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  1. Creutzfeldt-Jakob Disease

    MedlinePlus

    Creutzfeldt-Jakob disease (CJD) is a rare, degenerative brain disorder. Symptoms usually start around age 60. Memory problems, behavior changes, vision ... during a medical procedure Cattle can get a disease related to CJD called bovine spongiform encephalopathy (BSE) ...

  2. Creutzfeldt-Jakob disease.

    PubMed

    de Villemeur, Thierry Billette

    2013-01-01

    Prion diseases are rare in children. Three types are known: kuru, variant Creutzfeldt-Jakob disease (CJD), and iatrogenic CJD. All three affect children and young adults, and are transmitted by infectious contamination. Kuru was the result of ritual funeral practices similar to cannibalism; variant CJD affects young people who have eaten meat from cows with mad cow disease (mostly in the UK); and iatrogenic CJD is secondary to graft of human tissues performed in the 1980s (dura mater, pituitary extracted growth hormone). The disease appears after 4-30 years of incubation. The initial symptomatology is frequently neurological (cerebellar ataxia, oculomotor disturbance, peripheral nerve pain, pyramidal syndrome) followed by dementia. There is no biological test available that can give a definite diagnosis of prion disease apart from neuropathology, although prion accumulation in vCJD can be demonstrated in pharyngeal tonsil by immunohistochemical techniques. This devastating disease results inevitably in death. No specific treatment is available. PMID:23622328

  3. Creutzfeldt-Jakob disease.

    PubMed

    Gençer, Ali Görkem; Pelin, Zerrin; Küçükali, Cem İsmail; Topçuoğlu, Ozgür Bilgin; Yilmaz, Nuriye

    2011-06-01

    Creutzfeldt-Jakob disease (CJD) is a progressive, degenerative, and fatal disease of the central nervous system. It is caused by abnormal accumulation of prion proteins and is characterized mainly by progressive dementia, myoclonus, and cerebellar, pyramidal, and extrapyramidal findings. Psychiatric symptoms may also accompany CJD and are often the first signs of the disease. The incidence of CJD is approximately 1 in 1 000 000. In certain cases, a diagnosis can be made by demonstrating the accumulation of pathological prion proteins. However, in many cultures brain biopsies or post-mortem evaluations are not welcomed by either the patients or their relatives. In these cases, the importance of additional diagnostic tools increases. Herein, we report on a CJD patient who first consulted a psychiatrist with early psychiatric symptoms. The patient developed neurological symptoms later and was subsequently diagnosed as sporadic CJD based on clinical and laboratory findings rather than brain biopsy. Repeated electroencephalograms (EEG) played a pivotal role in our evaluation of the patient. This case is an interesting presentation of CJD both because of the timing of the symptoms and because of the typical EEG findings that led to the diagnosis. PMID:21707861

  4. Creutzfeldt-Jakob disease.

    PubMed

    Narayan, S K; Dutta, J K

    2005-09-01

    Cruetzfeldt-Jakob disease is a prion protein disease causing a transmissible, subacute, fatal neurodegenerative disease characterized by a spongiform encephalopathy. Though rare, ever since Pruisner described the pathogenesis in 1982, this disease kept the clinicians as well as biologists spellbound, because of its distinct clinical picture and the novel mechanism of transmission. There was a further quantum leap in the interest in the disease with the establishment of its new clinical variant, the so called 'mad cow disease' in the late 1990s and had led to more stringent measures to ensure the quality of cattle-feeds and cattle-derived food products. The sporadic genetic variants, the commonest form of the disease, continue to challenge the genetic scientists. Advances in neuroimaging, cerebrospinal fluid marker proteins and genetic linkage studies now offer excellent diagnostic methods, while advances in therapeutic medicine which use products from cadaveric extracts such as growth hormone for treatment of hypopituitarism, dural grafts for neurosurgical procedures and cornea for transplantation etc. have thrown new challenges in controlling this serious disease. PMID:16334625

  5. Creutzfeldt-Jakob disease

    MedlinePlus

    ... be the same one that causes vCJD in humans. Varient CJD causes less than 1% of all ... Scrapie (found in sheep) Other very rare inherited human diseases, such as Gerstmann-Straussler-Scheinker disease and ...

  6. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... the burden of neurological disease. The leading scientific theory at this time maintains that CJD is caused ... All NINDS-prepared information is in the public domain and may be freely copied. Credit to the ...

  7. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... acquired CJD. CJD belongs to a family of human and animal diseases known as the transmissible spongiform ... CJD is the most common of the known human TSEs. Other human TSEs include kuru, fatal familial ...

  8. Creutzfeldt-Jakob disease: implications for gastroenterology.

    PubMed

    Bramble, M G; Ironside, J W

    2002-06-01

    The current clinical views regarding variant Creutzfeldt-Jakob disease, and in particular transmission via endoscopy, of those representing both gastroenterology and the Spongiform Encephalopathy Advisory Committee are presented in an attempt to guide clinicians as to "best practice" given the current state of our knowledge. PMID:12010896

  9. CJD: Understanding Creutzfeldt-Jakob disease.

    PubMed

    Vacca, Vincent M

    2016-03-01

    Rare, transmissible, and rapidly progressive, Creutzfeldt-Jakob disease (CJD) is an ultimately fatal central nervous system infection caused by accumulation of abnormally shaped prion proteins in neurons (see Understanding prion proteins). Although categorized as an infection, CJD doesn't lead to the immune system or inflammatory response typical of most infectious diseases. This article discusses the pathophysiology and diagnosis of this terminal illness and nursing care for patients with suspected or confirmed CJD. PMID:26840797

  10. Variant Creutzfeldt-Jakob Disease (vCJD)

    MedlinePlus

    ... The CDC Cancel Submit Search The CDC Variant Creutzfeldt-Jakob Disease (vCJD) Note: Javascript is disabled or is not ... gov . Recommend on Facebook Tweet Share Compartir Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first ...

  11. Biomarkers for sporadic Creutzfeldt-Jakob disease.

    PubMed

    Soomro, Sanam; Mohan, Chandra

    2016-06-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare but fatal type of spongiform encephalopathy with unknown cause. Unfortunately, definitive diagnosis of this disease can only be done by examination of postmortem brain tissue. Presumptive diagnosis is done through a combination of clinical manifestations, radiology results, and cerebrospinal fluid (CSF) testing for CSF 14-3-3. Even with these guidelines, premortem diagnosis of sCJD can be unreliable with high rates of misdiagnosis. This calls for more reliable biomarkers of the disease, allowing for better diagnosis as well as understanding the pathogenesis of sCJD. This review compiles potential genetic, protein, biomolecular, and imaging biomarker studies for sCJD since 2010, highlighting the promise of proteins, cytokines, and composite biomarkers for improving the diagnosis as well as understanding the pathogenesis of this mysterious ailment. PMID:27547775

  12. Ocular Dipping in Creutzfeldt-Jakob Disease

    PubMed Central

    Llamas, Sara; Gonzalo, Juan Francisco; Sánchez Sánchez, Carmen

    2014-01-01

    Background Ocular dipping (OD), or inverse ocular bobbing, consists of slow, spontaneous downward eye movements with rapid return to the primary position. It has been mainly reported following hypoxic-ischemic encephalopathy, but has also been described in association with other types of diffuse or multifocal encephalopathies and structural brainstem damage. Case Report We report the case of a previously asymptomatic 66-year-old woman who presented with confusion, recent memory disturbances, and abnormal involuntary movements, followed by a coma. Abnormal spontaneous vertical eye movements consistent with OD developed from the fourth day after admission, and the patient died 20 days later. The pathological examination of the brain confirmed the diagnosis of Creutzfeldt-Jakob disease. Conclusions The precise location of damage causing OD is unknown. In contrast to ocular bobbing, OD has no localizing value itself, but structural brainstem damage is likely when it appears combined with other spontaneous vertical eye movements. PMID:24829603

  13. Creutzfeldt-Jakob disease in Austria.

    PubMed

    Hainfellner, J A; Jellinger, K; Diringer, H; Guentchev, M; Kleinert, R; Pilz, P; Maier, H; Budka, H

    1996-08-01

    Between 1969 and 30 September 1995, 79 Austrian patients had Creutzfeldt-Jakob disease (CJD) diagnosed neuropathologically by necropsy or biopsy. The annual incidence has significantly increased in recent years (average 0.18 per million in 1969-85, and 0.67 per million in 1986-94; estimate for 1995: 1.5 per million). Also, the percentage of patients with CJD over 70 years at death increased significantly until 1989 but is since in decline. There is no regional clustering, familial occurrence, or recognised iatrogenic risk. One patient had a 10 year history of intramuscular injection of purified bovine RNA preparation (Regeneresen) from various organs including the brian. The ages at death are symmetrically distributed around the median of 64 years. The median duration of disease is four months. Most patients (76%) died within six months of onset. Retrospectively, 86% of patients fulfilled clinical criteria of probable or possible CJD. Neuropathology showed the classic triad of spongiform change, astrogliosis, and neuronal loss in most cases. Two cases did not show unequivocal tissue alterations, but anti-PrP immunocytochemistry detected PrP deposits also in these cases. It is concluded that the recent rise in incidence of CJD in Austria most likely reflects increased awareness and diagnosis of CJD rather than a real increase. As bovine spongiform encephalopathy (BSE) has not been reported in Austria, the data do not support a link between a rise in incidence of sporadic CJD and BSE. PMID:8708680

  14. Rapid cognitive and functional decline: Creutzfeldt-Jakob disease.

    PubMed

    Dameron, Matthew

    2013-09-01

    The emergence of "mad cow disease" has sparked interest in prion diseases, including Creutzfeldt-Jakob disease, a spongiform encephalopathy that can mimic other rapidly progressive dementias. A systematic approach to evaluation and diagnostic testing can help rule out other causes. PMID:24317229

  15. Creutzfeldt-Jakob Disease Presenting as Progressive Aphasia

    PubMed Central

    Shuttleworth, Edwin C.; Yates, Allan J.; Paltan-Ortiz, Jose D.

    1985-01-01

    The syndrome of slowly progressive aphasia usually has been associated with Pick's disease, Alzheimer's disease, or an isolated focal degenerative disorder of unknown etiology involving the left perisylvian cortex. This report is of a patient with progressive aphasia due to Creutzfeldt-Jakob disease. ImagesFigure 1 PMID:3900429

  16. Deafness: an unusual onset of genetic Creutzfeldt-Jakob disease.

    PubMed

    Cataldi, M L; Restivo, O; Reggio, E; Restivo, D A; Reggio, A

    2000-02-01

    We describe a case of genetic Creutzfeldt-Jakob disease (CJD) with deafness at the onset. We report clinical features, 14-3-3 protein positivity, electroencephalography and brain stem auditory evoked potential abnormalities, and high signal on magnetic resonance imaging in basal ganglia and temporal cortex. Similarities with CJD Heidenhain variant are discussed. PMID:10938203

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

    PubMed

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

    2014-12-01

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

  18. Bitemporal hypometabolism in Creutzfeldt-Jakob disease measured by positron emission tomography with (/sup 18/F)-2-fluorodeoxyglucose

    SciTech Connect

    Friedland, R.P.; Prusiner, S.B.; Jagust, W.J.; Budinger, T.F.; Davis, R.L.

    1984-10-01

    It is well established that Creutzfeldt-Jakob disease (CJD) is caused by a slow infectious agent similar to the scrapie prion. However, the pathogenesis of this infection is poorly understood. Positron emission tomography (PET) was performed on a 54-year-old man with autopsy confirmed CJD using (18F)-2-fluorodeoxyglucose (FDG) and the Donner 280-crystal tomograph. Temporal lobe hypometabolism with hemispheric asymmetry was observed. These findings are similar to those previously obtained in PET-FDG studies of patients with clinically defined Alzheimer disease (AD). The similarities in the regional metabolic alterations between CJD and AD provide additional evidence for the possibility that AD may be caused by a slow infectious prion.

  19. Abnormal Eye Movements in Creutzfeldt-Jakob Disease

    NASA Technical Reports Server (NTRS)

    Grant, Michael P.; Cohen, Mark; Petersen, Robert B.; Halmagyi, G. Michael; McDougall, Alan; Tusa, Ronald J.; Leigh, R. John

    1993-01-01

    We report 3 patients with autopsy-proven Creutzfeldt-Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in one patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.

  20. A Heidenhain variant of Creutzfeldt-Jakob disease: forensic implication.

    PubMed

    Rizzo, M; Bruni, A; Barberio, C; Magro, G; Foncin, J F

    2004-12-01

    To investigate whether typical clinical, diagnostic and neuropathological findings can be identified in a patient with a postmortem diagnosis of a Heidenhain variant of Creutzfeldt-Jakob disease (CJD). We report a new case of CJD in a rare variant. A man admitted to hospital with cefalea and vision disorder. Clinical and neurological examination showed headache, vision reduction, psychomotor anxiety and progressive torpor. The patient died 4 h after admission to hospital. The autopsy findings included marked encephalic vascular congestion. Hystoneurology examination showed no macroscopic anomaly. Microscopy findings included neuronal loss, gliosis in striate area with arachnoid cells and cerebellum microspongiosis. Creutzfeldt-Jakob disease is a rare neurodegenerative human disorder. The prion hypothesis as an explanatory model is currently favoured by majority of researchers. A disease course described by Heidenhain including the leading symptoms of a visual disorder and rapid progression. This report emphasize the multidisciplinary role (forensic, neurogenetic and neurohistologic) for diagnosis and to standardize a protocol to investigate. PMID:15639587

  1. Creutzfeldt-Jakob Disease: A Case Report and Differential Diagnoses

    PubMed Central

    Tatsuno, Brent K; Inaba, Michiko; Velligas, Stephanie; Masaki, Kamal; Liow, Kore K

    2013-01-01

    Sporadic Creutzfeldt-Jakob disease is a rare neurodegenerative disorder of unknown etiology that causes rapidly progressive dementia. This disease is uniformly fatal and most patients die within 12 months. Clinical findings include myoclonus, visual disturbances, and cerebellar and pyramidal/extrapyramidal signs in addition to rapidly progressive cognitive and functional impairment. These findings are all non-specific and it is often difficult and challenging to diagnose premortem because of low awareness and clinical suspicion. We present a 66-year-old woman with a 5-month history of rapidly progressive dementia. After a series of extensive diagnostic examinations and continuous follow-up, she was diagnosed with probable sporadic Creutzfeldt-Jakob disease based on Centers for Disease Control and Prevention (CDC) criteria, with key findings of rapidly progressive dementia, blurry vision, extrapyramidal signs (cogwheel rigidity), and abnormal hyperintensity signals on diffusion-weighted MRI. Her symptoms progressively worsened and she died 7 months after the onset. The postmortem brain autopsy demonstrated the presence of abnormal protease-resistant prion protein by Western Blot analysis. A literature review was performed on differential diagnoses that present with rapidly progressive dementia and thereby mimic sporadic Creutzfeldt-Jakob disease. These include Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, meningoencephalitis, corticobasal degeneration, progressive supranuclear palsy, CADASIL, and paraneoplastic encephalomyelitis. PMID:23795314

  2. Bitemporal hypometabolism in Creutzfeldt-Jakob Disease measured by positron emission tomography with (F-18)2-fluorodeoxyglucose

    SciTech Connect

    Friedland, R.P.; Budinger, T.F.; Prusiner, S.B.; Jagust, W.J.

    1984-01-01

    It is well established that Creutzfeldt-Jakob Disease (CJD) is caused by a slow infectious agent similar to the scrapie prion. However, the pathogenesis of this infection is poorly understood. Positron emission tomography (PET) was performed on a 54 year old male subject with autopsy confirmed CJD using (F-18)2-fluorodeoxyglucose (FDG) and the Donner 280-crystal tomograph. An x-ray computed tomographic study of the brain performed 4 days prior to PET was normal. In the PET study the frontal to temporal cortex difference of activity densities was 30% on the left and 12% on the right, reflecting temporal hypometabolism. The left-right temporal cortex difference of activity density was 25%, documenting marked hemispheric asymmetry. These findings are similar to those previously obtained in PET-FDG studies of patients with clinically defined Alzheimer's Disease (AD) and are distinctly different from PET-FDG finding in patients with other dementing illnesses or in healthy aged subjects. Recent work has demonstrated extensive biological similarities between CJD, scrapie and AD. The similarities in the regional metabolic alterations between CJD and AD provide additional evidence for the hypothesis that AD is caused by a slow infectious (prion-like) pathogen.

  3. Evidence for case-to-case transmission of Creutzfeldt-Jakob disease

    PubMed Central

    Will, RG; Matthews, WB

    1982-01-01

    Three cases of probable iatrogenic transmission of Creutzfeldt-Jakob disease by neurosurgery are detailed together with a cluster of three cases in Eastern England possibly connected by dental procedures, and the development of Creutzfeldt-Jakob disease in a patient who had been in social contact with a familial case. PMID:7045290

  4. Standards for the assay of Creutzfeldt-Jakob disease specimens.

    PubMed

    Minor, P; Newham, J; Jones, N; Bergeron, C; Gregori, L; Asher, D; van Engelenburg, F; Stroebel, T; Vey, M; Barnard, G; Head, M

    2004-06-01

    Assays for the agent of Creutzfeldt-Jakob disease (CJD) include measurement of infectivity in different animal systems, such as wild-type or transgenic mice, and detection of PrP(Sc) by different methods and formats. The various assays could be best calibrated against each other by use of uniform readily available materials, and samples of four human brains, two from sporadic CJD patients, one from a variant CJD patient and one from a non-CJD patient, have been prepared as 10% homogenates dispensed in 2000 vials each for this purpose. Results of in vitro methods, particularly immunoblot assays, were compared in the first collaborative study described here. While dilution end-points varied, the minimum detectable volume was surprisingly uniform for most assays and differences in technical procedure, other than the sample volume tested, had no detectable systematic effect. The two specimens from sporadic CJD cases contained both type 1 and type 2 prion proteins in approximately equal proportions. The materials have been given the status of reference reagents by the World Health Organization and are available for further study and assessment of other in vitro or in vivo assay procedures. PMID:15166463

  5. Physical properties of the Creutzfeldt-Jakob disease agent

    SciTech Connect

    Sklaviadis, T.K.; Manuelidis, L.; Manuelidis, E.E.

    1989-03-01

    In this report, the authors present the first physical characterization of the Creutzfeld-Jakob disease agent. Preparations with high yields of infectivity (assayed infectious units) were obtained by a novel, gentle procedure in which initially sedimenting Gp34 (prion protein) was disaggregated by a variety of criteria with no subsequent loss of infectivity. Studies with this preparation indicate that most of the Creutzfeldt-Jakob disease agent has both a viruslike size and density. In velocity sedimentation and isopycnic sucrose gradients, infectivity comigrated with nucleic acid-protein complexes of appreciable size.

  6. From suspected Creutzfeldt-Jakob disease to confirmed histoplasma meningitis.

    PubMed

    Batra, Vivek; Khararjian, Armen; Wheat, Joseph; Zhang, Sean X; Crain, Barbara; Baras, Alexander

    2016-01-01

    A 77-year-old man with chronic obstructive lung disease who was on steroids, presented to the hospital after a fall with subacute headaches and ataxia. During the patient's hospital course, his clinical condition deteriorated with myoclonic jerks, fevers and severe encephalopathy. An extensive workup, including EEG, brain MRI and lumbar puncture, revealed possible Creutzfeldt-Jakob disease. Unfortunately, the patient failed to improve and died 12 days after admission. A brain-only autopsy revealed he had acute histoplasma meningitis with patchy superficial cerebritis. PMID:27389723

  7. Cortical restricted diffusion as the predominant MRI finding in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Talbott, Sabrina D; Plato, Brian M; Sattenberg, Ronald J; Parker, John; Heidenreich, Jens O

    2011-04-01

    Creutzfeldt-Jakob disease is a rare and fatal neurodegenerative disorder with MR findings predominantly limited to the grey matter of the cortex and the basal ganglia. Sporadic Creutzfeldt-Jakob disease can produce a spectrum of MR imaging findings of the brain, most notably on DWI and FLAIR sequences. Involvement of the basal ganglia and neocortex is the most common finding, but isolated involvement of the cortex can also be seen. We describe the clinical history and MRI findings of three patients with sporadic Creutzfeldt-Jakob disease confirmed by brain biopsy or autopsy and review the literature of imaging manifestations of this disease. PMID:21498372

  8. [Mad cow disease and the new variant of Creutzfeldt-Jakob disease].

    PubMed

    Pastoret, P P

    2001-08-01

    Bovine spongiform encephalopathy and the new variant of Creutzfeldt-Jakob disease (vCJD) belong to a family of similar diseases under the name of transmissible spongiform encephalopathies (TSE). It is demonstrated that the agent responsible for bovine spongiform encephalopathy (BSE) is also responsible for the new variant of Creutzfeldt-Jakob in man. This contribution describes the main characteristics of the two diseases. PMID:11584442

  9. [Creutzfeldt-Jakob disease: Report of one case].

    PubMed

    Ramírez, Marcos; Gallardo, Andrés; Vidal, Aarón; Cornejo, Sebastián; Ramírez, Darío; Medinas, Danilo; Bustamante, Gonzalo; Pasquali, Renzo; Hetz, Claudio

    2016-06-01

    Creutzfeldt-Jakob disease has a higher incidence in Chile than in other countries. The post mortem pathological characterization of brain tissue is necessary to reach a definitive diagnosis. We report a 73 years old man with a history compatible with of a rapidly progressive dementia, in which the first electroencephalographic study showed a pattern consistent with non-convulsive status epilepticus. Besides discarding this diagnosis, it was necessary to rule out other causes of rapidly progressive dementia such as Hashimoto encephalopathy. Finally, the sustained clinical deterioration with no response to anticonvulsants and corticosteroids, the imaging studies, a serial electroencephalographic monitoring study and the detection of 14-3-3 protein in cerebrospinal fluid were the keys to achieve the diagnosis of the disease. PMID:27598501

  10. Lymphomatosis cerebri mimicking iatrogenic Creutzfeldt-Jakob disease

    PubMed Central

    Rivero Sanz, Elena; Torralba Cabeza, Miguel Ángel; Portugal, Francisco Sanjuán; García-Bragado, Federico

    2014-01-01

    Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma (PCNSL) whereby individual lymphoma cells infiltrate the cerebral white matter without causing a mass effect. The disease characteristically presents as a rapidly progressive dementia, which opens an ample differential diagnosis of toxic, metabolic, neurodegenerative and infective causes. Other presentations also include changes in personality, myoclonus and psychotic symptoms. Here we report a patient who presented with a rapidly progressive dementia with a unique surgical history of a dural mater graft in the 1970s. The diagnosis of iatrogenic Creutzfeldt-Jakob disease (iCJD) was initially considered. However, the patient’s clinical status deteriorated rapidly with no response to symptomatic treatment and she died 2 months after symptom onset. A diagnosis of T-type LC was reached at autopsy. PMID:25199185

  11. Sporadic Creutzfeldt-Jakob disease presenting as a stroke mimic590.

    PubMed

    Hirst, Claire L

    2011-10-01

    Creutzfeldt-Jakob disease is a rare neurodegenerative disease in which there is an abnormal accumulation of prion protein. It occurs with an incidence of approximately 1 per million per year. Sporadic Creutzfeldt-Jakob disease occurs in approximately 85% of cases, with familial, variant and iatrogenic forms less common. Typically sporadic Creutzfeldt-Jakob disease presents with a rapidly progressive dementia, but sub-variants include the Heidenhain and Oppenheimer-Brownell variants. The former presents with visual disturbance and the latter with ataxia. This article describes a 75-year-old man with a Heidenhain variant of sporadic Creutzfeldt-Jakob disease who presented with a sudden onset of homonymous hemianopia mimicking a stroke. PMID:22041731

  12. An unusual case of sporadic Creutzfeldt-Jakob disease (CJD).

    PubMed

    Javed, Qaiser; Alam, Faouzi; Krishna, Sowmya; Jaganathan, Geetha

    2010-01-01

    A 49-year-old healthy white British female, not previously known to psychiatric services, presented with an acute onset of florid psychotic symptoms. Her symptoms included visual, auditory and tactile hallucinations as well as persecutory delusions. She was started on antipsychotic medication; however, her psychotic symptoms did not improve significantly in the first 3 months. Her blood tests were normal. Lumbar puncture was performed which was positive for protein 14-3-3. A computed tomography scan of the brain showed generalised atrophic changes. The history of early visual hallucinations, rapid cognitive decline and positive 14-3-3 result was in keeping with the Heidenhain variant of sporadic Creutzfeldt-Jakob disease (sCJD). Despite a short life expectancy as reported in literature, our patient, who was diagnosed with sCJD more than two-and-a-half years ago, is still alive. We therefore believe this is an important finding to report. PMID:22753302

  13. Severe hypoxia and multiple infarctions resembling Creutzfeldt-Jakob disease.

    PubMed

    Mittelbronn, Michel; Capper, David; Bader, Benedikt; Schittenhelm, Jens; Haybaeck, Johannes; Weber, Petra; Meyermann, Richard; Kretzschmar, Hans A; Wietholter, Horst

    2008-01-01

    Although neuropathological examination is still required for the definite diagnosis of Creutzfeldt-Jakob disease (CJD), specialised clinical assessment predicts probable CJD. Here we present a 73-year-old female patient presenting with rapid cognitive decline, visual, acoustic and cerebellar disturbances, ataxia and EEG changes compatible with early CJD stages. MRI revealed hyperintensities within the thalami, hypothalami, corpora mammillaria, the tectum and the cortex. Initial neuropathological examination showed severe cortical and subcortical spongiosis. However, both immunohistochemistry and Western blotting showed no pathological prion protein. Finally, small infarctions affecting the tectum, tegmentum, corpora mammillaria and global hypoxic-ischaemic changes could be identified as the probable reason for the changes interpreted as CJD-related pathology. Hypoxic-ischaemic CNS alterations mainly affecting the supply area of the basilar artery should be ruled out in case of probable CJD. In addition, severe spongiosis can be misleading in the histological examination, suggesting the diagnosis of a prion-induced spongiform encephalopathy. PMID:18587709

  14. Visual art therapy in sporadic Creutzfeldt-Jakob disease: a case study.

    PubMed

    Shrestha, Rajeet; Trauger-Querry, Barbara; Loughrin, Athena; Appleby, Brian S

    2016-01-01

    This paper describes the diagnostic and treatment utility of visual art therapy in a case of sporadic Creutzfeldt-Jakob disease. Visual art therapy was compared longitudinally with clinical and neuroimaging data over five-month period in an autopsy-confirmed case of sporadic Creutzfeldt-Jakob disease of MM2-cortical subtype. Art therapy sessions and content were useful in ascertaining neuropsychiatric symptoms during the course of her illness. Art therapy offered a unique emotional and cognitive outlet as illness progressed. Patients and families affected by sporadic Creutzfeldt-Jakob disease may benefit from art therapy despite the rapidly progressive nature of the illness. Art therapy can also be useful for assessment of patients with sporadic Creutzfeldt-Jakob disease by healthcare professionals. PMID:26782687

  15. Visual symptoms in the presentation of Creutzfeldt-Jakob disease.

    PubMed

    Wong, Aaron; Matheos, Kaliopy; Danesh-Meyer, Helen V

    2015-10-01

    We describe a 68-year-old man with a previous history of neurosurgical repair of a skull fracture, who presented to the ophthalmology clinic with progressive visual decline. His initial visual acuity was 6/30 in the right eye and 6/48 in the left, and over 2 weeks this progressed to hand movements in both eyes. No ocular abnormalities were identified. He was noted to be increasingly confused and a subsequent MRI showed extensive bilateral posterior cortical changes consistent with cytotoxic oedema. An electroencephalogram was suggestive of encephalopathy, particularly involving the occipital lobe. He was diagnosed with the Heidenhain variant of Creutzfeldt-Jakob disease (CJD), confirmed by a positive cerebrospinal fluid 14-3-3 protein. Classically, patients with CJD present with rapidly progressive cognitive decline, ataxia and myoclonus. However, visual symptoms are a common and perhaps underrecognised manifestation of CJD. Patients can present with isolated visual symptoms which precede cognitive decline by weeks due to predominantly occipital lobe disease. This presentation is classified as the Heidenhain variant of CJD. PMID:26355534

  16. Creutzfeldt-Jakob disease surveillance in Australia: update to December 2014.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Sarros, Shannon; Stehmann, Christiane; Simpson, Marion; McLean, Catriona; Masters, Colin L; Collins, Steven J

    2016-01-01

    Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2014, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2014, and retrospectively to 1970. PMID:27522131

  17. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kuo, Amy L.; Wong, Katherine S.; Haman, Aissa; Devereux, Gillian; Raudabaugh, Benjamin J.; Johnson, David Y.; Torres-Chae, Charles C.; Finley, Ron; Garcia, Paul; Thai, Julie N.; Cheng, Hugo Q.; Neuhaus, John M.; Forner, Sven A.; Duncan, Jacque L.; Possin, Katherine L.; DeArmond, Stephen J.; Prusiner, Stanley B.; Miller, Bruce L.

    2013-01-01

    Objective: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD). Methods: This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2. Results: Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months. Conclusion: This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials. Classification of evidence: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months. PMID:24122181

  18. Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease

    PubMed Central

    Maat, Peter; de Beukelaar, Janet W.; Jansen, Casper; Schuur, Maaike; van Duijn, Cornelia M.; van Coevorden, Marleen H.; de Graaff, Esther; Titulaer, Maarten; Rozemuller, Annemieke J.

    2015-01-01

    Objective: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). Methods: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998–2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. Results: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies. Conclusions: It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits. PMID:26601117

  19. Familial clustering of the ataxic form of Creutzfeldt-Jakob disease with Hirano bodies.

    PubMed Central

    Cartier, L; Gálvez, S; Gajdusek, D C

    1985-01-01

    A family cluster of the ataxic form of Creutzfeldt-Jakob disease with one probable and two autopsy proven cases that occurred in a single generation between 1974 and 1982 is reported. The clinical characteristics of the cases are closely similar to those of kuru patients, with a fair correlation between the prominent truncal ataxia and the intense devastation of the cerebellar cortex most marked in the vermis. Pathologically, the marked hippocampal involvement rarely seen in typical transmissible Creutzfeldt-Jakob disease and the finding of Hirano bodies in the Ammon's horn without specific Alzheimer's senile changes are noteworthy features. Images PMID:2984334

  20. [Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Part I].

    PubMed

    Zaborowski, Adam

    2004-01-01

    In the first part of this work the main problems of prion diseases--also called transmissible cerebral amyloidoses (TCA) or subacute (transmissible) encephalopathies (SSE, TSE)--and clinical symptoms of Creutzfeldt-Jakob disease are presented. Some problems of neuropathology of Creutzfeldt-Jakob disease and basic informations about other human prion diseases will be presented in the second part. The growth of the interest in prion diseases during last years is caused by the problem of bovine spongiform encephalopathy (BSE or "mad cow disease") and its transmission into a human. The new variant of Creutzfeldt-Jakob disease (nvCJD) has appeared. Prion diseases: Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal familial insomnia (FFI) and particularly the most frequent of them--Creutzfeldt-Jakob disease (CJD)--have nonspecific, sometimes variable clinical (psychopathological and neurological) symptoms. The imaging, EEG, cerebrospinal fluid tests and other laboratory tests are not specific either and their diagnostic value is limited. Neuropathological studies are needed but their interpretation is often difficult. The only certain diagnostic marker for TSE is the presence of PrP(Sc), the prion protein, which is presently believed to be a direct cause for all transmissible cerebral amyloidoses (TCA). PMID:15307293

  1. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns.

    PubMed Central

    Brown, P.; Will, R. G.; Bradley, R.; Asher, D. M.; Detwiler, L.

    2001-01-01

    The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom, which began in 1986 and has affected nearly 200,000 cattle, is waning to a conclusion, but leaves in its wake an outbreak of human Creutzfeldt-Jakob disease, most probably resulting from the consumption of beef products contaminated by central nervous system tissue. Although averaging only 10-15 cases a year since its first appearance in 1994, its future magnitude and geographic distribution (in countries that have imported infected British cattle or cattle products, or have endogenous BSE) cannot yet be predicted. The possibility that large numbers of apparently healthy persons might be incubating the disease raises concerns about iatrogenic transmissions through instrumentation (surgery and medical diagnostic procedures) and blood and organ donations. Government agencies in many countries continue to implement new measures to minimize this risk. PMID:11266289

  2. Photo essay. MRI and positron emission tomography findings in Heidenhain variant Creutzfeldt-Jakob disease.

    PubMed

    Prasad, Sashank; Lee, Edward B; Woo, John H; Alavi, Abass; Galetta, Steven L

    2010-09-01

    The typical presentation of Heidenhain variant Creutzfeldt-Jakob disease (CJD) is a rapidly progressive visual loss in the setting of a relatively normal ophthalmologic examination. At presentation, patients with this uniformly fatal illness frequently demonstrate only minor cortical abnormalities on MRI. Here, we document the clinical presentation and imaging results of a patient with Heidenhain variant CJD in whom abnormalities on positron emission tomographic imaging were more evident than changes on MRI. These changes were present in striate cortex and visual association areas, providing clinical-anatomical correlation with our patient's visual deficits. Nuclear imaging provides a considerably more sensitive measure of neural dysfunction early in the course of this disease. PMID:20581692

  3. Diagnosing Sporadic Creutzfeldt-Jakob Disease: Accuracy of CSF 14-3-3 Protein Test of the Spinal Fluid

    MedlinePlus

    ... JAKOB DISEASE: ACCURACY OF THE 14-3-3 PROTEIN TEST OF THE SPINAL FLUID This information sheet ... help you understand how the 14-3-3 protein test helps in diagnosing sporadic Creutzfeldt-Jakob disease ( ...

  4. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: how safe is eating beef?

    PubMed

    Roma, Andres A; Prayson, Richard A

    2005-03-01

    Cases of bovine spongiform encephalopathy (BSE, mad cow disease) have been found in North American cattle. Its human counterpart, called variant Creutzfeldt-Jakob disease (variant CJD), is rare but seems to be linked to eating diseased beef. Many questions remain about these diseases, such as why young people seem at greater risk of variant CJD. Also, are some people more genetically at risk for acquiring variant CJD than others? PMID:15825799

  5. The MM2-cortical form of sporadic Creutzfeldt-Jakob disease presenting with visual disturbance.

    PubMed

    Nozaki, I; Hamaguchi, T; Noguchi-Shinohara, M; Ono, K; Shirasaki, H; Komai, K; Kitamoto, T; Yamada, M

    2006-08-01

    A subclass of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by onset with visual symptoms (Heidenhain variant) has been reported to belong to the MM1 or MV1 type according to Parchi's classification. The authors report a 65-year-old woman with MM2-cortical sCJD with slowly progressive visual disturbance as the initial symptom. Diffusion-weighted MRIs revealed hyperintensity in both occipital cortices at an early stage. PMID:16894125

  6. Advanced tests for early and accurate diagnosis of Creutzfeldt-Jakob disease.

    PubMed

    Zanusso, Gianluigi; Monaco, Salvatore; Pocchiari, Maurizio; Caughey, Byron

    2016-06-01

    Early and accurate diagnosis of Creutzfeldt-Jakob disease (CJD) is a necessary to distinguish this untreatable disease from treatable rapidly progressive dementias, and to prevent iatrogenic transmission. Currently, definitive diagnosis of CJD requires detection of the abnormally folded, CJD-specific form of protease-resistant prion protein (PrP(CJD)) in brain tissue obtained postmortem or via biopsy; therefore, diagnosis of sporadic CJD in clinical practice is often challenging. Supporting investigations, including MRI, EEG and conventional analyses of cerebrospinal fluid (CSF) biomarkers, are helpful in the diagnostic work-up, but do not allow definitive diagnosis. Recently, novel ultrasensitive seeding assays, based on the amplified detection of PrP(CJD), have improved the diagnostic process; for example, real-time quaking-induced conversion (RT-QuIC) is a sensitive method to detect prion-seeding activity in brain homogenate from humans with any subtype of sporadic CJD. RT-QuIC can also be used for in vivo diagnosis of CJD: its diagnostic sensitivity in detecting PrP(CJD) in CSF samples is 96%, and its specificity is 100%. Recently, we provided evidence that RT-QuIC of olfactory mucosa brushings is a 97% sensitive and 100% specific for sporadic CJD. These assays provide a basis for definitive antemortem diagnosis of prion diseases and, in doing so, improve prospects for reducing the risk of prion transmission. Moreover, they can be used to evaluate outcome measures in therapeutic trials for these as yet untreatable infections. PMID:27174240

  7. Quantitative analysis of MRI signal intensity in new variant Creutzfeldt-Jakob disease.

    PubMed

    Coulthard, A; Hall, K; English, P T; Ince, P G; Burn, D J; Bates, D

    1999-08-01

    High signal intensity within the posterior thalamus (pulvinar nucleus) has been noted on MRI in patients with new variant Creutzfeldt-Jakob disease (nvCJD). In this study MRI examinations from three patients with proven nvCJD were compared with MRI examinations from a control group of 14 age-matched subjects with no neurological abnormalities. Mean signal intensity from seven target areas (periaqueductal tissue, posterior thalamus, dorsomedial thalamus, anterior thalamus, putamen, caudate head and frontal white matter) was calculated in each case. Absolute signal intensity measurements were not significantly different between the groups. Patients with nvCJD showed significantly higher signal intensity within dorsomedial thalamus, posterior thalamus and periaqueductal region than control patients when these measurements were normalized to the signal intensity of normal appearing white matter. Highly significant differences in posterior thalamus/putamen signal intensity ratio (PPR) and posterior thalamus/caudate ratio (PCR) were observed between the groups. For proton density images, PPR and PCR were greater than 1 for all nvCJD patients and less than 1 for all control patients. Both PPR and PCR are simple to calculate and offer a simple, non-invasive indicator of nvCJD. PMID:10624339

  8. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Forner, Sven A.; Takada, Leonel T.; Bettcher, Brianne M.; Lobach, Iryna V.; Tartaglia, Maria Carmela; Torres-Chae, Charles; Haman, Aissatou; Thai, Julie; Vitali, Paolo; Neuhaus, John; Bostrom, Alan; Miller, Bruce L.; Rosen, Howard J.

    2015-01-01

    Summary We assessed the diagnostic utility of 3 CSF biomarkers—14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)—from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92–1.00) and a diagnostic accuracy of 97% (CI 90%–100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03). PMID:26137420

  9. Creutzfeldt-Jakob disease: an emergency department presentation of a rare disease.

    PubMed

    Prince, Louise A; Mann, Deborah; Reilly, Tracey

    2006-07-01

    Creutzfeldt-Jakob Disease (CJD) is one of a group of neurodegenerative disorders causing spongiform encephalopathies. CJD is the most common human transmissible spongiform encephalopathy, or prion disease, but has an annual incidence of only 0.4-1.8 cases per million population worldwide. The prognosis for this disease is very poor and there is currently no cure. Patients typically present with non-specific neurological or psychiatric complaints and often have multiple physician visits before diagnosis, which requires histological examination of brain tissue. This patient had serial presentations to our Emergency Department, with progressive symptoms and multiple laboratory and radiological tests as well as consults, but her diagnosis remained unclear until her disease rapidly progressed and a brain biopsy was performed. With increasing concerns about prion diseases such as bovine spongiform encephalopathy (BSE)-or mad cow disease-and CJD, awareness of the symptoms and diagnostic challenges associated with these diseases will be helpful to emergency physicians. PMID:16798153

  10. Sporadic Creutzfeldt-Jakob disease with focal findings: caveats to current diagnostic criteria

    PubMed Central

    Mader, Edward C.; El-Abassi, Rima; Villemarette-Pittman, Nicole R.; Santana-Gould, Lenay; Olejniczak, Piotr W.; England, John D.

    2013-01-01

    The clinical diagnosis of Creutzfeldt-Jakob disease (CJD) is largely based on the 1998 World Health Organization diagnostic criteria. Unfortunately, rigid compliance with these criteria may result in failure to recognize sporadic CJD (sCJD), especially early in its course when focal findings predominate and traditional red flags are not yet present. A 61-year-old man presented with a 3-week history of epilepsia partialis continua (jerking of the left upper extremity) and a 2-week history of forgetfulness and left hemiparesis; left hemisensory neglect was also detected on admission. Repeated brain magnetic resonance imaging (MRI) showed areas of restricted diffusion in the cerebral cortex, initially on the right but later spreading to the left. Electroence-phalography (EEG) on hospital days 7, 10, and 14 showed right-sided periodic lateralized epileptiform discharges. On day 20, the EEG showed periodic sharp wave complexes leading to a diagnosis of probable sCJD and subsequently to definite sCJD with brain biopsy. Neurological decline was relatively fast with generalized myoclonus and akinetic mutism developing within 7 weeks from the onset of illness. CJD was not immediately recognized because of the patient's focal/lateralized manifestations. Focal/lateralized clinical, EEG, and MRI findings are not uncommon in sCJD and EEG/MRI results may not be diagnostic in the early stages of sCJD. Familiarity with these caveats and with the most current criteria for diagnosing probable sCJD (University of California San Francisco 2007, MRI-CJD Consortium 2009) will enhance the ability to recognize sCJD and implement early safety measures. PMID:23717780

  11. Heidenhain variant of Creutzfeldt-Jakob disease: An autopsy study from India.

    PubMed

    Kher, Monica; Rao, Medha Y; Acharya, P T; Mahadevan, Anita; Shankar, S K

    2009-01-01

    Prion diseases are rare, progressive and fatal neurodegenerative diseases characterized by long incubation period and short clinical course. We present a rare case of Heidenhain variant of Creutzfeldt-Jakob disease, occurring in a 55-year-old lady presenting with dementia, cortical blindness, and myoclonic jerks. She succumbed to the disease within 8 weeks of onset of symptoms. MRI revealed hyperintense signals on T2WI and fluid attenuated inversion recovery (FLAIR) images in basal ganglia and fronto-temporal and parietal cortex, sparing thalamus, striate cortex and globus pallidum. Abundant abnormal prion protein deposits (PrP(sc)) were detected in caudate, putamen, thalamus, cingulate and striate cortex, in comparison to frontal and parietal cortex while no deposits were found in globus pallidum. MRI changes did not correlate with degree of spongy change, gliosis or prion protein deposition. The cause for abnormal signal changes in MRI and FLAIR images remains unclear. PMID:20151011

  12. [Perioperative considerations for performing a brain biopsy on a patient with subtype VV2 sporadic Creutzfeldt-Jakob disease].

    PubMed

    Guerrero-Domínguez, R; Rubio-Romero, R; González-González, G; Jiménez, I

    2015-04-01

    Creutzfeldt-Jakob disease (CJD) is the most common transmissible spongiform encephalopathy. It is an infectious, progressive, degenerative neurological disorder, with a presumably long incubation period, but a rapid fatal course. CJD is transmitted by a proteinaceous infectious agent, or «prion». Because the prions are difficult to eradicate and are resistant to the currently used sterilization methods, special precautions must be taken with all surgical instruments. It is recommended the single-use equipment, destruction of contaminated equipment, decontamination of reusable instruments, use of protective clothing, and storing and quarantining surgical instruments. The single-use equipment and some tissues and body fluids from the patient with CJD are highly infectious and must be incinerated. We report a case of a patient who had undergone brain biopsy for suspected of CJD, being confirmed to have sporadic CJD. Specific preventive measures were taken to reduce the risk of transmission to healthcare workers. PMID:25146772

  13. Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease

    NASA Astrophysics Data System (ADS)

    Baker, Christopher A.; Manuelidis, Laura

    2003-01-01

    Previous studies in Creutzfeldt-Jakob disease (CJD) have shown that myeloid cells in the periphery as well as derivative microglial cells in the brain are infectious. Microglia can show an activated phenotype before prion protein (PrP) pathology is detectable in brain, and isolated infectious microglia contain very little PrP. To find whether a set of inflammatory genes are significantly induced or suppressed with infection, we analyzed RNA from isolated microglia with relevant cDNA arrays, and identified 30 transcripts not previously examined in any transmissible spongiform encephalopathy. This CJD expression profile contrasted with that of uninfected microglia exposed to prototypic inflammatory stimuli such as lipopolysaccharide and IFN-, as well as PrP amyloid. These findings underscore inflammatory pathways evoked by the infectious agent in brain. Transcript profiles unique for CJD microglia and other myeloid cells provide opportunities for more sensitive preclinical diagnoses of infectious and noninfectious neurodegenerative diseases.

  14. Creutzfeldt-Jakob disease not related to a common venue--New Jersey, 1995-2004.

    PubMed

    2004-05-14

    Beginning in June 2003, the New Jersey Department of Health and Senior Services (NJDHSS) and CDC were notified of a suspected cluster of deaths caused by Creutzfeldt-Jakob disease (CJD) in persons reportedly linked to Garden State Racetrack in Cherry Hill, New Jersey. Concerns were raised that these deaths might have resulted from consumption of meat contaminated with the agent causing bovine spongiform encephalopathy (BSE, commonly called "mad cow disease") served at racetrack restaurants during 1988-1992. Consumption of BSE-contaminated cattle products has been linked to a new variant form of CJD (vCJD) in humans. This report summarizes the results of an investigation that determined the deaths were not linked causally to a common source of infection. The findings underscore the need for physicians to arrange for brain autopsies of all patients with clinically suspected or diagnosed CJD. PMID:15138401

  15. [Creutzfeldt-Jakob disease: the most frequent spongiform encephalopathy in humans].

    PubMed

    Kulczycki, J

    2001-01-01

    Creutzfeldt-Jakob disease (CJD) which for many years was interpreted as one of degenerative brain processes is the most frequent spongiform encephalopathy caused by prions--molecules of erroneously conformed protein. In only few percent ill people occurrence of this pathogenic factor occurs as a result of mutation in gene PrP. Because transmissibility of prions was proved it should be supposed that in other cases CJD is a result of "infection" Susceptibility to prions depends in large part on specificity of host proteins. It creates certain individual and species specific barriers. At the present time we witness, fortunately only in single cases, occurrence in people variant CJD caused by prions originated from animals affected by "mad cow disease". Prognosis for human population is dependent on the effectiveness of between species barrier for prions. PMID:11556078

  16. Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications.

    PubMed

    Maheshwari, Atul; Fischer, Michael; Gambetti, Pierluigi; Parker, Alicia; Ram, Aarthi; Soto, Claudio; Concha-Marambio, Luis; Cohen, Yvonne; Belay, Ermias D; Maddox, Ryan A; Mead, Simon; Goodman, Clay; Kass, Joseph S; Schonberger, Lawrence B; Hussein, Haitham M

    2015-05-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient's exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD. PMID:25897712

  17. Creutzfeldt-Jakob disease presenting with visual symptoms: a case of the ‘Heidenhain variant’

    PubMed Central

    Verma, Rajesh; Junewar, Vivek; Sahu, Ritesh

    2013-01-01

    Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be caused by the abnormal folding of proteins called prion proteins. The ‘Heidenhain variant’ is a subclass of patients with CJD, who present with isolated visual symptoms at the onset without any cognitive decline. Here we report such a case of an elderly man presenting with progressive diminution of vision, forgetfulness, abnormal behaviour, myoclonic jerks and akinetic mutism since the last 5 months. On clinical examination, lead pipe rigidity was present in all four limbs, and plantars were bilateral extensors. In view of rapidly progressive dementia associated with myoclonus, a possibility of CJD was entertained. As visual symptoms preceded dementia, hence the Heidenhain variant was strongly suspected. MRI of the brain revealed cortical ribboning, and EEG showed periodic triphasic waveforms with background slowing. The patient succumbed to the illness within 1 month of hospitalisation. PMID:23365167

  18. Creutzfeldt-Jakob disease presenting with visual symptoms: a case of the 'Heidenhain variant'.

    PubMed

    Verma, Rajesh; Junewar, Vivek; Sahu, Ritesh

    2013-01-01

    Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be caused by the abnormal folding of proteins called prion proteins. The 'Heidenhain variant' is a subclass of patients with CJD, who present with isolated visual symptoms at the onset without any cognitive decline. Here we report such a case of an elderly man presenting with progressive diminution of vision, forgetfulness, abnormal behaviour, myoclonic jerks and akinetic mutism since the last 5 months. On clinical examination, lead pipe rigidity was present in all four limbs, and plantars were bilateral extensors. In view of rapidly progressive dementia associated with myoclonus, a possibility of CJD was entertained. As visual symptoms preceded dementia, hence the Heidenhain variant was strongly suspected. MRI of the brain revealed cortical ribboning, and EEG showed periodic triphasic waveforms with background slowing. The patient succumbed to the illness within 1 month of hospitalisation. PMID:23365167

  19. Mortality, neoplasia, and Creutzfeldt-Jakob disease in patients treated with human pituitary growth hormone in the United Kingdom.

    PubMed Central

    Buchanan, C R; Preece, M A; Milner, R D

    1991-01-01

    OBJECTIVE--To determine the cause of death and incidence of neoplasia in patients treated with human pituitary growth hormone. DESIGN--A long term cohort study established to receive details of death certification and tumour registrations through the Office of Population Censuses and Surveys and NHS central register. PATIENTS--All patients (1246 male, 662 female) treated for short stature with pituitary growth hormone under the Medical Research Council working party and health services human growth hormone committee. MAIN OUTCOME MEASURES--Death or development of neoplasia. RESULTS--110 patients died (68 male, 42 female; aged 0.9-57 years) from 1972 to 1990. Fifty three death were from neoplasia responsible for growth hormone deficiency (27 craniopharyngioma, 24 other intracranial tumour, two leukaemia); two from histiocytosis X; and 13 from pituitary insufficiency. Six patients died of Creutzfeldt-Jakob disease, six of other neurological disorders, and eight of acute infection. Other deaths were apparently unrelated to growth hormone deficiency or its treatment. Seventeen tumours (in 16 patients) were identified during or after growth hormone treatment. Four were in patients with previous intracranial neoplasia and two were after cranial irradiation. Thirteen were intracranial, the others being Hodgkin's lymphoma, osteosarcoma, carcinoma of colon, and basal cell carcinoma. CONCLUSIONS--Recurrence or progression of intracranial tumours and potentially avoidable metabolic consequences of hypopituitarism were the main causes of death. Growth hormone treatment probably did not contribute to new tumour development. Creutzfeldt-Jakob disease after pituitary growth hormone treatment continues to occur in the United Kingdom. This cohort must remain under long term review. PMID:2025705

  20. Autoimmune encephalitis mimicking sporadic Creutzfeldt-Jakob disease: A retrospective study.

    PubMed

    Chen, Yu; Xing, Xiao-Wei; Zhang, Jia-Tang; Wang, Ruo-Xi; Zhao, Wei; Tan, Qing-Che; Liu, Ruo-Zhuo; Wang, Xiang-Qing; Huang, Xu-Sheng; Yu, Sheng-Yuan

    2016-06-15

    Autoimmune encephalitis associated with anti-voltage-gated potassium channel antibodies are most likely to be misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Our goal was to delineate patients who were initially suspected to have CJD but were later found to have AE. We performed a retrospective clinical review of cases of individuals and made a comparison between groups of patients diagnosed with sCJD and AE. Patients who had rapidly progressing dementia and focal neurological impairment, such as aphasia, gait disturbance, visual disturbance, and depression, at onset were diagnosed with sCJD, whereas epilepsy, hyponatremia and dysautonomia were strong hints for AE. Fluoroscope-positron emission tomography (PET) of patients with AE revealed variable metabolism and normative and long-term immunosuppression were less likely to relapse. PMID:27235341

  1. Heidenhain variant of Creutzfeldt-Jakob disease: diffusion-weighted MRI and PET characteristics.

    PubMed

    Tsuji, Yoshihisa; Kanamori, Hiroshi; Murakami, Gaku; Yokode, Masayuki; Mezaki, Takahiro; Doh-ura, Katsumi; Taniguchi, Ken; Matsubayashi, Kozo; Fukuyama, Hidenao; Kita, Toru; Tanaka, Makoto

    2004-01-01

    Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressive dementia with a variety of neurological disorders and a fatal outcome. The authors present a case with visual disturbance as a leading symptom and rapid deterioration in global cognitive functions. The cerebrospinal fluid was positive for 14-3-3 protein, and diffusion-weighted magnetic resonance imaging (MRI) showed marked hyperintensity in the parieto-occipital cortices, where hypometabolism was clearly detected on positron emission tomography (PET). Pattern-reversal visual evoked potentials showed prolonged P100 latencies and increased N/5/P100 amplitudes. All these findings supported a diagnosis of the Heidenhain variant of CJD, whereas a long clinical course, a lack of myoclonus, and an absence of periodic synchronous discharges on electroencephalography were atypical. Diffusion-weighted MRI and PE1 in combination with visual evoked potential recording and 14-3-3 protein detection may be useful for the early diagnosis of CJD. PMID:14748211

  2. Population Screening for Variant Creutzfeldt-Jakob Disease Using a Novel Blood Test

    PubMed Central

    Jackson, Graham S.; Burk-Rafel, Jesse; Edgeworth, Julie Ann; Sicilia, Anita; Abdilahi, Sabah; Korteweg, Justine; Mackey, Jonathan; Thomas, Claire; Wang, Guosu; Schott, Jonathan M.; Mummery, Catherine; Chinnery, Patrick F.; Mead, Simon; Collinge, John

    2014-01-01

    IMPORTANCE Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy–unexposed population. In a clinical diagnostic capacity, the assay’s likelihood ratios dramatically change an individual’s pretest disease odds to posttest probabilities and can confirm vCJD infection. OBJECTIVES To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations. DESIGN, SETTING, AND PARTICIPANTS Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10). MAIN OUTCOME AND MEASURE Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder. RESULTS The assay’s specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples

  3. Transmission Properties of Atypical Creutzfeldt-Jakob Disease: a Clue to Disease Etiology?

    PubMed Central

    Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Brown, Paul; Saverioni, Daniela; Matsuura, Yuichi; Takeuchi, Atsuko; Mohri, Shirou

    2015-01-01

    ABSTRACT The genotype at polymorphic codon 129 of the PRNP gene has a profound influence on both phenotypic expression and prion strain susceptibility in humans. For example, while the most common sporadic Creutzfeldt-Jakob disease (CJD) subtype, sporadic CJD-MM1 (M1 strain), induces a single phenotype after experimental transmission regardless of the codon 129 genotype of the recipient animal, the phenotype elicited by sporadic CJD-VV2 (V2 strain), the second most common subtype, varies according to the host codon 129 genotype. In particular, the propagation of the V2 strain in codon 129 methionine homozygotes has been linked only to acquired forms of CJD such as plaque-type dura mater graft-associated CJD (dCJD), a subgroup of iatrogenic CJD with distinctive phenotypic features, but has never been observed in sporadic CJD cases. In the present report, we describe atypical CJD cases carrying codon 129 methionine homozygosity, in a neurosurgeon and in a patient with a medical history of neurosurgery without dural grafting, showing the distinctive phenotypic features and transmission properties of plaque-type dCJD. These findings raise the possibility that the two cases, previously thought to represent sporadic CJD, might actually represent acquired CJD caused by infection with the V2 strain. Thus, careful analyses of phenotypic features and transmission properties in atypical cases may be useful to distinguish acquired from sporadic cases of CJD. IMPORTANCE Susceptibility to and phenotypic expression of Creutzfeldt-Jakob disease (CJD) depend on both the prion strain and genotype at polymorphic codon 129 of the PRNP gene. For example, propagation of the second most common sporadic CJD strain (V2 strain) into codon 129 methionine homozygotes has been linked to plaque-type dura mater graft-associated CJD (dCJD), a subgroup of iatrogenic CJD with distinctive phenotypic features, but has never been observed in sporadic CJD. In the present report, we describe atypical

  4. Multitracer study in Heidenhain variant of Creutzfeldt-Jakob disease: mismatch pattern of cerebral hypometabolism and perfusion imaging.

    PubMed

    Pichler, Robert; Ciovica, Ioana; Rachinger, Johanna; Weiss, Serge; Aichner, Franz T

    2008-02-01

    Creutzfeldt-Jakob disease (CJD) is a subacute spongiform encephalopathy. This fatal prion disease is characterized by rapidly progressive dementia with a variety of neurological disorders. Diagnostic methods provided by nuclear medicine might be helpful for evaluation of patients with probable CJD as additional diagnostic tools to MRI and cerebro-spinal fluid evaluation. The experience with FDG-PET and brain perfusion SPECT is presented. PMID:18283251

  5. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy.

    PubMed

    Manix, Marc; Kalakoti, Piyush; Henry, Miriam; Thakur, Jai; Menger, Richard; Guthikonda, Bharat; Nanda, Anil

    2015-11-01

    Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative condition with a rapid disease course and a mortality rate of 100%. Several forms of the disease have been described, and the most common is the sporadic type. The most challenging aspect of this disease is its diagnosis-the gold standard for definitive diagnosis is considered to be histopathological confirmation-but newer tests are providing means for an antemortem diagnosis in ways less invasive than brain biopsy. Imaging studies, electroencephalography, and biomarkers are used in conjunction with the clinical picture to try to make the diagnosis of CJD without brain tissue samples, and all of these are reviewed in this article. The current diagnostic criteria are limited; test sensitivity and specificity varies with the genetics of the disease as well as the clinical stage. Physicians may be unsure of all diagnostic testing available, and may order outdated tests or prematurely request a brain biopsy when the diagnostic workup is incomplete. The authors review CJD, discuss the role of brain biopsy in this patient population, provide a diagnostic pathway for the patient presenting with rapidly progressive dementia, and propose newer diagnostic criteria. PMID:26646926

  6. Variant Creutzfeldt-Jakob disease (vCJD) and gastrointestinal endoscopy.

    PubMed

    Axon, A T; Beilenhoff, U; Bramble, M G; Ghosh, S; Kruse, A; McDonnell, G E; Neumann, C; Rey, J F; Spencer, K

    2001-12-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a transmissible form of spongiform encephalopathy believed to be contracted from the consumption of bovine spongiform encephalopathy (BSE) infected beef products. To date over 100 individuals have developed this incurable disease. There have been no documented cases of iatrogenic infection, but there is a theoretical risk that surgical procedures could transmit the disease. This review describes the background of the disease and assesses the possible risks of transmission through endoscopic procedures. The risk of transmission by endoscopy is small and probably negligible if suitable procedures are followed. The greatest potential danger arises from healthy individuals who are incubating the disease. Pathological prions (PrP(sc)) may be found in lymphatic tissue of these individuals (particularly tonsils), but smaller amounts have been identified in the appendix and Peyer's patches. These prions are resistant to all forms of conventional sterilization. There is a theoretical risk that biopsy forceps and the operating channel of endoscopes could become contaminated. This review gives recommendations as to how these small risks can be minimized. They include the employment of single-use forceps for biopsies taken from the terminal ileum, greater attention to the maintenance of endoscopic equipment and accessories, more rigorous manual cleaning of endoscopic equipment and the use of well designed, disposable cleaning brushes for the operating channel of the endoscope. PMID:11740649

  7. Codon 219 polymorphism of PRNP in healthy caucasians and Creutzfeldt-Jakob disease patients

    SciTech Connect

    Petraroli, R.; Pocchiari, M.

    1996-04-01

    A number of point and insert mutations of the PrP gene (PRNP) have been linked to familial Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker disease (GSS). Moreover, the methionine/valine homozygosity at the polymorphic codon 129 of PRNP may cause a predisposition to sporadic and iatrogenic CJD or may control the age at onset of familial cases carrying either the 144-bp insertion or codon 178, codon 198, and codon 210 pathogenic mutations in PRNP. In addition, the association of methionine or valine at codon 129 and the point mutation at codon 178 on the same allele seem to play an important role in determining either fatal familial insomnia or CJD. However, it is noteworthy that a relationship between codon 129 polymorphism and accelerated pathogenesis (early age at onset or shorter duration of the disease) has not been seen in familial CJD patients with codon 200 mutation or in GSS patients with codon 102 mutation, arguing that other, as yet unidentified, gene products or environmental factors, or both, may influence the clinical expression of these diseases. 17 refs.

  8. A transmissible Creutzfeldt-Jakob disease-like agent is prevalent in the human population.

    PubMed Central

    Manuelidis, E E; Manuelidis, L

    1993-01-01

    The etiology of most human dementias is unknown. Creutzfeldt-Jakob disease (CJD), a relatively uncommon human dementia, is caused by a transmissible virus-like agent. Molecular markers that are specific for the agent have not yet been defined. However, the infectious disease can be transmitted to rodents from both brain and infected buffy coat (blood) samples. To determine whether human CJD infections are more widespread than is apparent from the low incidence of neurological disease, we attempted to transmit CJD from buffy coat samples of 30 healthy volunteers who had no family history of dementing illness. Primary transmissions from 26 of 30 individuals produced CJD-like spongiform changes in the brains of recipient hamsters at 200-500 days postinoculation. This positive evidence of viremia was found for individuals in all age groups (20-30, 40-50, and 61-71 years old), whereas 12 negatively scored brain samples failed to produce similar changes in hamsters observed for > 900 days in the same setting. We suggest that a CJD agent endemically infects humans but only infrequently produces an infectious dementia. Disease expression is likely to be influenced by several host factors in combination with viral variants that have altered neurovirulence. Images Fig. 1 PMID:8356076

  9. Diffusion-weighted MRI findings and clinical correlations in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Gao, Ting; Lyu, Jin-Hao; Zhang, Jia-Tang; Lou, Xin; Zhao, Wei; Xing, Xiao-Wei; Yang, Ming; Yao, Yan; Tan, Qing-Che; Tian, Cheng-Lin; Huang, Xu-Sheng; Ma, Lin; Yu, Sheng-Yuan

    2015-06-01

    The objective of this study is to investigate the hyperintense lesions on diffusion-weighted magnetic resonance imaging (DWI) and its clinical correlation in sporadic Creutzfeldt-Jakob disease (sCJD). Patients who suffered from sCJD and followed up at the Department of Neurology at the General Hospital of the People's Liberation Army during the period of June 1, 2007 to July 1, 2014 were reviewed. The location of the hyperintense lesions on DWI, apparent diffusion coefficient (ADC) values of the hyperintense lesions were correlated with symptoms and clinical course. A total of 58 sCJD patients and ten healthy controls were included. Hyperintense lesions on DWI were observed in all the patients. The patients with basal ganglia (BG) hyperintense lesions on DWI had shorter disease duration and higher incidence of myoclonus (92 versus 44 %) than those without BG hyperintense lesions. The patients with occipital cortex hyperintense lesions on DWI had shorter disease duration between symptom onset and akinetic mutism than those without these lesions. The lower of the BG ADC value the faster presence of akinetic mutism and the shorter disease duration the patients will have. The presence of BG and occipital cortex hyperintense lesions on DWI and BG ADC values is correlated with the clinical course and clinical symptoms. PMID:25860342

  10. LGI1 antibody encephalopathy overlapping with sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kim, Boaz; Yoo, Patrick; Sutherland, Tom; Boyd, Alison; Stehmann, Christiane; McLean, Catriona

    2016-01-01

    Objective: To report a rare case of leucine-rich, glioma inactivated 1 (LGI1) antibody–mediated autoimmune encephalopathy clinically overlapping with pathologically confirmed sporadic Creutzfeldt-Jakob disease (CJD). Methods: The patient was investigated with repeated brain MRI, EEG, CSF examination, whole-body fluorodeoxy-glucose positron emission tomography, genetic analysis of the prion protein gene (PRNP), and extensive serologic screening for paraneoplastic and autoimmune encephalopathy markers. Written informed consent was obtained from the patient's next of kin for access to clinical files for research purposes and for publication. Results: The patient was a 77-year-old man who presented with faciobrachial dystonic seizures (FBDS) secondary to LGI1 antibody–mediated autoimmune encephalopathy, with suggestive MRI findings and a complete response to treatment with combinatorial immunosuppression. Stereotactic biopsy of a nonenhancing T1 hyperintense basal ganglia lesion during the initial FBDS phase, albeit following immunosuppression, did not disclose evidence of lymphocytic inflammation. Following full remission of the FBDS, the patient manifested a rapidly progressive dementia associated with gross motor decline confirmed to be CJD at autopsy (molecular subtype VV3), with no evidence of a pathogenic PRNP mutation. Conclusions: Our patient highlights that these rare diseases are not invariably mutually exclusive and underscores the benefits of comprehensive neuropathologic examination of the brain to achieve an accurate diagnosis, especially in complex cases when the clinical trajectory dramatically deviates and a concomitant disease may need to be conscientiously considered to best explain the new clinical course. PMID:27354985

  11. Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Karch, André; Hermann, Peter; Ponto, Claudia; Schmitz, Matthias; Arora, Amandeep; Zafar, Saima; Llorens, Franc; Müller-Heine, Annika; Zerr, Inga

    2015-05-01

    The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during lifetime. Because the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows premortem diagnosis of molecular subtype when codon 129 genotype is known. Two hundred ninety-six sCJD patients were tested for their cerebrospinal fluid total tau level at the time of diagnosis and were investigated for their sCJD subtype postmortem. There was a significant association between tau levels and the prion protein type in patients with codon 129 MM (p < 0.001), MV (p = 0.004), and VV (p = 0.001) genotype. Receiver operating characteristic analyses showed values of area under the curve of 0.76-0.80 for the different genotypes indicating a good diagnostic validity of the test. Total tau can be used as a diagnostic test for the assessment of prion protein type when codon 129 genotype is known. It provides valuable information for physicians and next of kin about the further course of disease. PMID:25749129

  12. Variant Creutzfeldt-Jakob Disease With Extremely Low Lymphoreticular Deposition of Prion Protein

    PubMed Central

    Mead, Simon; Wadsworth, Jonathan D. F.; Porter, Marie-Claire; Linehan, Jacqueline M.; Pietkiewicz, Wojciech; Jackson, Graham S.; Brandner, Sebastian; Collinge, John

    2014-01-01

    IMPORTANCE Human transmission of bovine spongiform encephalopathy causes the fatal neurodegenerative condition variant Creutzfeldt-Jakob disease (vCJD) and, based on recent human prevalence studies, significant subclinical prion infection of the UK population. To date, all clinical cases have been fatal, totaling 228 mostly young adults residing in the United Kingdom. OBSERVATIONS Here we describe the investigation and case history of a patient recently diagnosed as having vCJD in the United Kingdom. Although his presentation, imaging findings, cerebrospinal fluid investigation results, and clinical progression were typical of other cases, tonsillar biopsy and subsequent examination of multiple tissues at autopsy showed minimal deposition of disease-associated prion protein in peripheral lymphoreticular tissue. The result of a blood test for vCJD, the Direct Detection Assay for vCJD, was negative. CONCLUSIONS AND RELEVANCE These findings suggest that some patients with vCJD have very low peripheral prion colonization and therefore may not have detectable prion deposition in diagnostic tonsillar biopsy or markers of prion infection in blood. These results have implications for accurate interpretation of diagnostic tests and prevalence studies based on lymphoreticular tissue or blood. PMID:24445428

  13. Variant Creutzfeldt-Jakob disease: need for mental health and palliative care team collaboration.

    PubMed

    de Vries, Kay; Sque, Margaret; Bryan, Karen; Abu-Saad, Huda

    2003-12-01

    People with a dementia syndrome and a superimposed terminal illness are increasingly being referred to palliative care services. Creutzfeldt-Jakob disease (CJD) is a dementia syndrome in the early stages of which people experience a variety of psychological symptoms that may lead to them being admitted to psychiatric services. People with CJD have died in psychiatric units. There is clearly a need for collaboration between mental health and palliative care services in providing care for people with CJD and other dementia syndromes. An inductive qualitative study of one case of variant CJD (vCJD) was carried out to explore issues that were raised in providing care for a young person with the disease who had died in a hospice unit. The study, which was a pilot for a larger study, highlights some of the complexities of providing care for people with an end-stage dementia and identifies the need for the development of education initiatives to increase knowledge and understanding of the end-of-life needs of people with CJD and other dementia syndromes, and their families. PMID:14765007

  14. Creutzfeldt-Jakob Disease Presenting With Dizziness and Gaze-Evoked Nystagmus: A Case Report.

    PubMed

    Choi, Yun-Ju; Kang, Kyung-Wook; Lee, Sae-Young; Kang, Seung-Ho; Lee, Seung-Han; Kim, Byeong C

    2016-02-01

    Sporadic Creutzfeldt-Jakob disease (CJD) is clinically characterized by rapidly progressive dementia combined with other cardinal symptoms, such as myoclonus, visual or cerebellar disturbances, extrapyramidal or pyramidal disturbance, and akinetic mutism. However, as an initial manifestation, focal neurologic deficits other than the aforementioned or nonspecific generalized symptoms may lead to a misdiagnosis or a delayed diagnosis. The authors report a case of 66-year-old male patient with sporadic CJD who had dizziness, gaze-evoked nystagmus (GEN), and other central eye signs (impaired smooth pursuit, saccadic dysmetria) as an initial manifestation without dementia. The central eye signs led us to perform brain magnetic resonance images, which showed abnormal cortical high-signal intensity in both the cerebral and cerebellar hemispheres including the vestibulocerebellum. We reached a presumptive diagnosis of CJD, but the findings did not meet diagnostic criteria for probable CJD at that time. Three weeks after the initial work-ups, the patient presented with typical neurological findings of CJD: rapidly progressive dementia, akinetic mutism, and myoclonus of the left arm. Cerebrospinal fluid was positive for 14-3-3 protein, and electroencephalography showed periodic sharp wave complexes. In this patient, GEN and other central eye signs provided diagnostic clues for CJD. These unusual neurological manifestations may help physicians have a thorough knowledge of early deficits of CJD. PMID:26886621

  15. [A case of Creutzfeldt-Jakob disease presenting with arm levitation as an initial symptom].

    PubMed

    Kamogawa, Kenji; Ninomiya, Satoko; Okuda, Shinya; Matsumoto, Yushi; Tomita, Hitomi; Okamoto, Kensho; Okuda, Bungo

    2014-01-01

    A 74-year-old, right handed man, developed insidiously with levitation and clumsiness of the right upper limb. His right arm tended to levitate spontaneously, when he was examined. He could put the elevated arm down on command, while the arm resumed to antigravity posture when his attention was diverted. His right arm also exhibited unwilled elevation when performing complex finger movements on the right side. He had a feeling of strangeness of the elevated limb, especially with the eyes closed. In addition to asymmetric limb-kinetic apraxia, combined sensations such as stereognosis were disturbed on the right side. Brain MRI showed high signal lesions predominantly in the left cerebral cortices and basal ganglia. SPECT with (123)I-IMP revealed asymmetric hypoperfusion, predominantly in the left medial frontal and parietal regions. Two months after the onset, levitation of the arm gradually disappeared, with the development of rapidly progressive dementia, frontal signs, dystonia and generalized myoclonus. The diagnosis of Creutzfeldt-Jakob disease (CJD) was made based on the clinical features and cerebrospinal fluid biomarkers. The early manifestation of the patient mimicked corticobasal degeneration which presents with arm levitation or alien hand syndrome. It is suggested that CJD can represent involuntary movements with higher brain dysfunction resembling corticobasal degeneration at the early stage of the illness. Although the underlying mechanism of arm levitation is still unknown, frontal disinhibition and parietal cortical sensory disturbance may contribute to the development of involuntary arm levitation in our patient. PMID:25342014

  16. Metabolic disorders with clinical and radiologic features of sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Rosenbloom, Michael H.; Tartaglia, M. Carmela; Forner, Sven A.; Wong, Katherine K.; Kuo, Amy; Johnson, David Y.; Colacurcio, Valerie; Andrews, Bret D.; Miller, Bruce L.; DeArmond, Stephen J.

    2015-01-01

    Summary Two patients with metabolic disorders presented with clinical and radiologic features suggestive of sporadic Creutzfeldt-Jakob disease (sCJD). Case 1 was a 50-year-old man with rapid decline in cognitive, behavioral, and motor function following new-onset seizures. MRI was read as consistent with CJD, and he was referred for a treatment trial, but it was determined that he recently experienced rapid correction of hyponatremia resulting in extrapontine myelinolysis. Case 2 was a 66-year-old woman with poorly controlled diabetes mellitus who was found unconscious after a suspected insulin overdose. Examination showed altered mental status and neuroimaging was remarkable for cortical/striatal hyperintensities suggestive of sCJD. On autopsy, she had hypoglycemic/hypoxic nerve cell loss. Although characteristic MRI findings have high sensitivity and specificity for sCJD, potentially reversible metabolic disorders sometimes present rapidly and can resemble sCJD both clinically and radiologically. These cases highlight the importance of establishing a broad differential diagnosis when evaluating a patient with suspected sCJD. PMID:26137419

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

    PubMed

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

    2016-01-01

    Prion diseases are rare neurodegenerative disorders occurring worldwide and affecting both humans and animals. Herein, we present the case of a patient diagnosed with definite sporadic Creutzfeldt-Jakob disease in Cali, Colombia. Besides neurological examination, 14-3-3 and tau proteins were valuable tools supporting the diagnosis. We also present a brief perspective of the prion diseases reported in Colombia to date. Although the incidence of prion diseases is unknown in Colombia, our literature review revealed that one case of scrapie in 1981 and 29 human sporadic cases of Creutzfeldt-Jakob disease have been documented and published in our country. PMID:27622622

  18. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

    PubMed Central

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-01-01

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD) and sporadic Parkinson’s disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick’s disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression. PMID:26861289

  19. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies.

    PubMed

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-01-01

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD) and sporadic Parkinson's disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick's disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression. PMID:26861289

  20. The epidemics of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: current status and future prospects.

    PubMed Central

    Smith, Peter G.

    2003-01-01

    The large epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom has been in decline since 1992, but has spread to other countries. The extensive control measures that have been put in place across the European Union and also in Switzerland should have brought the transmission of BSE under control in these countries, provided that the measures were properly enforced. Postmortem tests on brain tissue enable infected animals to be detected during the late stages of the incubation period, but tests that can be performed on live animals (including humans) and that will detect infections early are urgently needed. The number of infected animals currently entering the food chain is probably small, and the controls placed on bovine tissues in the European Union and Switzerland should ensure that any risks to human health are small and diminishing. Vigilance is required in all countries, especially in those in which there has been within-species recycling of ruminant feed. Fewer than 150 people, globally, have been diagnosed with variant Creutzfeldt-Jakob disease (vCJD), but there are many uncertainties about the future course of the epidemic because of the long and variable incubation period. Better control measures are necessary to guard against the possibility of iatrogenic transmission through blood transfusion or contaminated surgical instruments. These measures will required sensitive and specific, diagnostic tests and improved decontamination methods. PMID:12751420

  1. Update: Creutzfeldt-Jakob disease associated with cadaveric dura mater grafts--Japan, 1978-2008.

    PubMed

    2008-10-24

    Creutzfeldt-Jakob disease (CJD) is the most common of the human prion diseases (also known as transmissible spongiform encephalopathies), which, according to the leading hypothesis, are caused by an abnormal protein (i.e., prion) that is able to induce abnormal folding of normal cellular prion proteins. Annual worldwide incidence of these always fatal neurodegenerative diseases is estimated at 0.5-2.0 cases per million population. CJD can occur sporadically, or as a genetic disease, or can be transmitted iatrogenically. In 1996, a new human prion disease, variant CJD (vCJD), was first described in the United Kingdom. This disease was believed to have resulted from human consumption of cattle products contaminated with the prions responsible for bovine spongiform encephalopathy (BSE, commonly known as mad cow disease). That year, in part to check for possible vCJD cases, a national survey was conducted in Japan; 821 CJD cases were identified, including 43 cases associated with receipt of cadaveric dura mater grafts. A single brand of dural graft (Lyodura) produced by a German manufacturer before May 1987 was identified as the most likely vehicle of transmission in all but one case. By 2003, continued surveillance in Japan had identified a total of 97 such cases. Since then, an additional 35 cases have been identified. This report updates previous reports and summarizes the investigation of all 132 cases to date linked to dural grafts. The results suggest that, because of the long incubation period between graft receipt and symptom onset (possibly >24.8 years), continued surveillance in Japan might identify additional CJD cases associated with dural grafts. PMID:18946463

  2. Role of the biomarkers for the diagnosis of Creutzfeldt-Jakob disease

    PubMed Central

    Dulamea, A; Solomon, E

    2016-01-01

    Objective: Sporadic Creutzfeldt-Jakob disease (CJD) is a human prion disease, rapidly progressive and fatal, characterized by spongiform encephalopathy. The characteristic triad of signs - rapidly progressive dementia, myoclonus and periodic sharp wave complexes (PSWC) on electroencephalography (EEG) - usually appear in the late stages of the disease. The clinical diagnosis of CJD ante-mortem involves the exclusion of the rapidly progressive non-prionic dementias, the definitive diagnosis requiring brain tissue confirmation. Authors evaluated the methods of clinical diagnosis for sporadic CJD. Methods: This study retrospectively reviewed the medical records of patients diagnosed with probable sporadic CJD, based on brain magnetic resonance imaging (MRI), EEG, cerebrospinal fluid (CSF) analysis and extensive laboratory work-up. Results: Four patients with a mean age of 67 years were included in our study. The mean duration from diagnosis until death was of 3.2 weeks. The clinical features of the disease at onset were atypical. In the final stage of the disease, all patients presented rapidly progressive dementia and myoclonus. High levels of 14-3-3 protein and tau protein and normal levels of amyloid β1-42 were found at CSF analysis, in all patients. PSWC on EEG were present in 3 out of 4 patients at different moments of the disease. MRI showed hyperintense lesions in brain cortex, caudate nucleus, and putamen on T2, FLAIR, and DWI. Conclusion: CJD may present various clinical features and, since brain biopsy is usually difficult to perform, a combination of biomarkers is useful in order to establish the diagnosis in the early phase of the disease. PMID:27453757

  3. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients

    PubMed Central

    Moore, Roger A.; Head, Mark W.; Ironside, James W.; Ritchie, Diane L.; Zanusso, Gianluigi; Pyo Choi, Young; Priola, Suzette A.

    2016-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrPSc). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrPC) into infectious PrPSc. By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrPSc. In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrPC allotype to PrPSc in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrPSc with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrPC containing an M or V at residue 129 having a similar propensity to misfold into PrPSc thus causing sCJD. By contrast, PrPSc with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrPSc containing V at residue 129. In both types of CJD, the PrPSc allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrPSc allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD. PMID:26840342

  4. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Moore, Roger A; Head, Mark W; Ironside, James W; Ritchie, Diane L; Zanusso, Gianluigi; Choi, Young Pyo; Pyo Choi, Young; Priola, Suzette A

    2016-02-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc). By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrP(Sc). In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrP(C) allotype to PrP(Sc) in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrP(Sc) with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrP(C) containing an M or V at residue 129 having a similar propensity to misfold into PrP(Sc) thus causing sCJD. By contrast, PrP(Sc) with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrP(Sc) containing V at residue 129. In both types of CJD, the PrP(Sc) allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrP(Sc) allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD. PMID:26840342

  5. Social cognitive predictors of intention to test for variant Creutzfeldt-Jakob disease in those affected by haemophilia and other clotting disorders.

    PubMed

    Rowland, Gemma; Robinson, Georgina; Chilcot, Joseph; Troop, Nicholas A

    2014-06-01

    Individuals with bleeding disorders are at increased risk of variant Creutzfeldt-Jakob disease. This study explored social cognitive predictors of screening intentions. Ninety men and women with bleeding disorders, recruited through the Haemophilia Society, completed an extended Theory of Planned Behaviour questionnaire to predict intention to screen for variant Creutzfeldt-Jakob disease. Extended Theory of Planned Behaviour variables accounted for 57 per cent of the variance in intention. Self-efficacy and anticipated affect predicted intention directly, while attitudes were mediated by anticipated affect. Simple interventions that already exist address relevant predictive components of intention to screen for variant Creutzfeldt-Jakob disease and could be used to aid decision-making. PMID:23520351

  6. Bioassay Studies Support the Potential for Iatrogenic Transmission of Variant Creutzfeldt Jakob Disease through Dental Procedures

    PubMed Central

    Vassey, Matthew; Dennis, Mike; Cornwall, Mark; McLeod, Neil; Smith, Andrew; Marsh, Philip D.; Walker, James T.; Sutton, J. Mark; Raven, Neil D. H.

    2012-01-01

    Background Evidence is required to quantify the potential risks of transmission of variant Creutzfeldt Jakob (vCJD) through dental procedures. Studies, using animal models relevant to vCJD, were performed to address two questions. Firstly, whether oral tissues could become infectious following dietary exposure to BSE? Secondly, would a vCJD-contaminated dental instrument be able to transmit disease to another patient? Methods BSE-301V was used as a clinically relevant model for vCJD. VM-mice were challenged by injection of infected brain homogenate into the small intestine (Q1) or by five minute contact between a deliberately-contaminated dental file and the gingival margin (Q2). Ten tissues were collected from groups of challenged mice at three or four weekly intervals, respectively. Each tissue was pooled, homogenised and bioassayed in indicator mice. Findings Challenge via the small intestine gave a transmission rate of 100% (mean incubation 157±17 days). Infectivity was found in both dental pulp and the gingival margin within 3 weeks of challenge and was observed in all tissues tested within the oral cavity before the appearance of clinical symptoms. Following exposure to deliberately contaminated dental files, 97% of mice developed clinical disease (mean incubation 234±33 days). Interpretation Infectivity was higher than expected, in a wider range of oral tissues, than was allowed for in previous risk assessments. Disease was transmitted following transient exposure of the gingiva to a contaminated dental file. These observations provide evidence that dental procedures could be a route of cross-infection for vCJD and support the enforcement of single-use for certain dental instruments. PMID:23226225

  7. Analyses of the mitochondrial mutations in the Chinese patients with sporadic Creutzfeldt-Jakob disease.

    PubMed

    Zhang, Jin; Zhang, Zhi-Xia; Du, Peng-Chen; Zhou, Wei; Wu, Su-Dong; Wang, Qi-Ling; Chen, Cao; Shi, Qi; Chen, Chen; Gao, Chen; Tian, Chan; Dong, Xiao-Ping

    2015-01-01

    Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause a variety of chronic diseases in central nervous system (CNS). However, the role of mtDNA mutations in sporadic Creutzfeldt-Jakob disease (sCJD) has still been unknown. In this study, we comparatively analyzed complete mtDNA sequences of 31 Chinese sCJD patients and 32 controls. Using MITOMASTER and PhyloTree, we characterized 520 variants in sCJD patients and 507 variants in control by haplogroup and allele frequencies. We classified the mtDNAs into 40 sub-haplogroups of 5 haplogroups, most of them being Asian-specific haplogroups. Haplogroup U, an European-specific haplogroups mtDNA, was found only in sCJD. The analysis to control region (CR) revealed a 31% increase in the frequency of mtDNA CR mutations in sCJD versus controls. In functional elements of the mtDNA CR, six CR mutations were in conserved sequence blocks I (CSBI) in sCJD, while only one in control (P<0.05). More mutants in transfer ribonucleic acid-Leu (tRNA-Leu) were detected in sCJD. The frequencies of two synonymous amino-acid changes, m.11467A>G, p.(=) in NADH dehydrogenase subunit 4 (ND4) and m.12372G>A, p.(=) in NADH dehydrogenase subunit 5 (ND5), in sCJD patients were higher than that of controls. Our study, for the first time, screened the variations of mtDNA of Chinese sCJD patients and identified some potential disease-related mutations for further investigations. PMID:24667788

  8. MRI and FDG PET/CT findings in a case of probable Heidenhain variant Creutzfeldt-Jakob disease.

    PubMed

    Clarençon, F; Gutman, F; Giannesini, C; Pénicaud, A; Galanaud, D; Kerrou, K; Marro, B; Talbot, J-N

    2008-10-01

    Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disease caused by the accumulation of a pathogenic isoform of a prion protein in neurons that is responsible for subacute dementia. The Heidenhain variant is an atypical form of CJD in which visual signs are predominant. This is a report of the case of a 65-year-old man with probable CJD of the Heidenhain variant, with topographical concordance between findings on magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) photopenic areas on positron emission tomography (PET)/computed tomography (CT) for cortical parietooccipital lesions. PMID:18466976

  9. Vision loss due to coincident ocular and central causes in a patient with Heidenhain variant Creutzfeldt-Jakob disease.

    PubMed

    Foundas, Maria; Donaldson, Mark D; McAllister, Ian L; Bridges, Leslie R

    2008-03-01

    Creutzfeldt-Jakob disease (CJD) is a degenerative disease of the brain associated with a rapidly progressive spongiform encephalopathy. Visual symptoms and neuro-ophthalmological signs are not infrequent, and presentation to an ophthalmologist may result. A case is reported of an 89-years-old gentleman who presented with a short history of isolated deterioration in vision. He underwent ocular intervention but subsequently developed progressive dementia, asterixis, myoclonus, cerebellar and extrapyramidal signs, and cortical blindness. An electroencephalogram was consistent with CJD. The patient progressively deteriorated and died 9 weeks after symptom onset. Limited post-mortem examination confirmed CJD. PMID:18065777

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

    PubMed

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

    2016-06-01

    As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP(Sc) ). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP(Sc) in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP(Sc) , represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases. PMID:26669818

  11. [Creutzfeldt-Jakob disease, Heidenhain variant: case report with MRI (DWI) findings].

    PubMed

    Arruda, Walter Oleschko; Bordignon, Kelly C; Milano, Jerônimo B; Ramina, Ricardo

    2004-06-01

    Creutzfeldt-Jakob disease (CJD) is a presenile dementia characterized by rapidly progressive mental deterioration, myoclonic jerking, and other less common neurological signs. Few autoctonous cases have been described in Brazil. A 54-year-old white woman, was admitted in our service with a month history of progressive, bilateral cortical blindness. After admission, she developed right partial motor seizures( right facial, upper and lower limbs), she became progressively aphasic( mixed aphasia). Seizures were controlled with phenytoin, but she developed choreoathetotic movements on her right dimidium, with partial control after introduction of chlorpromazine 25 mg q/d. She could no longer stand up or walk due to severe ataxia. The first EEG (October, 2001) showed left hemisphere severe seizure activity (status epilepticus partialis). She was delivered home with enteral nutrition, phenytoin, chlorpromazine and mepacrine 100 mg qd. The following laboratorial tests were negative or normal: blood series, platelets, ESR, kidney and liver function, copper, ceruloplasmin, VDRL, HIV, HTLV-1, lactate, and cerebral DSA (performed in other service).A spinal tap with normal opening pressure was perform and CSF examination was normal. CSF 14-3-3 protein was positive, CSF specific neuronal enolase 7.5 ng/ml(normal). Genetic study of PRNP gene did not disclosed any known mutation. A MRI (October, 2001) showed areas of hyperintense signal (T2 and FLAIR) without Gd-enhancement on T1, in the left temporal lobe and in both occipital lobes; basal ganglia have a normal appearance. DWI imaging showed bright areas at the same sites. An EEG (March, 2002) disclosed a periodical sharp triphasic waves pattern, suggestive of CJD. A second MRI (April, 2002) showed mild generalized atrophy, no ventricular dilatation, and the hyperintense sites disappeared. She remained clinically stable and under use of chlorpromazine and mepacrine until she died due to pulmonary complications on April, 2003

  12. Towards an Age-Dependent Transmission Model of Acquired and Sporadic Creutzfeldt-Jakob Disease

    PubMed Central

    de Pedro-Cuesta, Jesús; Mahillo-Fernandez, Ignacio; Calero, Miguel; Rábano, Alberto; Cruz, Mabel; Siden, Åke; Martínez-Martín, Pablo; Laursen, Henning; Ruiz-Tovar, María; Mølbak, Kåre

    2014-01-01

    Introduction Sporadic Creutzfeldt-Jakob disease (sCJD) might be transmitted by surgery. The purpose of this study was to investigate potential susceptibility to sCJD from surgery at juvenile age and in early adulthood. Methods From Danish and Swedish national registries we identified 167 definite and probable sCJD cases with onset from 1987 through 2003, and 835 age-, sex- and residence-matched controls along with their surgical histories. Main, anatomically or etiologically classified surgical procedures followed by a ≥20-year lag were analyzed using logistic regression, and stratified by age at first-registered surgical discharge. Results The risk of having a diagnosis of CJD depended strongly on age at first surgery with odds ratio (OR) of 12.80 (95% CI 2.56–64.0) in patients <30 years, 3.04 (95% 1.26–7.33) in 30–39 years, and 1.75 (95% CI 0.89–3.45) in ≥40 years, for anatomically classified surgical procedures. Similar figures were obtained for etiologically classified surgical procedures. Conclusions Risk of surgical-acquired sCJD depends on age at exposure; this pattern is similar to age-specific profiles reported for CJD accidentally transmitted by human pituitary-derived growth hormone and susceptibility curves for variant CJD estimated after adjustment for dietary exposure to bovine spongiform encephalopathy. There might be an age-at-exposure-related susceptibility to acquire all CJD forms, including sCJD from routine surgery. PMID:25279832

  13. [Prion, from crazy cows to iatrogenic Creutzfeldt-Jakob disease. Which risk in laboratory or in hospital?].

    PubMed

    Paul, J

    1995-02-01

    The long latency time, without any characteristic clinical sign, of transmissible degenerative encephalopathies, the transmissibility of the called "prion" infectious agent, associated with its exceptional resistance to normal inactivation methods, are resulting in accidental transmissions, both human (Creutzfeldt-Jakob disease), and animal (bovine spongiform encephalopathy). Among data about physical and chemical inactivation methods tested, we retain, to avoid professional or iatrogenic transmissions in the laboratory or in hospital, steam autoclaving and sodium hypochlorite or hydroxide treatment. But inactivation shall not be performed using the current processes as regarding parameters such as temperature, concentration and duration of exposure. PMID:7777380

  14. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

    PubMed Central

    Sanchez-Juan, Pascual; Bishop, Matthew T.; Kovacs, Gabor G.; Calero, Miguel; Aulchenko, Yurii S.; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J.; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G.; Collins, Steven J.; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S. G.; Will, Robert G.; van Duijn, Cornelia M.

    2015-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  15. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

    PubMed

    Sanchez-Juan, Pascual; Bishop, Matthew T; Kovacs, Gabor G; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G; Collins, Steven J; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S G; Will, Robert G; van Duijn, Cornelia M

    2014-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  16. Dietary Risk Factors for Sporadic Creutzfeldt-Jakob Disease: A Confirmatory Case-Control Study

    PubMed Central

    Davanipour, Zoreh; Sobel, Eugene; Ziogas, Argyrios; Smoak, Carey; Bohr, Thomas; Doram, Keith; Liwnicz, Boleslaw

    2014-01-01

    Aims This study’s primary purpose was to determine whether earlier findings suggesting an association between sporadic Creutzfeldt-Jakob disease (sCJD), a transmissible spongiform encephalopathy of humans and specific dietary components could be replicated. The a priori hypotheses were that consumption of (i) foods likely to contain organ tissue and (ii) raw/rare meat are associated with increased sCJD risk. Study Design Population-based case-control study. Place and Duration of Study Department of Neurology, School of Medicine, Loma Linda University, Loma Linda, CA, USA; 4 years. Methodology An 11-state case-control study of pathologically confirmed, definite sCJD cases, matched controls, and a sample of control-surrogates was conducted. Ninety-six percent (106/110) of the case data was obtained in 1991-1993, prior to variant CJD publicity. Results Using control self-responses, consumption of hot dogs, sausage, pepperoni, kielbasa, “other” canned meat, poultry liver, any stomach/intestine, beef stomach/intestine, any organ tissue, and beef organ tissue was individually associated with increased sCJD risk; odds ratios (OR) ranged from 2.4 to 7.2 (0.003

  17. No reactivation of JCV and CMV infections in the temporal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease patients

    PubMed Central

    Löffler, Judith; Krasemann, Susanne; Zerr, Inga; Matschke, Jakob; Glatzel, Markus

    2014-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by great phenotypic variability regarding clinical course and neuropathology. The most prominent disease modifiers are a polymorphism in Codon 129 of the prion protein gene and conformational variations of the misfolded prion protein. The cellular form of the prion protein restricts replication of viruses and may be involved in viral host defense, and viral infections influence the presentation and neuropathology in prion diseased mice. We investigated the occurrence of reactivated persistent viral infections of the brain in brain tissue samples of 25 sCJD patients. No evidence of reactivated JCV and CMV infections could be detected. This suggests that JCV and CMV infections are not reactivated as consequence of prion disease and do not act as disease modifiers in sCJD. PMID:25628966

  18. The variant Creutzfeldt-Jakob Disease: Risk, uncertainty or safety in the use of blood and blood derivatives?

    PubMed

    Liras, Antonio

    2008-01-01

    It has been long since French physician Jean-Baptiste Denys carried out the first successful blood transfusion to a human being. Using bird feathers as canules, sheep blood was transfused to a young man. The patient died soon after Denys' treatment and Denys was accused of murder. In the XXI century, known as the biotechnology century, we face new challenges in Medicine. New emerging and reemerging diseases, such as Creutzfeldt-Jakob disease (CJD) or "mad cow disease" and its human variant (vCJD), challenge the biosafety aspects of a widely extended and extremely useful technique, that is, the perfusion of blood, of its derived components and of other pharmacological products obtained from plasma. To face these new challenges we need innovative prevention strategies. PMID:18573217

  19. Creutzfeldt-Jakob Disease in a Tertiary Care Hospital in Thailand: A Case Series and Review of the Literature

    PubMed Central

    Lolekha, Praween; Rasheed, Ahmed; Yotsarawat, Chutanat

    2015-01-01

    Creutzfeldt-Jakob Disease (CJD) is an incurable and inevitably fatal neurodegenerative disorder. Although CJD has a worldwide distribution, there are no official statistics on CJD in Thailand. A diagnosis of CJD is suspected when a patient develops rapidly progressive dementia with myoclonus. However, CJD may be mistaken for a variety of illnesses because its initial presentation frequently consists of non-specific symptoms. Here, we examined cases of sporadic CJD (sCJD) from Thammasat University Hospital (a tertiary care hospital in Thailand) between January 1, 2012 and December 31, 2014. Three cases of probable and possible sCJD were collected. All cases presented with rapidly progressive cognitive dysfunction accompanied by spontaneous myoclonus. Classical electroencehalography changes and typical abnormal MRI features were observed. All of the cases died within a period of 8 months. None of the patients underwent brain biopsy. Our findings raise questions about the prevalence of CJD in Thailand, which needs further study. PMID:26413241

  20. Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program

    PubMed Central

    Lim, Jae-Sung; Kwon, Hyung-Min; Jang, Jae-Won; Ju, Young-Ran; Kim, SuYeon; Park, Young Ho; Park, So Young; Kim, SangYun

    2015-01-01

    Abstract Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician's reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD. PMID:25996401

  1. An alarming presentation of Creutzfeldt-Jakob disease following a self-inflicted gunshot wound to the head.

    PubMed

    Harnish, Carissa; Gross, Brian; Rittenhouse, Katelyn; Bupp, Katherine; Vellucci, Ashley; Anderson, Jeffrey; Riley, Deborah; Rogers, Frederick B

    2015-05-01

    Transmissible spongiform encephalopathies (TSE), also known as prion diseases, are characterized by rapid and fatal neurological decline. They not only detrimentally affect the patient, but also present additional challenges to healthcare systems due to the infectivity of the tissues and the difficulty of inactivating the prion. The most common TSE is Creutzfeldt-Jakob disease (CJD), which can occur after familial, spontaneous or acquired transmission. TSEs received more attention after the development of variant CJD (vCJD), also known as Mad Cow Disease, in the UK during the mid-1990s. Unlike familial or spontaneous CJD, this variant was connected to consumption of cattle contaminated with the prion disease, bovine spongiform encephalopathy.This development increased interest in the etiology of CJD and other TSEs and the risk it presents as an infectious disease. The following details the case of a 59-year-old male infected with CJD presented to our level II trauma center for treatment following a self-inflicted gunshot wound to the head. PMID:25530409

  2. Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD)

    SciTech Connect

    Gabizon, R.; Rosenmann, H.; Meiner, Z.; Kahana, I. ); Kahana, E. ); Shugart, Y.; Ott, J. ); Prusiner, S.B. )

    1993-10-01

    The inherited prion diseases are neurodegenerative disorders which are not only genetic but also transmissible. More than a dozen mutations in the prion protein gene that result in nonconservative amino acid substitutions segregate with the inherited prion diseases including familial Creutzfeldt-Jakob disease (CJD). In Israel, the incidence of CJD is about 1 case/10[sup 4] Libyan Jews. A Lys[sub 200] substitution segregates with CJD and is reported here to be genetically linked to CJD with a lod score of >4.8. Some healthy elderly Lys[sub 200] carriers > age 65 years were identified, suggesting the possibility of incomplete penetrance. In contrast, no linkage was found between the development of familial CJD and a polymorphism encoding either Met[sub 129] or Val[sub 129]. All Libyan Jewish CJD patients with the Lys[sub 200] mutation encode a Met[sub 129] on the mutant allele. Homozygosity for Met[sub 129] did not correlate with age at disease onset or the duration of illness. The frequency of the Met[sub 129] allele was higher in the affected pedigrees than in a control population of Libyan Jews. The frequency of the Met[sub 129] and Val[sub 129] alleles in the control Libyan population was similar to that found in the general Caucasian population. The identification of three Libyan Jews homozygous for the Lys[sub 200] mutation suggests frequent intrafamilial marriages, a custom documented by genealogical investigations. 26 refs., 3 figs., 6 tabs.

  3. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene

    SciTech Connect

    Goldfarb, L.G.; Brown, P.; McCombie, W.R.; Gibbs, C.J. Jr.; Gajdusek, D.C. ); Goldgaber, D. ); Swergold, G.D. ); Wills, P.R. ); Cervenakova, L. ); Baron, H. )

    1991-12-01

    The PRNP gene, encoding the amyloid precursor protein that is centrally involved in Creutzfeldt-Jakob disease (CJD), has an unstable region of five variant tandem octapeptide coding repeats between codons 51 and 91. The authors screened a total of 535 individuals for the presence of extra repeats in this region, including patients with sporadic and familial forms of spongiform encephalopathy, members of their families, other neurological and non-neurological patients, and normal controls. They identified three CJD families (in each of which the proband's disease was neuropathologically confirmed and experimentally transmitted to primates) that were heterozygous for alleles with 10, 12, or 13 repeats, some of which had wobble nucleotide substitutions. They also found one individual with 9 repeats and no nucleotide substitutions who had no evidence of neurological disease. These observations, together with data on published British patients with 11 and 14 repeats, strongly suggest that the occurrence of 10 or more octapeptide repeats in the encoded amyloid precursor protein predisposes to CJD.

  4. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

    PubMed

    Moda, Fabio; Suardi, Silvia; Di Fede, Giuseppe; Indaco, Antonio; Limido, Lucia; Vimercati, Chiara; Ruggerone, Margherita; Campagnani, Ilaria; Langeveld, Jan; Terruzzi, Alessandro; Brambilla, Antonio; Zerbi, Pietro; Fociani, Paolo; Bishop, Matthew T; Will, Robert G; Manson, Jean C; Giaccone, Giorgio; Tagliavini, Fabrizio

    2012-09-01

    In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form. PMID:22288561

  5. Clinical and MRI evaluation of anxiety as the first symptom of sporadic Creutzfeldt-Jakob disease: A case report

    PubMed Central

    LIU, WEIBO; LU, YUNRONG; ZHONG, GUODONG; JIANG, BIAO; PAN, ZHIJIE

    2016-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, transmissible prion disease of the brain, characterized by prominent neurological symptoms and progressive dementia. Early psychiatric manifestations as an initial or sole symptom of sCJD are relatively rare. The current report describes an elderly female patient with sCJD demonstrating anxiety as an initial symptom. The present patient was initially diagnosed with adjustment disorder and anxiety; however, the rapid deterioration of the patient's cognitive and neurological functioning led to a diagnosis of sCJD. Diffusion-weighted magnetic resonance images of the brain supported a diagnosis of sCJD, and it was posited that the abnormalities of gray matter that were observed within the bilateral cingulate cortex may be the pathophysiological basis of the anxiety associated with this case of sCJD. The patient eventually succumbed to inhalational bronchopneumonia 5 months after anxiety onset. The present case report emphasizes the importance of secondary causes of anxiety symptoms in elderly patients, and indicates that brain DWI is a non-invasive and useful examination in the early diagnosis of sCJD. PMID:27073474

  6. Surgery and Risk of Sporadic Creutzfeldt-Jakob Disease in Denmark and Sweden: Registry-Based Case-Control Studies

    PubMed Central

    Mahillo-Fernandez, Ignacio; de Pedro-Cuesta, Jesús; Bleda, Maria José; Cruz, Mabel; Mølbak, Kåre; Laursen, Henning; Falkenhorst, Gerhard; Martínez-Martín, Pablo; Siden, Åke

    2008-01-01

    Background Epidemiologic evidence of surgical transmission of sporadic Creutzfeldt-Jakob disease (sCJD) remains controversial. Methods From Danish and Swedish registries we selected 167 definite and probable sCJD cases (with onset between 1987 and 2003) and 3,059 controls (835 age-, sex-, and residence-matched, and 2,224 unmatched). Independent of case/control status, surgical histories were obtained from National Hospital Discharge Registries. Surgical procedures were categorized by body system group and lag time to onset of sCJD. Exposure frequencies were compared using logistic regression. Results A history of any major surgery, conducted ≥20 years before sCJD onset, was more common in cases than both matched (OR = 2.44, 95% CI = 1.46–4.07) and unmatched controls (OR = 2.25, 95% CI = 1.48–3.44). This observation was corroborated by a linear increase in risk per surgical discharge (OR = 1.57, 95% CI = 1.13–2.18; OR = 1.50, 95% CI = 1.18–1.91). Surgery of various body systems, including peripheral vessels, digestive system and spleen, and female genital organs, was significantly associated with increased sCJD risk. Conclusions A variety of major surgical procedures constitute a risk factor for sCJD following an incubation period of many years. A considerable number of sCJD cases may originate from health care-related accidental transmission. PMID:18843192

  7. Sporadic Creutzfeldt-Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties.

    PubMed

    Kobayashi, Atsushi; Matsuura, Yuichi; Iwaki, Toru; Iwasaki, Yasushi; Yoshida, Mari; Takahashi, Hitoshi; Murayama, Shigeo; Takao, Masaki; Kato, Shinsuke; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-01-01

    The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt-Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these "pure" cases, "mixed" cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co-occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft-associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1. PMID:25851836

  8. Sporadic Creutzfeldt-Jakob Disease: Prion Pathology in Medulla Oblongata—Possible Routes of Infection and Host Susceptibility

    PubMed Central

    Iacono, Diego; Ferrari, Sergio; Gelati, Matteo; Zanusso, Gianluigi; Mariotto, Sara; Monaco, Salvatore

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disorder, is characterized by remarkable phenotypic variability, which is influenced by the conformation of the pathologic prion protein and the methionine/valine polymorphic codon 129 of the prion protein gene. While the etiology of sCJD remains unknown, it has been hypothesized that environmental exposure to prions might occur through conjunctival/mucosal contact, oral ingestion, inhalation, or simultaneous involvement of the olfactory and enteric systems. We studied 21 subjects with definite sCJD to assess neuropathological involvement of the dorsal motor nucleus of the vagus and other medullary nuclei and to evaluate possible associations with codon 129 genotype and prion protein conformation. The present data show that prion protein deposition was detected in medullary nuclei of distinct sCJD subtypes, either valine homozygous or heterozygous at codon 129. These findings suggest that an “environmental exposure” might occur, supporting the hypothesis that external sources of contamination could contribute to sCJD in susceptible hosts. Furthermore, these novel data could shed the light on possible causes of sCJD through a “triple match” hypothesis that identify environmental exposure, host genotype, and direct exposure of specific anatomical regions as possible pathogenetic factors. PMID:26457299

  9. Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders.

    PubMed

    Lee, Sol Moe; Chung, Myungguen; Hyeon, Jae Wook; Jeong, Seok Won; Ju, Young Ran; Kim, Heebal; Lee, Jeongmin; Kim, SangYun; An, Seong Soo A; Cho, Sung Beom; Lee, Yeong Seon; Kim, Su Yeon

    2016-01-01

    Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10-15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer's disease or Parkinson's disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs. PMID:27341347

  10. Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders

    PubMed Central

    Lee, Sol Moe; Chung, Myungguen; Hyeon, Jae Wook; Jeong, Seok Won; Ju, Young Ran; Kim, Heebal; Lee, Jeongmin; Kim, SangYun; An, Seong Soo A.; Cho, Sung Beom; Lee, Yeong Seon; Kim, Su Yeon

    2016-01-01

    Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10–15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer’s disease or Parkinson’s disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs. PMID:27341347

  11. Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease.

    PubMed

    Tripathi, Ajai K; Singh, Neena

    2016-01-01

    Hemin is known to induce endocytosis of prion-protein (PrP(C)) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrP(Sc)) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrP(C) interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrP(C). Interestingly, PrP(C) is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we report that hemin binds PrP(C) on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrP(C) interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrP(C). A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α-globin in wild-type (PrP(+/+)) relative to PrP-knock-out (PrP(-/-)) samples. Furthermore, red blood cells and brain tissue from PrP(-/-) mice show significantly less α-globin relative to PrP(+/+) controls, indicating a positive effect of PrP(C) on Hb synthesis under physiological conditions as well. Surprisingly, levels of α-globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrP(C) that is likely to impact the therapeutic management of CH and sCJD. PMID:26836195

  12. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings.

    PubMed

    Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero

    2015-01-01

    The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2). PMID:26682685

  13. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings

    PubMed Central

    Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero

    2015-01-01

    The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2). PMID:26682685

  14. Sporadic Creutzfeldt-Jakob disease diagnostic accuracy is improved by a new CSF ELISA 14-3-3γ assay.

    PubMed

    Leitão, M J; Baldeiras, I; Almeida, M R; Ribeiro, M H; Santos, A C; Ribeiro, M; Tomás, J; Rocha, S; Santana, I; Oliveira, C R

    2016-05-13

    Protein 14-3-3 is a reliable marker of rapid neuronal damage, specifically increased in cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) patients. Its detection is usually performed by Western Blot (WB), prone to methodological issues. Our aim was to evaluate the diagnostic performance of a recently developed quantitative enzyme-linked immunosorbent (ELISA) assay for 14-3-3γ, in comparison with WB and other neurodegeneration markers. CSF samples from 145 patients with suspicion of prion disease, later classified as definite sCJD (n=72) or Non-prion diseases (Non-CJD; n=73) comprised our population. 14-3-3 protein was determined by WB and ELISA. Total Tau (t-Tau) and phosphorylated Tau (p-Tau) were also evaluated. Apolipoprotein E gene (ApoE) and prionic protein gene (PRNP) genotyping was assessed. ELISA 14-3-3γ levels were significantly increased in sCJD compared to Non-CJD patients (p<0.001), showing very good accuracy (AUC=0.982; sensitivity=97%; specificity=94%), and matching WB results in 81% of all cases. It strongly correlated with t-Tau and p-Tau (p<0.0001), showing slightly higher specificity (14-3-3 WB - 63%; Tau - 90%; p-Tau/t-Tau ratio - 88%). From WB inconclusive results (n=44), ELISA 14-3-3γ correctly classified 41 patients. Additionally, logistic regression analysis selected ELISA 14-3-3γ as the best single predictive marker for sCJD (overall accuracy=93%). ApoE and PRNP genotypes did not influence ELISA 14-3-3γ levels. Despite specificity for 14-3-3γ isoform, ELISA results not only match WB evaluation but also help discrimination of inconclusive results. Our results therefore reinforce this assay as a single screening test, allowing higher sample throughput and unequivocal results. PMID:26940479

  15. Validation of 14-3-3 Protein as a Marker in Sporadic Creutzfeldt-Jakob Disease Diagnostic.

    PubMed

    Schmitz, Matthias; Ebert, Elisabeth; Stoeck, Katharina; Karch, André; Collins, Steven; Calero, Miguel; Sklaviadis, Theodor; Laplanche, Jean-Louis; Golanska, Ewa; Baldeiras, Ines; Satoh, Katsuya; Sanchez-Valle, Raquel; Ladogana, Anna; Skinningsrud, Anders; Hammarin, Anna-Lena; Mitrova, Eva; Llorens, Franc; Kim, Yong Sun; Green, Alison; Zerr, Inga

    2016-05-01

    At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker test in suspected sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis. Increasing 14-3-3 test referrals in CJD reference laboratories in the last years have led to an urgent need to improve established 14-3-3 test methods. The main result of our study was the validation of a commercially available 14-3-3 ELISA next to the commonly used Western blot method as a high-throughput screening test. Hereby, 14-3-3 protein expression was quantitatively analyzed in CSF of 231 sCJD and 2035 control patients. We obtained excellent sensitivity/specificity values of 88 and 96% that are comparable to the established Western blot method. Since standard protocols and preanalytical sample handling have become more important in routine diagnostic, we investigated in a further step the reproducibility and stability of 14-3-3 as a biomarker for human prion diseases. Ring trial data from 2009 to 2013 revealed an increase of Fleiss' kappa from 0.51 to 0.68 indicating an improving reliability of 14-3-3 protein detection. The stability of 14-3-3 protein under short-term and long-term storage conditions at various temperatures and after repeated freezing/thawing cycles was confirmed. Contamination of CSF samples with blood appears likely to be an important factor at a concentration of more than 2500 erythrocytes/μL. Hemolysis of erythrocytes with significant release of 14-3-3 protein started after 2 days at room temperature. We first define clear standards for the sample handling, short- and long-term storage of CSF samples as well as the handling of blood- contaminated samples which may result in artificially elevated CSF levels of 14-3-3. PMID:25947081

  16. Cerebrospinal fluid real-time quaking-induced conversion is a robust and reliable test for sporadic creutzfeldt-jakob disease: An international study.

    PubMed

    McGuire, Lynne I; Poleggi, Anna; Poggiolini, Ilaria; Suardi, Silvia; Grznarova, Katarina; Shi, Song; de Vil, Bart; Sarros, Shannon; Satoh, Katsuya; Cheng, Keding; Cramm, Maria; Fairfoul, Graham; Schmitz, Matthias; Zerr, Inga; Cras, Patrick; Equestre, Michele; Tagliavini, Fabrizio; Atarashi, Ryuichiro; Knox, David; Collins, Steven; Haïk, Stéphane; Parchi, Piero; Pocchiari, Maurizio; Green, Alison

    2016-07-01

    Real-time quaking-induced conversion (RT-QuIC) has been proposed as a sensitive diagnostic test for sporadic Creutzfeldt-Jakob disease; however, before this assay can be introduced into clinical practice, its reliability and reproducibility need to be demonstrated. Two international ring trials were undertaken in which a set of 25 cerebrospinal fluid samples were analyzed by a total of 11 different centers using a range of recombinant prion protein substrates and instrumentation. The results show almost complete concordance between the centers and demonstrate that RT-QuIC is a suitably reliable and robust technique for clinical practice. Ann Neurol 2016;80:160-165. PMID:27130376

  17. Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutation

    PubMed Central

    2014-01-01

    Background Human prion diseases are caused by abnormal accumulation of misfolded prion protein in the brain tissue. Inherited prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), are associated with mutations of the prion protein gene (PRNP). The glutamate (E)-to-lysine (K) substitution at codon 200 (E200K) in PRNP is the most common pathogenic mutation causing fCJD, but the E200K pathogenic mutation alone is regarded insufficient to cause prion diseases; thus, additional unidentified factors are proposed to explain the penetrance of E200K-dependent fCJD. Here, exome differences and biological network analysis between fCJD patients with E200K and healthy individuals, including a non-CJD individual with E200K, were analysed to gain new insights into possible mechanisms for CJD in individuals carrying E200K. Methods Exome sequencing of the three CJD patients with E200K and 11 of the family of one patient (case1) were performed using the Illumina HiSeq 2000. The exome sequences of 24 Healthy Koreans were used as control. The bioinformatic analysis of the exome sequences was performed using the CLC Genomics Workbench v5.5. Sanger sequencing for variants validation was processed using a BigDye Terminator Cycle Sequencing Kit and an ABI 3730xl automated sequencer. Biological networks were created using Cytoscape (v2.8.3 and v3.0.2) and Pathway Studio 9.0 software. Results Nineteen sites were only observed in healthy individuals. Four proteins (NRXN2, KLKB1, KARS, and LAMA3) that harbour rarely observed single-nucleotide variants showed biological interactions that are associated with prion diseases and/or prion protein in our biological network analysis. Conclusion Through this study, we confirmed that individuals can have a CJD-free life, even if they carry a pathogenic E200K mutation. Our research provides a possible mechanism that involves a candidate protective factor; this could be exploited to prevent fCJD onset in individuals carrying E200K. PMID

  18. Late-in-life surgery associated with Creutzfeldt-Jakob disease: a methodological outline for evidence-based guidance

    PubMed Central

    2013-01-01

    Background There is increasing epidemiological evidence of etiological links between general surgery and sporadic Creutzfeldt-Jakob disease (sCJD) with long incubation periods. The purpose of this study was to identify specific surgical procedures potentially associated with sCJD to be targeted for preventive presurgical-intervention guidance. Results We propose a three-step clinical guidance outline where surgical procedures associated with sCJD clinical onset – potentially more contaminant - are taken into account. Data on hospital discharges and surgical procedures were obtained from Danish and Swedish national in-patient hospital registries for 167 sCJD cases, onset 1987–2003, and for 835 matched and 2,224 unmatched population controls. Surgery was allocated to different life-time periods as previously reported, and frequencies were compared using logistic regression analysis. In the year preceding clinical onset, persons with sCJD underwent a statistically significant higher number of minor surgical interventions (OR (95% CI): 17.50 (3.64-84.24)), transluminal endoscopies (OR: 2.73 (1.01–7.37)) and gastrointestinal operations (OR: 3.51 (1.21–10.19)) compared to matched controls. Surgical discharges clustered towards clinical onset. These differences increased during the clinical period, with statistically significant higher frequencies for both endoscopies and minor surgery (OR: 13.91 (5.87-32.95), and for main surgical procedures (OR: 2.10 (1.00-4.39)), particularly gastrointestinal surgery (OR: 6.00 (1.83-19.66)), and surgery contacting skeletal muscle. Comparisons with unmatched controls yielded similar results for neurosurgery in the clinical period (OR: 19.40 (2.22-168.34)). Conclusions These results suggest that some types of surgical procedures are associated with sCJD, after clinical onset or particularly just before onset. Selective planning of such surgery to minimize instrument/device contamination or quarantining might be feasible

  19. CSF Tau proteins reduce misdiagnosis of sporadic Creutzfeldt-Jakob disease suspected cases with inconclusive 14-3-3 result.

    PubMed

    Leitão, M J; Baldeiras, I; Almeida, M R; Ribeiro, M H; Santos, A C; Ribeiro, M; Tomás, J; Rocha, S; Santana, I; Oliveira, C R

    2016-09-01

    Cerebrospinal fluid (CSF) 14-3-3 protein supports sporadic Creutzfeldt-Jakob (sCJD) diagnosis, but often leads to weak-positive results and lacks standardization. In this study, we explored the added diagnostic value of Total Tau (t-Tau) and phosphorylated Tau (p-Tau) in sCJD diagnosis, particularly in the cases with inconclusive 14-3-3 result. 95 definite sCJD and 287 patients without prion disease (non-CJD) were included in this study. CSF samples were collected in routine clinical diagnosis and analysed for 14-3-3 detection by Western blot (WB). CSF t-Tau and p-Tau were quantified by commercial ELISA kits and PRNP and APOE genotyping assessed by PCR-RFLP. In a regression analysis of the whole cohort, 14-3-3 protein revealed an overall accuracy of 82 % (sensitivity = 96.7 %; specificity = 75.6 %) for sCJD. Regarding 14-3-3 clear positive results, we observed no added value either of t-Tau alone or p-Tau/t-Tau ratio in the model. On the other hand, considering 14-3-3 weak-positive cases, t-Tau protein increased the overall accuracy of 14-3-3 alone from 91 to 94 % and specificity from 74 to 93 % (p < 0.05), with no sensitivity improvement. However, inclusion of p-Tau/t-Tau ratio did not significantly improve the first model (p = 0.0595). Globally, t-Tau protein allowed a further discrimination of 65 % within 14-3-3 inconclusive results. Furthermore, PRNP MV genotype showed a trend to decrease 14-3-3 sensitivity (p = 0.051), but such effect was not seen on t-Tau protein. In light of these results, we suggest that t-Tau protein assay is of significant importance as a second marker in identifying 14-3-3 false-positive results among sCJD probable cases. PMID:27357003

  20. Co-Distribution of Aβ Plaques and Spongiform Degeneration in Familial Creutzfeldt - Jakob Disease with E200K-129M Haplotype

    PubMed Central

    Ghoshal, Nupur; Cali, Ignazio; Perrin, Richard Justin; Josephson, Scott Andrew; Sun, Ning; Gambetti, Pierluigi; Morris, John Carl

    2009-01-01

    BACKGROUND Dominantly inherited Creutzfeldt-Jakob disease (CJD) comprises 5–15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Co-existent amyloid-beta (Aβ) pathology has been reported in some transmissible spongiform encephalopathies but not in familial CJD with the E200K mutation. OBJECTIVE To characterize a CJD family in which Aβ pathology co-distributes with spongiform degeneration. DESIGN Clinicopathological and molecular study of a family with CJD with the E200K-129M haplotype. SETTING Alzheimer’s disease research center MAIN OUTCOME MEASURES Clinical, biochemical, and neuropathological observations of 2 generations of a family. RESULTS In this kindred, three autopsied individuals showed pathological changes typical for this haplotype: spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, two of these cases (ages 57 and 63) showed numerous Aβ plaques co-distributed with the spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE4 carrier but not in the APOE4 noncarrier. Two additional individuals exhibited incomplete penetrance as they had no clinical evidence of CJD at death after age 80 and yet had affected siblings and children. CONCLUSION This is the first description of Aβ pathology in familial CJD with the E200K mutation. The co-distribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely influence each other. The kindred described here provides support that PrPE200K may also result in increased Aβ deposition. PMID:19822779

  1. Creutzfeldt-Jakob-Like Syndrome due to Hypercalcemic Encephalopathy.

    PubMed

    Rösche, Johannes; Sieveking, Catharina; Kampf, Christina; Benecke, Reiner

    2015-10-01

    Hypercalcemia can cause a subacute syndrome of progressive dementia and marked changes in the electroencephalogram (EEG). We report a case of iatrogenic hypercalcemia with a close correlation between the clinical course and the EEG changes. A 73-year-old woman presented with a subacute syndrome of progressive dementia and bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on a low-voltage background activity in the EEG. Clinical and EEG abnormalities rapidly resolved after normalization of serum calcium levels. As part of the diagnostic workup of a subacute progressive dementia, a serum calcium level and an EEG should be obtained to detect a Creutzfeldt-Jakob like syndrome in hypercalcemia. Unlike in Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob-like syndrome induced by lithium intoxication, there are rarely myoclonic jerks and periodic discharges in hypercalcemic encephalopathy. PMID:24973231

  2. Alien hand and leg as the presenting feature of probable sporadic Creutzfeldt-Jakob disease: A rare presentation of a rare disease.

    PubMed

    Kumawat, Banshi Lal; Sharma, Chandra Mohan; Nath, Kunal; Acharya, Mihir; Khandelwal, Dinesh; Jain, Deepak

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) can have varied clinical presentation depending upon the genotype at codon 129. The common presenting clinical features of sCJD are rapid onset cognitive impairment, ataxia, psychosis and visual signs (field defects, distortion, cortical blindness). Alien limb sign was first described in patients with corpus callosal tumors and later with other neurodegenerative conditions like corticobasal degeneration. Alien hand complaints as the presenting feature of sCJD has been described in literature, but simultaneous alien hand and leg has been rarely described as presenting feature of sCJD. We describe here a case of a 55-year-old man who presented with progressive left alien hand and leg as the sole clinical manifestation of probable sCJD. PMID:25745324

  3. An experiential learning model applied to nurses working with patients with Creutzfeldt-Jakob disease.

    PubMed

    D'Amour, Rolande; Guimond, Pierrette

    2010-01-01

    Creutzfeldt-Jacob disease (C/D) is a rare neurological disease, transmissible, incurable and always fatal affecting humans, as well as animals. In the 1980s, the "mad cow disease" (MCD) epidemic in the United Kingdom popularized prion diseases worldwide. However, this contributed to the proliferation of disinformation, causing confusion between C/D and MCD in the public, as well as in some health care providers. The purpose of this article is to describe the process utilized to develop, implement, and evaluate a workshop on CJD for nurses and other health care providers. Kolb's experiential teaching/learning model was used as a framework for this workshop. A workbook was developed to complement the participants' learning. Fifteen health care providers from the Alzheimer Society of Canada's Dementia Network agreed to participate in this educational project. The results indicated that the participants had limited knowledge about C/D. They felt ill prepared and uncomfortable in providing quality care to this patient population. The workshop generated new insights and knowledge about the disease and the needs of the patients and their families. Participants exchanged ideas for tailored interventions. An experiential teaching/learning model is a highly effective approach to increase knowledge and skills, as well as fostering reflective practice. PMID:20533643

  4. Creutzfeldt-Jakob disease and mad cows: lessons learnt from yeast cells.

    PubMed

    Hofmann, J; Wolf, H; Grassmann, A; Arndt, V; Graham, J; Vorberg, I

    2012-01-01

    Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that affect mammals including humans. The proteinaceous nature of the infectious agent, the prion, and its propagation, challenge established dogmas in biology. It is now widely accepted that prion diseases are caused by unconventional agents principally composed of a misfolded host-encoded protein, PrP. Surprisingly, major break-throughs in prion research came from studies on functionally unrelated proteins in yeast and filamentous fungi. Aggregates composed of these proteins act as epigenetic elements of inheritance that can propagate their alternative states by a conformational switch into an ordered ß-sheet rich polymer just like mammalian prions. Since their discovery prions of lower eukaryotes have provided invaluable insights into all aspects of prion biogenesis. Importantly, yeast prions provide proof-of-principle that distinct protein conformers can be infectious and can serve as genetic elements that have the capacity to encipher strain specific information. As a powerful and tractable model system, yeast prions will continue to increase our understanding of prion-host cell interaction and potential mechanisms of protein-based epigenetic inheritance. PMID:22270552

  5. Creutzfeldt-Jakob disease

    MedlinePlus

    ... advice early in the course of the disorder. Advance directive , power of attorney, and other legal actions ... easier to control, give patients time to make advance directives and prepare for the end of life, ...

  6. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... damage leads to rapid decline in thinking and reasoning as well as involuntary muscle movements, confusion, difficulty ... been tested but have not shown any benefit. Clinical studies of potential CJD treatments are complicated by ...

  7. Sporadic MM2-thalamic + cortical Creutzfeldt-Jakob disease: Utility of diffusion tensor imaging in the detection of cortical involvement in vivo.

    PubMed

    Grau-Rivera, Oriol; Sánchez-Valle, Raquel; Bargalló, Nuria; Lladó, Albert; Gaig, Carles; Nos, Carlos; Ferrer, Isidre; Graus, Francesc; Gelpi, Ellen

    2016-04-01

    In sporadic Creutzfeldt-Jakob disease (sCJD), high signal intensity in fluid attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences in striatum and/or cortical regions of the brain are present in about 83% of cases, reflecting tissue damage, such as spongiform change and abnormal prion protein deposits. Novel diffusion sequences of MRI might improve the detection of CJD characteristic changes in the subset of patients in whom these alterations are absent or less evident. We report a neuropathologically confirmed case of the rare MM2 T + C subtype of sCJD, with mixed clinical and neuropathological features of MM2 thalamic and MM2 cortical subtypes, in whom the use of diffusion tensor imaging helped to identify cortical hyperintensities that could be easily overlooked with conventional DWI. PMID:26542448

  8. [Epidemics of bovine spongiform encephalopathy and new variant of Creutzfeldt-Jakob disease in humans. Most recent findings on prion disease].

    PubMed

    Calza, L; Manfredi, R; Chiodo, F

    2001-02-01

    Prion diseases have been popularized by extensive media coverage of bovine spongiform encephalopathy (BSE) or "mad cow disease" epidemic, observed in Great Britain since 1986, and new variant Creutzfeldt-Jakob disease (nvCJD), reported for the first time in 1996. In contrast to the classical form of the disease, nvCJD affects younger patients, presents a relatively longer duration of illness and is caused by the same agent as BSE. Evidence from laboratory studies now strongly supports the hypothesis that new variant represents human form of animal disease, linked to exposure, probably through food, to bovine prions. Number of BSE reports in the United Kingdom began to decline in 1993, and has continuously decreased year by year since then, but a great worry spread in European countries in association with new BSE reported cases outside of the Great Britain, and increasing incidence of nvCJD. New epidemiological, clinical, histopathological and experimental data on prion diseases are reviewed, focusing our attention on the possible transmission of prion proteins from animals to humans. PMID:11294108

  9. Thinking the unthinkable: Alzheimer's, Creutzfeldt-Jakob and Mad Cow disease: the age-related reemergence of virulent, foodborne, bovine tuberculosis or losing your mind for the sake of a shake or burger.

    PubMed

    Broxmeyer, Lawrence

    2005-01-01

    The possibility of the age-related reemergence of foodborne Mycobacterium bovis (bovine tuberculosis) as a vector for Creutzfeldt-Jakob Disease (CJD or human Mad Cow Disease) and Mad Cow disease itself is real. The CDC reported last May of an outbreak of CJD linked to the consumption of meat contaminated "with the agent causing" bovine spongiform encephalopathy (BSE) in a New Jersey racetrack between the time frame 1995-2004. In the opinion of experts, ample justification exists for considering a similar pathogenesis for Alzheimer's, Creutzfeldt-Jakob and the other spongiform encephalopathies such as Mad Cow disease. In fact, Creutzfeldt-Jakob and Alzheimer's often coexist and at this point are thought to differ merely by time-dependent physical changes. A recent study links up to 13% of all "Alzheimer's" victims as really having Creutzfeldt-Jakob disease. Bovine tuberculosis, which includes Mycobacterium bovis and M. avium-intracellulare or paratuberculosis, is and has always been the most prevalent threat to the cattle industry, and the USDA reports that between 20% and 40% of US dairy herds are infected with paratuberculosis alone. The health risk for milk tainted with M. bovis has been known for decades and there was a time not so long ago when "tuberculin-tested" was printed on every milk container. Schliesser stated that meat from tuberculous animals may also constitute a significant risk of infection. At the turn of the 20th century 25% of the many US deaths from TB in adults were caused by M. bovis. Dairy products aside, when past and present meat consumption are factored in, there is three times the risk of developing Alzheimer's in meat eaters as opposed to vegetarians. The investigation into the causal trail for Creutzfeldt-Jakob, indistinguishable from Alzheimer's except for its shorter, lethal course might have grown cold where it not for Roel's and others who linked mad cow in cattle with M. bovis and related paratuberculosis on clinical, pathologic

  10. Complete penetrance of Creutzfeldt-Jakob disease in Libyan Jews carrying the E200K mutation in the prion protein gene.

    PubMed Central

    Spudich, S.; Mastrianni, J. A.; Wrensch, M.; Gabizon, R.; Meiner, Z.; Kahana, I.; Rosenmann, H.; Kahana, E.; Prusiner, S. B.

    1995-01-01

    BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a prion disease which is manifest as a sporadic, inherited, and transmissible neurodegenerative disorder. The mean age at onset of CJD is approximately 60 years, and as such, many people destined to succumb undoubtedly die of other illnesses first. The delayed onset of CJD has complicated the analysis of inherited forms of the illness and led to the suggestion that mutations in the prion protein (PrP) gene are necessary but not sufficient for prion disease despite genetic linkage; indeed, an environmental factor such as a ubiquitous virus has been proposed as a second necessary factor. MATERIALS AND METHODS: To examine what appeared to be incomplete penetrance, we applied a life-table analysis to clinical and pedigree data from a cluster population of Libyan Jews in which the E200K mutation is prevalent. The study population included 42 affected and 44 unaffected members of 13 Libyan Jewish families, all of whom possessed the E200K mutation. RESULTS: The calculated value using life table analysis is 0.77 at age 70 which increases to 0.89 if a mutation carrier survives to age 80 and 0.96 if age 80 is surpassed. CONCLUSIONS: These data argue that the E200K mutation alone is sufficient to cause prion disease and does so in an age-dependent manner. PMID:8529127

  11. Failure to detect the presence of prions in the uterine and gestational tissues from a Gravida with Creutzfeldt-Jakob disease.

    PubMed

    Xiao, Xiangzhu; Miravalle, Leticia; Yuan, Jue; McGeehan, John; Dong, Zhiqian; Wyza, Robert; MacLennan, Gregory T; Golichowski, Alan M; Kneale, Geoff; King, Nicholas; Kong, Qingzhong; Spina, Salvatore; Vidal, Ruben; Ghetti, Bernardino; Roos, Karen; Gambetti, Pierluigi; Zou, Wen-Quan

    2009-05-01

    The vertical transmission of a prion disease from infected mothers to their offspring is believed to be one of the routes for the natural spread of animal prion diseases. Supporting this notion is the observation that prion infectivity occurs in the placenta of infected ewes. Furthermore, the prion protein (PrP), both in its cellular form (PrP(C)) and its pathological isoform (PrP(Sc)), has been observed at the fetal-maternal interface of scrapie-infected sheep. However, whether these features of prion infectivity also hold true for human prion diseases is currently unknown. To begin to address such an important question, we examined PrP in the uterus as well as gestational tissues, including the placenta and amniotic fluid, in a pregnant woman with sporadic Creutzfeldt-Jakob disease (CJD). Although the proteinase K (PK)-resistant prion protein, PrP27-30, was present in the brain tissues of the mother, the PrP detected in the uterus, placenta, and amniotic fluid was sensitive to PK digestion. Unlike PrP(C) in the brain and adjacent cerebrospinal fluid, the predominant PrP species in the reproductive and gestational tissues were N-terminally truncated, similar to urine PrP. Our study did not detect abnormal PrP in the reproductive and gestational tissues in this case of CJD. Nevertheless, examination by a highly sensitive bioassay is ongoing to ascertain possible prion infectivity from CJD in the amniotic fluid. PMID:19349373

  12. Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US

    PubMed Central

    Ponte, Maya L

    2006-01-01

    Background Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. Methods and Findings A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall

  13. A study of clinical profile, radiological and electroencephalographic characteristics of suspected Creutzfeldt-Jakob disease in a tertiary care centre in South India

    PubMed Central

    Mahale, Rohan R.; Javali, Mahendra; Mehta, Anish; Sharma, Suryanarayana; Acharya, Purushottam; Srinivasa, Rangasetty

    2015-01-01

    Introduction: Creutzfeldt-Jakob disease (CJD) is a progressive, fatal, neurodegenerative disease classified under transmissible spongiform encephalopathies (TSE) or prion diseases. It is characterized by long asymptomatic period followed by rapid clinical deterioration leading to the death within months. The disease is still under-reported in India. Objective: The aim of this study was to describe the clinical, radiological and electroencephalographic characteristics of eight cases of CJD encountered in MS Ramaiah Medical college and Hospital, Bangalore over the past 3 years (2010-2013). This was retrospective, observational, hospital-based study. Results: The mean age of patients was 66.6 years (range: 54-82) and there was female predominance (five patients). The main clinical manifestations were cognitive disturbance (8/8) and myoclonus (8/8), followed by behavioral disturbance (5/8), ataxia (5/8) and extra-pyramidal symptoms/signs (4/8). Time interval (mean) between onset of disease to death was 6.6 months (range: 3-14). Brain MRI abnormalities were noted in 6 patients: Fluid-attenuated inversion recovery hyperintensities with restriction on diffusion-weighted image/apparent diffusion coefficient (DWI/ADC) in caudate and putamen, and diffusion hyperintensities without restriction on ADC in parieto-occipital, frontal and temporal regions. Classical electroencephalogram (EEG) changes of periodic triphasic waves were seen in 87% of patients. The CSF 14-3-3 protein assay was positive in two patients (out of four). Seven cases were probable CJD and one was possible CJD. Conclusion: A strong clinical suspicion aided by characteristic brain MRI and EEG abnormalities is essential for timely diagnosis of this fatal disease. PMID:25552850

  14. The Levels of Tau Isoforms Containing Exon-2 and Exon-10 Segments Increased in the Cerebrospinal Fluids of the Patients with Sporadic Creutzfeldt-Jakob Disease.

    PubMed

    Chen, Cao; Zhou, Wei; Lv, Yan; Shi, Qi; Wang, Jing; Xiao, Kang; Chen, Li-Na; Zhang, Bao-Yun; Dong, Xiao-Ping

    2016-08-01

    The alteration of protein tau in the cerebrospinal fluid (CSF) of Creutzfeldt-Jakob disease (CJD) has been widely evaluated, possessing a significant diagnostic value for CJD. With the biotin-labeled tau-exon-specific mAbs, direct ELISA methods were established and the levels of tau isoforms containing exon-2 and exon-10 segments in CSF of the patients with various human prion diseases and in brain tissues of scrapie-infected animals were evaluated. The results showed that the levels of tau, especially containing four repeats in microtubule binding domain, were increased in the CSF samples of the patients with sporadic CJD (sCJD). Using the unlabeled (cold) mixed exon-specific mAbs, a competitive tau ELISA was conducted based on a commercial tau kit. It revealed that the majority of the increased tau in the CSF of sCJD cases was derived from the tau isoforms with exon-2 and exon-10 segments. Increases of CSF tau isoforms with exon-2 and exon-10 segments were also observed in the patients of E200K and T188K genetic CJD (gCJD), but not in the cases of fatal familiar insomnia (FFI). The increasing levels of tau isoforms with exon-2 and exon-10 segments in the group of sCJD correlated well with the positive 14-3-3 in CSF. Additionally, the similar alterative profiles of tau isoforms with exon-2 and exon-10 segments were also observed in the brain tissues of scrapie-infected rodents and a sCJD patient. Our data here propose the tau isoforms with exon-2 and exon-10 segments increase in CSF of sCJD and some types of gCJD, which may help to understand the physiological metabolism and pathological significance of various tau isoforms in the pathogenesis of prion diseases. PMID:26188647

  15. Is brain copper deficiency in Alzheimer's, Lewy body, and Creutzfeldt Jakob diseases the common key for a free radical mechanism and oxidative stress-induced damage?

    PubMed

    Deloncle, Roger; Guillard, Olivier

    2015-01-01

    In Alzheimer's (AD), Lewy body (LBD), and Creutzfeldt Jakob (CJD) diseases, similar pathological hallmarks have been described, one of which is brain deposition of abnormal protease-resistant proteins. For these pathologies, copper bound to proteins is able to protect against free radicals by reduction from cupric Cu++ to cupreous Cu+. We have previously demonstrated in bovine brain homogenate that free radicals produce proteinase K-resistant prion after manganese is substituted for copper. Since low brain copper levels have been described in transmissible spongiform encephalopathies, in substantia nigra in Parkinson's disease, and in various brain regions in AD, LBD, and CJD, a mechanism has been proposed that may underlie the neurodegenerative processes that occur when copper protection against free radicals is impaired. In peptide sequences, the alpha acid proton near the peptide bond is highly mobile and can be pulled out by free radicals. It will produce a trivalent α-carbon radical and induce a free radical chain process that will generate a D-amino acid configuration in the peptide sequence. Since only L-amino acids are physiologically present in mammalian (human) proteins, it may be supposed that only physiological L-peptides can be recycled by physiological enzymes such as proteases. If a D-amino acid is found in the peptide sequence subsequent to deficient copper protection against free radicals, it will not be recognized and might alter the proteasome L-amino acid recycling from brain peptides. In the brain, there will result an accumulation of abnormal protease-resistant proteins such as those observed in AD, LBD, and CJD. PMID:25125459

  16. Distinctive properties of plaque-type dura mater graft-associated Creutzfeldt-Jakob disease in cell-protein misfolding cyclic amplification.

    PubMed

    Takeuchi, Atsuko; Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Morita, Masanori; Uno, Shusei; Kitamoto, Tetsuyuki

    2016-05-01

    There are two distinct subtypes of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with methionine homozygosity at codon 129 of the PRNP gene. The majority of cases is represented by a non-plaque-type (np-dCJD) resembling sporadic CJD (sCJD)-MM1 or -MV1, while the minority by a plaque-type (p-dCJD). p-dCJD shows distinctive phenotypic features, namely numerous kuru plaques and an abnormal isoform of prion protein (PrP(Sc)) intermediate in size between types 1 and 2. Transmission studies have shown that the unusual phenotypic features of p-dCJD are linked to the V2 prion strain that is associated with sCJD subtypes VV2 or -MV2. In this study, we applied protein misfolding cyclic amplification (PMCA) using recombinant human prion protein as a substrate and demonstrated that p-dCJD prions show amplification features that are distinct from those of np-dCJD. Although no amplification of np-dCJD prions was observed with either 129 M or 129 V substrate, p-dCJD prions were drastically amplified with the 129 V substrates, despite the PRNP codon 129 incompatibility between seed and substrate. Moreover, by using a type 2 PrP(Sc)-specific antibody not recognizing PrP(Sc) in p-dCJD, we found that type 2 products are generated de novo from p-dCJD prions during PMCA with the 129 V substrates. These findings suggest that our cell-PMCA is a useful tool for easily and rapidly identifying acquired CJD associated with the transmission of the V2 CJD strain to codon 129 methionine homozygotes, based on the preference for the 129 V substrate and the type of the amplified products. PMID:26878132

  17. Analysis of the compliance and the related influence factors in the follow-up process of surveillance for Creutzfeldt-Jakob disease in China

    PubMed Central

    Zhang, Xiao-Mei; Xiao, Kang; Zhou, Wei; Chen, Cao; Lv, Yan; Chen, Li-Na; Shi, Qi; Dong, Xiao-Ping

    2014-01-01

    Creutzfeldt-Jakob disease (CJD) is a kind of rare, rapidly progressive fatal central nervous system disorders. In China, the surveillance for CJD has started since 2006. As one of the major issues in CJD surveillance, the follow-up process via telephone plays important role in CJD diagnosis and surveillance. Although the follow-up process was conducted by the experiential staffs from CJD surveillance center in China CDC, it is frequently encountered that some interviewed family members do not cooperate well during follow-up. To screen the possible factors influence on the compliances of the interviewees during CJD follow-up, 11 independent variables from patient aspect and 4 variables from interviewee aspect were selected and a questionnaire was prepared. Based on 199 suspected sporadic CJD cases reported to CJD surveillance center in 2013, a telephone-inquiring was conducted and the degree of compliances of the interviewees were given as good, fair or poor. After screened with univariate analysis and evaluated ordinal logistic regression analysis, several indictors, such as the patient gender, CJD diagnosis, numbers of clinical symptoms, continual medical treatment after diagnosis, medical treatment mode, as well as the relationship with the patient and CJD knowledge of the interviewees, showed influence on the compliance in CJD follow-up process significantly. The data here provide for the first time the factors related with the compliances of the interviewed family members of the suspected CJD patients during follow-up process, which supplies useful clue for us to improve CJD follow-up process and increase the capacity of CJD surveillance. PMID:25482599

  18. Rapid and Highly Sensitive Detection of Variant Creutzfeldt - Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies

    PubMed Central

    Belondrade, Maxime; Nicot, Simon; Béringue, Vincent; Coste, Joliette; Lehmann, Sylvain; Bougard, Daisy

    2016-01-01

    The prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE) by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA) technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA). This assay allowed the specific detection of minute quantities (10−8 brain dilution) of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions. PMID:26800081

  19. The reporting of theoretical health risks by the media: Canadian newspaper reporting of potential blood transmission of Creutzfeldt-Jakob disease

    PubMed Central

    Wilson, Kumanan; Code, Catherine; Dornan, Christopher; Ahmad, Nadya; Hébert, Paul; Graham, Ian

    2004-01-01

    Background The media play an important role at the interface of science and policy by communicating scientific information to the public and policy makers. In issues of theoretical risk, in which there is scientific uncertainty, the media's role as disseminators of information is particularly important due to the potential to influence public perception of the severity of the risk. In this article we describe how the Canadian print media reported the theoretical risk of blood transmission of Creutzfeldt-Jakob disease (CJD). Methods We searched 3 newspaper databases for articles published by 6 major Canadian daily newspapers between January 1990 and December 1999. We identified all articles relating to blood transmission of CJD. In duplicate we extracted information from the articles and entered the information into a qualitative software program. We compared the observations obtained from this content analysis with information obtained from a previous policy analysis examining the Canadian blood system's decision-making concerning the potential transfusion transmission of CJD. Results Our search identified 245 relevant articles. We observed that newspapers in one instance accelerated a policy decision, which had important resource and health implication, by communicating information on risk to the public. We also observed that newspapers primarily relied upon expert opinion (47 articles) as opposed to published medical evidence (28 articles) when communicating risk information. Journalists we interviewed described the challenges of balancing their responsibility to raise awareness of potential health threats with not unnecessarily arousing fear amongst the public. Conclusions Based on our findings we recommend that journalists report information from both expert opinion sources and from published studies when communicating information on risk. We also recommend researchers work more closely with journalists to assist them in identifying and appraising relevant

  20. Rapid and Highly Sensitive Detection of Variant Creutzfeldt-Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies.

    PubMed

    Belondrade, Maxime; Nicot, Simon; Béringue, Vincent; Coste, Joliette; Lehmann, Sylvain; Bougard, Daisy

    2016-01-01

    The prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE) by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA) technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA). This assay allowed the specific detection of minute quantities (10-8 brain dilution) of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions. PMID:26800081

  1. Prion Diseases: Update on Mad Cow Disease, Variant Creutzfeldt-Jakob Disease, and the Transmissible Spongiform Encephalopathies.

    PubMed

    Janka, Jacqueline; Maldarelli, Frank

    2004-08-01

    Transmissible spongiform encephalopathies (TSEs) are a group of progressive, fatal neurodegenerative disorders that share a common spongiform histopathology. TSEs may be transmitted in a sporadic, familial, iatrogenic, or zoonotic fashion. The putative infectious agent of TSE, the prion, represents a novel paradigm of infectious disease with disease transmission in the absence of nucleic acid. Several small but spectacular epidemics of TSEs in man have prompted widespread public health and food safety concerns. Although TSEs affect a comparatively small number of individuals, prion research has revealed fascinating insights of direct relevance to common illnesses. This paper reviews recent advances that have shed new light on the nature of prions and TSEs. PMID:15265460

  2. [Still a small problem with the mad cow disease? Creutzfeldt-Jakob disease and other prion diseases: current status].

    PubMed

    Lundberg, P O

    2001-01-10

    This review is based on recent published research on the BSE/CJD/vCJD problem mainly from UK, Germany and France. The situation in Sweden seems to be fortunate for several reasons. The use of meat and bonemeal as animal fodder was forbidden in this country 13 years ago. Sweden has not had any sheep with scrapie for many years. No animals with BSE have so far been found in our country. The incidence of sporadic CJD in this country followed retrospectively from 1985 to 1996 and prospectively from 1997 to 1999 has been around 1.2 per million per year with no significant increase. Only few cases of familial CJD are known. No patient with iatrogenic CJD has ever been found. The use of growth hormone derived from human pituitary glands was abandoned in 1985 when recombinant human growth hormone became available. So far there is no indication that any of the CJD cases diagnosed in Sweden has been of the vCJD type, the one linked to BSE. However, as the incubation period for prion diseases is very long and the Swedes are frequent travellers there is a risk that people from our country could have contracted vCJD through consuming meat products in countries with BSE. As a precaution the consumption of brain, spinal cord, lymphatic tissue, lungs, and gastrointestinal tract should be avoided. Human pituitary derived growth hormone is still available in some countries and might be illegally imported into Sweden. PMID:11213704

  3. Roles of methionine oxidation in E200K prion protein misfolding: Implications for the mechanism of pathogenesis in E200K linked familial Creutzfeldt-Jakob disease.

    PubMed

    Wang, Zonglin; Feng, Boya; Xiao, Gengfu; Zhou, Zheng

    2016-04-01

    Prion diseases are a group of neurodegenerative diseases caused by prion protein (PrP) conformational changes. More than 30 PRNP gene mutations have been associated with familial prion diseases. E200K-associated familial Creutzfeldt-Jakob disease (fCJD) is the most common inherited prion disease. One of the hallmarks of prion diseases is the accumulation of oxidative damage. The mechanism by which oxidative modification of methionine (Met) residues influence the E200K PrP misfolding remains unclear. Here, we examined the stability, structural change, oligomerization and proteinase K resistance of unoxidized/oxidized E200K PrP and Met-to-Leu mutants. We found that oxidation of surface-exposed Met109/112/129/134/154/166 residues significantly destabilized E200K PrP but had a limited impact on the protein's structure. The oxidation of Met213 was the initial step in the conformational conversion of E200K PrP and facilitated the further oxidation of Met205/206. The oxidation of Met213/205/206 led to the exposure of the inner hydrophobic core, disrupted the overall structure of E200K PrP and induced the formation of large soluble multimers at low pH. In addition, the aggregation behavior of oxidized E200K PrP at the cellular level was investigated using E200K PrP Met-to-Ser mutants. The results showed that M109/112/129/154S or M134/166S mutants were efficiently localized on the cell membrane, whereas the M213/205/206S mutant generated many of aggregated fluorescent dots in the cytoplasm. The present work provides important clues for understanding the special roles of methionine oxidation in E200K PrP misfolding and links oxidative stress and consequent misfolding of oxidative damaged E200K PrP with the pathogenic mechanism of E200K-associated fCJD. PMID:26779934

  4. Accelerated, Spleen-Based Titration of Variant Creutzfeldt-Jakob Disease Infectivity in Transgenic Mice Expressing Human Prion Protein with Sensitivity Comparable to That of Survival Time Bioassay

    PubMed Central

    Halliez, Sophie; Reine, Fabienne; Herzog, Laetitia; Jaumain, Emilie; Haïk, Stéphane; Rezaei, Human; Vilotte, Jean-Luc; Laude, Hubert

    2014-01-01

    ABSTRACT The dietary exposure of the human population to the prions responsible for the bovine spongiform encephalopathy (BSE) epizooty has led to the emergence of variant Creutzfeldt-Jakob disease (vCJD). This fatal, untreatable neurodegenerative disorder is a growing public health concern because the prevalence of the infection seems much greater than the disease incidence and because secondary transmission of vCJD by blood transfusion or use of blood products has occurred. A current limitation in variant CJD risk assessment is the lack of quantitative information on the infectivity of contaminated tissues. To address this limitation, we tested the potential of a transgenic mouse line overexpressing human prion protein (PrP), which was previously reported to propagate vCJD prions. Endpoint titration of vCJD infectivity in different tissues was evaluated by two different methods: (i) the “classical” bioassay, based on the appearance of clinical symptoms and the detection of pathological prion protein in tissues of the inoculated mouse, and (ii) a shortened bioassay based on the detection of the protein in the mouse spleen at defined time points. The two methods proved equally sensitive in quantifying infectivity, even after very-low-dose inoculation of infected material, but the time schedule was shortened from ∼2.5 years to ∼1 year with the spleen bioassay. Compared to the “gold-standard” RIII model routinely used for endpoint titration of vCJD/BSE prions, either method improved the sensitivity by >2 orders of magnitude and allowed reevaluating the infectious titer of spleen from a vCJD individual at disease end stage to >1,000-fold-higher values. IMPORTANCE Here, we provide key reevaluation of the infectious titer of variant CJD brain and spleen tissues. The highly sensitive, accelerated spleen-based assay should thus constitute a key advance for variant CJD epidemiological and risk assessment purposes and should greatly facilitate future titration

  5. Glucose metabolism in nine patients with probable sporadic Creutzfeldt-Jakob disease: FDG-PET study using SPM and individual patient analysis.

    PubMed

    Renard, Dimitri; Vandenberghe, Rik; Collombier, Laurent; Kotzki, Pierre-Olivier; Pouget, Jean-Pierre; Boudousq, Vincent

    2013-12-01

    Only one large series using statistical parametric mapping (SPM) reports on FDG-PET in sporadic (Heidenhain and non-Heidenhain variant) Creutzfeldt-Jakob disease (sCJD), describing hypometabolism in bilateral parietal, frontal, and occipital cortices. Our aim was to study FDG-PET in non-Heidenhain probable sCJD patients in order to assess the most pertinent FDG-PET pattern, and to compare FDG-PET and MRI data. We used both SPM and NeuroGam(®) software analysis, compared with healthy controls, to describe the FDG-PET abnormalities. Individual FDG-PET and MRI-DWI data were compared. SPM group analysis showed lateralized hypometabolism in the medial parietal cortex, the lateral and medial frontal (sparing Brodmann's area 4 and 6 and the anterior cingulate cortex), and lateral parietal cortex, in the absence of basal ganglia or cerebellar hypometabolism. The most severe hypometabolism was seen in Brodmann's area 31, and to a lesser degree area 23 (both areas correspond to the posterior cingulate cortex) and the precuneus. On individual analysis using NeuroGam(®) software, additional variable temporal cortex and frequent basal ganglia (with caudate nucleus as the most frequently involved structure) hypometabolism was seen, in the absence of cerebellar hypometabolism. The cerebral lobe cortex was more frequently and more severely hypometabolic than basal ganglia structures. Concordance between FDG-PET and MRI abnormalities was most often present for both the cerebral lobe cortex and the basal ganglia. In the case of discordance, FDG-PET was more sensitive than MRI for the cortex, whereas MRI was more sensitive than FDG-PET for the basal ganglia. When pathological, both cortical lobe cortex and basal ganglia involvement were slightly more often lateralized on FDG-PET than on MRI. Despite the presence of overlapping features with other diseases presenting with rapidly progressive dementia, the FDG-PET pattern we found in our non-Heidenhain sCJD patients may help in the

  6. Red-Backed Vole Brain Promotes Highly Efficient In Vitro Amplification of Abnormal Prion Protein from Macaque and Human Brains Infected with Variant Creutzfeldt-Jakob Disease Agent

    PubMed Central

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human

  7. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    USGS Publications Warehouse

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in v

  8. R3-R4 deletion in the PRNP gene is associated with Creutzfeldt-Jakob disease (CJD)

    SciTech Connect

    Cervenakova, L.; Brown, P.; Nagle, J.

    1994-09-01

    There are conflicting reports on the association of deletions in the PRNP gene on chromosome 20 with CJD, a rapidly progressive fatal spongiform encephalopathy. We accumulated data suggesting that a deletion of R3-R4 type (parts of the third and fourth repeats are deleted from the area of four repeating 24 bp sequences in the 5{prime} region of the gene) is causing CJD. Screening of 129 unaffected control individuals demonstrated presence of a deletion of R2 type in four (1.55% of the studied chromosomes), but none of them had the R3-R4 type. Of 181 screened patients with spongiform encephalopathies, two had a deletion of R3-R4 type with no other mutations in the coding sequence. Both patients had a classical rapidly progressive dementing disease and diffuse spongiform degeneration, and both cases were apparently sporadic. The same R3-R4 type of deletion was detected in three additional neuropathologically confirmed spongiform encephalopathy patients, of which two had other known pathogenic mutations in the PRNP gene: at codon 178 on the methionine allele exhibiting the phenotype of fatal familial insomnia, and codon 200 causing CJD with severe dementia; the third was a patient with iatrogenic CJD who developed the disease after treatment with growth hormone extracted from cadaveric human pituitary glands. In all cases the deletion coincided with a variant sequence at position 129 coding for methionine.

  9. Stability and Reproducibility Underscore Utility of RT-QuIC for Diagnosis of Creutzfeldt-Jakob Disease.

    PubMed

    Cramm, Maria; Schmitz, Matthias; Karch, André; Mitrova, Eva; Kuhn, Franziska; Schroeder, Bjoern; Raeber, Alex; Varges, Daniela; Kim, Yong-Sun; Satoh, Katsuya; Collins, Steven; Zerr, Inga

    2016-04-01

    Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP(Sc)). Recent studies applied the RT-QuIC methodology to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi-centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establishment as a diagnostic test in clinical practice. In the present study, we analysed CSF from 110 prion disease patients and 400 control patients using the RT-QuIC method under various conditions. In addition, "blinded" ring trials between different participating sites were performed to estimate reproducibility. Using the previously established cut-off of 10,000 relative fluorescence units (rfu), we obtained a sensitivity of 85% and a specificity of 99%. The multi-centre inter-laboratory reproducibility of RT-QuIC revealed a Fleiss' kappa value of 0.83 (95% CI: 0.40-1.00) indicating an almost perfect agreement. Moreover, we investigated the impact of short-term CSF storage at different temperatures, long-term storage, repeated freezing and thawing cycles and the contamination of CSF with blood on the RT-QuIC seeding response. Our data indicated that the PrP(Sc) seed in CSF is stable to any type of storage condition but sensitive to contaminations with blood (>1250 erythrocytes/μL), which results in a false negative RT-QuIC response. Fresh blood-contaminated samples (3 days) can be rescued by removal of erythrocytes. The present study underlines the reproducibility and high stability of RT-QuIC across various CSF storage conditions with a remarkable sensitivity and specificity, suggesting RT-QuIC as an innovative and robust diagnostic method. PMID:25823511

  10. 77 FR 34390 - Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures To...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-11

    ...The Food and Drug Administration (FDA) is announcing the availability of a draft document entitled ``Guidance for Industry: Amendment (revisions to labeling recommendations for potential risk of vCJD) to `Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and......

  11. Description and analysis of 12 years of surveillance for Creutzfeldt-Jakob disease in Denmark, 1997 to 2008.

    PubMed

    Gubbels, S; Bacci, S; Laursen, H; Hogenhaven, H; Cowan, S; Molbak, K; Christiansen, M

    2012-04-12

    Prospective surveillance of Creutzfeldt–Jakob disease (CJD) was initiated in Denmark in 1997, following the observation of variant CJD in the United Kingdom. Demographic, clinical and diagnostic information was collected for each patient with clinical suspicion of CJD. Here we describe the methods for surveillance and the observed outcomes between 1 January 1997 and 31 December 2008. A total of 83 patients were classified as sporadic CJD, 47 were definite diagnoses, 34 probable and two possible. This resulted in a mean incidence of 1.26 patients with probable and definite sporadic CJD per million inhabitants. Two sporadic CJD patients were found to have a genetic variant of unknown significance: Thr201Ser and Glu200Asp. One patient was diagnosed with Gerstmann-Sträussler-Scheinker syndrome. No patients were classified as having variant, iatrogenic or familial CJD. The Danish surveillance system, like those in other countries, has a multidisciplinary approach, which is labour-intensive and time-consuming but ensures the most complete set of information possible. With this approach we think that patients with variant CJD would have been detected had they occurred in Denmark. Certain aspects of CJD surveillance need further discussion at European level and beyond, in order to find a balance between efficiency of the systems and accuracy of surveillance data. PMID:22516048

  12. First Demonstration of Transmissible Spongiform Encephalopathy-associated Prion Protein (PrPTSE) in Extracellular Vesicles from Plasma of Mice Infected with Mouse-adapted Variant Creutzfeldt-Jakob Disease by in Vitro Amplification*

    PubMed Central

    Saá, Paula; Yakovleva, Oksana; de Castro, Jorge; Vasilyeva, Irina; De Paoli, Silvia H.; Simak, Jan; Cervenakova, Larisa

    2014-01-01

    The development of variant Creutzfeldt-Jakob disease (vCJD) in three recipients of non-leukoreduced red blood cells from asymptomatic donors who subsequently developed the disease has confirmed existing concerns about the possible spread of transmissible spongiform encephalopathies (TSEs) via blood products. In addition, the presence of disease-associated misfolded prion protein (PrPTSE), generally associated with infectivity, has been demonstrated in the blood of vCJD patients. However, its origin and distribution in this biological fluid are still unknown. Various studies have identified cellular prion protein (PrPC) among the protein cargo in human blood-circulating extracellular vesicles released from endothelial cells and platelets, and exosomes isolated from the conditioned media of TSE-infected cells have caused the disease when injected into experimental mice. In this study, we demonstrate the detection of PrPTSE in extracellular vesicles isolated from plasma samples collected during the preclinical and clinical phases of the disease from mice infected with mouse-adapted vCJD and confirm the presence of the exosomal marker Hsp70 in these preparations. PMID:25157106

  13. Batch recall of French plasma-derived products due to variant Creutzfeldt-Jakob disease risk: the psychological impact on haemophilic patients, changes in their therapeutic demands and behaviour and ethical considerations.

    PubMed

    Aouba, A; Harroche, A; Frenzel, L; Torchet, M-F; Rothschild, C; François, I; Mamzer-Bruneel, M-F

    2015-01-01

    The choice of plasma-derived products (PdP) vs. recombinant products (RP) for treating haemophilia is influenced by the infectious and perceived safety of the products. Batch recall of PdP due to the risk of variant Creutzfeldt-Jakob disease (vCJD) may have unfavourable psychological impacts on haemophilia patients and influence their product preferences. This study aimed to assess the psychological impact of batch recalls of PdP in six haemophilia patients and their therapeutic demands, and to discuss the ethical problems in physicians' management of this event. A survey was conducted using a new interview form and an existing anxiety and depression questionnaire. Batch recalls produce recurrent negative emotional outcomes in haemophiliacs and their families. The quality, understanding and efficiency of the batch recall announcements were unsatisfactory in some respects. Only one patient still had some of the vials in question, and only three patients understood the real reason for the batch recall. Four patients asked to change their PdP for RP; a fifth patient was considering doing so. Here, topics for discussion include the delivery of an unclear message to patients about a very uncertain risk of a frightening disease, the reasons to maintain PdP when RP are largely available, except in specific cases, and the related discomfort for caregivers. The ethical questions revealed by batch recalls and the high psychological impact of vCJD risk on patients can no longer be ignored, and require surveys assessing the rationales and choices of the healthcare authorities, manufacturers, prescribers and users. PMID:25545300

  14. Recent US Case of Variant Creutzfeldt-Jakob Disease—Global Implications

    PubMed Central

    Fischer, Michael; Gambetti, Pierluigi; Parker, Alicia; Ram, Aarthi; Soto, Claudio; Concha-Marambio, Luis; Cohen, Yvonne; Belay, Ermias D.; Maddox, Ryan A.; Mead, Simon; Goodman, Clay; Kass, Joseph S.; Schonberger, Lawrence B.; Hussein, Haitham M.

    2015-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient’s exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD. PMID:25897712

  15. Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of (99m)Tc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

    PubMed

    Hayashi, Yuichi; Iwasaki, Yasushi; Yoshikura, Nobuaki; Asano, Takahiko; Hatano, Taku; Tatsumi, Shinsui; Satoh, Katsuya; Kimura, Akio; Kitamoto, Tetsuyuki; Yoshida, Mari; Inuzuka, Takashi

    2015-11-15

    We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT. PMID:26421831

  16. Transmissible Spongiform Encephalopathies (Prion Diseases)

    MedlinePlus

    ... when brain tissue is viewed under a microscope. Creutzfeldt-Jakob disease (CJD) is the most well-known of the ... and Worldwide NINDS Clinical Trials Organizations Column1 Column2 Creutzfeldt-Jakob Disease (CJD) Foundation Inc. 341 W. 38th Street, Suite ...

  17. Parkinson's Disease Dementia

    MedlinePlus

    ... Is Dementia Types of Dementia Chronic Traumatic Encephalopathy (CTE) Creutzfeldt-Jakob Disease Dementia with Lewy Bodies Down ... Research Traumatic Brain Injury and Chronic Traumatic Encephalopathy (CTE) Awardees Year Researcher Study Name 2015 Jesse Mez ...

  18. Creutzfeldt-Jakob Disease Fact Sheet for Healthcare Workers and Morticians

    MedlinePlus

    ... incidence of CJD indicates that person-to-person transmission probably does not occur through normal contact. Spouses ... is still no definitive evidence for how this transmission took place, it is believed that transmission occurred ...

  19. New variant CJD-BSE (mad cow disease). The need for disposable ENT instruments.

    PubMed

    Bingham, Brian

    2002-02-25

    This paper outlines the development of Bovine Spongiform Encephalopathy (BSE) in the United Kingdom. The relationship between BSE and new variant Creutzfeldt-Jakob disease (vCJD) is considered and the risks of iatrogenic spread reviewed. The rationale for disposable surgical instruments in adenotonsillectomy to prevent iatrogenic spread is discussed. PMID:11852121

  20. Human tonsil-derived follicular dendritic-like cells are refractory to human prion infection in vitro and traffic disease-associated prion protein to lysosomes.

    PubMed

    Krejciova, Zuzana; De Sousa, Paul; Manson, Jean; Ironside, James W; Head, Mark W

    2014-01-01

    The molecular mechanisms involved in human cellular susceptibility to prion infection remain poorly defined. This is due, in part, to the absence of any well characterized and relevant cultured human cells susceptible to infection with human prions, such as those involved in Creutzfeldt-Jakob disease. In variant Creutzfeldt-Jakob disease, prion replication is thought to occur first in the lymphoreticular system and then spread into the brain. We have, therefore, examined the susceptibility of a human tonsil-derived follicular dendritic cell-like cell line (HK) to prion infection. HK cells were found to display a readily detectable, time-dependent increase in cell-associated abnormal prion protein (PrP(TSE)) when exposed to medium spiked with Creutzfeldt-Jakob disease brain homogenate, resulting in a coarse granular perinuclear PrP(TSE) staining pattern. Despite their high level of cellular prion protein expression, HK cells failed to support infection, as judged by longer term maintenance of PrP(TSE) accumulation. Colocalization studies revealed that exposure of HK cells to brain homogenate resulted in increased numbers of detectable lysosomes and that these structures immunostained intensely for PrP(TSE) after exposure to Creutzfeldt-Jakob disease brain homogenate. Our data suggest that human follicular dendritic-like cells and perhaps other human cell types are able to avoid prion infection by efficient lysosomal degradation of PrP(TSE). PMID:24183781

  1. Chronic wasting disease and atypical forms of BSE and scrapie are not transmissible to mice expressing wild-type levels of human PrP

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle TSEs can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several new TSEs in shee...

  2. Birefringence Measurements of Spherulites formed in β-Lactoglobulin

    NASA Astrophysics Data System (ADS)

    Hardin, Eric; Kirkwood, Brad; Loman, Jazmine; Herat, Athula; Mahmood, Rizwan; Domike, Kristin

    2009-03-01

    Many proteins have a propensity to aggregate into amyloid fibril containing spherulite-like structures. In some instances these spherulitic protein aggregates have been observed in people suffering from a number of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Creutzfeldt-Jakob's. However, the exact role these aggregates play in the body, their internal structure, and the aggregation mechanism still remains a mystery. The model protein used in our study, β-lactoglobulin (BLG), produce spherulites under low pH and high temperature conditions. We report birefringence measurement on BLG using phase retardation method as a function of temperature. Birefringence (˜0.0022 ± 0.0002) data suggest very weak ordering within the spherulites. These spherulites seem to disappear when we added an extensively studied thermotropic liquid crystal [4'-pentyl-4-cyanobiphenyl (5CB)] in β-Lactoglobulin + water+ hydrochloric acid. Our preliminary data suggests that the strong interaction energy between the two systems may lead to the destruction of spherulites.

  3. MAD COW DISEASE: New Recruits for French Prion Research.

    PubMed

    Casassus, B

    2000-12-01

    As panic over "mad cow disease" engulfs France and threatens to spread to other countries in Western Europe, French research minister Roger-Gérard Schwartzenberg last week unveiled detailed plans for spending $27 million the government has earmarked for prion disease research in 2001. Next year's budget for studying prions--infectious, abnormal proteins linked to bovine spongiform encephalopathy and its human form, variant Creutzfeldt-Jakob disease--will triple France's current prion research spending. PMID:17798203

  4. [From the Scrapie syndrome of sheep and goat to the mad cow disease - the history of the discovery of prion].

    PubMed

    Liu, Rui; Weng, Yi

    2009-05-01

    Since the discovery of Scrapie Syndrome in sheep and goats in 1730, there emerged a series of diseases such as Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc. In the research of kuru disease, the American scientist D. Carlteton Gajdusek found a new virus without the characteristic of DNA and RNA, which was awarded the Nobel Prize in physiology in 1976. Since then another American scientist, Stanley B. Prusiner, found a new virus-prion, taking protein as the genetic medium, which was awarded the Nobel prize in physiology and medicine in 1997. The discovery of prion is a great landmark in the research of life science, which laid a theoretical foundation for people to conquer a series of diseases such as Scrapie syndrome in sheep and goats, Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc. PMID:19930927

  5. Disease Burden of 32 Infectious Diseases in the Netherlands, 2007-2011

    PubMed Central

    Bouwknegt, Martijn; Kretzschmar, Mirjam E.; Mangen, Marie-Josée J.; Wallinga, Jacco; de Melker, Hester E.

    2016-01-01

    Background Infectious disease burden estimates provided by a composite health measure give a balanced view of the true impact of a disease on a population, allowing the relative impact of diseases that differ in severity and mortality to be monitored over time. This article presents the first national disease burden estimates for a comprehensive set of 32 infectious diseases in the Netherlands. Methods and Findings The average annual disease burden was computed for the period 2007–2011 for selected infectious diseases in the Netherlands using the disability-adjusted life years (DALY) measure. The pathogen- and incidence-based approach was adopted to quantify the burden due to both morbidity and premature mortality associated with all short and long-term consequences of infection. Natural history models, disease progression probabilities, disability weights, and other parameters were adapted from previous research. Annual incidence was obtained from statutory notification and other surveillance systems, which was corrected for under-ascertainment and under-reporting. The highest average annual disease burden was estimated for invasive pneumococcal disease (9444 DALYs/year; 95% uncertainty interval [UI]: 8911–9961) and influenza (8670 DALYs/year; 95% UI: 8468–8874), which represents 16% and 15% of the total burden of all 32 diseases, respectively. The remaining 30 diseases ranked by number of DALYs/year from high to low were: HIV infection, legionellosis, toxoplasmosis, chlamydia, campylobacteriosis, pertussis, tuberculosis, hepatitis C infection, Q fever, norovirus infection, salmonellosis, gonorrhoea, invasive meningococcal disease, hepatitis B infection, invasive Haemophilus influenzae infection, shigellosis, listeriosis, giardiasis, hepatitis A infection, infection with STEC O157, measles, cryptosporidiosis, syphilis, rabies, variant Creutzfeldt-Jakob disease, tetanus, mumps, rubella, diphtheria, and poliomyelitis. The very low burden for the latter five

  6. Human growth hormone-related latrogenic Creutzfeldt-Jakob disease: Search for a genetic susceptibility by analysis of the PRNP coding region

    SciTech Connect

    Jaegly, A.; Boussin, F.; Deslys, J.P.

    1995-05-20

    The human PRNP gene encoding PrP is located on chromosome 20 and consists of two exons and a single intron. The open reading frame is entirely fitted into the second exon. Genetic studies indicate that all of the familial and several sporadic forms of TSSEs are associated with mutations in the PRNP 759-bp coding region. Moreover, homozygosity at codon 129, a locus harboring a polymorphism among the general population, was proposed as a genetic susceptibility marker for both sporadic and iatrogenic CJD. To assess whether additional genetic predisposition markers exist in the PRNP gene, the authors sequenced the PRNP coding region of 17 of the 32 French patients who developed a hGH-related CJD.

  7. Prion disease tempo determined by host-dependent substrate reduction

    PubMed Central

    Mays, Charles E.; Kim, Chae; Haldiman, Tracy; van der Merwe, Jacques; Lau, Agnes; Yang, Jing; Grams, Jennifer; Di Bari, Michele A.; Nonno, Romolo; Telling, Glenn C.; Kong, Qingzhong; Langeveld, Jan; McKenzie, Debbie; Westaway, David; Safar, Jiri G.

    2014-01-01

    The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains. PMID:24430187

  8. Identification of misfolded proteins in body fluids for the diagnosis of prion diseases.

    PubMed

    Properzi, Francesca; Pocchiari, Maurizio

    2013-01-01

    Transmissible spongiform encephalopathy (TSE) or prion diseases are fatal rare neurodegenerative disorders affecting man and animals and caused by a transmissible infectious agent. TSE diseases are characterized by spongiform brain lesions with neuronal loss and the abnormal deposition in the CNS, and to less extent in other tissues, of an insoluble and protease resistant form of the cellular prion protein (PrP(C)), named PrP(TSE). In man, TSE diseases affect usually people over 60 years of age with no evident disease-associated risk factors. In some cases, however, TSE diseases are unequivocally linked to infectious episodes related to the use of prion-contaminated medicines, medical devices, or meat products as in the variant Creutzfeldt-Jakob disease (CJD). Clinical signs occur months or years after infection, and during this silent period PrP(TSE), the only reliable marker of infection, is not easily measurable in blood or other accessible tissues or body fluids causing public health concerns. To overcome the limit of PrP(TSE) detection, several highly sensitive assays have been developed, but attempts to apply these techniques to blood of infected hosts have been unsuccessful or not yet validated. An update on the latest advances for the detection of misfolded prion protein in body fluids is provided. PMID:24027585

  9. Identification of Misfolded Proteins in Body Fluids for the Diagnosis of Prion Diseases

    PubMed Central

    Pocchiari, Maurizio

    2013-01-01

    Transmissible spongiform encephalopathy (TSE) or prion diseases are fatal rare neurodegenerative disorders affecting man and animals and caused by a transmissible infectious agent. TSE diseases are characterized by spongiform brain lesions with neuronal loss and the abnormal deposition in the CNS, and to less extent in other tissues, of an insoluble and protease resistant form of the cellular prion protein (PrPC), named PrPTSE. In man, TSE diseases affect usually people over 60 years of age with no evident disease-associated risk factors. In some cases, however, TSE diseases are unequivocally linked to infectious episodes related to the use of prion-contaminated medicines, medical devices, or meat products as in the variant Creutzfeldt-Jakob disease (CJD). Clinical signs occur months or years after infection, and during this silent period PrPTSE, the only reliable marker of infection, is not easily measurable in blood or other accessible tissues or body fluids causing public health concerns. To overcome the limit of PrPTSE detection, several highly sensitive assays have been developed, but attempts to apply these techniques to blood of infected hosts have been unsuccessful or not yet validated. An update on the latest advances for the detection of misfolded prion protein in body fluids is provided. PMID:24027585

  10. Atypical transmissible spongiform encephalopathies in ruminants: a challenge for disease surveillance and control.

    PubMed

    Seuberlich, Torsten; Heim, Dagmar; Zurbriggen, Andreas

    2010-11-01

    Since 1987, when bovine spongiform encephalopathy (BSE) emerged as a novel disease in cattle, enormous efforts were undertaken to monitor and control the disease in ruminants worldwide. The driving force was its high economic impact, which resulted from trade restrictions and the loss of consumer confidence in beef products, the latter because BSE turned out to be a fatal zoonosis, causing variant Creutzfeldt-Jakob disease in human beings. The ban on meat and bone meal in livestock feed and the removal of specified risk materials from the food chain were the main measures to successfully prevent infection in cattle and to protect human beings from BSE exposure. However, although BSE is now under control, previously unknown, so-called atypical transmissible spongiform encephalopathies (TSEs) in cattle and small ruminants have been identified by enhanced disease surveillance. This report briefly reviews and summarizes the current level of knowledge on the spectrum of TSEs in cattle and small ruminants and addresses the question of the extent to which such atypical TSEs have an effect on disease surveillance and control strategies. PMID:21088166

  11. Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors.

    PubMed

    Kaski, Diego N; Pennington, Catherine; Beck, Jon; Poulter, Mark; Uphill, James; Bishop, Matthew T; Linehan, Jaqueline M; O'Malley, Catherine; Wadsworth, Jonathan D F; Joiner, Susan; Knight, Richard S G; Ironside, James W; Brandner, Sebastian; Collinge, John; Mead, Simon

    2011-06-01

    Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogeneous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of patients from the UK with four extra octapeptide repeats, which suggest that the risk of clinical disease is increased by a combination of the mutation and a susceptibility haplotype on the wild-type chromosome. The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities that closely resemble sporadic Creutzfeldt-Jakob disease. Autopsy shows perpendicular deposits of prion protein in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and suggests multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129. In addition, at a single nucleotide polymorphism upstream of PRNP thought to confer susceptibility to sporadic Creutzfeldt-Jakob disease (rs1029273), all patients were homozygous for the risk allele (combined P=5.9×10(-5)). The haplotype identified may also be a risk factor in other partially penetrant inherited prion diseases although it does not modify age of onset. Blood expression of PRNP in healthy individuals was modestly higher in carriers of the risk haplotype. These findings may provide a precedent for understanding apparently sporadic neurodegenerative diseases caused by rare high-risk mutations. PMID:21616973

  12. Proteomics analyses for the global proteins in the brain tissues of different human prion diseases.

    PubMed

    Shi, Qi; Chen, Li-Na; Zhang, Bao-Yun; Xiao, Kang; Zhou, Wei; Chen, Cao; Zhang, Xiao-Mei; Tian, Chan; Gao, Chen; Wang, Jing; Han, Jun; Dong, Xiao-Ping

    2015-04-01

    Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases. PMID:25616867

  13. SPONGIFORM DISEASE: Experts Downplay New vCJD Fears.

    PubMed

    Balter, M

    2000-09-01

    The chilling scenario of getting "mad cow disease" from eating products of other animals besides just cows was splashed across the mainstream British press last week based on a report from a leading U.K. lab that prions--abnormal proteins linked to bovine spongiform encephalopathy and its human form, variant Creutzfeldt-Jakob disease--can jump from one species to another more easily than previously believed. Although some experts say the findings raise concern about a threat to human health, others decry the media frenzy and contend that the new research adds little to what is known about the mysterious, fatal diseases. PMID:17811144

  14. The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations

    NASA Astrophysics Data System (ADS)

    Wu, Chun; Shea, Joan-Emma

    Protein aggregation involves the self-assembly of proteins into large β-sheet-rich complexes. This process can be the result of aberrant protein folding and lead to "amyloidosis," a condition characterized by deposits of protein aggregates known as amyloids on various organs of the body [1]. Amyloid-related diseases include, among others, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and type II diabetes [2, 3, 4]. In other instances, however, protein aggregation is not a pathological process, but rather a functional one, with aggregates serving as structural scaffolds in a number of organisms [5].

  15. Food Safety: Bovine Spongiform Encephalopathy (Mad Cow Disease).

    PubMed

    Acheson, David W. K.

    2002-01-01

    Bovine spongiform encephalopathy is just one of a group of diseases known as transmissible spongiform encephalopathies. Only recently has it become recognized that transmissible spongiform encephalopathies are likely due to proteins known as prions. Although it has been recognized that transmissible spongiform encephalopathies may readily spread within species, the recent observations that bovine spongiform encephalopathy in cattle may have originated from another transmissible spongiform encephalopathy in sheep, known as scrapie, is cause for concern. Further, bovine spongiform encephalopathy has now been strongly linked with a universally fatal human neurologic disease known as new variant Creutzfeldt-Jakob disease. Currently the only approach to preventing bovine spongiform encephalopathy, and subsequent new variant Creutzfeldt-Jakob disease in humans, from ingestion of bovine spongiform encephalopathy-infected material is to avoid consumption of contaminated food. Little can be done to treat food that will destroy prions and leave a palatable product. At this stage we are continuing to learn about transmissible spongiform encephalopathies and their implications on human health. This is an ever-changing situation and has an unpredictable element in terms of the extent of the current outbreaks in England and other parts of Europe. PMID:11984426

  16. Genetic prion disease with codon 196 PRNP mutation: clinical and pathological findings.

    PubMed

    Schelzke, Gabi; Eigenbrod, Sabina; Romero, Carlos; Varges, Daniela; Breithaupt, Maren; Taratuto, Ana L; Kretzschmar, Hans A; Zerr, Inga

    2011-04-01

    Ten percent to 15% of all human transmissible spongiform encephalopathy are characterized by a mutation in prion protein gene (PRNP). They are distinct with respect to clinical signs, disease onset, disease duration, and diagnostic findings. During our surveillance activities in Germany, we identified 7 patients with the rare mutation E196K in PRNP gene, thereof 4 patients belonging to 2 families. The clinical syndromes were characterized by nonspecific and psychiatric symptoms at disease onset and progressed to predominant motor signs. These patients showed a late median disease onset of 71 years and short disease duration of 6.5 months. In absence of family history, they mimicked sporadic Creutzfeldt-Jakob disease (CJD). In clinical tests they were 100% positive for 14-3-3 protein detection in cerebrospinal fluid and less sensitive for magnetic resonance imaging (MRI) and electroencephalogram (EEG) abnormalities. As a secondary magnetic resonance imaging (MRI) abnormality, we have seen conspicuous common involvement of the subcortical white matter in 57%. Four patients underwent autopsy-pathological lesions revealed striking similarity to sporadic Creutzfeldt-Jakob disease but also involvement of the white matter. PMID:21232818

  17. Hybrid molecules synergistically acting against protein aggregation diseases.

    PubMed

    Korth, Carsten; Klingenstein, Ralf; Müller-Schiffmann, Andreas

    2013-01-01

    An emerging common feature of the age-associated neurodegenerative disorders like Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) is the ability of many disease-associated protein aggregates to induce conversion of a normal counterpart conformer leading to an acceleration of disease progression. Curative pharmacotherapy has not been achieved so far despite successes in elucidating pathomechanisms. Here, we review the pharmaceutical strategy of generating hybrid compounds, i.e. compounds consisting of several independently acting moieties with synergistic effects, on key molecular players in AD and CJD. For prion diseases, we review hybrid compounds consisting of two different heterocyclic compounds, their synergistic effects on prion replication in a cell culture model and their ability to prolong survival of experimentally prion-infected mice in vivo. While a combination therapy of several antiprion compounds including quinacrine, clomipramine, simvastatin and tocopherol prolonged survival time to 10-25%, administration of hybrid compound quinpramine alone, a chimera of acridine and iminodibenzyl scaffolds, led to 10% survival time extension. For AD, we review a hybrid compound consisting of an Aβ recognizing D-peptide fused to a small molecule β-sheet breaker, an aminopyrazole. This molecule was able to diminish Aβ oligomers in cell culture and significantly decrease synaptotoxicity as measured by miniature excitatory postsynaptic responses in vitro. Hybrid compounds can dramatically increase potency of their single moieties and lead to novel functions when they act in a simultaneous or sequential manner thereby revealing synergistic properties. Their systematic generation combining different classes of compounds from peptides to small molecules has the potential to significantly accelerate drug discovery. PMID:24059335

  18. Transmission of scrapie prions to primate after an extended silent incubation period

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the past decades, c-BSE's zoonotic potential has been the driving force in establishing extensive protective measures for animal and human health. In compl...

  19. Prion diseases: immunotargets and therapy.

    PubMed

    Burchell, Jennifer T; Panegyres, Peter K

    2016-01-01

    Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP(Sc) conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4(+) cells to initiate an immune response. Adoptive transfer of CD4(+) T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion

  20. Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

    PubMed Central

    Risacher, Shannon L.; Saykin, Andrew J.

    2014-01-01

    Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer’s disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson’s disease with and without dementia, dementia with Lewy bodies, Huntington’s disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders. PMID:24234359

  1. [Doctor Francoise Cathala and history of prions diseases].

    PubMed

    Court, L; Hauw, J-J

    2015-12-01

    Doctor Françoise Cathala Pagesy, MD, MS, born on July 7, 1921 in Paris, passed away peacefully at home on November 5, 2012. Unconventional, passionate and enthusiastic neurologist and virologist, she devoted her life to research on latent and slow viral infections, specializing mainly on unconventional transmissible agents or prions. As a research member of Inserm (French Institute for Medical Research), she soon joined the team of Carlton Gajdusek (the NINCDS - National Institute of Nervous Central System and Stroke - of NIH), who first demonstrated the transmissibility of kuru and Creutzfeldt-Jakob disease to monkeys. When she came back to Paris, where she was followed by one of NIH members, Paul Brown, she joined the Centre de Recherches du Service de Santé des Armées (Army Health Research Center), in Percy-Clamart, where she found the experimental design and the attentive help needed for her research, which appeared heretical to many French virologists, including some authorities. A large number of research programs were set up with numerous collaborations involving CEA (Center for Atomic Energy) and other institutions in Paris and Marseilles on epidemiology, results of tissue inoculation, electrophysiology and neuropathology of human and animal prions diseases, and resistance of the infectious agent. International symposia were set up, where met, in the Val-de-Grâce hospital in Paris, the research community on "slow viral diseases". Stanley Prusiner introduced the concept - then badly accepted and still in evolution - of prion, a protein only infectious agent. Before retiring from Inserm, Françoise Cathala predicted and was involved in some of the huge sanitary crises in France. These were, first, Creutzfeldt-Jakob disease from contaminated growth hormone extracted from cadavers, which led parents to instigate legal procedure - a quite unusual practice in France. The second was Mad cow disease in the United Kingdom then in France, followed by new variant

  2. The immunobiology of prion diseases.

    PubMed

    Aguzzi, Adriano; Nuvolone, Mario; Zhu, Caihong

    2013-12-01

    Individuals infected with prions succumb to brain damage, and prion infections continue to be inexorably lethal. However, many crucial steps in prion pathogenesis occur in lymphatic organs and precede invasion of the central nervous system. In the past two decades, a great deal has been learnt concerning the cellular and molecular mechanisms of prion lymphoinvasion. These properties are diagnostically useful and have, for example, facilitated preclinical diagnosis of variant Creutzfeldt-Jakob disease in the tonsils. Moreover, the early colonization of lymphoid organs can be exploited for post-exposure prophylaxis of prion infections. As stromal cells of lymphoid organs are crucial for peripheral prion infection, the dedifferentiation of these cells offers a powerful means of hindering prion spread in infected individuals. In this Review, we discuss the current knowledge of the immunobiology of prions with an emphasis on how basic discoveries might enable translational strategies. PMID:24189576

  3. Canadian media representations of mad cow disease.

    PubMed

    Boyd, Amanda D; Jardine, Cynthia G; Driedger, S Michelle

    2009-01-01

    A Canadian case of bovine spongiform encephalopathy (BSE) or "mad cow disease" was confirmed in May, 2003. An in-depth content analysis of newspaper articles was conducted to understand the portrayal of BSE and variant Creutzfeldt-Jakob disease (vCJD) in the Canadian media. Articles in the "first 10 days" following the initial discovery of a cow with BSE in Canada on May 20, 2003, were examined based on the premise that these initial stories provide the major frames that dominate news media reporting of the same issue over time and multiple occurrences. Subsequent confirmed Canadian cases were similarly analyzed to determine if coverage changed in these later media articles. The results include a prominence of economic articles, de-emphasis of health aspects, and anchoring the Canadian outbreak to that of Britain's crisis. The variation in media representations between those in Canada and those documented in Britain are explored in this study. PMID:19697246

  4. Prionet Canada: a network of centres of excellence for research into prions and prion diseases.

    PubMed

    Wong, Michelle; Toth, Janie; Haney, Sandra; Tyshenko, Michael G; Darshan, Shalu; Krewski, Daniel; Leighton, Frederick A; Westaway, David; Moore, Stephen S; Ricketts, Maura; Cashman, Neil

    2009-01-01

    PrioNet Canada's strength in basic, applied, and social research is helping to solve the food, health safety, and socioeconomic problems associated with prion diseases. Prion diseases are transmissible, fatal neurodegenerative diseases of humans and animals. Examples of prion diseases include bovine spongiform encephalopathy (BSE, commonly known as "mad cow" disease), Creutzfeldt-Jakob disease in humans, and chronic wasting disease (CWD) in deer and elk. As of March 31, 2008, PrioNet's interdisciplinary network included 62 scientific members, 5 international collaborators, and more than 150 students and young professionals working in partnership with 25 different government, nongovernment, and industry partners. PrioNet's activities are developing strategies based on a sustained, rational approach that will mitigate, and ultimately control, prion diseases in Canada. PMID:19697232

  5. Copper and the Prion Protein: Methods, Structures, Function, and Disease

    NASA Astrophysics Data System (ADS)

    Millhauser, Glenn L.

    2007-05-01

    The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrPC, with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrPC function, and emerging connections between copper and prion disease.

  6. Copper and the prion protein: methods, structures, function, and disease.

    PubMed

    Millhauser, Glenn L

    2007-01-01

    The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrP(C) to PrP(Sc). Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrP(C) in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrP(C), with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrP(C) function, and emerging connections between copper and prion disease. PMID:17076634

  7. [The truth and present uncertainty about mad cow disease].

    PubMed

    Suárez Fernández, G

    2001-01-01

    A historical review is made about Spongiform Encephalopathies which affect both animals and man. This is the base for an epidemiological and predictive analysis of these type of diseases, especially Bovine Spongiform Encephalopathy (BSE) as a present health problem. The scientific certainties or truths, such as the prion theory (PrPc-PrPsc), the low natural infectivity of these group of diseases, the high dose of prions necessary to produce the experimental disease, the species barrier or specificity, the individual susceptibility due to genetic traits, and the low transmission efficiency by the oral route, compared to the parenteral route, agree with the epidemiological observations of human cases of the variant of the Creutzfeldt-Jakob disease (vCJD), which is 0.1 cases per million inhabitants and year. The present and future prediction of BSE should not be alarmist, taking into account the certainties that we know. PMID:11455757

  8. Prospects for safe and effective vaccines against prion diseases.

    PubMed

    Mabbott, Neil Andrew

    2015-01-01

    Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrP(Sc)) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt-Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved. PMID:25266267

  9. Endpoint Quaking-Induced Conversion: a Sensitive, Specific, and High-Throughput Method for Antemortem Diagnosis of Creutzfeldt-Jacob Disease

    PubMed Central

    Vendramelli, Robert; Sloan, Angela; Waitt, Brooks; Podhorodecki, Lisa; Godal, Debra

    2016-01-01

    The Prion Laboratory Section of the Public Health Agency of Canada supports heath care professionals dealing with patients suspected to have Creutzfeldt-Jakob disease (CJD) by testing cerebrospinal fluid (CSF) for protein markers of CJD. To better serve Canadian diagnostic requirements, a quaking-induced conversion (QuIC)-based assay has been added to the test panel. The QuIC tests exploit the ability of disease-associated prion protein, found in the CSF of a majority of CJD patients, to convert a recombinant prion protein (rPrP) into detectable amounts of a misfolded, aggregated form of rPrP. The rPrP aggregates interact with a specific dye, causing a measurable change in the dye's fluorescence emission spectrum. Optimal test and analysis parameters were empirically determined. Taking both practical and performance considerations into account, an endpoint QuIC (EP-QuIC) configuration was chosen. EP-QuIC uses a thermo-mixer to perform the shaking necessary to produce the quaking-induced conversions. Fluorescence readings are obtained from a microwell fluorescence reader only at the beginning and the end of EP-QuIC reactions. Samples for which the relative fluorescence unit ratio between the initial and final readings represent a ≥4 increase in signal intensity in at least two of the three replicates are classified as positive. A retrospective analysis of 91 CSF samples that included 45 confirmed cases of CJD and 46 non-CJD cases was used to estimate the performance characteristics of the EP-QuIC assay. The diagnostic sensitivity and specificity of the EP-QuIC test of this set of samples were 98 and 91%, respectively. PMID:27076662

  10. Endpoint Quaking-Induced Conversion: a Sensitive, Specific, and High-Throughput Method for Antemortem Diagnosis of Creutzfeldt-Jacob Disease.

    PubMed

    Cheng, Keding; Vendramelli, Robert; Sloan, Angela; Waitt, Brooks; Podhorodecki, Lisa; Godal, Debra; Knox, J David

    2016-07-01

    The Prion Laboratory Section of the Public Health Agency of Canada supports heath care professionals dealing with patients suspected to have Creutzfeldt-Jakob disease (CJD) by testing cerebrospinal fluid (CSF) for protein markers of CJD. To better serve Canadian diagnostic requirements, a quaking-induced conversion (QuIC)-based assay has been added to the test panel. The QuIC tests exploit the ability of disease-associated prion protein, found in the CSF of a majority of CJD patients, to convert a recombinant prion protein (rPrP) into detectable amounts of a misfolded, aggregated form of rPrP. The rPrP aggregates interact with a specific dye, causing a measurable change in the dye's fluorescence emission spectrum. Optimal test and analysis parameters were empirically determined. Taking both practical and performance considerations into account, an endpoint QuIC (EP-QuIC) configuration was chosen. EP-QuIC uses a thermo-mixer to perform the shaking necessary to produce the quaking-induced conversions. Fluorescence readings are obtained from a microwell fluorescence reader only at the beginning and the end of EP-QuIC reactions. Samples for which the relative fluorescence unit ratio between the initial and final readings represent a ≥4 increase in signal intensity in at least two of the three replicates are classified as positive. A retrospective analysis of 91 CSF samples that included 45 confirmed cases of CJD and 46 non-CJD cases was used to estimate the performance characteristics of the EP-QuIC assay. The diagnostic sensitivity and specificity of the EP-QuIC test of this set of samples were 98 and 91%, respectively. PMID:27076662

  11. Presence of voltage-gated potassium channel complex antibody in a case of genetic prion disease.

    PubMed

    Jammoul, Adham; Lederman, Richard J; Tavee, Jinny; Li, Yuebing

    2014-01-01

    Voltage-gated potassium channel (VGKC) complex antibody-mediated encephalitis is a recently recognised entity which has been reported to mimic the clinical presentation of Creutzfeldt-Jakob disease (CJD). Testing for the presence of this neuronal surface autoantibody in patients presenting with subacute encephalopathy is therefore crucial as it may both revoke the bleak diagnosis of prion disease and allow institution of potentially life-saving immunotherapy. Tempering this optimistic view is the rare instance when a positive VGKC complex antibody titre occurs in a definite case of prion disease. We present a pathologically and genetically confirmed case of CJD with elevated serum VGKC complex antibody titres. This case highlights the importance of interpreting the result of a positive VGKC complex antibody with caution and in the context of the overall clinical manifestation. PMID:24903967

  12. Prions and protein-folding diseases.

    PubMed

    Norrby, E

    2011-07-01

    Prions represent a group of proteins with a unique capacity to fold into different conformations. One isoform is rich in beta-pleated sheets and can aggregate into amyloid that may be pathogenic. This abnormal form propagates itself by imposing its confirmation on the homologous normal host cell protein. Pathogenic prions have been shown to cause lethal neurodegenerative diseases in humans and animals. These diseases are sometimes infectious and hence referred to as transmissible spongiform encephalopathies. In the present review, the remarkable evolution of the heterodox prion concept is summarized. The origin of this phenomenon is based on information transfer between homologous proteins, without the involvement of nucleic acid-encoded mechanisms. Historically, kuru and Creutzfeldt-Jakob disease (CJD) were the first infectious prion diseases to be identified in man. It was their relationship to scrapie in sheep and experimental rodents that allowed an unravelling of the particular molecular mechanism that underlie the disease process. Transmission between humans has been documented to have occurred in particular contexts, including ritual cannibalism, iatrogenic transmission because of pituitary gland-derived growth hormone or the use in neurosurgical procedures of dura mater from cadavers, and the temporary use of a prion-contaminated protein-rich feed for cows. The latter caused a major outbreak of bovine spongiform encephalopathy, which spread to man by human consumption of contaminated meat, causing approximately 200 cases of variant CJD. All these epidemics now appear to be over because of measures taken to curtail further spread of prions. Recent studies have shown that the mechanism of protein aggregation may apply to a wider range of diseases in and possibly also outside the brain, some of which are relatively common such as Alzheimer's and Parkinson's diseases. Furthermore, it has become apparent that the phenomenon of prion aggregation may have a wider

  13. Kuru

    MedlinePlus

    ... type to also change shape. Other TSEs include Creutzfeldt-Jakob disease and fatal familial insomnia in humans, bovine spongiform ... and Worldwide NINDS Clinical Trials Organizations Column1 Column2 Creutzfeldt-Jakob Disease (CJD) Foundation Inc. 341 W. 38th Street, Suite ...

  14. Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein.

    PubMed

    Wilson, Rona; Plinston, Chris; Hunter, Nora; Casalone, Cristina; Corona, Cristiano; Tagliavini, Fabrizio; Suardi, Silvia; Ruggerone, Margherita; Moda, Fabio; Graziano, Silvia; Sbriccoli, Marco; Cardone, Franco; Pocchiari, Maurizio; Ingrosso, Loredana; Baron, Thierry; Richt, Juergen; Andreoletti, Olivier; Simmons, Marion; Lockey, Richard; Manson, Jean C; Barron, Rona M

    2012-07-01

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans. PMID:22495232

  15. Prion diseases as transmissible zoonotic diseases.

    PubMed

    Lee, Jeongmin; Kim, Su Yeon; Hwang, Kyu Jam; Ju, Young Ran; Woo, Hee-Jong

    2013-02-01

    Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt-Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. PMID:24159531

  16. Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey

    PubMed Central

    Kelly, Carole M; Andrews, Nick; Vogliqi, Kelly; Mallinson, Gary; Kaisar, Maria; Hilton, David A; Ironside, James W; Edwards, Philip; McCardle, Linda M; Ritchie, Diane L; Dabaghian, Reza; Ambrose, Helen E; Gill, O Noel

    2009-01-01

    Objective To establish with improved accuracy the prevalence of disease related prion protein (PrPCJD) in the population of Britain and thereby guide a proportionate public health response to limit the threat of healthcare associated transmission of variant Creutzfeldt-Jakob disease (vCJD). Design Cross sectional opportunistic survey. Study samples Anonymised tonsil pairs removed at elective tonsillectomy throughout England and Scotland. Setting National anonymous tissue archive for England and Scotland. Main outcome measure Presence of PrPCJD determined by using two enzyme immunoassays based on different analytical principles, with further investigation by immunohistochemistry or immunoblotting of any samples reactive in either assay. Results Testing of 63 007 samples was completed by the end of September 2008. Of these, 12 753 were from the birth cohort in which most vCJD cases have arisen (1961-85) and 19 908 were from the 1986-95 cohort that would have been also exposed to bovine spongiform encephalopathy through infected meat or meat products. None of the samples tested was unequivocally reactive in both enzyme immunoassays. Only two samples were reactive in one or other enzyme immunoassay and equivocal in the other, and nine samples were equivocally reactive in both enzyme immunoassays. Two hundred and seventy six samples were initially reactive in one or other enzyme immunoassay; the repeat reactivity rate was 15% or less, depending on the enzyme immunoassay and cut-off definition. None of the samples (including all the 276 initially reactive in enzyme immunoassay) that were investigated by immunohistochemistry or immunoblotting was positive for the presence of PrPCJD. Conclusions The observed prevalence of PrPCJD in tonsils from the 1961-95 combined birth cohort was 0/32 661 with a 95% confidence interval of 0 to 113 per million. In the 1961-85 cohort, the prevalence of zero with a 95% confidence interval of 0 to 289 per million was lower than, but

  17. 21 CFR 1271.75 - How do I screen a donor?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... method that ensures freedom from contamination of the cells or tissue by infectious disease organisms...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease; (v) Treponema pallidum; and...

  18. The expanding universe of prion diseases.

    PubMed

    Watts, Joel C; Balachandran, Aru; Westaway, David

    2006-03-01

    Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded. PMID:16609731

  19. 75 FR 55803 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-14

    ... agents from blood components and chronic wasting disease. FDA intends to make background material... the variant Creutzfeldt-Jakob disease (vCJD) agent in U.S.-licensed plasma-derived Factor VIII and...

  20. Epidemiological characteristics of human prion diseases.

    PubMed

    Chen, Cao; Dong, Xiao-Ping

    2016-01-01

    Human prion diseases are a group of transmissible, progressive, and invariably fatal neurodegenerative disorders, which include Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. Human prion diseases affect approximately 1-2 persons per million worldwide annually, occurring in sporadic, inherited, and acquired forms. These diseases have attracted both scientific and public attention not only because of their mysterious pathogen, but also due to their considerable threat to public health since the emergence of the variant CJD.There are still no specific therapeutic and prophylactic interventions available for prion diseases, thus active surveillance of human prion diseases is critical for disease control and prevention. Since 1993, CJD surveillance systems have been established in many countries and regions, and several long-term multinational cooperative projects have been conducted.In this paper, the epidemiological characteristics of various human prion diseases and the active surveillance systems pertaining to them in different countries and regions are summarized and reviewed. PMID:27251305

  1. The Expanding Universe of Prion Diseases

    PubMed Central

    Watts, Joel C; Balachandran, Aru; Westaway, David

    2006-01-01

    Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrPC. Several mammalian species are affected by the diseases, and in the case of “mad cow disease” (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases—including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep—have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of “sporadic” disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded. PMID:16609731

  2. [Human prion diseases in the Czech Republic].

    PubMed

    Rohan, Z; Rusina, R; Marešová, M; Matěj, R

    2015-09-01

    Human prion diseases are a group of very rare diseases with a unique pathogenesis and, due to an inauspicious prognosis and unavailability of therapy, with fatal consequences. The etiopathogenetic background is the presence of pathologically misfolded prion protein, highly resistant to denaturation, the aggregation and presence of which in the brain tissue causes irreversible neuronal damage. The most frequent prion disease in humans is Creutzfeldt-Jakob disease (CJD) which occurs in sporadic, hereditary/familial, or acquired/infectious/iatrogenic forms. A new form of CJD, variant CJD, is considered to be linked to dietary exposure to beef products from cattle infected with bovine spongiform encephalopathy (BSE) and to infection via blood transfusion. The clinical picture of these diseases is characterized by a rapidly progressing dementia, cerebellar and extrapyramidal symptoms, and rather specific MRI, EEG, and CSF findings. Clinically, the diagnosis is described as possible or probable prion disease and needs to be confirmed by neuropathological or immunological investigation of the brain tissue. Epidemiological data from the Czech Republic spanning the last decade are presented. PMID:26448298

  3. 78 FR 11207 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-15

    ... to discuss FDA's draft risk assessment model for potential exposure to the variant Creutzfeldt-Jakob disease (vCJD) agent in Red Blood Cells for transfusion in the United States. FDA intends to...

  4. Mild Cognitive Impairment

    MedlinePlus

    ... Is Dementia Types of Dementia Chronic Traumatic Encephalopathy (CTE) Creutzfeldt-Jakob Disease Dementia with Lewy Bodies Down ... Research Traumatic Brain Injury and Chronic Traumatic Encephalopathy (CTE) Awardees Year Researcher Study Name 2015 Jesse Mez ...

  5. Types of Dementia

    MedlinePlus

    ... Is Dementia Types of Dementia Chronic Traumatic Encephalopathy (CTE) Creutzfeldt-Jakob Disease Dementia with Lewy Bodies Down ... Research Traumatic Brain Injury and Chronic Traumatic Encephalopathy (CTE) Awardees Year Researcher Study Name 2015 Jesse Mez ...

  6. Normal Pressure Hydrocephalus (NPH)

    MedlinePlus

    ... Is Dementia Types of Dementia Chronic Traumatic Encephalopathy (CTE) Creutzfeldt-Jakob Disease Dementia with Lewy Bodies Down ... Research Traumatic Brain Injury and Chronic Traumatic Encephalopathy (CTE) Awardees Year Researcher Study Name 2015 Jesse Mez ...

  7. Information for People Treated with Human Growth Hormone (Comprehensive Report)

    MedlinePlus

    ... I help with the follow-up study? How did Creutzfeldt-Jakob disease (CJD) occur in people treated ... help to clarify individual level of risk. [ Top ] Did the hormone I took cause CJD? We have ...

  8. Human prion disease and relative risk associated with chronic wasting disease.

    PubMed

    Mawhinney, Samantha; Pape, W John; Forster, Jeri E; Anderson, C Alan; Bosque, Patrick; Miller, Michael W

    2006-10-01

    The transmission of the prion disease bovine spongiform encephalopathy (BSE) to humans raises concern about chronic wasting disease (CWD), a prion disease of deer and elk. In 7 Colorado counties with high CWD prevalence, 75% of state hunting licenses are issued locally, which suggests that residents consume most regionally harvested game. We used Colorado death certificate data from 1979 through 2001 to evaluate rates of death from the human prion disease Creutzfeldt-Jakob disease (CJD). The relative risk (RR) of CJD for CWD-endemic county residents was not significantly increased (RR 0.81, 95% confidence interval [CI] 0.40-1.63), and the rate of CJD did not increase over time (5-year RR 0.92, 95% CI 0.73-1.16). In Colorado, human prion disease resulting from CWD exposure is rare or nonexistent. However, given uncertainties about the incubation period, exposure, and clinical presentation, the possibility that the CWD agent might cause human disease cannot be eliminated. PMID:17176567

  9. Prion diseases and the gastrointestinal tract.

    PubMed

    Davies, G A; Bryant, Adam R; Reynolds, John D; Jirik, Frank R; Sharkey, Keith A

    2006-01-01

    The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Although they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPsc propagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer's patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPsc in the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies. PMID:16432555

  10. Prions and prion diseases: fundamentals and mechanistic details.

    PubMed

    Ryou, Chongsuk

    2007-07-01

    Prion diseases, often called transmissible spongiform encephalopathies (TSEs), are infectious diseases that accompany neurological dysfunctions in many mammalian hosts. Prion diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, "mad cow disease") in cattle, scrapie in sheep, and chronic wasting disease (CWD) in deer and elks. The cause of these fatal diseases is a proteinaceous pathogen termed prion that lacks functional nucleic acids. As demonstrated in the BSE outbreak and its transmission to humans, the onset of disease is not limited to a certain species but can be transmissible from one host species to another. Such a striking nature ofprions has generated huge concerns in public health and attracted serious attention in the scientific communities. To date, the potential transmission ofprions to humans via foodbome infectiorn and iatrogenic routes has not been alleviated. Rather, the possible transmission of human to human or cervids to human aggravates the terrifying situation across the globe. In this review, basic features about prion diseases including clinical and pathological characteristics, etiology, and transmission of diseases are described. Based on recently accumulated evidences, the molecular and biochemical aspects of prions, with an emphasis on the molecular interactions involved in prion conversion that is critical during prion replication and pathogenesis, are also addressed. PMID:18051314

  11. Slow virus disease: deciphering conflicting data on the transmissible spongiform encephalopathies (TSE) also called prion diseases.

    PubMed

    Bastian, Frank O; Fermin, Cesar D

    2005-11-01

    The transmissible spongiform encephalopathies (TSE) that manifest as Creutzfeldt-Jakob disease in humans, as scrapie in sheep and goats, mad cow disease in cattle, or chronic wasting disease in cervids (deer) represent a serious human health crisis and a significant economical problem. Despite much research, the nature of the elusive pathogen directly involved with TSE is currently unresolved. This article reviews current pathogen-cell plasma membrane properties, showing that the primary biochemical marker of the prion disease is used as a receptor by the intracellular bacterium Brucella abortus. Such observation makes plausible the role for the prion in the pathogenesis of TSE, and supports the concept that Spiroplasma, a wall-less bacterium, may be a transmissible agent of TSE. Over the past three decades, we have published convincing evidence that Spiroplasma infection is associated with TSE. The bacterial-prion-receptor concept by other laboratories support a model for TSE wherein a Spiroplasma bacterium can bind to prion receptors (alone or with anchors) on the cell surface lipid raft, allowing entry of the microbe into the cell to initiate infection. The relevance of this new concept is that it offers a new window for future research involving a bacterium in the pathogenesis of TSE. Data from the bacterial-prion-receptor model will aid in the development diagnostic tests and/or treatment protocols for TSE. PMID:16276518

  12. Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases.

    PubMed

    Irwin, Michael H; Moos, Walter H; Faller, Douglas V; Steliou, Kosta; Pinkert, Carl A

    2016-05-01

    Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc. PMID:26899010

  13. Historical overview of prion diseases: a view from afar.

    PubMed

    Liberski, Pawel P

    2012-01-01

    The transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative disorders which include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia in men, natural scrapie in sheep, goats and mufflons, transmissible mink encephalopathy in ranch-reared mink, chronic wasting disease of mule deer and elk, bovine spongiform encephalopathy or "mad cow disease" and its analogues in several exotic species of antelopes and wild felids in zoological gardens, and feline spongiform encephalopathy in domestic cats. This short review summarizes the history of the research to find the nature of the scrapie agent, especially as I have witnessed it unfolding before my eyes. I review the historical background of TSEs starting from the first description of scrapie in 1732. In 1957, the first prion disease in humans, kuru was described and its transmissibility was demonstrated in 1965 by seminal work of Gajdusek, Gibbs and colleagues, followed by transmission of CJD and then, GSS. In 1982, Stanley B. Prusiner formulated "prion hypothesis" which has dominated the field for the last 30 years. This theory had been recently extended to cover other neurodegenerations which are caused by misfolded proteins; these disease are called prionoids. PMID:22505359

  14. Could ectoparasites act as vectors for prion diseases?

    PubMed

    Lupi, Omar

    2003-06-01

    Prion diseases are rare neurodegenerative diseases of humans and animals with a lethal evolution. Several cell types found on the human skin, including keratinocytes, fibroblasts and lymphocytes, are susceptible to the abnormal infective isoform of the prion protein, which transforms the skin to produce a potential target for prion infection. Iatrogenic transmission of Creutzfeldt-Jakob disease was also recognized after corneal transplants in humans, and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes, as well as cerebral inoculation and oral ingestion, could be important in prion infections. Animal prion infections, such as scrapie (sheep) and "mad cow disease" (cattle), have shown a pattern of horizontal transmission in farm conditions and several ectoparasites have been shown to harbor prion rods in laboratory experiments. Fly larvae and mites were exposed to brain-infected material and were readily able to transmit scrapie to hamsters. New lines of evidence have confirmed that adult flies are also able to express prion proteins. Because ocular and cerebral myiases and mite infestation are not rare worldwide, and most cases are caused by fly larvae or hay mites that usually affect sheep and cattle, it is important to discuss the possibility that these ectoparasites could eventually act as reservoirs and/or vectors for prion diseases. PMID:12786866

  15. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases.

    PubMed

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-07-01

    The term "prion" was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word "prion" has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the "mad cow" crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  16. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

    PubMed Central

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-01-01

    The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  17. Potential for transmission of prion disease by contact lenses: an assessment of risk.

    PubMed

    Hogan, R Nick

    2003-01-01

    Prions are small proteinaceous infectious agents known to cause central nervous system infections in both animals and humans. Interest in the pathogenesis of these diseases has grown since the emergence of bovine spongiform encephalopathy (BSE or "mad cow disease") in the United Kingdom and several other countries in Europe. Ingestion of meat products from animals infected with BSE has resulted in transmission of the disease to humans as a variant form of Creutzfeldt-Jakob Disease (vCJD). CJD has a long asymptomatic incubation period, is untreatable, and universally fatal. Hence concern has arisen over other possible routes of disease transmission. Because it is known that prions are found in low levels in the corneas of animals with experimentally induced prion disease, and that a case of human CJD transmission by corneal transplantation has occurred, the question of possible prion transmission through the reuse of diagnostic fitting of contact lenses has surfaced. This article reviews prion diseases of animals and humans, and the data regarding the presence and location of prions in the eye. Issues inherent in the question of corneal and contact lens transmission are discussed. Although some key information has yet to be derived, it appears that the chance of obtaining prion disease through contact lens use is negligible. PMID:12772730

  18. Small-Molecule Theranostic Probes: A Promising Future in Neurodegenerative Diseases

    PubMed Central

    Aulić, Suzana

    2013-01-01

    Prion diseases are fatal neurodegenerative illnesses, which include Creutzfeldt-Jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. They are caused by unconventional infectious agents consisting primarily of misfolded, aggregated, β-sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (PrPC). Many lines of evidence suggest that prions (PrPSc) act both as a template for this conversion and as a neurotoxic agent causing neuronal dysfunction and cell death. As such, PrPSc may be considered as both a neuropathological hallmark of the disease and a therapeutic target. Several diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, and prion disease). Examples of these probes are Congo red, thioflavin T, and their derivatives. We synthesized a series of styryl derivatives, denoted theranostics, and studied their therapeutic and/or diagnostic potentials. Here we review the salient traits of these small molecules that are able to detect and modulate aggregated forms of several proteins involved in protein misfolding diseases. We then highlight the importance of further studies for their practical implications in therapy and diagnostics. PMID:24324497

  19. Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

    NASA Astrophysics Data System (ADS)

    Guest, Will; Cashman, Neil; Plotkin, Steven

    2009-05-01

    Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

  20. Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

    PubMed Central

    Lau, Agnes; McDonald, Alex; Daude, Nathalie; Mays, Charles E; Walter, Eric D; Aglietti, Robin; Mercer, Robert CC; Wohlgemuth, Serene; van der Merwe, Jacques; Yang, Jing; Gapeshina, Hristina; Kim, Chae; Grams, Jennifer; Shi, Beipei; Wille, Holger; Balachandran, Aru; Schmitt-Ulms, Gerold; Safar, Jiri G; Millhauser, Glenn L; Westaway, David

    2015-01-01

    The cellular prion protein (PrPC) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrPSc in Creutzfeldt-Jakob disease. PrPC β-endoproteolysis to the C2 fragment allows PrPSc formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease. PMID:25661904

  1. Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation.

    PubMed

    Lau, Agnes; McDonald, Alex; Daude, Nathalie; Mays, Charles E; Walter, Eric D; Aglietti, Robin; Mercer, Robert C C; Wohlgemuth, Serene; van der Merwe, Jacques; Yang, Jing; Gapeshina, Hristina; Kim, Chae; Grams, Jennifer; Shi, Beipei; Wille, Holger; Balachandran, Aru; Schmitt-Ulms, Gerold; Safar, Jiri G; Millhauser, Glenn L; Westaway, David

    2015-03-01

    The cellular prion protein (PrP(C)) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrP(S) (c) in Creutzfeldt-Jakob disease. PrP(C) β-endoproteolysis to the C2 fragment allows PrP(S) (c) formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, 'S1' and 'S3', locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrP(S) (c) and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrP(S) (c) and infectivity can either uncouple or engage to drive the onset of clinical disease. PMID:25661904

  2. The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases

    PubMed Central

    Zeineddine, Rafaa; Yerbury, Justin J.

    2015-01-01

    With the onset of the rapidly aging population, the impact of age related neurodegenerative diseases is becoming a predominant health and economic concern. Neurodegenerative diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease (CJD), Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) result from the loss of a specific subsets of neurons, which is closely associated with accumulation and deposition of specific protein aggregates. Protein aggregation, or fibril formation, is a well-studied phenomenon that occurs in a nucleation-dependent growth reaction. Recently, there has been a swell of literature implicating protein aggregation and its ability to propagate cell-to-cell in the rapid progression of these diseases. In order for protein aggregation to be kindled in recipient cells it is a requisite that aggregates must be able to be released from one cell and then taken up by others. In this article we will explore the relationship between protein aggregates, their propagation and the role of macropinocytosis in their uptake. We highlight the ability of neurons to undergo stimulated macropinocytosis and identify potential therapeutic targets. PMID:26528186

  3. [The other dementias: the neuropathology of the non-Alzheimer's disease dementias].

    PubMed

    Hamilton, R L

    Alzheimer's disease (AD) is one of the most common causes of dementia, but requires neuropathological verification for a definitive diagnosis because there are a number of other neurodegenerative diseases that may present with dementia. Some of these disorders have considerable overlap both clinically and pathologically with AD, while others have distinct clinical and pathological profiles. Vascular dementia and dementia with Lewy bodies (DLB) have the greatest overlap with AD and considerable controversy still surrounds the exact contribution of the non AD pathology to the dementia syndrome. The frontotemporal dementias are loosely united by clinical presentation, but are pathologically heterogeneous and include Pick's disease, dementia lacking distinctive histopathology, motor neuron disease inclusion dementia and corticobasal degeneration (CBD). CBD can be difficult to distinguish from progressive supranuclear palsy, especially when the latter lacks the distinctive gaze palsy. Finally, Creutzfeldt Jakob disease (CJD) may be difficult to distinguish from AD when the symptoms progress at an atypically slow pace. Recently, a new variant of CJD (vCJD) that has been linked to bovine spongiform encephalopathy ('mad cow' disease) has heightened awareness of these prion protein disorders. The neuropathological criteria for the diagnosis of these non AD dementia disorders will be reviewed. PMID:12938072

  4. Preclinical detection of infectivity and disease-specific PrP in blood throughout the incubation period of prion disease.

    PubMed

    Sawyer, Elizabeth B; Edgeworth, Julie Ann; Thomas, Claire; Collinge, John; Jackson, Graham S

    2015-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder characterised by accumulation of pathological isoforms of the prion protein, PrP. Although cases of clinical vCJD are rare, there is evidence there may be tens of thousands of infectious carriers in the United Kingdom alone. This raises concern about the potential for perpetuation of infection via medical procedures, in particular transfusion of contaminated blood products. Accurate biochemical detection of prion infection is crucial to mitigate risk and we have previously reported a blood assay for vCJD. This assay is sensitive for abnormal PrP conformers at the earliest stages of preclinical prion disease in mice and precedes the maximum infectious titre in blood. Not only does this support the possibility of screening asymptomatic individuals, it will also facilitate the elucidation of the complex relationship that exists between the ensemble of abnormal PrP conformers present in blood and the relationship to infectivity. PMID:26631638

  5. Transcriptional modulation in a leukocyte-depleted splenic cell population during prion disease.

    PubMed

    Huzarewich, Rhiannon L C H; Medina, Sarah; Robertson, Catherine; Parchaliuk, Debra; Booth, Stephanie A

    2011-01-01

    Prion replication in the periphery precedes neuroinvasion in many experimental rodent scrapie models, and in natural sheep scrapie and chronic wasting disease (CWD) in cervids. Prions propagate in the germinal centers of secondary lymphoid organs and are strongly associated with follicular dendritic cells (FDC) and possibly circulating dendritic cells and macrophages. Given the importance of lymphoid organs in prion disease transmission and pathogenesis, gene expression studies may reveal host factors or biological pathways related to prion replication and accumulation. A procedure was developed to enrich for FDC, dendritic cells, and macrophages prior to the investigation of transcriptional alterations in murine splenic cells during prion pathogenesis. In total, 1753 transcripts exhibited fold changes greater than three (false discovery rates less than 2%) in this population isolated from spleens of prion-infected versus uninfected mice. The gene for the small leucine-rich proteoglycan decorin (DCN) was one of the genes most overexpressed in infected mice, and the splenic protein levels mirrored this in mice infected with scrapie as well as bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD). A number of groups of functionally related genes were also significantly decreased in infected spleens. These included genes related to iron metabolism and homeostasis, pathways that have also been implicated in prion pathogenesis in the brain. These gene expression alterations provide insights into the molecular mechanisms underlying prion disease pathogenesis and may serve as a pool of potential surrogate markers for the early detection and diagnosis of some prion diseases. PMID:22043911

  6. Phosphatidylinositol-Glycan-Phospholipase D Is Involved in Neurodegeneration in Prion Disease

    PubMed Central

    Jin, Jae-Kwang; Jang, Byungki; Jin, Hyoung Tae; Choi, Eun-Kyoung; Jung, Cha-Gyun; Akatsu, Hiroyasu; Kim, Jae-Il; Carp, Richard I.; Kim, Yong-Sun

    2015-01-01

    PrPSc is formed from a normal glycosylphosphatidylinositol (GPI)-anchored prion protein (PrPC) by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD) was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie), and in both the brains and cerebrospinal fluids (CSF) of sporadic and familial Creutzfeldt-Jakob disease (CJD) patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer’s disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases. PMID:25867459

  7. Spatial correlation between the prevalence of transmissible spongiform diseases and British soil geochemistry.

    PubMed

    Imrie, C E; Korre, A; Munoz-Melendez, G

    2009-02-01

    Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurological conditions affecting a number of mammals, including sheep and goats (scrapie), cows (BSE), and humans (Creutzfeldt-Jakob disease). The diseases are widely believed to be caused by the misfolding of the normal prion protein to a pathological isoform, which is thought to act as an infectious agent. Outbreaks of the disease are commonly attributed to contaminated feed and genetic susceptibility. However, the implication of copper and manganese in the pathology of the disease, and its apparent geographical clustering, have prompted suggestions of a link with trace elements in the environment. Nevertheless, studies of soils at regional scales have failed to provide evidence of an environmental risk factor. This study uses geostatistical techniques to investigate the correlations between the distribution of TSE prevalence and soil geochemical variables across the UK according to different spatial scales. A similar spatial pattern in scrapie and BSE occurrence is identified, which may be linked with increasing pH and total organic carbon, and decreasing iodine concentration. However, the pattern also resembles that of the density of dairy farming. Nevertheless, despite the low spatial resolution of the TSE data available for this study, the fact that significant correlations are detected indicates there is a possibility of a link between soil geochemistry, scrapie, and BSE. It is suggested that further investigations of the prevalence of TSE and environmental exposure to trace metals should take into account the factors affecting their bioavailability. PMID:18427934

  8. The alternative role of 14-3-3 zeta as a sweeper of misfolded proteins in disease conditions.

    PubMed

    Kaneko, Kiyotoshi; Hachiya, Naomi S

    2006-01-01

    Here, we propose a novel hypothesis that 14-3-3 zeta might act as a sweeper of misfolded proteins by facilitating the formation of aggregates, which are referred to as inclusion bodies. Studies on the localization of the 14-3-3 proteins in different types of inclusion bodies in the brain including neurofibrillary tangle in Alzheimer's disease, pick bodies in Pick's disease, Lewy body-like hyaline inclusions in sporadic amyotrophic lateral sclerosis, prion/florid plaques in sporadic/variant Creutzfeldt-Jakob disease, nuclear inclusions in spinocerebellar ataxia-1, and possibly Lewy bodies in Parkinson's disease suggest a close association of these diseases with 14-3-3 zeta. The highly conserved hydrophobic surface of the amphipathic groove in 14-3-3 zeta represents a general mechanism with diverse cellular proteins, and it may also allow for the molecular recognition of misfolded proteins by hydrophobic interaction in disease conditions. When the abnormal processing of misfolded proteins overwhelms the quality control systems of the cell, it is likely that 14-3-3 zeta is recruited to form deposits of protein aggregates with nonnative, misfolded proteins in order to protect the cell against toxicity. Hence, 14-3-3 zeta may be considered as an auxiliary therapeutic tool in the protein aggregation disorders. PMID:16516399

  9. Atypical sporadic CJD-MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease.

    PubMed

    Berghoff, Anna S; Trummert, Anita; Unterberger, Ursula; Ströbel, Thomas; Hortobágyi, Tibor; Kovacs, Gabor G

    2015-08-01

    We describe an atypical neuropathological phenotype of sporadic Creutzfeldt-Jakob disease in a 76-year-old man. The clinical symptoms were characterized by progressive dementia, gait ataxia, rigidity and urinary incontinence. The disease duration was 6 weeks. MRI did not show prominent atrophy or hyperintensities in cortical areas, striatum or thalamus. Biomarker examination of the cerebrospinal fluid deviated from that seen in pure Alzheimer's disease. Triphasic waves in the EEG were detected only later in the disease course, while 14-3-3 assay was positive. PRNP genotyping revealed methionine homozygosity (MM) at codon 129. Neuropathology showed classical CJD changes corresponding to the MM type 1 cases. However, a striking feature was the presence of abundant kuru-type plaques in the white matter. This rare morphology was associated with neuropathological signs of intranuclear inclusion body disease and advanced stage of argyrophilic grain disease. These alterations did not show correlation with each other, thus seemed to develop independently. This case further highlights the complexity of neuropathological alterations in the ageing brain. PMID:25783686

  10. Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

    PubMed Central

    Bouybayoune, Ihssane; Mantovani, Susanna; Del Gallo, Federico; Bertani, Ilaria; Restelli, Elena; Comerio, Liliana; Tapella, Laura; Baracchi, Francesca; Fernández-Borges, Natalia; Mangieri, Michela; Bisighini, Cinzia; Beznoussenko, Galina V.; Paladini, Alessandra; Balducci, Claudia; Micotti, Edoardo; Forloni, Gianluigi; Castilla, Joaquín; Fiordaliso, Fabio; Tagliavini, Fabrizio; Imeri, Luca; Chiesa, Roberto

    2015-01-01

    Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype. PMID:25880443

  11. Structure-Based Prediction of Unstable Regions in Proteins: Applications to Protein Misfolding Diseases

    NASA Astrophysics Data System (ADS)

    Guest, Will; Cashman, Neil; Plotkin, Steven

    2009-03-01

    Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and solution of the Poisson-Boltzmann equation. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

  12. Human prion protein sequence elements impede cross-species chronic wasting disease transmission

    PubMed Central

    Kurt, Timothy D.; Jiang, Lin; Fernández-Borges, Natalia; Bett, Cyrus; Liu, Jun; Yang, Tom; Spraker, Terry R.; Castilla, Joaquín; Eisenberg, David; Kong, Qingzhong; Sigurdson, Christina J.

    2015-01-01

    Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the β2-α2 loop (residues 165–175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a β2-α2 loop (residues 165–175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross-species prion transmission. PMID:25705888

  13. Extracellular vesicles--Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases.

    PubMed

    Coleman, Bradley M; Hill, Andrew F

    2015-04-01

    Many cell types, including neurons, are known to release small membranous vesicles known as exosomes. In addition to their protein content these vesicles have recently been shown to contain messenger RNA (mRNA) and micro RNA (miRNA) species. Roles for these vesicles include cell-cell signalling, removal of unwanted proteins, and transfer of pathogens (including prion-like misfolded proteins) between cells, such as infectious prions. Prions are the infectious particles that are responsible for transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Exosomes are also involved in processing the amyloid precursor protein (APP), which is associated with Alzheimer's disease (AD). As exosomes can be isolated from circulating fluids such as serum, urine, and cerebrospinal fluid (CSF), they provide a potential source of biomarkers for neurological conditions. Here, we review the roles these vesicles play in neurodegenerative disease and highlight their potential in diagnosing these disorders through analysis of their RNA content. PMID:25704308

  14. Anterior-posterior and lateral hemispheric alterations in cortical glucose utilization in Alzheimer's disease

    SciTech Connect

    Friedland, T.F.; Budinger, T.F.; Jaqust, W.J.; Yano, Y.; Huesman, R.H.; Knittel, B.; Koss, E.; Ober, B.A.

    1984-01-01

    The anatomical and chemical features of Alzheimer's disease (AD) are not distributed evenly throughout the brain. However, the nature of this focality has not been well established in vivo. Dynamic studies using the Donner 280-Crystal Positron Tomograph with (F-18)2-fluorodeoxyglucose were performed in 17 subjects meeting current research criteria for AD, and in 7 healthy age-matched control subjects. Glucose metabolic rates in the temporal-parietal cortex are 27% lower in AD than in controls. Ratios of activity density reveal consistently lower metabolic rates in temporal-parietal than frontal cortex in the AD group, while healthy aged subjects have equal metabolic rates in the two areas. Similar findings have been reported by other laboratories. A major finding is a striking lateral asymmetry of cortical metabolism in AD which does not favor either hemisphere. (The asymmetry is 13% in the AD group, 3% in controls, p<.005.) This has not been previously reported in AD. The consistency with which anterior-posterior metabolic differences are found in AD suggests that the focality of the metabolic changes may be used to develop a noninvasive diagnostic test for the disorder. The metabolic asymmetry in AD may be compared to the clinical and pathological asymmetry found in Creutzfeldt-Jakob disease, and may represent an additional link between AD and the subacute spongiform encephalopathies.

  15. Highly sensitive rapid fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Kovalev, Valeri I.; Bartona, James S.; Richardson, Patricia R.; Jones, Anita C.

    2006-07-01

    There is a risk of contamination of surgical instruments by infectious protein residues, in particular, prions which are the agents for Creutzfeldt-Jakob Disease in humans. They are exceptionally resistant to conventional sterilization, therefore it is important to detect their presence as contaminants so that alternative cleaning procedures can be applied. We describe the development of an optimized detection system for fluorescently labelled protein, suitable for in-hospital use. We show that under optimum conditions the technique can detect ~10 attomole/cm2 with a scan speed of ~3-10 cm2/s of the test instrument's surface. A theoretical analysis and experimental measurements will be discussed.

  16. Medicinal and other products and human and animal transmissible spongiform encephalopathies: memorandum from a WHO meeting.

    PubMed Central

    1997-01-01

    The report in March 1996 of 10 human cases of a novel from of Creutzfeldt-Jakob disease in the United Kingdom, and its possible link to the agent that causes bovine spongiform encephalopathy (BSE), raises many questions about the safety of animal-derived products and by-products entering the food chain or being used in medicine. This Memorandum updates the preventive measures put forward in 1991 to minimize the risks associated with the use of bovine-derived materials in medicinal products and medical devices. PMID:9509622

  17. Atypical prion diseases in humans and animals.

    PubMed

    Tranulis, Michael A; Benestad, Sylvie L; Baron, Thierry; Kretzschmar, Hans

    2011-01-01

    Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrP(Sc)), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans. PMID:21598097

  18. A vital fluid: risk, controversy and the politics of blood donation in the era of "mad cow disease".

    PubMed

    O'Neill, Kate

    2003-10-01

    This article examines the reasons for, and likely impact of, the decision by the US and other countries to permanently defer blood donors who have spent time in Britain or Europe, for fear they may transmit new variant Creutzfeldt-Jakob disease (vCJD), the human form of "mad cow disease". It begins by discussing how vCJD and blood transfusion are linked, and how these have been translated into policy. First, maintaining a safe and stable supply of blood entails not only maintaining the trust of recipients in the system, but also that of donors, who need to be assured that their blood will be welcomed and used. Often, the balance, once upset, is regained by sacrificing donors, but accompanying costs might also be high. Second, the article highlights the impact of various forms of globalization -of commerce, disease and travel, and immigration- on blood policies and public and policy attitudes. Third, it assesses the decision by the US to restrict blood donations from Europeans and travelers to combat such a pervasive risk. The conclusion discusses how donor deferral policies may be interpreted by the public in the light of earlier discussions, and raises issues for future research. PMID:14971395

  19. The impact of social amplification and attenuation of risk and the public reaction to mad cow disease in Canada.

    PubMed

    Lewis, Roxanne E; Tyshenko, Michael G

    2009-05-01

    Following the detection of bovine spongiform encephalopathy (BSE) in Canada, and subsequently in the United States, confidence in the safety of beef products remained high. Consumers actually increased their consumption of beef slightly after the news of an increased risk from mad cow disease, which has been interpreted as public support for beef farmers and confidence in government regulators. The Canadian public showed a markedly different reaction to the news of domestic BSE than the furious and panicked responses observed in the United Kingdom, Germany, and Japan. Using the social amplification of risk framework, we show that, while other countries displayed social amplification of risk, Canada experienced a social attenuation of risk. The attenuated reaction in Canada toward mad cow disease and increased human health risks from variant Creutzfeldt-Jakob disease (vCJD) was due to the social context at the time when BSE was discovered domestically. Mortality, morbidity, and psychosocial impacts resulting from other major events such as severe acute respiratory syndrome (SARS), West Nile virus (WNV), and the U.S.-Iraq war made the theoretical risks of BSE and vCJD a lower priority, reducing its concern as a risk issue. PMID:19192234

  20. Transgenic mice recapitulate the phenotypic heterogeneity of genetic prion diseases without developing prion infectivity: Role of intracellular PrP retention in neurotoxicity.

    PubMed

    Chiesa, Roberto; Restelli, Elena; Comerio, Liliana; Del Gallo, Federico; Imeri, Luca

    2016-03-01

    Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport. PMID:26864450

  1. Transgenic mice recapitulate the phenotypic heterogeneity of genetic prion diseases without developing prion infectivity: Role of intracellular PrP retention in neurotoxicity

    PubMed Central

    Chiesa, Roberto; Restelli, Elena; Comerio, Liliana; Del Gallo, Federico; Imeri, Luca

    2016-01-01

    abstract Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport. PMID:26864450

  2. Disease Activity Measures in Paediatric Rheumatic Diseases

    PubMed Central

    Luca, Nadia J.; Feldman, Brian M.

    2013-01-01

    Disease activity refers to potentially reversible aspects of a disease. Measurement of disease activity in paediatric rheumatic diseases is a critical component of patient care and clinical research. Disease activity measures are developed systematically, often involving consensus methods. To be useful, a disease activity measure must be feasible, valid, and interpretable. There are several challenges in quantifying disease activity in paediatric rheumatology; namely, the conditions are multidimensional, the level of activity must be valuated in the context of treatment being received, there is no gold standard for disease activity, and it is often difficult to incorporate the patient's perspective of their disease activity. To date, core sets of response variables are defined for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, and juvenile dermatomyositis, as well as definitions for improvement in response to therapy. Several specific absolute disease activity measures also exist for each condition. Further work is required to determine the optimal disease activity measures in paediatric rheumatology. PMID:24089617

  3. Human prion diseases: surgical lessons learned from iatrogenic prion transmission.

    PubMed

    Bonda, David J; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L; Schonberger, Lawrence B; Cali, Ignazio

    2016-07-01

    The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission

  4. Infection and disease: cause and cure.

    PubMed

    Herrington, C Simon; Douek, Daniel C

    2006-01-01

    Much can be learnt about the mechanisms by which micro-organisms cause disease from the ways that they interact with cells and tissues. This issue of The Journal of Pathology contains articles that address the roles that cell and tissue biology and pathology are playing in the elucidation of these mechanisms. A review of variant Creutzfeldt-Jakob disease is followed by a discussion of severe acute respiratory syndrome (SARS). Two articles on human papillomavirus (HPV) infection address the association between viral infection and neoplasia, as do reviews on viruses and lymphoma/leukaemia, and Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8, HHV8). The section on viral disease concludes with an article on morbilliviruses. The intracellular effects of bacteria are addressed in a review of Listeria infection and a further review outlines recent advances in our knowledge of syphilis. Reviews on Helicobacter and gastric neoplasia, innate defences against methicillin-resistant Staphylococcus aureus (MRSA) infection, and the function of granulomas in tuberculosis also address aspects of tissue responses to bacterial infection. Following a review of the function of immunoglobulin A in defence against infection, a group of articles considers vaccination and gene therapy approaches, the latter involving consideration of both viral and bacterial strategies. The reviews assembled here bridge several gaps: between microbiology and cellular pathology; between host and infecting organism; and between disease and therapy. It is clear that cell and tissue pathology approaches are of value in all of these spheres, providing cell and tissue relevance to microbiological and immunological observations. PMID:16362991

  5. Treatment of Prion Disease with Heterologous Prion Proteins

    PubMed Central

    Skinner, Pamela J.; Kim, Hyeon O.; Bryant, Damani; Kinzel, Nikilyn J.; Reilly, Cavan; Priola, Suzette A.; Ward, Anne E.; Goodman, Patricia A.; Olson, Katherine; Seelig, Davis M.

    2015-01-01

    Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for which there is no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrPC) into a protease resistant infectious form (PrPsc or PrPres). Both in vitro (cell culture and cell free conversion assays) and in vivo (animal) studies have demonstrated the strong dependence of this conversion process on protein sequence homology between the initial prion inoculum and the host’s own cellular prion protein. The presence of non-homologous (heterologous) proteins is often inhibitory to this conversion process. We hypothesize that the presence of heterologous prion proteins from one species might therefore constitute an effective treatment for prion disease in another species. To test this hypothesis, we infected mice intracerebrally with murine adapted RML-Chandler scrapie and treated them with heterologous prion protein (purified bacterially expressed recombinant hamster prion protein) or vehicle alone. Treated animals demonstrated reduced disease associated pathology, decreased accumulation of protease-resistant disease-associated prion protein, with delayed onset of clinical symptoms and motor deficits. This was concomitant with significantly increased survival times relative to mock-treated animals. These results provide proof of principle that recombinant hamster prion proteins can effectively and safely inhibit prion disease in mice, and suggest that hamster or other non-human prion proteins may be a viable treatment for prion diseases in humans. PMID:26134409

  6. Comparative quantitative study of 'signature' pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders.

    PubMed

    Armstrong, Richard A; Cairns, Nigel J

    2015-10-01

    The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of 'signature' pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer's disease (AD), Down's syndrome (DS), sporadic Creutzfeldt-Jakob disease, and variant Creutzfeldt-Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick's disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson's disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders. PMID:25929331

  7. Myiasis as a risk factor for prion diseases in humans.

    PubMed

    Lupi, O

    2006-10-01

    Prion diseases are transmissible spongiform encephalopathies of humans and animals. The oral route is clearly associated with some prion diseases, according to the dissemination of bovine spongiform encephalopathy (BSE or mad cow disease) in cattle and kuru in humans. However, other prion diseases such as scrapie (in sheep) and chronic wasting disease (CWD) (in cervids) cannot be explained in this way and are probably more associated with a pattern of horizontal transmission in both domestic and wild animals. The skin and mucous membranes are a potential target for prion infections because keratinocytes and lymphocytes are susceptible to the abnormal infective isoform of the prion protein. Iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) was also recognized after corneal transplants in humans and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes could also be important in prion infections. Some ectoparasites have been proven to harbour prion rods in laboratory experiments. Prion rods were identified in both fly larvae and pupae; adult flies are also able to express prion proteins. The most common causes of myiasis in cattle and sheep, closely related animals with previous prion infections, are Hypoderma bovis and Oestrus ovis, respectively. Both species of flies present a life cycle very different from human myiasis, as they have a long contact with neurological structures, such as spinal canal and epidural fat, which are potentially rich in prion rods. Ophthalmomyiases in humans is commonly caused by both species of fly larvae worldwide, providing almost direct contact with the central nervous system (CNS). The high expression of the prion protein on the skin and mucosa and the severity of the inflammatory response to the larvae could readily increase the efficiency of transmission of prions in both animals and humans. PMID:16987255

  8. Clinical Issues-May 2016.

    PubMed

    Van Wicklin, Sharon A

    2016-05-01

    Variations in documenting surgical wound classification Key words: surgical wound classification, clean, clean-contaminated, contaminated, dirty. Wearing long-sleeved jackets while preparing and packaging items for sterilization Key words: long-sleeved jackets, organic material, sterile processing. Endoscopic transmission of prions Key words: prions, high-risk tissue, low-risk tissue, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD). Wearing gloves when handling flexible endoscopes Key words: gloves, low-protein, powder-free, natural rubber latex gloves, latex-free gloves. PMID:27129755

  9. Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease

    PubMed Central

    Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G.; Grison, Alice; Gustincich, Stefano

    2016-01-01

    Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells’ own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID:27458372

  10. Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease.

    PubMed

    Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G; Grison, Alice; Gustincich, Stefano

    2016-01-01

    Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells' own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID:27458372

  11. The cognitive profile of prion disease: a prospective clinical and imaging study

    PubMed Central

    Caine, Diana; Tinelli, Renata J; Hyare, Harpreet; De Vita, Enrico; Lowe, Jessica; Lukic, Ana; Thompson, Andrew; Porter, Marie-Claire; Cipolotti, Lisa; Rudge, Peter; Collinge, John; Mead, Simon

    2015-01-01

    Objectives Prion diseases are dementing illnesses with poorly defined neuropsychological features. This is probably because the most common form, sporadic Creutzfeldt-Jakob disease, is often rapidly progressive with pervasive cognitive decline making detailed neuropsychological investigation difficult. This study, which includes patients with inherited, acquired (iatrogenic and variant) and sporadic forms of the disease, is the only large-scale neuropsychological investigation of this patient group ever undertaken and aimed to define a neuropsychological profile of human prion diseases. Methods A tailored short cognitive examination of all of the patients (n = 81), with detailed neuropsychological testing in a subset with mild disease (n = 30) and correlation with demographic, clinical, genetic (PRNP mutation and polymorphic codon 129 genotype), and other variables (MRI brain signal change in cortex, basal ganglia or thalamus; quantitative research imaging, cerebrospinal fluid 14-3-3 protein). Results Comparison with healthy controls showed patients to be impaired on all tasks. Principal components analysis showed a major axis of fronto-parietal dysfunction that accounted for approximately half of the variance observed. This correlated strongly with volume reduction in frontal and parietal gray matter on MRI. Examination of individual patients' performances confirmed early impairment on this axis, suggesting characteristic cognitive features in mild disease: prominent executive impairment, parietal dysfunction, a largely expressive dysphasia, with reduced motor speed. Interpretation Taken together with typical neurological features, these results complete a profile that should improve differential diagnosis in a clinical setting. We propose a tailored neuropsychological battery for early recognition of clinical onset of symptoms with potential for use in clinical trials involving at-risk individuals. PMID:26000326

  12. Retinal function and morphology are altered in cattle infected with the prion disease transmissible mink encephalopathy.

    PubMed

    Smith, J D; Greenlee, J J; Hamir, A N; Richt, J A; Greenlee, M H West

    2009-09-01

    Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy ("mad cow disease") to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Müller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of

  13. A naturally occurring variant of the human prion protein completely prevents prion disease.

    PubMed

    Asante, Emmanuel A; Smidak, Michelle; Grimshaw, Andrew; Houghton, Richard; Tomlinson, Andrew; Jeelani, Asif; Jakubcova, Tatiana; Hamdan, Shyma; Richard-Londt, Angela; Linehan, Jacqueline M; Brandner, Sebastian; Alpers, Michael; Whitfield, Jerome; Mead, Simon; Wadsworth, Jonathan D F; Collinge, John

    2015-06-25

    Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation. PMID:26061765

  14. A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Imbalance of brain iron homeostasis is a common feature of neurodegenerative conditions that include sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease, among others. However, the mechanisms underlying this change are unclear. In s...

  15. Detecting and quantifying prions: Mass spectrometry-based approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prions are novel pathogens that cause a set of rare fatal neurological diseases know as transmissible spongiform encephalopathies. Examples of these diseases include Creutzfeldt-Jakob disease, scrapie and chronic wasting disease. Prions are able to recruit a normal cellular prion protein and convert...

  16. Risk perception of the "mad cow disease" in France: determinants and consequences.

    PubMed

    Setbon, Michel; Raude, Jocelyn; Fischler, Claude; Flahault, Antoine

    2005-08-01

    Since 1996, when bovine spongiform encephalopathy (BSE) was assessed as a possible human transmissible disease, a variant of Creutzfeldt-Jakob disease (vCJD), French people have entered into a long period of fear and avoidance of beef and bovine byproducts, which produced an unprecedented collapse in the beef market. This article deals with the perceived risk of the "mad cow disease" (MCD) in the French general population. Two surveys were conducted on a representative sample of the adult population, the first one in 2000 during the peak of the crisis and the second one 13 months later in a quieter period. The main assumption we made was that changes in beef consumption are strongly related to the perceived risk of MCD, which we defined as people's cognitive and affective responses to hazard. Our objective was to identify the determinants and consequences of this perceived risk and to compare them in different sociopolitical contexts. The results issued from a bivariate and multivariate analysis show that: (i) the distribution of most of the variables significantly related to the perceived risk identified in the first survey had changed in the second survey, in relation with the reduction of worry and the resumption of national beef consumption; (ii) the propensity for self-protection through avoiding or ceasing beef eating was more related to feelings of worry than to subjective vCJD risk assessments; and (iii) the main determinant of less avoidance to beef products was the preference for beef, a feeling identified prior to emergence of the risk of MCD, remaining unchanged in various contexts. PMID:16268931

  17. Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that affects cattle and can be transmitted to human beings as new variant Creutzfeldt-Jakob disease (vCJD). A protease-resistant, disease-associated isoform of the prion protein (PrP**Sc) accumulates in the central ner...

  18. What Are the Risks of a Blood Transfusion?

    MedlinePlus

    ... the transfusion can safely be restarted. Viruses and Infectious Diseases Some infectious agents, such as HIV, can survive in blood and infect the person receiving the blood transfusion. To keep blood safe, blood ... Creutzfeldt-Jakob disease (vCJD). This disease is the human version of ...

  19. Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

    PubMed Central

    Webb, T. E. F.; Poulter, M.; Beck, J.; Uphill, J.; Adamson, G.; Campbell, T.; Linehan, J.; Powell, C.; Brandner, S.; Pal, S.; Siddique, D.; Wadsworth, J. D.; Joiner, S.; Alner, K.; Petersen, C.; Hampson, S.; Rhymes, C.; Treacy, C.; Storey, E.; Geschwind, M. D.; Nemeth, A. H.; Wroe, S.; Mead, S.

    2008-01-01

    The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the

  20. Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.

    PubMed

    Gobbi, Marco; Colombo, Laura; Morbin, Michela; Mazzoleni, Giulia; Accardo, Elena; Vanoni, Marco; Del Favero, Elena; Cantù, Laura; Kirschner, Daniel A; Manzoni, Claudia; Beeg, Marten; Ceci, Paolo; Ubezio, Paolo; Forloni, Gianluigi; Tagliavini, Fabrizio; Salmona, Mario

    2006-01-13

    Prion protein (PrP) amyloid formation is a central feature of genetic and acquired prion diseases such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. The major component of GSS amyloid is a PrP fragment spanning residues approximately 82-146, which when synthesized as a peptide, readily forms fibrils featuring GSS amyloid. The present study employed surface plasmon resonance (SPR) to characterize the binding events underlying PrP82-146 oligomerization at the first stages of fibrillization, according to evidence suggesting a pathogenic role of prefibrillar oligomers rather than mature amyloid fibrils. We followed in real time the binding reactions occurring during short term (seconds) addition of PrP82-146 small oligomers (1-5-mers, flowing species) onto soluble prefibrillar PrP82-146 aggregates immobilized on the sensor surface. SPR data confirmed very efficient aggregation/elongation, consistent with the hypothesis of nucleation-dependent polymerization process. Much lower binding was observed when PrP82-146 flowed onto the scrambled sequence of PrP82-146 or onto prefibrillar Abeta42 aggregates. As previously found with Abeta40, SPR data could be adequately fitted by equations modeling the "dock-and-lock" mechanism, in which the "locking" step is due to sequential conformational changes, each increasing the affinity of the monomer for the fibril until a condition of irreversible binding is reached. However, these conformational changes (i.e. the locking steps) appear to be faster and easier with PrP82-146 than with Abeta40. Such differences suggest that PrP82-146 has a greater propensity to polymerize and greater stability of the aggregates. PMID:16286452

  1. Mass Spectrometry of Prions: Approaches to Conformational Distinction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prions are the agents that cause a set of fatal neurological diseases that include Creutzfeldt-Jakob disease. Prions are composed solely of protein. Unlike viral, bacterial, or fungal pathogens, the information necessary to propagate the infection is contained in the conformation of the prion isofor...

  2. Toward the molecular basis of inherited prion diseases: NMR structure of the human prion protein with V210I mutation.

    PubMed

    Biljan, Ivana; Ilc, Gregor; Giachin, Gabriele; Raspadori, Andrea; Zhukov, Igor; Plavec, Janez; Legname, Giuseppe

    2011-09-30

    The development of transmissible spongiform encephalopathies (TSEs) is associated with the conversion of the cellular prion protein (PrP(C)) into a misfolded, pathogenic isoform (PrP(Sc)). Spontaneous generation of PrP(Sc) in inherited forms of disease is caused by mutations in gene coding for PrP (PRNP). In this work, we describe the NMR solution-state structure of the truncated recombinant human PrP (HuPrP) carrying the pathological V210I mutation linked to genetic Creutzfeldt-Jakob disease. The three-dimensional structure of V210I mutant consists of an unstructured N-terminal part (residues 90-124) and a well-defined C-terminal domain (residues 125-228). The C-terminal domain contains three α-helices (residues 144-156, 170-194 and 200-228) and a short antiparallel β-sheet (residues 129-130 and 162-163). Comparison with the structure of the wild-type HuPrP revealed that although two structures share similar global architecture, mutation introduces some local structural differences. The observed variations are mostly clustered in the α(2)-α(3) inter-helical interface and in the β(2)-α(2) loop region. Introduction of bulkier Ile at position 210 induces reorientations of several residues that are part of hydrophobic core, thus influencing α(2)-α(3) inter-helical interactions. Another important structural feature involves the alteration of conformation of the β(2)-α(2) loop region and the subsequent exposure of hydrophobic cluster to solvent, which facilitates intermolecular interactions involved in spontaneous generation of PrP(Sc). The NMR structure of V210I mutant offers new clues about the earliest events of the pathogenic conversion process that could be used for the development of antiprion drugs. PMID:21839748

  3. Transmission of scrapie prions to primate after an extended silent incubation period

    PubMed Central

    Comoy, Emmanuel E.; Mikol, Jacqueline; Luccantoni-Freire, Sophie; Correia, Evelyne; Lescoutra-Etchegaray, Nathalie; Durand, Valérie; Dehen, Capucine; Andreoletti, Olivier; Casalone, Cristina; Richt, Juergen A.; Greenlee, Justin J.; Baron, Thierry; Benestad, Sylvie L.; Brown, Paul; Deslys, Jean-Philippe

    2015-01-01

    Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie. PMID:26123044

  4. Transmission of scrapie prions to primate after an extended silent incubation period.

    PubMed

    Comoy, Emmanuel E; Mikol, Jacqueline; Luccantoni-Freire, Sophie; Correia, Evelyne; Lescoutra-Etchegaray, Nathalie; Durand, Valérie; Dehen, Capucine; Andreoletti, Olivier; Casalone, Cristina; Richt, Juergen A; Greenlee, Justin J; Baron, Thierry; Benestad, Sylvie L; Brown, Paul; Deslys, Jean-Philippe

    2015-01-01

    Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie. PMID:26123044

  5. Acute inferior homonymous quandrantanopia in a 71-year-old woman.

    PubMed

    Vachalová, Ivana; Gindl, Viola; Heckmann, Josef G

    2014-04-01

    A 71-year-old woman presented with acute inferior homonymous quadrantanopia initially mimicking acute ischemic stroke. As clinical signs and symptoms progressed to akinetic mutism with myoclonus the diagnosis of the Heidenhain variant of Creutzfeldt-Jakob disease was made. Brain MRI 4 days after symptom onset revealed ribbon-like high signal intensity in the medial occipital cortex. PMID:24210803

  6. Typical and atypical cases of bovine spongiform encephalopathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy of cattle, first detected in 1986 in the United Kingdom and subsequently in other countries. It is the most likely cause of variant Creutzfeldt-Jakob disease (vCJD) in humans, but the origin of BSE has not been eluci...

  7. Fluorescence of tissues fluororophores such as lipofuscin as a possible basis for the detection of CNS tissues on bovine carcasses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative transmissible spongiform encephalopathy (TSE) which is thought to cause variant of Creutzfeldt-Jakob disease (vCJD) in humans. It is believed that humans contract vCJD by consumption of meat contaminated with bovine tissue containi...

  8. Fundamental immunological problems associated with "transmissible spongiform encephalopathies".

    PubMed

    Ebringer, Alan; Rashid, Taha; Wilson, Clyde

    2015-02-01

    "Bovine spongiform encephalopathy", "scrapie", as well as Creutzfeldt-Jakob disease and kuru belong to a group of related neurological conditions termed "transmissible spongiform encephalopathies". These diseases are based on the LD50 measurement whereby saline brain homogenates are injected into experimental animals and when 50% of them develop symptoms, this is considered as transmission of the disease, but the gold standard for diagnosis is autopsy examination. However, an untenable assumption is being made in that saline brain homogenates do not cause tissue damage but it is known since the time of Pasteur, that they give rise to "post-rabies vaccination allergic encephalomyelitis". This is the fundamental flaw in the diagnosis of these diseases. A way forward, however, is to examine infectious agents, such as Acinetobacter which show molecular mimicry with myelin and elevated levels of antibodies to this microbe are found in multiple sclerosis patients and animals affected by "bovine spongiform encephalopathy". PMID:25573495

  9. Molecular aspects of disease pathogenesis in the transmissible spongiform encephalopathies.

    PubMed

    Priola, Suzette A; Vorberg, Ina

    2004-01-01

    The transmissible spongiform encephalopathy (TSE) diseases are a group of rare, fatal, and transmissible neurodegenerative diseases that include kuru and Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, transmissible mink encephalopathy (TME), and chronic wasting disease (CWD) in mule deer and elk. Over the last 20 yr, they have gone from a fascinating but relatively obscure group of diseases to one that is a major agricultural and economic problem as well as a threat to human health. The shift in the relative impact of the TSE diseases began in the late 1970s when the United Kingdom altered the process by which animal carcasses were rendered to provide a protein supplement (i.e., meat and bone meal) to sheep, cattle, and other livestock. Several years later a new disease was recognized in the British cattle population. The pathological and immunohistochemical characteristics of the disease clearly placed it among the TSEs. The new disease was named bovine spongiform encephalopathy (BSE) by the scientific community and "mad cow disease" by the less-than-scientific press. At its peak in the UK, several thousand cattle a year were diagnosed with BSE, and millions of cattle were slaughtered. Introduction of the specified offals ban as well as banning the practice of feeding ruminants to other ruminants has led to a drastic decrease in the number of yearly BSE cases in the UK (less than 500 in 2003), and the epidemic is clearly on the wane. However, BSE has now spread throughout the rest of Europe, as well as to Japan, Russia, Canada, and Israel and thus remains a worldwide problem.A primary concern following the identification of BSE in 1985 was that it might cross species barriers to infect humans. Initially, it was thought that transmission of BSE to humans was unlikely, given that humans appeared to be resistant to scrapie, an animal TSE that had been endemic in British sheep for centuries. However, a few years after BSE was first recognized, a

  10. Highly sensitive rapid fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Kovalev, Valeri I.; Barton, James S.; Richardson, Patricia R.; Jones, Anita C.

    2006-02-01

    There is a risk of contamination of surgical instruments by nfectious protein residues, in particular, prions which are the agents for Creutzfeldt-Jakob Disease in humans. They are exceptionally resistant to conventional sterilization, therefore it is important to detect their presence as contaminants so that alternative cleaning procedures can be applied. We describe the development of an optimized detection system for fluorescently labelled protein, suitable for in-hospital use. We show that under optimum conditions the technique can detect ~100 zeptomoles/mm2 with an area scan speed of ~20 cm2/s and for using the system to detect other agents of biomedical interest. A theoretical analysis and experimental measurements will be discussed.

  11. Highly Infectious Prions Generated by a Single Round of Microplate-Based Protein Misfolding Cyclic Amplification

    PubMed Central

    Moudjou, Mohammed; Sibille, Pierre; Fichet, Guillaume; Reine, Fabienne; Chapuis, Jérôme; Herzog, Laetitia; Jaumain, Emilie; Laferrière, Florent; Richard, Charles-Adrien; Laude, Hubert; Andréoletti, Olivier; Rezaei, Human; Béringue, Vincent

    2013-01-01

    ABSTRACT Measurements of the presence of prions in biological tissues or fluids rely more and more on cell-free assays. Although protein misfolding cyclic amplification (PMCA) has emerged as a valuable, sensitive tool, it is currently hampered by its lack of robustness and rapidity for high-throughput purposes. Here, we made a number of improvements making it possible to amplify the maximum levels of scrapie prions in a single 48-h round and in a microplate format. The amplification rates and the infectious titer of the PMCA-formed prions appeared similar to those derived from the in vivo laboratory bioassays. This enhanced technique also amplified efficiently prions from different species, including those responsible for human variant Creutzfeldt-Jakob disease. This new format should help in developing ultrasensitive, high-throughput prion assays for cognitive, diagnostic, and therapeutic applications. PMID:24381300

  12. Measurement of disease severity in cutaneous autoimmune diseases

    PubMed Central

    2013-01-01

    The development of disease-specific outcome instruments for several autoimmune skin diseases including cutaneous lupus erythematosus (CLE), dermatomyositis, vitiligo, pemphigus and alopecia areata has facilitated the objective assessment of disease in clinical trials. Validation of these instruments provides reliable tools to measure disease severity and therapeutic effect in clinical studies. However, the existence of multiple outcome measures for each disease and the lack of uniformity between studies has created a challenge in comparing results across trials. Efforts to address this issue include the Core Outcome Measures in Effectiveness Trials (COMET) initiative and international meetings directed at reaching a consensus. Other challenges with the use of outcome measures include difficulties measuring change in mild disease, measuring response in topical studies, and capturing disease activity in skin with extensive post-inflammatory hyperpigmentation. PMID:23755366

  13. Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route

    PubMed Central

    Douet, Jean-Yves; Lacroux, Caroline; Litaise, Claire; Lugan, Séverine; Corbière, Fabien; Arnold, Mark; Simmons, Hugh; Aron, Naima; Costes, Pierrette; Tillier, Cécile; Cassard, Hervé

    2016-01-01

    ABSTRACT Previous experiments carried out in a sheep scrapie model demonstrated that the transfusion of 200 μl of prion-infected whole blood has an apparent 100% efficacy for disease transmission. These experiments also indicated that, despite the apparent low infectious titer, the intravenous administration of white blood cells (WBC) resulted in efficient disease transmission. In the study presented here, using the same transmissible spongiform encephalopathy (TSE) animal model, our aim was to determine the minimal number of white blood cells and the specific abilities of mononucleated cell populations to transmit scrapie by the transfusion route. Our results confirmed that the transfusion of 100 μl, but not 10 μl, of fresh whole blood collected in asymptomatic scrapie-infected donor sheep can transmit the disease. The data also show that the intravenous administration of 105 WBCs is sufficient to cause scrapie in recipient sheep. Cell-sorted CD45R+ (predominantly B lymphocytes), CD4+/CD8+ (T lymphocytes), and CD14+ (monocytes/macrophages) blood cell subpopulations all were shown to contain prion infectivity by bioassays in ovine PrP transgenic mice. However, while the intravenous administration of 106 CD45+ or CD4+/8+ living cells was able to transmit the disease, similar numbers of CD14+ cells failed to infect the recipients. These data support the contention that mononucleated blood cell populations display different abilities to transmit TSE by the transfusion route. They also represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine. IMPORTANCE Interindividual variant Creutzfeldt-Jakob disease (vCJD) transmission through blood and blood-derived products is considered a major public health issue in transfusion medicine. Over the last decade, TSE in sheep has emerged as a

  14. Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

    PubMed

    Kabir, M Enamul; Safar, Jiri G

    2014-01-01

    There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and

  15. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years.

    PubMed

    Rudge, Peter; Jaunmuktane, Zane; Adlard, Peter; Bjurstrom, Nina; Caine, Diana; Lowe, Jessica; Norsworthy, Penny; Hummerich, Holger; Druyeh, Ron; Wadsworth, Jonathan D F; Brandner, Sebastian; Hyare, Harpreet; Mead, Simon; Collinge, John

    2015-11-01

    Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5-32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia

  16. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years

    PubMed Central

    Jaunmuktane, Zane; Adlard, Peter; Bjurstrom, Nina; Caine, Diana; Lowe, Jessica; Norsworthy, Penny; Hummerich, Holger; Druyeh, Ron; Wadsworth, Jonathan D. F.; Brandner, Sebastian; Hyare, Harpreet; Mead, Simon; Collinge, John

    2015-01-01

    Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5–32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia

  17. Computer measurement of arterial disease

    NASA Technical Reports Server (NTRS)

    Armstrong, J.; Selzer, R. H.; Barndt, R.; Blankenhorn, D. H.; Brooks, S.

    1980-01-01

    Image processing technique quantifies human atherosclerosis by computer analysis of arterial angiograms. X-ray film images are scanned and digitized, arterial shadow is tracked, and several quantitative measures of lumen irregularity are computed. In other tests, excellent agreement was found between computer evaluation of femoral angiograms on living subjects and evaluation by teams of trained angiographers.

  18. PrP(CWD) lymphoid cell targets in early and advanced chronic wasting disease of mule deer.

    PubMed

    Sigurdson, Christina J; Barillas-Mury, Carolina; Miller, Michael W; Oesch, Bruno; van Keulen, Lucien J M; Langeveld, Jan P M; Hoover, Edward A

    2002-10-01

    Up to 15% of free-ranging mule deer in northeastern Colorado and southeastern Wyoming, USA, are afflicted with a prion disease, or transmissible spongiform encephalopathy (TSE), known as chronic wasting disease (CWD). CWD is similar to a subset of TSEs including scrapie and variant Creutzfeldt-Jakob disease in which the abnormal prion protein isoform, PrP(CWD), accumulates in lymphoid tissue. Experimental scrapie studies have indicated that this early lymphoid phase is an important constituent of prion replication interposed between mucosal entry and central nervous system accumulation. To identify the lymphoid target cells associated with PrP(CWD), we used triple-label immunofluorescence and high-resolution confocal microscopy on tonsils from naturally infected deer in advanced disease. We detected PrP(CWD) primarily extracellularly in association with follicular dendritic and B cell membranes as determined by frequent co-localization with antibodies against membrane bound immunoglobulin and CD21. There was minimal co-localization with cytoplasmic labels for follicular dendritic cells (FDC). This finding could indicate FDC capture of PrP(CWD), potentially in association with immunoglobulin or complement, or PrP(C) conversion on FDC. In addition, scattered tingible body macrophages in the germinal centre contained coarse intracytoplasmic aggregates of PrP(CWD), reflecting either phagocytosis of PrP(CWD) on FDC processes, apoptotic FDC or B cells, or actual PrP(CWD) replication within tingible body macrophages. To compare lymphoid cell targets in early and advanced disease, we also examined: (i) PrP(CWD) distribution in lymphoid cells of fawns within 3 months of oral CWD exposure and (ii) tonsil biopsies from preclinical deer with naturally acquired CWD. These studies revealed that the early lymphoid cellular distribution of PrP(CWD) was similar to that in advanced disease, i.e. in a pattern suggesting FDC association. We conclude that in deer, PrP(CWD) accumulates

  19. Diagnosis and Evaluation of a Patient with Rapidly Progressive Dementia

    PubMed Central

    Bucelli, Robert C.; Ances, Beau M.

    2014-01-01

    While the most common dementia is Alzheimer’s disease (AD), a detailed history is needed to rule out rapidly progressive dementias (RPDs). RPDs are less than two years in duration and have a rate of progression faster typical neurodegenerative diseases. Identification of RPDs is important as some are treatable. This review focuses on the spectrum of RPDs, with special emphasis on paraneoplastic disorders and Creutzfeldt-Jakob disease (CJD). PMID:24279195

  20. Isolation of Prion with BSE Properties from Farmed Goat

    PubMed Central

    Lockey, Richard; Sallis, Rosemary E.; Terry, Linda A.; Thorne, Leigh; Holder, Thomas M.; Beck, Katy E.; Simmons, Marion M.

    2011-01-01

    Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that include variant Creutzfeldt-Jakob disease in humans, scrapie in small ruminants, and bovine spongiform encephalopathy (BSE) in cattle. Scrapie is not considered a public health risk, but BSE has been linked to variant Creutzfeldt-Jakob disease. Small ruminants are susceptible to BSE, and in 2005 BSE was identified in a farmed goat in France. We confirm another BSE case in a goat in which scrapie was originally diagnosed and retrospectively identified as suspected BSE. The prion strain in this case was further characterized by mouse bioassay after extraction from formaldehyde-fixed brain tissue embedded in paraffin blocks. Our data show that BSE can infect small ruminants under natural conditions and could be misdiagnosed as scrapie. Surveillance should continue so that another outbreak of this zoonotic transmissible spongiform encephalopathy can be prevented and public health safeguarded. PMID:22172149

  1. Uptake and Degradation of Protease-Sensitive and -Resistant Forms of Abnormal Human Prion Protein Aggregates by Human Astrocytes

    PubMed Central

    Choi, Young Pyo; Head, Mark W.; Ironside, James W.; Priola, Suzette A.

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease is the most common of the human prion diseases, a group of rare, transmissible, and fatal neurologic diseases associated with the accumulation of an abnormal form (PrPSc) of the host prion protein. In sporadic Creutzfeldt-Jakob disease, disease-associated PrPSc is present not only as an aggregated, protease-resistant form but also as an aggregated protease-sensitive form (sPrPSc). Although evidence suggests that sPrPSc may play a role in prion pathogenesis, little is known about how it interacts with cells during prion infection. Here, we show that protease-sensitive abnormal PrP aggregates derived from patients with sporadic Creutzfeldt-Jakob disease are taken up and degraded by immortalized human astrocytes similarly to abnormal PrP aggregates that are resistant to proteases. Our data suggest that relative proteinase K resistance does not significantly influence the astrocyte's ability to degrade PrPSc. Furthermore, the cell does not appear to distinguish between sPrPSc and protease-resistant PrPSc, suggesting that sPrPSc could contribute to prion infection. PMID:25280631

  2. Measuring Spatial Dependence for Infectious Disease Epidemiology

    PubMed Central

    Grabowski, M. Kate; Cummings, Derek A. T.

    2016-01-01

    Global spatial clustering is the tendency of points, here cases of infectious disease, to occur closer together than expected by chance. The extent of global clustering can provide a window into the spatial scale of disease transmission, thereby providing insights into the mechanism of spread, and informing optimal surveillance and control. Here the authors present an interpretable measure of spatial clustering, τ, which can be understood as a measure of relative risk. When biological or temporal information can be used to identify sets of potentially linked and likely unlinked cases, this measure can be estimated without knowledge of the underlying population distribution. The greater our ability to distinguish closely related (i.e., separated by few generations of transmission) from more distantly related cases, the more closely τ will track the true scale of transmission. The authors illustrate this approach using examples from the analyses of HIV, dengue and measles, and provide an R package implementing the methods described. The statistic presented, and measures of global clustering in general, can be powerful tools for analysis of spatially resolved data on infectious diseases. PMID:27196422

  3. Is mad cow disease caused by a bacteria?

    PubMed

    Broxmeyer, L

    2004-01-01

    Transmissible spongioform enchephalopathies (TSE's), include bovine spongiform encephalopathy (also called BSE or "mad cow disease"), Creutzfeldt-Jakob disease (CJD) in humans, and scrapie in sheep. They remain a mystery, their cause hotly debated. But between 1994 and 1996, 12 people in England came down with CJD, the human form of mad cow, and all had eaten beef from suspect cows. Current mad cow diagnosis lies solely in the detection of late appearing "prions", an acronym for hypothesized, gene-less, misfolded proteins, somehow claimed to cause the disease. Yet laboratory preparations of prions contain other things, which could include unidentified bacteria or viruses. Furthermore, the rigors of prion purification alone, might, in and of themselves, have killed the causative virus or bacteria. Therefore, even if samples appear to infect animals, it is impossible to prove that prions are causative. Manuelidis found viral-like particles, which even when separated from prions, were responsible for spongiform STE's. Subsequently, Lasmezas's study showed that 55% of mice injected with cattle BSE, and who came down with disease, had no detectable prions. Still, incredibly, prions, are held as existing TSE dogma and Heino Dringer, who did pioneer work on their nature, candidly predicts "it will turn out that the prion concept is wrong." Many animals that die of spongiform TSE's never show evidence of misfolded proteins, and Dr. Frank Bastian, of Tulane, an authority, thinks the disorder is caused by the bacterial DNA he found in this group of diseases. Recently, Roels and Walravens isolated Mycobacterium bovis it from the brain of a cow with the clinical and histopathological signs of mad cow. Moreover, epidemiologic maps of the origins and peak incidence of BSE in the UK, suggestively match those of England's areas of highest bovine tuberculosis, the Southwest, where Britain's mad cow epidemic began. The neurotoxic potential for cow tuberculosis was shown in pre-1960

  4. Measuring disease progression in corticobasal syndrome.

    PubMed

    Huang, Nancy; Hornberger, Michael; Hodges, John R; Burrell, James R

    2014-08-01

    Corticobasal syndrome (CBS) is a complex neurodegenerative disorder with marked clinical, neuropsychological, and pathological heterogeneity. Measurement of disease progression in CBS is complex and little understood. This study aimed to establish clinical and neuropsychological indicators of prognosis in CBS. Patients with CBS were retrospectively recruited from a frontotemporal dementia specific research clinic. All patients underwent detailed clinical and neuropsychological testing including the frontotemporal dementia rating scale (FRS). Using the differences in FRS logit scores over a period of 12 months, CBS patients were divided into rapid and slow progressor groups. Demographic, clinical and neuropsychological features were compared between the two groups. Sixteen participants who met defined criteria were included (9 males, 7 females; mean age 65.8 ± 22 years; median symptom duration 51.8 ± 22 years; mean duration of follow-up 11.4 ± 2.8 months). There were no significant differences between the rapid and slow progressors in age, gender, symptom duration, motor/cognitive presentation, and ACE-R scores at baseline. Clinically, slow progressors were significantly more likely to have a motor speech disorder, with a trend for more frequent dysgraphia, whereas rapid progressors were more likely to exhibit surface dyslexia. Rapid and slow progressor groups did not differ on neuropsychological performance. The presence of motor speech disorder, dysgraphia, and surface dyslexia may be useful in differentiating patients with rapid progression of CBS from those with a more indolent disease course. PMID:24893591

  5. [Prions and risks for blood transfusion: the situation in 2003].

    PubMed

    Deslys, J P

    2003-06-01

    In 2003, Prions still constitute a biological enigma and a public health concern. The risks of transmission of the so called "mad cow disease" are now under control but concerns still persist about potential secondary transmissions, notably via blood transfusion. Information obtained from diseases previously observed in animals (scrapie of sheep and goat) and in man (Kuru, Creutzfeldt-Jakob disease) demonstrate the complexity of the relations between these transmissible agents and their host. The difficulty in decontamination, the very long silent incubation period during which diagnosis is not possible and the lack of treatment are alarming elements which explain the increased perception of risk for these diseases. The development of rapid screening tests used on bovine at slaughterhouse has represented an important improvement in the development of a targeted protection against these agents. Today, technical evolutions in diagnosis let us imagine the possibility of blood detection for prions: on one hand new garanties for security may arise but on the other hand it points out the potential infectivity of blood with these agents responsible for constant fatal diseases. Precautionary security measures have to ensure an optimal ratio benefit/risk for the patient and thus, in this field, to balance the risk linked to prions with those clearly identified elsewhere. PMID:12798843

  6. The Role of the NADPH Oxidase NOX2 in Prion Pathogenesis

    PubMed Central

    Sorce, Silvia; Nuvolone, Mario; Keller, Annika; Falsig, Jeppe; Varol, Ahmet; Schwarz, Petra; Bieri, Monika; Budka, Herbert; Aguzzi, Adriano

    2014-01-01

    Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis. PMID:25502554

  7. Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

    SciTech Connect

    Goldsbury, C.; Wall, J.; Baxa, U.; Simon, M. N.; Steven, A. C.; Engel, A.; Aebi, U.; Muller, S. A.

    2011-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).

  8. Health, well-being, and measuring the burden of disease

    PubMed Central

    2012-01-01

    This essay asks whether the global burden of diseases, injuries, and risk factors (GBD) should be measured in terms of their consequences for health, as maintained by most of those who are attempting to measure the GBD, or in terms of their consequences for well-being, as argued by John Broome. It answers that the burden of disease should be understood in terms of the consequences of disease for health, and it defends the wider efforts to measure health by those who are in other ways skeptical of the project of measuring the GBD. PMID:22852827

  9. Growth Hormone and Cerebral Amyloidosis.

    PubMed

    Benvenga, S; Guarneri, F

    2016-08-01

    Great interest has recently been focused on a paper reporting characteristic deposits of amyloid-β protein associated with Alzheimer's disease in brains of adults who died of Creutzfeldt-Jakob disease. As they had contracted such disease after treatment with prion-contaminated human growth hormone extracted from cadaver-derived pituitaries, the authors have suggested that interhuman transmission of Alzheimer's disease had occurred. Our previous research led us to find that amyloid-forming peptides share amino acid sequence homology, summarized by a motif. Here, we probed the amino acid sequence of human growth hormone for such a motif, and found that 2 segments fit the motif and are potentially amyloid-forming. This finding was confirmed by Aggrescan, another well-known software for the prediction of amyloidogenic peptides. Our results, taken together with data from the literature that are missing in the aforementioned paper and associated commentaries, minimize the contagious nature of the iatrogenically-acquired coexistence of Creutzfeldt-Jakob disease and Alzheimer's disease. In particular, the above mentioned paper misses literature data on intratumoral amyloidosis in growth hormone- and prolactin-secreting adenomas, tumors relatively frequent in adults, which are often silent. It cannot be excluded that some pituitaries used to extract growth hormone contained clinically silent microadenomas, a fraction of which containing amyloid deposits, and patients might had received a fraction of growth hormone (with or without prolactin) that already was an amyloid seed. The intrinsic amyloidogenicity of growth hormone, in the presence of contaminating prion protein (and perhaps prolactin as well) and amyloid-β contained in some cadavers' pituitaries, may have led to the observed co-occurring of Creutzfeldt-Jakob disease and Alzheimer's disease. PMID:27214308

  10. Prospective associations between measures of adiposity and periodontal disease.

    PubMed

    Jimenez, Monik; Hu, Frank B; Marino, Miguel; Li, Yi; Joshipura, Kaumudi J

    2012-08-01

    Obesity induced inflammation may promote periodontal tissue destruction and bone resorption inducing tooth loss. We examined the association between measures of adiposity and self-reported periodontal disease, using data from 36,910 healthy male participants of the Health Professionals Follow-Up Study (HPFS) who were free of periodontal disease at baseline and followed for ≤20 years (1986-2006). Self-reported height, weight, and periodontal disease data were collected at baseline, weight and periodontal disease were additionally collected on biennial follow-up questionnaires and waist and hip circumference were self-reported in 1987. These self-reported measures have been previously validated. The multivariable adjusted associations between BMI (kg/m(2)), waist circumference (WC), waist-to-hip ratio (WHR), and first report of periodontal disease diagnosis were evaluated using time-varying Cox models. We observed 2,979 new periodontal disease diagnoses during 596,561 person-years of follow-up. Significant associations and trends were observed between all measures of adiposity and periodontal disease after adjusting for age, smoking, race, dental profession, physical activity, fruit and vegetable intake, alcohol consumption, and diabetes status at baseline. BMI ≥30 kg/m(2) compared to BMI 18.5-24.9 kg/m(2) was significantly associated with greater risk of periodontal disease (hazard ratios (HR) = 1.30; 95% confidence interval (CI): 1.17-1.45). Elevated WC and WHR were significantly associated with a greater risk of periodontal disease (HR for extreme quintiles: WC = 1.27, 95% CI: 1.11-1.46; WHR = 1.34, 95% CI: 1.17-1.54). The associations of BMI and WC were significant even among nondiabetics and never smokers. Given the high prevalence of overweight, obesity, and periodontal disease this association may be of substantial public health importance. PMID:21979390

  11. Outcome measures in neuromuscular disease: is the world still flat?

    PubMed

    Lunn, Michael P; Van den Bergh, Peter Y K

    2015-09-01

    Valid, responsive, and meaningful outcome measures for the measurement of the impairment, activity limitations, and quality of life in patients with neuromuscular disease are crucial to identify the natural history of disease and benefits of therapy in clinical practice and trials. Although understanding of many aspects of neuromuscular diseases has advanced dramatically, the development of outcome measures has received less attention. The scales developed from Rasch theory by the PeriNomS Group represent the biggest significant shift in thought in neuromuscular outcome measures for decades. There remain problems with many of them, and further developments are required. However, incorporating them into our outcome sets for daily use and in clinical trials will lead to the more efficient capture of meaningful change and will result in better assessment of individuals and groups of patients in both clinical trials and neurological practice. PMID:26114965

  12. Case Studies Illustrating Focal Alzheimer's, Fluent Aphasia, Late-Onset Memory Loss, and Rapid Dementia.

    PubMed

    Camsari, Gamze Balci; Murray, Melissa E; Graff-Radford, Neill R

    2016-08-01

    Many dementia subtypes have more shared signs and symptoms than defining ones. We review 8 cases with 4 overlapping syndromes and demonstrate how to distinguish the cases. These include focal cortical presentations of Alzheimer's disease (AD; posterior cortical atrophy and corticobasal syndrome [CBS]), fluent aphasia (semantic dementia and logopenic aphasia), late-onset slowly progressive dementia (hippocampal sclerosis and limbic predominant AD) and rapidly progressive dementia (Creutzfeldt-Jakob disease and limbic encephalitis). Recognizing the different syndromes can help the clinician to improve their diagnostic skills, leading to improved patient outcomes by early and accurate diagnosis, prompt treatment, and appropriate counseling and guidance. PMID:27445249

  13. Hiding in plain sight: a closer look at posterior cortical atrophy.

    PubMed

    Beh, Shin C; Muthusamy, Brinda; Calabresi, Peter; Hart, John; Zee, David; Patel, Vivek; Frohman, Elliot

    2015-02-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome dominated by deterioration of higher visual function (particularly visuospatial and visuoperceptual abilities). It is most commonly due to Alzheimer's disease pathology, but may also be caused by dementia with Lewy bodies, corticobasal degeneration or Creutzfeldt-Jakob disease. Patients often present to optometrists, ophthalmologists and/or neurologists with non-specific visual complaints, and unless clinicians seek the specific symptoms and signs of PCA (beyond that of the 'standard' neurological examination), this infrequent disorder is easily missed, delaying its diagnosis and treatment. We review the clinical features of PCA, focusing on its visual manifestations, to help neurologists recognise this important syndrome. PMID:25216669

  14. Kuru: the old epidemic in a new mirror.

    PubMed

    Goldfarb, Lev G

    2002-07-01

    The kuru epidemic lasted almost a century; it started in 1901-1902, reached epidemic proportions in the mid-1950s, and disappeared in the 1990s. Kuru is the prototype member of a group of disorders known as transmissible spongiform encephalopathies (TSEs) or prion diseases. Recent data on the genetics and pathogenesis of TSEs contribute to a better understanding of the documented kuru phenomena, and vice versa, observations made during the kuru epidemic are immensely helpful in understanding the epidemic of variant Creutzfeldt-Jakob disease that is currently developing in Europe. The major goal of this review is to identify and illustrate these points. PMID:12270735

  15. [Kuru].

    PubMed

    Mori, S

    1997-04-01

    Kuru, the progressive and fatal neurologic disorder which occurred exclusively among natives of the New Guinea Highlands, were reviewed. Early history of kuru investigation, epidemiology, clinical findings, pathological findings, successful transmission with chimpanzees, from unconventional virus to prion hypothesis and the similarities to "variant of Creutzfeldt-Jakob disease" were discussed in the literature. Although the incidence of kuru has markedly declined with the suppression of cannibalism, it is important from a historical perspective because it was the first human transmissible prion disease to be recognized. PMID:9103906

  16. Kuru: A Journey Back in Time from Papua New Guinea to the Neanderthals’ Extinction

    PubMed Central

    Liberski, Pawel P.

    2013-01-01

    Kuru, the first human transmissible spongiform encephalopathy was transmitted to chimpanzees by D. Carleton Gajdusek (1923–2008). In this review, I briefly summarize the history of this seminal discovery along its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century. PMID:25437203

  17. Infectious diseases following natural disasters: prevention and control measures.

    PubMed

    Kouadio, Isidore K; Aljunid, Syed; Kamigaki, Taro; Hammad, Karen; Oshitani, Hitoshi

    2012-01-01

    Natural disasters may lead to infectious disease outbreaks when they result in substantial population displacement and exacerbate synergic risk factors (change in the environment, in human conditions and in the vulnerability to existing pathogens) for disease transmission. We reviewed risk factors and potential infectious diseases resulting from prolonged secondary effects of major natural disasters that occurred from 2000 to 2011. Natural disasters including floods, tsunamis, earthquakes, tropical cyclones (e.g., hurricanes and typhoons) and tornadoes have been secondarily described with the following infectious diseases including diarrheal diseases, acute respiratory infections, malaria, leptospirosis, measles, dengue fever, viral hepatitis, typhoid fever, meningitis, as well as tetanus and cutaneous mucormycosis. Risk assessment is essential in post-disaster situations and the rapid implementation of control measures through re-establishment and improvement of primary healthcare delivery should be given high priority, especially in the absence of pre-disaster surveillance data. PMID:22149618

  18. Discriminating neurogenic from myopathic disease via measurement of muscle anisotropy.

    PubMed

    Garmirian, Lindsay P; Chin, Anne B; Rutkove, Seward B

    2009-01-01

    Skeletal muscle is electrically anisotropic, with a tendency for applied electrical current to flow more readily along muscle fibers than across them. In this study, we assessed a method for non-invasive measurement of anisotropy to determine its potential to serve as a new technique for distinguishing neurogenic from myopathic disease. Measurements were made on the biceps brachii and tibialis anterior muscles in 15 normal subjects and 12 patients with neuromuscular disease (6 with amyotrophic lateral sclerosis and 6 with various myopathies) using 50 kHZ applied current. Consistent multi-angle anisotropic patterns were found for reactance and phase in both muscles in normal subjects. Normalized anisotropy differences for each subject were defined, and group average values identified. The amyotrophic lateral sclerosis (ALS) patients demonstrated increased and distorted anisotropy patterns, whereas myopathic patients demonstrated normal or reduced anisotropy. These results suggest that non-invasive measurement of muscle anisotropy has potential for diagnosis of neuromuscular diseases. PMID:19058193

  19. Toward fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Richardson, Patricia R.; Jones, Anita C.; Baxter, Robert L.; Baxter, Helen C.; Whittaker, A. Gavin; Campbell, Gaynor A.

    2004-06-01

    Prion proteins are the infectious agents that cause Creutzfeldt-Jakob Disease (CJD) in humans. These proteins are particularly resistant to normal sterilization procedures, and the theoretical risk of prion transmission via surgical instruments is of current public and professional concern. We are currently investigating fluorescence methods for the detection of proteins on surfaces, with a view to developing an optical-fiber-based system for routine, online monitoring of residual protein contamination on surgical instruments, in hospital sterilization departments. This paper presents preliminary results on the detection of femtomole amounts of fluorescently labelled protein on surgical steel and discusses some of the problems involved in the detection of fluorescence from metal samples.

  20. Brain connectivity and novel network measures for Alzheimer's disease classification.

    PubMed

    Prasad, Gautam; Joshi, Shantanu H; Nir, Talia M; Toga, Arthur W; Thompson, Paul M

    2015-01-01

    We compare a variety of different anatomic connectivity measures, including several novel ones, that may help in distinguishing Alzheimer's disease (AD) patients from controls. We studied diffusion-weighted magnetic resonance imaging from 200 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative. We first evaluated measures derived from connectivity matrices based on whole-brain tractography; next, we studied additional network measures based on a novel flow-based measure of brain connectivity, computed on a dense 3-dimensional lattice. Based on these 2 kinds of connectivity matrices, we computed a variety of network measures. We evaluated the measures' ability to discriminate disease with a repeated, stratified 10-fold cross-validated classifier, using support vector machines, a supervised learning algorithm. We tested the relative importance of different combinations of features based on the accuracy, sensitivity, specificity, and feature ranking of the classification of 200 people into normal healthy controls and people with early or late mild cognitive impairment or AD. PMID:25264345

  1. Measurement of the area of involvement in skin disease

    NASA Astrophysics Data System (ADS)

    Roening, Juha; Kontinen, Jukka

    1996-10-01

    The ability to assess the severity of dermatoses by measuring the area of involvement is important in both clinical practice and research, but it has been shown that physicians, nurses and other groups are unable to do this accurately. A common practice in current use is the 'rule of nine' method, but wide variations have been found between observers' estimates. The purpose of this work was to test and demonstrate the feasibility of a computer vision technique for measuring the area of involvement in skin diseases by developing a system for psoriasis area assessment form slides, which can be operated in an image processing environment. The exact percentage of the slide area involved varied from 1 percent to 59 percent, thus providing realistic material for the system. The system proved sufficiently accurate, and the techniques evidently have a potential for inclusion as parts of a more accurate and rapid method for area measurement in the case of skin diseases.

  2. Suprasellar cistern measures as a reflection of dementia in Alzheimer's disease but not Huntington's disease.

    PubMed

    Aylward, E H; Karagiozis, H; Pearlson, G; Folstein, M F

    1991-01-01

    Four methods of measuring the suprasellar cistern (SSC), the SSC area ratio, the hexagonal area ratio, the width ratio, and perceptual rating, are described. All four are found to be reliable across raters, time, and procedure (light box vs. computer), and all are able to distinguish Alzheimer's Disease (AD) and Huntington's Disease (HD) patients from their respective age-matched controls. The width ratio, a measure of minimum distance between the two temporal lobes divided by brain width at the same level, was most effective in distinguishing HD from AD patients when age was used as a covariate. Because the width of the SSC measures separation of the temporal lobes at the level of the amygdala and entorhinal cortex, it is reasonable to expect this measure to distinguish between AD and HD, as the amygdala and entorhinal cortex are known to be particularly severely affected in AD, but not in HD, patients. The other measures of SSC were most highly correlated with cognitive status in AD patients. Several possible explanations for this finding are offered. No SSC measure was significantly correlated with cognitive status in HD. This suggests that atrophies of the frontal-temporal and basal forebrain areas are associated with cognitive decline in Alzheimer's Disease but not in Huntington's Disease. PMID:1827501

  3. Measuring the Burden of Neglected Tropical Diseases: The Global Burden of Disease Framework

    PubMed Central

    Mathers, Colin D.; Ezzati, Majid; Lopez, Alan D.

    2007-01-01

    Reliable, comparable information about the main causes of disease and injury in populations, and how these are changing, is a critical input for debates about priorities in the health sector. Traditional sources of information about the descriptive epidemiology of diseases, injuries, and risk factors are generally incomplete, fragmented, and of uncertain reliability and comparability. The Global Burden of Disease (GBD) study has provided a conceptual and methodological framework to quantify and compare the health of populations using a summary measure of both mortality and disability, the disability-adjusted life year (DALY). This paper describes key features of the Global Burden of Disease analytic approach, which provides a standardized measurement framework to permit comparisons across diseases and injuries, as well as risk factors, and a systematic approach to the evaluation of data. The paper describes the evolution of the GBD, starting from the first study for the year 1990, summarizes the methodological improvements incorporated into GBD revisions for the years 2000–2004 carried out by the World Health Organization, and examines priorities and issues for the next major GBD study, funded by the Bill & Melinda Gates Foundation, and commencing in 2007. The paper presents an overview of summary results from the Global Burden of Disease study 2002, with a particular focus on the neglected tropical diseases, and also an overview of the comparative risk assessment for 26 global risk factors. Taken together, trypanosomiasis, Chagas disease, schistosomiasis, leishmaniasis, lymphatic filariasis, onchocerciasis, intestinal nematode infections, Japanese encephalitis, dengue, and leprosy accounted for an estimated 177,000 deaths worldwide in 2002, mostly in sub-Saharan Africa, and about 20 million DALYs, or 1.3% of the global burden of disease and injuries. Further research is currently underway to revise and update these estimates. PMID:18060077

  4. New Invasive Assessment Measures of Coronary Artery Disease Severity.

    PubMed

    Khanna, Neel; Subramanian, Kathir S; Khera, Sahil; Aronow, Wilbert S; Frishman, William H

    2016-01-01

    Ischemic heart disease is the leading cause of mortality worldwide. The assessment and treatment of patients with ischemic heart disease have advanced greatly over the past decade. Particular attention has been given recently to the recognition of lesions that cause ischemia or that are prone to plaque rupture. New invasive measures of coronary artery disease have been developed, including fractional flow reserve, intravascular ultrasound, optical coherence tomography, and most recently, near-infrared spectroscopy. These technologies have helped to guide the assessment of hemodynamically significant lesions and have shown particular promise in guiding percutaneous coronary interventions. However, mortality and the rate of revascularization have shown mixed results to date. This review seeks to investigate the use and potential benefit of these technologies, with particular attention to clinical end points. PMID:26751263

  5. Molecular dynamics studies on the structural stability of wild-type dog prion protein.

    PubMed

    Zhang, Jiapu; Liu, David D W

    2011-06-01

    Prion diseases such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob diseases, Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia, Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (or 'mad-cow' disease) and chronic wasting disease in cattle are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. However, by now there have not been some effective therapeutic approaches to treat all these prion diseases. In 2008, canine mammals including dogs (canis familials) were the first time academically reported to be resistant to prion diseases (Vaccine 26: 2601-2614 (2008)). Thus, it is very worth studying the molecular structures of dog prion protein to obtain insights into the immunity of dogs to prion diseases. This paper studies the molecular structural dynamics of wild-type dog prion protein. The comparison analyses with rabbit prion protein show that the dog prion protein has stable molecular structures whether under neutral or low pH environments. We also find that the salt bridges such as D177-R163 contribute to the structural stability of wild-type rabbit prion protein under neutral pH environment. PMID:21469747

  6. The transmissible spongiform encephalopathies of livestock.

    PubMed

    Greenlee, Justin J; Greenlee, M Heather West

    2015-01-01

    Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal protein-misfolding neurodegenerative diseases. TSEs have been described in several species, including bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, chronic wasting disease (CWD) in cervids, transmissible mink encephalopathy (TME) in mink, and Kuru and Creutzfeldt-Jakob disease (CJD) in humans. These diseases are associated with the accumulation of a protease-resistant, disease-associated isoform of the prion protein (called PrP(Sc)) in the central nervous system and other tissues, depending on the host species. Typically, TSEs are acquired through exposure to infectious material, but inherited and spontaneous TSEs also occur. All TSEs share pathologic features and infectious mechanisms but have distinct differences in transmission and epidemiology due to host factors and strain differences encoded within the structure of the misfolded prion protein. The possibility that BSE can be transmitted to humans as the cause of variant Creutzfeldt-Jakob disease has brought attention to this family of diseases. This review is focused on the TSEs of livestock: bovine spongiform encephalopathy in cattle and scrapie in sheep and goats. PMID:25991695

  7. TRACTOGRAPHY DENSITY AND NETWORK MEASURES IN ALZHEIMER'S DISEASE.

    PubMed

    Prasad, Gautam; Nir, Talia M; Toga, Arthur W; Thompson, Paul M

    2013-04-01

    Brain connectivity declines in Alzheimer's disease (AD), both functionally and structurally. Connectivity maps and networks derived from diffusion-based tractography offer new ways to track disease progression and to understand how AD affects the brain. Here we set out to identify (1) which fiber network measures show greatest differences between AD patients and controls, and (2) how these effects depend on the density of fibers extracted by the tractography algorithm. We computed brain networks from diffusion-weighted images (DWI) of the brain, in 110 subjects (28 normal elderly, 56 with early and 11 with late mild cognitive impairment, and 15 with AD). We derived connectivity matrices and network topology measures, for each subject, from whole-brain tractography and cortical parcellations. We used an ODF lookup table to speed up fiber extraction, and to exploit the full information in the orientation distribution function (ODF). This made it feasible to compute high density connectivity maps. We used accelerated tractography to compute a large number of fibers to understand what effect fiber density has on network measures and in distinguishing different disease groups in our data. We focused on global efficiency, transitivity, path length, mean degree, density, modularity, small world, and assortativity measures computed from weighted and binary undirected connectivity matrices. Of all these measures, the mean nodal degree best distinguished diagnostic groups. High-density fiber matrices were most helpful for picking up the more subtle clinical differences, e.g. between mild cognitively impaired (MCI) and normals, or for distinguishing subtypes of MCI (early versus late). Care is needed in clinical analyses of brain connectivity, as the density of extracted fibers may affect how well a network measure can pick up differences between patients and controls. PMID:25404994

  8. Combining multiple anatomical MRI measures improves Alzheimer's disease classification.

    PubMed

    de Vos, Frank; Schouten, Tijn M; Hafkemeijer, Anne; Dopper, Elise G P; van Swieten, John C; de Rooij, Mark; van der Grond, Jeroen; Rombouts, Serge A R B

    2016-05-01

    Several anatomical MRI markers for Alzheimer's disease (AD) have been identified. Hippocampal volume, cortical thickness, and grey matter density have been used successfully to discriminate AD patients from controls. These anatomical MRI measures have so far mainly been used separately. The full potential of anatomical MRI scans for AD diagnosis might thus not yet have been used optimally. In this study, we therefore combined multiple anatomical MRI measures to improve diagnostic classification of AD. For 21 clinically diagnosed AD patients and 21 cognitively normal controls, we calculated (i) cortical thickness, (ii) cortical area, (iii) cortical curvature, (iv) grey matter density, (v) subcortical volumes, and (vi) hippocampal shape. These six measures were used separately and combined as predictors in an elastic net logistic regression. We made receiver operating curve plots and calculated the area under the curve (AUC) to determine classification performance. AUC values for the single measures ranged from 0.67 (cortical thickness) to 0.94 (grey matter density). The combination of all six measures resulted in an AUC of 0.98. Our results demonstrate that the different anatomical MRI measures contain complementary information. A combination of these measures may therefore improve accuracy of AD diagnosis in clinical practice. Hum Brain Mapp 37:1920-1929, 2016. © 2016 Wiley Periodicals, Inc. PMID:26915458

  9. The Canadian Management of Bovine Spongiform Encephalopathy in Historical and Scientific Perspective, 1990-2014.

    PubMed

    Quimby, Alexandra E; Shamy, Michel C F

    2015-11-01

    On February 11, 2015, the Canadian Food Inspection Agency announced that a cow born and raised in Alberta had tested positive for bovine spongiform encephalopathy (BSE), commonly known as mad cow disease. BSE is a prion disease of cattle that, when transmitted to humans, produces a fatal neurodegenerative disease known as variant Creutzfeldt-Jakob disease. We believe that this latest case of BSE in Canadian cattle suggests the timeliness of a review of the management of BSE in Canada from a historically and scientifically informed perspective. In this article, we ask: how did the Canadian management of BSE between 1990 and 2014 engage with the contemporary understanding of BSE's human health implications? We propose that Canadian policies largely ignored the implicit medical nature of BSE, treating it as a purely agricultural and veterinary issue. In this way, policies to protect Canadians were often delayed and incomplete, in a manner disturbingly reminiscent of Britain's failed management of BSE. Despite assurances to the contrary, it is premature to conclude that BSE (and with it the risk of variant Creutzfeldt-Jakob disease) is a thing of Canada's past: BSE remains very much an issue in Canada's present. PMID:26357946

  10. In vivo bone aluminum measurements in patients with renal disease

    SciTech Connect

    Ellis, K.J.; Kelleher, S.P.

    1986-01-01

    Contamination of the dialysis solution with trace amounts of aluminum and long-term use of aluminum-based phosphate binders have led to increased body burden of aluminum in patients with end-stage renal disease. A significant clinical problem associated with aluminum-overload is the early diagnosis of aluminum-induced dialysis dementia and osteomalacic osteodystrophy. There are few, if any, blood or urine indices that provide an early monitor of this bone disease, especially in the asymptomatic patient. Although a bone biopsy is usually the basis for the final clinical diagnosis, this procedure is not recommended for routine monitoring of patients. The present technique demonstrates the direct in vivo measurement of bone aluminum levels in patients with renal failure. The interference normally present from activation of bone phosphorus is eliminated by using a thermal/epithermal neutron beam. For the clinical management of the patients, the Al/Ca ratio for the hand may be more useful than an absolute measurement of the total body or skeletal aluminum burden. The relationship between the increased serum Al levels following disferrioxamine infusion and the direct in vivo measurement of bone aluminum using the Al/Ca ratio are currently under investigation. The neutron activation procedure presented in this pilot study is a promising new technique with an immediate clinical application. 5 refs., 3 figs., 1 tab.

  11. Measurement of Fractional Exhaled Nitric Oxide as a Marker of Disease Activity in Inflammatory Bowel Disease

    PubMed Central

    Ikonomi, Erkanda; Rothstein, Robin D.; Ehrlich, Adam C.; Friedenberg, Frank K.

    2016-01-01

    Background and Aims Definitive diagnosis of IBD requires endoscopic and pathologic confirmation. These tools are also used to classify disease activity. Our aim was to determine if the fractional exhaled nitric oxide (FeNO) could be utilized to screen for IBD and assess for disease activity. Methods We matched weighted IBD cases and controls from the 2009–2010 NHANES dataset. All subjects underwent measurement of FeNO using standardized techniques. We assessed for potential confounders for FeNO measurement including age, height, and asthma. For IBD subjects, we used the presence of diarrhea, fatigue, and weight loss as a proxy for IBD activity. Laboratory parameters examined to estimate disease activity included anemia (≤ 10 g/dl), iron deficiency (ferritin ≤ 20 ng/ml), hypoalbuminemia (≤ 3.2 g/dl), and CRP (≥ 1.1 mg/dl). Results The weighted sample represented 199,414,901 subjects. The weighted prevalence of IBD was 2,084,895 (1.0%). IBD subjects had nearly the same FeNO level as those without IBD (17.0 ± 16.2 vs. 16.7 ± 14.5 ppb). The odds of a FeNO > 25 ppb was half (OR=0.501; 95% CI 0.497–0.504) for subjects with IBD compared to those without IBD after controlling for confounders. The AUROC curve for FeNO was 0.47 (0.35–0.59). FeNO levels were not higher in patients with laboratory values suggestive of active disease. FeNO levels were higher in IBD patients with diarrhea, rectal urgency, and fatigue but were lower in those with unintentional weight loss. Conclusion Measurement of FeNO does not appear to be useful to screen for IBD or assess disease activity. PMID:27398403

  12. Kuru: genes, cannibals and neuropathology.

    PubMed

    Liberski, Pawel P; Sikorska, Beata; Lindenbaum, Shirley; Goldfarb, Lev G; McLean, Catriona; Hainfellner, Johannes A; Brown, Paul

    2012-02-01

    Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrP). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein-positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied. PMID:22249461

  13. Patient-reported outcome measures in inflammatory bowel disease

    PubMed Central

    El-Matary, Wael

    2014-01-01

    Patient-reported outcome measures (PROMs) are increasingly used in both research and clinical health settings. With the recent development of United States Food and Drug Administration guidance on PROMs, more attention is being devoted to their role and importance in health care. Several methodological challenges in the development, validation and implementation of PROMs must be resolved to ensure their appropriate utilization and interpretation. The present review discusses recent developments and updates in PROMs, with specific focus on the area of inflammatory bowel disease. PMID:25390615

  14. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection.

    PubMed

    Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L; Langeveld, Jan; Telling, Glenn C; Kong, Qingzhong; Safar, Jiri G

    2013-10-11

    The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrP(Sc)). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrP(Sc) particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrP(Sc) particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrP(C) substrate, the dominant PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrP(Sc) is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. PMID:23974118

  15. [Expert meeting obstructive airway disease measuring and evaluating in COPD].

    PubMed

    Lorenz, J; Bals, R; Ewert, R; Heussel, C P; Kauczor, H U; Randerath, W; Steinkamp, G; Watz, H; Worth, H

    2015-09-01

    This report gives an overview on the contributions presented in an expert meeting in February, 2015. They deal with the analysis and evaluation of the multiple dimensions of COPD. This complex disease not only interferes with pulmonary mechanics and gas exchange, but also with cardiopulmonary crosstalk and the ventilator pump. A bulk of inflammatory and microbial activity develops during the progression of disease. As a consequence, systemic effects on muscles, metabolism and psyche develop.The sections consider the value of multiple endpoints in clinical research. Quantifiable parameters of lung mechanics and gas exchange, of exercise tolerance and biomarkers improve the measurability of effects in interventions. However, do we really know in a biological sense what we are measuring? What conclusions can we draw in terms of prognosis?Vice versa, we have to look into the origin and meaning of integrative endpoints e.g. quality or life, dyspnoea and spontaneous physical activity. As a new dimension, the clinical significance of morphological findings in HRCT and MRT is analyzed. PMID:26335896

  16. Measuring Compounds in Exhaled Air to Detect Alzheimer's Disease and Parkinson’s Disease

    PubMed Central

    Hattesohl, Akira; Lubbe, Dirk; Schmid, Severin; Tackenberg, Björn; Rieke, Jürgen; Maddula, Sasidhar; Baumbach, Jörg Ingo; Nell, Christoph; Boeselt, Tobias; Michelis, Joan; Alferink, Judith; Heneka, Michael; Oertel, Wolfgang; Jessen, Frank; Janciauskiene, Sabina; Vogelmeier, Claus; Dodel, Richard; Koczulla, Andreas Rembert

    2015-01-01

    Background Alzheimer’s disease (AD) is diagnosed based upon medical history, neuropsychiatric examination, cerebrospinal fluid analysis, extensive laboratory analyses and cerebral imaging. Diagnosis is time consuming and labour intensive. Parkinson’s disease (PD) is mainly diagnosed on clinical grounds. Objective The primary aim of this study was to differentiate patients suffering from AD, PD and healthy controls by investigating exhaled air with the electronic nose technique. After demonstrating a difference between the three groups the secondary aim was the identification of specific substances responsible for the difference(s) using ion mobility spectroscopy. Thirdly we analysed whether amyloid beta (Aβ) in exhaled breath was causative for the observed differences between patients suffering from AD and healthy controls. Methods We employed novel pulmonary diagnostic tools (electronic nose device/ion-mobility spectrometry) for the identification of patients with neurodegenerative diseases. Specifically, we analysed breath pattern differences in exhaled air of patients with AD, those with PD and healthy controls using the electronic nose device (eNose). Using ion mobility spectrometry (IMS), we identified the compounds responsible for the observed differences in breath patterns. We applied ELISA technique to measure Aβ in exhaled breath condensates. Results The eNose was able to differentiate between AD, PD and HC correctly. Using IMS, we identified markers that could be used to differentiate healthy controls from patients with AD and PD with an accuracy of 94%. In addition, patients suffering from PD were identified with sensitivity and specificity of 100%. Altogether, 3 AD patients out of 53 participants were misclassified. Although we found Aβ in exhaled breath condensate from both AD and healthy controls, no significant differences between groups were detected. Conclusion These data may open a new field in the diagnosis of neurodegenerative disease

  17. Outcome Measures for Clinical Trials in Interstitial Lung Diseases

    PubMed Central

    Lammi, Matthew R.; Baughman, Robert P.; Birring, Surinder S.; Russell, Anne-Marie; Ryu, Jay H.; Scholand, Marybeth; Distler, Oliver; LeSage, Daphne; Sarver, Catherine; Antoniou, Katerina; Highland, Kristin B.; Kowal-Bielecka, Otylia; Lasky, Joseph A.; Wells, Athol U.; Saketkoo, Lesley Ann

    2015-01-01

    The chronic fibrosing idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous pulmonary parenchymal disorders described by radiologic and histological patterns termed usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). These include idiopathic pulmonary fibrosis (IPF) and those related to connective tissue disease (CTD) and are associated with substantial morbidity and mortality. Beyond the importance of establishing an appropriate diagnosis, designing optimal clinical trials for IIPs has been fraught with difficulties in consistency of clinical endpoints making power analyses, and the establishment of efficacy and interpretation of results across trials challenging. Preliminary recommendations, developed by rigorous consensus methods, proposed a minimum set of outcome measures, a ‘core set’, to be incorporated into future clinical trials (Saketkoo et al, THORAX. 2014.). This paper sets out to examine the candidate instruments for each domain (Dyspnea, Cough, Health Related Quality of Life, Imaging, Lung Physiology and Function, Mortality). Candidate measures that were not selected as well as measures that were not available for examination at the time of the consensus process will also be discussed. PMID:27019654

  18. Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy.

    PubMed

    Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano; Legname, Giuseppe

    2016-01-01

    Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions. PMID

  19. Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy

    PubMed Central

    Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano

    2016-01-01

    Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions. PMID

  20. Measurement of Blood Thiamine Metabolites for Alzheimer's Disease Diagnosis

    PubMed Central

    Pan, Xiaoli; Fei, Guoqiang; Lu, Jingwen; Jin, Lirong; Pan, Shumei; Chen, Zhichun; Wang, Changpeng; Sang, Shaoming; Liu, Huimin; Hu, Weihong; Zhang, Hua; Wang, Hui; Wang, Zhiliang; Tan, Qiong; Qin, Yan; Zhang, Qunying; Xie, Xueping; Ji, Yong; Cui, Donghong; Gu, Xiaohua; Xu, Jun; Yu, Yuguo; Zhong, Chunjiu

    2015-01-01

    Background Brain glucose hypometabolism is an invariant feature and has significant diagnostic value for Alzheimer's disease. Thiamine diphosphate (TDP) is a critical coenzyme for glucose metabolism and significantly reduced in brain and blood samples of patients with Alzheimer's disease (AD). Aims To explore the diagnostic value of the measurement of blood thiamine metabolites for AD. Methods Blood TDP, thiamine monophosphate, and thiamine levels were detected using high performance liquid chromatography (HPLC). The study included the exploration and validation phases. In the exploration phase, the samples of 338 control subjects and 43 AD patients were utilized to establish the models for AD diagnosis assayed by receiver operating characteristic (ROC) curve, including the variable γ that represents the best combination of thiamine metabolites and age to predict the possibility of AD. In the validation phase, the values of models were further tested for AD diagnosis using samples of 861 control subjects, 81 AD patients, 70 vascular dementia patients, and 13 frontotemporal dementia patients. Results TDP and the γ exhibited significant and consistent values for AD diagnosis in both exploration and validation phases. TDP had 0.843 and 0.837 of the areas under ROC curve (AUCs), 77.4% and 81.5% of sensitivities, and 78.1% and 77.2% of specificities respectively in the exploration and validation phases. The γ had 0.938 and 0.910 of AUCs, 81.4% and 80.2% of sensitivities, and 90.5% and 87.2% of specificities respectively in the exploration and validation phases. TDP and the γ can effectively distinguish AD from vascular dementia (64.3% for TDP, 67.1% for γ) and frontotemporal dementia (84.6% for TDP, 100.0% for γ). Interpretation. The measurement of blood thiamine metabolites by HPLC is an ideal diagnostic test for AD with inexpensive, easy to perform, noninvasive merits. PMID:26870826

  1. Measurement of the intestinal permeability in chronic kidney disease

    PubMed Central

    Terpstra, Matty L; Singh, Ramandeep; Geerlings, Suzanne E; Bemelman, Frederike J

    2016-01-01

    AIM: To evaluate methods measuring the intestinal per-meability in chronic kidney disease (CKD) and clarify whether there is an increased intestinal permeability in CKD. METHODS: We reviewed the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol and performed a systematic literature search through MEDline and EMBASE. All controlled trials and cohort studies using non-invasive methods to assess intestinal permeability in CKD patients were included. Excluded were: Conference abstracts and studies including patients younger than 18 years or animals. From the included studies we summarized the used methods and their advantages and disadvantages. For the comparison of their results we divided the included studies in two categories based on their included patient population, either assessing the intestinal permeability in mild to moderate CKD patients or in end stage renal disease (ESRD) patients. Results were graphically displayed in two plots, one comparing the intestinal permeability in mild to moderate CKD patients to healthy controls and one comparing the intestinal permeability in ESRD patients to healthy controls. RESULTS: From the 480 identified reports, 15 met our inclusion criteria. Methods that were used to assess the intestinal permeability varied from markers measured in plasma to methods based on calculating the urinary excretion of an orally administered test substance. None of the applied methods has been validated in CKD patients and the influence of decreased renal function on the different methods remains unclear to a certain extent. Methods that seem the least likely to be influenced by decreased renal function are the quantitative PCR (qPCR) for bacterial DNA in blood and D-lactate. Considering the results published by the included studies; the studies including patients with mild to moderate CKD conducted conflicting results. Some studies did report an increase in intestinal

  2. Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

    PubMed Central

    Angelantonio, Emanuele Di; Gao, Pei; Khan, Hassan; Butterworth, Adam S.; Wormser, David; Kaptoge, Stephen; Kondapally Seshasai, Sreenivasa Rao; Thompson, Alex; Sarwar, Nadeem; Willeit, Peter; Ridker, Paul M; Barr, Elizabeth L.M.; Khaw, Kay-Tee; Psaty, Bruce M.; Brenner, Hermann; Balkau, Beverley; Dekker, Jacqueline M.; Lawlor, Debbie A.; Daimon, Makoto; Willeit, Johann; Njølstad, Inger; Nissinen, Aulikki; Brunner, Eric J.; Kuller, Lewis H.; Price, Jackie F.; Sundström, Johan; Knuiman, Matthew W.; Feskens, Edith J. M.; Verschuren, W. M. M.; Wald, Nicholas; Bakker, Stephan J. L.; Whincup, Peter H.; Ford, Ian; Goldbourt, Uri; Gómez-de-la-Cámara, Agustín; Gallacher, John; Simons, Leon A.; Rosengren, Annika; Sutherland, Susan E.; Björkelund, Cecilia; Blazer, Dan G.; Wassertheil-Smoller, Sylvia; Onat, Altan; Marín Ibañez, Alejandro; Casiglia, Edoardo; Jukema, J. Wouter; Simpson, Lara M.; Giampaoli, Simona; Nordestgaard, Børge G.; Selmer, Randi; Wennberg, Patrik; Kauhanen, Jussi; Salonen, Jukka T.; Dankner, Rachel; Barrett-Connor, Elizabeth; Kavousi, Maryam; Gudnason, Vilmundur; Evans, Denis; Wallace, Robert B.; Cushman, Mary; D’Agostino, Ralph B.; Umans, Jason G.; Kiyohara, Yutaka; Nakagawa, Hidaeki; Sato, Shinichi; Gillum, Richard F.; Folsom, Aaron R.; van der Schouw, Yvonne T.; Moons, Karel G.; Griffin, Simon J.; Sattar, Naveed; Wareham, Nicholas J.; Selvin, Elizabeth; Thompson, Simon G.; Danesh, John

    2015-01-01

    IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294 998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5%to <7.5%), and high (≥7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20 840 incident fatal and nonfatal CVD outcomes (13 237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (−0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for

  3. Identification of a Compound That Disrupts Binding of Amyloid-β to the Prion Protein Using a Novel Fluorescence-based Assay*

    PubMed Central

    Risse, Emmanuel; Nicoll, Andrew J.; Taylor, William A.; Wright, Daniel; Badoni, Mayank; Yang, Xiaofan; Farrow, Mark A.; Collinge, John

    2015-01-01

    The prion protein (PrP) has been implicated both in prion diseases such as Creutzfeldt-Jakob disease, where its monomeric cellular isoform (PrPC) is recruited into pathogenic self-propagating polymers of misfolded protein, and in Alzheimer disease, where PrPC may act as a receptor for synaptotoxic oligomeric forms of amyloid-β (Aβ). There has been considerable interest in identification of compounds that bind to PrPC, stabilizing its native fold and thereby acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrPC could also inhibit the binding of toxic Aβ species and may have a role in treating Alzheimer disease, a highly prevalent dementia for which there are currently no disease-modifying treatments. However, the absence of a unitary, readily measurable, physiological function of PrP makes screening for ligands challenging, and the highly heterogeneous nature of Aβ oligomer preparations makes conventional competition binding assays difficult to interpret. We have therefore developed a high-throughput screen that utilizes site-specifically fluorescently labeled protein to identify compounds that bind to PrP and inhibit both Aβ binding and prion propagation. Following a screen of 1,200 approved drugs, we identified Chicago Sky Blue 6B as the first small molecule PrP ligand capable of inhibiting Aβ binding, demonstrating the feasibility of development of drugs to block this interaction. The interaction of Chicago Sky Blue 6B was characterized by isothermal titration calorimetry, and its ability to inhibit Aβ binding and reduce prion levels was established in cell-based assays. PMID:25995455

  4. Identification of a Compound That Disrupts Binding of Amyloid-β to the Prion Protein Using a Novel Fluorescence-based Assay.

    PubMed

    Risse, Emmanuel; Nicoll, Andrew J; Taylor, William A; Wright, Daniel; Badoni, Mayank; Yang, Xiaofan; Farrow, Mark A; Collinge, John

    2015-07-01

    The prion protein (PrP) has been implicated both in prion diseases such as Creutzfeldt-Jakob disease, where its monomeric cellular isoform (PrP(C)) is recruited into pathogenic self-propagating polymers of misfolded protein, and in Alzheimer disease, where PrP(C) may act as a receptor for synaptotoxic oligomeric forms of amyloid-β (Aβ). There has been considerable interest in identification of compounds that bind to PrP(C), stabilizing its native fold and thereby acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrP(C) could also inhibit the binding of toxic Aβ species and may have a role in treating Alzheimer disease, a highly prevalent dementia for which there are currently no disease-modifying treatments. However, the absence of a unitary, readily measurable, physiological function of PrP makes screening for ligands challenging, and the highly heterogeneous nature of Aβ oligomer preparations makes conventional competition binding assays difficult to interpret. We have therefore developed a high-throughput screen that utilizes site-specifically fluorescently labeled protein to identify compounds that bind to PrP and inhibit both Aβ binding and prion propagation. Following a screen of 1,200 approved drugs, we identified Chicago Sky Blue 6B as the first small molecule PrP ligand capable of inhibiting Aβ binding, demonstrating the feasibility of development of drugs to block this interaction. The interaction of Chicago Sky Blue 6B was characterized by isothermal titration calorimetry, and its ability to inhibit Aβ binding and reduce prion levels was established in cell-based assays. PMID:25995455

  5. Development of an ultra-rapid diagnostic method based on heart-type fatty acid binding protein levels in the CSF of CJD patients.

    PubMed

    Matsui, Yuki; Satoh, Katsuya; Mutsukura, Kazuo; Watanabe, Takuya; Nishida, Noriyuki; Matsuda, Hideo; Sugino, Masaichi; Shirabe, Susumu; Eguchi, Katsumi; Kataoka, Yasufumi

    2010-10-01

    Creutzfeldt-Jakob disease (CJD) is a transmissible, fatal, neurodegenerative disease in humans. Recently, various drugs have been reported to be useful in the treatment of CJD; however, for such treatments to be useful it is essential to rapidly and accurately diagnose CJD. 124 CJD patients and 87 with other diseases causing rapid progressive dementia were examined. Cerebral spinal fluid (CSF) from CJD patients was analyzed by 2D-PAGE and the protein expression pattern was compared with that from healthy subjects. One of three CJD-specific spots was found to be fatty acid binding protein (FABP), and heart-type FABP (H-FABP) was analyzed as a new biochemical marker for CJD. H-FABP ELISA results were compared between CJD patients and patients with other diseases (n = 211). Visual readout accuracy of the Rapicheck(®) H-FABP test panel for CSF was analyzed using an independent measure of CSF H-FABP concentration. The distribution of H-FABP in the brains of CJD patients was examined by immunohistochemistry. ELISA sensitivity and specificity were 90.3% and 92.9%, respectively, and Rapicheck(®) H-FABP sensitivity and specificity were 87.9% and 96.0%, respectively. ELISA and Rapicheck(®) H-FABP assays provided comparable results for 14-3-3 protein and total tau protein. Elevated H-FABP levels were associated with an accumulation of abnormal prion protein, astrocytic gliosis, and neuronal loss in the cerebral cortices of CJD patients. In conclusion, Rapicheck(®) H-FABP of CSF specimens enabled quick and frequent diagnosis of CJD. H-FABP represents a new biomarker for CJD distinct from 14-3-3 protein and total tau protein. PMID:20499272

  6. Communicating risk and promoting disease mitigation measures in epidemics and emerging disease settings

    PubMed Central

    Schiavo, Renata; Leung, May May; Brown, Mason

    2014-01-01

    Objective This review aims to identify and assess evidence on interventions to communicate risk and promote disease mitigation measures in epidemics and emerging disease outbreak settings. The study focuses on data that are relevant to low and middle-income country (LMIC) settings. Methods We conducted a comprehensive literature search using five major electronic databases (Pubmed Medline, Biomed Central, EMBASE, Science of Citation Index, and Cochrane Library) and other sources to identify relevant studies published from January 2002 to July 2013. The review was guided by the socio-ecological model/perspective of public health and the ideation theory and focused on interventions at the community, healthcare, and multi-sectoral settings, which also reflect key intervention levels of the Ottawa Charter for Health Promotion. Eligible quantitative studies were selected according to specific study criteria and assessed using the Critical Appraisal Skills Program (CASP) framework. Conversely, qualitative studies, reviews, case studies, and editorials were not included. Studies were selected by two independent reviewers. Results Twenty-nine relevant studies from 16 countries were included. Most studies focused on a single intervention or intervention level, rather than multi-sectoral interventions. The majority of the evidence relates to programs aimed at behavioral and social results (or relevant intermediate steps) within a specific population group. Two studies included implications for improvements in health service delivery, two studies examined the intervention’s impact on health systems-related outcomes, and three had also implications for environmental health outcomes. Cost- and health equity-related implications for select evidence were also discussed. Conclusions The paucity of well-designed quantitative evaluations of interventions to communicate health risk and promote disease control measures in LMICs does not allow for any definitive conclusions. Yet, the

  7. Differentiation of sCJD and vCJD forms by automated analysis of basal ganglia intensity distribution in multisequence MRI of the brain--definition and evaluation of new MRI-based ratios.

    PubMed

    Linguraru, Marius George; Ayache, Nicholas; Bardinet, Eric; Ballester, Miguel Angel González; Galanaud, Damien; Haïk, Stéphane; Faucheux, Baptiste; Hauw, Jean-Jacques; Cozzone, Patrick; Dormont, Didier; Brandel, Jean-Philippe

    2006-08-01

    We present a method for the analysis of basal ganglia (including the thalamus) for accurate detection of human spongiform encephalopathy in multisequence magnetic resonance imaging (MRI) of the brain. One common feature of most forms of prion protein diseases is the appearance of hyperintensities in the deep grey matter area of the brain in T2-weighted magnetic resonance (MR) images. We employ T1, T2, and Flair-T2 MR sequences for the detection of intensity deviations in the internal nuclei. First, the MR data are registered to a probabilistic atlas and normalized in intensity. Then smoothing is applied with edge enhancement. The segmentation of hyperintensities is performed using a model of the human visual system. For more accurate results, a priori anatomical data from a segmented atlas are employed to refine the registration and remove false positives. The results are robust over the patient data and in accordance with the clinical ground truth. Our method further allows the quantification of intensity distributions in basal ganglia. The caudate nuclei are highlighted as main areas of diagnosis of sporadic Creutzfeldt-Jakob Disease (sCJD), in agreement with the histological data. The algorithm permitted the classification of the intensities of abnormal signals in sCJD patient FLAIR images with a higher hypersignal in caudate nuclei (10/10) and putamen (6/10) than in thalami. Defining normalized MRI measures of the intensity relations between the internal grey nuclei of patients, we robustly differentiate sCJD and variant CJD (vCJD) patients, in an attempt to create an automatic classification tool of human spongiform encephalopathies. PMID:16894998

  8. Noninvasive Measures of Liver Fibrosis and Severity of Liver Disease

    PubMed Central

    Lucero, Catherine; Brown, Robert S.

    2016-01-01

    Determining the degree of fibrosis is an important step in the assessment of disease severity in patients with chronic liver disease. Liver biopsy has been the gold standard for estimating the extent of inflammation and fibrosis, although the procedure has limitations such as sampling error and variability. Noninvasive testing has been shown to be equally predictive in ruling out fibrosis or ruling in advanced fibrosis. Serum biomarkers and imaging-based tests have more limited predictive ability when classifying intermediate stages, but these tools can help identify which patients should receive antiviral treatment sooner and require ongoing cancer surveillance without the need for biopsy. Using a combination of serum markers and imaging tests may also be helpful in providing functional assessment of portal hypertension in patients with chronic liver disease.

  9. 28 CFR 549.15 - Infectious disease training and preventive measures.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Infectious disease training and preventive measures. 549.15 Section 549.15 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE INSTITUTIONAL MANAGEMENT MEDICAL SERVICES Infectious Disease Management § 549.15 Infectious disease training...

  10. Development of a Measure of Attitude toward Pulmonary Disease Prevention.

    ERIC Educational Resources Information Center

    McGaghie, William C.; And Others

    1993-01-01

    Systematic scale-development procedures, reliability analyses on 2,852 medical students (3 samples), and factor analysis were used to develop and refine a scale reflecting attitudes about pulmonary disease prevention. Development and verification samples included 110 and 2,691 students, respectively. The scale is promising for health education and…

  11. Prions and the blood and immune systems.

    PubMed

    Mabbott, Neil; Turner, Marc

    2005-04-01

    Prion diseases take a number of forms in animals and humans. They are caused by conformational change in widely expressed prion protein leading to the formation of intracellular aggregates. Although the main focus of disease is the central nervous system, it is known that involvement of the immune system occurs in peripherally transmitted disease in particular. Animal experiments suggest that in some prion diseases follicular dendritic cells in the germinal centers are a major site of initial accumulation, and that abnormal prion protein and infectivity are detectable in peripheral lymphoid tissue from the earliest phase of disease. This raises the possibility that in a human peripherally transmitted prion disease like variant Creutzfeldt-Jakob disease, further transmission could occur through blood or tissue products or contamination of surgical instrumentation. Indeed two recent reports confirm that this disease has been transmitted by blood, raising significant public health concerns. PMID:15820951

  12. Reevaluating Measures of Disease Progression in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Statland, Jeffrey M.; McDermott, Michael P.; Heatwole, Chad; Martens, William B.; Pandya, Shree; van der Kooi, E.L.; Kissel, John T.; Wagner, Kathryn R.; Tawil, Rabi

    2013-01-01

    Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials. PMID:23406877

  13. Transmissible amyloid.

    PubMed

    Tjernberg, L O; Rising, A; Johansson, J; Jaudzems, K; Westermark, P

    2016-08-01

    There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. PMID:27002185

  14. Skin involvement and outcome measures in systemic autoimmune diseases.

    PubMed

    Albrecht, J; Atzeni, F; Baldini, C; Bombardieri, S; Dalakas, M C; Demirkesen, C; Yazici, H; Mat, C; Werth, V P; Sarzi-Puttini, P

    2006-01-01

    This paper focuses on skin manifestations that can be observed in autoimmune diseases such as rheumatoid arthritis (RA), Sjögren syndrome (SS), dermatomyositis (DM) and Behçet syndrome (BS). In RA the most widely recognized skin lesion is the rheumatoid nodule. Other cutaneous manifestations can be observed either non-specific or related to the disease itself and/or to the commonly used drugs. Cutaneous manifestations are considered one of the most typical extraglandular features of primary SS, generally they are distinguished in vasculitic and non vasculitic lesions. Among non-vasculitc lesions, skin dryness (xerosis) has been shown to be very common in pSS while vasculitis lesions include typically flat and palpable purpura and urticarial vasculits. In DM the skin manifestations are also frequent and include a heliotrope rash (blue-purple discoloration) on the upper eyelids with edema, a flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption (Gottron rash). The most frequent mucocutaneous finding in BS is aphthous stomatitis which can not usually be differentiated from idiopatic reccurrent aphthous stomatitis on clinical grounds. The most typical skin manifestations are nodular lesions, which are commonly seen in BS and may be due to panniculitis [erythema nodosum (EN)-like lesions] or superficial thrombophlebitis. PMID:16466625

  15. Copper binding in the prion protein.

    PubMed

    Millhauser, Glenn L

    2004-02-01

    A conformational change of the prion protein is responsible for a class of neurodegenerative diseases called the transmissible spongiform encephalopathies that include mad cow disease and the human afflictions kuru and Creutzfeldt-Jakob disease. Despite the attention given to these diseases, the normal function of the prion protein in healthy tissue is unknown. Research over the past few years, however, demonstrates that the prion protein is a copper binding protein with high selectivity for Cu(2+). The structural features of the Cu(2+) binding sites have now been characterized and are providing important clues about the normal function of the prion protein and perhaps how metals or loss of protein function play a role in disease. The link between prion protein and copper may provide insight into the general, and recently appreciated, role of metals in neurodegenerative disease. PMID:14967054

  16. Neurodegeneration in humans caused by prions.

    PubMed Central

    Prusiner, S B

    1994-01-01

    Prion diseases include kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia of humans as well as scrapie and bovine spongiform encephalopathy of animals. For many years, the prion diseases were thought to be caused by viruses despite evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve aberrant metabolism of the prion protein. In many cases, the cellular prion protein is converted into the scrapie variant by a process after translation that involves a conformational change. Often the human prion diseases are transmissible experimentally to animals, and all of the inherited prion diseases segregate with prion protein gene mutations. Images PMID:7975565

  17. [Occupational lung diseases caused by exposure to chrysotile asbestos dust and the preventive measures].

    PubMed

    Pliukhin, A E; Burmistrova, T B

    2014-01-01

    To reveal major principles in system of occupational lung diseases prevention among workers engaged into extraction and usage of chrysotile asbestos, the authors specified main criteria for diagnosis of asbestos-related pulmonary diseases and signs of exposure to chrysotile dust, with identification of risk groups for occupational diseases development. The authors formulated main principles of prevention and rehabilitation for workers with asbestos-related pulmonary diseases. Special attention was paid to harmonization of all medical and technical measures aimed at prevention and liquidation of occupational asbestos-related diseases. PMID:25282798

  18. MEASURING THERAPEUTIC RESPONSE IN CHRONIC GRAFT-VERSUS-HOST DISEASE

    PubMed Central

    Lee, Stephanie J.; Wolff, Daniel; Kitko, Carrie; Koreth, John; Inamoto, Yoshihiro; Jagasia, Madan; Pidala, Joseph; Olivieri, Attilio; Martin, Paul J.; Przepiorka, Donna; Pusic, Iskra; Dignan, Fiona; Mitchell, Sandra A.; Lawitschka, Anita; Jacobsohn, David; Hall, Anne M.; Flowers, Mary E.D.; Schultz, Kirk R.; Vogelsang, Georgia; Pavletic, Steven

    2016-01-01

    In 2005, the NIH Chronic GVHD Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last nine years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. PMID:25796139

  19. CSF biomarkers in neurodegenerative and vascular dementias.

    PubMed

    Llorens, Franc; Schmitz, Matthias; Ferrer, Isidro; Zerr, Inga

    2016-01-01

    Neurodegenerative diseases with abnormal protein aggregates such as Alzheimer's disease, tauopathies, synucleinopathies, and prionopathies, together with vascular encephalopathies, are cause of cognitive impairment and dementia. Identification of reliable biomarkers in biological fluids, particularly in the cerebrospinal fluid (CSF), is of extreme importance in optimizing the precise early clinical diagnosis of distinct entities and predicting the outcome in particular settings. In addition, the study of CSF biomarkers is useful to identify and monitor the underlying pathological processes developing in the central nervous system of affected individuals. Evidence suggests that levels of key CSF molecules correlate, in some circumstances, with prediction, disease progression, and severity of cognitive decline. Correlation of CSF markers and underlying pathological molecular substrates in brain is an exciting field for further study. However, while some dementias such as Creutzfeldt-Jakob disease have accurate CSF biomarkers, other disease types such as dementia with Lewy bodies, vascular dementia, and frontotemporal dementia lack reliable biomarkers for their specific clinical diagnosis. PMID:27016008

  20. Pathological Propagation through Cell-to-Cell Transmission of Non-Prion Protein Aggregates in Neurodegenerative Disorders

    PubMed Central

    Lee, Seung-Jae; Desplats, Paula; Sigurdson, Christina; Tsigelny, Igor; Masliah, Eliezer

    2016-01-01

    Neurodegenerative disorders such as Alzheimer's Disease, Parkinson's Disease, fronto-temporal dementia, Huntington's Disease and Creutzfeldt-Jakob Disease (CJD) are characterized by progressive accumulation of protein aggregates in selected brain regions. Protein misfolding and templated assembly into aggregates might result from an imbalance between protein synthesis, aggregation and clearance. While protein misfolding and aggregation occur in most neurodegenerative disorders, the concept of spreading and infectivity of aggregates in the CNS has been reserved to prion diseases such as CJD and bovine spongiform encephalopathy. Emerging evidence suggests that prion-like spreading may occur in other neurodegenerative disorders, taking place with secreted proteins, such as amyloid-β,) and cytosolic proteins, such as tau, huntingtin and α-synuclein. Underlying molecular mechanisms and therapeutic implications are discussed. PMID:21045796

  1. Middle East respiratory syndrome coronavirus: epidemiology and disease control measures

    PubMed Central

    Al-Tawfiq, Jaffar A; Memish, Ziad A

    2014-01-01

    The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in 2012 resulted in an increased concern of the spread of the infection globally. MERS-CoV infection had previously caused multiple health-care-associated outbreaks and resulted in transmission of the virus within families. Community onset MERS-CoV cases continue to occur. Dromedary camels are currently the most likely animal to be linked to human MERS-CoV cases. Serologic tests showed significant infection in adult camels compared to juvenile camels. The control of MERS-CoV infection relies on prompt identification of cases within health care facilities, with institutions applying appropriate infection control measures. In addition, determining the exact route of transmission from camels to humans would further add to the control measures of MERS-CoV infection. PMID:25395865

  2. Reduced myo-inositol and total choline measured with cerebral MRS in acute thyrotoxic Graves' disease.

    PubMed

    Elberling, T V; Danielsen, E R; Rasmussen, A K; Feldt-Rasmussen, U; Waldemar, G; Thomsen, C

    2003-01-14

    Neuropsychiatric symptoms in the acute thyrotoxic phase of Graves' disease suggest involvement of brain processes. Short-echo-time proton MRS was used to measure the cerebral metabolite profile in newly diagnosed and untreated Graves' disease. Sixteen patients with Graves' disease and 18 age- and sex-matched healthy volunteers were studied. The patients had significantly reduced total choline and myo-inositol in the acute phase of Graves' thyrotoxicosis compared with the healthy volunteers. PMID:12525741

  3. Utilization of Leaf Reflectance Measurements in Louisiana Sugarcane Disease, Variety, and Harvest Management Systems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tests were initiated in 2005 to determine if visible and near-infrared leaf reflectance measurements could be used to predict sugarcane disease incidence, identify varieties, and estimate sucrose content. Leaf samples were collected from: sugarcane yellow leaf disease (SCYLD) and mosaic test plots; ...

  4. Safety Measures with Communicable Diseases. Courseware Evaluation for Vocational and Technical Education.

    ERIC Educational Resources Information Center

    Yarbrough, Stephen

    This courseware evaluation rates the "Safety Measures with Communicable Diseases" program developed by Lane Community College in Eugene, Oregon. (This program--not contained in this document--is designed to teach means of preventing the spread of communicable respiratory diseases and ways of protecting oneself.) Part A describes the program in…

  5. Prions in dentistry: A need to be concerned and known.

    PubMed

    Sushma, B; Gugwad, Sachin; Pavaskar, Rajdeep; Malik, Shambhvi A

    2016-01-01

    Prion diseases were first discovered by Stanley B. Prusiner who defined prions as infectious, transmissible proteinaceous particles that lack nucleic acid and are composed exclusively of a modified isoform of the noninfectious cellular prion protein (PrPC). These are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious or inherited in origin. Human prion diseases include Creutzfeldt-Jakob desease (CJD), Gerstmann- Straussler-Scheinker disease, Kuru and Fatal familial insomnia. Prions resist the conventional sterilization procedures and hence the dentists must be aware of such diseases so as to opt standard methods of infection control and decontamination for such infectious agents. This review article divulge the dentists with a brief overview of the characteristics of prions, the risk of transmission and the implications for infection control in dentist. PMID:27194872

  6. Functional Connectivity Measured with Magnetoencephalography Identifies Persons with HIV Disease

    PubMed Central

    Becker, James T.; Bajo, Ricardo; Fabrizio, Melissa; Sudre, Gustavo; Cuesta, Pablo; Aizenstein, Howard J.; Lopez, Oscar L.; Wolk, David; Parkkonen, Lauri; Maestu, Fernando; Bagic, Anto

    2012-01-01

    There is need for a valid and reliable biomarker for HIV Associated Neurocognitive Disorder (HAND). The purpose of the present study was to provide preliminary evidence of the potential utility of neuronal functional connectivity measures obtained using magnetoencephalography (MEG) to identify HIV-associated changes in brain function. Resting state, eyes closed, MEG data from 10 HIV-infected individuals and 8 seronegative controls were analyzed using mutual information (MI) between all pairs of MEG sensors to determine whether there were functional brain networks that distinguished between subject groups based on cognition (global and learning) or on serostatus. Three networks were identified across all subjects, but after permutation testing (at α < .005) only the one related to HIV serostatus was significant. The network included MEG sensors (planar gradiometers) above the right anterior region connecting to sensors above the left posterior region. A mean MI value was calculated across all connections from the anterior to the posterior groupings; that score distinguished between the serostatus groups with only one error (sensitivity = 1.00, specificity = .88 (X2 = 15.4, df = 1, p < .01, Relative Risk = .11). There were no significant associations between the MI value and the neuropsychological Global Impairment rating, substance abuse, mood disorder, age, education, CD4+ cell counts or HIV viral load. We conclude that using a measure of functional connectivity, it may be possible to distinguish between HIV-infected and uninfected individuals, suggesting that MEG may have the potential to serve as a sensitive, non-invasive biomarker for HAND. PMID:22328062

  7. Why and how should we measure disease activity and damage in lupus?

    PubMed

    Feld, Joy; Isenberg, David

    2014-06-01

    The assessment of disease activity and flare and differentiating them from permanent damage in patients with SLE is challenging. The SLEDAI, SLEDAI-2K and SELENA-SLEDAI measure global disease activity. The BILAG measures organ-specific activity. The BILAG better captures the change in the different organs at the expense of complexity. The SRI is a composite index incorporating both BILAG and SLEDAI indices and a physician's global assessment. It has been used in the most recent clinical trials. Damage correlates with prognosis; it is assessed by the SLICC/SDI index. This index scores damage whatever the cause, disease or treatment related, or the consequence of concomitant disease. The disease activity and damage indices do not correlate well with the patient's health related quality of life (HRQoL), the degree of disability or the impact of disease. The impact of the patients' joint disease on their HRQoL is assessed via the HAQ questionnaire and the global health status via the SF-36 index, or one of the more recently described lupus specific quality of life indices [Lupus QoL]. The global assessment instruments and the BILAG index can also be used in children and adolescents with SLE. However, a modified paediatric version of the SLICC/SDI damage index is advised. Many advances have been achieved in disease activity and damage measurement in the past 20 years but the problem of how best to capture flare accurately remains. PMID:24791651

  8. A rare case of rapidly progressive dementia with elevated RT-QuIC and negative 14-3-3 and tau proteins.

    PubMed

    Trikamji, Bhavesh; Hamlin, Clive; Baldwin, Kelly J

    2016-05-01

    Creutzfeldt-Jakob disease (CJD) is characterized by rapidly progressing dementia with death usually occurring within 6 months. There is no verified disease-specific pre-mortem diagnostic test besides brain biopsy. We describe a 66 y old previously high functioning male who presented with a 5 month history of rapidly progressive dementia. Neurological examination revealed a score of 19/30 on MOCA testing. An extensive workup into various causes of dementia including electroencephalography and imaging studies was unremarkable. The cerebrospinal fluid was sent to National Prion Disease Center and it revealed elevated RT-QuIC levels with negative 14-3-3 and T tau proteins. Based on literature review, our case is one of few living subjects with elevated RT-QuIC levels and negative 14-3-3 and tau proteins. PMID:27249661

  9. Concentration-dependent Cu(II) binding to prion protein

    NASA Astrophysics Data System (ADS)

    Hodak, Miroslav; Lu, Wenchang; Bernholc, Jerry

    2008-03-01

    The prion protein plays a causative role in several neurodegenerative diseases, including mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. The normal function of the prion protein is unknown, but it has been linked to its ability to bind copper ions. Experimental evidence suggests that copper can be bound in three distinct modes depending on its concentration, but only one of those binding modes has been fully characterized experimentally. Using a newly developed hybrid DFT/DFT method [1], which combines Kohn-Sham DFT with orbital-free DFT, we have examined all the binding modes and obtained their detailed binding geometries and copper ion binding energies. Our results also provide explanation for experiments, which have found that when the copper concentration increases the copper binding mode changes, surprisingly, from a stronger to a weaker one. Overall, our results indicate that prion protein can function as a copper buffer. 1. Hodak, Lu, Bernholc, JCP, in press.

  10. Cooperative binding modes of Cu(II) in prion protein

    NASA Astrophysics Data System (ADS)

    Hodak, Miroslav; Chisnell, Robin; Lu, Wenchang; Bernholc, Jerry

    2007-03-01

    The misfolding of the prion protein, PrP, is responsible for a group of neurodegenerative diseases including mad cow disease and Creutzfeldt-Jakob disease. It is known that the PrP can efficiently bind copper ions; four high-affinity binding sites located in the octarepeat region of PrP are now well known. Recent experiments suggest that at low copper concentrations new binding modes, in which one copper ion is shared between two or more binding sites, are possible. Using our hybrid Thomas-Fermi/DFT computational scheme, which is well suited for simulations of biomolecules in solution, we investigate the geometries and energetics of two, three and four binding sites cooperatively binding one copper ion. These geometries are then used as inputs for classical molecular dynamics simulations. We find that copper binding affects the secondary structure of the PrP and that it stabilizes the unstructured (unfolded) part of the protein.

  11. BSE safety standards: An evaluation of public health policies of Japan, Europe, and USA.

    PubMed

    Matibag, Gino C; Igarashi, Manabu; Tamashiro, Hiko

    2005-09-01

    Since the advent of bovine spongiform encephalopathy (BSE) in the United Kingdom in 1986, new BSE cases have recently become rare. However, in Japan and the United States, positive cases have started to be seen recently. The rise in BSE cases paved the way for the human form of this disease, the variant Creutzfeldt-Jakob disease (vCJD). The observed trends in the UK may be attributed to effective implementation of public health policies coupled with increased vigilance through advancement in science and technology, or they may well be a reflection of the natural disease progression. We aim to discuss the BSE chronology of events, and compare examination methods, costs and cost-efficiency, management, and public policies of Japan, Europe, and the USA. PMID:21432135

  12. Doppel: more rival than double to prion.

    PubMed

    Qin, K; O'Donnell, M; Zhao, R Y

    2006-08-11

    Conversion of normal cellular prion protein to the diseased form plays an essential role in transmissible spongiform encephalopathies such as mad cow disease and Creutzfeldt-Jakob disease. However, the normal physiological function of prion protein remains elusive. Doppel, a German synonym of double, was initially identified as a prion-like protein due to its structural and biochemical similarities. However, emerging evidence suggests that function of prion protein is more antagonistic to Doppel than synergistic. In this review, basic biochemical and structural similarities of prion protein and Doppel are introduced; evidence demonstrating antagonistic interaction of prion protein with Doppel is presented; and a potential novel activity of Doppel and prion protein in spermatogenesis, which could stimulate new avenues for research, is discussed. PMID:16781817

  13. Nitric oxide induces prion protein via MEK and p38 MAPK signaling.

    PubMed

    Wang, Vinchi; Chuang, Tzu-Chao; Hsu, Yaw-Don; Chou, Wei-Yuan; Kao, Ming-Ching

    2005-07-22

    The prion diseases or transmissible spongiform encephalopathy, such as human Creutzfeldt-Jakob disease (CJD) and so-called mad cow disease, are attributed to the causative agent, the scrapie variant of prion protein (PrP(Sc)) which causes fatal neurodegeneration. To investigate if stresses such as nitric oxide (NO) induced the cellular isoform of prion protein (PrP(C)), lipopolysaccharide, and sodium nitroprusside were used to treat N2a and NT2 cells, which resulted in elevated levels of the PRNP mRNA and prion protein. The signaling pathway for the NO-induced PrP(C) production involved guanylyl cyclase, MEK, and p38 MAPK as shown by the effect of specific pharmacological inhibitors ODQ, PD98059, and SB203580, respectively. Knowing the PrP induction by the biologically existing stimulus, this study provides useful information about the possible cellular mechanism and strategies for the treatment of CJD. PMID:15936714

  14. Using Twitter to Measure Public Discussion of Diseases: A Case Study

    PubMed Central

    Schwartz, H Andrew; Hill, Shawndra; Merchant, Raina M; Arango, Catalina; Ungar, Lyle

    2015-01-01

    Background Twitter is increasingly used to estimate disease prevalence, but such measurements can be biased, due to both biased sampling and inherent ambiguity of natural language. Objective We characterized the extent of these biases and how they vary with disease. Methods We correlated self-reported prevalence rates for 22 diseases from Experian’s Simmons National Consumer Study (n=12,305) with the number of times these diseases were mentioned on Twitter during the same period (2012). We also identified and corrected for two types of bias present in Twitter data: (1) demographic variance between US Twitter users and the general US population; and (2) natural language ambiguity, which creates the possibility that mention of a disease name may not actually refer to the disease (eg, “heart attack” on Twitter often does not refer to myocardial infarction). We measured the correlation between disease prevalence and Twitter disease mentions both with and without bias correction. This allowed us to quantify each disease’s overrepresentation or underrepresentation on Twitter, relative to its prevalence. Results Our sample included 80,680,449 tweets. Adjusting disease prevalence to correct for Twitter demographics more than doubles the correlation between Twitter disease mentions and disease prevalence in the general population (from .113 to .258, P <.001). In addition, diseases varied widely in how often mentions of their names on Twitter actually referred to the diseases, from 14.89% (3827/25,704) of instances (for stroke) to 99.92% (5044/5048) of instances (for arthritis). Applying ambiguity correction to our Twitter corpus achieves a correlation between disease mentions and prevalence of .208 ( P <.001). Simultaneously applying correction for both demographics and ambiguity more than triples the baseline correlation to .366 ( P <.001). Compared with prevalence rates, cancer appeared most overrepresented in Twitter, whereas high cholesterol appeared most

  15. A Low-Molecular-Weight Ferroxidase Is Increased in the CSF of sCJD Cases: CSF Ferroxidase and Transferrin as Diagnostic Biomarkers for sCJD

    PubMed Central

    Haldar, Swati; Beveridge, ’Alim J.; Wong, Joseph; Singh, Ajay; Galimberti, Daniela; Borroni, Barbara; Zhu, Xiongwei; Blevins, Janis; Greenlee, Justin; Perry, George; Mukhopadhyay, Chinmay K.; Schmotzer, Christine

    2013-01-01

    Abstract Aims: Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity. Results: We report that CJD-associated brain iron dyshomeostasis is reflected in the cerebrospinal fluid (CSF), providing disease-specific diagnostic biomarkers. Analysis of 290 premortem CSF samples from confirmed cases of CJD, Alzheimer's disease, and other dementias (DMs), and 52 non-DM (ND) controls revealed a significant difference in ferroxidase (Frx) activity and transferrin (Tf) levels in sporadic Creutzfeldt-Jakob disease (sCJD) relative to other DM and ND controls. A combination of CSF Frx and Tf discriminated sCJD from other DMs with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area-under-the receiver-operating-characteristic (ROC) curve of 0.94. This combination provided a similar diagnostic accuracy in discriminating CJD from rapidly progressing cases who died within 6 months of sample collection. Surprisingly, ceruloplasmin and amyloid precursor protein, the major brain Frxs, displayed minimal activity in the CSF. Most of the Frx activity was concentrated in the <3-kDa fraction in normal and diseased CSF, and resisted heat and proteinase-K treatment. Innovation: (i) A combination of CSF Frx and Tf provides disease-specific premortem diagnostic biomarkers for sCJD. (ii) A novel, nonenzymatic, nonprotein Frx predominates in human CSF that is distinct from the currently known CSF Frxs. Conclusion: The underlying cause of iron imbalance is distinct in sCJD relative to other DMs associated with the brain iron imbalance. Thus, change in the CSF levels of iron-management proteins can provide disease-specific biomarkers and insight into the cause of iron imbalance in neurodegenerative conditions. Antioxid. Redox Signal. 19, 1662–1675. PMID:23379482

  16. Quantitative Risk Assessment of Bovine Spongiform Encephalopathy

    NASA Astrophysics Data System (ADS)

    Tsutsui, Toshiyuki; Kasuga, Fumiko

    Bovine spongiform encephalopathy (BSE) is a progressive neurological disease of cattle affecting the central nervous system and was first diagnosed in the United Kingdom (UK) in 1986 (Wells et al., 1987). This disease is one of the transmissible spongiform encephalopathy (TSE) which includes Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep. The causative agent of TSE is considered to be an abnormal form of prion protein. However, the details of its pathogenic mechanism have not been fully identified. Scrapie, which causes neurological symptoms in sheep and goats, has existed in the UK for 200 years (Hoinville, 1996) and spread across the rest of the world in the 1900s (Detwiler & Baylis, 2003). There has been no report so far that scrapie can be transmitted to humans. Initially, BSE was also considered as a disease affecting only animals. However, a variant type of Creutzfeldt-Jakob disease (vCJD) was first reported in the UK, and exposure to a BSE agent was suspected (Collinge, Sidle, Meads, Ironside, & Hill, 1996). vCJD is clinically and pathologically different from the sporadic type of CJD, and age at clinical onset of vCJD is younger than sporadic type (Will et al., 1996). Since the UK government announced the possible association between BSE and vCJD in 1996, BSE has become a huge public health concern all over the world. Of particular concern about vCJD, the fatal disease in younger age, distorted consumer confidence in beef safety, and as a result reduced beef consumption has been seen in many BSE-affected countries.

  17. Heritability of Measures of Kidney Disease Among Zuni Indians: The Zuni Kidney Project

    PubMed Central

    MacCluer, Jean W.; Scavini, Marina; Shah, Vallabh O.; Cole, Shelley A.; Laston, Sandra L.; Voruganti, V. Saroja; Paine, Susan S.; Eaton, Alfred J.; Comuzzie, Anthony G.; Tentori, Francesca; Pathak, Dorothy R.; Bobelu, Arlene; Bobelu, Jeanette; Ghahate, Donica; Waikaniwa, Mildred; Zager, Philip G.

    2010-01-01

    Background The long-term goal of the GKDZI (Genetics of Kidney Disease in Zuni Indians) Study is to identify genes, environmental factors, and genetic-environmental interactions that modulate susceptibility to renal disease and intermediate phenotypes. Study Design A community-based participatory research approach was used to recruit family members of individuals with kidney disease. Setting & Participants The study was conducted in the Zuni Indians, a small endogamous tribe located in rural New Mexico. We recruited members of extended families, ascertained through a proband with kidney disease and at least 1 sibling with kidney disease. 821 participants were recruited, comprising 7,702 relative pairs. Predictor Outcomes & Measurements Urine albumin-creatinine ratio (UACR) and hematuria were determined in 3 urine samples and expressed as a true ratio. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation modified for American Indians. Probands were considered to have kidney disease if UACR was ≥0.2 in 2 or more of 3 spot urine samples or estimated GFR was decreased according to the CRIC (Chronic Renal Insufficiency Cohort) Study criteria. Results Kidney disease was identified in 192 participants (23.4%). There were significant heritabilities for estimated GFR, UACR, serum creatinine, serum urea nitrogen, and uric acid and a variety of phenotypes related to obesity, diabetes, and cardiovascular disease. There were significant genetic correlations of some kidney-related phenotypes with these other phenotypes. Limitations Limitations include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions. Conclusions Many phenotypes related to kidney disease showed significant heritabilities in Zuni Indians, and there were significant genetic correlations with phenotypes related to obesity, diabetes, and

  18. Molecular Modeling of Prion Transmission to Humans

    PubMed Central

    Levavasseur, Etienne; Privat, Nicolas; Martin, Juan-Carlos Espinosa; Simoneau, Steve; Baron, Thierry; Flan, Benoit; Torres, Juan-Maria; Haïk, Stéphane

    2014-01-01

    Using different prion strains, such as the variant Creutzfeldt-Jakob disease agent and the atypical bovine spongiform encephalopathy agents, and using transgenic mice expressing human or bovine prion protein, we assessed the reliability of protein misfolding cyclic amplification (PMCA) to model interspecies and genetic barriers to prion transmission. We compared our PMCA results with in vivo transmission data characterized by attack rates, i.e., the percentage of inoculated mice that developed the disease. Using 19 seed/substrate combinations, we observed that a significant PMCA amplification was only obtained when the mouse line used as substrate is susceptible to the corresponding strain. Our results suggest that PMCA provides a useful tool to study genetic barriers to transmission and to study the zoonotic potential of emerging prion strains. PMID:25279820

  19. Understanding amyloid aggregation by statistical analysis of atomic force microscopy images

    NASA Astrophysics Data System (ADS)

    Adamcik, Jozef; Jung, Jin-Mi; Flakowski, Jérôme; de Los Rios, Paolo; Dietler, Giovanni; Mezzenga, Raffaele

    2010-06-01

    The aggregation of proteins is central to many aspects of daily life, including food processing, blood coagulation, eye cataract formation disease and prion-related neurodegenerative infections. However, the physical mechanisms responsible for amyloidosis-the irreversible fibril formation of various proteins that is linked to disorders such as Alzheimer's, Creutzfeldt-Jakob and Huntington's diseases-have not yet been fully elucidated. Here, we show that different stages of amyloid aggregation can be examined by performing a statistical polymer physics analysis of single-molecule atomic force microscopy images of heat-denatured β-lactoglobulin fibrils. The atomic force microscopy analysis, supported by theoretical arguments, reveals that the fibrils have a multistranded helical shape with twisted ribbon-like structures. Our results also indicate a possible general model for amyloid fibril assembly and illustrate the potential of this approach for investigating fibrillar systems.

  20. Isolation of low-molecular-weight heparin/heparan sulfate from marine sources.

    PubMed

    Saravanan, Ramachandran

    2014-01-01

    The glycosaminoglycan (heparin and heparan sulfate) are polyanionic sulfated polysaccharides mostly recognized for its anticoagulant activity. In many countries, low-molecular-weight heparins have replaced the unfractionated heparin, owing to its high bioavailability, half-life, and less adverse effect. The low-molecular-weight heparins differ in mode of preparation (chemical or enzymatic synthesis and chromatography fractionations) and as a consequence in molecular weight distribution, chemical structure, and pharmacological activities. Bovine and porcine body parts are at present used for manufacturing of commercial heparins, and the appearance of mad cow disease and Creutzfeldt-Jakob disease in humans has limited the use of bovine heparin. Consequently, marine organisms come across the new resource for the production of low-molecular-weight heparin and heparan sulfate. The importance of this chapter suggests that the low-molecular-weight heparin and heparan sulfate from marine species could be alternative sources for commercial heparin. PMID:25081076

  1. Raft lipids as common components of human extracellular amyloid fibrils

    PubMed Central

    Gellermann, Gerald P.; Appel, Thomas R.; Tannert, Astrid; Radestock, Anja; Hortschansky, Peter; Schroeckh, Volker; Leisner, Christian; Lütkepohl, Tim; Shtrasburg, Shmuel; Röcken, Christoph; Pras, Mordechai; Linke, Reinhold P.; Diekmann, Stephan; Fändrich, Marcus

    2005-01-01

    Amyloid fibrils are fibrillar polypeptide aggregates from several degenerative human conditions, including Alzheimer's and Creutzfeldt-Jakob diseases. Analysis of amyloid fibrils derived from various human diseases (AA, ATTR, Aβ2M, ALλ, and ALκ amyloidosis) shows that these are associated with a common lipid component that has a conserved chemical composition and that is specifically rich in cholesterol and sphingolipids, the major components of cellular lipid rafts. This pattern is not notably affected by the purification procedure, and no tight lipid interactions can be detected when preformed fibrils are mixed with lipids. By contrast, the early and prefibrillar aggregates formed in an AA amyloid-producing cell system interact with the raft marker ganglioside-1, and amyloid formation is impaired by addition of cholesterol-reducing agents. These data suggest the existence of common cellular mechanisms in the generation of different types of clinical amyloid deposits. PMID:15851687

  2. Effects on instruments of the World Health Organization--recommended protocols for decontamination after possible exposure to transmissible spongiform encephalopathy-contaminated tissue.

    PubMed

    Brown, Stanley A; Merritt, Katharine; Woods, Terry O; Busick, Deanna N

    2005-01-15

    It has been recommended by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) that rigorous decontamination protocols be used on surgical instruments that have been exposed to tissue possibly contaminated with Creutzfeldt-Jakob disease (CJD). This study was designed to examine the effects of these protocols on various types of surgical instruments. The most important conclusions are: (1) autoclaving in 1N NaOH will cause darkening of some instruments; (2) soaking in 1N NaOH at room temperature damages carbon steel but not stainless steel or titanium; (3) soaking in chlorine bleach will badly corrode gold-plated instruments and will damage some, but not all, stainless-steel instruments, especially welded and soldered joints. Damage became apparent after the first exposure and therefore long tests are not necessary to establish which instruments will be damaged. PMID:15449256

  3. Correlation of striatal dopamine transporter imaging with post mortem substantia nigra cell counts.

    PubMed

    Kraemmer, Julia; Kovacs, Gabor G; Perju-Dumbrava, Laura; Pirker, Susanne; Traub-Weidinger, Tatiana; Pirker, Walter

    2014-12-01

    Dopamine transporter imaging is widely used for the differential diagnosis of parkinsonism. Only limited data are available on the relationship between striatal dopamine transporter binding and dopaminergic cell loss in the substantia nigra (SN). We analyzed postmortem SN cell counts in patients who had previously undergone dopamine transporter single-photon emission computed tomography (SPECT). Pathological diagnoses included Parkinson's disease (n = 1), dementia with Lewy bodies (n = 2), multiple system atrophy (n = 1), corticobasal degeneration (n = 2), atypical parkinsonism with multiple pathological conditions (n = 1), Alzheimer's disease (n = 1), and Creutzfeldt-Jakob disease (n = 1). [(12) (3) I]β-CIT SPECT had been performed in all subjects using a standardized protocol on the same triple-head gamma camera. The density of neuromelanin-containing and tyrosine hydroxylase-positive substantia nigra neurons/mm(2) was evaluated in paraffin-embedded tissue sections by morphometric methods. Mean disease duration at the time of dopamine transporter imaging was 2.3 years, and the mean interval from imaging to death was 29.3 months (range, 4-68 months). Visual analysis of dopamine transporter images showed reduced striatal uptake in all seven patients with neurodegenerative parkinsonism, but not in Alzheimer's and Creutzfeldt-Jakob disease cases. Averaged [(right+left)/2] striatal uptake was highly correlated with averaged SN cell counts (rs  = 0.98, P < 0.0005 for neuromelanin- and rs  = 0.96, P < 0.0005 for tyrosine hydroxylase-positive cells). Similar strong correlations were found in separate analyses for the right and left sides. Striatal dopamine transporter binding highly correlated with postmortem SN cell counts, confirming the validity of dopamine transporter imaging as an excellent in vivo marker of nigrostriatal dopaminergic degeneration. PMID:25048738

  4. Interval shifts in basophil measures correlate with disease activity in chronic spontaneous urticaria.

    PubMed

    Oliver, E T; Sterba, P M; Saini, S S

    2015-05-01

    Chronic spontaneous urticaria (CSU) significantly impacts the quality of life of those affected through symptoms of pruritus and recurrent skin lesions. In active CSU disease, reduced IgE-mediated basophil histamine release (HR) and basopenia are observed. We sought to examine the relationship between interval changes in basophil measures and shifts in patient-reported disease impairment. Simultaneous symptom and basophil evaluations were completed at two sequential study visits, and interval changes in measures were compared between visits for each subject (n = 38). These measures included Skindex-29, current itch and hives scores, total leukocyte histamine content (an indirect measure of blood basophil presence), and basophil HR in response to anti-IgE and formyl-methionine-leucine-phenylalanine. Overall, interval improvements in disease measures in CSU subjects were associated with increased basophil numbers (total leukocyte histamine content) and IgE-mediated HR. This suggests these measures are potential biomarkers for CSU disease improvement and further implicates a role for basophils in CSU. PMID:25631394

  5. Evidence for Cerebral Hemodynamic Measurement-based Therapy in Symptomatic Major Cerebral Artery Disease

    PubMed Central

    YAMAUCHI, Hiroshi

    In patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease, chronic reduction in cerebral perfusion pressure (chronic hemodynamic compromise) increases the risk of ischemic stroke and can be detected by directly measuring hemodynamic parameters. However, strategies for selecting treatments based on hemodynamic measurements have not been clearly established. Bypass surgery has been proven to improve hemodynamic compromise. However, the benefit of bypass surgery for reducing the stroke risk in patients with hemodynamic compromise is controversial. The results of the two randomized controlled trials were inconsistent. Hypertension is a major risk factor for stroke, and antihypertensive therapy provides general benefit to patients with symptomatic atherosclerotic major cerebral artery disease. However, the benefit of strict control of blood pressure for reducing the stroke risk in patients with hemodynamic compromise is a matter of debate. The results of the two observational studies were different. We must establish strategies for selecting treatments based on hemodynamic measurements in atherosclerotic major cerebral artery disease. PMID:26041631

  6. Biomagnetism: Measuring and Imaging the Natural and Disease Fields from the Human Body

    SciTech Connect

    Flynn, Edward

    2001-01-17

    Biomagnetism involves the measurement of the magnetic fields emanating from biological tissue with emphasis on human beings. The fields are small, ranging from femto- to pico-Tesla and are measured with sensitive instruments; typically SQUIDs with sensitivities of several fT. An example of natural field measurements is magnetoencephalography where large SQUID arrays are being used to image magnetic sources in normal and abnormal human brain behavior arising from neuronal currents. A new area of biomagnetism involves the use of targeted magnetic nanoparticles in the early detection of disease. These superparamagnetic particles offer unique characteristics for localizing disease sites ranging from various types of cancer to neurological diseases. By using small pulsed magnetic polarizing fields, SQUID sensors detect small numbers of cells in the body targeted by antibody-labeled nanoparticles through their decaying remanence fields. Localization of these biomagnetic sources in the body involves theoretical modeling of the inverse electromagnetic problem.

  7. Outcome measures for clinical trials assessing treatment of cystic fibrosis lung disease

    PubMed Central

    VanDevanter, Donald R; Konstan, Michael W

    2015-01-01

    Cystic fibrosis (CF) is a complex genetic disease characterized by death from loss of lung function. Therapies target pathophysiologic changes associated with pulmonary disease progression. Although therapeutic mechanisms differ, efficacy demonstration is limited to a few accepted outcome measures, each with shortcomings that are becoming more pronounced as CF population health improves. Pulmonary function improvement (as forced expiratory volume in 1 s [FEV1]) and reduction of pulmonary exacerbation risk are commonly used outcomes. Changes in FEV1 decline rate, quality of life, linear growth and/or weight gain are less utilized outcomes. Validated outcomes tend to work best in subjects with more aggressive or advanced lung disease and less so in healthier subjects. Assays of effects on primary therapeutic targets have yet to be validated as surrogate measures of clinical efficacy. As CF population health improves, it will become increasingly difficult to employ current clinical outcome measures to demonstrate efficacy. PMID:26146539

  8. How many biomarkers to discriminate neurodegenerative dementia?

    PubMed

    Sancesario, Giulia M; Bernardini, Sergio

    2015-01-01

    A number of cerebrospinal fluid (CSF) biomarkers are currently used for the diagnosis of dementia. Opposite changes in the level of amyloid-β(1-42) versus total tau and phosphorylated-tau181 in the CSF reflect the specific pathology of Alzheimer's disease (AD) in the brain. This panel of biomarkers has proven to be effective to differentiate AD from controls and from the major types of neurodegenerative dementia, and to evaluate the progression from mild cognitive impairment to AD. In the absence of specific biomarkers reflecting the pathologies of the other most common forms of dementia, such as Lewy Body disease, Frontotemporal lobar degeneration, Creutzfeldt-Jakob disease, etc., the evaluation of biomarkers of AD pathology is used, attempting to exclude rather than to confirm AD. Other biomarkers included in the common clinical practice do not clearly relate to the underlying pathology: progranulin (PGRN) is a selective marker of frontotemporal dementia with mutations in the PGRN gene; the 14-3-3 protein is a highly sensitive and specific marker for Creutzfeldt-Jakob disease, but has to be used carefully in differentiating rapid progressive dementia; and α-synuclein is an emerging candidate biomarker of the different forms of synucleinopathy. This review summarizes several biomarkers of neurodegenerative dementia validated based on the neuropathological processes occurring in brain tissue. Notwithstanding the paucity of pathologically validated biomarkers and their high analytical variability, the combinations of these biomarkers may well represent a key and more precise analytical and diagnostic tool in the complex plethora of degenerative dementia. PMID:26292074

  9. Live kidney donation from a person with haemophilia.

    PubMed

    McCauley, Christopher; Masengu, Agnes; Courtney, Aisling E; Benson, Gary

    2015-01-01

    There are many documented cases of a person with haemophilia successfully receiving a solid organ transplant, including liver and kidney. However, there is no literature reporting live organ donation by a person with haemophilia. Presumably, this is because the associated risks of excessive bleeding, inhibitor development after a period of intensive treatment with factor replacement and the possibility of variant Creutzfeldt-Jakob disease transmission in those previously treated with blood products, are considered excessive. This case describes a 24-year-old man who was diagnosed with mild haemophilia A during his pretransplant work up as a potential live kidney donor to his sister. He then went on to successfully donate his kidney, without complications. To the best of our knowledge, this is the first description of a person with haemophilia being a living organ donor. PMID:26628308

  10. [Differential diagnosis of status epilepticus].

    PubMed

    Navarro, V; Fischer, C; Convers, P

    2009-04-01

    The diagnosis of status epilepticus can be retained, wrongly, in several circumstances. Nonepileptic pseudoseizures from a psychiatric origin and some movement disorders can mimic convulsive status epilepticus. Encephalopathy of various causes (post-anoxic, metabolic, toxic, Creutzfeldt-Jakob disease) can be wrongly taken for non-convulsive status epilepticus, mainly due to inadequate interpretation of the electroencephalogram (EEG). In these encephalopathies, the existence of (non-epileptic) myoclonus and the abolition of the EEG abnormalities with the use of a benzodiazepine (without correction of the clinical symptoms) are additional confounding factors, leading to false diagnosis. Nevertheless, in general, the diagnosis of status epilepticus can be confirmed or rejected base on a combined analysis of the clinical data and the EEG. PMID:19217635

  11. Exploring energy landscapes of protein folding and aggregation.

    PubMed

    Mousseau, Normand; Derreumaux, Philippe

    2008-01-01

    Human diseases, such as Alzheimer's and Creutzfeldt-Jakob's are associated with misfolding and aggregation of specific proteins into amyloid fibrils sharing a generic cross-beta structure. The self-assembly process is complex, but once a nucleus is formed, rapid fibril formation occurs. Insight into the structures of the oligomers during the lag phase, varying between hours and days, is very difficult experimentally because these species are transient, and numerically using all-atom molecular dynamics because the time scale explored is on the order of 10-100 ns. It is therefore important to develop simplified protein models and alternative methods to sample more efficiently the conformational space. In the past few years, we have developed the activation-relaxation technique (ART nouveau) coupled to the OPEP coarse-grained force field. This review reports the application of ART-OPEP on protein folding and aggregation. PMID:18508525

  12. ERp57 as a novel cellular factor controlling prion protein biosynthesis: Therapeutic potential of protein disulfide isomerases.

    PubMed

    Sepulveda, Martin; Rozas, Pablo; Hetz, Claudio; Medinas, Danilo B

    2016-01-01

    Disturbance of endoplasmic reticulum (ER) proteostasis is observed in Prion-related disorders (PrDs). The protein disulfide isomerase ERp57 is a stress-responsive ER chaperone up-regulated in the brain of Creutzfeldt-Jakob disease patients. However, the actual role of ERp57 in prion protein (PrP) biogenesis and the ER stress response remained poorly defined. We have recently addressed this question using gain- and loss-of-function approaches in vitro and animal models, observing that ERp57 regulates steady-state levels of PrP. Our results revealed that ERp57 modulates the biosynthesis and maturation of PrP but, surprisingly, does not contribute to the global cellular reaction against ER stress in neurons. Here we discuss the relevance of ERp57 as a possible therapeutic target in PrDs and other protein misfolding disorders. PMID:26864548

  13. Current concepts and controversies in prion immunopathology.

    PubMed

    Heikenwalder, Mathias; Prinz, Marco; Heppner, Frank L; Aguzzi, Adriano

    2004-01-01

    Scrapie in sheep and new variant Creutzfeldt-Jakob disease in humans are typically initiated by extracerebral exposure to prions. Both exhibit early prion accumulation in sites of the peripheral lymphoreticular system, such as splenic or lymph nodal germinal centers. In germinal centers, follicular dendritic cells (FDCs), whose development and maintenance depend on lymphotoxin and tumor necrosis factor signaling, are believed to be the main cell type for efficient prion replication in the periphery. Here, we discuss the molecular requirements for prion replication competence in stromal and lymphoid compartments of lymphoid organs. In addition, we examine the preconditions of transepithelial passage of prions in the mucosal-associated lymphoid system. Our results suggest that under specific conditions, efficient prion replication in mesenteric and inguinal lymph nodes is possible in the absence of mature FDCs. M cells are a plausible candidate for the mucosal portal of prion infection. PMID:15126687

  14. Review. The changing face of kuru: a personal perspective.

    PubMed

    Mathews, John D

    2008-11-27

    The epidemic of kuru is now known to have been transmitted among the Fore by ritual consumption of infected organs from deceased relatives. As cannibalism was suppressed by government patrol officers during the 1950s, most transmission had ceased by 1957, when the kuru research programme first commenced. As predicted in the 1960s, the epidemic has waned, with progressive ageing of kuru-affected cohorts over the years to 2007. The few cases seen in the twenty-first century, with the longest incubation periods, were almost certainly exposed as children prior to 1960. Although the research programme had almost no role in bringing the kuru epidemic to an end, it did provide important knowledge that was to help the wider world in controlling the later epidemics of iatrogenic and variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. PMID:18672465

  15. Evidence for zoonotic potential of ovine scrapie prions.

    PubMed

    Cassard, Hervé; Torres, Juan-Maria; Lacroux, Caroline; Douet, Jean-Yves; Benestad, Sylvie L; Lantier, Frédéric; Lugan, Séverine; Lantier, Isabelle; Costes, Pierrette; Aron, Naima; Reine, Fabienne; Herzog, Laetitia; Espinosa, Juan-Carlos; Beringue, Vincent; Andréoletti, Olivier

    2014-01-01

    Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie prions remains unknown. Mice genetically engineered to overexpress the human prion protein (tgHu) have emerged as highly relevant models for gauging the capacity of prions to transmit to humans. These models can propagate human prions without any apparent transmission barrier and have been used used to confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie prions transmit to several tgHu mice models with an efficiency comparable to that of cattle BSE. The serial transmission of different scrapie isolates in these mice led to the propagation of prions that are phenotypically identical to those causing sporadic CJD (sCJD) in humans. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions. PMID:25510416

  16. Neotropical primate nursery in a squirrel monkey breeding unit in Brazil.

    PubMed

    Meireles, B C S; Goldschmidt, B; Resende, F C; Lopes, C A A; Nascimento, L W F

    2016-02-01

    Saimiri (squirrel monkey) is a neotropical primate of the Simian genus that has been bred in captivity for the development of research into human and animal health. They have been widely used in studies in ophthalmology, toxicology, pharmacology, psychiatry, neuroscience, vaccines and drug tests (such as malaria and measles agents), as well as effects on interactive behavior and cognition of Creutzfeldt-Jakob disease in man. The main concern of non-human primate (NHP) research centers is focused on the establishment of self-sustaining breeding colonies providing good quality research animals. Maternal rejection, dystocia and pneumonia are the main causes of newborn deaths in these species. Therefore, in order to ensure the survival of these valuable animals, the Laboratory Animals Breeding Center of the Oswaldo Cruz Foundation (CECAL)/Fiocruz, Rio de Janeiro, Brazil, has developed a protocol for the nursery rearing of these infants. PMID:25653170

  17. Doped diamond-like carbon coatings for surgical instruments reduce protein and prion-amyloid biofouling and improve subsequent cleaning.

    PubMed

    Secker, T J; Hervé, R; Zhao, Q; Borisenko, K B; Abel, E W; Keevil, C W

    2012-01-01

    Doped diamond-like carbon (DLC) coatings offer potential antifouling surfaces against microbial and protein attachment. In particular, stainless steel surgical instruments are subject to tissue protein and resilient prion protein attachment, making decontamination methods used in sterile service departments ineffective, potentially increasing the risk of iatrogenic Creutzfeldt-Jakob disease during surgical procedures. This study examined the adsorption of proteins and prion-associated amyloid to doped DLC surfaces and the efficacy of commercial cleaning chemistries applied to these spiked surfaces, compared to titanium nitride coating and stainless steel. Surfaces inoculated with ME7-infected brain homogenate were visualised using SYPRO Ruby/Thioflavin T staining and modified epi-fluorescence microscopy before and after cleaning. Reduced protein and prion amyloid contamination was observed on the modified surfaces and subsequent decontamination efficacy improved. This highlights the potential for a new generation of coatings for surgical instruments to reduce the risk of iatrogenic CJD infection. PMID:22694725

  18. Amygdalohippocampal MR volume measurements in the early stages of Alzheimer disease

    SciTech Connect

    Lehericy, S.; Baulac, M.; Chiras, J.; Pierot, L.; Martin, N.; Pillon, B.; Deweer, B.; Dubois, B.; Marsault, C.

    1994-05-01

    To evaluate the accuracy of hippocampal and amygdala volume measurements in diagnosing patients in the early stages of Alzheimer disease. Measurements of the hippocampal formation, amygdala, amygdalohippocampal complex (the two measurements summed), caudate nucleus, and ventricles, normalized for total intracranial volume, were obtained on coronal sections (1.5 T, 400/13 [repetition time/echo time], 5 mm) of 13 patients in the mild (minimental status {ge} 21) and five patients in the moderate stages of Alzheimer disease (10 < minimental status < 21), and eight age-matched control subjects. For patients with a minimental status score of 21 or greater, atrophy was significant for the amygdala and hippocampal formation (-36% and -25% for amygdala/total intracranial volume and hippocampal formation/total intracranial volume, respectively), but not for the caudate nucleus. No significant ventricular enlargement was found. For patients with a minimental status score less than 21, atrophy was more severe in all structures studied (amygdala/total intracranial volume -40%; hippocampal formation/total intracranial volume, -45%; caudate nucleus/total intracranial volume, -21%), and ventricles were enlarged (63%). No overlap was found between Alzheimer disease and control values for the amygdalohippocampal volume, even in the mild stages of the disease. In Alzheimer disease patients, hippocampal formation volumes correlated with the minimental status. Hippocampal and amygdala atrophy is marked and significant in the mild stages of Alzheimer disease. Volumetric measurements of the amygdala and the amygdalohippocampal complex appear more accurate than those of the hippocampal formation alone in distinguishing patients with Alzheimer disease. 46 refs., 8 figs., 2 tabs.

  19. Comparison of health-related quality of life measures in chronic obstructive pulmonary disease

    PubMed Central

    2011-01-01

    Background The aims of this study were: (1) to compare the discriminative ability of a disease-specific instrument, the St. George's Respiratory Questionnaire (SGRQ) to generic instruments (i.e., EQ-5D and SF-36); and (2), to evaluate the strength of associations among clinical and health-related quality of life (HRQL) measures in chronic obstructive pulmonary disease (COPD). Methods We analyzed data collected from 120 COPD patients in a Veterans Affairs hospital. Patients self-completed two generic HRQL measures (EQ-5D and SF-36) and the disease-specific SGRQ. The ability of the summary scores of these HRQL measures to discriminate COPD disease severity based on Global Obstructive Lung Disease (GOLD) stage was assessed using relative efficiency ratios (REs). Strength of correlation was used to further evaluate associations between clinical and HRQL measures. Results Mean total scores for PCS-36, EQ-VAS and SGRQ were significantly lower for the more severe stages of COPD (p < 0.05). Using SGRQ total score as reference, the summary scores of the generic measures (PCS-36, MCS-36, EQ index, and EQ-VAS) all had REs of <1. SGRQ exhibited a stronger correlation with clinical measures than the generic summary scores. For instance, SGRQ was moderately correlated with FEV1 (r = 0.43), while generic summary scores had trivial levels of correlation with FEV1 (r < 0.2). Conclusions The SGRQ demonstrated greater ability to discriminate among different levels of severity stages of COPD than generic measures of health, suggestive that SGRQ may provide COPD studies with greater statistical power than EQ-5D and SF-36 summary scores to capture meaningful differences in clinical severity. PMID:21501522

  20. Trends in scientific activity addressing transmissible spongiform encephalopathies: a bibliometric study covering the period 1973–2002

    PubMed Central

    Sanz-Casado, Elías; Ramírez-de Santa Pau, Margarita; Suárez-Balseiro, Carlos A; Iribarren-Maestro, Isabel; de Pedro-Cuesta, Jesús

    2006-01-01

    Background The purpose of this study is to analyse the trends in scientific research on transmissible spongiform encephalopathies by applying bibliometric tools to the scientific literature published between 1973 and 2002. Methods The data for the study were obtained from Medline database, in order to determine the volume of scientific output in the above period, the countries involved, the type of document and the trends in the subject matters addressed. The period 1973–2002 was divided in three sub-periods. Results We observed a significant growth in scientific production. The percentage of increase is 871.7 from 1973 to 2002. This is more evident since 1991 and particularly in the 1996–2001 period. The countries found to have the highest output were the United States, the United Kingdom, Japan, France and Germany. The evolution in the subject matters was almost constant in the three sub-periods in which the study was divided. In the first and second sub-periods, the subject matters of greatest interest were more general, i.e Nervous system or Nervous system diseases, Creutzfeldt-Jakob disease, Scrapie, and Chemicals and Drugs, but in the last sub-period, some changes were observed because the Prion-related matters had the greatest presence. Collaboration among authors is small from 1973 to 1992, but increases notably in the third sub-period, and also the number of authors and clusters formed. Some of the authors, like Gajdusek or Prusiner, appear in the whole period. Conclusion The study reveals a very high increase in scientific production. It is related also with the beginnings of research on bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease, with the establishment of progressive collaboration relationships and a reflection of public health concerns about this problem. PMID:17026743

  1. Kuru and "new variant" CJD.

    PubMed

    Verdrager, J

    1997-09-01

    Acquired transmissible spongiform encephalopathies in humans include Kuru (a disease which was associated with ritualistic cannibalism in Papua New Guinea), iatrogenic Creutzfeldt-Jakob disease and a newly recognized variant form of Creutzfeldt-Jakob disease (nvCJD). Clinical and neuropathological features of nvCJD are reminiscent of Kuru: early and progressive cerebellar ataxia and numerous characteristic Kuru-type amyloid plaques surrounded by spongiform change. In contrast to typical cases of sporadic CJD, Kuru and nvCJD affect young patients. The newly recognized form of CJD has been identified in ten young people in the UK in 1996, approximately 10 years after the beginning of the bovine spongiform encephalopathy (BSE) epidemic in the UK. Molecular analysis has shown that nvCJD has strain characteristics that are distinct from other types of CJD but similar to those of BSE. In the UK an estimated half a million BSE-infected cows entered the human food chain before the bovine offal ban of 1989. To be effective the oral route probably requires high-infectivity titers which are encountered only in the brain, spinal cord and eyes of naturally infected cows. In patients with Kuru, titers of more than 10(8) infectious doses per gram were reported in the brain tissues. As a result of the estimated very long incubation period of nvCJD (10 to 30 years or more) the predicted nvCJD epidemic will have the shape of a normal distribution curve with a peak expected in 2009. The epidemic may extend until 2030. There is already an example to illustrate such a curve in its descending line: the decline of Kuru deaths following the interruption of ritual cannibalism. PMID:9561604

  2. Measurements of muscle strength and performance in children with normal and diseased muscle.

    PubMed Central

    Hosking, J P; Bhat, U S; Dubowitz, V; Edwards, R H

    1976-01-01

    A study has been made of two simple means of measuring muscle power in children with normal and diseased muscle. In one the length of time that the leg and the head could be held at 45 degrees above the horizontal was measured with the child supine. In the second, measurements were made of the isometric strength of six muscle groups with the newly developed Hammersmith Myometer. In the timed performance tests only 5 (8%) of a group of 61 children known to have muscle disease achieved the minimum expected values for their ages. Myometer readings of the isometric power of the children with muscle disease also have values which were below those of a comparable group of normal children. The reproducibility of muscle strength measurements in young children has been shown to be good, whereas the timed performance tests, though able to differentiate normal children from children with muscle disease, did not show sufficient reporducibility for this test to be recommended for sequential measurements. Images FIG. 1 PMID:1015849

  3. The instrumented Timed Up and Go test: Potential outcome measure for disease modifying therapies in Parkinson's disease

    PubMed Central

    Zampieri, Cris; Salarian, Arash; Carlson-Kuhta, Patricia; Aminian, Kamiar; Nutt, John G.; Horak, Fay B.

    2011-01-01

    The Timed Up and Go (TUG) test has been used to assess balance and mobility in Parkinson’s Disease (PD). However, it is not known if this test is sensitive to subtle abnormalities present in early stages of the disease, when balance and gait problems are not clinically evident but may be detected with instrumented analysis of movement. We hypothesize that postural transitions and arm swing during gait will be the most sensitive characteristics of the TUG for early PD. In the present study, we instrumented the TUG test (iTUG) using portable inertial sensors, and extended the walking distance from 3 meters (traditional TUG) to 7 meters. Twelve subjects with early-to-moderate, untreated PD and 12 healthy individuals participated. Our findings show that although the stopwatch measure of TUG duration did not detect abnormalities in early-to-mid stage PD, the peak arm swing velocity on the more affected side, average turning velocity, cadence and peak trunk rotation velocity were significantly slower. These iTUG parameters were also correlated with the UPDRS Motor Scale. Thus, the iTUG test is sensitive to untreated PD and could potentially detect progression of PD and response to symptomatic and disease-modifying treatments. PMID:19726406

  4. Understanding the outcomes measures used in Huntington disease pharmacologicaltrials: A systematic review

    PubMed Central

    Carlozzi, Noelle E; Miciura, Angela; Migliore, Nicholas; Dayalu, Praveen

    2014-01-01

    Background The identification of the gene mutation causing Huntington disease has raised hopes for new treatments to ease symptoms and slow functional decline. As such, there has been a push towards designing efficient pharmacological trials (i.e., drug trials), especially with regard to selecting outcomes measures that are both brief and sensitive to changes across the course of the disease, from subtle prodromal changes, to more severe end-stage changes. Objectives Recently, to aid in efficient development of new HD research studies, the National Institute of Neurological Disorders and Stroke (NINDS) published recommendations for measurement selection in HD. While these recommendations are helpful, many of the recommended measures have little published data in HD. As such, we conducted a systematic review of the literature to identify the most common outcomes measures used in HD clinical trials. Methods Major medical databases, including PubMed, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, were used to identify peer-reviewed journal articles in English from 2001 through April 2013; 151 pharmacological trials were identified. Results The majority of HD clinical trials employed clinician-reported outcomes measures (93%); patient reported outcome measures (11%) and observer reported outcome measures (3%) were used with much less frequency. Conclusions We provide a review of the most commonly used measures across these trials, compare these measures to the clinical recommendations made by the NINDS working groups, and provide recommendations for selecting measures for future clinical trials that meet the Food and Drug Administration standards. PMID:25300328

  5. Measuring the Environmental Burden of Disease in South Korea: A Population-Based Study

    PubMed Central

    Yoon, Seok-Jun; Kim, Hyeong-Su; Ha, Jongsik; Kim, Eun-Jung

    2015-01-01

    Background: This study attempted to measure the environmental burden of disease by examining mortality and disability rates in South Korea, permitting international comparisons. Methods: Disability-adjusted life years (DALY) was used to analyze data from public records. Years of life lost (YLL) and years lost to disability (YLD) were measured in terms of incidence rate and number of deaths. Attributable risks were based on those for WHO Western Pacific Regions. For air pollution, attributable risk was calculated using local PM10 levels and relative risk. Results: The total Korean environmental burden of disease was 17.98 per 1000 persons and the most serious risk factor was air pollution, at 6.89per1000 persons. Occupation was the second highest contributing factor, at 3.29 per 1000 persons, followed by indoor air pollution at 2.91 per 1000 persons. The DALY of air-pollution (indoor and outdoor) was 9.80 per 1000 persons, accounting for more than half of the total environmental burden of disease. The burden of chronic obstructive pulmonary disease, lung cancer, and asthma were 4.07, 3.16, and 1.96 per 1000 persons, respectively. Conclusions: Respiratory illnesses comprised most of the disease burden, the majority of which was linked to air pollution. The present results are important as they could be used to make evidence-based decisions regarding the management of diseases and environmental-risk factors. PMID:26184265

  6. International Dermatology Outcome Measures Initiative as Applied to Psoriatic Disease Outcomes: An Update.

    PubMed

    Merola, Joseph F; Armstrong, April W; Saraiya, Ami; Latella, John; Garg, Amit; Callis Duffin, Kristina; Gottlieb, Alice B

    2016-05-01

    Previous publications have described the International Dermatology Outcome Measures (IDEOM) group, comprising patients, physicians, health economists, participating pharmaceutical industry partners, payers, and regulatory agencies. The goal of IDEOM is to create patient-centered, validated measures of dermatologic disease progression and treatment efficacy for use in both clinical trials and clinical practice. We provide an update of IDEOM activities as of our 2015 IDEOM meeting in Washington, DC, USA. PMID:27134269

  7. Pain and spinal cord imaging measures in children with demyelinating disease

    PubMed Central

    Barakat, Nadia; Gorman, Mark P.; Benson, Leslie; Becerra, Lino; Borsook, David

    2015-01-01

    Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis. PMID:26509120

  8. [Ebola virus disease: clinical and diagnostic aspects and organization of treatment-and-prophylactic measures].

    PubMed

    Fisun, A Ia; Zhdanov, K V; Zakharenko, S M; Kovalenko, A N

    2014-11-01

    The article presents data about world spread of Ebola virus disease, biological characteristics of the pathogen, the laws of the epidemic process in this disease, its pathogenesis, clinical manifestations and diagnosis. Pointed out that the current anti-viral agents, effective for the Ebola virus, have not been developed. Timely performed pathogenetic therapy improves the prognosis of the disease. The basis of this therapy is infusion-detoxification activities and replenishment of losses, of electrolytes, as well as anti-inflammatory and anti-emetic drugs. The Armed Forces of the Russian Federation received the guidelines for preventive measure that can reduce Ebola virus disease transmission. Recommendations for emergency anti-epidemic commission consisted of representatives of the command, specialists and medical services and logistics, are given. Fundamentally important condition for the effective anti-epidemic measures is not only the constant readiness of medical personnel in the detection of disease EVD, but also the appropriate level of equipment of medical institutions of medical supplies and equipment. PMID:25816675

  9. Farm-level plans and husbandry measures for aquatic animal disease emergencies.

    PubMed

    Mohan, C V; Phillips, M J; Bhat, B V; Umesh, N R; Padiyar, P A

    2008-04-01

    Disease is one of the gravest threats to the sustainability of the aquaculture industry. A good understanding of biosecurity and disease causation is essential for developing and implementing farm-level plans and husbandry measures to respond to disease emergencies. Using epidemiological approaches, it is possible to identify pond- and farm-level risk factors for disease outbreaks and develop intervention strategies. Better management practices (BMPs) should be simple, science-based, cost-effective and appropriate to their context if farmers are to adopt and implement them. As part of a regional initiative by the Network of Aquaculture Centres in Asia-Pacific (NACA) to control aquatic animal diseases, effective extension approaches to promote the widespread adoption of BMPs have been developed in India, Indonesia, Vietnam and Thailand, and have proved their worth. A highly successful programme, which addresses rising concerns about the effect of disease on the sustainability of shrimp farming in India, is now in its seventh year. In this paper, the authors present a brief insight into the details of the programme, its outcomes and impact, the lessons learned and the way forward. PMID:18666486

  10. Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

    PubMed Central

    Tatem, Kathleen S.; Quinn, James L.; Phadke, Aditi; Yu, Qing; Gordish-Dressman, Heather; Nagaraju, Kanneboyina

    2014-01-01

    The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial. PMID:25286313

  11. Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases.

    PubMed

    Tatem, Kathleen S; Quinn, James L; Phadke, Aditi; Yu, Qing; Gordish-Dressman, Heather; Nagaraju, Kanneboyina

    2014-01-01

    The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial. PMID:25286313

  12. Measures of health and disease in Africa: are current methods giving us useful information about trends in cardiovascular diseases?

    PubMed

    Cooper, Richard S; Bovet, Pascal

    2013-01-01

    An enormous burst of interest in the public health burden from chronic disease in Africa has emerged as a consequence of efforts to estimate global population health. Detailed estimates are now published for Africa as a whole and each country on the continent. These data have formed the basis for warnings about sharp increases in cardiovascular disease (CVD) in the coming decades. In this essay we briefly examine the trajectory of social development on the continent and its consequences for the epidemiology of CVD and potential control strategies. Since full vital registration has only been implemented in segments of South Africa and the island nations of Seychelles and Mauritius - formally part of WHO-AFRO - mortality data are extremely limited. Numerous sample surveys have been conducted but they often lack standardization or objective measures of health status. Trend data are even less informative. However, using the best quality data available, age-standardized trends in CVD are downward, and in the case of stroke, sharply so. While acknowledging that the extremely limited available data cannot be used as the basis for inference to the continent, we raise the concern that general estimates based on imputation to fill in the missing mortality tables may be even more misleading. No immediate remedies to this problem can be identified, however bilateral collaborative efforts to strength local educational institutions and governmental agencies rank as the highest priority for near term development. PMID:24267434

  13. Looking for Measures of Disease Severity in the Frontotemporal Dementia Continuum.

    PubMed

    Premi, Enrico; Gualeni, Vera; Costa, Paolo; Cosseddu, Maura; Gasparotti, Roberto; Padovani, Alessandro; Borroni, Barbara

    2016-04-16

    Frontotemporal dementia (FTD) is characterized by executive dysfunctions, behavioral disturbances, language deficits and extrapyramidal symptoms. Frontotemporal lobar degeneration-modified Clinical Dementia Rating Scale (FTLD modified-CDR) has been proposed to measure disease severity in behavioral variant FTD (bvFTD). No tools of global disease severity are available in the other FTLD phenotypes [primary progressive aphasias (PPAs), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS)]. This would be strategic as outcome measures in clinical trials. To this aim, we evaluated the association between brain volume (voxel based morphometry) and available clinical scales in FTD. In 176 FTD patients (64 bvFTD, 40 PPAs, 32 PSP, 40 CBS), instrumental activities of daily living (ADLs), FTLD-modified CDR, Mini-Mental State Examination (MMSE), Frontal Behavioral Inventory (FBI), and Neuropsychiatry Inventory (NPI) were administered and MRI performed. Whole-brain linear correlation between each clinical rating scale and brain volume was performed. In bvFTD and PPAs, FTLD-modified CDR was associated with regional brain volume, thereby providing evidence for validity of the FTLD-modified CDR. In PSP, none of the clinical indicators were associated with regional brain volume. In CBS, ADLs and MMSE correlated with frontotemporal lower volume. Considering monogenic disease, FTLD-modified CDR was the best measure. In FTD continuum, different measures able to correlate with brain damage should be considered for the different clinical phenotypes or genetic traits. PMID:27104906

  14. [Measurement of physical activity in patients with chronic obstructive pulmonary disease].

    PubMed

    Magnussen, Helgo; Waschki, Benjamin; Watz, Henrik

    2009-04-15

    Physical activity is an important parameter related to morbidity and mortality in cardiovascular disease, metabolic syndrome/diabetes, mental disorders, cancer, and chronic obstructive pulmonary disease (COPD). In COPD, lower levels of physical activity as reported by the patients are associated with a faster annual lung function decline, increased number of hospitalizations, and higher risk of mortality. Self-reported physical activity, however, correlates only poorly with objectively quantified physical activity in patients with COPD. Recent data show that physical activity can reliably be measured in a substantial number of patients with COPD. Extrapulmonary effects of COPD are associated with reduced physical activity. Clinical characteristics commonly used to assess disease severity like the forced expiratory volume in 1 s or the 6-min walk distance only incompletely reflect the physical activity of patients with COPD. PMID:19399389

  15. Entropy-based complexity measures for gait data of patients with Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Afsar, Ozgur; Tirnakli, Ugur; Kurths, Juergen

    2016-02-01

    Shannon, Kullback-Leibler, and Klimontovich's renormalized entropies are applied as three different complexity measures on gait data of patients with Parkinson's disease (PD) and healthy control group. We show that the renormalized entropy of variability of total reaction force of gait is a very efficient tool to compare patients with respect to disease severity. Moreover, it is a good risk predictor such that the sensitivity, i.e., the percentage of patients with PD who are correctly identified as having PD, increases from 25% to 67% while the Hoehn-Yahr stage increases from 2.5 to 3.0 (this stage goes from 0 to 5 as the disease severity increases). The renormalized entropy method for stride time variability of gait is found to correctly identify patients with a sensitivity of 80%, while the Shannon entropy and the Kullback-Leibler relative entropy can do this with a sensitivity of only 26.7% and 13.3%, respectively.

  16. Using measures of disease progression to determine therapeutic effect: a sirens' song.

    PubMed

    Granger, Christopher B; McMurray, John J V

    2006-08-01

    With an increasing burden of cardiovascular disease and many promising novel treatments in development, the need for efficient systems to evaluate treatments has never been greater. To understand whether a treatment should be used in practice, we need to know whether it makes patients live longer, feel better, prevents adverse events, or does these things with better tolerability or lower cost. But therapeutic development is expensive, inefficient, and is generally focused on short-term treatment effects, rather than on prevention and on long-term impact. Could measures of disease progression, combined with trends on clinical outcomes and post-marketing surveillance to assess safety, serve as the foundation for therapeutic development? Experience and principles of clinical research tell us no. Especially in the field of heart failure, numerous treatments have appeared promising based on disease markers, yet caused harm when tested in studies that assessed clinical outcomes. The intersection of complex human disease, intended and unintended targets of therapy, and overall risk and benefit make it impossible to accurately predict the effect on clinical outcomes based on impact on a disease marker. While reliable measures of disease progression are important to guide which treatments to study in trials, clinical outcome trials must remain the basis for informing clinicians on which treatments improve clinical outcomes. Improved reliability and capacity require the development of more efficient clinical trial methods, streamlined regulatory processes, rational use of privacy protection, leveraging of electronic medical records, and recruitment of a larger proportion of the clinical community to participate in clinical trials. PMID:16875965

  17. Skindex, a quality-of-life measure for patients with skin disease: reliability, validity, and responsiveness.

    PubMed

    Chren, M M; Lasek, R J; Quinn, L M; Mostow, E N; Zyzanski, S J

    1996-11-01

    To measure the effects of skin disease on patients' quality of life, we developed a 61-item self-administered survey instrument called Skindex. Skindex has eight scales, each of which addresses a construct, or an abstract component, in a comprehensive conceptual framework: cognitive effects, social effects, depression, fear, embarrassment, anger, physical discomfort, and physical limitations. Item responses are standardized from 0 (no effect) to 100 (maximal effect); a scale score is the average of responses to items addressing a construct. In 201 patients seen by dermatologists, mean scale scores (+/-SD) ranged from 14 (+/-17) for physical limitations to 31 (+/-22) for physical discomfort. Scale scores were reproducible after 72 h (r = 0.68-0.90) and were internally consistent (Cronbach's alpha = 0.76-0.86). Construct validity was assessed in two ways: (i) in a comparison of patients with inflammatory dermatoses and patients with isolated lesions, patients with inflammatory dermatoses had higher scale scores, and (ii) in an exploratory factor analysis, 78% of the common variance was explained by seven factors that correlated with the scale scores of Skindex. Most of the a priori scale scores changed in the expected direction in patients who reported that their skin conditions had improved or worsened after 6 mo. Finally, physicians' judgments of disease severity did not consistently correlate with Skindex scores. These preliminary data suggest that Skindex reliably and responsively measures the effects of skin disease on patients' quality of life and may supplement clinical judgments of disease severity. PMID:8875954

  18. Challenges in the clinical measurement of ocular surface disease in glaucoma patients.

    PubMed

    Pflugfelder, Stephen C; Baudouin, Christophe

    2011-01-01

    Ocular surface disease (OSD) is common among glaucoma patients. Clinical assessment of OSD can be challenging. This review focuses on some of the limitations relating to both subjective and objective measures of OSD, including dry eye. A survey of the literature was conducted to identify the caveats associated with different methods of assessing OSD. The effect of preservatives on the ocular surface, with respect to glaucoma patients in particular, was also reviewed. Objective methods for assessing ocular surface health and disease include the Schirmer test, tear break-up time, fluorescein turnover, corneal and conjunctival staining, tear osmolarity, and vital dyes. These measures all have limitations in terms of their ability to grade the severity of OSD. Previous studies using the OSD Index showed a mild-to-moderate correlation to dry eye disease severity. Other scoring systems for dry eye have shown a relationship to patient symptom scores or quality of life. Due to the challenges clinicians face concerning both subjective and objective ocular surface health assessments, discerning clinical improvement in ocular surface disease can be a challenge. Further research is needed in order to optimize existing clinical methods and/or identify alternative techniques for assessing OSD in the glaucoma population. PMID:22125404

  19. Challenges in the clinical measurement of ocular surface disease in glaucoma patients

    PubMed Central

    Pflugfelder, Stephen C; Baudouin, Christophe

    2011-01-01

    Ocular surface disease (OSD) is common among glaucoma patients. Clinical assessment of OSD can be challenging. This review focuses on some of the limitations relating to both subjective and objective measures of OSD, including dry eye. A survey of the literature was conducted to identify the caveats associated with different methods of assessing OSD. The effect of preservatives on the ocular surface, with respect to glaucoma patients in particular, was also reviewed. Objective methods for assessing ocular surface health and disease include the Schirmer test, tear break-up time, fluorescein turnover, corneal and conjunctival staining, tear osmolarity, and vital dyes. These measures all have limitations in terms of their ability to grade the severity of OSD. Previous studies using the OSD Index showed a mild-to-moderate correlation to dry eye disease severity. Other scoring systems for dry eye have shown a relationship to patient symptom scores or quality of life. Due to the challenges clinicians face concerning both subjective and objective ocular surface health assessments, discerning clinical improvement in ocular surface disease can be a challenge. Further research is needed in order to optimize existing clinical methods and/or identify alternative techniques for assessing OSD in the glaucoma population. PMID:22125404

  20. Alzheimer's disease progression model based on integrated biomarkers and clinical measures

    PubMed Central

    Qiu, Yue; Li, Liang; Zhou, Tian-yan; Lu, Wei

    2014-01-01

    Aim: Biomarkers and image markers of Alzheimer's disease (AD), such as cerebrospinal fluid Aβ42 and p-tau, are effective predictors of cognitive decline or dementia. The aim of this study was to integrate these markers with a disease progression model and to identify their abnormal ranges. Methods: The data of 395 participants, including 86 normal subjects, 108 early mild cognitive impairment (EMCI) subjects, 120 late mild cognitive impairment (LMCI) subjects, and 81 AD subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For the participants, baseline and long-term data on cerebrospinal fluid Aβ42 and p-tau, hippocampal volume, and ADAS-cog were available. Various linear and nonlinear models were tested to determine the associations among the ratio of Aβ42 to p-tau (the Ratio), hippocampal volume and ADAS-cog. Results: The most likely models for the Ratio, hippocampal volume, and ADAS-cog (logistic, Emax, and linear models, respectively) were used to construct the final model. Baseline disease state had an impact on all the 3 endpoints (the Ratio, hippocampal volume, and ADAS-cog), while APOEε4 genotype and age only influence the Ratio and hippocampal volume. Conclusion: The Ratio can be used to identify the disease stage for an individual, and clinical measures integrated with the Ratio improve the accuracy of mild cognitive impairment (MCI) to AD conversion forecasting. PMID:25088003

  1. Optical fiber spectroscopy measures perfusion of the brain in a murine Alzheimer's disease model

    NASA Astrophysics Data System (ADS)

    Ahn, Hyung Jin; Strickland, Sidney; Krueger, James; Gareau, Daniel

    2014-02-01

    Optical fiber spectroscopy is a versatile tool for measuring diffuse reflectance and extracting absorption information that can noninvasively quantify the presence of chromophores such as oxyhemoglobin and deoxy-hemoglobin in tissues. Cerebrovascular abnormalities were widely recognized in Alzheimer's disease (AD) patients. We analyzed blood volume fraction and level of oxygenated hemoglobin in Tg6799 mice, which are transgenic mice expressing five different familial Alzheimer disease-associated mutations in the human amyloid precursor protein and presenilin-1 genes. Diffuse reflectance spectra were iteratively fit as weighted sums of oxy- and deoxy-hemoglobin. Our observations showed slightly hypoxic conditions and significantly increased blood volume in the Alzheimer's mice versus wild type. These results suggest that hyperperfusion of our AD mice may be a compensating mechanism for impaired cerebral vascular function and somehow relevant with early stage of AD patients. Ongoing work focuses on developing a cannula fixture that allows measurement in awake, behaving animals.

  2. Regional magnetic resonance imaging measures for multivariate analysis in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Westman, Eric; Aguilar, Carlos; Muehlboeck, J-Sebastian; Simmons, Andrew

    2013-01-01

    Automated structural magnetic resonance imaging (MRI) processing pipelines are gaining popularity for Alzheimer's disease (AD) research. They generate regional volumes, cortical thickness measures and other measures, which can be used as input for multivariate analysis. It is not clear which combination of measures and normalization approach are most useful for AD classification and to predict mild cognitive impairment (MCI) conversion. The current study includes MRI scans from 699 subjects [AD, MCI and controls (CTL)] from the Alzheimer's disease Neuroimaging Initiative (ADNI). The Freesurfer pipeline was used to generate regional volume, cortical thickness, gray matter volume, surface area, mean curvature, gaussian curvature, folding index and curvature index measures. 259 variables were used for orthogonal partial least square to latent structures (OPLS) multivariate analysis. Normalisation approaches were explored and the optimal combination of measures determined. Results indicate that cortical thickness measures should not be normalized, while volumes should probably be normalized by intracranial volume (ICV). Combining regional cortical thickness measures (not normalized) with cortical and subcortical volumes (normalized with ICV) using OPLS gave a prediction accuracy of 91.5 % when distinguishing AD versus CTL. This model prospectively predicted future decline from MCI to AD with 75.9 % of converters correctly classified. Normalization strategy did not have a significant effect on the accuracies of multivariate models containing multiple MRI measures for this large dataset. The appropriate choice of input for multivariate analysis in AD and MCI is of great importance. The results support the use of un-normalised cortical thickness measures and volumes normalised by ICV. PMID:22890700

  3. Measuring tidal breathing parameters using a volumetric vest in neonates with and without lung disease.

    PubMed

    Olden, C; Symes, E; Seddon, P

    2010-11-01

    Lung function measurement is difficult in unsedated infants; tidal breathing parameters are a useful non-invasive surrogate, but even these measurements cause disturbance from applying a facemask. We investigated a novel volumetric vest system (FloRight), which measures volume changes of the respiratory system from changes in the magnetic fields induced by current-carrying coils around the entire chest and abdomen. Using a facemask and ultrasonic flowmeter as comparator, we assessed the validity and repeatability of tidal breathing parameters measured by FloRight in 10 healthy newborn infants during natural sleep. We also assessed the effect of a facemask on tidal volume and tidal expiratory flow parameters. To assess the ability of the FloRight system to detect disease, we compared the healthy infants with 11 infants suffering from bronchopulmonary dysplasia. Tidal parameters with the FloRight vest corresponded closely with facemask measurements. Mean difference, mask minus vest, for tidal volume was 0.096 ml (P < 0.05), with limits of agreement +4.5 to -4.3 ml. Coefficient of repeatability was similar for mask and vest measurements. Tidal volume measured by FloRight with mask in place (20.6 ml) was significantly higher than without mask (16.1 ml), but tidal expiratory flow parameters were not altered. FloRight measurements of tidal parameters were markedly different between the two groups of infants, with tidal volume per Kg significantly higher and tidal expiratory flow parameters significantly lower. Our findings suggest that the FloRight system is able to measure tidal breathing parameters accurately, in healthy newborn infants, without prior calibration on the infant. It appears to have at least sufficient sensitivity to detect severe respiratory disease. PMID:20872815

  4. Random forest-based similarity measures for multi-modal classification of Alzheimer's disease.

    PubMed

    Gray, Katherine R; Aljabar, Paul; Heckemann, Rolf A; Hammers, Alexander; Rueckert, Daniel

    2013-01-15

    Neurodegenerative disorders, such as Alzheimer's disease, are associated with changes in multiple neuroimaging and biological measures. These may provide complementary information for diagnosis and prognosis. We present a multi-modality classification framework in which manifolds are constructed based on pairwise similarity measures derived from random forest classifiers. Similarities from multiple modalities are combined to generate an embedding that simultaneously encodes information about all the available features. Multi-modality classification is then performed using coordinates from this joint embedding. We evaluate the proposed framework by application to neuroimaging and biological data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Features include regional MRI volumes, voxel-based FDG-PET signal intensities, CSF biomarker measures, and categorical genetic information. Classification based on the joint embedding constructed using information from all four modalities out-performs the classification based on any individual modality for comparisons between Alzheimer's disease patients and healthy controls, as well as between mild cognitive impairment patients and healthy controls. Based on the joint embedding, we achieve classification accuracies of 89% between Alzheimer's disease patients and healthy controls, and 75% between mild cognitive impairment patients and healthy controls. These results are comparable with those reported in other recent studies using multi-kernel learning. Random forests provide consistent pairwise similarity measures for multiple modalities, thus facilitating the combination of different types of feature data. We demonstrate this by application to data in which the number of features differs by several orders of magnitude between modalities. Random forest classifiers extend naturally to multi-class problems, and the framework described here could be applied to distinguish between multiple patient groups in the future

  5. Random forest-based similarity measures for multi-modal classification of Alzheimer’s disease

    PubMed Central

    Gray, Katherine R.; Aljabar, Paul; Heckemann, Rolf A.; Hammers, Alexander; Rueckert, Daniel

    2012-01-01

    Neurodegenerative disorders, such as Alzheimer’s disease, are associated with changes in multiple neuroimaging and biological measures. These may provide complementary information for diagnosis and prognosis. We present a multi-modality classification framework in which manifolds are constructed based on pairwise similarity measures derived from random forest classifiers. Similarities from multiple modalities are combined to generate an embedding that simultaneously encodes information about all the available features. Multimodality classification is then performed using coordinates from this joint embedding. We evaluate the proposed framework by application to neuroimaging and biological data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Features include regional MRI volumes, voxel-based FDG-PET signal intensities, CSF biomarker measures, and categorical genetic information. Classification based on the joint embedding constructed using information from all four modalities out-performs classification based on any individual modality for comparisons between Alzheimer’s disease patients and healthy controls, as well as between mild cognitive impairment patients and healthy controls. Based on the joint embedding, we achieve classification accuracies of 89% between Alzheimer’s disease patients and healthy controls, and 75% between mild cognitive impairment patients and healthy controls. These results are comparable with those reported in other recent studies using multi-kernel learning. Random forests provide consistent pairwise similarity measures for multiple modalities, thus facilitating the combination of different types of feature data. We demonstrate this by application to data in which the number of features differ by several orders of magnitude between modalities. Random forest classifiers extend naturally to multi-class problems, and the framework described here could be applied to distinguish between multiple patient groups in the

  6. The Skindex instruments to measure the effects of skin disease on quality of life.

    PubMed

    Chren, Mary-Margaret

    2012-04-01

    Skindex-29 and Skindex-16 are validated measures of the effects of skin diseases on patients' quality of life. This article reviews the development of both versions of Skindex, discusses their measurement properties and interpretability, and gives examples of how they have been used and adapted for dermatologic research internationally. Studies of quality of life in patients with nonmelanoma skin cancer are described to illustrate the use of Skindex to understand quality of life and to compare effectiveness of different treatments for this highly prevalent condition. PMID:22284137

  7. Disseminated disease severity as a measure of virulence of Mycobacterium tuberculosis in the guinea pig model.

    PubMed

    Palanisamy, Gopinath S; Smith, Erin E; Shanley, Crystal A; Ordway, Diane J; Orme, Ian M; Basaraba, Randall J

    2008-07-01

    Virulence is the measure of pathogenicity of a microorganism as determined by its ability to invade host tissues and to produce severe disease. In the low-dose aerosol guinea pig model the virulence of multiple strains of Mycobacterium tuberculosis was determined by measuring time of survival, bacterial loads in target organs, and the severity of pulmonary and extra-pulmonary lesions. Erdman K01, CSU93/CDC1551 and HN878 had shorter survival times compared to the common laboratory strain H37Rv. After 30 days of the infection bacilli had disseminated from the lungs resulting in microscopically visible lesions in peribronchial lymph nodes, peripancreatic lymph nodes, spleen, liver, pancreas, adrenal and heart. The extent of the lesion necrosis paralleled virulence when survival times were used as a measure as Erdman K01 and the two clinical isolates caused more necrosis and resulted in sooner death in infected animals than the H37Rv. The extent of extra-pulmonary lesion necrosis was a better predictor of virulence than the number of viable bacilli in the tissue. Overall, this study emphasizes the point that extra-pulmonary disease is a prominent feature of the guinea pig model and dissemination to organs not normally assayed such as the heart and adrenal glands should be taken into account in the assessment of the disease process. PMID:18321783

  8. How should we measure function in patients with chronic heart and lung disease?

    PubMed

    Guyatt, G H; Thompson, P J; Berman, L B; Sullivan, M J; Townsend, M; Jones, N L; Pugsley, S O

    1985-01-01

    To elucidate the characteristics of measures of function in patients with chronic heart failure and chronic lung disease we administered four functional status questionnaires, a 6-min walk test and a cycle ergometer exercise test, to 43 patients limited in their day to day activities as a result of their underlying heart or lung disease. Correlations between these measures were calculated using Spearman's rank order correlation coefficient. The walk test correlated well with the cycle ergometer (r = 0.579), and almost as well with the four functional status questionnaires (r = 0.473-0.590) as the questionnaires did with one another (0.423-0.729). On the other hand, correlations between cycle ergometer results and the questionnaires was in each case 0.295 or lower, and none of these correlations reached statistical significance. These results suggest that exercise capacity in the laboratory can be differentiated from functional exercise capacity (the ability to undertake physically demanding activities of daily living) and that the walk test provides a good measure of function in patients with heart and lung disease. PMID:4008592

  9. Virtual test: A student-centered software to measure student's critical thinking on human disease

    NASA Astrophysics Data System (ADS)

    Rusyati, Lilit; Firman, Harry

    2016-02-01

    The study "Virtual Test: A Student-Centered Software to Measure Student's Critical Thinking on Human Disease" is descriptive research. The background is importance of computer-based test that use element and sub element of critical thinking. Aim of this study is development of multiple choices to measure critical thinking that made by student-centered software. Instruments to collect data are (1) construct validity sheet by expert judge (lecturer and medical doctor) and professional judge (science teacher); and (2) test legibility sheet by science teacher and junior high school student. Participants consisted of science teacher, lecturer, and medical doctor as validator; and the students as respondent. Result of this study are describe about characteristic of virtual test that use to measure student's critical thinking on human disease, analyze result of legibility test by students and science teachers, analyze result of expert judgment by science teachers and medical doctor, and analyze result of trial test of virtual test at junior high school. Generally, result analysis shown characteristic of multiple choices to measure critical thinking was made by eight elements and 26 sub elements that developed by Inch et al.; complete by relevant information; and have validity and reliability more than "enough". Furthermore, specific characteristic of multiple choices to measure critical thinking are information in form science comic, table, figure, article, and video; correct structure of language; add source of citation; and question can guide student to critical thinking logically.

  10. Usefulness of Measuring Serum Procalcitonin Levels in Patients with Inflammatory Bowel Disease

    PubMed Central

    Chung, Sook Hee; Lee, Hye Won; Kim, Seung Won; Park, Soo Jung; Hong, Sung Pil; Kim, Tae Il; Kim, Won Ho; Cheon, Jae Hee

    2016-01-01

    Background/Aims The relationships between serum procalcitonin, inflammatory bowel disease (IBD) and intestinal Behçet’s disease (BD) have not been completely determined. We aimed to evaluate the usefulness of measuring serum procalcitonin levels to assess disease activity and infection stage in patients with IBD and intestinal BD. Methods We retrospectively analyzed clinical data from 129 patients with IBD and intestinal BD for whom serum procalcitonin and C-reactive protein (CRP) levels were measured between January 2006 and February 2013. Results The median serum procalcitonin levels in the IBD and intestinal BD with septic shock or sepsis (n=8), with localized infection (n=76), and without infection (n=45) were 3.46 ng/mL (range, 0.17 to 63.66 ng/mL), 0.22 ng/mL (range, 0.05 to 140.18 ng/mL), and 0.07 ng/mL (range, 0.00 to 31.50 ng/mL), respectively (p=0.001). The serum CRP levels in the IBD and intestinal BD patients did not differ according to the infection stage. Variations in serum procalcitonin levels were not observed in the IBD and intestinal BD patients with different disease activities. Conclusions Serum procalcitonin levels may not be affected by IBD and intestinal BD activity itself, although they may be affected by concomitant infection. Serum procalcitonin measurements could be more useful than CRP in determining the infection stage that reflects the severity of infection in IBD and intestinal BD patients. PMID:26780089

  11. Measuring Health Literacy Regarding Infectious Respiratory Diseases: A New Skills-Based Instrument

    PubMed Central

    Sun, Xinying; Chen, Juan; Shi, Yuhui; Zeng, Qingqi; Wei, Nanfang; Xie, Ruiqian; Chang, Chun; Du, Weijing

    2013-01-01

    Background There is no special instrument to measure skills-based health literacy where it concerns infectious respiratory diseases. This study aimed to explore and evaluate a new skills-based instrument on health literacy regarding respiratory infectious diseases. Methods This instrument was designed to measure not only an individual’s reading and numeracy ability, but also their oral communication ability and their ability to use the internet to seek information. Sixteen stimuli materials were selected to enable measurement of the skills, which were sourced from the WHO, China CDC, and Chinese Center of Health Education. The information involved the distribution of epidemics, immunization programs, early symptoms, means of disease prevention, individual’s preventative behavior, use of medications and thermometers, treatment plans and the location of hospitals. Multi-stage stratified cluster sampling was employed to collect participants. Psychometric properties were used to evaluate the reliability and validity of the instrument. Results The overall degree of difficulty and discrimination of the instrument were 0.693 and 0.482 respectively. The instrument demonstrated good internal consistency reliability with a Cronbach’s alpha of 0.864. As for validity, six factors were extracted from 30 items, which together explained 47.3% of the instrument’s variance. And based on confirmatory factor analysis, the items were grouped into five subscales representing prose, document, quantitative, oral and internet based information seeking skills (χ2 = 9.200, P>0.05, GFI = 0.998, TLI = 0.988, AGFI = 0.992, RMSEA = 0.028). Conclusion The new instrument has good reliability and validity, and it could be used to assess the health literacy regarding respiratory infectious disease status of different groups. PMID:23724029

  12. Methodologies for measuring travelers' risk perception of infectious diseases: A systematic review.

    PubMed

    Sridhar, Shruti; Régner, Isabelle; Brouqui, Philippe; Gautret, Philippe

    2016-01-01

    Numerous studies in the past have stressed the importance of travelers' psychology and perception in the implementation of preventive measures. The aim of this systematic review was to identify the methodologies used in studies reporting on travelers' risk perception of infectious diseases. A systematic search for relevant literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. There were 39 studies identified. In 35 of 39 studies, the methodology used was that of a knowledge, attitude and practice (KAP) survey based on questionnaires. One study used a combination of questionnaires and a visual psychometric measuring instrument called the 'pictorial representation of illness and self-measurement" or PRISM. One study used a self-representation model (SRM) method. Two studies measured psychosocial factors. Valuable information was obtained from KAP surveys showing an overall lack of knowledge among travelers about the most frequent travel-associated infections and associated preventive measures. This methodological approach however, is mainly descriptive, addressing knowledge, attitudes, and practices separately and lacking an examination of the interrelationships between these three components. Another limitation of the KAP method is underestimating psychosocial variables that have proved influential in health related behaviors, including perceived benefits and costs of preventive measures, perceived social pressure, perceived personal control, unrealistic optimism and risk propensity. Future risk perception studies in travel medicine should consider psychosocial variables with inferential and multivariate statistical analyses. The use of implicit measurements of attitudes could also provide new insights in the field of travelers' risk perception of travel-associated infectious diseases. PMID:27238906

  13. A comparative study of synchrony measures for the early diagnosis of Alzheimer's disease based on EEG.

    PubMed

    Dauwels, J; Vialatte, F; Musha, T; Cichocki, A

    2010-01-01

    It is well known that EEG signals of Alzheimer's disease (AD) patients are generally less synchronous than in age-matched control subjects. However, this effect is not always easily detectable. This is especially the case for patients in the pre-symptomatic phase, commonly referred to as mild cognitive impairment (MCI), during which neuronal degeneration is occurring prior to the clinical symptoms appearance. In this paper, various synchrony measures are studied in the context of AD diagnosis, including the correlation coefficient, mean-square and phase coherence, Granger causality, phase synchrony indices, information-theoretic divergence measures, state space based measures, and the recently proposed stochastic event synchrony measures. Experiments with EEG data show that many of those measures are strongly correlated (or anti-correlated) with the correlation coefficient, and hence, provide little complementary information about EEG synchrony. Measures that are only weakly correlated with the correlation coefficient include the phase synchrony indices, Granger causality measures, and stochastic event synchrony measures. In addition, those three families of synchrony measures are mutually uncorrelated, and therefore, they each seem to capture a specific kind of interdependence. For the data set at hand, only two synchrony measures are able to convincingly distinguish MCI patients from age-matched control patients, i.e., Granger causality (in particular, full-frequency directed transfer function) and stochastic event synchrony. Those two measures are used as features to distinguish MCI patients from age-matched control subjects, yielding a leave-one-out classification rate of 83%. The classification performance may be further improved by adding complementary features from EEG; this approach may eventually lead to a reliable EEG-based diagnostic tool for MCI and AD. PMID:19573607

  14. [Attitude of district physicians and the population toward measures regarding the prevention of ischemic heart disease].

    PubMed

    Chazova, L V; Ivanov, V M; Manukian, L M; Patoka, N A; Sats, L M

    1984-11-01

    The experience of the work on multifactorial prophylaxis of coronary heart disease performed on the basis of an urban out-patient center among 40-59-year-old males points to an inadequate response of the population to the primary (57 % after the mailing of 4 invitations) and repeated annual (50-60% of those who have had the primary examination) prophylactic examinations. Over 4 years, 22 % of patients with coronary heart disease and 32 % of patients with arterial hypertension refused to come for out-patient examinations. The number of responses was greater among individuals with risk factors of coronary heart disease. Most therapists from out-patient clinics believe it necessary to carry out prophylactic measures and would like to have more time for this purpose. Yet, many of them doubt that the population will follow medical advice with regard to changing the life style. The population is poorly aware of the role of prophylactic examinations, the effect of nutrition and bad habits on the development of cardiovascular diseases. PMID:6521209

  15. Alzheimer's disease: pathophysiological implications of measurement of plasma cortisol, plasma dehydroepiandrosterone sulfate, and lymphocytic corticosteroid receptors.

    PubMed

    Armanini, Decio; Vecchio, Franco; Basso, Alfonso; Milone, Francesco Ferro; Simoncini, Maria; Fiore, Cristina; Mattarello, Mee Joung; Sartorato, Paola; Karbowiak, Isabella

    2003-11-01

    Alzheimer's disease is often characterized by an increase in plasma cortisol without clinical evidence of hypercorticism. Twenty-three consecutive patients with Alzheimer's disease and 23 age- and sex-matched healthy controls were studied by measuring plasma cortisol and dehydroepiandrosterone sulfate (DHEAS) (by enzyme immunoassay), the number of type I and type II corticosteroid receptors in mononuclear leukocytes (by radio-receptor-assay), and the lymphocyte subpopulations (by cytofluorimetry). Results are expressed in terms of median and range. In Alzheimer's disease, plasma cortisol was higher than in controls (median 0.74, range 0.47-1.21 vs 0.47, 0.36-0.77 mmol/L; p < 0.001). Plasma DHEAS, the DHEAS/cortisol ratio, and the number of type II corticosteroid receptors were significantly lower in AD than in controls (DHEAS: median 1.81, range 0.21-3.69 vs 3.51, 1.35-9.07 micromol/L; DHEAS/ cortisol: 2.04, range 0.3-5.8 vs 6.8, range 2.7-24 and type II receptors: 1219, 1000-2700 vs 1950, 1035- 2750 receptors per cell; p < 0.001). No correlation was found between the hormonal parameters, age, and mini-mental test score. These data support the hypothesis of a dysregulation of the adrenal pituitary axis in Alzheimer's disease, which is probably the consequence of damage to target tissues by corticosteroids. PMID:14665714

  16. Artificial neural networks allow the use of simultaneous measurements of Alzheimer Disease markers for early detection of the disease

    PubMed Central

    Di Luca, Monica; Grossi, Enzo; Borroni, Barbara; Zimmermann, Martina; Marcello, Elena; Colciaghi, Francesca; Gardoni, Fabrizio; Intraligi, Marco; Padovani, Alessandro; Buscema, Massimo

    2005-01-01

    Background Previous studies have shown that in platelets of mild Alzheimer Disease (AD) patients there are alterations of specific APP forms, paralleled by alteration in expression level of both ADAM 10 and BACE when compared to control subjects. Due to the poor linear relation among each key-element of beta-amyloid cascade and the target diagnosis, the use of systems able to afford non linear tasks, like artificial neural networks (ANNs), should allow a better discriminating capacity in comparison with classical statistics. Objective To evaluate the accuracy of ANNs in AD diagnosis. Methods 37 mild-AD patients and 25 control subjects were enrolled, and APP, ADM10 and BACE measures were performed. Fifteen different models of feed-forward and complex-recurrent ANNs (provided by Semeion Research Centre), based on different learning laws (back propagation, sine-net, bi-modal) were compared with the linear discriminant analysis (LDA). Results The best ANN model correctly identified mild AD patients in the 94% of cases and the control subjects in the 92%. The corresponding diagnostic performance obtained with LDA was 90% and 73%. Conclusion This preliminary study suggests that the processing of biochemical tests related to beta-amyloid cascade with ANNs allows a very good discrimination of AD in early stages, higher than that obtainable with classical statistics methods. PMID:16048651

  17. A validated measure of adherence to antibiotic prophylaxis in children with sickle cell disease

    PubMed Central

    Duncan, Natalie A; Kronenberger, William G; Hampton, Kisha C; Bloom, Ellen M; Rampersad, Angeli G; Roberson, Christopher P; Shapiro, Amy D

    2016-01-01

    Background Antibiotic prophylaxis is a mainstay in sickle cell disease management. However, adherence is estimated at only 66%. This study aimed to develop and validate a Sickle Cell Antibiotic Adherence Level Evaluation (SCAALE) to promote systematic and detailed adherence evaluation. Methods A 28-item questionnaire was created, covering seven adherence areas. General Adherence Ratings from the parent and one health care provider and medication possession ratios were obtained as validation measures. Results Internal consistency was very good to excellent for the total SCAALE (α=0.89) and four of the seven subscales. Correlations between SCAALE scores and validation measures were strong for the total SCAALE and five of the seven subscales. Conclusion The SCAALE provides a detailed, quantitative, multidimensional, and global measurement of adherence and can promote clinical care and research. PMID:27354768

  18. An overview of animal models of pain: disease models and outcome measures

    PubMed Central

    Gregory, N; Harris, AL; Robinson, CR; Dougherty, PM; Fuchs, PN; Sluka, KA

    2013-01-01

    Pain is ultimately a perceptual phenomenon. It is built from information gathered by specialized pain receptors in tissue, modified by spinal and supraspinal mechanisms, and integrated into a discrete sensory experience with an emotional valence in the brain. Because of this, studying intact animals allows the multidimensional nature of pain to be examined. A number of animal models have been developed, reflecting observations that pain phenotypes are mediated by distinct mechanisms. Animal models of pain are designed to mimic distinct clinical diseases to better evaluate underlying mechanisms and potential treatments. Outcome measures are designed to measure multiple parts of the pain experience including reflexive hyperalgesia measures, sensory and affective dimensions of pain and impact of pain on function and quality of life. In this review we discuss the common methods used for inducing each of the pain phenotypes related to clinical pain syndromes, as well as the main behavioral tests for assessing pain in each model. PMID:24035349

  19. Measuring Physical Activity in Older Adults with and without Early Stage Alzheimer’s Disease

    PubMed Central

    Watts, Amber S.; Vidoni, Eric D.; Loskutova, Natalia; Johnson, David K.; Burns, Jeffrey M.

    2013-01-01

    We compared subjective reports of physical activity with objective measures of physical fitness including cardiorespiratory capacity, body composition, and physical performance in 146 older adults with and without early stage Alzheimer’s disease (ESAD). Respondents reported primarily unstructured and low-intensity activities, including walking and housework. Individuals with ESAD participated in fewer and lower intensity physical activities than those without ESAD. In those without ESAD, housework was related to lower body mass index, leisure walking was related to faster speed on a timed walking test, and participation in sports was related to higher peak oxygen intake. In individuals with ESAD, reported physical activities did not predict any of the physical fitness, body composition, or physical performance measures. We conclude that measures of physical activity require expansion of unstructured and low intensity activities to improve sensitivity in sedentary populations, especially in older adults with ESAD. PMID:24062599

  20. Review of outcome measurement instruments in Alzheimer's disease drug trials: psychometric properties of global scales.

    PubMed

    Oremus, M; Perrault, A; Demers, L; Wolfson, C

    2000-01-01

    The use of global outcome measures with strong psychometric properties in Alzheimer's disease (AD) drug trials is encouraged. This article focuses on Clinician Global Impression of Change scales, the Clinical Dementia Rating, and the Global Deterioration Scale to provide (1) a review of psychometric properties, (2) a critique of how these properties are assessed in the literature, and (3) a basis for evaluating, from the standpoint of psychometric properties, the appropriateness of using a given global scale in a drug trial. Reported reliability and validity estimates for the aforementioned scales range from fair to very good, but small sample sizes and/or inappropriate measures of correlation weaken the quality of the evidence. There is also a dearth of published information on responsiveness to change. Researchers planning AD drug trials should consider these issues, along with the interval between test administrations for test-retest reliability, to help select appropriate global outcome measurement instruments. PMID:11128059

  1. Need for Better Blood Pressure Measurement in Developing Countries to Improve Prevention of Cardiovascular Disease

    PubMed Central

    Modesti, Pietro Amedeo; Perruolo, Eleonora; Parati, Gianfranco

    2015-01-01

    Hypertension is now the foremost cause of disability and is responsible for the highest percentage of attributable death among risk factors. These global changes are mainly due to the increase in the prevalence of hypertension in most low- and middle-income countries (LMICs) as a consequence of relevant socioeconomic changes occurring during the last decades. Implementation of global prevention efforts urgently needs to be accelerated because of the increasing incidence of haemorrhagic stroke, renal failure, and hypertensive heart disease in developing countries. Blood pressure (BP) measurement has different implications in epidemiological studies performed in low-resource settings. First, the frequency of blood pressure measurement is a simple but reliable indicator of access to healthcare in epidemiological studies, which may disclose the favourable effects of urbanization; the opportunity to have BP measured increases hypertension awareness, facilitates drug treatment, and leads to better achievement of BP control. Second, BP measurement is a key element in cardiovascular risk stratification, focusing solely on the preferred strategy in low-resource settings where costs of biochemical tests might be less sustainable. Third, the issue of obtaining reliable estimation of BP values is crucial to achieve sound data on the burden of hypertension in LMICs, and some aspects of BP measurement, such as the use of reliable automated devices, the number of measurements/visits to achieve a consistent diagnosis of hypertension, and the possible confounding effect of environmental factors, must be closely considered. PMID:25420484

  2. Repeatability and Reproducibility of Noninvasive Keratograph 5M Measurements in Patients with Dry Eye Disease

    PubMed Central

    Tian, Lei; Qu, Jing-hao; zhang, Xiao-yu; Sun, Xu-guang

    2016-01-01

    Purpose. To determine the intraexaminer repeatability and interexaminer reproducibility of tear meniscus height (TMH) and noninvasive Keratograph tear breakup time (NIKBUT) measurements obtained with the Keratograph 5M (K5M) in a sample of healthy and dry eye populations. Methods. Forty-two patients with dry eye disease (DED group) and 42 healthy subjects (healthy group) were recruited in this prospective study. In all subjects, each eye received 3 consecutive measurements using the K5M for the TMH and NIKBUTs (NIKBUT-first and NIKBUT-average). And then a different examiner repeated the measurements. The repeatability and reproducibility of measurements were assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Results. The repeatability and reproducibility of TMH and NIKBUTs were good in both DED and healthy groups (CV% ≤ 26.1% and ICC ≥ 0.75 for all measurements). Patients with DED showed better intraexaminer repeatability for NIKBUTs, but worse for TMH than healthy subjects. Average TMH, NIKBUT-first, and NIKBUT-average were significantly lower in DED group than in healthy group (all P values < 0.05). Conclusions. Measurements of TMH and NIKBUTs obtained with the K5M may provide a simple, noninvasive screening test for dry eye with acceptable repeatability and reproducibility. The NIKBUTs were more reliable, but TMH was less reliable in patients with DED. PMID:27190639

  3. MRI measures of Alzheimer's disease and the AddNeuroMed study.

    PubMed

    Simmons, Andrew; Westman, Eric; Muehlboeck, Sebastian; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; Kłoszewska, Iwona; Wahlund, Lars-Olof; Soininen, Hilkka; Lovestone, Simon; Evans, Alan; Spenger, Christian

    2009-10-01

    Here we describe the AddNeuroMed multicenter magnetic resonance imaging (MRI) study for longitudinal assessment in Alzheimer's disease (AD). The study is similar to a faux clinical trial and has been established to assess longitudinal MRI changes in AD, mild cognitive impairment (MCI), and healthy control subjects using an image acquisition protocol compatible with the Alzheimer's Disease Neuroimaging Initiative (ADNI). The approach consists of a harmonized MRI acquisition protocol across centers, rigorous quality control, a central data analysis hub, and an automated image analysis pipeline. Comprehensive quality control measures have been established throughout the study. An intelligent web-accessible database holds details on both the raw images and data processed using a sophisticated image analysis pipeline. A total of 378 subjects were recruited (130 AD, 131 MCI, 117 healthy controls) of which a high percentage (97.3%) of the T1-weighted volumes passed the quality control criteria. Measurements of normalized whole brain volume, whole brain cortical thickness, and point-by-point group-based cortical thickness measurements, demonstrating the power of the automated image analysis techniques employed, are reported. PMID:19906260

  4. MEASURING AND IMPROVING RESPIRATORY OUTCOMES IN CYSTIC FIBROSIS LUNG DISEASE: OPPORTUNITIES AND CHALLENGES TO THERAPY

    PubMed Central

    Zemanick, Edith T.; Harris, J. Kirk; Conway, Steven; Konstan, Michael W.; Marshall, Bruce; Quittner, Alexandra L.; Retsch-Bogart, George; Saiman, Lisa; Accurso, Frank J.

    2010-01-01

    Cystic fibrosis (CF) is a life-shortening disease with significant morbidity. Despite overall improvements in survival, patients with CF experience frequent pulmonary exacerbations and declining lung function, which often accelerates during adolescence. New treatments target steps in the pathogenesis of lung disease, such as the basic defect in CF (CF Transmembrane Conductance Regulator [CFTR]), pulmonary infections, inflammation, and mucociliary clearance. These treatments offer hope but also present challenges to patients, clinicians, and researchers. Comprehensive assessment of efficacy is critical to identify potentially beneficial treatments. Lung function and pulmonary exacerbation are the most commonly used outcome measures in CF clinical research. Other outcome measures under investigation include measures of CFTR function; biomarkers of infection, inflammation, lung injury and repair; and patient-reported outcomes. Molecular diagnostics may help elucidate the complex CF airway microbiome. As new treatments are developed for patients with CF, efforts should be made to balance treatment burden with quality of life. This review highlights emerging treatments, obstacles to optimizing outcomes, and key future directions for research. PMID:19833563

  5. Blood Lead Level and Measured Glomerular Filtration Rate in Children with Chronic Kidney Disease

    PubMed Central

    Abraham, Alison G.; Navas-Acien, Ana; Guallar, Eliseo; Weaver, Virginia M.; Furth, Susan L.

    2013-01-01

    Background: The role of environmental exposure to lead as a risk factor for chronic kidney disease (CKD) and its progression remains controversial, and most studies have been limited by a lack of direct glomerular filtration rate (GFR) measurement. Objective: We evaluated the association between lead exposure and GFR in children with CKD. Methods: In this cross-sectional study, we examined the association between blood lead levels (BLLs) and GFR measured by the plasma disappearance of iohexol among 391 participants in the Chronic Kidney Disease in Children (CKiD) prospective cohort study. Results: Median BLL and GFR were 1.2 µg/dL and 44.4 mL/min per 1.73 m2, respectively. The average percent change in GFR for each 1-µg/dL increase in BLL was –2.1 (95% CI: –6.0, 1.8). In analyses stratified by CKD diagnosis, the association between BLL and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1-µg/dL increase in BLL was associated with a –12.1 (95% CI: –22.2, –1.9) percent change in GFR. In analyses stratified by anemia status, each 1-µg/dL increase in BLL among those with and without anemia was associated with a –0.3 (95% CI: –7.2, 6.6) and –4.6 (95% CI: –8.9, –0.3) percent change in GFR, respectively. Conclusions: There was no significant association between BLL and directly measured GFR in this relatively large cohort of children with CKD, although associations were observed in some subgroups. Longitudinal analyses are needed to examine the temporal relationship between lead and GFR decline, and to further examine the impact of underlying cause of CKD and anemia/hemoglobin status among patients with CKD. PMID:23694739

  6. Measuring midkine: the utility of midkine as a biomarker in cancer and other diseases

    PubMed Central

    Jones, D R

    2014-01-01

    Midkine (MK) is a pleiotropic growth factor prominently expressed during embryogenesis but down-regulated to neglible levels in healthy adults. Many published studies have demonstrated striking MK overexpression compared with healthy controls in various pathologies, including ischaemia, inflammation, autoimmunity and, most notably, in many cancers. MK expression is detectable in biopsies of diseased, but not healthy, tissues. Significantly, because it is a soluble cytokine, elevated MK is readily apparent in the blood and other body fluids such as urine and CSF, making MK a relatively convenient, accessible, non-invasive and inexpensive biomarker for population screening and early disease detection. The first diagnostic tests that quantify MK are just now receiving regulatory clearance and entering the clinic. This review examines the current state of knowledge pertaining to MK as a biomarker and highlights promising indications and clinical settings where measuring MK could make a difference to patient treatment. I also raise outstanding questions about reported variants of MK as well as MK's bio-distribution in vivo. Answering these questions in future studies will enhance our understanding of the significance of measured MK levels in both patients and healthy subjects, and may reveal further opportunities for measuring MK to diagnose disease. MK has already proven to be a biomarker that can significantly improve detection, management and treatment of cancer, and there is significant promise for developing further MK-based diagnostics in the future. Linked Article This article is part of a recent themed section on Midkine, published in volume 171 issue 4. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4 PMID:24460734

  7. Measurement of oral chronic graft-versus-host disease: results from the Chronic GVHD Consortium

    PubMed Central

    Treister, Nathaniel; Chai, Xiaoyu; Kurland, Brenda; Pavletic, Steve; Weisdorf, Daniel; Pidala, Joseph; Palmer, Jeanne; Martin, Paul; Inamoto, Yoshihiro; Arora, Mukta; Flowers, Mary; Jacobsohn, David; Jagasia, Madan; Arai, Sally; Lee, Stephanie J.; Cutler, Corey

    2014-01-01

    Oral chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the NIH criteria, and patients completed symptom and quality of life measures at each visit. Both rated change on an 8-point scale. Of 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4–5% for both groups (weighted kappa = 0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation. PMID:23353804

  8. Trapping volumetric measurement by multidetector CT in chronic obstructive pulmonary disease: Effect of CT threshold

    SciTech Connect

    Wang, Xiaohua; Yuan, Huishu; Duan, Jianghui; Du, Yipeng; Shen, Ning; He, Bei

    2013-08-15

    Purpose: The purpose of this study was to evaluate the effect of various computed tomography (CT) thresholds on trapping volumetric measurements by multidetector CT in chronic obstructive pulmonary disease (COPD).Methods: Twenty-three COPD patients were scanned with a 64-slice CT scanner in both the inspiratory and expiratory phase. CT thresholds of −950 Hu in inspiration and −950 to −890 Hu in expiration were used, after which trapping volumetric measurements were made using computer software. Trapping volume percentage (Vtrap%) under the different CT thresholds in the expiratory phase and below −950 Hu in the inspiratory phase was compared and correlated with lung function.Results: Mean Vtrap% was similar under −930 Hu in the expiratory phase and below −950 Hu in the inspiratory phase, being 13.18 ± 9.66 and 13.95 ± 6.72 (both lungs), respectively; this difference was not significant (P= 0.240). Vtrap% under −950 Hu in the inspiratory phase and below the −950 to −890 Hu threshold in the expiratory phase was moderately negatively correlated with the ratio of forced expiratory volume in one second to forced vital capacity and the measured value of forced expiratory volume in one second as a percentage of the predicted value.Conclusions: Trapping volumetric measurement with multidetector CT is a promising method for the quantification of COPD. It is important to know the effect of various CT thresholds on trapping volumetric measurements.

  9. Perceptions of coronary heart disease: the development and psychometric testing of a measurement scale.

    PubMed

    Chan, C W

    2014-01-01

    Individuals' perceptions of coronary heart disease (CHD) have implications for the ways in which they respond to the disease, process risks, make decisions, and take action to reduce CHD risks. This study aimed to develop and evaluate the psychometric properties of the perceptions of coronary heart disease scale (PCS) among a Hong Kong Chinese population. A cross-sectional study was conducted using a convenient sample (n = 232) of participants recruited from a variety of catchments including public domains, a cardiac unit, and a cardiac rehabilitation and prevention center. Exploratory factor analysis identified a nine-item, two-factor model that accounted for 52.5% of the total explained variance. The two factors were the perceived risk (five items) and perceived seriousness (four items) of CHD. The PCS demonstrated good content validity; acceptable total, and subscale internal consistency (.73, .61 - .81); and significant contrast-group differences with higher levels of CHD perceptions among males (p = .002), younger participants (p < .001), and those with higher educational levels (p < .001), suggesting excellent construct validity. The newly developed PCS demonstrates acceptable psychometric properties as a short measurement scale, which supports its use in future research. Future validation of this scale is warranted. PMID:23731251

  10. Entropy-based complexity measures for gait data of patients with Parkinson's disease.

    PubMed

    Afsar, Ozgur; Tirnakli, Ugur; Kurths, Juergen

    2016-02-01

    Shannon, Kullback-Leibler, and Klimontovich's renormalized entropies are applied as three different complexity measures on gait data of patients with Parkinson's disease (PD) and healthy control group. We show that the renormalized entropy of variability of total reaction force of gait is a very efficient tool to compare patients with respect to disease severity. Moreover, it is a good risk predictor such that the sensitivity, i.e., the percentage of patients with PD who are correctly identified as having PD, increases from 25% to 67% while the Hoehn-Yahr stage increases from 2.5 to 3.0 (this stage goes from 0 to 5 as the disease severity increases). The renormalized entropy method for stride time variability of gait is found to correctly identify patients with a sensitivity of 80%, while the Shannon entropy and the Kullback-Leibler relative entropy can do this with a sensitivity of only 26.7% and 13.3%, respectively. PMID:26931596

  11. The cost-benefit of biosecurity measures on infectious diseases in the Egyptian household poultry.

    PubMed

    Fasina, F O; Ali, A M; Yilma, J M; Thieme, O; Ankers, P

    2012-02-01

    Increased animal intensification presents with increasing risks of animal diseases. The Egyptian household poultry is peculiar in its management style and housing and this present with particular challenges of risk of infection to both the flock and humans. Biosecurity remains one of the most important means of reducing risks of infection in the household poultry, however not much information is available to support its feasibility at the household level of production. In this study financial feasibilities of biosecurity were modeled and evaluated based on certain production parameters. Risks of particular importance to the household poultry were categorized and highly pathogenic avian influenza H5N1 was the most risky disease while people-related risk was the most important risk category. It was observed that basic biosecurity measures were applicable in the household poultry and it would be 8.45 times better to implement biosecurity than to do nothing against HPAI H5N1; 4.88 times better against Newcastle disease and 1.49 times better against coccidiosis. Sensitivity analyses proved that the household poultry project was robust and would withstand various uncertainties. An uptake pathway for basic biosecurity was suggested. The outcome of this work should support decisions to implement biosecurity at the household sector of poultry production. PMID:21982688

  12. Continuous observation on heart-disease-model mice using biomagnetic measurement system

    NASA Astrophysics Data System (ADS)

    Kasai, Y.; Oikawa, T.; Saitoh, Y.; Ono, Y.; Ishiyama, A.; Kasai, N.; Odawara, A.; Chinone, K.

    2008-02-01

    Magnetocardiography (MCG) is a non-invasive method that can contribute to elucidating heart disease mechanisms and the verification of pharmacological effects. The object of our study is to show the potential of MCG for such study in mice. By using the developed MCG system, which adopts a single channel superconducting quantum interference device (SQUID) magnetometer with the spatial resolution of 500 μm, we continuously measured MCGs for 2 heart-disease-model mice with a high incidence of cardiac infarction from 7-weeks-old to death. An abnormal MCG appeared 1 or 2 weeks before death. The abnormal MCG changes indicate that the damaged place in the ventricles was different for each individual. In addition, we have developed a method to obtain MCGs for newborn mice in particular because they are small and frail. The MCGs of newborn mice were similar to those of adult mice. This study proved the potential of MCG for detecting abnormal cardiac excitation at the early stage of cardiac infarction and monitoring the progress of heart disease in detail from infancy to old age in mice.

  13. Modeling and Preventive Measures of Hand, Foot and Mouth Disease (HFMD) in China

    PubMed Central

    Li, Yong; Zhang, Jinhui; Zhang, Xinan

    2014-01-01

    This paper concentrates on the HFMD data of China from March 2009 to December 2012. We set up a mathematical model to fit those data with the goodness of fit and obtain the optimal parameter values of the model. By the Chi-square test of statistical inference, the optimal parameter values of the model are reasonable. We obtained the basic reproductive number of the disease for each year, and it is larger than 1. Thus, we conclude that HFMD will persist in China under the current conditions, so we investigate the preventive measures to control the HFMD. If the preventive measures proposed in our paper were implemented, HFMD would be controlled quickly and the number of infections would decline rapidly over a period of time. PMID:24633146

  14. Farmers’ Intentions to Implement Foot and Mouth Disease Control Measures in Ethiopia

    PubMed Central

    Jemberu, Wudu T.; Mourits, M. C. M.; Hogeveen, H.

    2015-01-01

    The objectives of this study were to explore farmers’ intentions to implement foot and mouth disease (FMD) control in Ethiopia, and to identify perceptions about the disease and its control measures that influence these intentions using the Health Belief Model (HBM) framework. Data were collected using questionnaires from 293 farmers in three different production systems. The influence of perceptions on the intentions to implement control measures were analyzed using binary logistic regression. The effect of socio-demographic and husbandry variables on perceptions that were found to significantly influence the intentions were analyzed using ordinal logistic regression. Almost all farmers (99%) intended to implement FMD vaccination free of charge. The majority of farmers in the pastoral (94%) and market oriented (92%) systems also had the intention to implement vaccination with charge but only 42% of the crop-livestock mixed farmers had the intention to do so. Only 2% of pastoral and 18% of crop-livestock mixed farmers had the intention to implement herd isolation and animal movement restriction continuously. These proportions increased to 11% for pastoral and 50% for crop-livestock mixed farmers when the measure is applied only during an outbreak. The majority of farmers in the market oriented system (>80%) had the intention to implement herd isolation and animal movement restriction measure, both continuously and during an outbreak. Among the HBM perception constructs, perceived barrier was found to be the only significant predictor of the intention to implement vaccination. Perceived susceptibility, perceived benefit and perceived barrier were the significant predictors of the intention for herd isolation and animal movement restriction measure. In turn, the predicting perceived barrier on vaccination control varied significantly with the production system and the age of farmers. The significant HBM perception predictors on herd isolation and animal movement

  15. Farmers' Intentions to Implement Foot and Mouth Disease Control Measures in Ethiopia.

    PubMed

    Jemberu, Wudu T; Mourits, M C M; Hogeveen, H

    2015-01-01

    The objectives of this study were to explore farmers' intentions to implement foot and mouth disease (FMD) control in Ethiopia, and to identify perceptions about the disease and its control measures that influence these intentions using the Health Belief Model (HBM) framework. Data were collected using questionnaires from 293 farmers in three different production systems. The influence of perceptions on the intentions to implement control measures were analyzed using binary logistic regression. The effect of socio-demographic and husbandry variables on perceptions that were found to significantly influence the intentions were analyzed using ordinal logistic regression. Almost all farmers (99%) intended to implement FMD vaccination free of charge. The majority of farmers in the pastoral (94%) and market oriented (92%) systems also had the intention to implement vaccination with charge but only 42% of the crop-livestock mixed farmers had the intention to do so. Only 2% of pastoral and 18% of crop-livestock mixed farmers had the intention to implement herd isolation and animal movement restriction continuously. These proportions increased to 11% for pastoral and 50% for crop-livestock mixed farmers when the measure is applied only during an outbreak. The majority of farmers in the market oriented system (>80%) had the intention to implement herd isolation and animal movement restriction measure, both continuously and during an outbreak. Among the HBM perception constructs, perceived barrier was found to be the only significant predictor of the intention to implement vaccination. Perceived susceptibility, perceived benefit and perceived barrier were the significant predictors of the intention for herd isolation and animal movement restriction measure. In turn, the predicting perceived barrier on vaccination control varied significantly with the production system and the age of farmers. The significant HBM perception predictors on herd isolation and animal movement

  16. SemFunSim: A New Method for Measuring Disease Similarity by Integrating Semantic and Gene Functional Association

    PubMed Central

    Ju, Peng; Peng, Jiajie; Wang, Yadong

    2014-01-01

    Background Measuring similarity between diseases plays an important role in disease-related molecular function research. Functional associations between disease-related genes and semantic associations between diseases are often used to identify pairs of similar diseases from different perspectives. Currently, it is still a challenge to exploit both of them to calculate disease similarity. Therefore, a new method (SemFunSim) that integrates semantic and functional association is proposed to address the issue. Methods SemFunSim is designed as follows. First of all, FunSim (Functional similarity) is proposed to calculate disease similarity using disease-related gene sets in a weighted network of human gene function. Next, SemSim (Semantic Similarity) is devised to calculate disease similarity using the relationship between two diseases from Disease Ontology. Finally, FunSim and SemSim are integrated to measure disease similarity. Results The high average AUC (area under the receiver operating characteristic curve) (96.37%) shows that SemFunSim achieves a high true positive rate and a low false positive rate. 79 of the top 100 pairs of similar diseases identified by SemFunSim are annotated in the Comparative Toxicogenomics Database (CTD) as being targeted by the same therapeutic compounds, while other methods we compared could identify 35 or less such pairs among the top 100. Moreover, when using our method on diseases without annotated compounds in CTD, we could confirm many of our predicted candidate compounds from literature. This indicates that SemFunSim is an effective method for drug repositioning. PMID:24932637

  17. Clinical, electrophysiological, and serum biochemical measures of progressive neurological and hepatic dysfunction in feline Niemann-Pick type C disease

    PubMed Central

    Vite, Charles H; Ding, Wenge; Bryan, Caroline; O’Donnell, Patricia; Cullen, Karyn; Aleman, David; Haskins, Mark E.; van Winkle, Thomas

    2011-01-01

    Niemann-Pick type C (NP-C) disease is a neurovisceral lysosomal storage disease characterized by neurological dysfunction, hepatosplenomegaly, and early death. Natural history studies are very difficult to perform due to the low incidence and high heterogeneity of disease in the human population. Sixteen cats with a spontaneously occurring missense mutation in NPC1 were evaluated over time to define the progression of neurological and hepatic disease. Affected cats had remarkably regular onsets of specific signs of cerebellar and vestibular system dysfunction with progressive severity of dysfunction quantified by post-rotatory nystagmus and brain stem auditory evoked response measures. NP-C disease cats also showed increasing serum activity of alanine aminotransferase, asparate aminotransferase, and cholesterol with advancing age. Affected cats lived to a mean age of 20.5 +/- 4.8 weeks. Central nervous system and hepatic lesions were similar to those described in human patients. These data are the first to document progressive hepatic disease in the feline model and demonstrate the importance of liver disease as part of the NP-C disease phenotype. Both neurological and hepatic measures of disease onset and severity can be used as a baseline with which to assess the efficacy of experimental therapies of NP-C disease in the feline model. PMID:18614965

  18. Exploring outcome measures for exercise intervention in people with Parkinson's disease.

    PubMed

    King, L A; Salarian, A; Mancini, M; Priest, K C; Nutt, J; Serdar, A; Wilhelm, J; Schlimgen, J; Smith, M; Horak, F B

    2013-01-01

    Background. It is widely believed that exercise improves mobility in people with Parkinson's disease (PD). However, it is difficult to determine whether a specific type of exercise is the most effective. The purpose of this study was to determine which outcome measures were sensitive to exercise intervention and to explore the effects of two different exercise programs for improving mobility in patients with PD. Methods. Participants were randomized into either the Agility Boot Camp (ABC) or treadmill training; 4x/week for 4 weeks. Outcome measures were grouped by the International Classification of Function/Disability (ICF). To determine the responsiveness to exercise, we calculated the standardized response means. t-tests were used to compare the relative benefits of each exercise program. Results. Four of five variables at the structure/function level changed after exercise: turn duration (P = 0.03), stride velocity (P = 0.001), peak arm speed (P = 0.001), and horizontal trunk ROM during gait (P = 0.02). Most measures improved similarly for both interventions. The only variable that detected a difference between groups was postural sway in ABC group (F = 4.95; P = 0.03). Conclusion. Outcome measures at ICF body structure/function level were most effective at detecting change after exercise and revealing differences in improvement between interventions. PMID:23738230

  19. Evaluation of risk and vulnerability using a Disease Flow Centrality measure in dynamic cattle trade networks.

    PubMed

    Natale, Fabrizio; Savini, Lara; Giovannini, Armando; Calistri, Paolo; Candeloro, Luca; Fiore, Gianluca

    2011-02-01

    A new method for the calculation of a centrality measure (Disease Flow Centrality, DFC), which takes into account temporal dynamics of livestock movement networks, is proposed. The method is based on a network traversal algorithm which represents an epidemic process more realistically compared with traditional graph traversal algorithms used in the calculation of centrality measures on static networks. The new approach was tested on networks generated from all the registered movements of cattle in Italy in the years 2007, 2008 and 2009 and the results were compared to those obtained by classical centrality measures. The results show that DFC values often differ substantially from those of other centrality measures and that these DFC values tend to be more unstable in time. The DFC offers several advantages for assessing risk and vulnerability of specific holdings and of an entire network, using recent movement data from national livestock databases. Some examples also indicate how the basic approach in the DFC calculation could be expanded into a more complex epidemic model by incorporating weights and how it could be combined with a geo-spatial perspective. PMID:21159393

  20. Automated Measurement of Heterogeneity in CT Images of Healthy and Diseased Rat Lungs using Variogram Analysis of an Octree Decomposition

    SciTech Connect

    Jacob, Rick E.; Carson, James P.

    2014-01-01

    Elastase dosed mice, whole lung and single lobe groups. Combines octree image decomposition with variogram-based analysis Results in promising novel approach for characterizing and measuring lung disease at different stages

  1. Use of computed tomography for measurement of kidneys in dogs without renal disease.

    PubMed

    Hoey, Seamus E; Heder, Brianne L; Hetzel, Scott J; Waller, Kenneth R

    2016-02-01

    OBJECTIVE To determine the size of the left and right kidneys by use of CT in dogs of various breeds without evidence of renal disease. DESIGN Retrospective, observational study. ANIMALS 21 client-owned dogs. PROCEDURES Renal length, diameter of the abdominal aorta, and length of the L2 vertebral body were measured independently on multiplanar reformatted non-contrast-enhanced CT images by 3 observers at 3 time points. Intraobserver and interobserver agreement for renal length were determined. Associations of renal length with body weight, aorta diameter, and L2 vertebral body length were assessed by calculation of Pearson correlation coefficients and 95% confidence intervals. Renal measurements were normalized to patient size by calculating renal length-to-aorta diameter and renal length-to-L2 vertebral body length ratios for comparison with previously published radiographic and ultrasonographic measurements. RESULTS All kidneys were identified and measured on CT images by all observers. Intraobserver and interobserver agreement were excellent. Body weight, aorta diameter, and length of the L2 vertebral body were significantly correlated with renal length. Renal length-to-aorta diameter and renal length-to-L2 vertebral body length ratios (7.4 and 2.7, respectively) fell within the ranges of previously published values for these measurements. CONCLUSIONS AND CLINICAL RELEVANCE As CT becomes more widely available in general practice, knowledge of typical renal measurements and anatomic ratios obtained with this modality in dogs may be useful. A prospective study with a larger population of dogs, ideally including formulation of a reference range, is needed. PMID:26799106

  2. Unilateral Subthalamic Nucleus Stimulation Has a Measurable Ipsilateral Effect on Rigidity And Bradykinesia in Parkinson Disease

    PubMed Central

    Tabbal, Samer D.; Ushe, Mwiza; Mink, Jonathan W.; Revilla, Fredy J.; Wernle, Angie R.; Hong, Minna; Karimi, Morvarid; Perlmutter, Joel S.

    2008-01-01

    Background Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function in Parkinson disease (PD). However, little is known about the quantitative effects on motor behavior of unilateral STN DBS. Methods In 52 PD subjects with STN DBS, we quantified in a double-blinded manner rigidity (n= 42), bradykinesia (n= 38), and gait speed (n= 45). Subjects were tested in four DBS conditions: both on, left on, right on and both off. A force transducer was used to measure rigidity across the elbow, and gyroscopes were used to measure angular velocity of hand rotations for bradykinesia. About half of the subjects were rated using the Unified Parkinson Disease Rating Scale (part III) motor scores for arm rigidity and repetitive hand rotation simultaneously during the kinematic measurements. Subjects were timed walking 25 feet. Results All subjects had significant improvement with bilateral STN DBS. Contralateral, ipsilateral and bilateral stimulation significantly reduced rigidity and bradykinesia. Bilateral stimulation improved rigidity more than unilateral stimulation of either side, but there was no significant difference between ipsilateral and contralateral stimulation. Although bilateral stimulation also increased hand rotation velocity more than unilateral stimulation of either side, contralateral stimulation increased hand rotation significantly more than ipsilateral stimulation. All stimulation conditions improved walking time but bilateral stimulation provided the greatest improvement. Conclusions Unilateral STN DBS decreased rigidity and bradykinesia contralaterally as well ipsilaterally. As expected, bilateral DBS improved gait more than unilateral DBS. These findings suggest that unilateral STN DBS alters pathways that affect rigidity and bradykinesia bilaterally but do not support the clinical use of unilateral STN DBS since bilateral DBS clearly provides greater benefit. PMID:18329019

  3. Concordance and Discriminatory Power of Cough Measurement Devices for Individuals With Parkinson Disease

    PubMed Central

    Carnaby-Mann, Giselle; Pitts, Teresa; Davenport, Paul; Okun, Michael S.; Sapienza, Christine

    2014-01-01

    Background: Dysphagia and aspiration pneumonia are two causes of morbidity in Parkinson disease (PD). In PD, impaired airway clearance can lead to penetration of foreign material, resulting in a high prevalence of aspiration pneumonia and death. This study examines three different devices for measurement of peak airflow during voluntary cough in healthy control subjects and those with PD. Two simple and low-cost devices for measuring peak cough airflow were compared with the “gold standard” pneumotachograph. Methods: Thirty-five healthy control subjects and 35 individuals with PD produced voluntary cough at three perceived strengths (weak, moderate, and strong cough) for each of the three devices. Results: A significant difference in mean peak cough airflow was demonstrated for disease (F[1,56] = 4.0, P < .05) and sex (F[1,56] = 9.59, P < .003) across devices. The digital and analog meters were comparable to the gold standard demonstrating no significant difference (statistical) by device (digital vs analog) in receiver operating characteristic curve analysis. Both devices were discriminative of the presence of PD. Conclusions: The analog and digital peak airflow meters are suitable alternatives to the gold standard pneumotachograph due to their low cost, portability, ease of use, and high sensitivity relative to normative peak cough airflows. Voluntary cough airflow measures may serve as a noninvasive means of screening for aspiration risk in target populations. Additionally, quantification of cough strength through use of predetermined limens for weak, moderate, and strong cough may assist clinicians in better describing and tracking cough strength as a contributing factor to aspiration risk. PMID:24264124

  4. Anthropometric measurements and periodontal diseases in children and adolescents: a systematic review and meta-analysis.

    PubMed

    Li, Ling-Wei; Wong, Hai Ming; Sun, Ling; Wen, Yi Feng; McGrath, Colman P

    2015-11-01

    The aim of this systematic review was to identify and summarize evidence of the association between anthropometric measurements and periodontal status in children and adolescents. We searched PubMed, Institute for Scientific Information Web of Knowledge, Cochrane Library, and 7 additional databases, following the guidance of Preferred Reporting Items for Systematic Reviews and Meta-Analyses, up to December 2014. Observational studies reporting data on the association between anthropometric measurements and periodontal diseases in 2-18-y-old participants were included. An initial search identified 4191 papers; 278 potentially effective studies (k = 0.82) and 16 effective studies (k = 0.83) were included after screening. The mean quality of evidence among the studies was 20.3, according to the Strengthening the Reporting of Observational studies in Epidemiology checklist (k = 0.79). Meta-analyses showed that obesity (measured by body mass index) was significantly associated with visible plaque index (OR: 4.75; 95% CI: 2.42, 9.34), bleeding on probing (OR: 5.41; 95% CI: 2.75, 10.63), subgingival calculus (OR: 3.07; 95% CI: 1.10, 8.62), probing depth (OR: 14.15; 95% CI: 5.10, 39.25) and flow rate of salivary secretion (standardized mean difference: -0.89; 95% CI: -1.18, -0.61). However, various results were reported in the effective studies that were not included in meta-analyses. In conclusion, obesity is associated with some signs of periodontal disease in children and adolescents. Further studies with a comprehensive prospective cohort design and more potential variables are recommended. PMID:26567204

  5. 14-3-3β protein expression in eosinophilic meningitis caused by Angiostrongylus cantonensis infection

    PubMed Central

    2014-01-01

    Background Angiostrongylus cantonensis is a parasite endemic in the Southeast Asian and Pacific regions. Humans are incidentally infected either by eating uncooked intermediate hosts or by consuming vegetables containing the living third-stage larvae. The 14-3-3β protein is a cerebrospinal fluid (CSF) marker of neuronal damage during the development of Creutzfeldt-Jakob disease. In addition, increased 14-3-3β protein is also found in CSF from patients with a variety of neurological disorders. The goal of this study is to determine the roles of serum/CSF14-3-3β protein in patients with eosinophilic meningitis. Methods In a cohort study among nine Thai laborers with eosinophilic meningitis due to eating raw snails (Pomacea canaliculata), we examined the CSF weekly while patients were still hospitalized and followed up the serum for 6 months. The levels of 14-3-3β protein in CSF were analyzed by western blot and an in-house 14-3-3β enzyme-linked immunosorbent assay (ELISA) measurement was established and tested in an animal model of eosinophilic meningitis. Results The elevated 14-3-3β level was detected in the CSF from eight out of nine (81%) patients After 2 weeks of treatment, all patients showed a declined level or cleared of 14-3-3β protein in the CSF. By developing an in-house ELISA for measurement of 14-3-3β protein, it was found that the serum 14-3-3β level was significantly increased in patients during initial visit. . This finding was consistent to the animal experiment result in which there was severe blood brain barrier damage three weeks after infection and increased 14-3-3β protein expression in the CSF and serum by western blot and in house ELISA. After treatment, the serum 14-3-3β level in meningitis patients was rapidly returned to normal threshold. There was a correlation between initial CSF 14-3-3β level with severity of headache (r = 0.692, p = 0.039), CSF pleocytosis (r = 0.807, p = 0.009) and eosinophilia (r = 0

  6. CSF beta-amyloid 1–42 – what are we measuring in Alzheimer's disease?

    PubMed Central

    Hu, William T; Watts, Kelly D; Shaw, Leslie M; Howell, Jennifer C; Trojanowski, John Q; Basra, Sundeep; Glass, Jonathan D; Lah, James J; Levey, Allan I

    2015-01-01

    Objective To characterize biological and technical factors which influence cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, including the presence of apolipoprotein E (APOE) ε4 allele, AD diagnosis, Aβ-binding proteins, sample processing, and preanalytical handling. Methods CSF was collected from 140 subjects with normal cognition, mild cognitive impairment, AD, and non-AD dementia. CSF levels of beta-amyloid 1–42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) were analyzed following the standard and modified protocols. CSF levels of apoJ, apoE, albumin, and α-synuclein were measured in a subgroup (n = 69), and their effects on measured AD biomarker levels were also determined in vitro using human CSF samples. Results CSF Aβ42 levels measured using the AD Neuro-imaging Initiative (ADNI) protocol (which we call suspended Aβ42 or susAβ) were lower than total measurable CSF Aβ42 in all groups, and on average represents 57% of the latter. Logistic regression analysis showed this proportion (% susAβ) to be directly correlated with CSF Aβ42 and apoJ levels, but inversely correlated with CSF t-Tau levels. Finally, we showed in vitro that increasing apoE and apoJ levels directly increased % susAβ. Conclusion CSF susAβ levels are influenced by biological and technical factors, and may represent a marker of Aβ susceptible to lipoprotein-mediated clearance. Clinical trials should include total measurable Aβ42 and susAβ to better inform outcomes. PMID:25750918

  7. Implementing organizational systems to measure outcome-related processes of end-stage renal disease care.

    PubMed

    Capelli, J P

    1994-08-01

    The process to implement a continuous quality improvement program for the patient with end-stage renal disease requires a basic understanding of the complex medical and often psychological circumstances that affect these patients. The organizational elements require, therefore, a recognition and integration of functions from all those involved in delivering care. This includes the medical, nursing, social work, dietary, and technical staff. In the development and establishment of the quality assessment and improvement program at Our Lady of Lourdes Medical Center, experience has identified certain basic elements to use in the organizational and functional aspects of the system to achieve a measurable level of success. The primary element in establishing such a program begins with the commitment at the highest level of the organizational structure. Selection of leadership whose responsibility is to provide education and direction of staff participants should follow. Through leadership, education, and early staff involvement, physician support is gained that provides the operational elements for a successful program. A multidisciplinary team, representative of the various aspects of care, can then develop a quality assessment and improvement plan that establishes clinical indicators used to measure various quality components. A data collection and review process is the next phase of implementation of the organizational system to measure the various types of outcome and/or processes of care. The process is one of continued education based on outcome data for all staff members involved in care. PMID:8048443

  8. Diagnostic Value of Measuring Platelet Von Willebrand Factor in Von Willebrand Disease

    PubMed Central

    Casonato, Alessandra; Cattini, Maria Grazia; Daidone, Viviana; Pontara, Elena; Bertomoro, Antonella; Prandoni, Paolo

    2016-01-01

    Von Willebrand disease (VWD) may be caused by an impaired von Willebrand factor (VWF) synthesis, its increased clearance or abnormal function, or combinations of these factors. It may be difficult to recognize the different contributions of these anomalies. Here we demonstrate that VWD diagnostics gains from measuring platelet VWF, which can reveal a defective VWF synthesis. Measuring platelet VWF revealed that: severe type 1 VWD always coincided with significantly lower platelet and plasma VWF levels, whereas mild forms revealed low plasma VWF levels associated with low or normal platelet VWF levels, and the latter were associated with a slightly shorter VWF survival; type Vicenza (the archetype VWD caused by a reduced VWF survival) featured normal platelet VWF levels despite significantly reduced plasma VWF levels; type 2B patients could have either normal platelet VWF levels associated with abnormal multimer patterns, or reduced platelet VWF levels associated with normal multimer patterns; type 2A patients could have reduced or normal platelet VWF levels, the former associated mainly with type 2A-I, the latter with type 2A-II; plasma and platelet VWF levels were normal in type 2N, except when the defect was associated with a quantitative VWF mutation. Our findings show that measuring platelet VWF helps to characterize VWD, especially the ambiguous phenotypes, shedding light on the mechanisms underlying the disorder. PMID:27532107

  9. Visual associations cued recall A Paradigm for Measuring Episodic Memory Decline in Alzheimer's Disease.

    PubMed

    Meyer, Sascha R A; Spaan, Pauline E J; Boelaarts, Leo; Ponds, Rudolf W H M; Schmand, Ben; de Jonghe, Jos F M

    2016-09-01

    Repeated measurements of episodic memory are needed for monitoring amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD). Most episodic memory tests may pose a challenge to patients, even when they are in the milder stages of the disease. This cross-sectional study compared floor effects of the Visual Association Test (VAT) and the Rey Auditory Verbal Learning Test (RAVLT) in healthy elderly controls and in patients with aMCI or AD (N = 125). A hierarchical multiple regression analysis was used to examine whether linear or quadratic trends best fitted the data of cognitive test performance across global cognitive impairment. Results showed that VAT total scores decreased linearly across the range of global cognitive impairment, whereas RAVLT total scores showed a quadratic trend, with total scores levelling off for 90% of aMCI patients and 94% of AD patients. We conclude that the VAT shows few if any floor effects in patients with aMCI and mild AD and is therefore a potentially promising cognitive test for monitoring episodic memory impairment. PMID:26853620

  10. Comparing Supervised Exercise Therapy to Invasive Measures in the Management of Symptomatic Peripheral Arterial Disease

    PubMed Central

    Aherne, Thomas; McHugh, Seamus; Kheirelseid, Elrasheid A.; Lee, Michael J.; McCaffrey, Noel; Moneley, Daragh; Leahy, Austin L.; Naughton, Peter

    2015-01-01

    Peripheral arterial disease (PAD) is associated with considerable morbidity and mortality. Consensus rightly demands the incorporation of supervised exercise training (SET) into PAD treatment protocols. However, the exact role of SET particularly its relationship with intervention requires further clarification. While supervised exercise is undoubtedly an excellent tool in the conservative management of mild PAD its use in more advanced disease as an adjunct to open or endovascular intervention is not clearly defined. Indeed its use in isolation in this cohort is incompletely reported. The aim of this review is to clarify the exact role of SET in the management of symptomatic PAD and in particular to assess its role in comparison with or as an adjunct to invasive intervention. A systematic literature search revealed a total 11 randomised studies inclusive of 969 patients. All studies compared SET and intervention with monotherapy. Study results suggest that exercise is a complication-free treatment. Furthermore, it appears to offer significant improvements in patients walk distances with a combination of both SET and intervention offering a superior walking outcome to monotherapy in those requiring invasive measures. PMID:26601122

  11. Measuring root disease suppression in response to a compost water extract.

    PubMed

    Curlango-Rivera, Gilberto; Pew, Tom; VanEtten, Hans D; Zhongguo, Xiong; Yu, Naitong; Hawes, Martha C

    2013-03-01

    Commercial application of compost to prevent plant disease is hindered by variable performance. Here, we describe the use of a growth pouch assay to measure impact of a compost water extract (CWE) on root infection under controlled conditions. Most pea roots (≥95%) inoculated with Fusarium solani or Phoma pinodella spores rapidly develop a single local lesion in the region of elongation. In the presence of CWE, infection of pea roots grown in pouches was reduced by 93 to 100%. CWE used as a drench on pea seedlings grown in sand also resulted in 100% protection but, in a heavy clay soil, infection was reduced by <50%. CWE filtered to remove microorganisms did not inhibit frequency of F. solani infection, and resulted in increased local lesion development on individual roots. CWE inhibited mycelial growth of both pea- and cucumber-infecting isolates of F. solani in culture but exerted <40% protection against cucumber root infection. CWE treatment of pea but not cucumber was associated with retention of a sheath of border cells interspersed with bacteria covering the region of elongation. Growth pouch assays may provide a system to monitor effects of specific compost mixtures on root-rhizosphere interactions, and to identify variables influencing disease control. PMID:23402629

  12. A measure of quality of life for clinical trials in chronic lung disease.

    PubMed

    Guyatt, G H; Berman, L B; Townsend, M; Pugsley, S O; Chambers, L W

    1987-10-01

    Since the relationships between pulmonary function, exercise capacity, and functional state or quality of life are generally weak, a self report questionnaire has been developed to determine the effect of treatment on quality of life in clinical trials. One hundred patients with chronic airflow limitation were asked how their quality of life was affected by their illness, and how important their symptoms and limitations were. The most frequent and important items were used to construct a questionnaire evaluating four dimensions: dyspnoea, fatigue, emotional function, and the patient's feeling of control over the disease (mastery). Reproducibility, tested by repeated administration to patients in a stable condition, was excellent: the coefficient of variation was less than 12% for all four dimensions. Responsiveness (sensitivity to change) was tested by administering the questionnaire to 13 patients before and after optimisation of their drug treatment and to another 28 before and after participation in a respiratory rehabilitation programme. In both cases large, statistically significant improvements in all four dimensions were noted. Changes in questionnaire score were correlated with changes in spirometric values, exercise capacity, and patients' and physicians' global ratings. Thus it has been shown that the questionnaire is precise, valid, and responsive. It can therefore serve as a useful disease specific measure of quality of life for clinical trials. PMID:3321537

  13. 28 CFR 549.15 - Infectious disease training and preventive measures.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Infectious disease training and... INSTITUTIONAL MANAGEMENT MEDICAL SERVICES Infectious Disease Management § 549.15 Infectious disease training and..., incorporating a question-and-answer session, about infectious diseases to all newly committed inmates,...

  14. 28 CFR 549.15 - Infectious disease training and preventive measures.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Infectious disease training and... INSTITUTIONAL MANAGEMENT MEDICAL SERVICES Infectious Disease Management § 549.15 Infectious disease training and..., incorporating a question-and-answer session, about infectious diseases to all newly committed inmates,...

  15. 28 CFR 549.15 - Infectious disease training and preventive measures.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Infectious disease training and... INSTITUTIONAL MANAGEMENT MEDICAL SERVICES Infectious Disease Management § 549.15 Infectious disease training and..., incorporating a question-and-answer session, about infectious diseases to all newly committed inmates,...

  16. 28 CFR 549.15 - Infectious disease training and preventive measures.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Infectious disease training and... INSTITUTIONAL MANAGEMENT MEDICAL SERVICES Infectious Disease Management § 549.15 Infectious disease training and..., incorporating a question-and-answer session, about infectious diseases to all newly committed inmates,...

  17. Economic Theory and Self-Reported Measures of Presenteeism in Musculoskeletal Disease.

    PubMed

    Jones, Cheryl; Payne, Katherine; Gannon, Brenda; Verstappen, Suzanne

    2016-08-01

    This study had two objectives: to describe the historical development of self-reported presenteeism instruments that can be used to identify and measure presenteeism as a result of musculoskeletal disease (MSD) and to identify if, and how many of these, presenteeism instruments are underpinned by economic theory. Systematic search methods were applied to identify self-report instruments used to quantify presenteeism caused by MSD. A total of 24 self-reported presenteeism instruments were identified; 24 were designed for use in general health, and 1 was specifically designed for use in rheumatoid arthritis. One generic self-reported presenteeism instrument was explicitly reported to be underpinned by economic theory. Overtime, self-reported presenteeism instruments have become more differentiated and complex by incorporating many different contextual factors that may impact levels of presenteeism. Researchers are encouraged to further develop presenteeism instruments that are underpinned by relevant economic theory and informed by robust empirical research. PMID:27402110

  18. Application of mobile computers in a measuring system supporting examination of posture diseases

    NASA Astrophysics Data System (ADS)

    Piekarski, Jacek; Klimiec, Ewa; Zaraska, Wiesław

    2013-07-01

    Measuring system designed and manufactured by the authors and based on mobile computers (smartphones and tablets) working as data recorders has been invented to support diagnosis of orthopedic, especially feet, diseases. The basic idea is to examine a patient in his natural environment, during the usual activities (such as walking or running). The paper describes the proposed system with sensors manufactured from piezoelectric film (PVDF film) and placed in the shoe insole. The mechanical reliability of PVDF film is excellent, though elimination of the pyroelectric effect is required. A possible solution of the problem and the test results are presented in the paper. Data recording is based on wireless transmission to a mobile device used as a data logger.

  19. Brain energy metabolism and dopaminergic function in Huntington's disease measured in vivo using positron emission tomography

    SciTech Connect

    Leenders, K.L.; Frackowiak, R.S.; Quinn, N.; Marsden, C.D.

    1986-01-01

    A 48-year-old man with typical Huntington's disease was investigated with computed tomography (CT) and positron emission tomography. Regional cerebral blood flow, oxygen extraction, oxygen and glucose utilization, L-Dopa uptake, and dopamine (D2) receptor binding were measured using several positron-labelled tracers. CT showed slight atrophy of the head of caudate but no cortical atrophy, although distinct frontal lobe dysfunction was present on psychometric testing. Oxygen and glucose metabolism and cerebral blood flow were decreased in the striata and to a lesser extent in frontal cortex. Cerebral blood flow was in the low normal range throughout the remainder of the brain. A normal metabolic ratio was found in all regions, since the changes in glucose utilization paralleled those in oxygen consumption. The capacity of the striatum to store dopamine as assessed by L-( YF)-fluorodopa uptake was normal, but dopamine (D2) receptor binding was decreased when compared to normal subjects.

  20. A comparison of two brief screening measures of cognitive impairment in Huntington's disease.

    PubMed

    Mickes, Laura; Jacobson, Mark; Peavy, Guerry; Wixted, John T; Lessig, Stephanie; Goldstein, Jody L; Corey-Bloom, Jody

    2010-10-15

    The goal of this study was to explore whether the Montreal Cognitive Assessment (MoCA), a new screening instrument, would be more sensitive to mild to moderate cognitive impairment in Huntington's disease (HD) than an established screening measure, the Mini Mental State Exam (MMSE). Our reasoning for this query is that the MoCA includes a broader range of test items and an additional assessment of executive functioning and attention compared with the MMSE. Using the receiver operating characteristic (ROC) analysis to examine performance of HD and control groups on both tests on overall scores and scores from various subdomains (i.e., visuospatial abilities) revealed that the MoCA achieved higher sensitivity without sacrificing specificity in many domains relative to the MMSE. PMID:20721924

  1. Gluten measurement and its relationship to food toxicity for celiac disease patients

    PubMed Central

    Lester, Diane R

    2008-01-01

    The gluten analysis of foods has long had limitations, which have precluded food standards authorities from issuing standards for gluten-free foods based on final gluten content. The Codex Alimentarius and the Food and Drug Administration have taken steps towards such standards in which they favour the R5-enzyme-linked immunosorbent assay for gluten analysis. If this method is to be widely employed, its limitations should be recognised. Above all, it should be noted the ability of R5-enzyme-linked immunosorbent assay, and other methods, to measure gluten's toxicity toward celiac disease patients is not validated clinically. Gluten is a complex mixture of proteins and its toxicity is not fully understood. Analytical methods are a valuable tool in the definition of gluten-free foods, but they should be employed with appropriate caveats in ensuring the safety of the foods. PMID:18957072

  2. Review of outcome measurement instruments in Alzheimer's disease drug trials: introduction.

    PubMed

    Demers, L; Oremus, M; Perrault, A; Wolfson, C

    2000-01-01

    This article introduces a four-part series on outcome scales used in Alzheimer's disease drug trials. First, it discusses the division of scales into four domains: cognition, functional ability/quality of life, behavior/mood, and global. Within each domain, the shortcomings of existing literature reviews are outlined, and the need for a more coherent view of the psychometric properties of the scales is emphasized. Second, the key concepts of reliability, validity, and responsiveness to change are defined and explained. This explanation also provides an overview of the statistical techniques used to assess measurement properties. Finally, the methods used to select the scales for review in the subsequent articles are explained, and each article is briefly introduced. PMID:11128056

  3. Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging.

    PubMed

    van de Haar, Harm J; Jansen, Jacobus F A; van Osch, Matthias J P; van Buchem, Mark A; Muller, Majon; Wong, Sau May; Hofman, Paul A M; Burgmans, Saartje; Verhey, Frans R J; Backes, Walter H

    2016-09-01

    The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimer's Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD. PMID:27459939

  4. Cowden disease: gene marker studies and measurements of epidermal growth factor.

    PubMed Central

    Carlson, H E; Burns, T W; Davenport, S L; Luger, A M; Spence, M A; Sparkes, R S; Orth, D N

    1986-01-01

    Cowden disease (CD) is a familial syndrome characterized by tumors of the skin, oral mucosa, breast, thyroid, and intestinal epithelium. Since the syndrome is inherited as an autosomal dominant, we examined a battery of gene markers in a family with CD to detect linkage between the CD gene and known marker genes. There was no positive evidence for linkage of a CD locus with any of the markers; other investigators can add to our data to confirm and extend these findings. Additionally, we measured epidermal growth factor (EGF) in body fluids from CD patients and controls to determine if elevated EGF levels might be responsible for the widespread epithelial proliferation in CD. EGF levels in saliva, serum, plasma, and urine were similar in CD patients and control subjects. Although alterations in growth factors or their receptors may play a role in CD, excess circulating EGF is not responsible for the manifestations of the syndrome. Images Fig. 2 PMID:3487976

  5. OroSTIFF: Face-referenced measurement of perioral stiffness in health and disease

    PubMed Central

    Chu, Shin-Ying; Kieweg, Douglas; Lee, Jaehoon

    2010-01-01

    A new device and automated measurement technology known as OroSTIFF is described to characterize non-participatory perioral stiffness in healthy adults for eventual application to patients with orofacial movement disorders associated with neuromotor disease, traumatic injury, or congenital clefts of the upper lip. Previous studies of perioral biomechanics required head stabilization for extended periods of time during measurement which precluded sampling patients with involuntary body/head movements (dyskinesias), or pediatric subjects. The OroSTIFF device is face-referenced and avoids the complications associated with head-restraint. Supporting data of non-participatory perioral tissue stiffness using OroSTIFF are included from 10 male and 10 female healthy subjects. The OroSTIFF device incorporates a pneumatic glass air cylinder actuator instrumented for pressure, and an integrated subminiature displacement sensor to encode lip aperture. Perioral electromyograms were simultaneously sampled to confirm passive muscle state for the superior and inferior divisions of the orbicularis oris muscles. Perioral stiffness, derived as a quotient from resultant force (ΔF) and interangle span (ΔX), was modeled with multilevel regression techniques. Real-time calculation of the perioral stiffness function demonstrated a significant quadratic relation between imposed interangle stretch and resultant force. This stiffness growth function also differed significantly between males and females. This study demonstrates the OroSTIFF ‘proof-of-concept’ for cost-effective non-invasive stimulus generation and derivation of perioral stiffness in a group of healthy unrestrained adults, and a case study to illustrate the dose-dependent effects of Levodopa on perioral stiffness in an individual with advanced Parkinson’s disease who exhibited marked dyskinesia and rigidity. PMID:20185131

  6. Can FreeSurfer Compete with Manual Volumetric Measurements in Alzheimer's Disease?

    PubMed

    Clerx, Lies; Gronenschild, Ed H B M; Echavarri, Carmen; Verhey, Frans; Aalten, Pauline; Jacobs, Heidi I L

    2015-01-01

    Alzheimer's disease-related pathology results in tremendous structural and functional changes in the brain. These morphological changes might lead to a less precise performance of automated brain segmentation techniques in AD-patients, which in turn could possibly lead to false allocations of gray matter, white matter or cerebrospinal fluid. FreeSurfer has been shown to operate as an accurate and reliable instrument to measure cortical thickness and volume of neuroanatomical structures. Considering the principal role of FreeSurfer in the imaging field of AD, the present study aims to investigate the robustness of FreeSurfer to capture morphological changes in the brain against varying processing variables in comparison to manual measurements (the gold standard). T1-weighted MRI scan data were used pertaining to a sample of 53 individuals (18 healthy participants, 18 patients with mild cognitive impairment, and 18 patients with mild AD). Data were analyzed with different FreeSurfer versions (v4.3.1, v4.5.0, v5.0.0, v5.1.0), on a custom-built cluster (LINUX) and a Macintosh (UNIX) workstation. Group differences across versions and workstations were most consistent for both the hippocampus and posterior cingulate, regions known to be affected in the earliest stages of the disease. The results showed that later versions of FreeSurfer were more sensitive to identify group differences and corresponded best with the results of gold standard manual volumetric methods. In conclusion, later versions of FreeSurfer were more accurate than earlier versions, especially in medial temporal and posterior parietal regions. This development is very promising for future applications of FreeSurfer in research studies and encourages the future role of FreeSurfer output as a candidate marker in clinical practice. PMID:25817249

  7. Removal of Transmissible Spongiform Encephalopathy Prion from Large Volumes of Cell Culture Media Supplemented with Fetal Bovine Serum by Using Hollow Fiber Anion-Exchange Membrane Chromatography

    PubMed Central

    Chou, Ming Li; Bailey, Andy; Avory, Tiffany; Tanimoto, Junji; Burnouf, Thierry

    2015-01-01

    Cases of variant Creutzfeldt-Jakob disease in people who had consumed contaminated meat products from cattle with bovine spongiform encephalopathy emphasize the need for measures aimed at preventing the transmission of the pathogenic prion protein (PrPSc) from materials derived from cattle. Highly stringent scrutiny is required for fetal bovine serum (FBS), a growth-medium supplement used in the production of parenteral vaccines and therapeutic recombinant proteins and in the ex vivo expansion of stem cells for transplantation. One such approach is the implementation of manufacturing steps dedicated to removing PrPSc from materials containing FBS. We evaluated the use of the QyuSpeed D (QSD) adsorbent hollow-fiber anion-exchange chromatographic column (Asahi Kasei Medical, Tokyo, Japan) for the removal of PrPSc from cell culture media supplemented with FBS. We first established that QSD filtration had no adverse effect on the chemical composition of various types of culture media supplemented with 10% FBS or the growth and viability characteristics of human embryonic kidney (HEK293) cells, baby hamster kidney (BHK-21) cells, African green monkey kidney (Vero) cells, and Chinese hamster ovary (CHO-k1) cells propagated in the various culture-medium filtrates. We used a 0.6-mL QSD column for removing PrPSc from up to 1000 mL of Dulbecco’s modified Eagle’s medium containing 10% FBS previously spiked with the 263K strain of hamster-adapted scrapie. The Western blot analysis, validated alongside an infectivity assay, revealed that the level of PrPSc in the initial 200mL flow-through was reduced by 2.5 to > 3 log10, compared with that of the starting material. These results indicate that QSD filtration removes PrPSc from cell culture media containing 10% FBS, and demonstrate the ease with which QSD filtration can be implemented in at industrial-scale to improve the safety of vaccines, therapeutic recombinant proteins, and ex vivo expanded stem cells produced using

  8. Use of the Hayling Task to Measure Inhibition of Prepotent Responses in Normal Aging and Alzheimer's Disease

    ERIC Educational Resources Information Center

    Belleville, Sylvie; Rouleau, Nancie; Van der Linden, Martial

    2006-01-01

    This study measures the effect of Alzheimer's disease (AD) and normal aging on the inhibition of prepotent responses. AD patients, normal aged controls, and young subjects were tested with the Hayling task, which measures the ability to inhibit a semantically constrained response, and with the Stroop procedure. AD patients showed a severe deficit…

  9. Periodontal disease activity: a development strategy for its investigation by means of accurate 3-dimensional clinical measurement.

    PubMed

    Watts, T L; Beards, C f; Ewing, P D; Leeman, S

    1995-03-01

    The central problem in all previous approaches to clinical assessment of periodontal disease activity is the use of unidimensional measurement, which implies a number of unjustifiable assumptions. In addition, the use of unidimensional probing measurement has established that there are several distinct problems of validity and reliability in currently available techniques. The present paper begins with an analysis of these matters, leading to an approach to accurate clinical measurement of periodontitis in 3 dimensions, with the possibility of future development of a valid system for assessing the nature of disease activity. PMID:7790525

  10. A Prospective Cohort Study of Periodontal Disease Measures and Cardiovascular Disease Markers in HIV-Infected Adults

    PubMed Central

    Babineau, Denise C.; Demko, Catherine A.; Lederman, Michael M.; Wang, Xuelei; Toossi, Zahra; Weinberg, Aaron; Rodriguez, Benigno

    2011-01-01

    Abstract The determinants of HIV-associated cardiovascular disease (CVD) are not well understood. Periodontal disease (PD) has been linked to CVD but this connection has not been examined in HIV infection. We followed a cohort of HIV-infected adults to ascertain whether PD was associated with carotid artery intima media thickness (IMT) and brachial artery flow-mediated dilation (FMD). We performed a longitudinal observational study of HIV-infected adults on HAART for <2 years with no known heart disease. PD was characterized clinically and microbiologically. Cardiovascular disease was assessed by IMT/FMD. Linear mixed models assessed cross-sectional and longitudinal associations between PD and FMD/IMT. Forty three HIV+ adults completed a median of 24 (6–44) months on the study. Defining delta to be the change in a variable between baseline and a follow-up time, longitudinally, on average and after adjusting for change in time, CVD-specific and HIV-specific potential confounding covariates, a 1-log10 increase in delta Porphyromonas gingivalis was associated with a 0.013 mm increase in delta IMT (95% CI: 0.0006–0.0262; p=0.04). After adjusting for the same potential confounding covariates, a 10% increase in delta gingival recession was associated with a 2.3% increase in delta FMD (95% CI: 0.4–4.2; p=0.03). In a cohort of HIV-infected adults, an increase in subgingival Porphyromonas gingivalis, a known periodontal pathogen, was significantly associated with longitudinal increases in IMT, while increased gingival recession, which herein may represent PD resolution, was significantly associated with longitudinal improvement in FMD. In the context of HIV infection, PD may contribute to CVD risk. Intervention studies treating PD may help clarify this association. PMID:21443451

  11. Mixed model of repeated measures versus slope models in Alzheimer's disease clinical trials.

    PubMed

    Donohue, M C; Aisen, P S

    2012-04-01

    Randomized clinical trials of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) typically assess intervention efficacy with measures of cognitive or functional assessments repeated every six months for one to two years. The Mixed Model of Repeated Measures (MMRM), which assumes an "unstructured mean" by treating time as categorical, is attractive because it makes no assumptions about the shape of the mean trajectory of the outcome over time. However, categorical time models may be over-parameterized and inefficient in detecting treatment effects relative to continuous time models of, say, the linear trend of the outcome over time. Mixed effects models can also be extended to model quadratic time effects, although it is questionable whether the duration and interval of observations in AD and MCI studies is sufficient to support such models. Furthermore, it is unknown which of these models are most robust to missing data, which plagues AD and MCI studies. We review the literature and compare estimates of treatment effects from four potential models fit to data from five AD Cooperative Study (ADCS) trials in MCI and AD. PMID:22499459

  12. Sexual health in the International Classification of Diseases (ICD): implications for measurement and beyond.

    PubMed

    Chou, Doris; Cottler, Sara; Khosla, Rajat; Reed, Geoffrey M; Say, Lale

    2015-11-01

    This paper examines different dimensions of sexual health as related to the measurement of sexual health indicators and the proposed changes in the International Classification of Diseases to address issues related to sexuality and sexual health with an aim of informing health policy-making and programming. The lack of mechanisms for monitoring and evaluating sexual health outcomes has impeded the development of policies and programmes that support sexual health. The potential impact of changes to the ICD-11 is major and far-reaching given that the ICD is used by countries to define eligibility and access to health services and to formulate relevant policies and laws, and is used by health professionals as a basis for conceptualizing health conditions, treatments and outcomes. Improving the measurement of sexual health-related indicators builds the evidence base on scientific knowledge of sex, sexuality, sexual health and rights. As we stand on the cusp of the post-2015 era and the development agenda transitions to the Sustainable Development Goals, a unique opportunity presents itself to further consider how sexual health is defined, conceptualized, and monitored. PMID:26719010

  13. [A motor function measurement scale for neuromuscular diseases - description and validation study].

    PubMed

    Bérard, C; Payan, C; Fermanian, J; Girardot, F

    2006-04-01

    A new scale for motor function measurement has been developed for neuromuscular diseases. After the study of a preliminary and a first version, the validation study included 303 patients, aged 6 to 62 years. Seventy-two patients had Duchenne muscular dystrophy, 32 Becker muscular dystrophy, 30 limb-girdle muscular dystrophy, 39 facio-scapulo-humeral dystrophy, 29 myotonic dystrophy, 21 congenital myopathy, 10 congenital muscular dystrophy, 35 spinal muscular atrophy and 35 hereditary neuropathy. The sensitivity for change was evaluated with 152 patients one year after. The scale comprised 32 items, in three dimensions: standing position and transfers, axial and proximal motor function, distal motor function. High correlations (>0.80) were found between the total score and other scores: Vignos and Brooke grades, Functional Independence Measure, the global severity of disability evaluated with visual analog scales by physicians and physiotherapists. This scale is reliable, does not require any special equipment and is well accepted by patients. It takes an average of 36 min (range 8-75) to complete the scale. Preliminary results of the second evaluation showed good sensitivity to change since last visit, considering rating by patient, investigator or physiotherapist. Also, significant differences in scores are obtained with the greatest deterioration observed in Duchenne patients. PMID:16585909

  14. The Effects of Media Reports on Disease Spread and Important Public Health Measurements.

    PubMed

    Collinson, Shannon; Khan, Kamran; Heffernan, Jane M

    2015-01-01

    Controlling the spread of influenza to reduce the effects of infection on a population is an important mandate of public health. Mass media reports on an epidemic or pandemic can provide important information to the public, and in turn, can induce positive healthy behaviour practices (i.e., handwashing, social distancing) in the individuals, that will reduce the probability of contracting the disease. Mass media fatigue, however, can dampen these effects. Mathematical models can be used to study the effects of mass media reports on epidemic/pandemic outcomes. In this study we employ a stochastic agent based model to provide a quantification of mass media reports on the variability in important public health measurements. We also include mass media report data compiled by the Global Public Health Intelligence Network, to study the effects of mass media reports in the 2009 H1N1 pandemic. We find that the report rate and the rate at which individuals relax their healthy behaviours (media fatigue) greatly affect the variability in important public health measurements. When the mass media reporting data is included in the model, two peaks of infection result. PMID:26528909

  15. Lifestyle measures in the management of gastro-oesophageal reflux disease: clinical and pathophysiological considerations

    PubMed Central

    Kang, J.H.-E.

    2015-01-01

    Several lifestyle and dietary factors are commonly cited as risk factors for gastro-oesophageal reflux disease (GORD) and modification of these factors has been advocated as first-line measures for the management of GORD. We performed a systematic review of the literature from 2005 to the present relating to the effect of these factors and their modification on GORD symptoms, physiological parameters of reflux as well as endoscopic appearances. Conflicting results existed for the association between smoking, alcohol and various dietary factors in the development of GORD. These equivocal findings are partly due to methodology problems. There is recent good evidence that weight reduction and smoking cessation are beneficial in reducing GORD symptoms. Clinical and physiological studies also suggest that some physical measures as well as modification of meal size and timing can also be beneficial. However, there is limited evidence for the role of avoiding alcohol and certain dietary ingredients including carbonated drinks, caffeine, fat, spicy foods, chocolate and mint. PMID:25729556

  16. The Effects of Media Reports on Disease Spread and Important Public Health Measurements

    PubMed Central

    Collinson, Shannon; Khan, Kamran; Heffernan, Jane M.

    2015-01-01

    Controlling the spread of influenza to reduce the effects of infection on a population is an important mandate of public health. Mass media reports on an epidemic or pandemic can provide important information to the public, and in turn, can induce positive healthy behaviour practices (i.e., handwashing, social distancing) in the individuals, that will reduce the probability of contracting the disease. Mass media fatigue, however, can dampen these effects. Mathematical models can be used to study the effects of mass media reports on epidemic/pandemic outcomes. In this study we employ a stochastic agent based model to provide a quantification of mass media reports on the variability in important public health measurements. We also include mass media report data compiled by the Global Public Health Intelligence Network, to study the effects of mass media reports in the 2009 H1N1 pandemic. We find that the report rate and the rate at which individuals relax their healthy behaviours (media fatigue) greatly affect the variability in important public health measurements. When the mass media reporting data is included in the model, two peaks of infection result. PMID:26528909

  17. Lifestyle measures in the management of gastro-oesophageal reflux disease: clinical and pathophysiological considerations.

    PubMed

    Kang, J H-E; Kang, J Y

    2015-03-01

    Several lifestyle and dietary factors are commonly cited as risk factors for gastro-oesophageal reflux disease (GORD) and modification of these factors has been advocated as first-line measures for the management of GORD. We performed a systematic review of the literature from 2005 to the present relating to the effect of these factors and their modification on GORD symptoms, physiological parameters of reflux as well as endoscopic appearances. Conflicting results existed for the association between smoking, alcohol and various dietary factors in the development of GORD. These equivocal findings are partly due to methodology problems. There is recent good evidence that weight reduction and smoking cessation are beneficial in reducing GORD symptoms. Clinical and physiological studies also suggest that some physical measures as well as modification of meal size and timing can also be beneficial. However, there is limited evidence for the role of avoiding alcohol and certain dietary ingredients including carbonated drinks, caffeine, fat, spicy foods, chocolate and mint. PMID:25729556

  18. Prediction of manifest Huntington disease with clinical and imaging measures: A 12-year prospective observational study

    PubMed Central

    Paulsen, Jane S.; Long, Jeffrey D.; Ross, Christopher A.; Harrington, Deborah L.; Erwin, Cheryl J.; Williams, Janet K.; Westervelt, Holly James; Johnson, Hans J.; Aylward, Elizabeth H.; Zhang, Ying; Bockholt, H. Jeremy; Barker, Roger A.

    2015-01-01

    BACKGROUND Although correlation between cytosine-adenine-guanine (CAG) repeat length and age of Huntington disease (HD) onset is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counseling. We compared genetic, demographic, motor, cognitive, psychiatric, functional and imaging measures for tracking progression and predicting conversion to manifest HD. METHODS N=1078 research participants with the gene mutation for HD, but without a rating of 4 on the Diagnostic Confidence Level (DCL) following administration of the 15-item motor assessment of the Unified Huntington’s Disease Rating Scale. Participants were from 33 world wide sites and followed for up to 12 years (mean=5, SD=3·3) over the period 2001–2013. A subset of 225 participants prospectively converted to manifest HD according to the DCL (“meets the operational definition of the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder in a subject at risk for HD” with ≥99% confidence). Joint modeling of longitudinal and survival data was used to examine the extent to which baseline and change of 40 variables analyzed separately was predictive of CAG-adjusted age at motor diagnosis. FINDINGS Cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors in the top three phenotypic domains were total motor score (motor), putamen volume (imaging), and Stroop word test (cognitive). A one standard deviation (SD) difference in total motor score increased the risk of a motor diagnosis by 3·1 times (95% CI=[2·3,4·2]), one SD loss in putamen volume increased risk by 3·3 times ([2·4,4·7]) and one SD cognitive decline increased risk by 2·3 ([1·9,2·9]). INTERPRETATION Prediction of HD diagnosis can be considerably improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors

  19. Measurement of Beryllium in Biological Samples by Accelerator Mass Spectrometry: Applications for Studying Chronic Beryllium Disease

    SciTech Connect

    Chiarappa-Zucca, M L; Finkel, R C; Martinelli, R E; McAninch, J E; Nelson, D O; Turtletaub, K W

    2004-04-15

    A method using accelerator mass spectrometry (AMS) has been developed for quantifying attomoles of beryllium (Be) in biological samples. This method provides the sensitivity to trace Be in biological samples at very low doses with the purpose of identifying the molecular targets involved in chronic beryllium disease. Proof of the method was tested by administering 0.001, 0.05, 0.5 and 5.0 {micro}g {sup 9}Be and {sup 10}Be by intraperitoneal injection to male mice and removing spleen, liver, femurs, blood, lung, and kidneys after 24 h exposure. These samples were prepared for AMS analysis by tissue digestion in nitric acid, followed by further organic oxidation with hydrogen peroxide and ammonium persulfate and lastly, precipitation of Be with ammonium hydroxide, and conversion to beryllium oxide at 800 C. The {sup 10}Be/{sup 9}Be ratio of the extracted beryllium oxide was measured by AMS and Be in the original sample was calculated. Results indicate that Be levels were dose-dependent in all tissues and the highest levels were measured in the spleen and liver. The measured {sup 10}Be/{sup 9}Be ratios spanned 4 orders of magnitude, from 10{sup -10} to 10{sup -14}, with a detection limit of 3.0 x 10{sup -14}, which is equivalent to 0.8 attomoles of {sup 10}Be. These results show that routine quantification of nanogram levels of Be in tissues is possible and that AMS is a sensitive method that can be used in biological studies to understand the molecular dosimetry of Be and mechanisms of toxicity.

  20. Identifying and measuring stakeholder preferences for disease prioritisation: A case study of the pig industry in Australia.

    PubMed

    Brookes, V J; Hernández-Jover, M; Neslo, R; Cowled, B; Holyoake, P; Ward, M P

    2014-01-01

    potential impacts, and that the weights were implicitly related to the scale of measurement of disease criteria. Validation of the results of the criterion weights against real diseases - a step rarely used in MCDA - added scientific rigour to the process. The study demonstrated that these are useful techniques for elicitation of criterion weights for disease prioritisation by stakeholders who are not disease experts. Preference modelling for zoonotic diseases needs further characterisation in this context. PMID:24211106

  1. Effectiveness and Cost-Effectiveness of Measuring Fecal Calprotectin in Diagnosis of Inflammatory Bowel Disease

    PubMed Central

    Yang, Zhuo; Clark, Nick; Park, KT

    2013-01-01

    Background & Aims The level of fecal calprotectin (FC) can predict the onset of inflammatory bowel disease (IBD) with high accuracy and precision. We evaluated the cost-effectiveness of using measurements of FC to identify adults and children who require endoscopic confirmation of IBD. METHODS We constructed a decision analytic tree to compare the cost-effectiveness of measuring FC before endoscopy examination with that of direct endoscopic evaluation alone. A second decision analytic tree was constructed to evaluate the cost-effectiveness of FC cut-off levels of 100 µg/g vs 50 µg/g (typically used to screen for intestinal inflammation). The primary outcome measure was the incremental cost required to avoid 1 false-negative result using FC level to diagnose new-onset IBD. RESULTS In adults, FC screening saved $417/patient but delayed diagnosis for 2.2/32 patients with IBD, among 100 screened patients. In children, FC screening saved $300/patient but delayed diagnosis for 4.8/61 patients with IBD, among 100 screened patients. If endoscopic biopsy analysis remained the standard for diagnosis, direct endoscopic evaluation would cost an additional $18,955 in adults and $6250 in children to avoid 1 false negative result from FC screening. Sensitivity analyses showed that cost effectiveness of FC screening varied with the sensitivity of the test and the pre-test probability of IBD in adults and children. Pre-test probabilities for IBD of ≤75% in adults and ≤65% in children made FC screening cost-effective, but cost ineffective if the probabilities were ≥85% and ≥78% in adults and children, respectively. Compared to the FC cut-off level of 100 µg/g, the cut-off level of 50 µg/g cost an additional $55 and $43 for adults and children, respectively, but yielded 2.4 and 6.1 additional accurate diagnoses of IBD per 100 screened adults and children. CONCLUSIONS Screening adults and children to measure fecal levels of calprotectin is effective and cost-effective in

  2. Age and the Association of Kidney Measures with Mortality and End-Stage Renal Disease

    PubMed Central

    Hallan, Stein I.; Matsushita, Kunihiro; Sang, Yingying; Mahmoodi, Bakhtawar K.; Black, Corri; Ishani, Areef; Kleefstra, Nanne; Naimark, David; Roderick, Paul; Tonelli, Marcello; Wetzels, Jack F.M.; Astor, Brad C.; Gansevoort, Ron T.; Levin, Adeera; Wen, Chi-Pang; Coresh, Josef

    2014-01-01

    Context Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial. Objective To evaluate possible effect modification (interaction) of age on the association of estimated GFR and albuminuria with clinical risk examining both relative and absolute risk. Design, Setting, Participants We investigated 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australesia, Europe, and North/South America conducted during 1972–2011 with mean follow-up time of 5.8 years (range 0–31 years). Main Outcome Measures Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholestserol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates. Results Mortality (112,325 deaths) and ESRD (8,411 events) risk were higher at lower eGFR and higher albuminuria in every age category. In general/high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age: e.g., adjusted HRs (95% CI) at eGFR 45 vs. 80 ml/min/1.73m2 were 3.50 (2.55–4.81), 2.21 (2.02–2.41), 1.59 (1.42–1.77), and 1.35 (1.23–1.48) in age categories 18–54, 55–64, 65–74 and 75+ years, respectively (P-values for age interaction <0.05). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0–12.8], 12.2 [10.3–14.3], 13.3 [9.0–18.6], and 27.2 [13.5–45.5] excess deaths per 1,000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age were less evident, while differences in absolute risk were higher in the older age categories (7.5 [95% CI, 4.3–11.9], 12.2 [7.9–17

  3. Screening for Fabry Disease by Urinary Globotriaosylceramide Isoforms Measurement in Patients with Left Ventricular Hypertrophy

    PubMed Central

    Gaggl, Martina; Lajic, Natalija; Heinze, Georg; Voigtländer, Till; Sunder-Plassmann, Raute; Paschke, Eduard; Fauler, Günter; Sunder-Plassmann, Gere; Mundigler, Gerald

    2016-01-01

    Background: Left ventricular hypertrophy (LVH) is a frequent echocardiographic feature in Fabry disease (FD) and in severe cases may be confused with hypertrophic cardiomyopathy (HCM) of other origin. The prevalence of FD in patients primarily diagnosed with HCM varies considerably in screening and case finding studies, respectively. In a significant proportion of patients, presenting with only mild or moderate LVH and unspecific clinical signs FD may remain undiagnosed. Urinary Gb3 isoforms have been shown to detect FD in both, women and men. We examined whether this non-invasive method would help to identify new FD cases in a non-selected cohort of patients with various degree of LVH. Methods and results: Consecutive patients older than 18 years with a diastolic interventricular septal wall thickness of ≥12mm determined by echocardiography were included. Referral diagnosis was documented and spot urine was collected. Gb3 was measured by mass spectroscopy. Subjects with an elevated Gb3-24:18 ratio were clinically examined for signs of FD, α-galactosidase-A activity in leukocytes was determined and GLA-mutation-analysis was performed. We examined 2596 patients. In 99 subjects urinary Gb3 isoforms excretion were elevated. In these patients no new cases of FD were identified by extended FD assessment. In two of three patients formerly diagnosed with FD Gb3-24:18 ratio was elevated and would have led to further diagnostic evaluation. Conclusion: Measurement of urinary Gb3 isoforms in a non-selected cohort with LVH was unable to identify new cases of FD. False positive results may be prevented by more restricted inclusion criteria and may improve diagnostic accuracy of this method. PMID:27226774

  4. Repellents and acaricides as personal protection measures in the prevention of tick-borne diseases.

    PubMed

    Cisak, Ewa; Wójcik-Fatla, Angelina; Zając, Violetta; Dutkiewicz, Jacek

    2012-01-01

    A number of preventive measures for the protection of humans against tick-borne diseases were evaluated. Measures involving the avoidance of tick bites with the use of protective clothing and insect repellents are the simplest and most effective. Repellents are applied directly to the skin or clothing and other fabrics, such as bednets, tents and anti-mosquito screens. Currently, DEET (N,N-diethyl-m-toluamide) is considered the most efficient arthropod repellent reference substance. The registered and recommended active repellent ingredients for skin and/or cloths application, among others, are: DEET, 1-methyl-propyl-2- (hydroxyethyl)-1-piperidinecarboxylate (picaridin), p-menthane-3,8-diol (PMD), ethyl butylactyloaminopropionate ( IR3535), 1S,2S-2-methylpiperidinyl-3-cyclohexene-1-carboxamide (SS220), racemic 2-methylpiperidinyl-3-cyclohexene-1-carboxamide (AI3-37220) and synthethic pyrethroid - 3-phenoxybenzyl-cis-trans-3(2,2 dichlorovinyl)-2,2-dimethylcyclopropancarboxylate (permethrin) - an acaricide with repellent properties. To achieve the protection from tick bites by avoiding attachment and/or engorgement by the arthropod, acaricides with repellent properties, such as synthetic pyrethroid-permethrin are used. This pyrethroid is an acaricide of choice used for clothing impregnation, which is effective for personal protection against all three parasitic stages of western black-legged ticks. Products based on natural compounds, e.g. eugenol from Ocimum basilicum, 2-undecanone originally derived from wild tomato, geraniol - a natural product extracted from plants, and many others, represent an interesting alternative to common synthetic repellents and/or acaricides. PMID:23311778

  5. Quantitative measurement of the blood flow in peripheral vascular diseases by a new radionuclide plethysmography

    SciTech Connect

    Kawakami, K.; Mori, Y.; Mashima, Y.; Shimada, T.; Fukuoka, M.

    1985-05-01

    The purpose of the study is to introduce a new plethysmography using radionuclide (RN) for a quantitative measurement of the blood flow in the extremities following the routine RN angiography. Seventy five patients with various peripheral artery diseases have been examined. RN pletysmography was performed in the supine position 15 min. after the RN angiography using 15 mCi of Tc-99m RBC. The blood flow (F) was calculated by the equation (1) which consists of three parameters, the initial slope of the time-activity curve (dc/dt*t=0) after the venous occlusion on the thigh, changes of radio-activity (C-Co) before and after avascularization by inflation of cuff with 200 mmHg pressure at calf, and the blood volume per unit tissue volume (..beta..=Vb/V,ml/100g tissue). F (ml/min/100g) = ..beta.. (dc/dt*t=0)/C-Co. The blood flow measured simultaneously by RN plethysmography and admittance plethysmography was significantly correlated (r = 0.906,n = 16). The blood flow in 67 normal subjects was 2.78 +- 0.75 ml/min/100g. In the patients with intermittent claudication the blood flow was decreased (1.89 +- 0.75 ml/min/100g,n = 75). In the cases with poorly developed colateral circulation the blood flow markedly decreased (1.62 +- 0.29 ml/min/100g,n = 10). Increases of blood flow after exercise was small in the cases with stenosis, even in patients with collaterals. This method is very useful to evaluate quantitatively the peripheral hemodynamics following the routine RN angiographic examination.

  6. Measurement of fluorescent probes concentration ratio in the cerebrospinal fluid for early detection of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Harbater, Osnat; Gannot, Israel

    2014-03-01

    The pathogenic process of Alzheimer's Disease (AD), characterized by amyloid plaques and neurofibrillary tangles in the brain, begins years before the clinical diagnosis. Here, we suggest a novel method which may detect AD up to nine years earlier than current exams, minimally invasive, with minimal risk, pain and side effects. The method is based on previous reports which relate the concentrations of biomarkers in the Cerebrospinal Fluid (CSF) (Aβ and Tau proteins) to the future development of AD in mild cognitive impairment patients. Our method, which uses fluorescence measurements of the relative concentrations of the CSF biomarkers, replaces the lumbar puncture process required for CSF drawing. The process uses a miniature needle coupled trough an optical fiber to a laser source and a detector. The laser radiation excites fluorescent probes which were prior injected and bond to the CSF biomarkers. Using the ratio between the fluorescence intensities emitted from the two biomarkers, which is correlated to their concentration ratio, the patient's risk of developing AD is estimated. A theoretical model was developed and validated using Monte Carlo simulations, demonstrating the relation between fluorescence emission and biomarker concentration. The method was tested using multi-layered tissue phantoms simulating the epidural fat, the CSF in the sub-arachnoid space and the bone. These phantoms were prepared with different scattering and absorption coefficients, thicknesses and fluorescence concentrations in order to simulate variations in human anatomy and in the needle location. The theoretical and in-vitro results are compared and the method's accuracy is discussed.

  7. Comparison of Test Your Memory and Montreal Cognitive Assessment Measures in Parkinson's Disease

    PubMed Central

    Chu, Howard; Gaunt, Daisy M.; Whone, Alan L.; Ben-Shlomo, Yoav; Lyell, Veronica

    2016-01-01

    Background. MoCA is widely used in Parkinson's disease (PD) to assess cognition. The Test Your Memory (TYM) test is a cognitive screening tool that is self-administered. Objectives. We sought to determine (a) the optimal value of TYM to discriminate between PD patients with and without cognitive deficits on MoCA testing, (b) equivalent MoCA and TYM scores, and (c) interrater reliability in TYM testing. Methods. We assessed the discriminant ability of TYM and the equivalence between TYM and MoCA scores and measured the interrater reliability between three raters. Results. Of the 135 subjects that completed both tests, 55% had cognitive impairment according to MoCA. A MoCA score of 25 was equivalent to a TYM score of 43-44. The area under the receiver operator characteristic (ROC) curve for TYM to differentiate between PD-normal and PD-cognitive impairment was 0.82 (95% CI 0.75 to 0.89). The optimal cutoff to distinguish PD-cognitive impairment from PD-normal was ≤45 (sensitivity 90.5%, specificity 59%) thereby correctly classifying 76.3% of patients with PD-cognitive impairment. Interrater agreement was high (0.97) and TYM was completed in under 7 minutes (interquartile range 5.33 to 8.52 minutes). Conclusions. The TYM test is a useful and less resource intensive screening test for cognitive deficits in PD. PMID:27478678

  8. Laryngeal Measurements and Diagnostic Tools for Diagnosis of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Casado, Verónica; Navarro, Sandra M.; Alvarez, Andrés E.; Villafañe, Mercedes; Miranda, Ana; Spaans, Natalia

    2015-01-01

    PURPOSE The purpose of this study was to evaluate sensitivity, specificity, and positive and negative likelihood ratios of laryngeal height, lung function, and diagnostic questionnaires for screening and diagnosis of chronic obstructive pulmonary disease (COPD). METHODS We undertook a cross-sectional study of 233 people aged between 40 and 75 years. Measured variables were age, sex, weight, height, body mass index, tobacco use, maximum laryngeal height, and spirometry, and we administered a COPD questionnaire and the Lung Function Questionnaire. RESULTS For laryngeal height, we found a positive likelihood ratio of 5.21, and for the Lung Function Questionnaire, we found a negative likelihood ratio of 0.10. Combining a maximum laryngeal height of ≤4 cm with Lung Function Questionnaire findings of ≤18 yielded a positive likelihood ratio of 29.06, and a negative likelihood ratio of 0.26. CONCLUSIONS The intrinsic validity of the lung function questionnaire makes it useful for screening. Combining Lung Function Questionnaire results and laryngeal height can help confirm or dismiss COPD. PMID:25583892

  9. Bayesian hierarchical model for multiple repeated measures and survival data: an application to Parkinson's disease.

    PubMed

    Luo, Sheng; Wang, Jue

    2014-10-30

    Multilevel item response theory models have been increasingly used to analyze the multivariate longitudinal data of mixed types (e.g., continuous and categorical) in clinical studies. To address the possible correlation between multivariate longitudinal measures and time to terminal events (e.g., death and dropout), joint models that consist of a multilevel item response theory submodel and a survival submodel have been previously developed. However, in multisite studies, multiple patients are recruited and treated by the same clinical site. There can be a significant site correlation because of common environmental and socioeconomic status, and similar quality of care within site. In this article, we develop and study several hierarchical joint models with the hazard of terminal events dependent on shared random effects from various levels. We conduct extensive simulation study to evaluate the performance of various models under different scenarios. The proposed hierarchical joint models are applied to the motivating deprenyl and tocopherol antioxidative therapy of Parkinsonism study to investigate the effect of tocopherol in slowing Parkinson's disease progression. PMID:24935619

  10. [Binocular photometer for measuring light perception in diseases of the visual pathway].

    PubMed

    Stave, J; Guthoff, R

    1995-04-01

    In patients with a reduction in visual function because of optic nerve neuritis, light sensitivity is tested to detect differences between the right and left eye in combination with the swinging flashlight test and visual evoked potential (VEP). A binocular Zeiss microscope was modified to use integrated photometer-controlled binocular stimulus fields and a central light system for fixation and variation of the contrast (background illumination). For exact binocular measurements of light sensitivity on both eyes, electronically controlled test fields (visual angle 5 degrees-20 degrees) guarantees only macular or overfoveolar stimulation. In addition, splitting the light for each stimulus field from only one halogen lamp guarantees wave-length-independent testing. Patients with various retinal diseases and neuritis nervi optici pathology were examined using pattern VEP, testing of the absolute lower threshold of light sensitivity, and binocular comparison over the range of luminous density. This binocular optical photometer system allowed minimal differences to be identified in the present visual function and after the eye had recovered from optic nerve neuritis. PMID:7780279

  11. Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis

    PubMed Central

    Grayson, Peter C.; Monach, Paul A.; Pagnoux, Christian; Cuthbertson, David; Carette, Simon; Hoffman, Gary S.; Khalidi, Nader A.; Koening, Curry L.; Langford, Carol A.; Maksimowicz-McKinnon, Kathleen; Seo, Philip; Specks, Ulrich; Ytterberg, Steven R.

    2015-01-01

    Objective. The aim of this study was to assess the clinical value of absolute eosinophil count, serum IgE, ESR and CRP as longitudinal biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA). Methods. Patients were selected from an observational EGPA cohort. Absolute eosinophil count, IgE, ESR and CRP were measured quarterly. Disease activity was defined by validated assessment tools. The association of tests with disease activity was assessed via regression models, adjusting for repeated measures and treatment status. Survival analysis was used to determine if laboratory tests were predictive of the 3 month future flare risk. Results. Seventy-four per cent of 892 study visits in 141 patients occurred while patients were on treatment, mostly during remission or mild disease activity, defined as a BVAS for Wegener’s granulomatosis (BVAS/WG) of 1 or 2. Correlations between absolute eosinophil count, IgE, ESR and CRP were mostly low or non-significant (r = −0.08 to 0.44). There were few weak associations with disease activity [absolute eosinophil count: OR) 1.01/100 U (95% CI 1.01, 1.02); ESR: OR 1.15/10 mg/l increase (95% CI 1.04, 1.27)]. When BVAS/WG ≥1 defined active disease, the absolute eosinophil count [hazard ratio (HR) 1.01/100 U (95% CI 1.01, 1.02)] was weakly predictive of flare. When BVAS/WG ≥3 defined active disease, ESR was weakly predictive of flare [HR 1.52/10 mm/h increase (95% CI 1.17, 1.67)]. Conclusion. The absolute eosinophil count, IgE, ESR and CRP have limitations as longitudinal biomarkers of disease activity or predictors of flare in EGPA. These findings suggest that novel biomarkers of disease activity for EGPA are needed. PMID:25406357

  12. Correlation of Promis Scales and Clinical Measures Among Chronic Obstructive Pulmonary Disease Patients With and Without Exacerbations

    PubMed Central

    Irwin, Debra E.; Atwood, Charles A.; Hays, Ron D.; Spritzer, Karen; Liu, Honghu; Donohue, James F.; Leidy, Nancy Kline; Yount, Susan E.; DeWalt, Darren A.

    2014-01-01

    Purpose The Patient-Reported Outcomes Measurement Information System (PROMIS®) initiative was developed to advance the methodology of PROs applicable to chronic diseases. Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease associated with poor health. This study was designed to examine the correlation of PROMIS health-related quality of life (HRQOL) scales and clinical measures among COPD patients. Methods A cross-sectional analysis was conducted comparing patients who were stable (n = 100) with those currently experiencing a COPD exacerbation (n=85). All PROMIS measures for adults available at the time of the study (2008), disease-targeted and other HRQOL instruments, health literacy, percent predicted FEV1, and a 6-minute walk distance were assessed when patients were considered clinically stable. Results Stable COPD patients reported significantly (p≤0.05) better health-related quality of life on PROMIS domains than patients experiencing an exacerbation. PROMIS domain scores were significantly (p≤0.01) correlated with each of legacy measures. Six-minute walk scores were most highly correlated with the PROMIS physical function domain scores (r=0.53) followed by the fatigue (r=-0.26), social (r=0.24) and to a lesser extent depression (r=-0.23) and anxiety (r=-0.22) domain scores. Percent predicted FEV1 score was significantly associated with PROMIS physical function scores (r=0.27). Conclusion This study provides support for the validity of the PROMIS measures in COPD patients. PMID:25307510

  13. Measuring the Quality of Provided Services for Patients With Chronic Kidney Disease

    PubMed Central

    Bahadori, Mohammadkarim; Raadabadi, Mehdi; Heidari Jamebozorgi, Majid; Salesi, Mahmood; Ravangard, Ramin

    2014-01-01

    Background: The healthcare organizations need to develop and implement quality improvement plans for their survival and success. Measuring quality in the healthcare competitive environment is an undeniable necessity for these organizations and will lead to improved patient satisfaction. Objectives: This study aimed to measure the quality of provided services for patients with chronic kidney disease in Kerman in 2014. Patients and Methods: This cross-sectional, descriptive-analytic study was performed from 23 January 2014 to 14 February 2014 in four hemodialysis centers in Kerman. All of the patients on chronic hemodialysis (n = 195) who were referred to these four centers were selected and studied using census method. The required data were collected using the SERVQUAL questionnaire, consisting of two parts: questions related to the patients' demographic characteristics, and 28 items to measure the patients' expectations and perceptions of the five dimensions of service quality, including tangibility, reliability, responsiveness, assurance, and empathy. The collec