaluation and from previous medical records. The genetic analysis of the CSF1R gene was done in two autopsy-confirmed ALSP cases and two cases where ALSP was suspected based on the clinical and neuroimaging characteristics. We identified two known mutations: c.2342C>T (p.A781V) in one autopsy-proven HDLS and clinically ALSP-suspected case and c.2345G>A (p.R782H) in another autopsy-proven POLD case. We also found a novel mutation (c.2296A>G; p.M766V) in a patient presenting with hand tremor, stuttering and hesitant speech, and abnormal behavior whose father died from a possible diagnosis of spinocerebellar ataxia. To the best of our knowledge, this is the first documented ALSP-linked CSF1R mutation in Korea and supports the suggestion that HDLS and POLD, with pathological characteristics that are somewhat different but which are caused by CSF1R mutations, are the same spectrum of disease, ALSP.

  11. Adult onset leukodystrophy with neuroaxonal spheroids and pigmented glia: report of a family, historical perspective, and review of the literature.

    PubMed

    Marotti, Jonathan D; Tobias, Sharon; Fratkin, Jonathan D; Powers, James M; Rhodes, C Harker

    2004-06-01

    We present a two-generation family consisting of a father and two daughters, who had an adult-onset leukodystrophy characterized by widespread destruction of cerebral white matter with neuroaxonal spheroids. The mode of inheritance appears to be autosomal dominant. All three patients presented with a variety of motor and cognitive symptoms, including frontal lobe signs, 4-7 years before death. Each followed a chronic course until death at ages 39, 46, and 51. At autopsy, the white matter loss was widespread but most prominent in the cerebrum with descending corticospinal tract degeneration and relative sparing of subcortical U-fibers. Pigmented glial cells were present, most of which appear to be macrophages, but inconstantly Prussian blue-positive. This disease is consistent with published reports of hereditary diffuse leukoencephalopathy with spheroids (HDLS). However, a review of the literature and a personal review of the neuropathology of the original case of the pigmentary type of orthochromatic leukodystrophy (POLD) reveal overlapping clinical and neuropathologic features between these two previously distinct entities, suggesting a common pathogenetic and perhaps etiological relationship between the two.

  12. Retrospective study of 61 patients with adult-onset Still's disease admitted with fever of unknown origin in China.

    PubMed

    Chen, Pei-Dong; Yu, Sheng-Lei; Chen, Shu; Weng, Xin-Hua

    2012-01-01

    Adult-onset Still's disease (AOSD), as a category of connective tissue diseases, has about 5∼9% of fever of unknown origin (FUO) cases. Diagnosis of AOSD was challenging because of its nonspecific characteristics. The present study analyzed clinical manifestations and laboratory findings in a series of patients with AOSD from eastern China. Medical records of 61 patients admitted with FUO and with a discharge diagnosis of AOSD were retrospectively evaluated and analyzed with special focus on clinical manifestations and laboratory findings. Compared with previous reports, most features of our patients had a similar incidence rate. Rash (79%), arthralgia (80%), and sore throat (84%) were the most frequent clinical manifestations in our series. Leukocytosis (80%), elevated ESR (98%) and CRP (100%), negative ANA (90%) and RF (93%), and high ferritin level (94%) were the most sensitive laboratory findings in our patients. AOSD was not a rare reason of FUO in eastern China. Fever, arthralgia, rash, sore throat, leukocytosis, neutrophilia, elevated ESR and CRP, negative ANA and RF, and high ferritin level were the most common clinical features in our series. The lack of highly specific characteristic makes the diagnosis of AOSD difficult compared with other diseases in FUO.

  13. A series of 22 patients with adult-onset Still's disease presenting with fever of unknown origin. A difficult diagnosis?

    PubMed

    Baxevanos, Gerasimos; Tzimas, Thomas; Pappas, Georgios; Akritidis, Nikolaos

    2012-01-01

    Adult-onset Still's disease (AOSD) remains a perplexing, difficult to diagnose clinical entity, with clinical characteristics that are often broad and encountered in numerous other clinical entities. This vague clinical presentation is depicted in the commonly used diagnostic criteria, as the ones by Yamaguchi and Fautrel. The authors sought to investigate how diagnostic criteria apply in a series of 22 new cases of AOSD patients presenting with fever of unknown origin (FUO) and diagnosed at the Internal Medicine Department of Hatzikosta General Hospital of Ioannina, Greece. The aims of the study were: (1) to study the incidence of AOSD and (2) to retrospectively apply different classifications to the data of these patients in search of a more efficient way of diagnosing these patients in the future. The annual incidence of AOSD was estimated at two new cases per 10(5). The clinical manifestations of the patients are discussed, with an emphasis on specific manifestations being considered as criteria by Yamaguchi and Fautrel classifications. Four patients exhibited markedly increased serum D: -dimers, a finding of which the potential pathophysiologic implications are discussed. Serum ferritin levels have additive values, both for diagnostic and cost-reduction purposes in cases presenting as FUO; serum ferritin values are not included in any diagnostic set of criteria at present. The finding of high levels of D-dimers in AOSD needs further studies.

  14. Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review.

    PubMed

    Ortiz-Sanjuán, Francisco; Blanco, Ricardo; Riancho-Zarrabeitia, Leyre; Castañeda, Santos; Olivé, Alejandro; Riveros, Anne; Velloso-Feijoo, María L; Narváez, Javier; Jiménez-Moleón, Inmaculada; Maiz-Alonso, Olga; Ordóñez, Carmen; Bernal, José A; Hernández, María V; Sifuentes-Giraldo, Walter A; Gómez-Arango, Catalina; Galíndez-Agirregoikoa, Eva; Blanco-Madrigal, Juan; Ortiz-Santamaria, Vera; del Blanco-Barnusell, Jordi; De Dios, Juan R; Moreno, Mireia; Fiter, Jordi; de los Riscos, Marina; Carreira, Patricia; Rodriguez-Valls, María J; González-Vela, M Carmen; Calvo-Río, Vanesa; Loricera, Javier; Palmou-Fontana, Natalia; Pina, Trinitario; Llorca, Javier; González-Gay, Miguel A

    2015-09-01

    Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3-47.5] mg/day at ANK onset to 5 [0-10] at 12 months. After a median [IQR] follow-up of 16 [5-50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations.

  15. Metabolic programming effects initiated in the suckling period predisposing for adult-onset obesity cannot be reversed by calorie restriction

    PubMed Central

    Srinivasan, Malathi; Mahmood, Saleh

    2013-01-01

    Neonatal rats reared on high-carbohydrate (HC) milk formula developed chronic hyperinsulinemia and adult-onset obesity due to programming of islets and the hypothalamic energy circuitry. In this study, calorie restriction by pair-feeding was imposed on HC male rats (HC/PF) to normalize food intake similar to that of mother-fed (MF) rats from weaning until postnatal day 140. A group of HC/PF rats was switched over to ad libitum feeding (HC/PF/AL) from days 90 to 140. Pair-feeding reduced body weight gains and serum insulin and leptin levels in HC/PF rats compared with HC rats, but these parameters were restored to HC levels in the HC/PF/AL rats after ad libitum feeding. Interestingly, the heightened insulin secretory response of isolated islets from adult HC/PF and HC/PF/ AL rats to glucose, acetylcholine, and oxymetazoline were not significantly different from the responses of islets from HC rats. Similarly, the expression of neuropeptide Y and proopiomelanocortin in the hypothalamus was not significantly different among HC, HC/PF, and HC/PF/AL rats. Expression of the leptin receptor in the hypothalami from the HC, HC/PF, and HC/PF/AL rats mirrored that of serum leptin, whereas suppressor of cytokine signaling 3 (Socs3) expression remained high in these three groups. The results indicate that, although calorie restriction resulted in reduction in body weight gain and normalized the serum hormonal pattern, the programed predisposition for the hypersecretory capacity of islets and the hypothalamic hyperphagic response in the HC rats could not be permanently overcome by the pair-feeding imposed on HC rats. PMID:23249696

  16. A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q

    SciTech Connect

    Morissette, J.; Plante, M.; Raymond, V.

    1995-06-01

    Primary open-angle glaucoma (POAG), which causes progressive loss of the visual fields, was subdivided into two groups according to age at onset: (1) chronic open-angle glaucoma (COAG) diagnosed after 40 years and (2) juvenile open-angle glaucoma (JOAG) diagnosed between 3 years of age and early adulthood. A JOAG gene (GLC1A) was recently mapped to chromosome 1q. We studied 142 members of a huge multigenerational French Canadian family affected with autosomal dominant POAG. Either JOAG or COAG was diagnosed with ocular hypertension (OHT), which may lead to POAG. To localize a common disease gene that might be responsible for both glaucoma subsets, we performed linkage analysis considering JOAG and COAG under the same phenotypic category. JOAG/COAG was tightly linked to seven microsatellite markers on chromosome 1q23-q25; a maximum lod score of 6.62 was obtained with AF-M278ye5. To refine the disease locus, we exploited a recombination mapping strategy based on a unique founder effect. The same characteristic haplotype, composed of 14 markers spanning 12 cM between loci D1S196 and D1S212, was recognized in all persons affected by JOAG, COAG, or OHT, but it did not occur in unaffected spouses and in normal family members >35 years of age, except for three obligatory carriers. Key combination events confined the disease region within a 9-cM interval between loci D1S445 and D1S416/D1S480. These observations demonstrate that the GLC1A gene is responsible for both adult-onset and juvenile glaucomas and suggest that the JOAG and COAG categories within this family may be part of a clinical continuum artificially divided at age 40 years. 49 refs., 4 figs., 2 tabs.

  17. [Anomalies in fatty acids distribution and superoxide dismutase activity in lymphocytes of an adult with atypical ceroid lipofuscinosis].

    PubMed

    Rumbach, L; Warter, J M; Coquillat, G; Marescaux, C; Collard, M; Rohmer, F; Bieth, R; Zawislak, R

    1983-01-01

    A 27-year-old Algerian patient presented a slowly progressive disease clinically characterized by a cerebellar syndrome, absence of deep reflexes, bilateral sign of Babinski, deep sensory disturbances, ophthalmologic disorders and pes cavus. The diagnosis of ceroid lipofuscinosis resulted from the presence of lipofuscin deposits evidenced as autofluorescent bodies, and a particular type of curvilinear, crystalloid ultrastructural inclusion bodies in muscle, lymphocytes and liver. Biochemical tests showed reduction in levels of linoleic and arachidonic acids, and of superoxide dismutase activity in lymphocytes. These findings suggest that the biochemical anomalies result from disturbances in polyunsaturated fatty acids metabolism. These results can be related to pathogenetic hypotheses for ceroid lipofuscinosis suggesting a predominant role for peroxidation of fatty acids.

  18. Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

    PubMed Central

    Mukai, Mayumi; Takahashi, Keiko; Hayashi, Yuzo; Nakachi, Kei; Kusunoki, Yoichiro

    2012-01-01

    rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. Conclusion Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC. PMID:23050789

  19. Adult onset asymmetric upper limb tremor misdiagnosed as Parkinson’s disease: A clinical and electrophysiological study

    PubMed Central

    Schwingenschuh, Petra; Ruge, Diane; Edwards, Mark J; Terranova, Carmen; Katschnig, Petra; Carrillo, Fatima; Silveira-Moriyama, Laura; Schneider, Susanne A; Kägi, Georg; Dickson, John; Lees, Andrew J; Quinn, Niall; Mir, Pablo; Rothwell, John C; Bhatia, Kailash P

    2010-01-01

    different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adult-onset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs. PMID:20131394

  20. Genes Interacting with Occupational Exposures to Low Molecular Weight Agents and Irritants on Adult-Onset Asthma in Three European Studies

    PubMed Central

    Rava, Marta; Ahmed, Ismail; Kogevinas, Manolis; Le Moual, Nicole; Bouzigon, Emmanuelle; Curjuric, Ivan; Dizier, Marie-Hélène; Dumas, Orianne; Gonzalez, Juan R.; Imboden, Medea; Mehta, Amar J.; Tubert-Bitter, Pascale; Zock, Jan-Paul; Jarvis, Deborah; Probst-Hensch, Nicole M.; Demenais, Florence; Nadif, Rachel

    2016-01-01

    Background: The biological mechanisms by which cleaning products and disinfectants—an emerging risk factor—affect respiratory health remain incompletely evaluated. Studying genes by environment interactions (G × E) may help identify new genes related to adult-onset asthma. Objectives: We identified interactions between genetic polymorphisms of a large set of genes involved in the response to oxidative stress and occupational exposures to low molecular weight (LMW) agents or irritants on adult-onset asthma. Methods: Our data came from three large European cohorts: Epidemiological Family-based Study of the Genetics and Environment of Asthma (EGEA), Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), and European Community Respiratory Health Survey in Adults (ECRHS). A candidate pathway–based strategy identified 163 genes involved in the response to oxidative stress and potentially related to exposures to LMW agents/irritants. Occupational exposures were evaluated using an asthma job-exposure matrix and job-specific questionnaires for cleaners and healthcare workers. Logistic regression models were used to detect G × E interactions, adjusted for age, sex, and population ancestry, in 2,599 adults (mean age, 47 years; 60% women, 36% exposed, 18% asthmatics). p-Values were corrected for multiple comparisons. Results: Ever exposure to LMW agents/irritants was associated with current adult-onset asthma [OR = 1.28 (95% CI: 1.04, 1.58)]. Eight single nucleotide polymorphism (SNP) by exposure interactions at five loci were found at p < 0.005: PLA2G4A (rs932476, chromosome 1), near PLA2R1 (rs2667026, chromosome 2), near RELA (rs931127, rs7949980, chromosome 11), PRKD1 (rs1958980, rs11847351, rs1958987, chromosome 14), and PRKCA (rs6504453, chromosome 17). Results were consistent across the three studies and after accounting for smoking. Conclusions: Using a pathway-based selection process, we identified novel genes potentially involved

  1. When uncommon and common coalesce: adult onset Still's disease associated with breast augmentation as part of autoimmune syndrome induced by adjuvants (ASIA).

    PubMed

    Dagan, A; Kogan, M; Shoenfeld, Y; Segal, G

    2016-06-01

    Adult onset Still's disease (AOSD) is an uncommon, multisystemic, auto-inflammatory disorder, while breast augmentation is a very common cosmetic procedure. We describe a case in which these two coalesce, AOSD, manifested with pleuritis and pericarditis, developed after breast mammoplasty. The pathogenetic, missing link, behind the development of AOSD following mammoplasty, is thought to be the autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA). We reviewed other cases of AOSD associated with breast mammoplasty published to date and the literature regarding AOSD and ASIA syndrome. The review is followed by a short debate of whether silicone implants should be explanted in similar, future cases.

  2. Adult-onset deficiency in growth hormone and insulin-like growth factor-I alters oligodendrocyte turnover in the corpus callosum.

    PubMed

    Hua, Kun; Forbes, M Elizabeth; Lichtenwalner, Robin J; Sonntag, William E; Riddle, David R

    2009-08-01

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) provide trophic support during development and also appear to influence cell structure, function and replacement in the adult brain. Recent studies demonstrated effects of the GH/IGF-I axis on adult neurogenesis, but it is unclear whether the GH/IGF-I axis influences glial turnover in the normal adult brain. In the current study, we used a selective model of adult-onset GH and IGF-I deficiency to evaluate the role of GH and IGF-I in regulating glial proliferation and survival in the adult corpus callosum. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete via twice daily injections of GH starting at postnatal day 28 (P28), approximately the age at which GH pulse amplitude increases in developing rodents. GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Quantitative analyses revealed that adult-onset GH/IGF-I deficiency decreased cell proliferation in the white matter and decreased the survival of newborn oligodendrocytes. These findings are consistent with the hypothesis that aging-related changes in the GH/IGF-I axis produce deficits in ongoing turnover of oligodendrocytes, which may contribute to aging-related cognitive changes and deficits in remyelination after injury.

  3. Limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies as a cause of adult-onset mesial temporal lobe epilepsy.

    PubMed

    Toyota, Tomoko; Akamatsu, Naoki; Tsuji, Sadatoshi; Nishizawa, Shigeru

    2014-06-01

    Recently, some reports have indicated that limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies (VGKC-Ab) is a cause of adult-onset mesial temporal lobe epilepsy (MTLE). We report a 53-year-old woman who had her first epileptic seizure at the age of 50 years old. Examination by 3-Tesla brain MRI revealed left hippocampal high signal intensity and swelling on fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging at 2 months after her first seizure. The patient received intravenous methylprednisolone and carbamazepine 300 mg/day. One month later, MRI revealed improvement of her left hippocampal abnormalities. Thereafter, she had no seizures, however, three years after her first seizure, EEG revealed a seizure pattern in the left temporal region. Brain MRI revealed left hippocampal high signal intensity and brain fluorodeoxyglucose positron emission tomography revealed hypermetabolism. Her serum VGKC-Ab levels were 118 pM(normal < 100 pM). Intravenous methylprednisolone therapy was reinitiated. Two months later, her hippocampal abnormalities had improved and 3 months later her VGKC-Ab levels decreased to 4.4 pM. Remission of the epileptic seizures was also observed. This MTLE in the middle age was considered as limbic encephalitis associated with anti- VGKC-Ab. In cases of unexplained adult-onset MTLE, limbic encephalitis associated with anti-VGKC-Ab, which responds well to immunotherapy, should be considered in the differential diagnosis.

  4. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: Different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation

    SciTech Connect

    Hanna, M.G.; Nelson, I.; Sweeney, M.G.; Cooper, J.M.; Watkins, P.J.; Morgan-Hughes, J.A.; Harding, A.E.

    1995-05-01

    We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus. 43 refs., 4 figs., 1 tab.

  5. A case of adult-onset reducing body myopathy presenting a novel clinical feature, asymmetrical involvement of the sternocleidomastoid and trapezius muscles.

    PubMed

    Fujii, Takayuki; Hayashi, Shintaro; Kawamura, Nobutoshi; Higuchi, Masa-Aki; Tsugawa, Jun; Ohyagi, Yasumasa; Hayashi, Yukiko K; Nishino, Ichizo; Kira, Jun-Ichi

    2014-08-15

    We herein report a 32-year-old woman with adult-onset reducing body myopathy (RBM) who had a mutation in the four-and-a-half LIM domain 1 gene (FHL1) and showed a marked asymmetrical involvement of sternocleidomastoid and trapezius muscles. At 30 years of age she noticed bilateral foot drop, and over the next two years developed difficulty raising her right arm. At 32 years of age she was admitted to our hospital for a diagnostic evaluation. Neurological examination showed moderate weakness and atrophy of her right sternocleidomastoid muscle, right trapezius muscle, and bilateral upper proximal muscles. There were severe weakness and atrophy of her bilateral tibialis anterior muscles. Her deep tendon reflexes were hypoactive in her upper extremities. Her serum creatine kinase level was mildly increased. Muscle biopsy specimens from the left tibialis anterior muscle revealed marked variation in fiber size, some necrotic or regenerating fibers, and reducing bodies. Gene analysis of FHL1 demonstrated a mutation: a heterozygous missense mutation of c.377G>A (p. C126T) in FHL1. Compared with previous adult-onset RBM cases harboring mutations in FHL1, our case was characterized by asymmetrical atrophy of the sternocleidomastoid and trapezius muscles.

  6. Vapor, Dust and Smoke Exposure in relation to adult-onset asthma and chronic respiratory symptoms: The Singapore Chinese Health Study

    PubMed Central

    LeVan, Tricia D.; Koh, Woon-Puay; Lee, Hin-Peng; Koh, David; Yu, Mimi C.; London, Stephanie J.

    2006-01-01

    Occupational factors contribute to a significant fraction of respiratory disease and symptoms. We evaluated the role of occupational exposures on asthma, chronic bronchitis, and respiratory symptoms in a population-based cohort, the Singapore Chinese Health Study. History of occupations, occupational exposures, and respiratory conditions were collected by interviews with 52,325 Singaporeans born 1918–1953. Exposure to dusts, from cotton, wood, metal, mineral and/or asbestos, was associated with non-chronic cough and/or phlegm (OR = 1.19, 95% CI = 1.08, 1.30), chronic bronchitis (OR = 1.26, 95% CI = 1.01, 1.57) and adult-onset asthma (OR = 1.14, 95% CI = 1.00, 1.30). Cotton dust was the major component contributing to respiratory symptoms. Vapor exposure, from chemical solvents, dyes, cooling oils, paints, wood preservatives and/or pesticides, was associated with non-chronic cough or phlegm (OR = 1.14, 95% CI = 1.03, 1.27), chronic dry cough (OR = 1.55, 95% CI = 1.19, 2.01) and adult-onset asthma (OR = 1.34, 95% CI = 1.15, 1.56). Chemical solvents, cooling oils and pesticides were the major sources contributing to respiratory symptoms. These data support the role of occupational exposures in the etiology of respiratory illness in a population-based cohort in Singapore with a low prevalence of atopic illness. PMID:16707657

  7. Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development.

    PubMed

    Issa, Fadi A; Mock, Allan F; Sagasti, Alvaro; Papazian, Diane M

    2012-11-01

    Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease caused by mutations in the Kv3.3 voltage-gated potassium (K(+)) channel. SCA13 exists in two forms: infant onset is characterized by severe cerebellar atrophy, persistent motor deficits and intellectual disability, whereas adult onset is characterized by progressive ataxia and progressive cerebellar degeneration. To test the hypothesis that infant- and adult-onset mutations have differential effects on neuronal development that contribute to the age at which SCA13 emerges, we expressed wild-type Kv3.3 or infant- or adult-onset mutant proteins in motor neurons in the zebrafish spinal cord. We characterized the development of CaP (caudal primary) motor neurons at ∼36 and ∼48 hours post-fertilization using confocal microscopy and 3D digital reconstruction. Exogenous expression of wild-type Kv3.3 had no significant effect on CaP development. In contrast, CaP neurons expressing the infant-onset mutation made frequent pathfinding errors, sending long, abnormal axon collaterals into muscle territories that are normally innervated exclusively by RoP (rostral primary) or MiP (middle primary) motor neurons. This phenotype might be directly relevant to infant-onset SCA13 because interaction with inappropriate synaptic partners might trigger cell death during brain development. Importantly, pathfinding errors were not detected in CaP neurons expressing the adult-onset mutation. However, the adult-onset mutation tended to increase the complexity of the distal axonal arbor. From these results, we speculate that infant-onset SCA13 is associated with marked changes in the development of Kv3.3-expressing cerebellar neurons, reducing their health and viability early in life and resulting in the withered cerebellum seen in affected children.

  8. Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Caused by a Novel R782G Mutation in CSF1R

    PubMed Central

    Foulds, Nicola; Pengelly, Reuben J.; Hammans, Simon R.; Nicoll, James A. R.; Ellison, David W.; Ditchfield, Adam; Beck, Sarah; Ennis, Sarah

    2015-01-01

    We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the Colony-Stimulating Factor 1 Receptor gene (CSF1R). Neuropathology of two affected family members showed cerebral white matter degeneration with axonal swellings and pigmented macrophages. The few recently reported families with CSF1R mutations had been previously labelled “hereditary diffuse leukencephalopathy with axonal spheroids” (HDLS) and “pigmentary orthochromatic leukodystrophy” (POLD), disorders which now appear to form a disease continuum. The term “adult-onset leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP) has been proposed to encompass this spectrum. As CSF1R regulates microglia this mutation implies that dysregulation of microglia is the primary cause of the disease. PMID:25975230

  9. Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Caused by a Novel R782G Mutation in CSF1R.

    PubMed

    Foulds, Nicola; Pengelly, Reuben J; Hammans, Simon R; Nicoll, James A R; Ellison, David W; Ditchfield, Adam; Beck, Sarah; Ennis, Sarah

    2015-05-15

    We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the Colony-Stimulating Factor 1 Receptor gene (CSF1R). Neuropathology of two affected family members showed cerebral white matter degeneration with axonal swellings and pigmented macrophages. The few recently reported families with CSF1R mutations had been previously labelled "hereditary diffuse leukencephalopathy with axonal spheroids" (HDLS) and "pigmentary orthochromatic leukodystrophy" (POLD), disorders which now appear to form a disease continuum. The term "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP) has been proposed to encompass this spectrum. As CSF1R regulates microglia this mutation implies that dysregulation of microglia is the primary cause of the disease.

  10. Adult-onset deficiency of acyl CoA:monoacylglycerol acyltransferase 2 protects mice from diet-induced obesity and glucose intolerance[S

    PubMed Central

    Banh, Taylor; Nelson, David W.; Gao, Yu; Huang, Ting-Ni; Yen, Mei-I; Yen, Chi-Liang E.

    2015-01-01

    Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption. We previously demonstrated that mice without a functional MGAT2-coding gene (Mogat2−/−) exhibit increased energy expenditure and resistance to obesity induced by excess calories. One critical question raised is whether lacking MGAT2 during early development is required for the metabolic phenotypes in adult mice. In this study, we found that Mogat2−/− pups grew slower than wild-type littermates during the suckling period. To determine whether inactivating MGAT2 in adult mice is sufficient to confer resistance to diet-induced obesity, we generated mice with an inducible Mogat2-inactivating mutation. Mice with adult-onset MGAT2 deficiency (Mogat2AKO) exhibited a transient decrease in food intake like Mogat2−/− mice when fed a high-fat diet and a moderate increase in energy expenditure after acclimatization. They gained less weight than littermate controls, but the difference was smaller than that between wild-type and Mogat2−/− mice. The moderate reduction in weight gain was associated with reduced hepatic TAG and improved glucose tolerance. Similar protective effects were also observed in mice that had gained weight on a high-fat diet before inactivating MGAT2. These findings suggest that adult-onset MGAT2 deficiency mitigates metabolic disorders induced by high-fat feeding and that MGAT2 modulates early postnatal nutrition and may program metabolism later in life. PMID:25535286

  11. Congenital and prolonged adult-onset deafness cause distinct degradations in neural ITD coding with bilateral cochlear implants.

    PubMed

    Hancock, Kenneth E; Chung, Yoojin; Delgutte, Bertrand

    2013-06-01

    Bilateral cochlear implant (CI) users perform poorly on tasks involving interaural time differences (ITD), which are critical for sound localization and speech reception in noise by normal-hearing listeners. ITD perception with bilateral CI is influenced by age at onset of deafness and duration of deafness. We previously showed that ITD coding in the auditory midbrain is degraded in congenitally deaf white cats (DWC) compared to acutely deafened cats (ADC) with normal auditory development (Hancock et al., J. Neurosci, 30:14068). To determine the relative importance of early onset of deafness and prolonged duration of deafness for abnormal ITD coding in DWC, we recorded from single units in the inferior colliculus of cats deafened as adults 6 months prior to experimentation (long-term deafened cats, LTDC) and compared neural ITD coding between the three deafness models. The incidence of ITD-sensitive neurons was similar in both groups with normal auditory development (LTDC and ADC), but significantly diminished in DWC. In contrast, both groups that experienced prolonged deafness (LTDC and DWC) had broad distributions of best ITDs around the midline, unlike the more focused distributions biased toward contralateral-leading ITDs present in both ADC and normal-hearing animals. The lack of contralateral bias in LTDC and DWC results in reduced sensitivity to changes in ITD within the natural range. The finding that early onset of deafness more severely degrades neural ITD coding than prolonged duration of deafness argues for the importance of fitting deaf children with sound processors that provide reliable ITD cues at an early age.

  12. Remote Assessment of Cognitive Function in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) – a Pilot Study of Feasibility and Reliability

    PubMed Central

    Ragbeer, Shayne N.; Augustine, Erika F.; Mink, Jonathan W.; Thatcher, Alyssa R.; Vierhile, Amy E.; Adams, Heather R.

    2015-01-01

    Remote technology provides an opportunity to extend the reach of clinical care and research for pediatric rare disease. This pilot study evaluated the feasibility and reliability of neuropsychological evaluation, using remote audiovisual technology, in the assessment of children with juvenile Batten disease. Three children with Batten disease and one healthy sibling completed a standardized cognitive assessment. Results indicated high agreement between an in-person and a remote evaluator, when comparing the subjects’ cognitive test scores. This initial test of remote cognitive assessment suggests it is feasible and reliable in children with pediatric neurodegenerative disease, for whom disease burden may limit travel and access to expert care and/or clinical trials. PMID:26336202

  13. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    DOE PAGES

    Giorgio, E.; Robyr, D.; Spielmann, M.; ...

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in amore » postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.« less

  14. Iron Deficiency Anemia in Adult Onset Still's Disease with a Serum Ferritin of 26,387 μg/L.

    PubMed

    Patel, Sheetal; Monemian, Seyed; Khalid, Ayesha; Dosik, Harvey

    2011-01-01

    Serum ferritin rises in the anemia of chronic inflammation reflecting increased iron storage and other changes mediated by inflammation. When iron deficiency coexists, the ferritin may not always decline into the subnormal range. We describe the rare interaction of iron deficiency with the extreme hyperferritinemia characteristic of adult onset Still's disease. The combination has clinical relevance and allows deductions about the presence of serum ferritin at 26,387 μg/L despite obvious iron depletion. The diagnosis of iron deficiency anemia was delayed and became fully obvious when her Still's disease remitted and serum ferritin decreased to 6.5 μg/L. The coexistence of iron deficiency should be considered when evaluating a patient with anemia of chronic inflammation even when the ferritin level is elevated several hundredfold. Further insights on ferritin metabolism in Still's disease are suggested by the likelihood that the patient's massive hyperferritinemia in the acute phase of Still's disease was almost entirely of the iron-free apoferritin form.

  15. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    PubMed Central

    Giorgio, Elisa; Robyr, Daniel; Spielmann, Malte; Ferrero, Enza; Di Gregorio, Eleonora; Imperiale, Daniele; Vaula, Giovanna; Stamoulis, Georgios; Santoni, Federico; Atzori, Cristiana; Gasparini, Laura; Ferrera, Denise; Canale, Claudio; Guipponi, Michel; Pennacchio, Len A.; Antonarakis, Stylianos E.; Brussino, Alessandro; Brusco, Alfredo

    2015-01-01

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes. PMID:25701871

  16. Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.

    PubMed

    Veth, Kerry N; Willer, Jason R; Collery, Ross F; Gray, Matthew P; Willer, Gregory B; Wagner, Daniel S; Mullins, Mary C; Udvadia, Ava J; Smith, Richard S; John, Simon W M; Gregg, Ronald G; Link, Brian A

    2011-02-01

    The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.

  17. Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma

    PubMed Central

    Veth, Kerry N.; Willer, Jason R.; Collery, Ross F.; Gray, Matthew P.; Willer, Gregory B.; Wagner, Daniel S.; Mullins, Mary C.; Udvadia, Ava J.; Smith, Richard S.; John, Simon W. M.; Gregg, Ronald G.; Link, Brian A.

    2011-01-01

    The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, Bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals—but not all—develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease. PMID:21379331

  18. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    SciTech Connect

    Giorgio, E.; Robyr, D.; Spielmann, M.; Ferrero, E.; Di Gregorio, E.; Imperiale, D.; Vaula, G.; Stamoulis, G.; Santoni, F.; Atzori, C.; Gasparini, L.; Ferrera, D.; Canale, C.; Guipponi, M.; Pennacchio, L. A.; Antonarakis, S. E.; Brussino, A.; Brusco, A.

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.

  19. Adult Onset Asthma and Periocular Xanthogranuloma (AAPOX), a Rare Entity With a Strong Link to IgG4-Related Disease: An Observational Case Report Study.

    PubMed

    London, Jonathan; Martin, Antoine; Soussan, Michael; Badelon, Isabelle; Gille, Thomas; Uzunhan, Yurdagul; Giroux-Leprieur, Bénédicte; Warzocha, Ursula; Régent, Alexis; Galatoire, Olivier; Dhote, Robin; Abad, Sébastien

    2015-10-01

    Adult onset asthma and periocular xanthogranuloma (AAPOX) is a rare non-Langerhans histiocytosis characterized histopathologically by a periocular infiltration of foamy histiocytes and Touton giant cells. Benign hyperplasia with plasma cell infiltration is classically described in eyelids or lymph nodes of AAPOX patients. It is also a characteristic feature of IgG4-related disease (IgG4-RD), a new entity defined by an IgG4-bearing plasma cell infiltration of organs.To determine if AAPOX syndrome shares clinical, biological, and histopathological characteristics with IgG4-RD, we used the comprehensive clinical diagnostic criteria for IgG4-RD in a retrospective case series of three consecutive patients with histologically-proven AAPOX. Patients who were diagnosed with AAPOX at a French academic referral center for orbital inflammation between November 1996 and March 2013 were enrolled. Biopsies from ocular adnexa or other organs were systematically reexamined. For each patient, clinical and serological data, radiologic findings, and treatment were retrospectively analyzed.Two AAPOX patients fulfilled all of the diagnostic criteria for a definite IgG4-RD. One patient who lacked the serological criteria fulfilled the criteria of a probable IgG4-RD.These 3 cases of AAPOX patients fulfilled the IgG4-RD comprehensive clinical diagnostic criteria. To our knowledge, this is the first observational case report study to clearly show a strong relationship between IgG4-RD and AAPOX syndrome.

  20. Highly Expression of CD11b and CD32 on Peripheral Blood Mononuclear Cells from Patients with Adult-Onset Still’s Disease

    PubMed Central

    Kim, Hyoun-Ah; Choi, Bunsoon; Suh, Chang-Hee; Han, Mi Hwa; Jung, Ju-Yang; Sayeed, Hasan M.; Kim, Ye Won; Sohn, Seonghyang

    2017-01-01

    Background: We investigated the potential role of several pattern-recognition receptors (PRRs; CD11b, CD11c, CD32, CD206, CD209, and dectin-1) in adult-onset Still’s disease (AOSD). Methods: The study included 13 untreated AOSD patients, 19 rheumatoid arthritis (RA) patients (as a disease control), and 19 healthy controls (HCs). The PRRs were quantified in peripheral blood using flow cytometry. The serum levels of interleukin-17 (IL-17), IL-18, and IL-23 were measured by enzyme-linked immunosorbent assay. Results: Significantly higher mean frequencies of cells presenting CD11b and CD32 from whole blood were observed in patients with AOSD than in patients with RA or HC. The levels of IL-17, IL-18, and IL-23 were elevated in AOSD patients compared to HCs. CD11b frequencies from whole cells correlated with systemic scores, lactate dehydrogenase (LDH) levels, aspartate transaminase levels, interleukin-23 (IL-23) levels, and IL-18. Frequencies of CD209 from granulocytes were significantly correlated with systemic scores, and the erythrocyte sedimentation rate and levels of C-reactive protein, ferritin, LDH, IL-23, and interleukin-18 (IL-18). Conclusions: Elevated frequencies of circulating CD11b-positive cells and positive correlations with disease activity markers suggest that circulating CD11b-positive cells contribute to the pathogenesis of AOSD. PMID:28106835

  1. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).

    PubMed

    Giorgio, Elisa; Robyr, Daniel; Spielmann, Malte; Ferrero, Enza; Di Gregorio, Eleonora; Imperiale, Daniele; Vaula, Giovanna; Stamoulis, Georgios; Santoni, Federico; Atzori, Cristiana; Gasparini, Laura; Ferrera, Denise; Canale, Claudio; Guipponi, Michel; Pennacchio, Len A; Antonarakis, Stylianos E; Brussino, Alessandro; Brusco, Alfredo

    2015-06-01

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.

  2. Co-existing spinal intradural ependymal cyst and sacral Tarlov cyst in adult-onset tethered cord syndrome with syringomyelia: Case report and literature review

    PubMed Central

    Rai, Hamid H.; Khan, Muhammad F.; Enam, Syed Ather; Hashmi, Imtiaz

    2016-01-01

    Background: Synchronous spinal intradural ependymal cysts and sacral Tarlov cysts in adult onset tethered cord syndrome are extremely rare. Case Description: A 23-year-old male presented with back pain radiating into both lower extremities, accompanied by acute onset of gait difficulty and sphincter dysfunction. Magnetic resonance imaging identified a low lying conus medullaris, syringomyelia with septations extending from T12 to S1, a tethered cord, and a thickened filum terminale with a sacral Tarlov cyst. The patient underwent a L3-4 laminectomy for decompression of syringomyelia and excision/biopsy of a space occupying lesion along with S1-2 laminectomy for cord untethering and Tarlov cyst fenestration. Postoperative histopathology confirmed that the lesion was an ependymal cyst. Clinically, patient showed marked improvement in the neurological status. Conclusion: Simultaneous decompressive laminectomy of L3-4 and S1-2 effectively decompressed the syringomyelia while allowing for excision/biopsy of a space occupying lesion at the former and untethering and Tarlov cyst fenestration at the latter levels. PMID:27843691

  3. An autopsied case of adult-onset bulbospinalform Alexander disease with a novel S393R mutation in the GFAP gene.

    PubMed

    Iwasaki, Yasushi; Saito, Yufuko; Mori, Keiko; Ito, Masumi; Mimuro, Maya; Aiba, Ikuko; Saito, Kozo; Mizuta, Ikuko; Yoshida, Tomokatsu; Nakagawa, Masanori; Yoshida, Mari

    2015-01-01

    A 50-year-old Japanese man with no apparent family history noticed diplopia. He gradually showed gait disturbance and dysuria. Abducens disorder of eye movement with nystagmus, tongue atrophy with fasciculation, spastic tetraparesis, and sensory disturbance were also observed. MRI showed severe atrophy of the medulla oblongata to the cervical cord ("tadpole appearance"). Tracheotomy and gastrostomy were performed 7 years after onset due to the development of bulbar palsy. Death occurred following respiratory failure after 11 years total disease duration. The brain weighed 1,380 g. The cerebrum, cerebellum, midbrain, and upper pons were preserved from atrophy, but the medulla oblongata to the cervical cord showed severe atrophy. A few Rosenthal fibers were observed in the cerebral white matter, basal ganglia, and cerebellum, whereas numerous Rosenthal fibers were observed in the medulla oblongata to the cervical cord. Myelin loss with relatively preserved axons was extensively observed from the middle of the pons to the spinal cord. The clinicopathological diagnosis was adult-onset bulbospinal-form Alexander disease. Glial fibrillary acidic protein (GFAP) gene analysis revealed a novel mutation of S393R. Expression patterns of S393R mutant GFAP using adrenal carcinoma-derived cells (SW13 cells) showed a decreased number of filamentous structures and abnormal aggregates.

  4. Maturity of judgement in decision making for predictive testing for nontreatable adult-onset neurogenetic conditions: a case against predictive testing of minors.

    PubMed

    Richards, F H

    2006-11-01

    International guidelines developed to minimize harm from predictive testing for adult-onset, nontreatable neurogenetic conditions such as Huntington disease (HD) state that such testing should not be available to minors. Some authors have proposed that predictive testing for these conditions should be available to minors at the request of parents and/or of younger adolescents themselves. They highlight the lack of empirical evidence that predictive testing of minors causes harm and suggest that refusing to test minors may be detrimental. The current study focuses on the context of predictive test requests by adolescents younger than 18 years, and presents arguments and evidence that the risk of potential harm from testing such young people is sufficiently high to justify continued caution in this area. A study based on a model of psychosocial maturity found that the 3 factors involved in maturity of judgement in decision making - responsibility, temperance and perspective - continue to develop into late adolescence. There is also evidence that the prefrontal areas of the brain, which are involved in executive functions such as decision making, are not fully developed until early adulthood. Combined with evidence of adverse long-term effects, from research with adults who have undergone predictive testing, these findings constitute grounds for retaining a minimum age of 18 years for predictive testing for nontreatable conditions. Further research on assessment of maturity will assist with reaching a consensus on this issue.

  5. [Adult-onset rare diseases].

    PubMed

    Pfliegler, György; Kovács, Erzsébet; Kovács, György; Urbán, Krisztián; Nagy, Valéria; Brúgós, Boglárka

    2014-03-02

    The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.).

  6. Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases

    PubMed Central

    Chakrabarti, Saikat; Ray, Kunal

    2016-01-01

    Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID:27243976

  7. Sex-specific associations of low birth weight with adult-onset diabetes and measures of glucose homeostasis: Brazilian Longitudinal Study of Adult Health

    PubMed Central

    Yarmolinsky, James; Mueller, Noel T; Duncan, Bruce B; Chor, Dóra; Bensenor, Isabela M; Griep, Rosane H; Appel, Lawrence J; Barreto, Sandhi M; Schmidt, Maria Inês

    2016-01-01

    Emerging evidence suggests sex differences in the early origins of adult metabolic disease, but this has been little investigated in developing countries. We investigated sex-specific associations between low birth weight (LBW; <2.5 kg) and adult-onset diabetes in 12,525 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Diabetes was defined by self-reported information and laboratory measurements. In confounder-adjusted analyses, LBW (vs. 2.5–4 kg) was associated with higher prevalence of diabetes in women (Prevalence Ratio (PR) 1.54, 95% CI: 1.32–1.79), not in men (PR 1.06, 95% CI: 0.91–1.25; Pheterogeneity = 0.003). The association was stronger among participants with maternal diabetes (PR 1.60, 95% CI: 1.35–1.91), than those without (PR 1.15, 95% CI: 0.99–1.32; Pheterogeneity = 0.03). When jointly stratified by sex and maternal diabetes, the association was observed for women with (PR 1.77, 95% CI: 1.37–2.29) and without (PR 1.45, 95% CI: 1.20–1.75) maternal diabetes. In contrast, in men, LBW was associated with diabetes in participants with maternal diabetes (PR 1.45, 95% CI: 1.15–1.83), but not in those without (PR 0.92, 95% CI: 0.74–1.14). These sex-specific findings extended to continuous measures of glucose homeostasis. LBW was associated with higher diabetes prevalence in Brazilian women, and in men with maternal diabetes, suggesting sex-specific intrauterine effects on adult metabolic health. PMID:27845438

  8. Metabolic Disturbances in Adult-Onset Still’s Disease Evaluated Using Liquid Chromatography/Mass Spectrometry-Based Metabolomic Analysis

    PubMed Central

    Chen, Der-Yuan; Hsieh, Chia-Wei; Chen, Hsin-Hua; Hung, Wei-Ting

    2016-01-01

    Objective Liquid chromatography/mass spectrometry (LC/MS)-based comprehensive analysis of metabolic profiles with metabolomics approach has potential diagnostic and predictive implications. However, no metabolomics data have been reported in adult-onset Still’s disease (AOSD). This study investigated the metabolomic profiles in AOSD patients and examined their association with clinical characteristics and disease outcome. Methods Serum metabolite profiles were determined on 32 AOSD patients and 30 healthy controls (HC) using ultra-performance liquid chromatography (UPLC)/MS analysis, and the differentially expressed metabolites were quantified using multiple reactions monitoring (MRM)/MS analysis in 44 patients and 42 HC. Pure standards were utilized to confirm the presence of the differentially expressed metabolites. Results Eighteen differentially expressed metabolites were identified in AOSD patents using LC/MS-based analysis, of which 13 metabolites were validated by MRM/MS analysis. Among them, serum levels of lysoPC(18:2), urocanic acid and indole were significantly lower, and L-phenylalanine levels were significantly higher in AOSD patients compared with HC. Moreover, serum levels of lysoPC(18:2), PhePhe, uridine, taurine, L-threonine, and (R)-3-Hydroxy-hexadecanoic acid were significantly correlated with disease activity scores (all p<0.05) in AOSD patients. A different clustering of metabolites was associated with a different disease outcome, with significantly lower levels of isovalerylsarcosine observed in patients with chronic articular pattern (median, 77.0AU/ml) compared with monocyclic (341.5AU/ml, p<0.01) or polycyclic systemic pattern (168.0AU/ml, p<0.05). Conclusion Thirteen differentially expressed metabolites identified and validated in AOSD patients were shown to be involved in five metabolic pathways. Significant associations of metabolic profiles with disease activity and outcome of AOSD suggest their involvement in AOSD pathogenesis. PMID

  9. Localization of a locus (GLC1B) for adult-onset primary open angle glaucoma to the 2cen-q13 region

    SciTech Connect

    Stoilova, D.; Trifan, O.C.; Sarfarazi, M.

    1996-08-15

    Primary open angle glaucoma (GLC1) is a common ocular disorder with a characteristic degeneration of the optic nerve and visual field defects that is often associated with an elevated intraocular pressure. The severe but rare juvenile-onset type has previously been mapped to 1q21-q31, and its genetic heterogeneity has been established. Herein, we present a new locus (GLC1B) for one form of GLC1 on chromosome 2cen-q13 with a clinical presentation of low to moderate intraocular pressure, onset in late 40s, and a good response to medical treatment. Two-point and haplotype analyses of affected and unaffected meioses in six families provided maximum linkage information with D2S417, GATA112EO3, D2S113, D2S373, and D2S274 (lod scores ranging from 3.11 to 6.48) within a region of 8.5 cM that is flanked by D2S2161 and D2S2264. Analysis of affected meioses alone revealed no recombination with an additional two markers (D2S2264 and D2S135) in a region of 11.2 cM that is flanked by D2S2161 and D2S176. Analysis of unaffected meioses identified only one healthy 86-year-old male who has inherited the entire affected haplotype and, hence, is a gene carrier for this condition. Eight additional families with similar and/or different clinical presentation did not show any linkage to this region and, therefore, provided evidence for genetic heterogeneity of adult-onset primary open angle glaucoma. 63 refs., 2 figs., 2 tabs.

  10. Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu-Hakola disease: lesion staging and dynamic changes of axons and microglial subsets.

    PubMed

    Oyanagi, Kiyomitsu; Kinoshita, Michiaki; Suzuki-Kouyama, Emi; Inoue, Teruhiko; Nakahara, Asa; Tokiwai, Mika; Arai, Nobutaka; Satoh, Jun-Ichi; Aoki, Naoya; Jinnai, Kenji; Yazawa, Ikuru; Arai, Kimihito; Ishihara, Kenji; Kawamura, Mitsuru; Ishizawa, Keisuke; Hasegawa, Kazuko; Yagisita, Saburo; Amano, Naoji; Yoshida, Kunihiro; Terada, Seishi; Yoshida, Mari; Akiyama, Haruhiko; Mitsuyama, Yoshio; Ikeda, Shu-Ichi

    2016-09-08

    The brains of 10 Japanese patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) and eight Japanese patients with Nasu-Hakola disease (N-HD) and five age-matched Japanese controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets. In both diseases, the pathognomonic neuropathological features included spherically swollen axons (spheroids and globules), axon loss and changes of microglia in the white matter. In ALSP, four lesion stages based on the degree of axon loss were discernible: Stage I, patchy axon loss in the cerebral white matter without atrophy; Stage II, large patchy areas of axon loss with slight atrophy of the cerebral white matter and slight dilatation of the lateral ventricles; Stage III, extensive axon loss in the cerebral white matter and dilatation of the lateral and third ventricles without remarkable axon loss in the brainstem and cerebellum; Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. Internal capsule and pontine base were relatively well preserved in the N-HD, even at Stage IV, and the swollen axons were larger with a higher density in the ALSP. Microglial cells immunopositive for CD68, CD163 or CD204 were far more obvious in ALSP, than in N-HD, and the shape and density of the cells changed in each stage. With progression of the stage, clinical symptoms became worse to apathetic state, and epilepsy was frequently observed in patients at Stages III and IV in both diseases. From these findings, it is concluded that (i) shape, density and subsets of microglia change dynamically along the passage of stages and (ii) increase of IBA-1-, CD68-, CD163- and CD204-immunopositive cells precedes loss of axons in ALSP.

  11. TLR4 Endogenous Ligand S100A8/A9 Levels in Adult-Onset Still’s Disease and Their Association with Disease Activity and Clinical Manifestations

    PubMed Central

    Kim, Hyoun-Ah; Han, Jae Ho; Kim, Woo-Jung; Noh, Hyun Jin; An, Jeong-Mi; Yim, Hyunee; Jung, Ju-Yang; Kim, You-Sun; Suh, Chang-Hee

    2016-01-01

    S100A8/A9 has been suggested as a marker of disease activity in patients with adult-onset Still’s disease (AOSD). We evaluated the clinical significance of S100A8/A9 as a biomarker and its pathogenic role in AOSD. Blood samples were collected prospectively from 20 AOSD patients and 20 healthy controls (HCs). Furthermore, skin and lymph node biopsy specimens of AOSD patients were investigated for S100A8/A9 expression levels via immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) of active AOSD patients and HCs were investigated for S100A8/A9 cell signals. S100A8/A9, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in active AOSD patients were higher than those of HCs. S100A8/A9 levels correlated positively with IL-1β, TNF-α and C-reactive protein. The inflammatory cells expressing S100A8/A9 were graded from one to three in skin and lymph node biopsies of AOSD patients. The grading for S100A8/A9 was more intense in the skin lesions with karyorrhexis, mucin deposition, and neutrophil infiltration. Like lipopolysaccharide (LPS), S100A8/A9 induced phosphorylation of p38 and c-Jun amino-terminal kinase (JNK) in PBMCs, suggesting that S100A8/A9 activates Toll-like receptor 4 signaling pathways. These findings suggest that S100A8/A9 may be involved in the inflammatory response with induction of proinflammatory cytokines and may serve as a clinicopathological marker for disease activity in AOSD. PMID:27537874

  12. Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice.

    PubMed

    Hafler, Brian P; Klein, Zoe A; Jimmy Zhou, Z; Strittmatter, Stephen M

    2014-11-07

    Prior investigations have shown that patients with neuronal ceroid lipofuscinosis (NCL) develop neurodegeneration characterized by vision loss, motor dysfunction, seizures, and often early death. Neuropathological analysis of patients with NCL shows accumulation of intracellular autofluorescent storage material, lipopigment, throughout neurons in the central nervous system including in the retina. A recent study of a sibling pair with adult onset NCL and retinal degeneration showed linkage to the region of the progranulin (GRN) locus and a homozygous mutation was demonstrated in GRN. In particular, the sibling pair with a mutation in GRN developed retinal degeneration and optic atrophy. This locus for this form of adult onset neuronal ceroid lipofuscinosis was designated neuronal ceroid lipofuscinosis-11 (CLN11). Based on these clinical observations, we wished to determine whether Grn-null mice develop accumulation of autofluorescent particles and retinal degeneration. Retinas of both wild-type and Progranulin deficient mice were examined by immunostaining and autofluorescence. Accumulation of autofluorescent material was present in Progranulin deficient mice at 12 months. Degeneration of multiple classes of neurons including photoreceptors and retinal ganglion cells was noted in mice at 12 and 18 months. Our data shows that Grn(-/-) mice develop degenerative pathology similar to features of human CLN11.

  13. X-ray microprobe analysis of the retina and RPE in sheep with ovine ceroid-lipofuscinosis

    SciTech Connect

    Samuelson, D.A.; Armstrong, D.; Jolly, R. )

    1990-11-01

    Ovine ceroid-lipofuscinosis (OCL) is one animal model for the human condition, and because autofluorescent lipopigments are prominent in the brain and eye, it may also prove useful as a model for aging. For example, a progressive decline in electrical recording from brain and retina are observed in both aging and OCL. Samples of retinal and retinal pigment epithelial (RPE) tissues were obtained from a young control. 2 animals with OCL and a normal aged sheep. Specimens were cryo-fractured and examined by scanning electron microscopy/x-ray microanalysis. Measurements made of 6 individual cells in the ganglion layer of OCL specimens, the remainder of the retina, and RPE showed age-related changes in zinc, iron, and copper which were associated with lipopigment accumulation in the RPE. There was marked decrease in phosphate, sulfur, and manganese levels, as photoreceptor cells and their outer segments are lost in the disease process. This is the first report of metal analysis in the retina and RPE in a disease entity, and as a function of normal aging.

  14. Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: Case report and literature review

    PubMed Central

    Ogaki, Kotaro; Koga, Shunsuke; Aoki, Naoya; Lin, Wenlang; Suzuki, Kinuko; Ross, Owen A.; Dickson, Dennis W.

    2015-01-01

    X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy confirmed cases exceedingly rare. We report a 69-year-old white man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison’s disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities, and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss, and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of multiple system atrophy. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be

  15. Adult onset-hypothyroidism: alterations in hippocampal field potentials in the dentate gyrus are largely associated with anaesthesia-induced hypothermia.

    PubMed

    Sánchez-Huerta, K; Pacheco-Rosado, J; Gilbert, M E

    2015-01-01

    Thyroid hormone (TH) is essential for a number of physiological processes and is particularly critical during nervous system development. The hippocampus is strongly implicated in cognition and is sensitive to developmental hypothyroidism. The impact of TH insufficiency in the foetus and neonate on hippocampal synaptic function has been fairly well characterised. Although adult onset hypothyroidism has also been associated with impairments in cognitive function, studies of hippocampal synaptic function with late onset hypothyroidism have yielded inconsistent results. In the present study, we report hypothyroidism induced by the synthesis inhibitor propylthiouracil (10 p.p.m., 0.001%, minimum of 4 weeks), resulted in marginal alterations in excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude in the dentate gyrus measured in vivo. No effects were seen in tests of short-term plasticity, and a minor enhancement of long-term potentiation of the EPSP slope was observed. The most robust synaptic alteration evident in hypothyroid animals was an increase in synaptic response latency, which was paralleled by a failure to maintain normal body temperature under anaesthesia, despite warming on a heating pad. Latency shifts could be reversed in hypothyroid animals by increasing the external heat source and, conversely, synaptic delays could be induced in control animals by removing the heat source, with a consequent drop in body and brain temperature. Thermoregulation is TH- dependent, and anaesthesia necessary for surgical procedures posed a thermoregulatory challenge that was differentially met in control and hypothyroid animals. Minor increases in field potential EPSP slope, decreases in PS amplitudes and increased latencies are consistent with previous reports of hypothermia in naive control rats. We conclude that failures in thyroid-dependent temperature regulation rather than direct action of TH in synaptic physiology are responsible for the

  16. Sex-comparative study of mouse cerebellum physiology under adult-onset hypothyroidism: The significance of GC-MS metabolomic data normalization in meta-analysis.

    PubMed

    Maga-Nteve, Christoniki; Vasilopoulou, Catherine G; Constantinou, Caterina; Margarity, Marigoula; Klapa, Maria I

    2017-01-15

    A systematic data quality validation and normalization strategy is an important component of the omic profile meta-analysis, ensuring comparability of the profiles and exclusion of experimental biases from the derived biological conclusions. In this study, we present the normalization methodology applied on the sets of cerebellum gas chromatography-mass spectrometry metabolic profiles of 124days old male and female animals in an adult-onset-hypothyroidism (AOH) mouse model before combining them into a sex-comparative analysis. The employed AOH model concerns the monitoring of the brain physiology of Balb/cJ mice after eight-week administration of 1%w/v KClO4 in the drinking water, initiated on the 60th day of their life. While originating from the same animal study, the tissues of the two sexes were processed and their profiles acquired and analyzed at different time periods. Hence, the previously published profile set of male mice was first re-annotated based on the presently available resources. Then, after being validated as acquired under the same analytical conditions, both profiles sets were corrected for derivatization biases and filtered for low-confidence measurements based on the same criteria. The final normalized 73-metabolite profiles contribute to the currently few available omic datasets of the AOH effect on brain molecular physiology, especially with respect to sex differentiation. Multivariate statistical analysis indicated one (unknown) and three (succinate, benzoate, myristate) metabolites with significantly higher and lower, respectively, cerebellum concentration in the hypothyroid compared to the euthyroid female mice. The respective numbers for the males were two and 24. Comparison of the euthyroid cerebellum metabolic profiles between the two sexes indicated 36 metabolites, including glucose, myo- and scyllo-inositol, with significantly lower concentration in the females versus the males. This implies that the female mouse cerebellum has been

  17. Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region.

    PubMed Central

    Sarfarazi, M; Child, A; Stoilova, D; Brice, G; Desai, T; Trifan, O C; Poinoosawmy, D; Crick, R P

    1998-01-01

    One of the major causes of blindness is primary open-angle glaucoma, which affects millions of elderly people worldwide. Genetic studies have so far mapped three loci for the adult-onset form of this condition to the 2cen-q13, 3q21-q24, and 8q23 regions. Herein, we report the localization of a fourth locus, to the 10p15-p14 region, in one large British family with a classical form of normal-tension open-angle glaucoma. Of the 42 meioses genotyped in this pedigree, 39 subjects (16 affected) inherited a haplotype compatible with their prior clinical designation, whereas the remaining 3 were classified as unknown. Although a maximum LOD score of 10.00 at a recombination fraction of straight theta=.00 was obtained with D10S1216, 21 other markers provided significant values, varying between 3.77 and 9.70. When only the affected meioses of this kindred were analyzed, LOD scores remained statistically significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Two critical recombinational events in the affected subjects positioned this new locus to a region of approximately 21 cM, flanked by D10S1729 and D10S1664. However, an additional recombination in a 59-year-old unaffected female suggests that this locus resides between D10S585 (or D10S1172) and D10S1664, within a genetic distance of 5-11 cM. However, the latter minimum region must be taken cautiously, because the incomplete penetrance has previously been documented for this group of eye conditions. A partial list of genes that positionally are considered as candidates includes NET1, PRKCT, ITIH2, IL2RA, IL15RA, IT1H2, hGATA3, the mRNA for open reading frame KIAA0019, and the gene for D123 protein. PMID:9497264

  18. Glycosylation, transport, and complex formation of palmitoyl protein thioesterase 1 (PPT1) – distinct characteristics in neurons

    PubMed Central

    Lyly, Annina; von Schantz, Carina; Salonen, Tarja; Kopra, Outi; Saarela, Jani; Jauhiainen, Matti; Kyttälä, Aija; Jalanko, Anu

    2007-01-01

    Background Neuronal ceroid lipofuscinoses (NCLs) are collectively the most common type of recessively inherited childhood encephalopathies. The most severe form of NCL, infantile neuronal ceroid lipofuscinosis (INCL), is caused by mutations in the CLN1 gene, resulting in a deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). The deficiency of PPT1 causes a specific death of neocortical neurons by a mechanism, which is currently unclear. To understand the function of PPT1 in more detail, we have further analyzed the basic properties of the protein, especially focusing on possible differences in non-neuronal and neuronal cells. Results Our study shows that the N-glycosylation of N197 and N232, but not N212, is essential for PPT1's activity and intracellular transport. Deglycosylation of overexpressed PPT1 produced in neurons and fibroblasts demonstrates differentially modified PPT1 in different cell types. Furthermore, antibody internalization assays showed differences in PPT1 transport when compared with a thoroughly characterized lysosomal enzyme aspartylglucosaminidase (AGA), an important observation potentially influencing therapeutic strategies. PPT1 was also demonstrated to form oligomers by size-exclusion chromatography and co-immunoprecipitation assays. Finally, the consequences of disease mutations were analyzed in the perspective of our new results, suggesting that the mutations increase both the degree of glycosylation of PPT1 and its ability to form complexes. Conclusion Our current study describes novel properties for PPT1. We observe differences in PPT1 processing and trafficking in neuronal and non-neuronal cells, and describe for the first time the ability of PPT1 to form complexes. Understanding the basic characteristics of PPT1 is fundamental in order to clarify the molecular pathogenesis behind neurodegeneration in INCL. PMID:17565660

  19. Molecular basis of adult-onset and chronic G sub M2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the. alpha. -subunit of. beta. -hexosaminidase

    SciTech Connect

    Paw, B.H.; Kaback, M.M.; Neufeld, E.F. )

    1989-04-01

    Chronic and adult-onset G{sub M2} gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of {beta}-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective {alpha}-subunit that failed to associate with the {beta}-subunit. The authors have now found a guanosine to adenosine transition at the 3{prime} end of exon 7, which causes substitution of serine for glycine at position 269 of the {alpha}-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly {yields} Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly {yields} Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G{sub M2} gangliosidosis.

  20. Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: clinical features and (99m)Tc-ECD brain perfusion SPECT findings.

    PubMed

    Doi, Hiroshi; Koyano, Shigeru; Miyatake, Satoko; Matsumoto, Naomichi; Kameda, Tomoaki; Tomita, Atsuko; Miyaji, Yosuke; Suzuki, Yume; Sawaishi, Yukio; Kuroiwa, Yoshiyuki

    2010-03-15

    Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz syndrome (HSS), is an autosomal recessive neurodegenerative disorder characterized by iron accumulation in the brain. Mutations in the pantothenate kinase 2 (PANK2) gene are known to be responsible for PKAN. Several studies have revealed correlations between clinical phenotypes and particular PANK2 mutations. The adult-onset slowly progressive type of PKAN with PANK2 mutations is very rare. In this report, we describe siblings with the adult-onset slowly progressive type of PKAN with a novel mutation, Ile346Ser, in PANK2. The siblings had the same mutation in PANK2 and had common clinical signs such as misalignment of teeth, a high arched palate, hollow feet, a slight cognitive decline, and an apparent executive dysfunction, although they showed different patterns of movement disorders. Thus, even if PKAN patients have identical mutations, it is likely that they will present with different types of movement disorders. Brain perfusion single photon emission computed tomography in both patients showed decreased regional cerebral blood flow in the bilateral frontoparietal lobes, the globus pallidus, the striatum, and around the ventriculus quartus. Cardiac uptake of [(123)I] meta-iodobenzylguanidine was normal in both patients. Analysis of genotype-phenotype correlations and the elucidation of mutational effects on pantothenate kinase 2 function, expression, and structure are important for understanding the mechanisms of PKAN.

  1. The NMDA receptor antagonist MK-801 abolishes the increase in both p53 and Bax/Bcl2 index induced by adult-onset hypothyroidism in rat.

    PubMed

    Alva-Sanchez, Claudia; Rodriguez, Adair; Villanueva, Ivan; Anguiano, Brenda; Aceves, Carmen; Pacheco-Rosado, Jorge

    2014-01-01

    Hypothyroidism affects neuron population dynamics in the hippocampus of the adult rat, with neuronal damage as the main feature of its effect. This effect is prevented by the blockade of NMDA receptors, which suggests that glutamatergic activity mediates cell death in this condition. Glutamate can also stimulate cell proliferation and survival of newborn neurons, indicating that it can affect different stages of the cell cycle. In this work we measured the expression of specific proteins that control cell proliferation (cycline-D1), cell arrest (p21), damage (p53) or apoptosis (Bax and Bcl2) in the hippocampus of hypothyroid rats treated with the NMDA receptor (NMDAR) blocker MK-801 during the induction of hypothyroidism. The results show that hypothyroidism increases the expression of markers of DNA damage, cell arrest, and apoptosis, but does not affect the marker of cell proliferation. NMDAR blockade prevents the increase on markers of DNA damage and apoptosis, but does not influence cell arrest or cell proliferation. This suggests that hypothyroidism promotes cell death mainly by an excitotoxic effect of glutamate.

  2. Advances in motor neurone disease.

    PubMed

    Bäumer, Dirk; Talbot, Kevin; Turner, Martin R

    2014-01-01

    Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.

  3. An atypical presentation of adult-onset Still’s disease complicated by pulmonary hypertension and macrophage activation syndrome treated with immunosuppression: a case-based review of the literature

    PubMed Central

    Manson, Daniel K.; Horn, Evelyn M.; Haythe, Jennifer

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a known complication of rheumatologic diseases, but it is only rarely associated with adult-onset Still’s disease (AOSD). We describe the case of a 30-year-old woman who presented in a pulmonary hypertension crisis and was found to have underlying AOSD with PAH and nonspecific interstitial pneumonia (NSIP) with a course complicated by macrophage activation syndrome (MAS). She dramatically improved with steroids, cyclosporine A, and anakinra, with total resolution of the MAS and significant improvement of her pulmonary arterial pressures. While there are only select case reports of AOSD associated with PAH, this is the first reported case of (1) AOSD complicated by both PAH and MAS and (2) AOSD complicated by biopsy-proven NSIP. Clinically, this case highlights the efficacy of immunosuppressive agents in the treatment of PAH and MAS from underlying AOSD and supports their use in this setting. PMID:27162622

  4. A 12-week, randomized, parallel-group, proof-of-concept study of tulobuterol patch and salmeterol inhaler as add-on therapy in adult-onset mild-to-moderate asthma.

    PubMed

    Inoue, Hideki; Niimi, Akio; Matsumoto, Hisako; Ito, Isao; Oguma, Tsuyoshi; Otsuka, Kojiro; Takeda, Tomoshi; Nakaji, Hitoshi; Tajiri, Tomoko; Iwata, Toshiyuki; Nagasaki, Tadao; Mishima, Michiaki

    2017-01-01

    Patch formulation of tulobuterol has been used in asthma treatment as a long-acting β2 -agonist (LABA) through sustained skin absorption. Its treatment efficacy, especially in small airways, remains poorly understood. The study aim was to investigate LABA add-on effects of tulobuterol patch (TP) and salmeterol inhaler (SA) on pulmonary function, asthma control and health status. Patients who had adult-onset under-control asthma, despite taking inhaled corticosteroids, were enrolled in a randomized, open-label, parallel-group, proof-of-concept study of 12-week add-on treatment with TP (n=16) or SA (n=17). Spirometry, impulse oscillometry (IOS), exhaled nitric oxide levels, and clinical questionnaires of asthma control, health status (St. George's Respiratory Questionnaire: SGRQ), and symptoms were evaluated every 4 weeks. Add-on treatment of SA significantly improved the spirometric indices of small airway obstruction (forced expiratory flow between 25% and 75% of FVC: FEF25-75 , and maximum expiratory flow at 25% of FVC: MEF25 ) and IOS indices of whole respiratory resistance (resistance at 5 Hz) as compared to TP. In intra-group comparisons, add-on treatment of TP improved the scores of the asthma control test and the total SGRQ, as well as the symptom and impact components of the SGRQ. SA add-on treatment improved FEV1 and IOS parameters of resistance at 20 Hz and reactance at 5 Hz. Neither of the treatments improved exhaled nitric oxide levels. In conclusion, add-on treatment of TP improved asthma control and health status, whereas SA improved pulmonary function measures associated with large and small airway involvement among patients with adult-onset mild-to-moderate asthma.

  5. A plural role for lipids in motor neuron diseases: energy, signaling and structure

    PubMed Central

    Schmitt, Florent; Hussain, Ghulam; Dupuis, Luc; Loeffler, Jean-Philippe; Henriques, Alexandre

    2013-01-01

    Motor neuron diseases (MNDs) are characterized by selective death of motor neurons and include mainly adult-onset amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Neurodegeneration is not the single pathogenic event occurring during disease progression. There are multiple lines of evidence for the existence of defects in lipid metabolism at peripheral level. For instance, hypermetabolism is well characterized in ALS, and dyslipidemia correlates with better prognosis in patients. Lipid metabolism plays also a role in other MNDs. In SMA, misuse of lipids as energetic nutrients is described in patients and in related animal models. The composition of structural lipids in the central nervous system is modified, with repercussion on membrane fluidity and on cell signaling mediated by bioactive lipids. Here, we review the main epidemiologic and mechanistic findings that link alterations of lipid metabolism and motor neuron degeneration, and we discuss the rationale of targeting these modifications for therapeutic management of MNDs. PMID:24600344

  6. Magnetic resonance findings of the corpus callosum in canine and feline lysosomal storage diseases.

    PubMed

    Hasegawa, Daisuke; Tamura, Shinji; Nakamoto, Yuya; Matsuki, Naoaki; Takahashi, Kimimasa; Fujita, Michio; Uchida, Kazuyuki; Yamato, Osamu

    2013-01-01

    Several reports have described magnetic resonance (MR) findings in canine and feline lysosomal storage diseases such as gangliosidoses and neuronal ceroid lipofuscinosis. Although most of those studies described the signal intensities of white matter in the cerebrum, findings of the corpus callosum were not described in detail. A retrospective study was conducted on MR findings of the corpus callosum as well as the rostral commissure and the fornix in 18 cases of canine and feline lysosomal storage diseases. This included 6 Shiba Inu dogs and 2 domestic shorthair cats with GM1 gangliosidosis; 2 domestic shorthair cats, 2 familial toy poodles, and a golden retriever with GM2 gangliosidosis; and 2 border collies and 3 chihuahuas with neuronal ceroid lipofuscinoses, to determine whether changes of the corpus callosum is an imaging indicator of those diseases. The corpus callosum and the rostral commissure were difficult to recognize in all cases of juvenile-onset gangliosidoses (GM1 gangliosidosis in Shiba Inu dogs and domestic shorthair cats and GM2 gangliosidosis in domestic shorthair cats) and GM2 gangliosidosis in toy poodles with late juvenile-onset. In contrast, the corpus callosum and the rostral commissure were confirmed in cases of GM2 gangliosidosis in a golden retriever and canine neuronal ceroid lipofuscinoses with late juvenile- to early adult-onset, but were extremely thin. Abnormal findings of the corpus callosum on midline sagittal images may be a useful imaging indicator for suspecting lysosomal storage diseases, especially hypoplasia (underdevelopment) of the corpus callosum in juvenile-onset gangliosidoses.

  7. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

    PubMed

    Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

    2017-03-31

    The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

  8. Motor neurone disease: a practical update on diagnosis and management.

    PubMed

    Wood-Allum, Clare; Shaw, Pamela J

    2010-06-01

    Motor neurone disease (MND) is an adult-onset neurodegenerative disease which leads inexorably via weakness of limb, bulbar and respiratory muscles to death from respiratory failure three to five years later. Most MND is sporadic but approximately 10% is inherited. In exciting recent breakthroughs two new MND genes have been identified. Diagnosis is clinical and sometimes difficult--treatable mimics must be excluded before the diagnosis is ascribed. Riluzole prolongs life by only three to four months and is only available for the amyotrophic lateral sclerosis (ALS) form of MND. Management therefore properly focuses on symptom relief and the preservation of independence and quality of life. Malnutrition is a poor prognostic factor. In appropriate patients enteral feeding is recommended although its use has yet to be shown to improve survival. In ALS patients with respiratory failure and good or only moderately impaired bulbar function non-invasive positive pressure ventilation prolongs life and improves quality of life.

  9. Unusual sequelae of adult-onset dermatomyositis

    PubMed Central

    Naffaa, Mohammad Ebrahim; Bishara, Rema; Braun-Moscovici, Yolanda; Balbir-Gurman, Alexandra

    2014-01-01

    A 44-year-old woman diagnosed with dermatomyositis 5 years ago based on progressive proximal muscle weakness, elevated creatine kinase, typical findings on electromyography and muscle biopsy. Despite the treatment, in contrast to improvement in her muscle symptoms, the heliotrope rash of her eyelids persisted. After several years, the patient developed multiple limited skin retraction lesions with hyperpigmentation on both lower limbs. Palpation of these lesions revealed dry, cold and very firm skin on both thighs and calves, particularly in the distal areas. X-ray and ultrasound imaging of the calves showed multiple subcutaneous calcifications in the distal muscles. PMID:25085949

  10. Adult-onset acute rheumatic fever.

    PubMed

    Nakashima, Dainari; Ueda, Kohei; Tsukuda, Kyozo; Utsu, Noriaki; Kohki, Shimazu; Fushimi, Hiroaki; Miyakoshi, Kazuho

    2012-01-01

    A 62-year-old man was hospitalized for acute rheumatic fever. He had previously suffered from rheumatic fever at 15 years of age. The rheumatic fever was complicated by carditis, which caused valve disease that required surgical treatment. The incidence of rheumatic fever has decreased in most developed countries with improvements in sanitary conditions. The low incidence of this disease makes a timely and accurate diagnosis difficult. Due to the fact that both the first occurrence and recurrence of acute rheumatic fever can occur in the elderly and adults, this potential disease should not be overlooked when making a differential diagnosis.

  11. Similar L-dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation.

    PubMed

    Li, Li; Sagot, Ben; Zhou, Fu-Ming

    2015-07-30

    The transcription factor Pitx3 null mutant (Pitx3Null) mice have a constitutive perinatal-onset and symmetric bilateral dopamine (DA) loss in the striatum. In these mice l-3,4-dihydroxyphenylalanine (l-dopa) induces apparently normal horizontal movements (walking) but also upward movements consisting of the vertical body trunk and waving paws that are absent in normal animals and in animals with the classic unilateral 6-hydroxydopamine (6-OHDA) lesion-induced DA denervation. Thus, a concern is that the perinatal timing of the DA loss and potential developmental abnormalities in Pitx3Null mice may underlie these upward movements, thus reducing the usefulness as a DA denervation model. Here we show that in normal wild-type (Pitx3WT) mice with adult-onset symmetric, bilateral 6-OHDA-induced DA lesion in the dorsal striatum, l-dopa induces normal horizontal movements and upward movements that are qualitatively identical to those in Pitx3Null mice. Furthermore, after unilateral 6-OHDA lesion of the residual DA innervation in the striatum in Pitx3Null mice, l-dopa induces contraversive rotation that is similar to that in Pitx3WT mice with the classic unilateral 6-OHDA lesion. These results indicate that in Pitx3Null mice, the bilateral symmetric DA denervation in the dorsal striatum is sufficient for expressing the l-dopa-induced motor phenotype and the perinatal timing of their DA loss is not a determining factor, providing further evidence that Pitx3Null mice are a convenient and suitable mouse model to study the consequences of DA loss and dopaminergic replacement therapy in Parkinson's disease.

  12. Role of CYP1B1, MYOC, OPTN and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian patients

    PubMed Central

    Basavaraj, Manjunath G.; Gupta, Santosh K.; Qamar, Imteyaz; Ali, Abdullah Mahmood; Bajaj, Vineeta; Ramesh, T.K.; Prakash, D. Ravi; Shetty, Jyoti S.; Dorairaj, Syril K.

    2007-01-01

    Purpose Mutations in the CYP1B1, MYOC, OPTN, and WDR36 genes result in glaucoma. Given its expression in the optic nerve, it is likely a mutation in the OPTC gene is also involved in initiating glaucoma. This study was designed to evaluate the involvement of the CYP1B1, MYOC, OPTN, and OPTC genes in the etiology of adult-onset primary open-angle glaucoma (POAG) found in 251 Indian patients. Methods Blood samples were obtained from individuals for DNA isolation. A combination of polymerase chain reaction-single strand conformation polymorphism, allele-specific PCR, and DNA sequencing techniques were used to detect mutations in four genes. Four microsatellite markers from the CYP1B1 candidate region and three intragenic CYP1B1 single nucleotide polymorphisms (SNPs) were used to determine the origin of the most common CYP1B1 mutations. Results Three previously known mutations (Pro193Leu, Glu229Lys, and Arg368His) and one novel (Met292Lys) mutation were found in the CYP1B1 gene. Frequencies of the most common mutations, Glu229Lys and Arg368His, in patients were 5.12% and 3.98%, respectively. The Glu229Lys and Arg368His mutations were also found in normal controls at frequencies of 5% and 2%, respectively, suggesting that these mutations might be polymorphic variants in our population. The absence of allele sharing for D2S177, D2S1346, D2S2974, and D2S2331 markers and three intragenic CYP1B1 SNPs in patients suggested multiple origins for the Glu229Lys and Arg368His variants. Two of 251 (0.8%) patients had the Gln48His mutation in MYOC. There was no difference in the frequency of a MYOC -83G>A promoter polymorphism between patients and controls. A novel OPTN mutation, Thr202Arg, was detected in one of 251 (0.4%) patients. The OPTN variant Met98Lys was detected in similar frequencies in patients and controls. No mutation was detected in OPTC. Taken together, 3.59% (9/251) of our POAG patients had mutations in the CYP1B1, MYOC, and OPTN genes. Conclusions This is the

  13. Diverse role of survival motor neuron protein.

    PubMed

    Singh, Ravindra N; Howell, Matthew D; Ottesen, Eric W; Singh, Natalia N

    2017-03-01

    The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners. Reduced expression of SMN causes spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA displays a broad spectrum ranging from embryonic lethality to an adult onset. Aberrant expression and/or localization of SMN has also been associated with male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. This review provides a summary of various SMN functions with implications to a better understanding of SMA and other pathological conditions.

  14. [Neuronal ageing].

    PubMed

    Piechota, Małgorzata; Sunderland, Piotr

    2014-01-01

    Ageing leads to irreversible alterations in the nervous system, which to various extent impair its functions such as capacity to learn and memory. In old neurons and brain, similarly to what may take place in other cells, there is increased oxidative stress, disturbed energetic homeostasis and metabolism, accumulation of damage in proteins and nucleic acids. Characteristic of old neurons are alterations in plasticity, synaptic transmission, sensitivity to neurotrophic factors and cytoskeletal changes. Some markers of senescence, whose one of them is SA-beta-galactosidase were used to show the process of neuronal ageing both in vitro, and in vivo. Some research suggest that, despite the fact that neurons are postmitotic cells, it is cell cycle proteins which play a certain role in their biology, e.g. differentiation. However, their role in neuronal ageing is not known or explained. Ageing is the serious factor of development of neurodegenerative diseases among others Alzheimer disease.

  15. Peripherin-mediated death of motor neurons rescued by overexpression of neurofilament NF-H proteins.

    PubMed

    Beaulieu, Jean-Martin; Julien, Jean-Pierre

    2003-04-01

    In previous studies, we showed that overexpression of peripherin, a neuronal intermediate filament (IF) protein, in mice deficient for neurofilament light (NF-L) subunits induced a progressive adult-onset degeneration of spinal motor neurons characterized by the presence of IF inclusion bodies reminiscent of axonal spheroids found in amyotrophic lateral sclerosis (ALS). In contrast, the overexpression of human neurofilament heavy (NF-H) proteins provoked the formation of massive perikaryal IF protein accumulations with no loss of motor neurons. To further investigate the toxic properties of IF protein inclusions, we generated NF-L null mice that co-express both peripherin and NF-H transgenes. The axonal count in L5 ventral roots from 6 and 8-month-old transgenic mice showed that NF-H overexpression rescued the peripherin-mediated degeneration of motor neurons. Our analysis suggests that the protective effect of extra NF-H proteins is related to the sequestration of peripherin into the perikaryon of motor neurons, thereby abolishing the development of axonal IF inclusions that might block transport. These findings illustrate the importance of IF protein stoichiometry in formation, localization and toxicity of neuronal inclusion bodies.

  16. Amyotrophic Lateral Sclerosis 2-Deficiency Leads to Neuronal Degeneration in Amyotrophic Lateral Sclerosis through Altered AMPA Receptor Trafficking

    PubMed Central

    Lai, Chen; Xie, Chengsong; McCormack, Stefanie G.; Chiang, Hsueh-Cheng; Michalak, Marta K.; Lin, Xian; Chandran, Jayanth; Shim, Hoon; Shimoji, Mika; Cookson, Mark R.; Huganir, Richard L.; Rothstein, Jeffrey D.; Price, Donald L.; Wong, Philip C.; Martin, Lee J.; Zhu, J. Julius; Cai, Huaibin

    2008-01-01

    Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease is caused by a selective loss of motor neurons. One form of juvenile onset autosomal recessive ALS (ALS2) has been linked to the loss of function of the ALS2 gene. The pathogenic mechanism of ALS2-deficiency, however, remains unclear. To further understand the function of alsin that is encoded by the full-length ALS2 gene, we screened proteins interacting with alsin. Here, we report that alsin interacted with glutamate receptor interacting protein 1 (GRIP1) both in vitro and in vivo, and colocalized with GRIP1 in neurons. In support of the physiological interaction between alsin and GRIP1, the subcellular distribution of GRIP1 was altered in ALS2-/- spinal motor neurons, which correlates with a significant reduction of AMPA-type glutamate receptor subunit 2 (GluR2) at the synaptic/cell surface of ALS2-/- neurons. The decrease of calcium-impermeable GluR2-containing AMPA receptors at the cell/synaptic surface rendered ALS2-/- neurons more susceptible to glutamate receptor-mediated neurotoxicity. Our findings reveal a novel function of alsin in AMPA receptor trafficking and provide a novel pathogenic link between ALS2-deficiency and motor neuron degeneration, suggesting a protective role of alsin in maintaining the survival of motor neurons. PMID:17093100

  17. Modeling Huntington׳s disease with patient-derived neurons.

    PubMed

    Mattis, Virginia B; Svendsen, Clive N

    2017-02-01

    Huntington׳s Disease (HD) is a fatal neurodegenerative disorder caused by expanded polyglutamine repeats in the Huntingtin (HTT) gene. While the gene was identified over two decades ago, it remains poorly understood why mutant HTT (mtHTT) is initially toxic to striatal medium spiny neurons (MSNs). Models of HD using non-neuronal human patient cells and rodents exhibit some characteristic HD phenotypes. While these current models have contributed to the field, they are limited in disease manifestation and may vary in their response to treatments. As such, human HD patient MSNs for disease modeling could greatly expand the current understanding of HD and facilitate the search for a successful treatment. It is now possible to use pluripotent stem cells, which can generate any tissue type in the body, to study and potentially treat HD. This review covers disease modeling in vitro and, via chimeric animal generation, in vivo using human HD patient MSNs differentiated from embryonic stem cells or induced pluripotent stem cells. This includes an overview of the differentiation of pluripotent cells into MSNs, the established phenotypes found in cell-based models and transplantation studies using these cells. This review not only outlines the advancements in the rapidly progressing field of HD modeling using neurons derived from human pluripotent cells, but also it highlights several remaining controversial issues such as the 'ideal' series of pluripotent lines, the optimal cell types to use and the study of a primarily adult-onset disease in a developmental model. This article is part of a Special Issue entitled SI: Exploiting human neurons.

  18. ALS-related misfolded protein management in motor neurons and muscle cells.

    PubMed

    Galbiati, Mariarita; Crippa, Valeria; Rusmini, Paola; Cristofani, Riccardo; Cicardi, Maria Elena; Giorgetti, Elisa; Onesto, Elisa; Messi, Elio; Poletti, Angelo

    2014-12-01

    Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression.

  19. Lamin B1 protein is required for dendrite development in primary mouse cortical neurons.

    PubMed

    Giacomini, Caterina; Mahajani, Sameehan; Ruffilli, Roberta; Marotta, Roberto; Gasparini, Laura

    2016-01-01

    Lamin B1, a key component of the nuclear lamina, plays an important role in brain development and function. A duplication of the human lamin B1 (LMNB1) gene has been linked to adult-onset autosomal dominant leukodystrophy, and mouse and human loss-of-function mutations in lamin B1 are susceptibility factors for neural tube defects. In the mouse, experimental ablation of endogenous lamin B1 (Lmnb1) severely impairs embryonic corticogenesis. Here we report that in primary mouse cortical neurons, LMNB1 overexpression reduces axonal outgrowth, whereas deficiency of endogenous Lmnb1 results in aberrant dendritic development. In the absence of Lmnb1, both the length and complexity of dendrites are reduced, and their growth is unresponsive to KCl stimulation. This defective dendritic outgrowth stems from impaired ERK signaling. In Lmnb1-null neurons, ERK is correctly phosphorylated, but phospho-ERK fails to translocate to the nucleus, possibly due to delocalization of nuclear pore complexes (NPCs) at the nuclear envelope. Taken together, these data highlight a previously unrecognized role of lamin B1 in dendrite development of mouse cortical neurons through regulation of nuclear shuttling of specific signaling molecules and NPC distribution.

  20. Lamin B1 protein is required for dendrite development in primary mouse cortical neurons

    PubMed Central

    Giacomini, Caterina; Mahajani, Sameehan; Ruffilli, Roberta; Marotta, Roberto; Gasparini, Laura

    2016-01-01

    Lamin B1, a key component of the nuclear lamina, plays an important role in brain development and function. A duplication of the human lamin B1 (LMNB1) gene has been linked to adult-onset autosomal dominant leukodystrophy, and mouse and human loss-of-function mutations in lamin B1 are susceptibility factors for neural tube defects. In the mouse, experimental ablation of endogenous lamin B1 (Lmnb1) severely impairs embryonic corticogenesis. Here we report that in primary mouse cortical neurons, LMNB1 overexpression reduces axonal outgrowth, whereas deficiency of endogenous Lmnb1 results in aberrant dendritic development. In the absence of Lmnb1, both the length and complexity of dendrites are reduced, and their growth is unresponsive to KCl stimulation. This defective dendritic outgrowth stems from impaired ERK signaling. In Lmnb1-null neurons, ERK is correctly phosphorylated, but phospho-ERK fails to translocate to the nucleus, possibly due to delocalization of nuclear pore complexes (NPCs) at the nuclear envelope. Taken together, these data highlight a previously unrecognized role of lamin B1 in dendrite development of mouse cortical neurons through regulation of nuclear shuttling of specific signaling molecules and NPC distribution. PMID:26510501

  1. Zebrafish models of human motor neuron diseases: advantages and limitations.

    PubMed

    Babin, Patrick J; Goizet, Cyril; Raldúa, Demetrio

    2014-07-01

    Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.

  2. Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy

    PubMed Central

    Wang, Xuejing; Ma, Mingming; Teng, Junfang; Che, Xiangqian; Zhang, Wenwen; Feng, Shuman; Zhou, Shuang; Zhang, Ying; Wu, Erxi; Ding, Xuebing

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease. To date, there is no any effective pharmacological treatment for improving patients' symptoms and quality of life. Rapidly emerging evidence suggests that C-terminal fragments (CTFs) of TAR DNA-binding protein of 43 kDa (TDP-43), including TDP-35 and TDP-25, may play an important role in ALS pathogenesis. Valproate (VPA), a widely used antiepileptic drug, has neuroprotective effects on neurodegenerative disorders. As for ALS, preclinical studies also provide encouraging evidence for multiple beneficial effects in ALS mouse models. However, the potential molecular mechanisms have not been explored. Here, we show protective effects of VPA against TDP-43 CTFs-mediated neuronal toxicity and its underlying mechanisms in vitro. Remarkably, TDP-43 CTFs induced neuronal damage via endoplastic reticulum (ER) stress-mediated apoptosis. Furthermore, autophagic self-defense system was activated to reduce TDP-43 CTFs-induced neuronal death. Finally, VPA attenuated TDP-25-induced neuronal toxicity via suppressing ER stress-mediated apoptosis and enhancing autophagy. Taken together, these results demonstrate that VPA exerts neuroprotective effects against TDP-43 CTFs-induced neuronal damage. Thus, we provide new molecular evidence for VPA treatment in patients with ALS and other TDP-43 proteinopathies. PMID:26078717

  3. Characterization of thoracic motor and sensory neurons and spinal nerve roots in canine degenerative myelopathy, a potential disease model of amyotrophic lateral sclerosis.

    PubMed

    Morgan, Brandie R; Coates, Joan R; Johnson, Gayle C; Shelton, G Diane; Katz, Martin L

    2014-04-01

    Canine degenerative myelopathy (DM) is a progressive, adult-onset, multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced-stage DM. To determine whether other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MNs) and dorsal root ganglia (DRG) and in motor and sensory nerve root axons from DM-affected boxers and Pembroke Welsh corgis (PWCs). No alterations in MNs or motor root axons were observed in either breed. However, advanced-stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, nor of their axons. Axonal loss in thoracic sensory roots and sensory neuron death suggest that sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS.

  4. Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function*

    PubMed Central

    Chandrachud, Uma; Walker, Mathew W.; Simas, Alexandra M.; Heetveld, Sasja; Petcherski, Anton; Klein, Madeleine; Oh, Hyejin; Wolf, Pavlina; Zhao, Wen-Ning; Norton, Stephanie; Haggarty, Stephen J.; Lloyd-Evans, Emyr; Cotman, Susan L.

    2015-01-01

    Abnormal accumulation of undigested macromolecules, often disease-specific, is a major feature of lysosomal and neurodegenerative disease and is frequently attributed to defective autophagy. The mechanistic underpinnings of the autophagy defects are the subject of intense research, which is aided by genetic disease models. To gain an improved understanding of the pathways regulating defective autophagy specifically in juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), a neurodegenerative disease of childhood, we developed and piloted a GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) screening assay to identify, in an unbiased fashion, genotype-sensitive small molecule autophagy modifiers, employing a JNCL neuronal cell model bearing the most common disease mutation in CLN3. Thapsigargin, a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ pump inhibitor, reproducibly displayed significantly more activity in the mouse JNCL cells, an effect that was also observed in human-induced pluripotent stem cell-derived JNCL neural progenitor cells. The mechanism of thapsigargin sensitivity was Ca2+-mediated, and autophagosome accumulation in JNCL cells could be reversed by Ca2+ chelation. Interrogation of intracellular Ca2+ handling highlighted alterations in endoplasmic reticulum, mitochondrial, and lysosomal Ca2+ pools and in store-operated Ca2+ uptake in JNCL cells. These results further support an important role for the CLN3 protein in intracellular Ca2+ handling and in autophagic pathway flux and establish a powerful new platform for therapeutic screening. PMID:25878248

  5. Neuronal Migration Disorders

    MedlinePlus

    ... Understanding Sleep The Life and Death of a Neuron Order Publications Support Resources Patient Organizations Professional Societies ... birth defects caused by the abnormal migration of neurons in the developing brain and nervous system. In ...

  6. Neurofibromin and Neuronal Apoptosis

    DTIC Science & Technology

    2005-07-01

    for these differences in the response of Nfl-/- neurons. "So What" Section. The learning disabilities associated with NF I constitute a highly variable...and +/+ neurons appear to become more significant with age. Our results may have implications for two areas: 1) the pathogenesis of learning ... disabilities in children with NF I, and 2) therapeutic strategies or targets for prolonging neuron survival, or for increasing neuronal response to protective

  7. Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo.

    PubMed

    Kim, Hyung-Wook; Choi, Won-Seok; Sorscher, Noah; Park, Hyung Joon; Tronche, François; Palmiter, Richard D; Xia, Zhengui

    2015-09-01

    Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron

  8. Giant Intradural Mucocele in a Patient with Adult Onset Seizures

    PubMed Central

    Kechagias, E.; Georgakoulias, N.; Ioakimidou, C.; Kyriazi, S.; Kontogeorgos, G.; Seretis, A.

    2009-01-01

    A rare case of mucopyocele in a patient who presented with epileptic seizures is reported. The computed tomography scan (CT) and the magnetic resonance (MR) imaging revealed an intradural extension of a giant fronto-ethmoidal mucopyocele, eroding the cribriform plate and compressing both frontal lobes. The lesion was removed by craniotomy with elimination of the mass effect and reconstruction of the anterior skull base. An intracranial-intradural mucopyocele is an extremely rare cause of generalized convulsion as a presenting symptom, with only 6 cases reported in the literature. The total removal of the lesion associated with anterior fossa reconstruction is the treatment of choice. PMID:20847833

  9. Sandhoff disease mimicking adult-onset bulbospinal neuronopathy.

    PubMed Central

    Thomas, P K; Young, E; King, R H

    1989-01-01

    A 32 year old male is described with an onset of upper limb postural tremor in adolescence followed by muscle cramps. Progressive proximal amyotrophy and weakness in the limbs developed late in the third decade. Examination disclosed, in addition, bilateral facial weakness and mild dysarthria. Enzyme studies revealed hexosaminidase A and B deficiency, indicating a diagnosis of Sandhoff disease. Intra-axonal membranocytoplasmic bodies were present in a rectal biopsy. The presentation, which resembled that of X-linked bulbospinal neuronopathy, widens the clinical spectrum for disorders related to G(M2) gangliosidosis. Images PMID:2795083

  10. Childhood adversities and adult-onset asthma: a cohort study

    PubMed Central

    Korkeila, Jyrki; Lietzen, Raija; Sillanmäki, Lauri H; Rautava, Päivi; Korkeila, Katariina; Kivimäki, Mika; Koskenvuo, Markku; Vahtera, Jussi

    2012-01-01

    Objectives Childhood adversities may be important determinants of later illnesses and poor health behaviour. However, large-scale prospective studies on the associations between childhood adversities and the onset of asthma in adulthood are lacking. Design Prospective cohort study with 7-year follow-up. Setting Nationally representative study. Data were collected from the Health and Social Support (HeSSup) survey and national registers. Participants The participants represent the Finnish population from the following age groups: 20–24, 30–34, 40–44, and 50–54 years at baseline in 1998 (24 057 survey participants formed the final cohort of this study). The occurrence of childhood adversities was assessed at baseline with a six-item survey scale. The analyses were adjusted for sociodemographic characteristics, behavioural health risks and common mental disorders. Primary and secondary outcomes The survey data were linked to data from national health registers on incident asthma during a 7-year follow-up to define new-onset asthma cases with verified diagnoses. Results A total of 12 126 (59%) participants reported that they encountered a childhood adversity. Of them 3677 (18% of all) endured three to six adversities. During a follow-up of 7 years, 593 (2.9%) participants were diagnosed with incident asthma. Those who reported three or more childhood adversities had a 1.6-fold (95% CI 1.31 to 2.01) greater risk of asthma compared to those without childhood adversities. This hazard attenuated but remained statistically significant after adjustment for conventional risk factors (HR 1.33; 95% CI 1.06 to 1.67). Conclusions Adults who report having encountered adversities in childhood may have an increased risk of developing asthma. PMID:23069774

  11. Adult Onset of Xanthelasmoid Mastocytosis: Report of a Rare Entity

    PubMed Central

    Nabavi, Nafiseh Sadat; Nejad, Masumeh Hosseini; Feli, Shahab; Bakhshoodeh, Behnoosh; Layegh, Pouran

    2016-01-01

    Xanthelasmoid or pseudoxanthomatous mastocytosis is an extremely rare variant of diffuse cutaneous mastocytosis. Herein, we describe an adult male with cutaneous mastocytosis showing multiple widespread yellowish ovoid papules like eruptive xanthoma. A 60-year-old male visited our outpatient clinic with a 1-year history of generalized yellowish, ovoid, and skin color papular eruption located on the trunk, groin, extremities, with the modest pruritus. Vital signs were stable, and Darier's sign was negative. No other subjective and objective signs were detected during the examination. No abnormality was detected in his diagnostic laboratory tests. Skin biopsy was taken, and histopathologic examination revealed proliferation of mast cells with ovoid and spindle nuclei with distinct cytoplasm borders around the capillaries, which was compatible with mastocytosis. Antihistamine was prescribed for pruritus control which was successful, but eruptions were persistent, and even 1-year phototherapy was not useful. PMID:27512209

  12. Adult onset Hallervorden-Spatz disease with psychotic symptoms.

    PubMed

    del Valle-López, Pilar; Pérez-García, Rosa; Sanguino-Andrés, Rosa; González-Pablos, Emilio

    2011-01-01

    Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia.

  13. Adult-Onset Esophageal Crohn’s Disease

    PubMed Central

    Kasarala, George; Durrett, Sam

    2016-01-01

    Crohn’s disease (CD) is an idiopathic inflammatory bowel disease that can involve any part of the gastrointestinal tract. Esophageal involvement is rarely seen in adults, especially at the initial diagnosis of CD. Esophageal symptoms as primary manifestations of the disease are extremely rare. We report a case of a CD with esophageal involvement at the time of her initial diagnosis of CD. PMID:27761477

  14. Adult-Onset Asthma to Coronary Heart Disease and Stroke

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Asthma has been associated with atherosclerotic disease in several studies with some evidence that this association may be limited to women. However, most previous studies have failed to account for the heterogeneity of asthma subtypes. We previously reported increased carotid intima medial thickne...

  15. Characterization of Thoracic Motor and Sensory Neurons and Spinal Nerve Roots in Canine Degenerative Myelopathy, a Potential Disease Model of Amyotrophic Lateral Sclerosis

    PubMed Central

    Morgan, Brandie R.; Coates, Joan R.; Johnson, Gayle C.; Shelton, G. Diane; Katz, Martin L.

    2014-01-01

    Canine Degenerative Myelopathy (DM) is a progressive adult-onset multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced stage DM. To determine if other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MN) and dorsal root ganglia (DRG), and in motor and sensory nerve root axons from DM-affected Boxers and Pembroke Welsh Corgis (PWCs). No alterations in MNs, or motor root axons were observed in either breed. However, advanced stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, or of their axons. Axonal loss in thoracic sensory roots and sensory nerve death suggest sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS. PMID:24375814

  16. Cajal bodies in neurons.

    PubMed

    Lafarga, Miguel; Tapia, Olga; Romero, Ana M; Berciano, Maria T

    2016-09-14

    Cajal is commonly regarded as the father of modern neuroscience in recognition of his fundamental work on the structure of the nervous system. But Cajal also made seminal contributions to the knowledge of nuclear structure in the early 1900s, including the discovery of the "accessory body" later renamed "Cajal body" (CB). This important nuclear structure has emerged as a center for the assembly of ribonucleoproteins (RNPs) required for splicing, ribosome biogenesis and telomere maintenance. The modern era of CB research started in the 1990s with the discovery of coilin, now known as a scaffold protein of CBs, and specific probes for small nuclear RNAs (snRNAs). In this review, we summarize what we have learned in the recent decades concerning CBs in post-mitotic neurons, thereby ruling out dynamic changes in CB functions during the cell cycle. We show that CBs are particularly prominent in neurons, where they frequently associate with the nucleolus. Neuronal CBs are transcription-dependent nuclear organelles. Indeed, their number dynamically accommodates to support the high neuronal demand for splicing and ribosome biogenesis required for sustaining metabolic and bioelectrical activity. Mature neurons have canonical CBs enriched in coilin, survival motor neuron protein and snRNPs. Disruption and loss of neuronal CBs associate with severe neuronal dysfunctions in several neurological disorders such as motor neuron diseases. In particular, CB depletion in motor neurons seems to reflect a perturbation of transcription and splicing in spinal muscular atrophy, the most common genetic cause of infant mortality.

  17. An ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) Na(+)-Activated K(+) Channels in Aplysia Neurons.

    PubMed

    Zhang, Yalan; Ni, Weiming; Horwich, Arthur L; Kaczmarek, Leonard K

    2017-02-22

    development and function. We find that injection of oligomers of mutant superoxide dismutase 1 (SOD1) into the cytoplasm of invertebrate neurons rapidly suppresses these Na(+)-activated K(+) currents and that this effect is mediated by a MAP kinase cascade, including ASK1 and c-Jun N-terminal kinase. Because amyotrophic lateral sclerosis is a fatal adult-onset neurodegenerative disease produced by mutations in SOD1 that cause the enzyme to form toxic oligomers, our findings suggest that suppression of Slack channels may be an early step in the progression of the disease.

  18. Pacemaking Kisspeptin Neurons

    PubMed Central

    Kelly, Martin J.; Zhang, Chunguang; Qiu, Jian; Rønnekleiv, Oline K.

    2013-01-01

    Kisspeptin (Kiss1) neurons are vital for reproduction. GnRH neurons express the kisspeptin receptor, GPR 54, and kisspeptins potently stimulate the release of GnRH by depolarising and inducing sustained action potential firing in GnRH neurons. As such Kiss1 neurons may be the pre-synaptic pacemaker neurons in the hypothalamic circuitry that controls reproduction. There are at least two different populations of Kiss1 neurons: one in the rostral periventricular area (RP3V) that is stimulated by oestrogens and the other in the arcuate nucleus that is inhibited by oestrogens. How each of these Kiss1 neuronal populations participate in the regulation of the reproductive cycle is currently under intense investigation. Based on electrophysiological studies in the guinea pig and mouse, Kiss1 neurons in general are capable of generating burst firing behavior. Essentially all Kiss1 neurons, which have been studied thus far in the arcuate nucleus, express the ion channels necessary for burst firing, which include hyperpolarization-activated, cyclic nucleotide gated cation (HCN) channels and the T-type calcium (Cav3.1) channels. Under voltage clamp conditions, these channels produce distinct currents that under current clamp conditions can generate burst firing behavior. The future challenge is to identify other key channels and synaptic inputs involved in the regulation of the firing properties of Kiss1 neurons and the physiological regulation of the expression of these channels and receptors by oestrogens and other hormones. The ultimate goal is to understand how Kiss1 neurons control the different phases of GnRH neurosecretion and hence reproduction. PMID:23884368

  19. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.

    PubMed

    Cortes, Constanza J; Ling, Shuo-Chien; Guo, Ling T; Hung, Gene; Tsunemi, Taiji; Ly, Linda; Tokunaga, Seiya; Lopez, Edith; Sopher, Bryce L; Bennett, C Frank; Shelton, G Diane; Cleveland, Don W; La Spada, Albert R

    2014-04-16

    X-linked spinal and bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA and suggest muscle-directed therapies as effective treatments.

  20. Human GnRH Deficiency: A Unique Disease Model to Unravel the Ontogeny of GnRH Neurons

    PubMed Central

    Balasubramanian, Ravikumar; Dwyer, Andrew; Seminara, Stephanie B.; Pitteloud, Nelly; Kaiser, Ursula B.; Crowley, William F.

    2010-01-01

    Evolutionary survival of a species is largely a function of its reproductive fitness. In mammals, a sparsely populated and widely dispersed network of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons, serve as the pilot light of reproduction via coordinated secretion of GnRH. Since it first description, human GnRH deficiency has been recognized both clinically and genetically as a heterogeneous disease. A spectrum of different reproductive phenotypes comprised of congenital GnRH deficiency with anosmia (Kallmann syndrome), congenital GnRH deficiency with normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism), and adult-onset hypogonadotropic hypogonadism has been described. In the last two decades, several genes and pathways which govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. More importantly, detailed study of these patients has highlighted the emerging theme of oligogenicity and genotypic synergism, and also expanded the phenotypic diversity with the documentation of reversal of GnRH deficiency later in adulthood in some patients. The underlying genetic defect has also helped understand the associated nonreproductive phenotypes seen in some of these patients. These insights now provide practicing clinicians with targeted genetic diagnostic strategies and also impact on clinical management. PMID:20606386

  1. Corticospinal mirror neurons.

    PubMed

    Kraskov, A; Philipp, R; Waldert, S; Vigneswaran, G; Quallo, M M; Lemon, R N

    2014-01-01

    Here, we report the properties of neurons with mirror-like characteristics that were identified as pyramidal tract neurons (PTNs) and recorded in the ventral premotor cortex (area F5) and primary motor cortex (M1) of three macaque monkeys. We analysed the neurons' discharge while the monkeys performed active grasp of either food or an object, and also while they observed an experimenter carrying out a similar range of grasps. A considerable proportion of tested PTNs showed clear mirror-like properties (52% F5 and 58% M1). Some PTNs exhibited 'classical' mirror neuron properties, increasing activity for both execution and observation, while others decreased their discharge during observation ('suppression mirror-neurons'). These experiments not only demonstrate the existence of PTNs as mirror neurons in M1, but also reveal some interesting differences between M1 and F5 mirror PTNs. Although observation-related changes in the discharge of PTNs must reach the spinal cord and will include some direct projections to motoneurons supplying grasping muscles, there was no EMG activity in these muscles during action observation. We suggest that the mirror neuron system is involved in the withholding of unwanted movement during action observation. Mirror neurons are differentially recruited in the behaviour that switches rapidly between making your own movements and observing those of others.

  2. Culturing rat hippocampal neurons.

    PubMed

    Audesirk, G; Audesirk, T; Ferguson, C

    2001-01-01

    Cultured neurons are widely used to investigate the mechanisms of neurotoxicity. Embryonic rat hippocampal neurons may be grown as described under a wide variety of conditions to suit differing experimental procedures, including electrophysiology, morphological analysis of neurite development, and various biochemical and molecular analyses.

  3. Neuronal Mechanisms of Intelligence.

    DTIC Science & Technology

    1986-03-21

    The underlying premise of this research is that the neuron itself is the functional unit in the brain for positive reinforcement . Our early studies...preference studies (an alternative method to self-stimulation for measuring reward). Keywords: Neuronal conditioning; Positive reinforcement ; Learning; and Adaptive networks.

  4. Neuronal signaling through endocytosis.

    PubMed

    Cosker, Katharina E; Segal, Rosalind A

    2014-02-01

    The distinctive morphology of neurons, with complex dendritic arbors and extensive axons, presents spatial challenges for intracellular signal transduction. The endosomal system provides mechanisms that enable signaling molecules initiated by extracellular cues to be trafficked throughout the expanse of the neuron, allowing intracellular signals to be sustained over long distances. Therefore endosomes are critical for many aspects of neuronal signaling that regulate cell survival, axonal growth and guidance, dendritic branching, and cell migration. An intriguing characteristic of neuronal signal transduction is that endosomal trafficking enables physiological responses that vary based on the subcellular location of signal initiation. In this review, we will discuss the specialized mechanisms and the functional significance of endosomal signaling in neurons, both during normal development and in disease.

  5. Neuronal Signaling through Endocytosis

    PubMed Central

    Cosker, Katharina E.; Segal, Rosalind A.

    2014-01-01

    The distinctive morphology of neurons, with complex dendritic arbors and extensive axons, presents spatial challenges for intracellular signal transduction. The endosomal system provides mechanisms that enable signaling molecules initiated by extracellular cues to be trafficked throughout the expanse of the neuron, allowing intracellular signals to be sustained over long distances. Therefore endosomes are critical for many aspects of neuronal signaling that regulate cell survival, axonal growth and guidance, dendritic branching, and cell migration. An intriguing characteristic of neuronal signal transduction is that endosomal trafficking enables physiological responses that vary based on the subcellular location of signal initiation. In this review, we will discuss the specialized mechanisms and the functional significance of endosomal signaling in neurons, both during normal development and in disease. PMID:24492712

  6. NEURON and Python

    PubMed Central

    Hines, Michael L.; Davison, Andrew P.; Muller, Eilif

    2008-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications. PMID:19198661

  7. Imaging calcium in neurons.

    PubMed

    Grienberger, Christine; Konnerth, Arthur

    2012-03-08

    Calcium ions generate versatile intracellular signals that control key functions in all types of neurons. Imaging calcium in neurons is particularly important because calcium signals exert their highly specific functions in well-defined cellular subcompartments. In this Primer, we briefly review the general mechanisms of neuronal calcium signaling. We then introduce the calcium imaging devices, including confocal and two-photon microscopy as well as miniaturized devices that are used in freely moving animals. We provide an overview of the classical chemical fluorescent calcium indicators and of the protein-based genetically encoded calcium indicators. Using application examples, we introduce new developments in the field, such as calcium imaging in awake, behaving animals and the use of calcium imaging for mapping single spine sensory inputs in cortical neurons in vivo. We conclude by providing an outlook on the prospects of calcium imaging for the analysis of neuronal signaling and plasticity in various animal models.

  8. NEURON and Python.

    PubMed

    Hines, Michael L; Davison, Andrew P; Muller, Eilif

    2009-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications.

  9. Dopaminergic neurons modulate GABA neuron migration in the embryonic midbrain.

    PubMed

    Vasudevan, Anju; Won, Chungkil; Li, Suyan; Erdélyi, Ferenc; Szabó, Gábor; Kim, Kwang-Soo

    2012-09-01

    Neuronal migration, a key event during brain development, remains largely unexplored in the mesencephalon, where dopaminergic (DA) and GABA neurons constitute two major neuronal populations. Here we study the migrational trajectories of DA and GABA neurons and show that they occupy ventral mesencephalic territory in a temporally and spatially specific manner. Our results from the Pitx3-deficient aphakia mouse suggest that pre-existing DA neurons modulate GABA neuronal migration to their final destination, providing novel insights and fresh perspectives concerning neuronal migration and connectivity in the mesencephalon in normal as well as diseased brains.

  10. Neuromorphic Silicon Neuron Circuits

    PubMed Central

    Indiveri, Giacomo; Linares-Barranco, Bernabé; Hamilton, Tara Julia; van Schaik, André; Etienne-Cummings, Ralph; Delbruck, Tobi; Liu, Shih-Chii; Dudek, Piotr; Häfliger, Philipp; Renaud, Sylvie; Schemmel, Johannes; Cauwenberghs, Gert; Arthur, John; Hynna, Kai; Folowosele, Fopefolu; Saighi, Sylvain; Serrano-Gotarredona, Teresa; Wijekoon, Jayawan; Wang, Yingxue; Boahen, Kwabena

    2011-01-01

    Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain–machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance-based Hodgkin–Huxley models to bi-dimensional generalized adaptive integrate and fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips. PMID:21747754

  11. Neuronal ubiquitin homeostasis

    PubMed Central

    Hallengren, Jada; Chen, Ping-Chung; Wilson, Scott M.

    2013-01-01

    Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post-translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson’s disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating synaptic activity. PMID:23686613

  12. Motor neurone disease.

    PubMed

    2016-03-23

    Essential facts Motor neurone disease describes a group of related diseases, affecting the neurones in the brain and spinal cord. Progressive, incurable and life-limiting, MND is rare, with about 1,100 people developing it each year in the UK and up to 5,000 people affected at any one time. One third of people will die within a year of diagnosis and more than half within two years. About 5% to 10% are alive at ten years.

  13. Neuronal Mechanisms of Intelligence

    DTIC Science & Technology

    1987-11-01

    numbtr) FIELOD GROUP ]SUB-GROJP operant conditioning; neuronal conditioning; positive reinforcement ; reward; learning; adaptive networks; self...gratuitous capacity for operant conditioning, the individual neuron could be an important functional unit for positive reinforcement in the brain. These...the following conditions: 1) if a brain cell with the capacity for positive reinforcement discharges in a burst of activity, and 2) if that cell’s

  14. Ghrelin in Central Neurons

    PubMed Central

    Ferrini, F; Salio, C; Lossi, L; Merighi, A

    2009-01-01

    Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, is released in the bloodstream in response to a negative energetic status. Since discovery, the hypothalamus was identified as the main source of ghrelin in the CNS, and effects of the peptide have been mainly observed in this area of the brain. In recent years, an increasing number of studies have reported ghrelin synthesis and effects in specific populations of neurons also outside the hypothalamus. Thus, ghrelin activity has been described in midbrain, hindbrain, hippocampus, and spinal cord. The spectrum of functions and biological effects produced by the peptide on central neurons is remarkably wide and complex. It ranges from modulation of membrane excitability, to control of neurotransmitter release, neuronal gene expression, and neuronal survival and proliferation. There is not at present a general consensus concerning the source of ghrelin acting on central neurons. Whereas it is widely accepted that the hypothalamus represents the most important endogenous source of the hormone in CNS, the existence of extra-hypothalamic ghrelin-synthesizing neurons is still controversial. In addition, circulating ghrelin can theoretically be another natural ligand for central ghrelin receptors. This paper gives an overview on the distribution of ghrelin and its receptor across the CNS and critically analyses the data available so far as regarding the effects of ghrelin on central neurotransmission. PMID:19721816

  15. Ghrelin in central neurons.

    PubMed

    Ferrini, F; Salio, C; Lossi, L; Merighi, A

    2009-03-01

    Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, is released in the bloodstream in response to a negative energetic status. Since discovery, the hypothalamus was identified as the main source of ghrelin in the CNS, and effects of the peptide have been mainly observed in this area of the brain. In recent years, an increasing number of studies have reported ghrelin synthesis and effects in specific populations of neurons also outside the hypothalamus. Thus, ghrelin activity has been described in midbrain, hindbrain, hippocampus, and spinal cord. The spectrum of functions and biological effects produced by the peptide on central neurons is remarkably wide and complex. It ranges from modulation of membrane excitability, to control of neurotransmitter release, neuronal gene expression, and neuronal survival and proliferation. There is not at present a general consensus concerning the source of ghrelin acting on central neurons. Whereas it is widely accepted that the hypothalamus represents the most important endogenous source of the hormone in CNS, the existence of extra-hypothalamic ghrelin-synthesizing neurons is still controversial. In addition, circulating ghrelin can theoretically be another natural ligand for central ghrelin receptors. This paper gives an overview on the distribution of ghrelin and its receptor across the CNS and critically analyses the data available so far as regarding the effects of ghrelin on central neurotransmission.

  16. Neuron-Microdevice Connections.

    NASA Astrophysics Data System (ADS)

    Regehr, Wade Gordon

    1988-12-01

    A new method for long-term recording and stimulation applicable to cultured neurons has been developed. Silicon -based microelectrodes have been fabricated using integrated -circuit technology and micromachining. The chronic connection is made by positioning the electrode tip into contact with the cell body, and gluing the device to the bottom of the culture dish. These "diving-board electrodes" consist of an insulated lead exposed only at the tip sealed to the cell body of a cultured neuron: A two-way electrical connection to Helisoma B19 neurons has been established for up to four days. Preliminary experiments with cultured superior cervical ganglion neurons indicate diving-board electrodes can be used with cultured neurons larger than 20mum in diameter. In a related technique Helisoma neurons grown on a special dish containing a multielectrode array were found to seal to the dish electrodes, establishing similar long-term connections. This capability will make it possible to conduct experiments with either diving-board electrodes or dishes that cannot be performed using conventional techniques.

  17. NeuronBank: A Tool for Cataloging Neuronal Circuitry

    PubMed Central

    Katz, Paul S.; Calin-Jageman, Robert; Dhawan, Akshaye; Frederick, Chad; Guo, Shuman; Dissanayaka, Rasanjalee; Hiremath, Naveen; Ma, Wenjun; Shen, Xiuyn; Wang, Hsui C.; Yang, Hong; Prasad, Sushil; Sunderraman, Rajshekhar; Zhu, Ying

    2010-01-01

    The basic unit of any nervous system is the neuron. Therefore, understanding the operation of nervous systems ultimately requires an inventory of their constituent neurons and synaptic connectivity, which form neural circuits. The presence of uniquely identifiable neurons or classes of neurons in many invertebrates has facilitated the construction of cellular-level connectivity diagrams that can be generalized across individuals within a species. Homologous neurons can also be recognized across species. Here we describe NeuronBank.org, a web-based tool that we are developing for cataloging, searching, and analyzing neuronal circuitry within and across species. Information from a single species is represented in an individual branch of NeuronBank. Users can search within a branch or perform queries across branches to look for similarities in neuronal circuits across species. The branches allow for an extensible ontology so that additional characteristics can be added as knowledge grows. Each entry in NeuronBank generates a unique accession ID, allowing it to be easily cited. There is also an automatic link to a Wiki page allowing an encyclopedic explanation of the entry. All of the 44 previously published neurons plus one previously unpublished neuron from the mollusc, Tritonia diomedea, have been entered into a branch of NeuronBank as have 4 previously published neurons from the mollusc, Melibe leonina. The ability to organize information about neuronal circuits will make this information more accessible, ultimately aiding research on these important models. PMID:20428500

  18. Synapse-to-neuron ratio is inversely related to neuronal density in mature neuronal cultures.

    PubMed

    Cullen, D Kacy; Gilroy, Meghan E; Irons, Hillary R; Laplaca, Michelle C

    2010-11-04

    Synapse formation is a fundamental process in neurons that occurs throughout development, maturity, and aging. Although these stages contain disparate and fluctuating numbers of mature neurons, tactics employed by neuronal networks to modulate synapse number as a function of neuronal density are not well understood. The goal of this study was to utilize an in vitro model to assess the influence of cell density and neuronal maturity on synapse number and distribution. Specifically, cerebral cortical neurons were plated in planar culture at densities ranging from 10 to 5000 neurons/mm², and synapse number and distribution were evaluated via immunocytochemistry over 21 days in vitro (DIV). High-resolution confocal microscopy revealed an elaborate three-dimensional distribution of neurites and synapses across the heights of high-density neuronal networks by 21 DIV, which were up to 18 μm thick, demonstrating the complex degree of spatial interactions even in planar high-density cultures. At 7 DIV, the mean number of synapses per neuron was less than 5, and this did not vary as a function of neuronal density. However, by 21 DIV, the number of synapses per neuron had jumped 30- to 80-fold, and the synapse-to-neuron ratio was greatest at lower neuronal densities (< 500 neurons/mm²; mean approximately 400 synapses/neuron) compared to mid and higher neuronal densities (500-4500 neurons/mm²; mean of approximately 150 synapses/neuron) (p<0.05). These results suggest a relationship between neuronal density and synapse number that may have implications in the neurobiology of developing neuronal networks as well as processes of cell death and regeneration.

  19. Neuronal survival in the brain: neuron type-specific mechanisms.

    PubMed

    Pfisterer, Ulrich; Khodosevich, Konstantin

    2017-03-02

    Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die. To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development.

  20. Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation

    PubMed Central

    Han, Yongmei; Ripley, Barry; Serada, Satoshi; Naka, Tetsuji; Fujimoto, Minoru

    2016-01-01

    Background & Aim Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease. Recent evidence indicates that inflammation is associated with many neurodegenerative diseases including ALS. Previously, abnormal levels of inflammatory cytokines including IL-1β, IL-6 and TNF-α were described in ALS patients and/or in mouse ALS models. In addition, one study showed that blocking IL-1β could slow down progression of ALS-like symptoms in mice. In this study, we examined a role for IL-6 in ALS, using an animal model for familial ALS. Methods Mice with mutant SOD1 (G93A) transgene, a model for familial ALS, were used in this study. The expression of the major inflammatory cytokines, IL-6, IL-1β and TNF-α, in spinal cords of these SOD1 transgenic (TG) mice were assessed by real time PCR. Mice were then crossed with IL-6(-/-) mice to generate SOD1TG/IL-6(-/-) mice. SOD1 TG/IL-6(-/-) mice (n = 17) were compared with SOD1 TG/IL-6(+/-) mice (n = 18), SOD1 TG/IL-6(+/+) mice (n = 11), WT mice (n = 15), IL-6(+/-) mice (n = 5) and IL-6(-/-) mice (n = 8), with respect to neurological disease severity score, body weight and the survival. We also histologically compared the motor neuron loss in lumber spinal cords and the atrophy of hamstring muscles between these mouse groups. Results Levels of IL-6, IL-1β and TNF-α in spinal cords of SOD1 TG mice was increased compared to WT mice. However, SOD1 TG/IL-6(-/-) mice exhibited weight loss, deterioration in motor function and shortened lifespan (167.55 ± 11.52 days), similarly to SOD1 TG /IL-6(+/+) mice (164.31±12.16 days). Motor neuron numbers and IL-1β and TNF-α levels in spinal cords were not significantly different in SOD1 TG /IL-6(-/-) mice and SOD1 TG /IL-6 (+/+) mice. Conclusion These results provide compelling preclinical evidence indicating that IL-6 does not directly contribute to motor neuron disease caused by SOD1 mutations. PMID:27070121

  1. Nanoresolution radiology of neurons

    NASA Astrophysics Data System (ADS)

    Wu, H. R.; Chen, S. T.; Chu, Y. S.; Conley, R.; Bouet, N.; Chien, C. C.; Chen, H. H.; Lin, C. H.; Tung, H. T.; Chen, Y. S.; Margaritondo, G.; Je, J. H.; Hwu, Y.

    2012-06-01

    We report recent advances in hard-x-ray optics—including record spatial resolution—and in staining techniques that enable synchrotron microradiology to produce neurobiology images of quality comparable to electron and visible microscopy. In addition, microradiology offers excellent penetration and effective three-dimensional detection as required for many neuron studies. Our tests include tomographic reconstruction based on projection image sets.

  2. The Reliability of Neurons

    PubMed Central

    Bullock, Theodore Holmes

    1970-01-01

    The prevalent probabilistic view is virtually untestable; it remains a plausible belief. The cases usually cited can not be taken as evidence for it. Several grounds for this conclusion are developed. Three issues are distinguished in an attempt to clarify a murky debate: (a) the utility of probabilistic methods in data reduction, (b) the value of models that assume indeterminacy, and (c) the validity of the inference that the nervous system is largely indeterministic at the neuronal level. No exception is taken to the first two; the second is a private heuristic question. The third is the issue to which the assertion in the first two sentences is addressed. Of the two kinds of uncertainty, statistical mechanical (= practical unpredictability) as in a gas, and Heisenbergian indeterminancy, the first certainly exists, the second is moot at the neuronal level. It would contribute to discussion to recognize that neurons perform with a degree of reliability. Although unreliability is difficult to establish, to say nothing of measure, evidence that some neurons have a high degree of reliability, in both connections and activity is increasing greatly. An example is given from sternarchine electric fish. PMID:5462670

  3. Nanoresolution radiology of neurons

    SciTech Connect

    Wu, H. R.; Chen, S. T.; Chu, Y. S.; Conley, R.; Bouet, N.; Chien, C. C.; Chen, H. H.; Lin, C. H.; Tung, H. T.; Chen, Y. S.; Margaritondo, G.; Je, J. H.; Hwu, Y.

    2012-05-29

    We report recent advances in hard-x-ray optics—including record spatial resolution—and in staining techniques that enable synchrotron microradiology to produce neurobiology images of quality comparable to electron and visible microscopy. In addition, microradiology offers excellent penetration and effective three-dimensional detection as required for many neuron studies. Our tests include tomographic reconstruction based on projection image sets.

  4. Nanoresolution radiology of neurons

    SciTech Connect

    Wu, H.R.; Chen, S.T.; Chu, Y.S.; Conley, R.; Bouet, N.; Chien, C.C.; Chen, H.H.; Lin, C.H.; Tung, H.T.; Chen, Y.S.; Margaritondo, G.; Je, J.H.; Hwu, Y.

    2013-04-08

    We report recent advances in hard-x-ray optics - including record spatial resolution - and in staining techniques that enable synchrotron microradiology to produce neurobiology images of quality comparable to electron and visible microscopy. In addition, microradiology offers excellent penetration and effective three-dimensional detection as required for many neuron studies. Our tests include tomographic reconstruction based on projection image sets.

  5. Clustered protocadherins and neuronal diversity.

    PubMed

    Hirayama, Teruyoshi; Yagi, Takeshi

    2013-01-01

    Neuronal diversity is a fundamental requirement for complex neuronal networks and brain function. The clustered protocadherin (Pcdh) family possesses several characteristic features that are important for the molecular basis of neuronal diversity. Clustered Pcdhs are expressed predominantly in the central nervous system, in neurites, growth cones, and synapses. They consist of about 60 isoforms, and their expression is stochastically and combinatorially regulated in individual neurons. The multiple clustered Pcdhs expressed in individual neurons form heteromultimeric protein complexes that exhibit homophilic adhesion properties. Theoretically, the clustered Pcdhs could generate more than 3×10(10) possible variations in each neuron and 12,720 types of cis-tetramers per neuron. The clustered Pcdhs are important for normal neuronal development. The clustered Pcdh genes have also attracted attention as a target for epigenetic regulation.

  6. Genetics Home Reference: CLN3 disease

    MedlinePlus

    ... role in regulating anterograde and retrograde post-Golgi trafficking. Clin Lipidol. 2012 Feb;7(1):79-91. ... D, Hermey G. Revisiting the neuronal localization and trafficking of CLN3 in juvenile neuronal ceroid lipofuscinosis. J ...

  7. The Large Conductance, Calcium-activated K+ (BK) Channel is regulated by Cysteine String Protein

    PubMed Central

    Kyle, Barry D.; Ahrendt, Eva; Braun, Andrew P.; Braun, Janice E. A.

    2013-01-01

    Large-conductance, calcium-activated-K+ (BK) channels are widely distributed throughout the nervous system, where they regulate action potential duration and firing frequency, along with presynaptic neurotransmitter release. Our recent efforts to identify chaperones that target neuronal ion channels have revealed cysteine string protein (CSPα) as a key regulator of BK channel expression and current density. CSPα is a vesicle-associated protein and mutations in CSPα cause the hereditary neurodegenerative disorder, adult-onset autosomal dominant neuronal ceroid lipofuscinosis (ANCL). CSPα null mice show 2.5 fold higher BK channel expression compared to wild type mice, which is not seen with other neuronal channels (i.e. Cav2.2, Kv1.1 and Kv1.2). Furthermore, mutations in either CSPα's J domain or cysteine string region markedly increase BK expression and current amplitude. We conclude that CSPα acts to regulate BK channel expression, and consequently CSPα-associated changes in BK activity may contribute to the pathogenesis of neurodegenerative disorders, such as ANCL. PMID:23945775

  8. Neuronal cell cycle: the neuron itself and its circumstances.

    PubMed

    Frade, José M; Ovejero-Benito, María C

    2015-01-01

    Neurons are usually regarded as postmitotic cells that undergo apoptosis in response to cell cycle reactivation. Nevertheless, recent evidence indicates the existence of a defined developmental program that induces DNA replication in specific populations of neurons, which remain in a tetraploid state for the rest of their adult life. Similarly, de novo neuronal tetraploidization has also been described in the adult brain as an early hallmark of neurodegeneration. The aim of this review is to integrate these recent developments in the context of cell cycle regulation and apoptotic cell death in neurons. We conclude that a variety of mechanisms exists in neuronal cells for G1/S and G2/M checkpoint regulation. These mechanisms, which are connected with the apoptotic machinery, can be modulated by environmental signals and the neuronal phenotype itself, thus resulting in a variety of outcomes ranging from cell death at the G1/S checkpoint to full proliferation of differentiated neurons.

  9. Add neurons, subtract anxiety

    PubMed Central

    Kheirbek, Mazen A.; Hen, René

    2014-01-01

    IN BRIEF To keep memories from becoming jumbled, the brain must encode the distinct features of events and situations in a way that allows them to be distinguished from one another—a process called pattern separation. Pattern separation enables us to distinguish dangerous situations from similar ones that pose no risk. People with defects in this ability may be prone to anxiety disorders. The process occurs in one of the two regions of the brain that generate neurons throughout life. These fledgling cells seem to be critical to pattern separation. Interventions that specifically boost the ranks of rookie neurons could provide new ways to regulate mood and possibly treat conditions such as post-traumatic stress disorder. PMID:24974712

  10. Micropatterning neuronal networks.

    PubMed

    Hardelauf, Heike; Waide, Sarah; Sisnaiske, Julia; Jacob, Peter; Hausherr, Vanessa; Schöbel, Nicole; Janasek, Dirk; van Thriel, Christoph; West, Jonathan

    2014-07-07

    Spatially organised neuronal networks have wide reaching applications, including fundamental research, toxicology testing, pharmaceutical screening and the realisation of neuronal implant interfaces. Despite the large number of methods catalogued in the literature there remains the need to identify a method that delivers high pattern compliance, long-term stability and is widely accessible to neuroscientists. In this comparative study, aminated (polylysine/polyornithine and aminosilanes) and cytophobic (poly(ethylene glycol) (PEG) and methylated) material contrasts were evaluated. Backfilling plasma stencilled PEGylated substrates with polylysine does not produce good material contrasts, whereas polylysine patterned on methylated substrates becomes mobilised by agents in the cell culture media which results in rapid pattern decay. Aminosilanes, polylysine substitutes, are prone to hydrolysis and the chemistries prove challenging to master. Instead, the stable coupling between polylysine and PLL-g-PEG can be exploited: Microcontact printing polylysine onto a PLL-g-PEG coated glass substrate provides a simple means to produce microstructured networks of primary neurons that have superior pattern compliance during long term (>1 month) culture.

  11. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus

    PubMed Central

    Hernández, Vivian M.; Hegeman, Daniel J.; Cui, Qiaoling; Kelver, Daniel A.; Fiske, Michael P.; Glajch, Kelly E.; Pitt, Jason E.; Huang, Tina Y.; Justice, Nicholas J.

    2015-01-01

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. SIGNIFICANCE STATEMENT Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping

  12. Interactions of neurons with topographic nano cues affect branching morphology mimicking neuron-neuron interactions.

    PubMed

    Baranes, Koby; Kollmar, Davida; Chejanovsky, Nathan; Sharoni, Amos; Shefi, Orit

    2012-08-01

    We study the effect of topographic nano-cues on neuronal growth-morphology using invertebrate neurons in culture. We use photolithography to fabricate substrates with repeatable line-pattern ridges of nano-scale heights of 10-150 nm. We plate leech neurons atop the patterned-substrates and compare their growth pattern to neurons plated atop non-patterned substrates. The model system allows us the analysis of single neurite-single ridge interactions. The use of high resolution electron microscopy reveals small filopodia processes that attach to the line-pattern ridges. These fine processes, that cannot be detected in light microscopy, add anchoring sites onto the side of the ridges, thus additional physical support. These interactions of the neuronal process dominantly affect the neuronal growth direction. We analyze the response of the entire neuronal branching tree to the patterned substrates and find significant effect on the growth patterns compared to non-patterned substrates. Moreover, interactions with the nano-cues trigger a growth strategy similarly to interactions with other neuronal cells, as reflected in their morphometric parameters. The number of branches and the number of neurites originating from the soma decrease following the interaction demonstrating a tendency to a more simplified neuronal branching tree. The effect of the nano-cues on the neuronal function deserves further investigation and will strengthen our understanding of the interplay between function and form.

  13. Aging and Neuronal Vulnerability

    PubMed Central

    Mattson, Mark P.; Magnus, Tim

    2011-01-01

    Everyone ages, but only some will acquire a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress resulting in excessive accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins, and repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal aging process suggests that successful neural aging is possible for most, but also cautions that cures for neurodegenerative disorders are unlikely in the near future. PMID:16552414

  14. DNA Damage Induced Neuronal Death

    DTIC Science & Technology

    1999-10-01

    Experiments are proposed to examine the molecular mechanism by which mustard chemical warfare agents induce neuronal cell death . DNA damage is the...proposed underlying mechanism of mustard-induced neuronal cell death . We propose a novel research strategy to test this hypothesis by using mice with...perturbed DNA repair to explore the relationship between mustard-induced DNA damage and neuronal cell death . Initial in vitro studies (Years 1, 2 & 3

  15. [Neuronal plasticity and gene expression].

    PubMed

    Sokolova, O O; Shtark, M B; Lisachev, P D

    2010-01-01

    Neuronal plasticity--a fundamental feature of brain--provides adequate interactions with dynamic environment. One of the most deeply investigated forms of the neuronal plasticity is a long-term potentiation (LTP)--a phenomenon underlying learning and memory. Signal paths activated during LTP converge into the nuclear of the neuron, giving rise to launch of the molecular-genetic programs, which mediate structural and functional remodeling of synapses. In the review data concerning involvement of multilevel gene expression into plastic change under neuronal activation are summarized.

  16. The straintronic spin-neuron.

    PubMed

    Biswas, Ayan K; Atulasimha, Jayasimha; Bandyopadhyay, Supriyo

    2015-07-17

    In artificial neural networks, neurons are usually implemented with highly dissipative CMOS-based operational amplifiers. A more energy-efficient implementation is a 'spin-neuron' realized with a magneto-tunneling junction (MTJ) that is switched with a spin-polarized current (representing weighted sum of input currents) that either delivers a spin transfer torque or induces domain wall motion in the soft layer of the MTJ to mimic neuron firing. Here, we propose and analyze a different type of spin-neuron in which the soft layer of the MTJ is switched with mechanical strain generated by a voltage (representing weighted sum of input voltages) and term it straintronic spin-neuron. It dissipates orders of magnitude less energy in threshold operations than the traditional current-driven spin neuron at 0 K temperature and may even be faster. We have also studied the room-temperature firing behaviors of both types of spin neurons and find that thermal noise degrades the performance of both types, but the current-driven type is degraded much more than the straintronic type if both are optimized for maximum energy-efficiency. On the other hand, if both are designed to have the same level of thermal degradation, then the current-driven version will dissipate orders of magnitude more energy than the straintronic version. Thus, the straintronic spin-neuron is superior to current-driven spin neurons.

  17. The biophysics of neuronal growth

    NASA Astrophysics Data System (ADS)

    Franze, Kristian; Guck, Jochen

    2010-09-01

    For a long time, neuroscience has focused on biochemical, molecular biological and electrophysiological aspects of neuronal physiology and pathology. However, there is a growing body of evidence indicating the importance of physical stimuli for neuronal growth and development. In this review we briefly summarize the historical background of neurobiophysics and give an overview over the current understanding of neuronal growth from a physics perspective. We show how biophysics has so far contributed to a better understanding of neuronal growth and discuss current inconsistencies. Finally, we speculate how biophysics may contribute to the successful treatment of lesions to the central nervous system, which have been considered incurable until very recently.

  18. Aberrant association of misfolded SOD1 with Na(+)/K(+)ATPase-α3 impairs its activity and contributes to motor neuron vulnerability in ALS.

    PubMed

    Ruegsegger, Céline; Maharjan, Niran; Goswami, Anand; Filézac de L'Etang, Audrey; Weis, Joachim; Troost, Dirk; Heller, Manfred; Gut, Heinz; Saxena, Smita

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific antibody B8H10 which recognizes a misfolded state of SOD1 (misfSOD1) to longitudinally identify its interactome during early disease stage in SOD1G93A mice. This strategy identified a direct isozyme-specific association of misfSOD1 with Na(+)/K(+)ATPase-α3 leading to the premature impairment of its ATPase activity. Pharmacological inhibition of Na(+)/K(+)ATPase-α3 altered glutamate receptor 2 expression, modified cholinergic inputs and accelerated disease pathology. After mapping the site of direct association of misfSOD1 with Na(+)/K(+)ATPase-α3 onto a 10 amino acid stretch that is unique to Na(+)/K(+)ATPase-α3 but not found in the closely related Na(+)/K(+)ATPase-α1 isozyme, we generated a misfSOD1 binding deficient, but fully functional Na(+)/K(+)ATPase-α3 pump. Adeno associated virus (AAV)-mediated expression of this chimeric Na(+)/K(+)ATPase-α3 restored Na(+)/K(+)ATPase-α3 activity in the spinal cord, delayed pathological alterations and prolonged survival of SOD1G93A mice. Additionally, altered Na(+)/K(+)ATPase-α3 expression was observed in the spinal cord of individuals with sporadic and familial ALS. A fraction of sporadic ALS cases also presented B8H10 positive misfSOD1 immunoreactivity, suggesting that similar mechanism might contribute to the pathology.

  19. Hippocampal neurons in schizophrenia

    PubMed Central

    Heckers, S.; Konradi, C.

    2014-01-01

    Summary The hippocampus is crucial for normal brain function, especially for the encoding and retrieval of multimodal sensory information. Neuropsychiatric disorders such as temporal lobe epilepsy, amnesia, and the dementias are associated with structural and functional abnormalities of specific hippocampal neurons. More recently we have also found evidence for a role of the hippocampus in the pathophysiology of schizophrenia. The most consistent finding is a subtle, yet significant volume difference in schizophrenia. Here we review the cellular and molecular basis of smaller hippocampal volume in schizophrenia. In contrast to neurodegenerative disorders, total hippocampal cell number is not markedly decreased in schizophrenia. However, the intriguing finding of a selective loss of hippocampal inter-neurons deserves further study. Two neurotransmitter receptors, the GABAA and AMPA/kainate glutamate receptors, appear to be abnormal, whereas changes of the NMDA glutamate receptor are less robust. The expression of several genes, including those related to the GABAergic system, neurodevelopment, and synaptic function, is decreased in schizophrenia. Taken together, recent studies of hippocampal cell number, protein expression, and gene regulation point towards an abnormality of hippocampal architecture in schizophrenia. PMID:12111476

  20. Synchronization by elastic neuronal latencies

    NASA Astrophysics Data System (ADS)

    Vardi, Roni; Timor, Reut; Marom, Shimon; Abeles, Moshe; Kanter, Ido

    2013-01-01

    Psychological and physiological considerations entail that formation and functionality of neuronal cell assemblies depend upon synchronized repeated activation such as zero-lag synchronization. Several mechanisms for the emergence of this phenomenon have been suggested, including the global network quantity, the greatest common divisor of neuronal circuit delay loops. However, they require strict biological prerequisites such as precisely matched delays and connectivity, and synchronization is represented as a stationary mode of activity instead of a transient phenomenon. Here we show that the unavoidable increase in neuronal response latency to ongoing stimulation serves as a nonuniform gradual stretching of neuronal circuit delay loops. This apparent nuisance is revealed to be an essential mechanism in various types of neuronal time controllers, where synchronization emerges as a transient phenomenon and without predefined precisely matched synaptic delays. These findings are described in an experimental procedure where conditioned stimulations were enforced on a circuit of neurons embedded within a large-scale network of cortical cells in vitro, and are corroborated and extended by simulations of circuits composed of Hodgkin-Huxley neurons with time-dependent latencies. These findings announce a cortical time scale for time controllers based on tens of microseconds stretching of neuronal circuit delay loops per spike. They call for a reexamination of the role of the temporal periodic mode in brain functionality using advanced in vitro and in vivo experiments.

  1. Neuronal avalanches and coherence potentials

    NASA Astrophysics Data System (ADS)

    Plenz, D.

    2012-05-01

    The mammalian cortex consists of a vast network of weakly interacting excitable cells called neurons. Neurons must synchronize their activities in order to trigger activity in neighboring neurons. Moreover, interactions must be carefully regulated to remain weak (but not too weak) such that cascades of active neuronal groups avoid explosive growth yet allow for activity propagation over long-distances. Such a balance is robustly realized for neuronal avalanches, which are defined as cortical activity cascades that follow precise power laws. In experiments, scale-invariant neuronal avalanche dynamics have been observed during spontaneous cortical activity in isolated preparations in vitro as well as in the ongoing cortical activity of awake animals and in humans. Theory, models, and experiments suggest that neuronal avalanches are the signature of brain function near criticality at which the cortex optimally responds to inputs and maximizes its information capacity. Importantly, avalanche dynamics allow for the emergence of a subset of avalanches, the coherence potentials. They emerge when the synchronization of a local neuronal group exceeds a local threshold, at which the system spawns replicas of the local group activity at distant network sites. The functional importance of coherence potentials will be discussed in the context of propagating structures, such as gliders in balanced cellular automata. Gliders constitute local population dynamics that replicate in space after a finite number of generations and are thought to provide cellular automata with universal computation. Avalanches and coherence potentials are proposed to constitute a modern framework of cortical synchronization dynamics that underlies brain function.

  2. Cryopreservation of adherent neuronal networks.

    PubMed

    Ma, Wu; O'Shaughnessy, Thomas; Chang, Eddie

    2006-07-31

    Neuronal networks have been widely used for neurophysiology, drug discovery and toxicity testing. An essential prerequisite for future widespread application of neuronal networks is the development of efficient cryopreservation protocols to facilitate their storage and transportation. Here is the first report on cryopreservation of mammalian adherent neuronal networks. Dissociated spinal cord cells were attached to a poly-d-lysine/laminin surface and allowed to form neuronal networks. Adherent neuronal networks were embedded in a thin film of collagen gel and loaded with trehalose prior to transfer to a freezing medium containing DMSO, FBS and culture medium. This was followed by a slow rate of cooling to -80 degrees C for 24 h and then storage for up to 2 months in liquid nitrogen at -196 degrees C. The three components: DMSO, collagen gel entrapment and trehalose loading combined provided the highest post-thaw viability, relative to individual or two component protocols. The post-thaw cells with this protocol demonstrated similar neuronal and astrocytic markers and morphological structure as those detected in unfrozen cells. Fluorescent dye FM1-43 staining revealed active recycling of synaptic vesicles upon depolarizing stimulation in the post-thaw neuronal networks. These results suggest that a combination of DMSO, collagen gel entrapment and trehalose loading can significantly improve conventional slow-cooling methods in cryopreservation of adherent neuronal networks.

  3. Cell biology of neuronal endocytosis.

    PubMed

    Parton, R G; Dotti, C G

    1993-09-01

    Endocytosis is the process by which cells take in fluid and components of the plasma membrane. In this way cells obtain nutrients and trophic factors, retrieve membrane proteins for degradation, and sample their environment. In neuronal cells endocytosis is essential for the recycling of membrane after neurotransmitter release and plays a critical role during early developmental stages. Moreover, alterations of the endocytic pathway have been attributed a crucial role in the pathophysiology of certain neurological diseases. Although well characterized at the ultrastructural level, little is known of the dynamics and molecular organization of the neuronal endocytic pathways. In this respect most of our knowledge comes from studies of non-neuronal cells. In this review we will examine the endocytic pathways in neurons from a cell biological viewpoint by making comparisons with non-neuronal cells and in particular with another polarized cell, the epithelial cell.

  4. Phenotypic checkpoints regulate neuronal development.

    PubMed

    Ben-Ari, Yehezkel; Spitzer, Nicholas C

    2010-11-01

    Nervous system development proceeds by sequential gene expression mediated by cascades of transcription factors in parallel with sequences of patterned network activity driven by receptors and ion channels. These sequences are cell type- and developmental stage-dependent and modulated by paracrine actions of substances released by neurons and glia. How and to what extent these sequences interact to enable neuronal network development is not understood. Recent evidence demonstrates that CNS development requires intermediate stages of differentiation providing functional feedback that influences gene expression. We suggest that embryonic neuronal functions constitute a series of phenotypic checkpoint signatures; neurons failing to express these functions are delayed or developmentally arrested. Such checkpoints are likely to be a general feature of neuronal development and constitute presymptomatic signatures of neurological disorders when they go awry.

  5. [Neurons and values].

    PubMed

    Camps, Victoria

    2013-09-01

    This article examines the advances made by neuroscience in the attempt to find an answer to the question regarding the origin and foundation of moral judgements and of human behaviour in compliance with them. The conception of the brain as something dynamic and capable of adapting to the social and cultural surroundings is seen to be an important point for philosophy. At the same time, the complexity of ethical issues that cannot be reduced to observations based strictly on neurons alone also becomes quite apparent. Nevertheless, scientists and philosophers should get together and communicate with one another so as to be able to pose their questions with greater rigour and take advantage of each other's respective knowledge.

  6. Neuron's function revealed

    SciTech Connect

    2009-01-01

    There's a new way to explore biologys secrets. With a flash of light, scientists from the U.S. Department of Energys Lawrence Berkeley National Laboratory and the University of California, Berkeley zeroed in on the type of neural cell that controls swimming in larval zebrafish. Using innovative light-activated proteins and gene expression techniques, the scientists zapped several zebrafish with a pulse of light, and initiated a swimming action in a subset of fish that was traced back to the type of neuron that drives the side-to-side motion of their tail fins. The technique behind this needle-in-haystack search for the neural roots of a specific behavior could become a powerful way to learn how any biological system works. http://newscenter.lbl.gov/press-releases/2009/09/16/light-activated-protein/

  7. Multiplying with Neurons

    NASA Astrophysics Data System (ADS)

    Gabbiani, F.; Krapp, H.; Koch, C.; Laurent, G.

    1998-03-01

    LGMD and DCMD are a pair of identified neurons in the locust brain thought to be involved in visually triggered escape behavior. LGMD integrates visual inputs in its dendritic arbor, converts them into spikes transmitted in a 1:1 manner to DCMD which relays this information to motor centers. We measured the spike activity of DCMD during simulated object approach and observed that its peak occured prior to the expected collision. The time difference between peak activity and collision depended linearly on the ratio of object size to approach velocity, as expected if LGMD/DCMD were detecting the moment in time when the approaching object reaches a fixed angular threshold θ_thresh on the locust's retina. The response of LGMD/DCMD could be fitted by multiplying the angular velocity at which an approaching object is increasing in size over the retina, dot θ, with an exponential function of the object's angular size, θ: f(t) = g(dot θ(t-δ) e^-α θ(t-δ)) where g is a static non-linearity, α a constant related to the angular threshold detected by LGMD/DCMD (θ_thresh = arctan (2/α)) and δ denotes the lag of the neuronal response with respect to the stimulus. This suggests that LGMD/DCMD derives its angular threshold sensitivity by multiplying dot θ with an exponential of θ. A biophysical implementation would be through linear summation of excitatory and inhibitory inputs proportional to log(dot θ) and -α θ, followed by a conversion to spike rate according to the static non-linearity (g circ exp). We have performed several experiments to test this hypothesis.

  8. Neuronal cell lines as model dorsal root ganglion neurons

    PubMed Central

    Yin, Kathleen; Baillie, Gregory J

    2016-01-01

    Background Dorsal root ganglion neuron-derived immortal cell lines including ND7/23 and F-11 cells have been used extensively as in vitro model systems of native peripheral sensory neurons. However, while it is clear that some sensory neuron-specific receptors and ion channels are present in these cell lines, a systematic comparison of the molecular targets expressed by these cell lines with those expressed in intact peripheral neurons is lacking. Results In this study, we examined the expression of RNA transcripts in the human neuroblastoma-derived cell line, SH-SY5Y, and two dorsal root ganglion hybridoma cell lines, F-11 and ND7/23, using Illumina next-generation sequencing, and compared the results with native whole murine dorsal root ganglions. The gene expression profiles of these three cell lines did not resemble any specific defined dorsal root ganglion subclass. The cell lines lacked many markers for nociceptive sensory neurons, such as the Transient receptor potential V1 gene, but expressed markers for both myelinated and unmyelinated neurons. Global gene ontology analysis on whole dorsal root ganglions and cell lines showed similar enrichment of biological process terms across all samples. Conclusions This paper provides insights into the receptor repertoire expressed in common dorsal root ganglion neuron-derived cell lines compared with whole murine dorsal root ganglions, and illustrates the limits and potentials of these cell lines as tools for neuropharmacological exploration. PMID:27130590

  9. The Chandelier Neuron in Schizophrenia

    PubMed Central

    Lewis, David A.

    2010-01-01

    Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. These alterations are most marked in cortical layers 2–3. In addition, other determinants of the function of chandelier cell-pyramidal neuron synapses, such as ankyrin-G (which regulates the recruitment of sodium channels to the AIS), are also selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia. Each of these components of chandelier cell-pyramidal neuron connectivity exhibits distinctive developmental trajectories in the primate DLPFC, suggesting that disturbances in these trajectories could contribute to the pathogenesis of schizophrenia. Recent findings that inputs from neocortical chandelier neurons are excitatory provide new ideas about the role of this circuitry in the pathophysiology of cortical dysfunction in schizophrenia. PMID:21154915

  10. The chandelier neuron in schizophrenia.

    PubMed

    Lewis, David A

    2011-01-01

    Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABA(A) receptor α2 subunit is increased in postsynaptic AIS. These alterations are most marked in cortical layers 2-3. In addition, other determinants of the function of chandelier cell-pyramidal neuron synapses, such as ankyrin-G (which regulates the recruitment of sodium channels to the AIS), are also selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia. Each of these components of chandelier cell-pyramidal neuron connectivity exhibits distinctive developmental trajectories in the primate DLPFC, suggesting that disturbances in these trajectories could contribute to the pathogenesis of schizophrenia. Recent findings that inputs from neocortical chandelier neurons are excitatory provide new ideas about the role of this circuitry in the pathophysiology of cortical dysfunction in schizophrenia.

  11. Dopaminergic regulation of orexin neurons.

    PubMed

    Bubser, Michael; Fadel, Jim R; Jackson, Lela L; Meador-Woodruff, James H; Jing, Deqiang; Deutch, Ariel Y

    2005-06-01

    Orexin/hypocretin neurons in the lateral hypothalamus and adjacent perifornical area (LH/PFA) innervate midbrain dopamine (DA) neurons that project to corticolimbic sites and subserve psychostimulant-induced locomotor activity. However, it is not known whether dopamine neurons in turn regulate the activity of orexin cells. We examined the ability of dopamine agonists to activate orexin neurons in the rat, as reflected by induction of Fos. The mixed dopamine agonist apomorphine increased Fos expression in orexin cells, with a greater effect on orexin neurons located medial to the fornix. Both the selective D1-like agonist, A-77636, and the D2-like agonist, quinpirole, also induced Fos in orexin cells, suggesting that stimulation of either receptor subtype is sufficient to activate orexin neurons. Consistent with this finding, combined SCH 23390 (D1 antagonist)-haloperidol (D2 antagonist) pretreatment blocked apomorphine-induced activation of medial as well as lateral orexin neurons; in contrast, pretreatment with either the D1-like or D2-like antagonists alone did not attenuate apomorphine-induced activation of medial orexin cells. In situ hybridization histochemistry revealed that LH/PFA cells rarely express mRNAs encoding dopamine receptors, suggesting that orexin cells are transsynaptically activated by apomorphine. We therefore lesioned the nucleus accumbens, a site known to regulate orexin cells, but this treatment did not alter apomorphine-elicited activation of medial or lateral orexin neurons. Interestingly, apomorphine failed to activate orexin cells in isoflurane-anaesthetized animals. These data suggest that apomorphine-induced arousal but not accumbens-mediated hyperactivity is required for dopamine to transsynaptically activate orexin neurons.

  12. Ensemble Neuron Tracer for 3D Neuron Reconstruction.

    PubMed

    Wang, Ching-Wei; Lee, Yu-Ching; Pradana, Hilmil; Zhou, Zhi; Peng, Hanchuan

    2017-02-09

    Tracing of neuron paths is important in neuroscience. Recent studies have shown that it is possible to segment and reconstruct three-dimensional morphology of axons and dendrites using fully automatic neuron tracing methods. A specific tracer may be better than others for a specific dataset, but another tracer could perform better for some other datasets. Ensemble of learners is an effective way to improve learning accuracy in machine learning. We developed automatic ensemble neuron tracers, which consistently perform well on 57 datasets of 5 species collected from 7 laboratories worldwide. Quantitative evaluation based on the data generated by human annotators shows that the proposed ensemble tracers are valuable for 3D neuron tracing and can be widely applied to different datasets.

  13. Neuronal pathway finding: from neurons to initial neural networks.

    PubMed

    Roscigno, Cecelia I

    2004-10-01

    Neuronal pathway finding is crucial for structured cellular organization and development of neural circuits within the nervous system. Neuronal pathway finding within the visual system has been extensively studied and therefore is used as a model to review existing knowledge regarding concepts of this developmental process. General principles of neuron pathway finding throughout the nervous system exist. Comprehension of these concepts guides neuroscience nurses in gaining an understanding of the developmental course of action, the implications of different anomalies, as well as the theoretical basis and nursing implications of some provocative new therapies being proposed to treat neurodegenerative diseases and neurologic injuries. These therapies have limitations in light of current ethical, developmental, and delivery modes and what is known about the development of neuronal pathways.

  14. Towards Automatic Classification of Neurons

    PubMed Central

    Armañanzas, Rubén; Ascoli, Giorgio A.

    2015-01-01

    The classification of neurons into types has been much debated since the inception of modern neuroscience. Recent experimental advances are accelerating the pace of data collection. The resulting information growth of morphological, physiological, and molecular properties encourages efforts to automate neuronal classification by powerful machine learning techniques. We review state-of-the-art analysis approaches and availability of suitable data and resources, highlighting prominent challenges and opportunities. The effective solution of the neuronal classification problem will require continuous development of computational methods, high-throughput data production, and systematic metadata organization to enable cross-lab integration. PMID:25765323

  15. A fish on the hunt, observed neuron by neuron

    SciTech Connect

    2010-01-01

    This three-dimensional microscopy image reveals an output neuron of the optic tectum lighting up in response to visual information from the retina. The scientists used this state-of-the-art imaging technology to learn how neurons in the optic tectum take visual information and convert it into an output that drives action. More information: http://newscenter.lbl.gov/feature-stories/2010/10/29/zebrafish-vision/

  16. Npas1+ Pallidal Neurons Target Striatal Projection Neurons

    PubMed Central

    Glajch, Kelly E.; Kelver, Daniel A.; Hegeman, Daniel J.; Cui, Qiaoling; Xenias, Harry S.; Augustine, Elizabeth C.; Hernández, Vivian M.; Verma, Neha; Huang, Tina Y.; Luo, Minmin; Justice, Nicholas J.

    2016-01-01

    Compelling evidence demonstrates that the external globus pallidus (GPe) plays a key role in processing sensorimotor information. An anatomical projection from the GPe to the dorsal striatum has been described for decades. However, the cellular target and functional impact of this projection remain unknown. Using cell-specific transgenic mice, modern monosynaptic tracing techniques, and optogenetics-based mapping, we discovered that GPe neurons provide inhibitory inputs to direct and indirect pathway striatal projection neurons (SPNs). Our results indicate that the GPe input to SPNs arises primarily from Npas1-expressing neurons and is strengthened in a chronic Parkinson's disease (PD) model. Alterations of the GPe-SPN input in a PD model argue for the critical position of this connection in regulating basal ganglia motor output and PD symptomatology. Finally, chemogenetic activation of Npas1-expressing GPe neurons suppresses motor output, arguing that strengthening of the GPe-SPN connection is maladaptive and may underlie the hypokinetic symptoms in PD. SIGNIFICANCE STATEMENT An anatomical projection from the pallidum to the striatum has been described for decades, but little is known about its connectivity pattern. The authors dissect the presynaptic and postsynaptic neurons involved in this projection, and show its cell-specific remodeling and strengthening in parkinsonian mice. Chemogenetic activation of Npas1+ pallidal neurons that give rise to the principal pallidostriatal projection increases the time that the mice spend motionless. This argues that maladaptive strengthening of this connection underlies the paucity of volitional movements, which is a hallmark of Parkinson's disease. PMID:27194328

  17. Neuronal boost to evolutionary dynamics.

    PubMed

    de Vladar, Harold P; Szathmáry, Eörs

    2015-12-06

    Standard evolutionary dynamics is limited by the constraints of the genetic system. A central message of evolutionary neurodynamics is that evolutionary dynamics in the brain can happen in a neuronal niche in real time, despite the fact that neurons do not reproduce. We show that Hebbian learning and structural synaptic plasticity broaden the capacity for informational replication and guided variability provided a neuronally plausible mechanism of replication is in place. The synergy between learning and selection is more efficient than the equivalent search by mutation selection. We also consider asymmetric landscapes and show that the learning weights become correlated with the fitness gradient. That is, the neuronal complexes learn the local properties of the fitness landscape, resulting in the generation of variability directed towards the direction of fitness increase, as if mutations in a genetic pool were drawn such that they would increase reproductive success. Evolution might thus be more efficient within evolved brains than among organisms out in the wild.

  18. Neuronal boost to evolutionary dynamics

    PubMed Central

    de Vladar, Harold P.; Szathmáry, Eörs

    2015-01-01

    Standard evolutionary dynamics is limited by the constraints of the genetic system. A central message of evolutionary neurodynamics is that evolutionary dynamics in the brain can happen in a neuronal niche in real time, despite the fact that neurons do not reproduce. We show that Hebbian learning and structural synaptic plasticity broaden the capacity for informational replication and guided variability provided a neuronally plausible mechanism of replication is in place. The synergy between learning and selection is more efficient than the equivalent search by mutation selection. We also consider asymmetric landscapes and show that the learning weights become correlated with the fitness gradient. That is, the neuronal complexes learn the local properties of the fitness landscape, resulting in the generation of variability directed towards the direction of fitness increase, as if mutations in a genetic pool were drawn such that they would increase reproductive success. Evolution might thus be more efficient within evolved brains than among organisms out in the wild. PMID:26640653

  19. Neuronal migration and protein kinases

    PubMed Central

    Ohshima, Toshio

    2015-01-01

    The formation of the six-layered structure of the mammalian cortex via the inside-out pattern of neuronal migration is fundamental to neocortical functions. Extracellular cues such as Reelin induce intracellular signaling cascades through the protein phosphorylation. Migrating neurons also have intrinsic machineries to regulate cytoskeletal proteins and adhesion properties. Protein phosphorylation regulates these processes. Moreover, the balance between phosphorylation and dephosphorylation is modified by extracellular cues. Multipolar-bipolar transition, radial glia-guided locomotion and terminal translocation are critical steps of radial migration of cortical pyramidal neurons. Protein kinases such as Cyclin-dependent kinase 5 (Cdk5) and c-Jun N-terminal kinases (JNKs) involve these steps. In this review, I shall give an overview the roles of protein kinases in neuronal migration. PMID:25628530

  20. Polyphenolic Antioxidants and Neuronal Regeneration

    PubMed Central

    Ataie, Amin; Shadifar, Mohammad; Ataee, Ramin

    2016-01-01

    Many studies indicate that oxidative stress is involved in the pathophysiology of neurodegenerative diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling and ultimately leads to neuronal death by apoptosis or necrosis. To review antioxidants preventive effects on oxidative stress and neurodegenerative diseases we accumulated data from international medical journals and academic informations’ sites. According to many studies, antioxidants could reduce toxic neuronal damages and many studies confirmed the efficacy of polyphenol antioxidants in fruits and vegetables to reduce neuronal death and to diminish oxidative stress. This systematic review showed the antioxidant activities of phytochemicals which play as natural neuroprotectives with low adverse effects against some neurodegenerative diseases as Parkinson or Alzheimer diseases. PMID:27303602

  1. [Some characteristics of vertigo in vestibular neuronitis].

    PubMed

    Skliut, I A; Likhachev, S A; Rybina, O V

    2004-01-01

    The authors present a detailed clinical analysis of objective neurological symptoms and vertigo in patients with vestibular neuronitis. Diagnostic criteria are specified allowing differentiation between vertigo and dizziness, pathognomonic signs of vestibular neuronitis are outlined. Peripheral location of the pathological process in vestibular neuronitis is suggested. How rotating vertigo is forming in patients with vestibular neuronitis is hypothesized.

  2. Centrosome localization determines neuronal polarity.

    PubMed

    de Anda, Froylan Calderon; Pollarolo, Giulia; Da Silva, Jorge Santos; Camoletto, Paola G; Feiguin, Fabian; Dotti, Carlos G

    2005-08-04

    Neuronal polarization occurs shortly after mitosis. In neurons differentiating in vitro, axon formation follows the segregation of growth-promoting activities to only one of the multiple neurites that form after mitosis. It is unresolved whether such spatial restriction makes use of an intrinsic program, like during C. elegans embryo polarization, or is extrinsic and cue-mediated, as in migratory cells. Here we show that in hippocampal neurons in vitro, the axon consistently arises from the neurite that develops first after mitosis. Centrosomes, the Golgi apparatus and endosomes cluster together close to the area where the first neurite will form, which is in turn opposite from the plane of the last mitotic division. We show that the polarized activities of these organelles are necessary and sufficient for neuronal polarization: (1) polarized microtubule polymerization and membrane transport precedes first neurite formation, (2) neurons with more than one centrosome sprout more than one axon and (3) suppression of centrosome-mediated functions precludes polarization. We conclude that asymmetric centrosome-mediated dynamics in the early post-mitotic stage instruct neuronal polarity, implying that pre-mitotic mechanisms with a role in division orientation may in turn participate in this event.

  3. Network synchronization in hippocampal neurons.

    PubMed

    Penn, Yaron; Segal, Menahem; Moses, Elisha

    2016-03-22

    Oscillatory activity is widespread in dynamic neuronal networks. The main paradigm for the origin of periodicity consists of specialized pacemaking elements that synchronize and drive the rest of the network; however, other models exist. Here, we studied the spontaneous emergence of synchronized periodic bursting in a network of cultured dissociated neurons from rat hippocampus and cortex. Surprisingly, about 60% of all active neurons were self-sustained oscillators when disconnected, each with its own natural frequency. The individual neuron's tendency to oscillate and the corresponding oscillation frequency are controlled by its excitability. The single neuron intrinsic oscillations were blocked by riluzole, and are thus dependent on persistent sodium leak currents. Upon a gradual retrieval of connectivity, the synchrony evolves: Loose synchrony appears already at weak connectivity, with the oscillators converging to one common oscillation frequency, yet shifted in phase across the population. Further strengthening of the connectivity causes a reduction in the mean phase shifts until zero-lag is achieved, manifested by synchronous periodic network bursts. Interestingly, the frequency of network bursting matches the average of the intrinsic frequencies. Overall, the network behaves like other universal systems, where order emerges spontaneously by entrainment of independent rhythmic units. Although simplified with respect to circuitry in the brain, our results attribute a basic functional role for intrinsic single neuron excitability mechanisms in driving the network's activity and dynamics, contributing to our understanding of developing neural circuits.

  4. Genetics Home Reference: CLN2 disease

    MedlinePlus

    ... Z, Mole SE, Noher de Halac I, Pearce DA, Poupetova H, Schulz A, Specchio N, Xin W, ... Jul 25. Citation on PubMed Getty AL, Pearce DA. Interactions of the proteins of neuronal ceroid lipofuscinosis: ...

  5. Neuronal polarization in the developing cerebral cortex

    PubMed Central

    Sakakibara, Akira; Hatanaka, Yumiko

    2015-01-01

    Cortical neurons consist of excitatory projection neurons and inhibitory GABAergic interneurons, whose connections construct highly organized neuronal circuits that control higher order information processing. Recent progress in live imaging has allowed us to examine how these neurons differentiate during development in vivo or in in vivo-like conditions. These analyses have revealed how the initial steps of polarization, in which neurons establish an axon, occur. Interestingly, both excitatory and inhibitory cortical neurons establish neuronal polarity de novo by undergoing a multipolar stage reminiscent of the manner in which polarity formation occurs in hippocampal neurons in dissociated culture. In this review, we focus on polarity formation in cortical neurons and describe their typical morphology and dynamic behavior during the polarization period. We also discuss cellular and molecular mechanisms underlying polarization, with reference to polarity formation in dissociated hippocampal neurons in vitro. PMID:25904841

  6. Neuronize: a tool for building realistic neuronal cell morphologies

    PubMed Central

    Brito, Juan P.; Mata, Susana; Bayona, Sofia; Pastor, Luis; DeFelipe, Javier; Benavides-Piccione, Ruth

    2013-01-01

    This study presents a tool, Neuronize, for building realistic three-dimensional models of neuronal cells from the morphological information extracted through computer-aided tracing applications. Neuronize consists of a set of methods designed to build 3D neural meshes that approximate the cell membrane at different resolution levels, allowing a balance to be reached between the complexity and the quality of the final model. The main contribution of the present study is the proposal of a novel approach to build a realistic and accurate 3D shape of the soma from the incomplete information stored in the digitally traced neuron, which usually consists of a 2D cell body contour. This technique is based on the deformation of an initial shape driven by the position and thickness of the first order dendrites. The addition of a set of spines along the dendrites completes the model, building a final 3D neuronal cell suitable for its visualization in a wide range of 3D environments. PMID:23761740

  7. Spinal Cord Neuronal Precursors Generate Multiple Neuronal Phenotypes in Culture

    PubMed Central

    Kalyani, Anjali J.; Piper, David; Mujtaba, Tahmina; Lucero, Mary T.; Rao, Mahendra S.

    2010-01-01

    Neuronal restricted precursors (NRPs) (Mayer-Proschel et al., 1997) can generate multiple neurotransmitter phenotypes during maturation in culture. Undifferentiated E-NCAM+ (embryonic neural cell adhesion molecule) immunoreactive NRPs are mitotically active and electrically immature, and they express only a subset of neuronal markers. Fully mature cells are postmitotic, process-bearing cells that are neurofilament-M and synaptophysin immunoreactive, and they synthesize and respond to different subsets of neurotransmitter molecules. Mature neurons that synthesize and respond to glycine, glutamate, GABA, dopamine, and acetylcholine can be identified by immunocytochemistry, RT-PCR, and calcium imaging in mass cultures. Individual NRPs also generate heterogeneous progeny as assessed by neurotransmitter response and synthesis, demonstrating the multipotent nature of the precursor cells. Differentiation can be modulated by sonic hedgehog (Shh) and bone morphogenetic protein (BMP)-2/4 molecules. Shh acts as a mitogen and inhibits differentiation (including cholinergic differentiation). BMP-2 and BMP-4, in contrast, inhibit cell division and promote differentiation (including cholinergic differentiation). Thus, a single neuronal precursor cell can differentiate into multiple classes of neurons, and this differentiation can be modulated by environmental signals. PMID:9742154

  8. Neurons on Parafilm: versatile elastic substrates for neuronal cell cultures.

    PubMed

    Yoo, Sang Jin; Nam, Yoonkey

    2012-02-15

    A variety of materials has been applied to neuronal cell culture substrates to improve the efficiency of the culture and to provide pertinent cell growth environment. Here we report the application of Parafilm(®) M ('Parafilm') as a novel substrate for neuronal culture and patterning. Cell culture results show that elastic Parafilm had effects on cell viability, length and number of neurites, and soma spreading. Parafilm was also an effective substrate to obtain patterned neuronal cultures using a conventional micro-contract printing (μCP) technique. Polylysine micropatterns in line or grid forms were readily transferred from PDMS stamp to bare Parafilm surfaces and spatially confined neuronal cultures were successfully maintained for over three weeks. We also demonstrate that batch-processing cell culture substrates can be easily fabricated using a piece of Parafilm. The softness, plasticity, and hydrophobicity were main features that made it attractive for Parafilm to be considered as a practical cell culture platform. The results can be extended to develop an inexpensive and practical neuronal culture substrates in tissue engineering and biochip applications.

  9. Neuronal SUMOylation: Mechanisms, Physiology, and Roles in Neuronal Dysfunction

    PubMed Central

    Henley, Jeremy M.; Craig, Tim J.; Wilkinson, Kevin A.

    2014-01-01

    Protein SUMOylation is a critically important posttranslational protein modification that participates in nearly all aspects of cellular physiology. In the nearly 20 years since its discovery, SUMOylation has emerged as a major regulator of nuclear function, and more recently, it has become clear that SUMOylation has key roles in the regulation of protein trafficking and function outside of the nucleus. In neurons, SUMOylation participates in cellular processes ranging from neuronal differentiation and control of synapse formation to regulation of synaptic transmission and cell survival. It is a highly dynamic and usually transient modification that enhances or hinders interactions between proteins, and its consequences are extremely diverse. Hundreds of different proteins are SUMO substrates, and dysfunction of protein SUMOylation is implicated in a many different diseases. Here we briefly outline core aspects of the SUMO system and provide a detailed overview of the current understanding of the roles of SUMOylation in healthy and diseased neurons. PMID:25287864

  10. ApoSOD1 lacking dismutase activity neuroprotects motor neurons exposed to beta-methylamino-L-alanine through the Ca2+/Akt/ERK1/2 prosurvival pathway

    PubMed Central

    Petrozziello, Tiziana; Secondo, Agnese; Tedeschi, Valentina; Esposito, Alba; Sisalli, MariaJosè; Scorziello, Antonella; Di Renzo, Gianfranco; Annunziato, Lucio

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe human adult-onset neurodegenerative disease affecting lower and upper motor neurons. In >20% of cases, the familial form of ALS is caused by mutations in the gene encoding Cu,Zn-superoxide dismutase (SOD1). Interestingly, administration of wild-type SOD1 to SOD1G93A transgenic rats ameliorates motor symptoms through an unknown mechanism. Here we investigated whether the neuroprotective effects of SOD1 are due to the Ca2+-dependent activation of such prosurvival signaling pathway and not to its catalytic activity. To this aim, we also examined the mechanism of neuroprotective action of ApoSOD1, the metal-depleted state of SOD1 that lacks dismutase activity, in differentiated motor neuron-like NSC-34 cells and in primary motor neurons exposed to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA). Preincubation of ApoSOD1 and SOD1, but not of human recombinant SOD1G93A, prevented cell death in motor neurons exposed to L-BMAA. Moreover, ApoSOD1 elicited ERK1/2 and Akt phosphorylation in motor neurons through an early increase of intracellular Ca2+ concentration ([Ca2+]i). Accordingly, inhibition of ERK1/2 by siMEK1 and PD98059 counteracted ApoSOD1- and SOD1-induced neuroprotection. Similarly, transfection of the dominant-negative form of Akt in NSC-34 motor neurons and treatment with the selective PI3K inhibitor LY294002 prevented ApoSOD1- and SOD1-mediated neuroprotective effects in L-BMAA-treated motor neurons. Furthermore, ApoSOD1 and SOD1 prevented the expression of the two markers of L-BMAA-induced ER stress GRP78 and caspase-12. Collectively, our data indicate that ApoSOD1, which is devoid of any catalytic dismutase activity, exerts a neuroprotective effect through an early activation of Ca2+/Akt/ERK1/2 pro-survival pathway that, in turn, prevents ER stress in a neurotoxic model of ALS. PMID:28085149

  11. Energy Model of Neuron Activation.

    PubMed

    Romanyshyn, Yuriy; Smerdov, Andriy; Petrytska, Svitlana

    2017-02-01

    On the basis of the neurophysiological strength-duration (amplitude-duration) curve of neuron activation (which relates the threshold amplitude of a rectangular current pulse of neuron activation to the pulse duration), as well as with the use of activation energy constraint (the threshold curve corresponds to the energy threshold of neuron activation by a rectangular current pulse), an energy model of neuron activation by a single current pulse has been constructed. The constructed model of activation, which determines its spectral properties, is a bandpass filter. Under the condition of minimum-phase feature of the neuron activation model, on the basis of Hilbert transform, the possibilities of phase-frequency response calculation from its amplitude-frequency response have been considered. Approximation to the amplitude-frequency response by the response of the Butterworth filter of the first order, as well as obtaining the pulse response corresponding to this approximation, give us the possibility of analyzing the efficiency of activating current pulses of various shapes, including analysis in accordance with the energy constraint.

  12. Neuronal factors determining high intelligence.

    PubMed

    Dicke, Ursula; Roth, Gerhard

    2016-01-05

    Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. With respect to mammals, a much-discussed trait concerns absolute and relative brain size, either uncorrected or corrected for body size. However, the correlation of both with degrees of intelligence yields large inconsistencies, because although they are regarded as the most intelligent mammals, monkeys and apes, including humans, have neither the absolutely nor the relatively largest brains. The best fit between brain traits and degrees of intelligence among mammals is reached by a combination of the number of cortical neurons, neuron packing density, interneuronal distance and axonal conduction velocity--factors that determine general information processing capacity (IPC), as reflected by general intelligence. The highest IPC is found in humans, followed by the great apes, Old World and New World monkeys. The IPC of cetaceans and elephants is much lower because of a thin cortex, low neuron packing density and low axonal conduction velocity. By contrast, corvid and psittacid birds have very small and densely packed pallial neurons and relatively many neurons, which, despite very small brain volumes, might explain their high intelligence. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner.

  13. Stochastic phase-change neurons

    NASA Astrophysics Data System (ADS)

    Tuma, Tomas; Pantazi, Angeliki; Le Gallo, Manuel; Sebastian, Abu; Eleftheriou, Evangelos

    2016-08-01

    Artificial neuromorphic systems based on populations of spiking neurons are an indispensable tool in understanding the human brain and in constructing neuromimetic computational systems. To reach areal and power efficiencies comparable to those seen in biological systems, electroionics-based and phase-change-based memristive devices have been explored as nanoscale counterparts of synapses. However, progress on scalable realizations of neurons has so far been limited. Here, we show that chalcogenide-based phase-change materials can be used to create an artificial neuron in which the membrane potential is represented by the phase configuration of the nanoscale phase-change device. By exploiting the physics of reversible amorphous-to-crystal phase transitions, we show that the temporal integration of postsynaptic potentials can be achieved on a nanosecond timescale. Moreover, we show that this is inherently stochastic because of the melt-quench-induced reconfiguration of the atomic structure occurring when the neuron is reset. We demonstrate the use of these phase-change neurons, and their populations, in the detection of temporal correlations in parallel data streams and in sub-Nyquist representation of high-bandwidth signals.

  14. Stochastic phase-change neurons.

    PubMed

    Tuma, Tomas; Pantazi, Angeliki; Le Gallo, Manuel; Sebastian, Abu; Eleftheriou, Evangelos

    2016-08-01

    Artificial neuromorphic systems based on populations of spiking neurons are an indispensable tool in understanding the human brain and in constructing neuromimetic computational systems. To reach areal and power efficiencies comparable to those seen in biological systems, electroionics-based and phase-change-based memristive devices have been explored as nanoscale counterparts of synapses. However, progress on scalable realizations of neurons has so far been limited. Here, we show that chalcogenide-based phase-change materials can be used to create an artificial neuron in which the membrane potential is represented by the phase configuration of the nanoscale phase-change device. By exploiting the physics of reversible amorphous-to-crystal phase transitions, we show that the temporal integration of postsynaptic potentials can be achieved on a nanosecond timescale. Moreover, we show that this is inherently stochastic because of the melt-quench-induced reconfiguration of the atomic structure occurring when the neuron is reset. We demonstrate the use of these phase-change neurons, and their populations, in the detection of temporal correlations in parallel data streams and in sub-Nyquist representation of high-bandwidth signals.

  15. Brain Neurons as Quantum Computers:

    NASA Astrophysics Data System (ADS)

    Bershadskii, A.; Dremencov, E.; Bershadskii, J.; Yadid, G.

    The question: whether quantum coherent states can sustain decoherence, heating and dissipation over time scales comparable to the dynamical timescales of brain neurons, has been actively discussed in the last years. A positive answer on this question is crucial, in particular, for consideration of brain neurons as quantum computers. This discussion was mainly based on theoretical arguments. In the present paper nonlinear statistical properties of the Ventral Tegmental Area (VTA) of genetically depressive limbic brain are studied in vivo on the Flinders Sensitive Line of rats (FSL). VTA plays a key role in the generation of pleasure and in the development of psychological drug addiction. We found that the FSL VTA (dopaminergic) neuron signals exhibit multifractal properties for interspike frequencies on the scales where healthy VTA dopaminergic neurons exhibit bursting activity. For high moments the observed multifractal (generalized dimensions) spectrum coincides with the generalized dimensions spectrum calculated for a spectral measure of a quantum system (so-called kicked Harper model, actively used as a model of quantum chaos). This observation can be considered as a first experimental (in vivo) indication in the favor of the quantum (at least partially) nature of brain neurons activity.

  16. Neuronal Mitophagy in Neurodegenerative Diseases

    PubMed Central

    Martinez-Vicente, Marta

    2017-01-01

    Neuronal homeostasis depends on the proper functioning of different quality control systems. All intracellular components are subjected to continuous turnover through the coordinated synthesis, degradation and recycling of their constituent elements. Autophagy is the catabolic mechanism by which intracellular cytosolic components, including proteins, organelles, aggregates and any other intracellular materials, are delivered to lysosomes for degradation. Among the different types of selective autophagy described to date, the process of mitophagy involves the selective autophagic degradation of mitochondria. In this way, mitophagy is responsible for basal mitochondrial turnover, but can also be induced under certain physiological or pathogenic conditions to eliminate unwanted or damaged mitochondria. Dysfunctional cellular proteolytic systems have been linked extensively to neurodegenerative diseases (ND) like Alzheimer’s disease (AD), Parkinson’s disease (PD), or Huntington’s disease (HD), with autophagic failure being one of the main factors contributing to neuronal cell death in these diseases. Neurons are particularly vulnerable to autophagic impairment as well as to mitochondrial dysfunction, due mostly to their particular high energy dependence and to their post-mitotic nature. The accurate and proper degradation of dysfunctional mitochondria by mitophagy is essential for maintaining control over mitochondrial quality and quantity in neurons. In this report, I will review the role of mitophagy in neuronal homeostasis and the consequences of its dysfunction in ND. PMID:28337125

  17. Neuronal factors determining high intelligence

    PubMed Central

    Dicke, Ursula; Roth, Gerhard

    2016-01-01

    Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. With respect to mammals, a much-discussed trait concerns absolute and relative brain size, either uncorrected or corrected for body size. However, the correlation of both with degrees of intelligence yields large inconsistencies, because although they are regarded as the most intelligent mammals, monkeys and apes, including humans, have neither the absolutely nor the relatively largest brains. The best fit between brain traits and degrees of intelligence among mammals is reached by a combination of the number of cortical neurons, neuron packing density, interneuronal distance and axonal conduction velocity—factors that determine general information processing capacity (IPC), as reflected by general intelligence. The highest IPC is found in humans, followed by the great apes, Old World and New World monkeys. The IPC of cetaceans and elephants is much lower because of a thin cortex, low neuron packing density and low axonal conduction velocity. By contrast, corvid and psittacid birds have very small and densely packed pallial neurons and relatively many neurons, which, despite very small brain volumes, might explain their high intelligence. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner. PMID:26598734

  18. Network synchronization in hippocampal neurons

    PubMed Central

    Penn, Yaron; Segal, Menahem; Moses, Elisha

    2016-01-01

    Oscillatory activity is widespread in dynamic neuronal networks. The main paradigm for the origin of periodicity consists of specialized pacemaking elements that synchronize and drive the rest of the network; however, other models exist. Here, we studied the spontaneous emergence of synchronized periodic bursting in a network of cultured dissociated neurons from rat hippocampus and cortex. Surprisingly, about 60% of all active neurons were self-sustained oscillators when disconnected, each with its own natural frequency. The individual neuron’s tendency to oscillate and the corresponding oscillation frequency are controlled by its excitability. The single neuron intrinsic oscillations were blocked by riluzole, and are thus dependent on persistent sodium leak currents. Upon a gradual retrieval of connectivity, the synchrony evolves: Loose synchrony appears already at weak connectivity, with the oscillators converging to one common oscillation frequency, yet shifted in phase across the population. Further strengthening of the connectivity causes a reduction in the mean phase shifts until zero-lag is achieved, manifested by synchronous periodic network bursts. Interestingly, the frequency of network bursting matches the average of the intrinsic frequencies. Overall, the network behaves like other universal systems, where order emerges spontaneously by entrainment of independent rhythmic units. Although simplified with respect to circuitry in the brain, our results attribute a basic functional role for intrinsic single neuron excitability mechanisms in driving the network’s activity and dynamics, contributing to our understanding of developing neural circuits. PMID:26961000

  19. The Bifurcating Neuron network 1.

    PubMed

    Lee, G; Farhat, N H

    2001-01-01

    The Bifurcating Neuron (BN), a chaotic integrate-and-fire neuron, is a model of a neuron augmented by coherent modulation from its environment. The BN is mathematically equivalent to the sine-circle map, and this equivalence relationship allowed us to apply the mathematics of one-dimensional maps to the design of BN networks. The study of symmetry in the BN revealed that the BN can be configured to exhibit bistability that is controlled by attractor-merging crisis. Also, the symmetry of the bistability can be controlled by the introduction of a sinusoidal fluctuation to the threshold level of the BN. These two observations led us to the design of the BN Network 1 (BNN-1), a chaotic pulse-coupled neural network exhibiting associative memory. In numerical simulations, the BNN-1 showed a better performance than the continuous-time Hopfield network, as far as the spurious-minima problem is concerned and exhibited many biologically plausible characteristics.

  20. Chimera states in bursting neurons

    NASA Astrophysics Data System (ADS)

    Bera, Bidesh K.; Ghosh, Dibakar; Lakshmanan, M.

    2016-01-01

    We study the existence of chimera states in pulse-coupled networks of bursting Hindmarsh-Rose neurons with nonlocal, global, and local (nearest neighbor) couplings. Through a linear stability analysis, we discuss the behavior of the stability function in the incoherent (i.e., disorder), coherent, chimera, and multichimera states. Surprisingly, we find that chimera and multichimera states occur even using local nearest neighbor interaction in a network of identical bursting neurons alone. This is in contrast with the existence of chimera states in populations of nonlocally or globally coupled oscillators. A chemical synaptic coupling function is used which plays a key role in the emergence of chimera states in bursting neurons. The existence of chimera, multichimera, coherent, and disordered states is confirmed by means of the recently introduced statistical measures and mean phase velocity.

  1. Towards a Neuronal Gauge Theory

    PubMed Central

    Sengupta, Biswa; Tozzi, Arturo; Cooray, Gerald K.; Douglas, Pamela K.; Friston, Karl J.

    2016-01-01

    Given the amount of knowledge and data accruing in the neurosciences, is it time to formulate a general principle for neuronal dynamics that holds at evolutionary, developmental, and perceptual timescales? In this paper, we propose that the brain (and other self-organised biological systems) can be characterised via the mathematical apparatus of a gauge theory. The picture that emerges from this approach suggests that any biological system (from a neuron to an organism) can be cast as resolving uncertainty about its external milieu, either by changing its internal states or its relationship to the environment. Using formal arguments, we show that a gauge theory for neuronal dynamics—based on approximate Bayesian inference—has the potential to shed new light on phenomena that have thus far eluded a formal description, such as attention and the link between action and perception. PMID:26953636

  2. Axon specification in hippocampal neurons.

    PubMed

    Fukata, Yuko; Kimura, Toshihide; Kaibuchi, Kozo

    2002-08-01

    Neurons are the most highly polarized cells, comprised of two structurally and functionally distinct parts, axons and dendrites. This asymmetry enables a vectorial flow of signaling within neurons. One of the most fundamental questions still to be answered in neuroscience is how these two specialized processes initially develop. The first manifestation of polarization occurs when one of the immature neurites acquires axonal characteristics. We review recent advances that have highlighted the involvement of several cellular events in the initial formation of the axon, including membrane traffic and cytoskeletal rearrangement. We then discuss the molecular mechanisms underlying axon formation, focusing on the Rho family small GTPases and an axon-inducing neuronal protein, CRMP-2.

  3. Copying and Evolution of Neuronal Topology

    PubMed Central

    Fernando, Chrisantha; Karishma, K. K.; Szathmáry, Eörs

    2008-01-01

    We propose a mechanism for copying of neuronal networks that is of considerable interest for neuroscience for it suggests a neuronal basis for causal inference, function copying, and natural selection within the human brain. To date, no model of neuronal topology copying exists. We present three increasingly sophisticated mechanisms to demonstrate how topographic map formation coupled with Spike-Time Dependent Plasticity (STDP) can copy neuronal topology motifs. Fidelity is improved by error correction and activity-reverberation limitation. The high-fidelity topology-copying operator is used to evolve neuronal topologies. Possible roles for neuronal natural selection are discussed. PMID:19020662

  4. Calcium signals in olfactory neurons.

    PubMed

    Tareilus, E; Noé, J; Breer, H

    1995-11-09

    Laser scanning confocal microscopy in combination with the fluorescent calcium indicators Fluo-3 and Fura-Red was employed to estimate the intracellular concentration of free calcium ions in individual olfactory receptor neurons and to monitor temporal and spatial changes in the Ca(2+)-level upon stimulation. The chemosensory cells responded to odorants with a significant increase in the calcium concentration, preferentially in the dendritic knob. Applying various stimulation paradigma, it was found that in a population of isolated cells, subsets of receptor neurons display distinct patterns of responsiveness.

  5. [What mirror neurons have revealed: revisited].

    PubMed

    Murata, Akira; Maeda, Kazutaka

    2014-06-01

    The first paper on mirror neurons was published in 1992. In the span of over two decades since then, much knowledge about the relationship between social cognitive function and the motor control system has been accumulated. Direct matching of visual actions and their corresponding motor representations is the most important functional property of mirror neuron. Many studies have emphasized intrinsic simulation as a core concept for mirror neurons. Mirror neurons are thought to play a role in social cognitive function. However, the function of mirror neurons in the macaque remains unclear, because such cognitive functions are limited or lacking in macaque monkeys. It is therefore important to discuss these neurons in the context of motor function. Rizzolatti and colleagues have stressed that the most important function of mirror neurons in macaques is recognition of actions performed by other individuals. I suggest that mirror neurons in the Macaque inferior pariental lobule might be correlated with body schema. In the parieto-premotor network, matching of corollary discharge and actual sensory feedback is an essential neuronal operation. Recently, neurons showing mirror properties were found in some cortical areas outside the mirror neuron system. The current work would revisit the outcomes of mirror neuron studies to discuss the function of mirror neurons in the monkey.

  6. Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons?

    PubMed Central

    Kim, Ji-il; Cho, Hye-Yeon; Han, Jin-Hee

    2016-01-01

    During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression. PMID:27122991

  7. Neuronal circuits of fear extinction.

    PubMed

    Herry, Cyril; Ferraguti, Francesco; Singewald, Nicolas; Letzkus, Johannes J; Ehrlich, Ingrid; Lüthi, Andreas

    2010-02-01

    Fear extinction is a form of inhibitory learning that allows for the adaptive control of conditioned fear responses. Although fear extinction is an active learning process that eventually leads to the formation of a consolidated extinction memory, it is a fragile behavioural state. Fear responses can recover spontaneously or subsequent to environmental influences, such as context changes or stress. Understanding the neuronal substrates of fear extinction is of tremendous clinical relevance, as extinction is the cornerstone of psychological therapy of several anxiety disorders and because the relapse of maladaptative fear and anxiety is a major clinical problem. Recent research has begun to shed light on the molecular and cellular processes underlying fear extinction. In particular, the acquisition, consolidation and expression of extinction memories are thought to be mediated by highly specific neuronal circuits embedded in a large-scale brain network including the amygdala, prefrontal cortex, hippocampus and brain stem. Moreover, recent findings indicate that the neuronal circuitry of extinction is developmentally regulated. Here, we review emerging concepts of the neuronal circuitry of fear extinction, and highlight novel findings suggesting that the fragile phenomenon of extinction can be converted into a permanent erasure of fear memories. Finally, we discuss how research on genetic animal models of impaired extinction can further our understanding of the molecular and genetic bases of human anxiety disorders.

  8. Neuronal Inhibition under the Spotlight.

    PubMed

    Mortensen, Martin; Smart, Trevor G

    2015-12-02

    In this issue of Neuron,Lin et al. (2015) report an optical method to precisely manipulate the activity of GABAA receptors by designing a mutant receptor that binds photosensitive compounds. This allows for studying GABAA receptors in situ and represents a valuable tool to investigate how inhibition affects brain physiology.

  9. Motor neurone disease: an overview.

    PubMed

    Kent, Anna

    Motor neurone disease (MND) is a relatively rare, progressive and incurable neurological condition affecting patients' speech, mobility and respiratory function. Care of patients with MND is complex and involves various healthcare professionals and services. There is a need to discuss symptom management and promote palliative and end of life care from the point of diagnosis to ensure appropriate holistic care is provided.

  10. Optimal compensation for neuron loss

    PubMed Central

    Barrett, David GT; Denève, Sophie; Machens, Christian K

    2016-01-01

    The brain has an impressive ability to withstand neural damage. Diseases that kill neurons can go unnoticed for years, and incomplete brain lesions or silencing of neurons often fail to produce any behavioral effect. How does the brain compensate for such damage, and what are the limits of this compensation? We propose that neural circuits instantly compensate for neuron loss, thereby preserving their function as much as possible. We show that this compensation can explain changes in tuning curves induced by neuron silencing across a variety of systems, including the primary visual cortex. We find that compensatory mechanisms can be implemented through the dynamics of networks with a tight balance of excitation and inhibition, without requiring synaptic plasticity. The limits of this compensatory mechanism are reached when excitation and inhibition become unbalanced, thereby demarcating a recovery boundary, where signal representation fails and where diseases may become symptomatic. DOI: http://dx.doi.org/10.7554/eLife.12454.001 PMID:27935480

  11. Bifurcating neuron: computation and learning.

    PubMed

    Lysetskiy, Mykola; Zurada, Jacek M

    2004-03-01

    The ability of bifurcating processing units and their networks to rapidly switch between different dynamic modes has been used in recent research efforts to model new computational properties of neural systems. In this spirit, we devise a bifurcating neuron based on control of chaos collapsing to a period-3 orbit in the dynamics of a quadratic logistic map (QLM). Proposed QLM3 neuron is constructed with the third iterate of QLM and uses an external input, which governs its dynamics. The input shifts the neuron's dynamics from chaos to one of the stable fixed points. This way the inputs from certain ranges (clusters) are mapped to stable fixed points, while the rest of the inputs is mapped to chaotic or periodic output dynamics. It has been shown that QLM3 neuron is able to learn a specific mapping by adaptively adjusting its bifurcation parameter, the idea of which is based on the principles of parametric control of logistic maps [Proceedings of the International Symposium on Nonlinear Theory and its Applications (NOLTA'97), Honolulu, HI, 1997; Proceedings of SPIE, 2000]. Learning algorithm for the bifurcation parameter is proposed, which employs the error gradient descent method.

  12. Biomechanics of Single Cortical Neurons

    PubMed Central

    Bernick, Kristin B.; Prevost, Thibault P.; Suresh, Subra; Socrate, Simona

    2011-01-01

    This study presents experimental results and computational analysis of the large strain dynamic behavior of single neurons in vitro with the objective of formulating a novel quantitative framework for the biomechanics of cortical neurons. Relying on the atomic force microscopy (AFM) technique, novel testing protocols are developed to enable the characterization of neural soma deformability over a range of indentation rates spanning three orders of magnitude – 10, 1, and 0.1 μm/s. Modified spherical AFM probes were utilized to compress the cell bodies of neonatal rat cortical neurons in load, unload, reload and relaxation conditions. The cell response showed marked hysteretic features, strong non-linearities, and substantial time/rate dependencies. The rheological data were complemented with geometrical measurements of cell body morphology, i.e. cross-diameter and height estimates. A constitutive model, validated by the present experiments, is proposed to quantify the mechanical behavior of cortical neurons. The model aimed to correlate empirical findings with measurable degrees of (hyper-) elastic resilience and viscosity at the cell level. The proposed formulation, predicated upon previous constitutive model developments undertaken at the cortical tissue level, was implemented into a three-dimensional finite element framework. The simulated cell response was calibrated to the experimental measurements under the selected test conditions, providing a novel single cell model that could form the basis for further refinements. PMID:20971217

  13. [The ontogeny of the mirror neuron system].

    PubMed

    Myowa-Yamakoshi, Masako

    2014-06-01

    Abstract Humans utilize the mirror neuron system to understand and predict others' actions. However, the ontogeny of the mirror neuron system remains unknown. Whether mirror neuron function is an innate trait or whether mirror neurons acquire their sensorimotor matching properties ontogenetically remains to be clarified. In this paper, I review the ontogenetic theory of the mirror neuron system. I then discuss the functioning of the mirror neuron system in the context of social cognitive abilities, which are unique to humans. Recently, some researchers argue that it is too early to interpret the function of mirror neurons as an understanding of the underlying psychological states of others. They imply that such functioning would require inferential cognitive processes that are known to involve areas outside the mirror neuron system. Filling in this missing link may be the key to elucidating the unique ability of humans to understand others' actions.

  14. Neuronal development: neighbors have to be different.

    PubMed

    Hummel, Thomas

    2007-12-18

    The assembly of neurons into functional circuits requires a multitude of cellular recognition events. Recent work on the hypervariable Drosophila Dscam gene revealed how a vast number of cell adhesion proteins contributes to neuronal patterning.

  15. Advances in applications of spiking neuron networks

    NASA Astrophysics Data System (ADS)

    Cios, Krzysztof J.; Sala, Dorel M.

    2000-03-01

    In this paper, we present new findings in constructing and applications of artificial neural networks that use a biologically inspired spiking neuron model. The used model is a point neuron with the interaction between neurons described by postsynaptic potentials. The synaptic plasticity is achieved by using a temporal correlation learning rule, specified as a function of time difference between the firings of pre- and post-synaptic neurons. Using this rule we show how certain associations between neurons in a network of spiking neurons can be implemented. As an example we analyze the dynamic properties of networks of laterally connected spiking neurons and we show their capability to self-organize into topological maps in response to external stimulation. In another application we explore the capability networks of spiking neurons to solve graph algorithms by using temporal coding of distances in a given spatial configuration. The paper underlines the importance of temporal dimension in artificial neural network information processing.

  16. Shape, connectedness and dynamics in neuronal networks.

    PubMed

    Comin, Cesar Henrique; da Fontoura Costa, Luciano

    2013-11-15

    The morphology of neurons is directly related to several aspects of the nervous system, including its connectedness, health, development, evolution, dynamics and, ultimately, behavior. Such interplays of the neuronal morphology can be understood within the more general shape-function paradigm. The current article reviews, in an introductory way, some key issues regarding the role of neuronal morphology in the nervous system, with emphasis on works developed in the authors' group. The following topics are addressed: (a) characterization of neuronal shape; (b) stochastic synthesis of neurons and neuronal systems; (c) characterization of the connectivity of neuronal networks by using complex networks concepts; and (d) investigations of influences of neuronal shape on network dynamics. The presented concepts and methods are useful also for several other multiple object systems, such as protein-protein interaction, tissues, aggregates and polymers.

  17. Network of hypothalamic neurons that control appetite.

    PubMed

    Sohn, Jong-Woo

    2015-04-01

    The central nervous system (CNS) controls food intake and energy expenditure via tight coordinations between multiple neuronal populations. Specifically, two distinct neuronal populations exist in the arcuate nucleus of hypothalamus (ARH): the anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC) neurons and the orexigenic (appetite-increasing) neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. The coordinated regulation of neuronal circuit involving these neurons is essential in properly maintaining energy balance, and any disturbance therein may result in hyperphagia/obesity or hypophagia/starvation. Thus, adequate knowledge of the POMC and NPY/AgRP neuron physiology is mandatory to understand the pathophysiology of obesity and related metabolic diseases. This review will discuss the history and recent updates on the POMC and NPY/AgRP neuronal circuits, as well as the general anorexigenic and orexigenic circuits in the CNS.

  18. Prospective Coding by Spiking Neurons

    PubMed Central

    Brea, Johanni; Gaál, Alexisz Tamás; Senn, Walter

    2016-01-01

    Animals learn to make predictions, such as associating the sound of a bell with upcoming feeding or predicting a movement that a motor command is eliciting. How predictions are realized on the neuronal level and what plasticity rule underlies their learning is not well understood. Here we propose a biologically plausible synaptic plasticity rule to learn predictions on a single neuron level on a timescale of seconds. The learning rule allows a spiking two-compartment neuron to match its current firing rate to its own expected future discounted firing rate. For instance, if an originally neutral event is repeatedly followed by an event that elevates the firing rate of a neuron, the originally neutral event will eventually also elevate the neuron’s firing rate. The plasticity rule is a form of spike timing dependent plasticity in which a presynaptic spike followed by a postsynaptic spike leads to potentiation. Even if the plasticity window has a width of 20 milliseconds, associations on the time scale of seconds can be learned. We illustrate prospective coding with three examples: learning to predict a time varying input, learning to predict the next stimulus in a delayed paired-associate task and learning with a recurrent network to reproduce a temporally compressed version of a sequence. We discuss the potential role of the learning mechanism in classical trace conditioning. In the special case that the signal to be predicted encodes reward, the neuron learns to predict the discounted future reward and learning is closely related to the temporal difference learning algorithm TD(λ). PMID:27341100

  19. Spiking neuron network Helmholtz machine

    PubMed Central

    Sountsov, Pavel; Miller, Paul

    2015-01-01

    An increasing amount of behavioral and neurophysiological data suggests that the brain performs optimal (or near-optimal) probabilistic inference and learning during perception and other tasks. Although many machine learning algorithms exist that perform inference and learning in an optimal way, the complete description of how one of those algorithms (or a novel algorithm) can be implemented in the brain is currently incomplete. There have been many proposed solutions that address how neurons can perform optimal inference but the question of how synaptic plasticity can implement optimal learning is rarely addressed. This paper aims to unify the two fields of probabilistic inference and synaptic plasticity by using a neuronal network of realistic model spiking neurons to implement a well-studied computational model called the Helmholtz Machine. The Helmholtz Machine is amenable to neural implementation as the algorithm it uses to learn its parameters, called the wake-sleep algorithm, uses a local delta learning rule. Our spiking-neuron network implements both the delta rule and a small example of a Helmholtz machine. This neuronal network can learn an internal model of continuous-valued training data sets without supervision. The network can also perform inference on the learned internal models. We show how various biophysical features of the neural implementation constrain the parameters of the wake-sleep algorithm, such as the duration of the wake and sleep phases of learning and the minimal sample duration. We examine the deviations from optimal performance and tie them to the properties of the synaptic plasticity rule. PMID:25954191

  20. Spiking neuron network Helmholtz machine.

    PubMed

    Sountsov, Pavel; Miller, Paul

    2015-01-01

    An increasing amount of behavioral and neurophysiological data suggests that the brain performs optimal (or near-optimal) probabilistic inference and learning during perception and other tasks. Although many machine learning algorithms exist that perform inference and learning in an optimal way, the complete description of how one of those algorithms (or a novel algorithm) can be implemented in the brain is currently incomplete. There have been many proposed solutions that address how neurons can perform optimal inference but the question of how synaptic plasticity can implement optimal learning is rarely addressed. This paper aims to unify the two fields of probabilistic inference and synaptic plasticity by using a neuronal network of realistic model spiking neurons to implement a well-studied computational model called the Helmholtz Machine. The Helmholtz Machine is amenable to neural implementation as the algorithm it uses to learn its parameters, called the wake-sleep algorithm, uses a local delta learning rule. Our spiking-neuron network implements both the delta rule and a small example of a Helmholtz machine. This neuronal network can learn an internal model of continuous-valued training data sets without supervision. The network can also perform inference on the learned internal models. We show how various biophysical features of the neural implementation constrain the parameters of the wake-sleep algorithm, such as the duration of the wake and sleep phases of learning and the minimal sample duration. We examine the deviations from optimal performance and tie them to the properties of the synaptic plasticity rule.

  1. BlastNeuron for Automated Comparison, Retrieval and Clustering of 3D Neuron Morphologies.

    PubMed

    Wan, Yinan; Long, Fuhui; Qu, Lei; Xiao, Hang; Hawrylycz, Michael; Myers, Eugene W; Peng, Hanchuan

    2015-10-01

    Characterizing the identity and types of neurons in the brain, as well as their associated function, requires a means of quantifying and comparing 3D neuron morphology. Presently, neuron comparison methods are based on statistics from neuronal morphology such as size and number of branches, which are not fully suitable for detecting local similarities and differences in the detailed structure. We developed BlastNeuron to compare neurons in terms of their global appearance, detailed arborization patterns, and topological similarity. BlastNeuron first compares and clusters 3D neuron reconstructions based on global morphology features and moment invariants, independent of their orientations, sizes, level of reconstruction and other variations. Subsequently, BlastNeuron performs local alignment between any pair of retrieved neurons via a tree-topology driven dynamic programming method. A 3D correspondence map can thus be generated at the resolution of single reconstruction nodes. We applied BlastNeuron to three datasets: (1) 10,000+ neuron reconstructions from a public morphology database, (2) 681 newly and manually reconstructed neurons, and (3) neurons reconstructions produced using several independent reconstruction methods. Our approach was able to accurately and efficiently retrieve morphologically and functionally similar neuron structures from large morphology database, identify the local common structures, and find clusters of neurons that share similarities in both morphology and molecular profiles.

  2. Neuronal communication: firing spikes with spikes.

    PubMed

    Brecht, Michael

    2012-08-21

    Spikes of single cortical neurons can exert powerful effects even though most cortical synapses are too weak to fire postsynaptic neurons. A recent study combining single-cell stimulation with population imaging has visualized in vivo postsynaptic firing in genetically identified target cells. The results confirm predictions from in vitro work and might help to understand how the brain reads single-neuron activity.

  3. Ecological constraints on the origin of neurones.

    PubMed

    Monk, Travis; Paulin, Michael G; Green, Peter

    2015-12-01

    The basic functional characteristics of spiking neurones are remarkably similar throughout the animal kingdom. Their core design and function features were presumably established very early in their evolutionary history. Identifying the selection pressures that drove animals to evolve spiking neurones could help us interpret their design and function today. This paper provides a quantitative argument, based on ecology, that animals evolved neurones after they started eating each other, about 550 million years ago. We consider neurones as devices that aid an animal's foraging performance, but incur an energetic cost. We introduce an idealised stochastic model ecosystem of animals and their food, and obtain an analytic expression for the probability that an animal with a neurone will fix in a neurone-less population. Analysis of the fixation probability reveals two key results. First, a neurone will never fix if an animal forages low-value food at high density, even if that neurone incurs no cost. Second, a neurone will fix with high probability if an animal is foraging high-value food at low density, even if that neurone is expensive. These observations indicate that the transition from neurone-less to neurone-armed animals can be facilitated by a transition from filter-feeding or substrate grazing to episodic feeding strategies such as animal-on-animal predation (macrophagy).

  4. Semaphorins as mediators of neuronal apoptosis.

    PubMed

    Shirvan, A; Ziv, I; Fleminger, G; Shina, R; He, Z; Brudo, I; Melamed, E; Barzilai, A

    1999-09-01

    Shrinkage and collapse of the neuritic network are often observed during the process of neuronal apoptosis. However, the molecular and biochemical basis for the axonal damage associated with neuronal cell death is still unclear. We present evidence for the involvement of axon guidance molecules with repulsive cues in neuronal cell death. Using the differential display approach, an up-regulation of collapsin response mediator protein was detected in sympathetic neurons undergoing dopamine-induced apoptosis. A synchronized induction of mRNA of the secreted collapsin-1 and the intracellular collapsin response mediator protein that preceded commitment of neurons to apoptosis was detected. Antibodies directed against a conserved collapsin-derived peptide provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. Moreover, neuronal apoptosis was inhibited by antibodies against neuropilin-1, a putative component of the semaphorin III/collapsin-1 receptor. Induction of neuronal apoptosis was also caused by exposure of neurons to semaphorin III-alkaline phosphatase secreted from 293EBNA cells. Anti-collapsin-1 antibodies were effective in blocking the semaphorin III-induced death process. We therefore suggest that, before their death, apoptosis-destined neurons may produce and secrete destructive axon guidance molecules that can affect their neighboring cells and thus transfer a "death signal" across specific and susceptible neuronal populations.

  5. Forward engineering neuronal diversity using direct reprogramming.

    PubMed

    Tsunemoto, Rachel K; Eade, Kevin T; Blanchard, Joel W; Baldwin, Kristin K

    2015-06-03

    The nervous system is comprised of a vast diversity of distinct neural cell types. Differences between neuronal subtypes drive the assembly of neuronal circuits and underlie the subtype specificity of many neurological diseases. Yet, because neurons are irreversibly post-mitotic and not readily available from patients, it has not been feasible to study specific subtypes of human neurons in larger numbers. A powerful means to study neuronal diversity and neurological disease is to establish methods to produce desired neuronal subtypes in vitro. Traditionally this has been accomplished by treating pluripotent or neural stem cells with growth factors and morphogens that recapitulate exogenous developmental signals. These approaches often require extended periods of culture, which can limit their utility. However, more recently, it has become possible to produce neurons directly from fibroblasts using transcription factors and/or microRNAs. This technique referred to as direct reprogramming or transdifferentiation has proven to be a rapid, robust, and reproducible method to generate mature neurons of many different subtypes from multiple cell sources. Here, we highlight recent advances in generating neurons of specific subtypes using direct reprogramming and outline various scenarios in which induced neurons may be applied to studies of neuronal function and neurological disease.

  6. Interactive Exploration for Continuously Expanding Neuron Databases.

    PubMed

    Li, Zhongyu; Metaxas, Dimitris N; Lu, Aidong; Zhang, Shaoting

    2017-02-15

    This paper proposes a novel framework to help biologists explore and analyze neurons based on retrieval of data from neuron morphological databases. In recent years, the continuously expanding neuron databases provide a rich source of information to associate neuronal morphologies with their functional properties. We design a coarse-to-fine framework for efficient and effective data retrieval from large-scale neuron databases. In the coarse-level, for efficiency in large-scale, we employ a binary coding method to compress morphological features into binary codes of tens of bits. Short binary codes allow for real-time similarity searching in Hamming space. Because the neuron databases are continuously expanding, it is inefficient to re-train the binary coding model from scratch when adding new neurons. To solve this problem, we extend binary coding with online updating schemes, which only considers the newly added neurons and update the model on-the-fly, without accessing the whole neuron databases. In the fine-grained level, we introduce domain experts/users in the framework, which can give relevance feedback for the binary coding based retrieval results. This interactive strategy can improve the retrieval performance through re-ranking the above coarse results, where we design a new similarity measure and take the feedback into account. Our framework is validated on more than 17,000 neuron cells, showing promising retrieval accuracy and efficiency. Moreover, we demonstrate its use case in assisting biologists to identify and explore unknown neurons.

  7. Stiff substrates enhance cultured neuronal network activity.

    PubMed

    Zhang, Quan-You; Zhang, Yan-Yan; Xie, Jing; Li, Chen-Xu; Chen, Wei-Yi; Liu, Bai-Lin; Wu, Xiao-an; Li, Shu-Na; Huo, Bo; Jiang, Lin-Hua; Zhao, Hu-Cheng

    2014-08-28

    The mechanical property of extracellular matrix and cell-supporting substrates is known to modulate neuronal growth, differentiation, extension and branching. Here we show that substrate stiffness is an important microenvironmental cue, to which mouse hippocampal neurons respond and integrate into synapse formation and transmission in cultured neuronal network. Hippocampal neurons were cultured on polydimethylsiloxane substrates fabricated to have similar surface properties but a 10-fold difference in Young's modulus. Voltage-gated Ca(2+) channel currents determined by patch-clamp recording were greater in neurons on stiff substrates than on soft substrates. Ca(2+) oscillations in cultured neuronal network monitored using time-lapse single cell imaging increased in both amplitude and frequency among neurons on stiff substrates. Consistently, synaptic connectivity recorded by paired recording was enhanced between neurons on stiff substrates. Furthermore, spontaneous excitatory postsynaptic activity became greater and more frequent in neurons on stiff substrates. Evoked excitatory transmitter release and excitatory postsynaptic currents also were heightened at synapses between neurons on stiff substrates. Taken together, our results provide compelling evidence to show that substrate stiffness is an important biophysical factor modulating synapse connectivity and transmission in cultured hippocampal neuronal network. Such information is useful in designing instructive scaffolds or supporting substrates for neural tissue engineering.

  8. Adult-onset cystic hygroma: A case report of rare entity

    PubMed Central

    Bahl, Sumit; Shah, Vandana; Anchlia, Sonal; Vyas, Siddharth

    2016-01-01

    Cystic hygroma is a benign congenital malformation of the lymphatic system that occurs in infant or children younger than 2 years of age. Although cystic hygroma is well recognized in pediatric practice, it seldom presents de novo in adulthood. These are commonly present in head and neck but can be present anywhere. Cystic hygroma is very rare in adults, but it should be considered in the differential diagnosis of adult neck swellings. Patients presenting with a painless, soft, fluctuant, and enlarging neck mass should have a careful history and physical examination along with radiological imaging to assist with diagnosis. Surgical intervention is the treatment of choice for this rare condition. Here, we are reporting a case of cystic hygroma in a 32-year-old male patient in the neck region. The objectives of this case report are to discuss the clinical presentation, diagnosis, histopathological findings and management of this malformation. PMID:27134456

  9. Is Chronic Stress During Childhood Associated with Adult-Onset Vulvodynia?

    PubMed Central

    Khandker, Maheruh; Brady, Sonya S.; Stewart, Elizabeth G.

    2014-01-01

    Abstract Background: Vulvodynia is an unexplained chronic vulvar pain condition. Case-control studies provide opportunities to examine potential mechanisms by which vulvodynia may develop. Findings inform etiological models that can be tested in subsequent prospective studies. Methods: A survey of interpersonal relationships and the Structured Clinical Interview for DSM-IV Axis I Disorders was administered to 215 case-control pairs of women with and without vulvodynia. Conditional logistic regression was used to examine associations between affect-based chronic stressors (i.e., living in fear of abuse, perceived abuse, and antecedent mood disorders) with vulvodynia. These associations were then examined among women with and without a history of childhood abuse. Results: Among women with a history of severe childhood abuse, those with vulvodynia had three times the odds of living in fear of any abuse compared to women without vulvodynia (95% confidence interval: 1.0, 11.0), after adjustment for childhood poverty. Among women with no history of childhood abuse, those with vulvodynia had over six times the odds of antecedent mood disorder compared to women without vulvodynia (95% confidence interval: 1.9,19.6). Conclusion: Our findings suggest that affect-based chronic stressors may be important to the psychobiological mechanisms of vulvodynia. Prospective studies are recommended to test biopsychosocial models of the etiology of vulvodynia. PMID:25046165

  10. Adult onset-hypothyroidism increases response latency and long-term potentiation (LTP) in rat hippocampus

    EPA Science Inventory

    Thyroid hormones (TH) influence central nervous system (CNS) function during both development and in adulthood. The hippocampus is critical for some types of learning and memory and is particularly sensitive to thyroid hormone deficiency. Hypothyroidism in adulthood has been ass...

  11. RNASEH1 Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy

    PubMed Central

    Reyes, Aurelio; Melchionda, Laura; Nasca, Alessia; Carrara, Franco; Lamantea, Eleonora; Zanolini, Alice; Lamperti, Costanza; Fang, Mingyan; Zhang, Jianguo; Ronchi, Dario; Bonato, Sara; Fagiolari, Gigliola; Moggio, Maurizio; Ghezzi, Daniele; Zeviani, Massimo

    2015-01-01

    Chronic progressive external ophthalmoplegia (CPEO) is common in mitochondrial disorders and is frequently associated with multiple mtDNA deletions. The onset is typically in adulthood, and affected subjects can also present with general muscle weakness. The underlying genetic defects comprise autosomal-dominant or recessive mutations in several nuclear genes, most of which play a role in mtDNA replication. Next-generation sequencing led to the identification of compound-heterozygous RNASEH1 mutations in two singleton subjects and a homozygous mutation in four siblings. RNASEH1, encoding ribonuclease H1 (RNase H1), is an endonuclease that is present in both the nucleus and mitochondria and digests the RNA component of RNA-DNA hybrids. Unlike mitochondria, the nucleus harbors a second ribonuclease (RNase H2). All affected individuals first presented with CPEO and exercise intolerance in their twenties, and these were followed by muscle weakness, dysphagia, and spino-cerebellar signs with impaired gait coordination, dysmetria, and dysarthria. Ragged-red and cytochrome c oxidase (COX)-negative fibers, together with impaired activity of various mitochondrial respiratory chain complexes, were observed in muscle biopsies of affected subjects. Western blot analysis showed the virtual absence of RNase H1 in total lysate from mutant fibroblasts. By an in vitro assay, we demonstrated that altered RNase H1 has a reduced capability to remove the RNA from RNA-DNA hybrids, confirming their pathogenic role. Given that an increasing amount of evidence indicates the presence of RNA primers during mtDNA replication, this result might also explain the accumulation of mtDNA deletions and underscores the importance of RNase H1 for mtDNA maintenance. PMID:26094573

  12. Adult-onset demyelinating neuropathy associated with FBLN5 gene mutation.

    PubMed

    Cheng, Si; Lv, He; Zhang, Wei; Wang, Zhaoxia; Shi, Xin; Liang, Wei; Yuan, Yun

    2017-03-23

    Rare forms of autosomal-dominant Charcot-Marie-Tooth disease (AD-CMT) may be associated with mutations in Fibulin-5 (FBLN5) as AD-CMT is genetically heterogeneous. Here, we report the first pathological study of an Asian family. The proband was a 46-year-old man with slowly progressive distal numbness and weakness for 12 years. He had a history of diabetes mellitus for 12 years. His mother was 81 years old and had mild polyneuropathy. His 16-year-old daughter was asymptomatic. The nerve conduction velocities (NCVs) and compound muscular action potential (CMAP) amplitudes were moderately to severely reduced in the proband, and moderately reduced in his daughter and mother. A sensory response could not be elicited in the proband and was moderately to severely decreased in the daughter and mother. Nerve ultrasound indicated a general enlargement of the peripheral nerves in the proband, daughter, and mother. A sural nerve biopsy from the proband demonstrated a pronounced depletion of myelinated fibers, thin myelinated fibers, and onion-bulb formations. A reported heterozygous mutation of c.1117C>T in FBLN5 was identified in the proband, mother, and daughter. These findings confirm a novel subtype of AD-CMT 1 due to a mutation in the FBLN5 gene.
.

  13. Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations.

    PubMed

    Depondt, Chantal; Donatello, Simona; Simonis, Nicolas; Rai, Myriam; van Heurck, Roxane; Abramowicz, Marc; D'Hooghe, Marc; Pandolfo, Massimo

    2014-05-13

    Autosomal recessive ataxias affect about 1 person in 20,000. Friedreich ataxia accounts for one-third of the cases in Caucasians; the others are due to a growing list of very rare molecular defects, including mild forms of metabolic diseases. In nearly 50%, the genetic cause remains undetermined.

  14. The clinical implications of adult-onset henoch-schonelin purpura

    PubMed Central

    2011-01-01

    Henoch-Schonlein Purpura (HSP) is a small vessel vasculitis mediated by IgA-immune complex deposition. It is characterized by the clinical tetrad of non-thrombocytopenic palpable purpura, abdominal pain, arthritis and renal involvement. Pathologically, it can be considered a form of immune complex-mediated leukocytoclastic vasculitis (LCV) involving the skin and other organs. Though it primarily affects children (over 90% of cases), the occurrence in adults has been rarely reported. Management often involves the use of immunomodulatory or immune-suppressive regimens. PMID:21619657

  15. Adult-onset cystic hygroma: A case report of rare entity.

    PubMed

    Bahl, Sumit; Shah, Vandana; Anchlia, Sonal; Vyas, Siddharth

    2016-01-01

    Cystic hygroma is a benign congenital malformation of the lymphatic system that occurs in infant or children younger than 2 years of age. Although cystic hygroma is well recognized in pediatric practice, it seldom presents de novo in adulthood. These are commonly present in head and neck but can be present anywhere. Cystic hygroma is very rare in adults, but it should be considered in the differential diagnosis of adult neck swellings. Patients presenting with a painless, soft, fluctuant, and enlarging neck mass should have a careful history and physical examination along with radiological imaging to assist with diagnosis. Surgical intervention is the treatment of choice for this rare condition. Here, we are reporting a case of cystic hygroma in a 32-year-old male patient in the neck region. The objectives of this case report are to discuss the clinical presentation, diagnosis, histopathological findings and management of this malformation.

  16. Adult-onset lymphoplasmacytic orchitis in a Labrador retriever stud dog.

    PubMed

    Davidson, Autumn P; von Dehn, Benita J; Schlafer, Donald H

    2015-03-01

    A formerly fertile 5-year-old 45-kg Labrador retriever was evaluated for azoospermia noted during routine semen collection for an artificial insemination. Over the past 3 years, the dog had sired 4 litters of anticipated size for the breed out of 5 breedings, the most recent a litter of 10 conceived and whelped 2 months previously. Physical examination findings were normal with the exception of bilaterally small and soft testes. An open excisional wedge biopsy of the right testis was performed under general anesthesia. Histopathology findings supported an immunologic, autoimmune pathogenesis that had resulted in infertility over the previous 4 months.

  17. Two clinicopathological cases of a dominantly inherited, adult onset orthochromatic leucodystrophy

    PubMed Central

    Letournel, F; Etcharry-Bouyx, F; Verny, C; Barthelaix, A; Dubas, F

    2003-01-01

    The first patient, aged 58 years, had frontal dementia and epilepsy; the second, aged 38 years, had motor signs and dementia, but no epilepsy. The histopathological features of our two cases were leucodystrophy of orthochromatic subtype. However, the radiological features (MRI and mostly FLAIR sequences) of the first case did not suggest leucodystrophy. PMID:12700318

  18. The first case of adult-onset PFAPA syndrome in Japan.

    PubMed

    Kutsuna, Satoshi; Ohmagari, Norio; Tanizaki, Ryutaro; Hagino, Noboru; Nishikomori, Ryuta; Ujiie, Mugen; Takeshita, Nozomi; Hayakawa, Kayoko; Kato, Yasuyuki; Kanagawa, Shuzo

    2016-01-01

    A 26-year-old woman presented with fever and pharyngitis. She previously experienced four periodic febrile episodes at 30- to 40-day intervals. We suspected periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, and prescribed predisolone, thereby her fever rapidly subsided. Her febrile episodes improved after daily cimetidine treatment. Genetic testing results of genomic DNA for periodic fever syndromes were negative, although she was heterozygous for p.Glu148Gln variation in MEFV, supporting the diagnosis of PFAPA syndrome.

  19. Prevalence of Mental Health Illness Among Patients with Adult-onset Strabismus

    PubMed Central

    Hassan, Mohamed Basil; Hodge, David O.

    2016-01-01

    Background Children diagnosed with some forms of strabismus were recently found to have an increased risk of developing mental illness by early adulthood. The purpose of this case-controlled study was to determine if adults with non-paralytic forms of strabismus are similarly at an elevated risk for developing mental illness. Methods The medical records of all patients diagnosed as adults (≥ 19 years of age) with convergence insufficiency (CI, n=118), divergence insufficiency (DI, n=80), and small angle hypertropia (HT, n=99) from January 1, 1985, through December 31, 2004, were retrospectively reviewed. Each case was compared with a sex- and birthdate-matched non-strabismic control. The medical records were reviewed for mental health diagnoses, including inpatient and outpatient encounters, psychiatric ER visits, and medication use. Results Mental health disorders were diagnosed in 65 (55.1%) patients with CI compared to 54 (45.8%) controls (p=0.15), in 51 (63.8%) patients with DI compared to 42 (52.5%) controls (p=0.15), and in 63 (63.6%) patients with HT compared to 57 (57.6%) controls (p=0.38). CI patients were not more likely to have mental health disorders than their controls (p=0.15). Mental health hospitalizations (p=0.02), psychiatric medication use (p=0.04), and unspecified anxiety disorders (p=0.03) were higher in DI patients compared to controls. HT patients were found to have more generalized anxiety disorders (p=0.003) than controls. Conclusions Adults with some forms of strabismus (DI and HT) appear to have an increased risk of mental illness and its comorbidities, compared to age- and gender-matched non-strabismic controls. PMID:26559866

  20. Fatal adult-onset antibody deficiency syndrome in a patient with cartilage hair hypoplasia.

    PubMed

    Horn, Julia; Schlesier, Michael; Warnatz, Klaus; Prasse, Antje; Superti-Furga, Andrea; Peter, Hans-Hartmut; Salzer, Ulrich

    2010-09-01

    Cartilage hair hypoplasia (CHH) is an autosomal recessive disorder caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene. Although its most constant feature is metaphyseal dysplasia with short stature, CHH is associated with extraskeletal defects such as thin hair, anemia, immunodeficiency, and increased incidence of lymphomas. The spectrum of immunologic phenotypes in CHH translates into clinical severity. Whereas T-cell deficiency may remain subclinical or may result in severe combined immunodeficiency or Omenn syndrome, humoral immunodeficiency has only rarely been noted in these patients. Here we report the diagnosis of CHH in a woman who presented with severe short stature and a full-blown antibody deficiency, clinically resembling common variable immunodeficiency. Sequencing of the RMRP gene revealed compound heterozygosity for two novel mutations (g.68_69delinsTT and g.76C>T). Despite the late onset of immunodeficiency in the patient, its clinical course was severe, and the patient died 3 years after the first diagnosis.

  1. Fever of unknown origin and leukemoid reaction as initial presentation of adult-onset Still's disease.

    PubMed

    Pardo-Cabello, Alfredo José; Manzano-Gamero, Victoria; Javier-Martínez, Rosario

    2014-01-01

    Adult Still's Disease has been reported as cause of Fever of Unknown Origin. Leukocytosis has been described as a common haematological abnormality in Adult Still's Disease. In some rare cases, leukemoid reaction has been reported associated to Still's Disease. We report the case of Adult Still's Disease presenting as Fever of Unknown Origin and leukemoid reaction in a patient with Down Syndrome. The patient needed high dosage of corticosteroids to control the disease and haematological findings.

  2. A Rare Case of Adult Onset Intussusception Complicated By Narcotic Dependence

    PubMed Central

    Khan, Saira J; Desmarais, Ashley M; Joseph, Bellal

    2017-01-01

    This report describes a rare case of adult intussusception in a patient with a history of a Roux-en-Y gastric bypass procedure; complicated by a history of narcotic abuse, methadone dependence, and methamphetamine abuse. Adult patients who have undergone a Roux-en-Y gastric bypass procedure may be at an increased risk of developing intussusception, and clinicians involved in their care should be aware of this potential complication. PMID:28191368

  3. Adult-onset Kaposiform hemangioendothelioma of the tongue: case report and review of the literature

    PubMed Central

    Vashi, P.; Abboud, E.; Bier-Laning, C.; Gupta, D.

    2016-01-01

    We present here a very rare clinical case of a 38-year-old man with Kaposiform hemangioendothelioma (khe) of the tongue who presented to our institution with a growth under the left side of the tongue with no pain or discomfort. There were no enlarged lymph nodes and no significant neurologic findings. Diagnostic histopathology confirmed the lesion to be khe. The tumour was removed surgically, and the surgical specimen confirmed the diagnosis. Follow-up at 3 months shows no clinical evidence of recurrence. PMID:27803613

  4. Molecular profiling of neurons based on connectivity.

    PubMed

    Ekstrand, Mats I; Nectow, Alexander R; Knight, Zachary A; Latcha, Kaamashri N; Pomeranz, Lisa E; Friedman, Jeffrey M

    2014-05-22

    The complexity and cellular heterogeneity of neural circuitry presents a major challenge to understanding the role of discrete neural populations in controlling behavior. While neuroanatomical methods enable high-resolution mapping of neural circuitry, these approaches do not allow systematic molecular profiling of neurons based on their connectivity. Here, we report the development of an approach for molecularly profiling projective neurons. We show that ribosomes can be tagged with a camelid nanobody raised against GFP and that this system can be engineered to selectively capture translating mRNAs from neurons retrogradely labeled with GFP. Using this system, we profiled neurons projecting to the nucleus accumbens. We then used an AAV to selectively profile midbrain dopamine neurons projecting to the nucleus accumbens. By comparing the captured mRNAs from each experiment, we identified a number of markers specific to VTA dopaminergic projection neurons. The current method provides a means for profiling neurons based on their projections.

  5. Calcium imaging in neuron cell death.

    PubMed

    Calvo, María; Villalobos, Carlos; Núñez, Lucía

    2015-01-01

    Intracellular Ca2+ is involved in control of a large variety of cell functions including apoptosis and neuron cell death. For example, intracellular Ca2+ overload is critical in neuron cell death induced by excitotoxicity. Thus, single cell monitoring of intracellular Ca2+ concentration ([Ca2+]cyt ) in neurons concurrently with apoptosis and neuron cell death is widely required. Procedures for culture and preparation of primary cultures of hippocampal rat neurons and fluorescence imaging of cytosolic Ca2+ concentration in Fura2/AM -loaded neurons are described. We also describe a method for apoptosis detection by immunofluorescence imaging. Finally, a simple method for concurrent measurements of [Ca2+]cyt and apoptosis in the same neurons is described.

  6. Using light to probe neuronal function

    NASA Astrophysics Data System (ADS)

    Daria, Vincent R.; Bachor, Hans-A.

    2015-08-01

    In the last few years a multi-disciplinary approach has been launched to investigate the brain using new techniques, which are capable of probing neuronal function across the entire length scales of the brain. Here, we discuss optical tools and spatial light patterning techniques to investigate brain function from the perspective of individual neurons and neuronal circuits. We discuss both biochemical and genetic tools to stimulate neurons, as well as techniques to record neuronal activity. We discuss optical projection and imaging tricks that can be dynamically customized to a particular neuron morphology and neuronal circuit layout facilitating a systematic study of their input/output transfer functions. These optical techniques will play a major role towards understanding the operation of a brain.

  7. Oscillatory integration windows in neurons

    PubMed Central

    Gupta, Nitin; Singh, Swikriti Saran; Stopfer, Mark

    2016-01-01

    Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking. PMID:27976720

  8. Oscillatory integration windows in neurons.

    PubMed

    Gupta, Nitin; Singh, Swikriti Saran; Stopfer, Mark

    2016-12-15

    Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking.

  9. Neuronal Analogues of Conditioning Paradigms

    DTIC Science & Technology

    1984-04-24

    Although the mechanisms of interneuronal communication have been well established, the changes underlying most forms of learning have thus far eluded...stimulating electrodes on one of the connectives was adjusted so as to produce a small excitatory postsynaptic potential ( EPSP ) in the impaled cell...two stimuli would constitute a neuronal analogue of conditioning by producing an increased EPSP in response to the test stimulus alone. If so, then

  10. Automated identification of neurons and their locations.

    PubMed

    Inglis, A; Cruz, L; Roe, D L; Stanley, H E; Rosene, D L; Urbanc, B

    2008-06-01

    Individual locations of many neuronal cell bodies (>10(4)) are needed to enable statistically significant measurements of spatial organization within the brain such as nearest-neighbour and microcolumnarity measurements. In this paper, we introduce an Automated Neuron Recognition Algorithm (ANRA) which obtains the (x, y) location of individual neurons within digitized images of Nissl-stained, 30 microm thick, frozen sections of the cerebral cortex of the Rhesus monkey. Identification of neurons within such Nissl-stained sections is inherently difficult due to the variability in neuron staining, the overlap of neurons, the presence of partial or damaged neurons at tissue surfaces, and the presence of non-neuron objects, such as glial cells, blood vessels, and random artefacts. To overcome these challenges and identify neurons, ANRA applies a combination of image segmentation and machine learning. The steps involve active contour segmentation to find outlines of potential neuron cell bodies followed by artificial neural network training using the segmentation properties (size, optical density, gyration, etc.) to distinguish between neuron and non-neuron segmentations. ANRA positively identifies 86 +/- 5% neurons with 15 +/- 8% error (mean +/- SD) on a wide range of Nissl-stained images, whereas semi-automatic methods obtain 80 +/- 7%/17 +/- 12%. A further advantage of ANRA is that it affords an unlimited increase in speed from semi-automatic methods, and is computationally efficient, with the ability to recognize approximately 100 neurons per minute using a standard personal computer. ANRA is amenable to analysis of huge photo-montages of Nissl-stained tissue, thereby opening the door to fast, efficient and quantitative analysis of vast stores of archival material that exist in laboratories and research collections around the world.

  11. Neuronal regulation of tendon homoeostasis.

    PubMed

    Ackermann, Paul W

    2013-08-01

    The regulation of tendon homoeostasis, including adaptation to loading, is still not fully understood. Accumulating data, however, demonstrates that in addition to afferent (sensory) functions, the nervous system, via efferent pathways which are associated with through specific neuronal mediators plays an active role in regulating pain, inflammation and tendon homeostasis. This neuronal regulation of intact-, healing- and tendinopathic tendons has been shown to be mediated by three major groups of molecules including opioid, autonomic and excitatory glutamatergic neuroregulators. In intact healthy tendons the neuromediators are found in the surrounding structures: paratenon, endotenon and epitenon, whereas the proper tendon itself is practically devoid of neurovascular supply. This neuroanatomy reflects that normal tendon homoeostasis is regulated from the tendon surroundings. After injury and during tendon repair, however, there is extensive nerve ingrowth into the tendon proper, followed by a time-dependent emergence of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and regulate tendon regeneration. In tendinopathic condition, excessive and protracted presence of sensory and glutamatergic neuromediators has been identified, suggesting involvement in inflammatory, nociceptive and hypertrophic (degenerative) tissue responses. Under experimental and clinical conditions of impaired (e.g. diabetes) as well as excessive (e.g. tendinopathy) neuromediator release, dysfunctional tendon homoeostasis develops resulting in chronic pain and gradual degeneration. Thus there is a prospect that in the future pharmacotherapy and tissue engineering approaches targeting neuronal mediators and their receptors may prove to be effective therapies for painful, degenerative and traumatic tendon disorders.

  12. Neuronal Responses to Physiological Stress

    PubMed Central

    Kagias, Konstantinos; Nehammer, Camilla; Pocock, Roger

    2012-01-01

    Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. It can be divided into three different aspects: environmental stress, intrinsic developmental stress, and aging. Throughout life all living organisms are challenged by changes in the environment. Fluctuations in oxygen levels, temperature, and redox state for example, trigger molecular events that enable an organism to adapt, survive, and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner chemistry during normal development. For example, conditions such as intrinsic hypoxia and oxidative stress, due to an increase in tissue mass, have to be confronted by developing embryos in order to complete their development. Finally, organisms face the challenge of stochastic accumulation of molecular damage during aging that results in decline and eventual death. Studies have shown that the nervous system plays a pivotal role in responding to stress. Neurons not only receive and process information from the environment but also actively respond to various stresses to promote survival. These responses include changes in the expression of molecules such as transcription factors and microRNAs that regulate stress resistance and adaptation. Moreover, both intrinsic and extrinsic stresses have a tremendous impact on neuronal development and maintenance with implications in many diseases. Here, we review the responses of neurons to various physiological stressors at the molecular and cellular level. PMID:23112806

  13. Neuronal regulation of tendon homoeostasis

    PubMed Central

    Ackermann, Paul W

    2013-01-01

    The regulation of tendon homoeostasis, including adaptation to loading, is still not fully understood. Accumulating data, however, demonstrates that in addition to afferent (sensory) functions, the nervous system, via efferent pathways which are associated with through specific neuronal mediators plays an active role in regulating pain, inflammation and tendon homeostasis. This neuronal regulation of intact-, healing- and tendinopathic tendons has been shown to be mediated by three major groups of molecules including opioid, autonomic and excitatory glutamatergic neuroregulators. In intact healthy tendons the neuromediators are found in the surrounding structures: paratenon, endotenon and epitenon, whereas the proper tendon itself is practically devoid of neurovascular supply. This neuroanatomy reflects that normal tendon homoeostasis is regulated from the tendon surroundings. After injury and during tendon repair, however, there is extensive nerve ingrowth into the tendon proper, followed by a time-dependent emergence of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and regulate tendon regeneration. In tendinopathic condition, excessive and protracted presence of sensory and glutamatergic neuromediators has been identified, suggesting involvement in inflammatory, nociceptive and hypertrophic (degenerative) tissue responses. Under experimental and clinical conditions of impaired (e.g. diabetes) as well as excessive (e.g. tendinopathy) neuromediator release, dysfunctional tendon homoeostasis develops resulting in chronic pain and gradual degeneration. Thus there is a prospect that in the future pharmacotherapy and tissue engineering approaches targeting neuronal mediators and their receptors may prove to be effective therapies for painful, degenerative and traumatic tendon disorders. PMID:23718724

  14. Results on a binding neuron model and their implications for modified hourglass model for neuronal network.

    PubMed

    Arunachalam, Viswanathan; Akhavan-Tabatabaei, Raha; Lopez, Cristina

    2013-01-01

    The classical models of single neuron like Hodgkin-Huxley point neuron or leaky integrate and fire neuron assume the influence of postsynaptic potentials to last till the neuron fires. Vidybida (2008) in a refreshing departure has proposed models for binding neurons in which the trace of an input is remembered only for a finite fixed period of time after which it is forgotten. The binding neurons conform to the behaviour of real neurons and are applicable in constructing fast recurrent networks for computer modeling. This paper develops explicitly several useful results for a binding neuron like the firing time distribution and other statistical characteristics. We also discuss the applicability of the developed results in constructing a modified hourglass network model in which there are interconnected neurons with excitatory as well as inhibitory inputs. Limited simulation results of the hourglass network are presented.

  15. Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia.

    PubMed

    Homma, Taku; Mochizuki, Yoko; Komori, Takashi; Isozaki, Eiji

    2016-10-01

    Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease, which is characterized clinically by parkinsonism, cerebellar ataxia and/or autonomic dysfunction, and pathologically by alpha-synuclein-related multisystem neurodegeneration, so-called alpha-synucleinopathy, which particularly involves the striatonigral and olivopontocerebellar systems, with glial cytoplasmic inclusions and neuronal cytoplasmic/nuclear inclusions (NCIs/NNIs). In the recent consensus criteria for the diagnosis of MSA, dementia is described as one of the features not supporting a diagnosis of MSA. However, MSA with dementia has been reported, although the location of the lesion responsible for the dementia remains unclear. In the present study, we aimed to investigate where this lesion may be found, by analyzing 12 autopsy-proven MSA cases, with a particular focus on the medial temporal region. Three of 12 cases with MSA had dementia (MSA-D). Compared with MSA cases without dementia, MSA-D cases had frequent globular NCIs (G-NCIs) in the medial temporal region, especially in their subiculum. In addition, MSA-D cases could be divided into two types; MSA-D with distinct fronto-temporal lobar degeneration (FTLD type) and without distinct fronto-temporal lobar degeneration (non-FTLD type). There was no association between dementia and Alzheimer pathologies, such as neurofibrillary tangles and senile plaques. We suggest that frequent G-NCIs in the medial temporal region, and particularly the subiculum, is one of the important pathological findings of MSA-D, even when a case with MSA-D reveals no significant cerebral atrophy.

  16. Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

    PubMed Central

    Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

    2016-01-01

    The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

  17. Optimization Methods for Spiking Neurons and Networks

    PubMed Central

    Russell, Alexander; Orchard, Garrick; Dong, Yi; Mihalaş, Ştefan; Niebur, Ernst; Tapson, Jonathan; Etienne-Cummings, Ralph

    2011-01-01

    Spiking neurons and spiking neural circuits are finding uses in a multitude of tasks such as robotic locomotion control, neuroprosthetics, visual sensory processing, and audition. The desired neural output is achieved through the use of complex neuron models, or by combining multiple simple neurons into a network. In either case, a means for configuring the neuron or neural circuit is required. Manual manipulation of parameters is both time consuming and non-intuitive due to the nonlinear relationship between parameters and the neuron’s output. The complexity rises even further as the neurons are networked and the systems often become mathematically intractable. In large circuits, the desired behavior and timing of action potential trains may be known but the timing of the individual action potentials is unknown and unimportant, whereas in single neuron systems the timing of individual action potentials is critical. In this paper, we automate the process of finding parameters. To configure a single neuron we derive a maximum likelihood method for configuring a neuron model, specifically the Mihalas–Niebur Neuron. Similarly, to configure neural circuits, we show how we use genetic algorithms (GAs) to configure parameters for a network of simple integrate and fire with adaptation neurons. The GA approach is demonstrated both in software simulation and hardware implementation on a reconfigurable custom very large scale integration chip. PMID:20959265

  18. Neurons containing hypocretin (orexin) project to multiple neuronal systems.

    PubMed

    Peyron, C; Tighe, D K; van den Pol, A N; de Lecea, L; Heller, H C; Sutcliffe, J G; Kilduff, T S

    1998-12-01

    The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep-waking cycle.

  19. Glutamatergic Nonpyramidal Neurons From Neocortical Layer VI and Their Comparison With Pyramidal and Spiny Stellate Neurons

    PubMed Central

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L.; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-01-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription–polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity. PMID:19052106

  20. Glutamatergic nonpyramidal neurons from neocortical layer VI and their comparison with pyramidal and spiny stellate neurons.

    PubMed

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-02-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription-polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity.

  1. Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro

    PubMed Central

    Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian

    2016-01-01

    For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467

  2. Selective Neuronal Vulnerability in Human Prion Diseases

    PubMed Central

    Guentchev, Marin; Wanschitz, Julia; Voigtländer, Till; Flicker, Helga; Budka, Herbert

    1999-01-01

    Human transmissible spongiform encephalopathies (TSEs) or prion diseases are neurodegenerative disorders of infectious, inherited or sporadic origin and include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), kuru and fatal familial insomnia (FFI). Clinicopathologic features of FFI differ markedly from other human TSEs. Previous studies demonstrated selective neuronal vulnerability of parvalbumin positive (PV+) GABAergic inhibitory interneurons in sporadic CJD and experimental TSEs. In this report we show uniform severe loss of PV+ neurons also in other TSEs such as GSS, kuru, new variant and familial CJD. In contrast, these neurons are mostly well preserved, or only moderately reduced, in FFI. Only PV+ neurons surrounded by isolectin-B4 positive perineuronal nets were severely affected in TSEs, suggesting a factor residing in this type of extracellular matrix around PV+ neurons as modulator for the selective neuronal vulnerability. PMID:10550300

  3. Morphological Neuron Classification Using Machine Learning.

    PubMed

    Vasques, Xavier; Vanel, Laurent; Villette, Guillaume; Cif, Laura

    2016-01-01

    Classification and quantitative characterization of neuronal morphologies from histological neuronal reconstruction is challenging since it is still unclear how to delineate a neuronal cell class and which are the best features to define them by. The morphological neuron characterization represents a primary source to address anatomical comparisons, morphometric analysis of cells, or brain modeling. The objectives of this paper are (i) to develop and integrate a pipeline that goes from morphological feature extraction to classification and (ii) to assess and compare the accuracy of machine learning algorithms to classify neuron morphologies. The algorithms were trained on 430 digitally reconstructed neurons subjectively classified into layers and/or m-types using young and/or adult development state population of the somatosensory cortex in rats. For supervised algorithms, linear discriminant analysis provided better classification results in comparison with others. For unsupervised algorithms, the affinity propagation and the Ward algorithms provided slightly better results.

  4. MRI of neuronal plasticity in rodent models.

    PubMed

    Pelled, Galit

    2011-01-01

    Modifications in the behavior and architecture of neuronal networks are well documented to occur in association with learning and memory, as well as following injury. These plasticity mechanisms are crucial to ensure adequate processing of stimuli, and they also dictate the degree of recovery following peripheral or central nervous system injury. Nevertheless, the underlying neuronal mechanisms that determine the degree of plasticity of neuronal pathways are not fully understood. Recent developments in animal-dedicated magnetic resonance imaging (MRI) scanners and related hardware afford a high spatial and temporal resolution, making functional MRI and manganese-enhanced MRI emerging tools for studying reorganization of neuronal pathways in rodent models. Many of the observed changes in neuronal functions in rodent's brains following injury discussed here agree with clinical human fMRI findings. This demonstrates that animal model imaging can have a significant clinical impact in the neuronal plasticity and rehabilitation arenas.

  5. Morphological Neuron Classification Using Machine Learning

    PubMed Central

    Vasques, Xavier; Vanel, Laurent; Villette, Guillaume; Cif, Laura

    2016-01-01

    Classification and quantitative characterization of neuronal morphologies from histological neuronal reconstruction is challenging since it is still unclear how to delineate a neuronal cell class and which are the best features to define them by. The morphological neuron characterization represents a primary source to address anatomical comparisons, morphometric analysis of cells, or brain modeling. The objectives of this paper are (i) to develop and integrate a pipeline that goes from morphological feature extraction to classification and (ii) to assess and compare the accuracy of machine learning algorithms to classify neuron morphologies. The algorithms were trained on 430 digitally reconstructed neurons subjectively classified into layers and/or m-types using young and/or adult development state population of the somatosensory cortex in rats. For supervised algorithms, linear discriminant analysis provided better classification results in comparison with others. For unsupervised algorithms, the affinity propagation and the Ward algorithms provided slightly better results. PMID:27847467

  6. Anisotropic path searching for automatic neuron reconstruction.

    PubMed

    Xie, Jun; Zhao, Ting; Lee, Tzumin; Myers, Eugene; Peng, Hanchuan

    2011-10-01

    Full reconstruction of neuron morphology is of fundamental interest for the analysis and understanding of their functioning. We have developed a novel method capable of automatically tracing neurons in three-dimensional microscopy data. In contrast to template-based methods, the proposed approach makes no assumptions about the shape or appearance of neurite structure. Instead, an efficient seeding approach is applied to capture complex neuronal structures and the tracing problem is solved by computing the optimal reconstruction with a weighted graph. The optimality is determined by the cost function designed for the path between each pair of seeds and by topological constraints defining the component interrelations and completeness. In addition, an automated neuron comparison method is introduced for performance evaluation and structure analysis. The proposed algorithm is computationally efficient and has been validated using different types of microscopy data sets including Drosophila's projection neurons and fly neurons with presynaptic sites. In all cases, the approach yielded promising results.

  7. A chimeric path to neuronal synchronization

    NASA Astrophysics Data System (ADS)

    Essaki Arumugam, Easwara Moorthy; Spano, Mark L.

    2015-01-01

    Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy is likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an "all or none" phenomenon, but can pass through an intermediate stage (chimera).

  8. A chimeric path to neuronal synchronization

    SciTech Connect

    Essaki Arumugam, Easwara Moorthy; Spano, Mark L.

    2015-01-15

    Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy is likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an “all or none” phenomenon, but can pass through an intermediate stage (chimera)

  9. A chimeric path to neuronal synchronization.

    PubMed

    Essaki Arumugam, Easwara Moorthy; Spano, Mark L

    2015-01-01

    Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy is likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an "all or none" phenomenon, but can pass through an intermediate stage (chimera).

  10. Nasal neuron PET imaging quantifies neuron generation and degeneration

    PubMed Central

    Van de Bittner, Genevieve C.; Riley, Misha M.; Cao, Luxiang; Herrick, Scott P.; Ricq, Emily L.; O’Neill, Michael J.; Ahmed, Zeshan; Murray, Tracey K.; Smith, Jaclyn E.; Wang, Changning; Schroeder, Frederick A.; Albers, Mark W.; Hooker, Jacob M.

    2017-01-01

    Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics. PMID:28112682

  11. Nasal neuron PET imaging quantifies neuron generation and degeneration.

    PubMed

    Van de Bittner, Genevieve C; Riley, Misha M; Cao, Luxiang; Ehses, Janina; Herrick, Scott P; Ricq, Emily L; Wey, Hsiao-Ying; O'Neill, Michael J; Ahmed, Zeshan; Murray, Tracey K; Smith, Jaclyn E; Wang, Changning; Schroeder, Frederick A; Albers, Mark W; Hooker, Jacob M

    2017-02-01

    Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics.

  12. Neuronal Networks on Nanocellulose Scaffolds.

    PubMed

    Jonsson, Malin; Brackmann, Christian; Puchades, Maja; Brattås, Karoline; Ewing, Andrew; Gatenholm, Paul; Enejder, Annika

    2015-11-01

    Proliferation, integration, and neurite extension of PC12 cells, a widely used culture model for cholinergic neurons, were studied in nanocellulose scaffolds biosynthesized by Gluconacetobacter xylinus to allow a three-dimensional (3D) extension of neurites better mimicking neuronal networks in tissue. The interaction with control scaffolds was compared with cationized nanocellulose (trimethyl ammonium betahydroxy propyl [TMAHP] cellulose) to investigate the impact of surface charges on the cell interaction mechanisms. Furthermore, coatings with extracellular matrix proteins (collagen, fibronectin, and laminin) were investigated to determine the importance of integrin-mediated cell attachment. Cell proliferation was evaluated by a cellular proliferation assay, while cell integration and neurite propagation were studied by simultaneous label-free Coherent anti-Stokes Raman Scattering and second harmonic generation microscopy, providing 3D images of PC12 cells and arrangement of nanocellulose fibrils, respectively. Cell attachment and proliferation were enhanced by TMAHP modification, but not by protein coating. Protein coating instead promoted active interaction between the cells and the scaffold, hence lateral cell migration and integration. Irrespective of surface modification, deepest cell integration measured was one to two cell layers, whereas neurites have a capacity to integrate deeper than the cell bodies in the scaffold due to their fine dimensions and amoeba-like migration pattern. Neurites with lengths of >50 μm were observed, successfully connecting individual cells and cell clusters. In conclusion, TMAHP-modified nanocellulose scaffolds promote initial cellular scaffold adhesion, which combined with additional cell-scaffold treatments enables further formation of 3D neuronal networks.

  13. Neuronal representation of object orientation.

    PubMed

    Karnath, H O; Ferber, S; Bülthoff, H H

    2000-01-01

    The dissociation between object identity and object orientation observed in six patients with brain damage, has been taken as evidence for a view-invariant model of object recognition. However, there was also some indication that these patients were not generally agnosic for object orientation but were able to gain access to at least some information about objects' canonical upright. We studied a new case (KB) with spared knowledge of object identity and impaired perception of object orientation using a forced choice paradigm to contrast directly the patient's ability to perceive objects' canonical upright vs non-upright orientations. We presented 2D-pictures of objects with unambiguous canonical upright orientations in four different orientations (0 degrees, -90 degrees, +90 degrees, 180 degrees ). KB showed no impairment in identifying letters, objects, animals, or faces irrespective of their given orientation. Also, her knowledge of upright orientation of stimuli was perfectly preserved. In sharp contrast, KB was not able to judge the orientation when the stimuli were presented in a non-upright orientation. The findings give further support for a distributed view-based representation of objects in which neurons become tuned to the features present in certain views of an object. Since we see more upright than inverted animals and familiar objects, the statistics of these images leads to a larger number of neurons tuned for objects in an upright orientation. We suppose that probably for this reason KB's knowledge of upright orientation was found to be more robust against neuronal damage than knowledge of other orientations.

  14. Performance limitations of relay neurons.

    PubMed

    Agarwal, Rahul; Sarma, Sridevi V

    2012-01-01

    Relay cells are prevalent throughout sensory systems and receive two types of inputs: driving and modulating. The driving input contains receptive field properties that must be transmitted while the modulating input alters the specifics of transmission. For example, the visual thalamus contains relay neurons that receive driving inputs from the retina that encode a visual image, and modulating inputs from reticular activating system and layer 6 of visual cortex that control what aspects of the image will be relayed back to visual cortex for perception. What gets relayed depends on several factors such as attentional demands and a subject's goals. In this paper, we analyze a biophysical based model of a relay cell and use systems theoretic tools to construct analytic bounds on how well the cell transmits a driving input as a function of the neuron's electrophysiological properties, the modulating input, and the driving signal parameters. We assume that the modulating input belongs to a class of sinusoidal signals and that the driving input is an irregular train of pulses with inter-pulse intervals obeying an exponential distribution. Our analysis applies to any [Formula: see text] order model as long as the neuron does not spike without a driving input pulse and exhibits a refractory period. Our bounds on relay reliability contain performance obtained through simulation of a second and third order model, and suggest, for instance, that if the frequency of the modulating input increases or the DC offset decreases, then relay increases. Our analysis also shows, for the first time, how the biophysical properties of the neuron (e.g. ion channel dynamics) define the oscillatory patterns needed in the modulating input for appropriately timed relay of sensory information. In our discussion, we describe how our bounds predict experimentally observed neural activity in the basal ganglia in (i) health, (ii) in Parkinson's disease (PD), and (iii) in PD during therapeutic deep

  15. Shockwaves Cause Synaptic Degeneration in Cultured Neurons

    DTIC Science & Technology

    2009-11-02

    constructed of delrin. A piezoresistive pressure sensor (Endevco Model 8530C) was mounted flush with the plate, coaxial with the center of the gene gun ...biolostic gene gun to deliver shockwaves to cultured hippocampal or cortical neurons. These cultured cells form abundant synapses in vitro, and after a 24-48...neurons, we used a biolostic gene gun to deliver shockwaves to cultured hippocampal or cortical neurons. These cultured cells form abundant synapses in

  16. The genealogy of genealogy of neurons

    PubMed Central

    Moroz, Leonid L

    2014-01-01

    Two scenarios of neuronal evolution (monophyly and polyphyly) are discussed in the historical timeline starting from the 19th century. The recent genomic studies on Ctenophores re-initiated a broad interest in the hypotheses of independent origins of neurons. However, even earlier work on ctenophores suggested that their nervous systems are unique in many aspects of their organization and a possibility of the independent origin of neurons and synapses was introduced well before modern advances in genomic biology. PMID:26478767

  17. High-Degree Neurons Feed Cortical Computations.

    PubMed

    Timme, Nicholas M; Ito, Shinya; Myroshnychenko, Maxym; Nigam, Sunny; Shimono, Masanori; Yeh, Fang-Chin; Hottowy, Pawel; Litke, Alan M; Beggs, John M

    2016-05-01

    Recent work has shown that functional connectivity among cortical neurons is highly varied, with a small percentage of neurons having many more connections than others. Also, recent theoretical developments now make it possible to quantify how neurons modify information from the connections they receive. Therefore, it is now possible to investigate how information modification, or computation, depends on the number of connections a neuron receives (in-degree) or sends out (out-degree). To do this, we recorded the simultaneous spiking activity of hundreds of neurons in cortico-hippocampal slice cultures using a high-density 512-electrode array. This preparation and recording method combination produced large numbers of neurons recorded at temporal and spatial resolutions that are not currently available in any in vivo recording system. We utilized transfer entropy (a well-established method for detecting linear and nonlinear interactions in time series) and the partial information decomposition (a powerful, recently developed tool for dissecting multivariate information processing into distinct parts) to quantify computation between neurons where information flows converged. We found that computations did not occur equally in all neurons throughout the networks. Surprisingly, neurons that computed large amounts of information tended to receive connections from high out-degree neurons. However, the in-degree of a neuron was not related to the amount of information it computed. To gain insight into these findings, we developed a simple feedforward network model. We found that a degree-modified Hebbian wiring rule best reproduced the pattern of computation and degree correlation results seen in the real data. Interestingly, this rule also maximized signal propagation in the presence of network-wide correlations, suggesting a mechanism by which cortex could deal with common random background input. These are the first results to show that the extent to which a neuron

  18. High-Degree Neurons Feed Cortical Computations

    PubMed Central

    Timme, Nicholas M.; Ito, Shinya; Shimono, Masanori; Yeh, Fang-Chin; Litke, Alan M.; Beggs, John M.

    2016-01-01

    Recent work has shown that functional connectivity among cortical neurons is highly varied, with a small percentage of neurons having many more connections than others. Also, recent theoretical developments now make it possible to quantify how neurons modify information from the connections they receive. Therefore, it is now possible to investigate how information modification, or computation, depends on the number of connections a neuron receives (in-degree) or sends out (out-degree). To do this, we recorded the simultaneous spiking activity of hundreds of neurons in cortico-hippocampal slice cultures using a high-density 512-electrode array. This preparation and recording method combination produced large numbers of neurons recorded at temporal and spatial resolutions that are not currently available in any in vivo recording system. We utilized transfer entropy (a well-established method for detecting linear and nonlinear interactions in time series) and the partial information decomposition (a powerful, recently developed tool for dissecting multivariate information processing into distinct parts) to quantify computation between neurons where information flows converged. We found that computations did not occur equally in all neurons throughout the networks. Surprisingly, neurons that computed large amounts of information tended to receive connections from high out-degree neurons. However, the in-degree of a neuron was not related to the amount of information it computed. To gain insight into these findings, we developed a simple feedforward network model. We found that a degree-modified Hebbian wiring rule best reproduced the pattern of computation and degree correlation results seen in the real data. Interestingly, this rule also maximized signal propagation in the presence of network-wide correlations, suggesting a mechanism by which cortex could deal with common random background input. These are the first results to show that the extent to which a neuron

  19. Boronate-tau mediated uptake in neurons.

    PubMed

    Pérez, Mar; Cuadros, Raquel; Pallas-Bazarra, Noemi; García, Carlos; Langa, Elena; Jurado-Arjona, Jerónimo; Hernández, Félix; Avila, Jesús

    2014-01-01

    We modified tau protein with boronic acid to facilitate its delivery into non neural or neural cultured cells lacking tau protein. Our results indicate that the incorporated tau promotes the formation of cytoplasmic extensions in non-neuronal cells, as well as the appearance of neurites in cultured tau knockout hippocampal neurons. In addition, boronated tau is incorporated into hippocampal neurons of tau knockout mice after intracranial injection in vivo. These findings describe a novel method to deliver exogenous tau protein into cells.

  20. Graded Synaptic Transmission between Spiking Neurons

    NASA Astrophysics Data System (ADS)

    Graubard, Katherine; Raper, Jonathan A.; Hartline, Daniel K.

    1980-06-01

    Graded synaptic transmission occurs between spiking neurons of the lobster stomatogastric ganglion. In addition to eliciting spike-evoked inhibitory potentials in postsynaptic cells, these neurons also release functionally significant amounts of transmitter below the threshold for action potentials. The spikeless postsynaptic potentials grade in amplitude with presynaptic voltage and can be maintained for long periods. Graded synaptic transmission can be modulated by synaptic input to the presynaptic neuron.

  1. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

    PubMed

    Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H Sophie; Wahis, Jérôme; da Silva Gouveia, Miriam; Tang, Yan; Ciobanu, Alexandru Cristian; Triana del Rio, Rodrigo; Roth, Lena C; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L; Mitre, Mariela; Froemke, Robert C; Chao, Moses V; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

    2016-03-16

    Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

  2. Macroscopic Description for Networks of Spiking Neurons

    NASA Astrophysics Data System (ADS)

    Montbrió, Ernest; Pazó, Diego; Roxin, Alex

    2015-04-01

    A major goal of neuroscience, statistical physics, and nonlinear dynamics is to understand how brain function arises from the collective dynamics of networks of spiking neurons. This challenge has been chiefly addressed through large-scale numerical simulations. Alternatively, researchers have formulated mean-field theories to gain insight into macroscopic states of large neuronal networks in terms of the collective firing activity of the neurons, or the firing rate. However, these theories have not succeeded in establishing an exact correspondence between the firing rate of the network and the underlying microscopic state of the spiking neurons. This has largely constrained the range of applicability of such macroscopic descriptions, particularly when trying to describe neuronal synchronization. Here, we provide the derivation of a set of exact macroscopic equations for a network of spiking neurons. Our results reveal that the spike generation mechanism of individual neurons introduces an effective coupling between two biophysically relevant macroscopic quantities, the firing rate and the mean membrane potential, which together govern the evolution of the neuronal network. The resulting equations exactly describe all possible macroscopic dynamical states of the network, including states of synchronous spiking activity. Finally, we show that the firing-rate description is related, via a conformal map, to a low-dimensional description in terms of the Kuramoto order parameter, called Ott-Antonsen theory. We anticipate that our results will be an important tool in investigating how large networks of spiking neurons self-organize in time to process and encode information in the brain.

  3. Spiking Neurons for Analysis of Patterns

    NASA Technical Reports Server (NTRS)

    Huntsberger, Terrance

    2008-01-01

    Artificial neural networks comprising spiking neurons of a novel type have been conceived as improved pattern-analysis and pattern-recognition computational systems. These neurons are represented by a mathematical model denoted the state-variable model (SVM), which among other things, exploits a computational parallelism inherent in spiking-neuron geometry. Networks of SVM neurons offer advantages of speed and computational efficiency, relative to traditional artificial neural networks. The SVM also overcomes some of the limitations of prior spiking-neuron models. There are numerous potential pattern-recognition, tracking, and data-reduction (data preprocessing) applications for these SVM neural networks on Earth and in exploration of remote planets. Spiking neurons imitate biological neurons more closely than do the neurons of traditional artificial neural networks. A spiking neuron includes a central cell body (soma) surrounded by a tree-like interconnection network (dendrites). Spiking neurons are so named because they generate trains of output pulses (spikes) in response to inputs received from sensors or from other neurons. They gain their speed advantage over traditional neural networks by using the timing of individual spikes for computation, whereas traditional artificial neurons use averages of activity levels over time. Moreover, spiking neurons use the delays inherent in dendritic processing in order to efficiently encode the information content of incoming signals. Because traditional artificial neurons fail to capture this encoding, they have less processing capability, and so it is necessary to use more gates when implementing traditional artificial neurons in electronic circuitry. Such higher-order functions as dynamic tasking are effected by use of pools (collections) of spiking neurons interconnected by spike-transmitting fibers. The SVM includes adaptive thresholds and submodels of transport of ions (in imitation of such transport in biological

  4. Stages of neuronal network formation

    NASA Astrophysics Data System (ADS)

    Woiterski, Lydia; Claudepierre, Thomas; Luxenhofer, Robert; Jordan, Rainer; Käs, Josef A.

    2013-02-01

    Graph theoretical approaches have become a powerful tool for investigating the architecture and dynamics of complex networks. The topology of network graphs revealed small-world properties for very different real systems among these neuronal networks. In this study, we observed the early development of mouse retinal ganglion cell (RGC) networks in vitro using time-lapse video microscopy. By means of a time-resolved graph theoretical analysis of the connectivity, shortest path length and the edge length, we were able to discover the different stages during the network formation. Starting from single cells, at the first stage neurons connected to each other ending up in a network with maximum complexity. In the further course, we observed a simplification of the network which manifested in a change of relevant network parameters such as the minimization of the path length. Moreover, we found that RGC networks self-organized as small-world networks at both stages; however, the optimization occurred only in the second stage.

  5. Essential roles of mitochondrial depolarization in neuron loss through microglial activation and attraction toward neurons.

    PubMed

    Nam, Min-Kyung; Shin, Hyun-Ah; Han, Ji-Hye; Park, Dae-Wook; Rhim, Hyangshuk

    2013-04-10

    As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron-microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease.

  6. Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses.

    PubMed

    Sudhakar, Shyam Kumar; Torben-Nielsen, Benjamin; De Schutter, Erik

    2015-12-01

    Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it.

  7. Electrophysiology of globus pallidus neurons in vitro.

    PubMed

    Nambu, A; Llinaś, R

    1994-09-01

    1. We investigated the electrical properties of globus pallidus neurons intracellularly using brain slices from adult guinea pigs. Three types of neurons were identified according to their intrinsic electrophysiological properties. 2. Type I neurons (59%) were silent at the resting membrane level (-65 +/- 10 mV, mean +/- SD) and generated a burst of spikes, with strong accommodation, to depolarizing current injection. Calcium-dependent low-frequency (1-8 Hz) membrane oscillations were often elicited by membrane depolarization (-53 +/- 8 mV). A low-threshold calcium conductance and an A-current were also identified. The mean input resistance of this neuronal type was 70 +/- 22 M omega. 3. Type II neurons (37%) fired spontaneously at the resting membrane level (-59 +/- 9 mV). Their repetitive firing (< or = 200 Hz) was very sensitive to the amplitude of injected current and showed weak accommodation. Sodium-dependent high-frequency (20-100 Hz) subthreshold membrane oscillations were often elicited by membrane depolarization. This neuronal type demonstrated a low-threshold calcium spike and had the highest input resistance (134 +/- 62 M omega) of the three neuron types. 4. Type III neurons (4%) did not fire spontaneously at the resting membrane level (-73 +/- 5 mV). Their action potentials were characterized by a long duration (2.3 +/- 0.6 ms). Repetitive firing elicited by depolarizing current injection showed weak or no accommodation. This neuronal type had an A-current and showed the lowest input resistance (52 +/- 35 M omega) of the three neuron types. 5. Stimulation of the caudoputamen evoked inhibitory postsynaptic potentials (IPSPs) in Type I and II neurons. In Type II neurons the IPSPs were usually followed by rebound firing. Excitatory postsynaptic potentials and antidromic responses were also elicited in some Type I and II neurons. The estimated conduction velocity of the striopallidal projection was < 1 m/s (Type I neurons, 0.49 +/- 0.37 m/s; Type II

  8. Morphometry of myenteric neurons in stomach.

    PubMed

    Saini, Narbada; Gupta, Madhur

    2007-06-01

    The wall of the gastrointestinal tract presents extensive plexuses of nerve fibres and neuronal cell bodies responsible for the modulation of the rhythmic gastrointestinal peristaltic activities, among other functions. One of the most developed ganglionated plexuses of the gastrointestinal tract is the Myenteric plexus located between the inner circular layer and outer longitudinal layer of the smooth muscle tunica. The musculature of fundus, body and pyloric parts of stomach are differently disposed and they perform different functions. Thus the present study was conducted to study the myenteric plexus of all parts of stomach by counting the number of collections of neurons, number of neurons in each collection, diameter and area of the neurons of the plexus. The stomach walls of 1 cm in size were taken from 5 cadavers of medical post mortem cases from Postgraduate Institute of Medical Sciences and Research, Chandigarh and were processed for paraffin sections. 5 and 10 micro thick sections were stained with haematoxylin and Eosin and examined under light microscope. Randomly selected sections were photomicrographed using digital camera and morphometrical analysis was done using Image-Pro Express software. Number of collections of neurons was maximum in fundus with an average of 4.521 and each collection on an average contain 5.27 neurons ranging from 1-31, while body had 3.292 collections containing 1-19 neurons (mean: 3.198), pylorus had 3.883 collections of neurons which contained 1-16 neurons (mean: 4.411). The neurons were classified as small, medium and large according to the size of the area of their cell bodies. In this way, 11.3% neurons were found to be small, 69.5% medium and 19.1% large in fundus, 8.7% small, 80.6% medium and 11.2% large in body and 11.1% small, 74.3% medium and 14.5% large in pylorus.

  9. Neuron Morphology Influences Axon Initial Segment Plasticity.

    PubMed

    Gulledge, Allan T; Bravo, Jaime J

    2016-01-01

    In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of voltage-gated sodium and potassium channels. It has recently been proposed that neurons use plasticity of AIS length and/or location to regulate their intrinsic excitability. Here we quantify the impact of neuron morphology on AIS plasticity using computational models of simplified and realistic somatodendritic morphologies. In small neurons (e.g., dentate granule neurons), excitability was highest when the AIS was of intermediate length and located adjacent to the soma. Conversely, neurons having larger dendritic trees (e.g., pyramidal neurons) were most excitable when the AIS was longer and/or located away from the soma. For any given somatodendritic morphology, increasing dendritic membrane capacitance and/or conductance favored a longer and more distally located AIS. Overall, changes to AIS length, with corresponding changes in total sodium conductance, were far more effective in regulating neuron excitability than were changes in AIS location, while dendritic capacitance had a larger impact on AIS performance than did dendritic conductance. The somatodendritic influence on AIS performance reflects modest soma-to-AIS voltage attenuation combined with neuron size-dependent changes in AIS input resistance, effective membrane time constant, and isolation from somatodendritic capacitance. We conclude that the impact of AIS plasticity on neuron excitability will depend largely on somatodendritic morphology, and that, in some neurons, a shorter or more distally located AIS may promote, rather than limit, action potential generation.

  10. Motor neurons and the generation of spinal motor neuron diversity

    PubMed Central

    Stifani, Nicolas

    2014-01-01

    Motor neurons (MNs) are neuronal cells located in the central nervous system (CNS) controlling a variety of downstream targets. This function infers the existence of MN subtypes matching the identity of the targets they innervate. To illustrate the mechanism involved in the generation of cellular diversity and the acquisition of specific identity, this review will focus on spinal MNs (SpMNs) that have been the core of significant work and discoveries during the last decades. SpMNs are responsible for the contraction of effector muscles in the periphery. Humans possess more than 500 different skeletal muscles capable to work in a precise time and space coordination to generate complex movements such as walking or grasping. To ensure such refined coordination, SpMNs must retain the identity of the muscle they innervate. Within the last two decades, scientists around the world have produced considerable efforts to elucidate several critical steps of SpMNs differentiation. During development, SpMNs emerge from dividing progenitor cells located in the medial portion of the ventral neural tube. MN identities are established by patterning cues working in cooperation with intrinsic sets of transcription factors. As the embryo develop, MNs further differentiate in a stepwise manner to form compact anatomical groups termed pools connecting to a unique muscle target. MN pools are not homogeneous and comprise subtypes according to the muscle fibers they innervate. This article aims to provide a global view of MN classification as well as an up-to-date review of the molecular mechanisms involved in the generation of SpMN diversity. Remaining conundrums will be discussed since a complete understanding of those mechanisms constitutes the foundation required for the elaboration of prospective MN regeneration therapies. PMID:25346659

  11. Heavy metals in locus ceruleus and motor neurons in motor neuron disease

    PubMed Central

    2013-01-01

    Background The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Results Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Conclusions Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons. PMID:24330485

  12. Local and commissural IC neurons make axosomatic inputs on large GABAergic tectothalamic neurons.

    PubMed

    Ito, Tetsufumi; Oliver, Douglas L

    2014-10-15

    Large GABAergic (LG) neurons are a distinct type of neuron in the inferior colliculus (IC) identified by their dense vesicular glutamate transporter 2 (VGLUT2)-containing axosomatic synaptic terminals. Yet the sources of these terminals are unknown. Since IC glutamatergic neurons express VGLUT2, and IC neurons are known to have local collaterals, we tested the hypothesis that these excitatory, glutamatergic axosomatic inputs on LG neurons come from local axonal collaterals and commissural IC neurons. We injected a recombinant viral tracer into the IC which enabled Golgi-like green fluorescent protein (GFP) labeling in both dendrites and axons. In all cases, we found terminals positive for both GFP and VGLUT2 (GFP+/VGLUT2+) that made axosomatic contacts on LG neurons. One to six axosomatic contacts were made on a single LG cell body by a single axonal branch. The GFP-labeled neurons giving rise to the VGLUT2+ terminals on LG neurons were close by. The density of GFP+/VGLUT2+ terminals on the LG neurons was related to the number of nearby GFP-labeled cells. On the contralateral side, a smaller number of LG neurons received axosomatic contacts from GFP+/VGLUT2+ terminals. In cases with a single GFP-labeled glutamatergic neuron, the labeled axonal plexus was flat, oriented in parallel to the fibrodendritic laminae, and contacted 9-30 LG cell bodies within the plexus. Our data demonstrated that within the IC microcircuitry there is a convergence of inputs from local IC excitatory neurons on LG cell bodies. This suggests that LG neurons are heavily influenced by the activity of the nearby laminar glutamatergic neurons in the IC.

  13. Dopaminergic Neurons and Brain Reward Pathways

    PubMed Central

    Luo, Sarah X.; Huang, Eric J.

    2017-01-01

    Midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive functions, including motivation, reward associations, and habit learning. Dysfunctions in DA neuron circuitry have been implicated in several neuropsychiatric disorders, including addiction and schizophrenia, whereas selective degeneration of DA neurons in substantia nigra pars compacta is a key neuropathological feature in Parkinson disease. Efforts to understand these disorders have focused on dissecting the underlying causes, as well as developing therapeutic strategies to replenish dopamine deficiency. In particular, the promise of cell replacement therapies for clinical intervention has led to extensive research in the identification of mechanisms involved in DA neuron development. It is hoped that a comprehensive understanding of these mechanisms will lead to therapeutic strategies that improve the efficiency of DA neuron production, engraftment, and function. This review provides a comprehensive discussion on how Wnt/β-catenin and sonic hedgehog–Smoothened signaling mechanisms control the specification and expansion of DA progenitors and the differentiation of DA neurons. We also discuss how mechanisms involving transforming growth factor-β and transcriptional cofactor homeodomain interacting protein kinase 2 regulate the survival and maturation of DA neurons in early postnatal life. These results not only reveal fundamental mechanisms regulating DA neuron development, but also provide important insights to their potential contributions to neuropsychiatric and neurodegenerative diseases. PMID:26724386

  14. Mirror neurons: functions, mechanisms and models.

    PubMed

    Oztop, Erhan; Kawato, Mitsuo; Arbib, Michael A

    2013-04-12

    Mirror neurons for manipulation fire both when the animal manipulates an object in a specific way and when it sees another animal (or the experimenter) perform an action that is more or less similar. Such neurons were originally found in macaque monkeys, in the ventral premotor cortex, area F5 and later also in the inferior parietal lobule. Recent neuroimaging data indicate that the adult human brain is endowed with a "mirror neuron system," putatively containing mirror neurons and other neurons, for matching the observation and execution of actions. Mirror neurons may serve action recognition in monkeys as well as humans, whereas their putative role in imitation and language may be realized in human but not in monkey. This article shows the important role of computational models in providing sufficient and causal explanations for the observed phenomena involving mirror systems and the learning processes which form them, and underlines the need for additional circuitry to lift up the monkey mirror neuron circuit to sustain the posited cognitive functions attributed to the human mirror neuron system.

  15. Optimization of Neuronal-Computer Interface

    DTIC Science & Technology

    2009-06-23

    directed against nonphosphorylated epitopes of neurofilaments as a general neuronal marker, and with a second antibody directed against the receptor ...for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) receptor subunit as a general marker of inhibitory neurons (Beck et al., 1993...immunofluorescent analyses for neurofilaments (anti-NF) using monoclonal antibody SMI-32 and a polyclonal antibody directed against the GABA receptor

  16. Calcium Phosphate Transfection of Primary Hippocampal Neurons

    PubMed Central

    DiBona, Victoria L.; Wu, Qian; Zhang, Huaye

    2013-01-01

    Calcium phosphate precipitation is a convenient and economical method for transfection of cultured cells. With optimization, it is possible to use this method on hard-to-transfect cells like primary neurons. Here we describe our detailed protocol for calcium phosphate transfection of hippocampal neurons cocultured with astroglial cells. PMID:24300106

  17. Adaptive Neurons For Artificial Neural Networks

    NASA Technical Reports Server (NTRS)

    Tawel, Raoul

    1990-01-01

    Training time decreases dramatically. In improved mathematical model of neural-network processor, temperature of neurons (in addition to connection strengths, also called weights, of synapses) varied during supervised-learning phase of operation according to mathematical formalism and not heuristic rule. Evidence that biological neural networks also process information at neuronal level.

  18. Targeting neurons and photons for optogenetics.

    PubMed

    Packer, Adam M; Roska, Botond; Häusser, Michael

    2013-07-01

    Optogenetic approaches promise to revolutionize neuroscience by using light to manipulate neural activity in genetically or functionally defined neurons with millisecond precision. Harnessing the full potential of optogenetic tools, however, requires light to be targeted to the right neurons at the right time. Here we discuss some barriers and potential solutions to this problem. We review methods for targeting the expression of light-activatable molecules to specific cell types, under genetic, viral or activity-dependent control. Next we explore new ways to target light to individual neurons to allow their precise activation and inactivation. These techniques provide a precision in the temporal and spatial activation of neurons that was not achievable in previous experiments. In combination with simultaneous recording and imaging techniques, these strategies will allow us to mimic the natural activity patterns of neurons in vivo, enabling previously impossible 'dream experiments'.

  19. Central auditory neurons have composite receptive fields

    PubMed Central

    Kozlov, Andrei S.; Gentner, Timothy Q.

    2016-01-01

    High-level neurons processing complex, behaviorally relevant signals are sensitive to conjunctions of features. Characterizing the receptive fields of such neurons is difficult with standard statistical tools, however, and the principles governing their organization remain poorly understood. Here, we demonstrate multiple distinct receptive-field features in individual high-level auditory neurons in a songbird, European starling, in response to natural vocal signals (songs). We then show that receptive fields with similar characteristics can be reproduced by an unsupervised neural network trained to represent starling songs with a single learning rule that enforces sparseness and divisive normalization. We conclude that central auditory neurons have composite receptive fields that can arise through a combination of sparseness and normalization in neural circuits. Our results, along with descriptions of random, discontinuous receptive fields in the central olfactory neurons in mammals and insects, suggest general principles of neural computation across sensory systems and animal classes. PMID:26787894

  20. Dendritic trafficking for neuronal growth and plasticity.

    PubMed

    Ehlers, Michael D

    2013-12-01

    Among the largest cells in the body, neurons possess an immense surface area and intricate geometry that poses many unique cell biological challenges. This morphological complexity is critical for neural circuit formation and enables neurons to compartmentalize cell-cell communication and local intracellular signalling to a degree that surpasses other cell types. The adaptive plastic properties of neurons, synapses and circuits have been classically studied by measurement of electrophysiological properties, ionic conductances and excitability. Over the last 15 years, the field of synaptic and neural electrophysiology has collided with neuronal cell biology to produce a more integrated understanding of how these remarkable highly differentiated cells utilize common eukaryotic cellular machinery to decode, integrate and propagate signals in the nervous system. The present article gives a very brief and personal overview of the organelles and trafficking machinery of neuronal dendrites and their role in dendritic and synaptic plasticity.

  1. Kisspeptin Excitation of GnRH Neurons

    PubMed Central

    Rønnekleiv, Oline K.; Kelly, Martin J.

    2014-01-01

    Kisspeptin binding to its cognate G protein-coupled receptor (GPR54, aka Kiss1R) in gonadotropin-releasing hormone (GnRH) neurons stimulates peptide release and activation of the reproductive axis in mammals. Kisspeptin has pronounced pre- and postsynaptic effects, with the latter dominating the excitability of GnRH neurons. Presynaptically, kisspeptin increases the excitatory drive (both GABA-A and glutamate) to GnRH neurons and postsynaptically, kisspeptin inhibits an A-type and inwardly rectifying K + (Kir 6.2 and GIRK) currents and activates nonselective cation (TRPC) currents to cause long-lasting depolarization and increased action potential firing. The signaling cascades and the multiple intracellular targets of kisspeptin actions in native GnRH neurons are continuing to be elucidated. This review summarizes our current state of knowledge about kisspeptin signaling in GnRH neurons. PMID:23550004

  2. [Impact of opiates on dopaminergic neurons].

    PubMed

    Kaufling, Jennifer; Freund-Mercier, Marie-José; Barrot, Michel

    2016-01-01

    Since the work of Johnson and North, it is known that opiates increase the activity of dopaminergic neurons by a GABA neuron-mediated desinhibition. This model should however be updated based on recent advances. Thus, the neuroanatomical location of the GABA neurons responsible for this desinhibition has been recently detailed: they belong to a brain structure in continuity with the posterior part of the ventral tegmental area and discovered this past decade. Other data also highlighted the critical role played by glutamatergic transmission in the opioid regulation of dopaminergic neuron activity. During protracted opiate withdrawal, the inhibitory/excitatory balance exerted on dopaminergic neurons is altered. These results are now leading to propose an original hypothesis for explaining the impact of protracted opiate withdrawal on mood.

  3. Mirror Neurons through the Lens of Epigenetics

    PubMed Central

    Ferrari, Pier F.; Tramacere, Antonella; Simpson, Elizabeth A.; Iriki, Atsushi

    2013-01-01

    The consensus view in mirror neuron research is that mirror neurons comprise a uniform, stable execution-observation matching system. In this article, we argue that, in light of recent evidence, this is, at best, an incomplete and oversimplified view of mirror neurons, whose activity is actually quite variable and more plastic than previously theorized. We propose an epigenetic account for understanding developmental changes in sensorimotor systems, including variations in mirror neuron activity. Although extant associative and genetic accounts fail to consider the complexity of genetic and non-genetic interactions, we propose a new Evo-Devo perspective, which predicts that environmental differences early in development, or through sensorimotor training, should produce variations in mirror neuron response patterns, tuning them to the social environment. PMID:23953747

  4. Attractor dynamics in local neuronal networks

    PubMed Central

    Thivierge, Jean-Philippe; Comas, Rosa; Longtin, André

    2014-01-01

    Patterns of synaptic connectivity in various regions of the brain are characterized by the presence of synaptic motifs, defined as unidirectional and bidirectional synaptic contacts that follow a particular configuration and link together small groups of neurons. Recent computational work proposes that a relay network (two populations communicating via a third, relay population of neurons) can generate precise patterns of neural synchronization. Here, we employ two distinct models of neuronal dynamics and show that simulated neural circuits designed in this way are caught in a global attractor of activity that prevents neurons from modulating their response on the basis of incoming stimuli. To circumvent the emergence of a fixed global attractor, we propose a mechanism of selective gain inhibition that promotes flexible responses to external stimuli. We suggest that local neuronal circuits may employ this mechanism to generate precise patterns of neural synchronization whose transient nature delimits the occurrence of a brief stimulus. PMID:24688457

  5. Pacemaking Property of RVLM Presympathetic Neurons

    PubMed Central

    Accorsi-Mendonça, Daniela; da Silva, Melina P.; Souza, George M. P. R.; Lima-Silveira, Ludmila; Karlen-Amarante, Marlusa; Amorim, Mateus R.; Almado, Carlos E. L.; Moraes, Davi J. A.; Machado, Benedito H.

    2016-01-01

    Despite several studies describing the electrophysiological properties of RVLM presympathetic neurons, there is no consensus in the literature about their pacemaking property, mainly due to different experimental approaches used for recordings of neuronal intrinsic properties. In this review we are presenting a historical retrospective about the pioneering studies and their controversies on the intrinsic electrophysiological property of auto-depolarization of these cells in conjunction with recent studies from our laboratory documenting that RVLM presympathetic neurons present pacemaking capacity. We also discuss whether increased sympathetic activity observed in animal models of neurogenic hypertension (CIH and SHR) are dependent on changes in the intrinsic electrophysiological properties of these cells or due to changes in modulatory inputs from neurons of the respiratory network. We also highlight the key role of INaP as the major current contributing to the pacemaking property of RVLM presympathetic neurons. PMID:27713705

  6. Automated Neuron Tracing Methods: An Updated Account.

    PubMed

    Acciai, Ludovica; Soda, Paolo; Iannello, Giulio

    2016-10-01

    The reconstruction of neuron morphology allows to investigate how the brain works, which is one of the foremost challenges in neuroscience. This process aims at extracting the neuronal structures from microscopic imaging data. The great advances in microscopic technologies have made a huge amount of data available at the micro-, or even lower, resolution where manual inspection is time consuming, prone to error and utterly impractical. This has motivated the development of methods to automatically trace the neuronal structures, a task also known as neuron tracing. This paper surveys the latest neuron tracing methods available in the scientific literature as well as a selection of significant older papers to better place these proposals into context. They are categorized into global processing, local processing and meta-algorithm approaches. Furthermore, we point out the algorithmic components used to design each method and we report information on the datasets and the performance metrics used.

  7. PRIMARY CULTURES OF DISSOCIATED SYMPATHETIC NEURONS

    PubMed Central

    Mains, Richard E.; Patterson, Paul H.

    1973-01-01

    Rat sympathetic ganglia were disrupted by mechanical agitation to yield dissociated primary neurons, and the conditions for long-term growth in culture of the isolated neurons were examined. The neurons were grown with or without non-neural cells, simply by the addition or deletion of bicarbonate during growth in culture. Fluorescence histochemistry indicated that the isolated neurons contained catecholamines; incubations with radioactive precursors were used to verify the synthesis and accumulation of both dopamine and norepinephrine. The neurons also produced octopamine using tyramine as precursor, but not with tyrosine as the precursor. In the presence of eserine, older cultures synthesized and stored small amounts of acetylcholine. The cultures did not synthesize and accumulate detectable levels of radioactive γ-aminobutyric acid, 5-hydroxytryptamine, or histamine. PMID:4616046

  8. Multidisciplinary Interventions in Motor Neuron Disease

    PubMed Central

    Williams, U. E.; Philip-Ephraim, E. E.; Oparah, S. K.

    2014-01-01

    Motor neuron disease is a neurodegenerative disease characterized by loss of upper motor neuron in the motor cortex and lower motor neurons in the brain stem and spinal cord. Death occurs 2–4 years after the onset of the disease. A complex interplay of cellular processes such as mitochondrial dysfunction, oxidative stress, excitotoxicity, and impaired axonal transport are proposed pathogenetic processes underlying neuronal cell loss. Currently evidence exists for the use of riluzole as a disease modifying drug; multidisciplinary team care approach to patient management; noninvasive ventilation for respiratory management; botulinum toxin B for sialorrhoea treatment; palliative care throughout the course of the disease; and Modafinil use for fatigue treatment. Further research is needed in management of dysphagia, bronchial secretion, pseudobulbar affect, spasticity, cramps, insomnia, cognitive impairment, and communication in motor neuron disease. PMID:26317009

  9. Interaction function of coupled bursting neurons

    NASA Astrophysics Data System (ADS)

    Xia, Shi; Jiadong, Zhang

    2016-06-01

    The interaction functions of electrically coupled Hindmarsh-Rose (HR) neurons for different firing patterns are investigated in this paper. By applying the phase reduction technique, the phase response curve (PRC) of the spiking neuron and burst phase response curve (BPRC) of the bursting neuron are derived. Then the interaction function of two coupled neurons can be calculated numerically according to the PRC (or BPRC) and the voltage time course of the neurons. Results show that the BPRC is more and more complicated with the increase of the spike number within a burst, and the curve of the interaction function oscillates more and more frequently with it. However, two certain things are unchanged: ϕ = 0, which corresponds to the in-phase synchronization state, is always the stable equilibrium, while the anti-phase synchronization state with ϕ = 0.5 is an unstable equilibrium. Project supported by the National Natural Science Foundation of China (Grant Nos. 11272065 and 11472061).

  10. Vestibular efferent neurons project to the flocculus

    NASA Technical Reports Server (NTRS)

    Shinder, M. E.; Purcell, I. M.; Kaufman, G. D.; Perachio, A. A.

    2001-01-01

    A bilateral projection from the vestibular efferent neurons, located dorsal to the genu of the facial nerve, to the cerebellar flocculus and ventral paraflocculus was demonstrated. Efferent neurons were double-labeled by the unilateral injections of separate retrograde tracers into the labyrinth and into the floccular and ventral parafloccular lobules. Efferent neurons were found with double retrograde tracer labeling both ipsilateral and contralateral to the sites of injection. No double labeling was found when using a fluorescent tracer with non-fluorescent tracers such as horseradish peroxidase (HRP) or biotinylated dextran amine (BDA), but large percentages of efferent neurons were found to be double labeled when using two fluorescent substances including: fluorogold, microruby dextran amine, or rhodamine labeled latex beads. These data suggest a potential role for vestibular efferent neurons in modulating the dynamics of the vestibulo-ocular reflex (VOR) during normal and adaptive conditions.

  11. An overview of the neuron ring model

    NASA Technical Reports Server (NTRS)

    Taber, Rod

    1991-01-01

    The Neuron Ring model employs an avalanche structure with two important distinctions at the neuron level. Each neuron has two memory latches; one traps maximum neuronal activation during pattern presentation, and the other records the time of latch content change. The latches filter short term memory. In the process, they preserve length 1 snapshots of activation theory history. The model finds utility in pattern classification. Its synaptic weights are first conditioned with sample spectra. The model then receives a test or unknown signal. The objective is to identify the sample closest to the test signal. Class decision follows complete presentation of the test data. The decision maker relies exclusively on the latch contents. Presented here is an overview of the Neuron Ring at the seminar level.

  12. Timing control by redundant inhibitory neuronal circuits

    SciTech Connect

    Tristan, I. Rulkov, N. F.; Huerta, R.; Rabinovich, M.

    2014-03-15

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model.

  13. Independent component analysis in spiking neurons.

    PubMed

    Savin, Cristina; Joshi, Prashant; Triesch, Jochen

    2010-04-22

    Although models based on independent component analysis (ICA) have been successful in explaining various properties of sensory coding in the cortex, it remains unclear how networks of spiking neurons using realistic plasticity rules can realize such computation. Here, we propose a biologically plausible mechanism for ICA-like learning with spiking neurons. Our model combines spike-timing dependent plasticity and synaptic scaling with an intrinsic plasticity rule that regulates neuronal excitability to maximize information transmission. We show that a stochastically spiking neuron learns one independent component for inputs encoded either as rates or using spike-spike correlations. Furthermore, different independent components can be recovered, when the activity of different neurons is decorrelated by adaptive lateral inhibition.

  14. Neuron Biomechanics Probed by Atomic Force Microscopy

    PubMed Central

    Spedden, Elise; Staii, Cristian

    2013-01-01

    Mechanical interactions play a key role in many processes associated with neuronal growth and development. Over the last few years there has been significant progress in our understanding of the role played by the substrate stiffness in neuronal growth, of the cell-substrate adhesion forces, of the generation of traction forces during axonal elongation, and of the relationships between the neuron soma elastic properties and its health. The particular capabilities of the Atomic Force Microscope (AFM), such as high spatial resolution, high degree of control over the magnitude and orientation of the applied forces, minimal sample damage, and the ability to image and interact with cells in physiologically relevant conditions make this technique particularly suitable for measuring mechanical properties of living neuronal cells. This article reviews recent advances on using the AFM for studying neuronal biomechanics, provides an overview about the state-of-the-art measurements, and suggests directions for future applications. PMID:23921683

  15. Effects of surface asymmetry on neuronal growth

    NASA Astrophysics Data System (ADS)

    Staii, Cristian

    Understanding the brain is of tremendous fundamental importance, but it is immensely challenging because of the complexity of both its architecture and function. A growing body of evidence shows that physical stimuli (stiffness of the growth substrate, gradients of various molecular species, geometry of the surrounding environment, traction forces etc.) play a key role in the wiring up of the nervous system. I will present a systematic experimental and theoretical investigation of neuronal growth on substrates with asymmetric geometries and textures. The experimental results show unidirectional axonal growth on these substrates. We demonstrate that the unidirectional bias is imparted by the surface ratchet geometry and quantify the geometrical guidance cues that control neuronal growth. Our results provide new insight into the role played by physical cues in neuronal growth, and could lead to new methods for stimulating neuronal regeneration and the engineering of artificial neuronal tissue. We acknowledge support from NSF through CBET 1067093.

  16. A single-neuron tracing study of arkypallidal and prototypic neurons in healthy rats.

    PubMed

    Fujiyama, Fumino; Nakano, Takashi; Matsuda, Wakoto; Furuta, Takahiro; Udagawa, Jun; Kaneko, Takeshi

    2016-12-01

    The external globus pallidus (GP) is known as a relay nucleus of the indirect pathway of the basal ganglia. Recent studies in dopamine-depleted and healthy rats indicate that the GP comprises two main types of pallidofugal neurons: the so-called "prototypic" and "arkypallidal" neurons. However, the reconstruction of complete arkypallidal neurons in healthy rats has not been reported. Here we visualized the entire axonal arborization of four single arkypallidal neurons and six single prototypic neurons in rat brain using labeling with a viral vector expressing membrane-targeted green fluorescent protein and examined the distribution of axon boutons in the target nuclei. Results revealed that not only the arkypallidal neurons but nearly all of the prototypic neurons projected to the striatum with numerous axon varicosities. Thus, the striatum is a major target nucleus for pallidal neurons. Arkypallidal and prototypic GP neurons located in the calbindin-positive and calbindin-negative regions mainly projected to the corresponding positive and negative regions in the striatum. Because the GP and striatum calbindin staining patterns reflect the topographic organization of the striatopallidal projection, the striatal neurons in the sensorimotor and associative regions constitute the reciprocal connection with the GP neurons in the corresponding regions.

  17. Neuron-derived IgG protects neurons from complement-dependent cytotoxicity.

    PubMed

    Zhang, Jie; Niu, Na; Li, Bingjie; McNutt, Michael A

    2013-12-01

    Passive immunity of the nervous system has traditionally been thought to be predominantly due to the blood-brain barrier. This concept must now be revisited based on the existence of neuron-derived IgG. The conventional concept is that IgG is produced solely by mature B lymphocytes, but it has now been found to be synthesized by murine and human neurons. However, the function of this endogenous IgG is poorly understood. In this study, we confirm IgG production by rat cortical neurons at the protein and mRNA levels, with 69.0 ± 5.8% of cortical neurons IgG-positive. Injury to primary-culture neurons was induced by complement leading to increases in IgG production. Blockage of neuron-derived IgG resulted in more neuronal death and early apoptosis in the presence of complement. In addition, FcγRI was found in microglia and astrocytes. Expression of FcγR I in microglia was increased by exposure to neuron-derived IgG. Release of NO from microglia triggered by complement was attenuated by neuron-derived IgG, and this attenuation could be reversed by IgG neutralization. These data demonstrate that neuron-derived IgG is protective of neurons against injury induced by complement and microglial activation. IgG appears to play an important role in maintaining the stability of the nervous system.

  18. Role of neuronal activity in regulating the structure and function of auditory neurons

    SciTech Connect

    Born, D.E.

    1986-01-01

    The role of afferent activity in maintaining neuronal structure and function was investigated in second order auditory neurons in nucleus magnocellularis (NM) of the chicken. The cochlea provides the major excitatory input to NM neurons via the eighth nerve. Removal of the cochlea causes dramatic changes in NM neurons. To determine if the elimination of neuronal activity is responsible for the changes in NM seen after cochlea removal, tetrodotoxin was used block action potentials in the cochlear ganglion cells. Tetrodotoxin injections into the perilymph reliably blocked neuronal activity in the cochlear nerve and NM. Far field recordings of sound-evoked potentials revealed that responses returned within 6 hours. Changes in amino acid incorporation in NM neurons were measured by giving intracardiac injections of /sup 3/H-leucine and preparing tissue for autoradiographic demonstration of incorporated amino acid. Grain counts over individual neurons revealed that a single injection of tetrodotoxin produced a 40% decrease in grain density in ipsilateral NM neurons. It is concluded that neuronal activity plays an important contribution to the maintenance of the normal properties of NM neurons.

  19. Active properties of neuronal dendrites.

    PubMed

    Johnston, D; Magee, J C; Colbert, C M; Cristie, B R

    1996-01-01

    Dendrites of neurons in the central nervous system are the principal sites for excitatory synaptic input. Although little is known about their function, two disparate perspectives have arisen to describe the activity patterns inherent to these diverse tree-like structures. Dendrites are thus considered either passive or active in their role in integrating synaptic inputs. This review follows the history of dendritic research from before the turn of the century to the present, with a primary focus on the hippocampus. A number of recent techniques, including high-speed fluorescence imaging and dendritic patch clamping, have provided new information and perspectives about the active properties of dendrites. The results support previous notions about the dendritic propagation of action potentials and also indicate which types of voltage-gated sodium and calcium channels are expressed and functionally active in dendrites. Possible roles for the active properties of dendrites in synaptic plasticity and integration are also discussed.

  20. Molecular chaperones and neuronal proteostasis

    PubMed Central

    Smith, Heather L.; Li, Wenwen; Cheetham, Michael E.

    2015-01-01

    Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms. PMID:25770416

  1. Quo vadis motor neuron disease?

    PubMed Central

    Balendra, Rubika; Patani, Rickie

    2016-01-01

    Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The aetio-pathogenesis of MND remains unresolved and no effective treatments exist. The only Food and Drug Administration approved disease modifying therapy is riluzole, a glutamate antagonist, which prolongs survival by up to 3 mo. Current management is largely symptomatic/supportive. There is therefore a desperate and unmet clinical need for discovery of disease mechanisms to guide novel therapeutic strategy. In this review, we start by introducing the organizational anatomy of the motor system, before providing a clinical overview of its dysfunction specifically in MND. We then summarize insights gained from pathological, genetic and animal models and conclude by speculating on optimal strategies to drive the step change in discovery, which is so desperately needed in this arena. PMID:27019797

  2. Parallel network simulations with NEURON.

    PubMed

    Migliore, M; Cannia, C; Lytton, W W; Markram, Henry; Hines, M L

    2006-10-01

    The NEURON simulation environment has been extended to support parallel network simulations. Each processor integrates the equations for its subnet over an interval equal to the minimum (interprocessor) presynaptic spike generation to postsynaptic spike delivery connection delay. The performance of three published network models with very different spike patterns exhibits superlinear speedup on Beowulf clusters and demonstrates that spike communication overhead is often less than the benefit of an increased fraction of the entire problem fitting into high speed cache. On the EPFL IBM Blue Gene, almost linear speedup was obtained up to 100 processors. Increasing one model from 500 to 40,000 realistic cells exhibited almost linear speedup on 2,000 processors, with an integration time of 9.8 seconds and communication time of 1.3 seconds. The potential for speed-ups of several orders of magnitude makes practical the running of large network simulations that could otherwise not be explored.

  3. Pathological Changes of von Economo Neuron and Fork Neuron in Neuropsychiatric Diseases.

    PubMed

    Liu, Jia; Wang, Lu-ning; Arzberger, Thomas; Zhu, Ming-wei

    2016-02-01

    von Economo neuron (VEN) is a bipolar neuron characterized by a large spindle-shaped soma. VEN is generally distributed in the layer V of anterior insular lobe and anterior cingulate cortex. Fork neuron is another featured bipolar neuron. In recent years,many studies have illustrated that VEN and fork neurons are correlated with complicated cognition such as self-consciousness and social emotion. Studies in the development and morpholigies of these two neurons as well as their pathological changes in various neurological and psychiatric disorders have found that the abnormal number and functions of VEN can cause corresponding dysfunctions in social recognition and emotions both during the neuro-developmental stages of childhood and during the nerve degeneration in old age stage. Therefore, more attentions should be paid on the research of VEN and fork neurons in neuropsychiatric diseases.

  4. Dynamical estimation of neuron and network properties III: network analysis using neuron spike times.

    PubMed

    Knowlton, Chris; Meliza, C Daniel; Margoliash, Daniel; Abarbanel, Henry D I

    2014-06-01

    Estimating the behavior of a network of neurons requires accurate models of the individual neurons along with accurate characterizations of the connections among them. Whereas for a single cell, measurements of the intracellular voltage are technically feasible and sufficient to characterize a useful model of its behavior, making sufficient numbers of simultaneous intracellular measurements to characterize even small networks is infeasible. This paper builds on prior work on single neurons to explore whether knowledge of the time of spiking of neurons in a network, once the nodes (neurons) have been characterized biophysically, can provide enough information to usefully constrain the functional architecture of the network: the existence of synaptic links among neurons and their strength. Using standardized voltage and synaptic gating variable waveforms associated with a spike, we demonstrate that the functional architecture of a small network of model neurons can be established.

  5. Orexinergic neurons and barbiturate anesthesia.

    PubMed

    Kushikata, T; Hirota, K; Yoshida, H; Kudo, M; Lambert, D G; Smart, D; Jerman, J C; Matsuki, A

    2003-01-01

    Orexins (OXs) regulate sleep with possible interactions with brain noradrenergic neurons. In addition, noradrenergic activity affects barbiturate anesthesia. As we have also recently reported that OXs selectively evoke norepinephrine release from rat cerebrocortical slices we hypothesized that barbiturate anesthesia may result from of an interaction with central orexinergic systems. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo, the effects of i.c.v. OX A, B and SB-334867-A (OX1 receptor antagonist) on pentobarbital, thiopental or phenobarbital-induced anesthesia times (loss of righting reflex) was assessed. In vitro effects of barbiturates and SB-334867-A on OX-evoked norepinephrine release from cerebrocortical slice was examined. In Chinese hamster ovary cells expressing human OX1/OX2 receptors OX A- and B-evoked increases in intracellular Ca2+ were measured with and without barbiturates. OX A and B significantly decreased pentobarbital, thiopental and phenobarbital anesthesia times by 15-40%. SB-334867-A increased thiopental-induced anesthesia time by approximately by 40%, and reversed the decrease produced by OX A. In vitro, all anesthetic barbiturates inhibited OX-evoked norepinephrine release with clinically relevant IC50 values. A GABAA antagonist, bicuculline, did not modify the inhibitory effects of thiopental and the GABAA agonist, muscimol, did not inhibit norepinephrine release. In addition there was no interaction of barbiturates with either OX1 or OX2 receptors. Collectively our data suggest that orexinergic neurons may be an important target for barbiturates, and GABAA, OX1 and OX2 receptors may not be involved in this interaction.

  6. Effect of cholecystokinin on experimental neuronal aging

    PubMed Central

    Sun, Xiao-Jiang; Lu, Qin-Chi; Cai, Yan

    2005-01-01

    AIM: To observe the effect of cholecystokinin (CCK) on lipofusin value, neuronal dendrite and spine ultrastructure, and total cellular protein during the process of experimental neuronal aging. METHODS: Experimental neuronal aging study model was established by NBA2 cellular serum-free culture method. By using single intracellular lipofusin value from microspectrophotometry, morphology of neuronal dendrites and spines from the scanner electron microscopy, and total cellular protein as the indexes of experimental neuronal aging, we observed the effect of CCK8 on the process of experimental neuronal aging. RESULTS: Under the condition of serum-free culture, intracellular fluorescence value (%) increased with the extension of culture time (1 d 8.51±3.43; 5 d 10.12±3.03; 10 d 20.54±10.3; 15 d 36.88±10.49; bP<0.01). When CCK was added to serum-free culture medium, intracellular lipofusin value (%) decreased remarkably after consecutive CCK reaction for 10 and 15 d (control 36.88±10.49; 5 d 32.03±10.01; 10 d 14.37±5.55; 15 d 17.31±4.80; bP<0.01). As the time of serum-free culturing was prolonged, the number of neuronal dendrite and spine cells decreased. The later increased in number when CCK8 was added. CCK8 could improve the total cellular protein in the process of experimental neuronal aging. CONCLUSION: CCK8 may prolong the process of experimental neuronal aging by maintaining the structure and the number of neuronal dendrite and spine cells and changing the total cellular protein. PMID:15641144

  7. Mirror neurons: from origin to function.

    PubMed

    Cook, Richard; Bird, Geoffrey; Catmur, Caroline; Press, Clare; Heyes, Cecilia

    2014-04-01

    This article argues that mirror neurons originate in sensorimotor associative learning and therefore a new approach is needed to investigate their functions. Mirror neurons were discovered about 20 years ago in the monkey brain, and there is now evidence that they are also present in the human brain. The intriguing feature of many mirror neurons is that they fire not only when the animal is performing an action, such as grasping an object using a power grip, but also when the animal passively observes a similar action performed by another agent. It is widely believed that mirror neurons are a genetic adaptation for action understanding; that they were designed by evolution to fulfill a specific socio-cognitive function. In contrast, we argue that mirror neurons are forged by domain-general processes of associative learning in the course of individual development, and, although they may have psychological functions, they do not necessarily have a specific evolutionary purpose or adaptive function. The evidence supporting this view shows that (1) mirror neurons do not consistently encode action "goals"; (2) the contingency- and context-sensitive nature of associative learning explains the full range of mirror neuron properties; (3) human infants receive enough sensorimotor experience to support associative learning of mirror neurons ("wealth of the stimulus"); and (4) mirror neurons can be changed in radical ways by sensorimotor training. The associative account implies that reliable information about the function of mirror neurons can be obtained only by research based on developmental history, system-level theory, and careful experimentation.

  8. Death of Neurons following Injury Requires Conductive Neuronal Gap Junction Channels but Not a Specific Connexin

    PubMed Central

    Fontes, Joseph D.; Ramsey, Jon; Polk, Jeremy M; Koop, Andre; Denisova, Janna V.; Belousov, Andrei B.

    2015-01-01

    Pharmacological blockade or genetic knockout of neuronal connexin 36 (Cx36)-containing gap junctions reduces neuronal death caused by ischemia, traumatic brain injury and NMDA receptor (NMDAR)-mediated excitotoxicity. However, whether Cx36 gap junctions contribute to neuronal death via channel-dependent or channel-independent mechanism remains an open question. To address this, we manipulated connexin protein expression via lentiviral transduction of mouse neuronal cortical cultures and analyzed neuronal death twenty-four hours following administration of NMDA (a model of NMDAR excitotoxicity) or oxygen-glucose deprivation (a model of ischemic injury). In cultures prepared from wild-type mice, over-expression and knockdown of Cx36-containing gap junctions augmented and prevented, respectively, neuronal death from NMDAR-mediated excitotoxicity and ischemia. In cultures obtained form from Cx36 knockout mice, re-expression of functional gap junction channels, containing either neuronal Cx36 or non-neuronal Cx43 or Cx31, resulted in increased neuronal death following insult. In contrast, the expression of communication-deficient gap junctions (containing mutated connexins) did not have this effect. Finally, the absence of ethidium bromide uptake in non-transduced wild-type neurons two hours following NMDAR excitotoxicity or ischemia suggested the absence of active endogenous hemichannels in those neurons. Taken together, these results suggest a role for neuronal gap junctions in cell death via a connexin type-independent mechanism that likely relies on channel activities of gap junctional complexes among neurons. A possible contribution of gap junction channel-permeable death signals in neuronal death is discussed. PMID:26017008

  9. Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting.

    PubMed

    Morozova, Ekaterina O; Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C; Kuznetsov, Alexey

    2016-10-01

    In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca(2+)) concentration, thus reducing the Ca(2+)-dependent potassium (K(+)) current. In this way, the GABA-mediated hyperpolarization replaces Ca(2+)-dependent K(+) current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally.

  10. Developmental history of the subplate zone, subplate neurons and interstitial white matter neurons: relevance for schizophrenia.

    PubMed

    Kostović, Ivica; Judaš, Miloš; Sedmak, Goran

    2011-05-01

    The subplate zone is a transient cytoarchitectonic compartment of the fetal telencephalic wall and contains a population of subplate neurons which are the main neurons of the fetal neocortex and play a key role in normal development of cerebral cortical structure and connectivity. While the subplate zone disappears during the perinatal and early postnatal period, numerous subplate neurons survive and remain embedded in the superficial (gyral) white matter of adolescent and adult brain as so-called interstitial neurons. In both fetal and adult brain, subplate/interstitial neurons belong to two major classes of cortical cells: (a) projection (glutamatergic) neurons and (b) local circuit (GABAergic) interneurons. As interstitial neurons remain strategically positioned at the cortical/white matter interface through which various cortical afferent systems enter the deep cortical layers, they probably serve as auxiliary interneurons involved in differential "gating" of cortical input systems. It is widely accepted that prenatal lesions which alter the number of surviving subplate neurons (i.e., the number of interstitial neurons) and/or the nature of their involvement in cortical circuitry represent an important causal factor in pathogenesis of at least some types of schizophrenia--e.g., in the subgroup of patients with cognitive impairment and deficits of frontal lobe functions. The abnormal functioning of cortical circuitry in schizophrenia becomes manifest during the adolescence, when there is an increased demand for proper functioning of the prefrontal cortex. In this review, we describe developmental history of subplate zone, subplate neurons and surviving interstitial neurons, as well as presumed consequences of the increased number of GABAergic interstitial neurons in the prefrontal cortex. We propose that the increased number of GABAergic interstitial neurons leads to the increased inhibition of prefrontal cortical neurons. This inhibitory action of GABAergic

  11. Taotie neurons regulate appetite in Drosophila

    PubMed Central

    Zhan, Yin Peng; Liu, Li; Zhu, Yan

    2016-01-01

    The brain has an essential role in maintaining a balance between energy intake and expenditure of the body. Deciphering the processes underlying the decision-making for timely feeding of appropriate amounts may improve our understanding of physiological and psychological disorders related to feeding control. Here, we identify a group of appetite-enhancing neurons in a behavioural screen for flies with increased appetite. Manipulating the activity of these neurons, which we name Taotie neurons, induces bidirectional changes in feeding motivation. Long-term stimulation of Taotie neurons results in flies with highly obese phenotypes. Furthermore, we show that the in vivo activity of Taotie neurons in the neuroendocrine region reflects the hunger/satiety states of un-manipulated animals, and that appetitive-enhancing Taotie neurons control the secretion of insulin, a known regulator of feeding behaviour. Thus, our study reveals a new set of neurons regulating feeding behaviour in the high brain regions that represents physiological hunger states and control feeding behaviour in Drosophila. PMID:27924813

  12. Imaging and Optically Manipulating Neuronal Ensembles.

    PubMed

    Carrillo-Reid, Luis; Yang, Weijian; Kang Miller, Jae-Eun; Peterka, Darcy S; Yuste, Rafael

    2017-03-15

    The neural code that relates the firing of neurons to the generation of behavior and mental states must be implemented by spatiotemporal patterns of activity across neuronal populations. These patterns engage selective groups of neurons, called neuronal ensembles, which are emergent building blocks of neural circuits. We review optical and computational methods, based on two-photon calcium imaging and two-photon optogenetics, to detect, characterize, and manipulate neuronal ensembles in three dimensions. We review data using these methods in the mammalian cortex that demonstrate the existe