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1.
Ann Neurol ; 85(5): 782-787, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801763

RESUMO

Disease-associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease-associated prion protein (PrPSc ) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt-Jakob disease (CJD), we applied 3 different anti-PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. Four of 31 VV-2 type sporadic CJD and 7 of 30 genetic CJD cases showed vagal PrPSc immunodeposits with distinct morphology. Thus, PrPSc in CJD affects the vagus nerve analogously to α-synuclein in Parkinson disease. The morphologically diverse deposition of PrPSc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrPSc . Ann Neurol 2019;85:782-787.


Assuntos
Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Proteínas Priônicas/metabolismo , Nervo Vago/metabolismo , Nervo Vago/patologia , Estudos de Coortes , Humanos , Proteínas Priônicas/análise , Estudos Retrospectivos , Nervo Vago/química
3.
Med Sci Law ; 58(4): 257-260, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30124101

RESUMO

Ethylene glycol (EG) may be acutely toxic following ingestion. In fatal cases, microscopic examination of urine and kidney specimens can establish a post-mortem diagnosis of EG poisoning. We describe the main renal histopathologic changes during different stages of EG poisoning, which might be helpful when dating the EG poisoning itself. A single-centre retrospective study conducted on all EG poisoning cases demonstrated that in an early stage of EG poisoning, fine dust-like crystals were deposited to the tubular cell basement membrane, followed by internalisation of calcium oxalate crystals into the epithelial cells. Later, the crystals formed larger aggregates within the epithelial cells. As the changes became advanced, pronounced tubular epithelial damage occurred, with detachment of epithelial cells from the basement membrane. In the final stage, coarse calcium oxalate crystals were recognised in the tubular lumen, with cellular debris from damaged epithelial cells. Our study shows that the time-dependent histological changes described follow the clinical stages of EG poisoning and may therefore provide a rough estimate of the time of EG ingestion before death.


Assuntos
Etilenoglicol/envenenamento , Rim/patologia , Adulto , Idoso , Calcinose/patologia , Oxalato de Cálcio , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Ophthalmic Epidemiol ; 25(5-6): 436-442, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30081705

RESUMO

PURPOSE: Properly conducted controlled clinical trials (CCTs) provide the highest level of evidence for optimising decision-making in healthcare. Electronic search strategies do not exhaustively retrieve them, because of issues related to indexing, exclusion of journals in languages other than English, among others. A handsearch approach is therefore warranted. We aimed to identify all CCTs published in Ophthalmology journals in Spain, to describe their main features, and to submit them to the Cochrane Register of CCTs (CENTRAL). METHODS: After identifying all Spanish Ophthalmology Journals, we conducted a systematic handsearch following Cochrane guidelines. When appropriate, results were compared against electronic searches. A descriptive analysis was completed, including risk of bias assessment. RESULTS: We identified 18 eligible journals; 10 074 original articles, editorials, letters to the editor, abstracts and conference proceedings were assessed via handsearching for inclusion. Of these, 136 were subject to title and abstract screening, after which 102 were classified as CCTs. We identified three articles via electronic searches that had not been detected via handsearch, for a total of 105 CCTs. Among these, the most investigated pathologies were cataracts (32/105; 30.5%) and glaucoma (23/105 21.9%). Regarding risk of bias, 104/105 (99.0%) were deemed as "high risk of bias", mainly due to flaws in sequence generation and allocation concealment. 15/105 (14.3%) mentioned conflicts of interest, half of which had something to declare. No CCT reported adherence to CONSORT. CONCLUSION: Spanish Ophthalmology journals publish a low number of CCTs, with limited methodological quality. Handsearching was more sensitive than the electronic searching. Abbreviations CCT: Controlled clinical trial.


Assuntos
Ensaios Clínicos Controlados como Assunto , Tomada de Decisões , Oftalmopatias/terapia , Oftalmologia , Publicações Periódicas como Assunto , Humanos , Espanha
6.
Med Sci Law ; 57(2): 84-90, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28438099

RESUMO

This study aimed to establish the number of deaths in infants under 1 year of age that were being reported for medico-legal examination at a single large academic centre in Hungary, as well as the method of these investigations with special emphasis on histopathology, ancillary techniques and the adherence of our current practice to international recommendations. A single-centre, retrospective audit was conducted on all suspected sudden infant death cases. After the review there were eight infectious background sudden infant death syndrome (SIDS) cases, infectious respiratory tract disease in 14 cases, cardiac septal tumour in one case, and hepatic, possibly metabolic, disorder in one case. Our study has highlighted that even in a single institution there is a huge heterogeneity of approaches which needs standardisation. A reclassification of infant cases according to the San Diego definition resulted in a decreased number of SIDS cases in our material. The San Diego definition and related international recommendations were found to be practical and the classification provides a guide to the standardisation of current practice.


Assuntos
Causas de Morte , Morte Súbita do Lactente , Autopsia/normas , Feminino , Humanos , Hungria/epidemiologia , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Morte Súbita do Lactente/epidemiologia
7.
Biol Psychiatry ; 81(7): 585-594, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27863698

RESUMO

BACKGROUND: Opiate abuse and overdose reached epidemic levels in the United States. However, despite significant advances in animal and in vitro models, little knowledge has been directly accrued regarding the neurobiology of the opiate-addicted human brain. METHODS: We used postmortem human brain specimens from a homogeneous European Caucasian population of heroin users for transcriptional and epigenetic profiling, as well as direct assessment of chromatin accessibility in the striatum, a brain region central to reward and emotion. A rat heroin self-administration model was used to obtain translational molecular and behavioral insights. RESULTS: Our transcriptome approach revealed marked impairments related to glutamatergic neurotransmission and chromatin remodeling in the human striatum. A series of biochemical experiments tracked the specific location of the epigenetic disturbances to hyperacetylation of lysine 27 of histone H3, showing dynamic correlations with heroin use history and acute opiate toxicology. Targeted investigation of GRIA1, a glutamatergic gene implicated in drug-seeking behavior, verified the increased enrichment of lysine-27 acetylated histone H3 at discrete loci, accompanied by enhanced chromatin accessibility at hyperacetylated regions in the gene body. Analogous epigenetic impairments were detected in the striatum of heroin self-administering rats. Using this translational model, we showed that bromodomain inhibitor JQ1, which blocks the functional readout of acetylated lysines, reduced heroin self-administration and cue-induced drug-seeking behavior. CONCLUSIONS: Overall, our data suggest that heroin-related histone H3 hyperacetylation contributes to glutamatergic transcriptional changes that underlie addiction behavior and identify JQ1 as a promising candidate for targeted clinical interventions in heroin use disorder.


Assuntos
Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Epigênese Genética , Dependência de Heroína/genética , Dependência de Heroína/metabolismo , Histonas/metabolismo , Receptores de AMPA/genética , Acetilação , Animais , Azepinas/administração & dosagem , Encéfalo/efeitos dos fármacos , Montagem e Desmontagem da Cromatina , Comportamento de Procura de Droga/efeitos dos fármacos , Epigenômica , Grupo com Ancestrais do Continente Europeu , Perfilação da Expressão Gênica , Humanos , Masculino , Ratos , Ratos Long-Evans , Receptores de AMPA/metabolismo , Autoadministração , Triazóis/administração & dosagem
8.
Arthritis Rheumatol ; 68(12): 2953-2963, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27333332

RESUMO

OBJECTIVE: To compare the phenotype, clinical course, and outcome of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener's) (GPA) to proteinase 3 (PR3)-ANCA-positive GPA and to MPO-ANCA-positive microscopic polyangiitis (MPA). METHODS: We characterized all MPO-ANCA-positive patients classified as having GPA by the European Medicines Agency algorithm who attended our center, in a retrospective chart review. A second cohort of patients with PR3-ANCA-positive GPA matched for age and sex was characterized. Patients with MPO-ANCA-positive MPA from a recently published cohort were also included in the analysis. All patients were diagnosed and treated according to a standardized interdisciplinary approach at a vasculitis referral center. RESULTS: Comprehensive data were available for 59 patients with MPO-ANCA-positive GPA, and they were compared to 118 patients with PR3-ANCA-positive GPA and 138 patients with MPO-ANCA-positive MPA. We observed a distinct phenotype in MPO-ANCA-positive GPA as compared to the other 2 cohorts. Patients with MPO-ANCA-positive GPA frequently had limited disease without severe organ involvement, had a high prevalence of subglottic stenosis, and had less need for aggressive immunosuppressive therapy (cyclophosphamide/rituximab). The patients with MPO-ANCA-positive GPA were also younger than the MPA patients and were predominantly female (significantly different than the MPA cohort). While GPA patients had higher survival rates compared to MPA patients (due to a high prevalence of pulmonary fibrosis in MPA), patients with MPO-ANCA had significantly lower relapse rates than those with PR3-ANCA. CONCLUSION: Patients with MPO-ANCA-positive GPA show significantly different clinical courses compared to those with PR3-ANCA-positive GPA or MPO-ANCA-positive MPA, which should be considered in their clinical management. Classification according to ANCA specificity may improve the evaluation of relapse risk.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Granulomatose com Poliangiite/imunologia , Peroxidase/imunologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Estudos de Casos e Controles , Ciclofosfamida/uso terapêutico , Oftalmopatias/epidemiologia , Oftalmopatias/etiologia , Feminino , Alemanha , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/epidemiologia , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Nefropatias/epidemiologia , Nefropatias/etiologia , Laringoestenose/epidemiologia , Laringoestenose/etiologia , Masculino , Pessoa de Meia-Idade , Mieloblastina/imunologia , Otorrinolaringopatias/epidemiologia , Otorrinolaringopatias/etiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/etiologia , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Rituximab/uso terapêutico , Taxa de Sobrevida , Adulto Jovem
9.
Mol Cell Proteomics ; 15(6): 2203-13, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27087653

RESUMO

Dysregulated proteolysis represents a hallmark of numerous diseases. In recent years, increasing number of studies has begun looking at the protein termini in hope to unveil the physiological and pathological functions of proteases in clinical research. However, the availability of cryopreserved tissue specimens is often limited. Alternatively, formalin-fixed, paraffin-embedded (FFPE) tissues offer an invaluable resource for clinical research. Pathologically relevant tissues are often stored as FFPE, which represent the most abundant resource of archived human specimens. In this study, we established a robust workflow to investigate native and protease-generated protein N termini from FFPE specimens. We demonstrate comparable N-terminomes of cryopreserved and formalin-fixed tissue, thereby showing that formalin fixation/paraffin embedment does not proteolytically damage proteins. Accordingly, FFPE specimens are fully amenable to N-terminal analysis. Moreover, we demonstrate feasibility of FFPE-degradomics in a quantitative N-terminomic study of FFPE liver specimens from cathepsin L deficient or wild-type mice. Using a machine learning approach in combination with the previously determined cathepsin L specificity, we successfully identify a number of potential cathepsin L cleavage sites. Our study establishes FFPE specimens as a valuable alternative to cryopreserved tissues for degradomic studies.


Assuntos
Fígado/metabolismo , Peptídeo Hidrolases/metabolismo , Proteínas/química , Proteômica/métodos , Animais , Cromatografia Líquida , Criopreservação , Aprendizado de Máquina , Camundongos , Inclusão em Parafina , Proteólise , Espectrometria de Massas em Tandem , Fixação de Tecidos
10.
Neuron ; 89(1): 129-46, 2016 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-26748090

RESUMO

Spinocerebellar ataxia type 1 (SCA1), due to the expansion of a polyglutamine repeat within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), the cause of which is poorly understood. Here, we identified the unique proteomic signature of Sca1(154Q/2Q) PCs at an early stage of disease, highlighting extensive alterations in proteins associated with synaptic functioning, maintenance, and transmission. Focusing on Homer-3, a PC-enriched scaffold protein regulating neuronal activity, revealed an early decline in its expression. Impaired climbing fiber-mediated synaptic transmission diminished mTORC1 signaling, paralleling Homer-3 reduction in Sca1(154Q/2Q) PCs. Ablating mTORC1 within PCs or pharmacological inhibition of mTORC1 identified Homer-3 as its downstream target. mTORC1 knockout in Sca1(154Q/2Q) PCs exacerbated and accelerated pathology. Reinstating Homer-3 expression in Sca1(154Q/2Q) PCs attenuated cellular dysfunctions and improved motor deficits. Our work reveals that impaired mTORC1-Homer-3 activity underlies PC susceptibility in SCA1 and presents a promising therapeutic target.


Assuntos
Ataxina-1/metabolismo , Proteínas de Transporte/metabolismo , Complexos Multiproteicos/metabolismo , Células de Purkinje/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Modelos Animais de Doenças , Proteínas de Arcabouço Homer , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteômica/métodos
11.
Rheumatology (Oxford) ; 55(1): 71-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26297628

RESUMO

OBJECTIVE: To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. METHODS: We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. RESULTS: Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. CONCLUSION: MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.


Assuntos
Poliangiite Microscópica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Alemanha/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Poliangiite Microscópica/tratamento farmacológico , Poliangiite Microscópica/epidemiologia , Pessoa de Meia-Idade , Indução de Remissão/métodos , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Adulto Jovem
12.
Neurobiol Aging ; 36(11): 3100-3107, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26254956

RESUMO

The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer disease-related changes. The present study focused on evaluating additional neurodegeneration-related proteins, including α-synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19-40 years) and compared with 11 controls (age: 15-40 years). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and Alzheimer disease. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or α-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Dependência de Heroína/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas tau/metabolismo , Adolescente , Adulto , Doença de Alzheimer/metabolismo , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Dependência de Heroína/patologia , Humanos , Masculino , Fosforilação , Adulto Jovem , alfa-Sinucleína/metabolismo
13.
Biomed Chromatogr ; 29(12): 1859-65, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26104502

RESUMO

A liquid chromatography-electrospray-mass spectrometry method (LC/MS) has been developed and validated for determination of praziquantel (PZQ), pyrantel (PYR), febantel (FBT), and the active metabolites fenbendazole (FEN) and oxfendazole (OXF), in dog plasma, using mebendazole as internal standard (IS). The method consists of solid-phase extractions on Strata-X polymeric cartridges. Chromatographic separation was carried out on a Phenomenex Gemini C6 -Phenyl column using binary gradient elution containing methanol and 50 mm ammonium-formate (pH 3). The method was linear (r(2) ≥ 0.990) over concentration ranges of 3-250 ng/mL for PYR andFEB, 5-250 ng/mL for OXF and FEN, and 24-1000 ng/mL for PZQ. The mean precisions were 1.3-10.6% (within-run) and 2.5-9.1% (between-run), and mean accuracies were 90.7-109.4% (within-run) and 91.6-108.2% (between-run). The relative standard deviations (RSD) were <9.1%. The mean recoveries of five targeted compounds from dog plasma ranged from 77 to 94%.The new LC/MS method described herein was fully validated and successfully applied to the bioequivalence studies of different anthelmintic formulations such as tablets containing PZQ, PYR embonate and FBT in dogs after oral administration.


Assuntos
Benzimidazóis/sangue , Cromatografia Líquida/métodos , Fenbendazol/sangue , Guanidinas/sangue , Espectrometria de Massas/métodos , Praziquantel/sangue , Pamoato de Pirantel/sangue , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Cães , Feminino , Fenbendazol/química , Fenbendazol/farmacocinética , Guanidinas/química , Guanidinas/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Praziquantel/química , Praziquantel/farmacocinética , Pamoato de Pirantel/química , Pamoato de Pirantel/farmacocinética , Reprodutibilidade dos Testes , Extração em Fase Sólida , Equivalência Terapêutica
14.
Proteomics ; 15(14): 2470-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26013158

RESUMO

Protein N-termini provide useful information for the understanding of posttranslational processing of proteins. The majority of proteins undergo N-terminal processing, such as proteolytic truncation or modifications like acetylation. Multiple methods currently exist for the enrichment of N-terminal peptides for proteomic analyses. Here, we report a novel, simple, and straightforward N-terminomic strategy, based on charge reversal of internal peptides followed by their removal through strong cation exchange chromatography. Our initial proof-of-concept study shows the feasibility of this technique, yielding over 3000 identifications of protein N-termini. We further show the application of this strategy in investigating the N-terminome of mouse embryonic fibroblasts cells deficient for both cathepsin B and L in comparison to wild type) control cells. Finally, we demonstrate that this workflow can be used in combination with a gel-based strategy, allowing preseparation of proteins and thus providing an estimate of the molecular weight of the identified cleavage products.


Assuntos
Cromatografia por Troca Iônica/métodos , Peptídeos/química , Proteínas/química , Proteômica/métodos , Animais , Catepsina B/genética , Catepsina L/genética , Linhagem Celular , Fibroblastos/química , Fibroblastos/metabolismo , Deleção de Genes , Camundongos , Peptídeos/isolamento & purificação , Peptídeos/metabolismo , Conformação Proteica , Proteínas/isolamento & purificação , Proteínas/metabolismo , Proteólise , Eletricidade Estática , Espectrometria de Massas em Tandem
15.
Forensic Sci Int ; 248: 181-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25671307

RESUMO

Identification of abuse and frequency patterns of stimulant designer drugs (SDDs) provides important information for their risk assessment and legislative control. In the present study urine and/or blood samples of suspected drug users in criminal cases were analysed by GC-MS for 38 SDDs, and for the most frequent illicit and psychoactive licit drugs in Hungary. Between July 2012 and June 2013, 2744 suspected drug users were sampled in Budapest and during 2012 and 2013, 774 persons were sampled in South-East Hungary (Csongrád County - neighbour the Romanian and Serbian borders). In Budapest 71.4% of cases, and in South-East Hungary 61% of cases were positive for at least one substance. Pentedrone was the most frequent SDD in both regions; however, the frequency distribution of the remaining drugs was highly diverse. SDDs were frequently present in combination with other drugs - generally with amphetamine or other stimulants, cannabis and/or benzodiazepines. The quarterly distribution of positive samples indicated remarkable seasonal changes in the frequency and pattern of consumption. Substances placed on the list of illicit drugs (mephedrone, 4-fluoro-amphetamine, MDPV, methylone, 4-MEC) showed a subsequent drop in frequency and were replaced by other SDDs (pentedrone, 3-MMC, methiopropamine, etc.). Newly identified compounds from seized materials were added to the list of new psychoactive substances ("Schedule C"). While the risk assessment of substances listed in Schedule C has to be performed within 2 years after scheduling, continuous monitoring of their presence and frequency among drug users is essential. In summary, our results suggest which substances should be dropped from the list of SDDs measured in biological samples; while the appearance of new substances from seized materials indicate the need for developing adequate standard analytical methods.


Assuntos
Drogas Desenhadas , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Drogas Desenhadas/análise , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hungria/epidemiologia , /urina , Masculino , Pessoa de Meia-Idade , Prevalência , Distribuição por Sexo , Transtornos Relacionados ao Uso de Substâncias/sangue , Transtornos Relacionados ao Uso de Substâncias/urina , Adulto Jovem
17.
Rheumatology (Oxford) ; 53(5): 882-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24425780

RESUMO

OBJECTIVES: The aim of this study was to investigate the period prevalences of ANCA-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA)/Churg-Strauss and GCA, in an urban and rural population in northern Germany in 2006 and to compare the data with our previous study performed in 1994. METHODS: We identified of all patients with AAV or GCA via questionnaires to all hospital departments, physicians, health insurance providers, pension funds, reference laboratories for autoimmune diseases and death registries in Luebeck (city) and the rural region of Segeberg (population 468 962) between January and December 2006. The type of vasculitis, gender, year of birth, postal code and death were documented and re-evaluated. RESULTS: One-hundred and fifty patients were identified, indicating a prevalence of 320 per million inhabitants for the complete catchment area (95% CI 285, 355). GCA was more prevalent than AAV: 171 (146, 197) vs 149 (126, 174). GCA and AAV have almost doubled since 1994. GCA increased from 240 (164, 315) to 440 (399, 481) per million in the population ≥ 50 years of age and AAV increased from 74 to 149 cases per million. GCA and AAV were more prevalent in the urban compared with the rural region. CONCLUSION: The prevalence rates of AAV and GCA almost doubled from 1994 to 2006 for this region with a stable population and using an identical study design. Increased awareness has led to an earlier diagnosis of systemic vasculitis and improved activity-adapted treatment mostly based on randomized controlled trials has led to longer survival. Aspects such as environmental factors and exposure to certain substances need further research.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Arterite de Células Gigantes/epidemiologia , População Rural , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Síndrome de Churg-Strauss/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Poliangiite Microscópica/epidemiologia , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Inquéritos e Questionários , Adulto Jovem
18.
J Clin Invest ; 123(12): 5334-41, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24231353

RESUMO

Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.


Assuntos
Tonsila do Cerebelo/metabolismo , Transtorno Depressivo Maior/metabolismo , Encefalinas/fisiologia , Dependência de Heroína/metabolismo , Precursores de Proteínas/fisiologia , Adulto , Tonsila do Cerebelo/química , Tonsila do Cerebelo/diagnóstico por imagem , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Corticosterona/sangue , Transtorno Depressivo Maior/genética , Drogas Desenhadas/farmacocinética , Encefalinas/análise , Encefalinas/biossíntese , Encefalinas/deficiência , Encefalinas/genética , Feminino , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Dependência de Heroína/genética , Humanos , Hungria , Sistema Límbico/química , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/metabolismo , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Neurônios/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Precursores de Proteínas/análise , Precursores de Proteínas/biossíntese , Precursores de Proteínas/deficiência , Precursores de Proteínas/genética , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Compostos Radiofarmacêuticos , Ratos , Ratos Long-Evans , Proteínas Recombinantes de Fusão/metabolismo , Estados Unidos
19.
Biol Psychiatry ; 74(7): 511-9, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23702428

RESUMO

BACKGROUND: Abuse of heroin and prescription opiate medications has grown to disturbing levels. Opioids mediate their effects through mu opioid receptors (MOR), but minimal information exists regarding MOR-related striatal signaling relevant to the human condition. The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders. METHODS: We examined molecular mechanisms related to MOR in postmortem human brain striatal specimens from a homogenous European Caucasian population of heroin abusers and control subjects and in an animal model of heroin self-administration. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history. RESULTS: A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed ~20% of downregulated genes in human heroin abusers are ELK1 targets. Using chromatin immune precipitation, we confirmed decreased ELK1 promoter occupancy of the target gene Use1. CONCLUSIONS: ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1.


Assuntos
Corpo Estriado/metabolismo , Dependência de Heroína/metabolismo , Núcleo Accumbens/metabolismo , Receptores Opioides mu/metabolismo , Proteínas Elk-1 do Domínio ets/metabolismo , Animais , Feminino , Dependência de Heroína/genética , Humanos , Masculino , Polimorfismo Genético , Ratos , Ratos Long-Evans , Receptores Opioides mu/genética , Transdução de Sinais , Proteínas Elk-1 do Domínio ets/genética
20.
Neuropsychopharmacol Hung ; 15(4): 253-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24380966

RESUMO

Rates of illicit drug use and drug-related deaths have continuously increased in developed countries since the 1960s even though the patterns of use and thus the related mortality differ from region to region. In Europe heroin is the drug most often implicated in overdoses. The decedents are most often male, between 20 and 30 years of age and have a long history of drug use. According to the majority of available studies a concomitant use of alcohol and benzodiazepines is one of the risk factors of heroin overdose. In our study we have examined the basic demographic and toxicological features of illicit drug related death cases in Budapest, Hungary between 1994 and 2012. Drug overdose death cases have been divided into two subgroups according to the substances responsible for the death of the subjects: an opioid group and a non-opioid group. The huge majority (87.9%) of decedents died due to heroin overdose and were male (87%). There has been a significant increase in the mean age of the opioid group for the past 19 years. The majority of heroin overdose cases (58%) has had no other psychofarmacons present at the toxicological examination. We have found a slight but significant positive correlation (p=0.0204, r=0.349) between the number of heroin overdose death cases and the mean concentration of street level purity heroin. Most of the examined demographic and toxicological features of the population studied have been in concordance with data previously reported. However, in contrast to other studies we report a strikingly high proportion of "pure" heroin overdose cases where no other psychoactive substances were found. The reason for this is currently unknown; we can only speculate that it can be related to the fact that heroin is used and abused differently from other countries. The remarkable phenomenon of the "ageing" of heroin users may also support a change in the drug use habits of the youngest population. The emergence and spread of new designer drugs also change the mortality characteristics of the youngest abusers and pose a new challenge for researchers.


Assuntos
Overdose de Drogas/epidemiologia , Dependência de Heroína/epidemiologia , Problemas Sociais/tendências , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Overdose de Drogas/história , Overdose de Drogas/mortalidade , Feminino , Dependência de Heroína/história , Dependência de Heroína/mortalidade , História do Século XX , História do Século XXI , Humanos , Hungria/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistemas Políticos , Fatores de Risco , Problemas Sociais/história , Transtornos Relacionados ao Uso de Substâncias/epidemiologia
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