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1.
Alcohol ; 116: 1-8, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-37774959

RESUMO

Ethanol-Paired Conditioned Stimuli (CS) can increase ethanol-responding either in extinction or occurring at low rates late in a session. To examine the generality of CS-induced increases in ethanol-responding, we examined whether a CS could increase responding suppressed by Conditioned-Taste-Aversion (CTA), which presumably suppresses responding by changing ethanol's valence from positive to negative. Rats were trained to respond for ethanol under a Random Interval (RI) schedule. We then removed the lever and paired Random-Time ethanol deliveries with illumination of a stimulus light (i.e., CS) for 10 sessions. Results were compared with a Truly Random Control group, in which the light and ethanol deliveries occurred independently. In a subsequent experiment, rats were treated similarly, except the light served as a discriminative stimulus, as the lever was extended and ethanol deliveries were available under a RI during light presentations. After this training, the lever was returned and rats again responded for ethanol. Subsequently, sessions were followed by LiCl administration. When responding reached low levels, LiCl administration stopped and the light was occasionally illuminated during the session. Responding during the light presentation was compared to responding during the period preceding light presentation. Responding partially recovered across 10 sessions and was greater during light presentations than in the period before it in all three groups. Increases were not reliably different between the groups, indicating that explanations for these increases such as CS-induced increases in motivation or approach toward the light are unlikely to be correct. The most likely explanation for these light-induced increases is that during sessions in which the light had been presented previously, LiCl had never been presented and thus, the light had come to signal that ethanol was safe to drink.


Assuntos
Etanol , Paladar , Ratos , Animais , Etanol/farmacologia , Condicionamento Operante , Condicionamento Clássico , Motivação
2.
Clin Neurophysiol ; 137: 152-158, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35316624

RESUMO

OBJECTIVE: To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities. METHODS: Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0-6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression. RESULTS: Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45-0.69; p < 0.01) and follow-up (Rho: 0.59-0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R2adj: 0.24), while EDSS and age did not. Tibial qSEP (R2adj: 0.22) and qMEP (R2adj: 0.26) were the best single modality predictors, outperformed by their combination (R2adj: 0.32). CONCLUSIONS: Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. SIGNIFICANCE: Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Biomarcadores , Avaliação da Deficiência , Progressão da Doença , Potenciais Evocados/fisiologia , Humanos , Esclerose Múltipla Crônica Progressiva/diagnóstico , Prognóstico
3.
Eur J Trauma Emerg Surg ; 48(5): 3439-3448, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34519864

RESUMO

INTRODUCTION: In an emergency department, the majority of pediatric trauma patients present because of minor injuries. The aim of this study was to evaluate temporal changes in age-related injury pattern, trauma mechanism, and surgeries in pediatric patients. METHODS: This retrospective study included patients < 18 years of age following trauma from 01/2009 to 12/2018 at a level I trauma center. They were divided into two groups: group A (A: 01/2009 to 12/2013) and group B (B: 01/2014 to 12/2018). Injury mechanism, injury pattern, and surgeries were analyzed. As major injuries fractures, dislocations, and organ injuries and as minor injuries contusions and superficial wounds were defined. RESULTS: 23,582 patients were included (58% male, median age 8.2 years). There was a slight increase in patients comparing A (n = 11,557) and B (n = 12,025) with no difference concerning demographic characteristics. Significant more patients (A: 1.9%; B: 2.4%) were admitted to resuscitation room, though the number of multiple injured patients was not significantly different. In A (25.5%), major injuries occurred significantly less frequently than in B (27.0%), minor injuries occurred equally. Extremity fractures were significantly more frequent in B (21.5%) than in A (20.2%), peaking at 8-12 years. Most trauma mechanisms of both groups were constant, with a rising of sport injuries at 8-12 years. CONCLUSION: Although number of patients increases only slightly over a decade, there was a clear increase in major injuries, particularly extremity fractures, peaking at 8-12 years. At this age also sport accidents significantly increased. At least, admittance to resuscitation room rose but without an increase of multiple injured patients.


Assuntos
Acidentes , Fraturas Ósseas , Criança , Extremidades , Feminino , Fraturas Ósseas/epidemiologia , Humanos , Masculino , Estudos Retrospectivos , Centros de Traumatologia
4.
Sci Rep ; 11(1): 12204, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108549

RESUMO

The worldwide shortage of medical-grade ventilators is a well-known issue, that has become one of the central topics during the COVID-19 pandemic. Given that these machines are expensive and have long lead times, one approach is to vacate them for patients in critical conditions while patients with mild to moderate symptoms are treated with stripped-down ventilators. We propose a mass-producible solution that can create such ventilators with minimum effort. The central part is a module that can be attached to CPAP machines and repurpose them as low-pressure ventilators. Here, we describe the concept and first measurements which underline the potential of our solution. Our approach may serve as a starting point for open-access ventilator technologies.

5.
Nature ; 582(7810): E1, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32494072

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
Nature ; 575(7782): 315-319, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31590178

RESUMO

An axion insulator is a correlated topological phase, which is predicted to arise from the formation of a charge-density wave in a Weyl semimetal1,2-that is, a material in which electrons behave as massless chiral fermions. The accompanying sliding mode in the charge-density-wave phase-the phason-is an axion3,4 and is expected to cause anomalous magnetoelectric transport effects. However, this axionic charge-density wave has not yet been experimentally detected. Here we report the observation of a large positive contribution to the magnetoconductance in the sliding mode of the charge-density-wave Weyl semimetal (TaSe4)2I for collinear electric and magnetic fields. The positive contribution to the magnetoconductance originates from the anomalous axionic contribution of the chiral anomaly to the phason current, and is locked to the parallel alignment of the electric and magnetic fields. By rotating the magnetic field, we show that the angular dependence of the magnetoconductance is consistent with the anomalous transport of an axionic charge-density wave. Our results show that it is possible to find experimental evidence for axions in strongly correlated topological condensed matter systems, which have so far been elusive in any other context.

7.
BMC Public Health ; 19(1): 232, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808333

RESUMO

BACKGROUND: Mental health problems have an adverse effect on the course of cardiac disease. The integration of their diagnosis and treatment into cardiology care is generally poor. It is particularly challenging in cultural environments where mental health problems are stigmatized. The objective of the current study was to investigate the proportion of cardiac patients with depression and anxiety as well as factors associated with the presence of these symptoms in a Palestinian population. METHODS: This cross-sectional hospital-based study was conducted on patients consecutively admitted with a new or existing cardiac diagnosis to one of the four main hospitals in Nablus, Palestine over an eight-month period. Data was obtained from hospital medical charts and an in-person interview, using a structured questionnaire with a sequence of validated instruments. All subjects were screened for depression and anxiety using the Cardiac Depression Scale (CDS) and the Depression Anxiety Stress Scale (DASS-42). Multivariate ordered logistic regression analyses were performed to identify factors among four categories (socio-demographic, clinical, psychosocial, lifestyle) independently associated with depression and anxiety. RESULTS: In total, 1053 patients with a confirmed cardiac diagnosis were included in the study with a participation rate of 96%. Based on the CDS and DASS-42, 54% met the criteria for severe depression (CDS > 100) and 19.2% for severe-to-very severe anxiety (DASS-anxiety > 15), respectively. Symptoms of depression and anxiety were more prevalent among females and less educated patients. Factors independently associated with both depressive and anxiety symptoms were post-traumatic stress disorder symptoms, low level of self-esteem, high somatic symptoms, low physical and mental health component scores, active smoking, physical inactivity, and longer disease duration. Patients with depressive and anxiety symptoms also reported poor social support and lower resilience. CONCLUSION: There was a high level of depression and anxiety in this sample of cardiac patients. The results point to characteristics of patients in particular need for mental health screening and suggest possible targets for intervention such as strengthening of social support and of physical activity. The integration of mental health services into cardiac rehabilitation in Palestine and comparable cultural settings is warranted from the time of first diagnosis and onward.


Assuntos
Transtornos de Ansiedade/complicações , Ansiedade/complicações , Doenças Cardiovasculares/complicações , Depressão/complicações , Transtorno Depressivo/complicações , Saúde Mental , Idoso , Ansiedade/epidemiologia , Transtornos de Ansiedade/epidemiologia , Árabes , Doenças Cardiovasculares/psicologia , Estudos Transversais , Depressão/epidemiologia , Transtorno Depressivo/epidemiologia , Exercício Físico , Feminino , Hospitalização , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Oriente Médio/epidemiologia , Prevalência , Escalas de Graduação Psiquiátrica , Autoimagem , Apoio Social , Transtornos de Estresse Pós-Traumáticos/complicações , Inquéritos e Questionários
8.
Clin Microbiol Infect ; 25(1): 107.e1-107.e7, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29581053

RESUMO

OBJECTIVES: To describe the prevalence of respiratory pathogens in tuberculosis (TB) patients and in their household contact controls, and to determine the clinical significance of respiratory pathogens in TB patients. METHODS: We studied 489 smear-positive adult TB patients and 305 household contact controls without TB with nasopharyngeal swab samples within an ongoing prospective cohort study in Dar es Salaam, Tanzania, between 2013 and 2015. We used multiplex real-time PCR to detect 16 respiratory viruses and seven bacterial pathogens from nasopharyngeal swabs. RESULTS: The median age of the study participants was 33 years; 61% (484/794) were men, and 21% (168/794) were HIV-positive. TB patients had a higher prevalence of HIV (28.6%; 140/489) than controls (9.2%; 28/305). Overall prevalence of respiratory viral pathogens was 20.4% (160/794; 95%CI 17.7-23.3%) and of bacterial pathogens 38.2% (303/794; 95%CI 34.9-41.6%). TB patients and controls did not differ in the prevalence of respiratory viruses (Odds Ratio [OR] 1.00, 95%CI 0.71-1.44), but respiratory bacteria were less frequently detected in TB patients (OR 0.70, 95%CI 0.53-0.94). TB patients with both respiratory viruses and respiratory bacteria were likely to have more severe disease (adjusted OR [aOR] 1.6, 95%CI 1.1-2.4; p 0.011). TB patients with respiratory viruses tended to have more frequent lung cavitations (aOR 1.6, 95%CI 0.93-2.7; p 0.089). CONCLUSIONS: Respiratory viruses are common for both TB patients and household controls. TB patients may present with more severe TB disease, particularly when they are co-infected with both bacteria and viruses.


Assuntos
Bactérias/isolamento & purificação , Coinfecção/epidemiologia , Tuberculose/microbiologia , Tuberculose/virologia , Vírus/isolamento & purificação , Adulto , Estudos de Casos e Controles , Coinfecção/microbiologia , Coinfecção/virologia , Características da Família , Feminino , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Nasofaringe/microbiologia , Nasofaringe/virologia , Razão de Chances , Prevalência , Estudos Prospectivos , Escarro/microbiologia , Tanzânia/epidemiologia , Tuberculose/epidemiologia , Tuberculose Pulmonar , Adulto Jovem
9.
Sci Rep ; 8(1): 3933, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500454

RESUMO

Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (Ptime*group = 0.195), hormone-sensitive lipase (HSL) (Ptime*group = 0.458), HSL-ser660 phosphorylation (Ptime*group = 0.340), NP receptor-A (NPRA) (Ptime*group = 0.829) and OXPHOS complexes (Ptime*group = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Obesidade/metabolismo , Proteínas/metabolismo , Tetrazóis/uso terapêutico , Transcriptoma , Tecido Adiposo/metabolismo , Adulto , Aminobutiratos/farmacologia , Anlodipino/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Compostos de Bifenilo , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Gordura Subcutânea/metabolismo , Tetrazóis/farmacologia , Valsartana
10.
Clin Pharmacol Ther ; 101(2): 254-263, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27542885

RESUMO

Natriuretic peptide (NP) deficiency and sustained renin-angiotensin system activation are associated with impaired oxidative metabolism and predispose to type-2 diabetes. We hypothesized that sacubitril/valsartan (LCZ696), which augments NP through neprilysin inhibition while blocking angiotensin II type-1 (AT1 )-receptors, improves insulin sensitivity, lipid mobilization, and oxidation. After 8 weeks of treatment of obese patients with hypertension, sacubitril/valsartan 400 mg q.d., but not amlodipine 10 mg q.d., was associated with a significant increase from baseline in the insulin sensitivity index (hyperinsulinemic-euglycemic clamp), and tended to be higher in patients treated with sacubitril/valsartan compared to amlodipine. Abdominal adipose tissue interstitial glycerol concentrations increased with sacubitril/valsartan, but decreased with amlodipine. Whole-body lipolysis and substrate oxidation did not change with either treatment. Results confirm that sacubitril/valsartan treatment leads to a metabolic benefit in the study population and supports the relevance of neprilysin inhibition along with AT1 -receptor blockade in the regulation of human glucose and lipid metabolism.


Assuntos
Aminobutiratos/farmacologia , Anti-Hipertensivos/farmacologia , Resistência à Insulina/fisiologia , Neprilisina/antagonistas & inibidores , Obesidade/metabolismo , Tetrazóis/farmacologia , Tecido Adiposo/efeitos dos fármacos , Adulto , Aminobutiratos/uso terapêutico , Anlodipino/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Compostos de Bifenilo , Combinação de Medicamentos , Metabolismo Energético/efeitos dos fármacos , Feminino , Glicerol/análise , Humanos , Hipertensão/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Peptídeos Natriuréticos/genética , Peptídeos Natriuréticos/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Tetrazóis/uso terapêutico , Valsartana
11.
Drug Alcohol Depend ; 159: 181-9, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26775284

RESUMO

BACKGROUND: Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use. METHODS: Eight male rhesus monkeys with long histories of intravenous methamphetamine self-administration were evaluated 1 day, and 1, 4, 12, 26, and 52 weeks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. A control group consisted of 10 age and gender matched drug naïve monkeys. Cardiovascular responses to methamphetamine were followed for 2.5h. Echocardiograms were acquired at 3 and 12 months of abstinence and in the control animals. RESULTS: No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased heart rate and blood pressure in controls. However, immediately following the self-administration period, the blood pressure response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150-min average heart rate increases, as well as peak blood pressure increases following methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. Echocardiography demonstrated decreased left ventricular ejection fraction and cardiac output at 3 months of abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence. CONCLUSIONS: Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Metanfetamina/administração & dosagem , Metanfetamina/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Estudos de Casos e Controles , Tolerância a Medicamentos , Ecocardiografia , Macaca mulatta , Masculino , Metanfetamina/sangue , Autoadministração , Fatores de Tempo
12.
Clin Neuroradiol ; 25 Suppl 2: 259-66, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26329611

RESUMO

Pharmacological magnetic resonance imaging (phMRI) of the central nervous system (CNS) addresses the increasing demands in the biopharma industry for new methods that can accurately predict, as early as possible, whether novel CNS agents will be effective and safe. Imaging of physiological and molecular-level function can provide a more direct measure of a drug mechanism of action, enabling more predictive measures of drug activity. The availability of phMRI of the nervous system within the professional infrastructure of the Clinical Research Center (CRC) Hannover as proof of concept center ensures that advances in basic science progress swiftly into benefits for patients. Advanced standardized MRI techniques including quantitative MRI, kurtosis determination, functional MRI, and spectroscopic imaging of the entire brain are necessary for phMRI. As a result, MR scanners will evolve into high-precision measuring instruments for assessment of desirable and undesirable effects of drugs as the basic precondition for individually tailored therapy. The CRC's Imaging Unit with high-end large-scale equipment will allow the following unique opportunities: for example, identification of MR-based biomarkers to assess the effect of drugs (surrogate parameters), establishment of normal levels and reference ranges for MRI-based biomarkers, evaluation of the most relevant MRI sequences for drug monitoring in outpatient care. Another very important prerequisite for phMRI is the MHH Core Facility as the scientific and operational study unit of the CRC partner Hannover Medical School. This unit is responsible for the study coordination, conduction, complete study logistics, administration, and application of the quality assurance system based on required industry standards.


Assuntos
Encefalopatias/tratamento farmacológico , Encefalopatias/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Monitoramento de Medicamentos/métodos , Imageamento por Ressonância Magnética/métodos , Encefalopatias/metabolismo , Humanos , Espectroscopia de Ressonância Magnética/métodos , Imagem Molecular/métodos , Resultado do Tratamento
13.
Chem Commun (Camb) ; 51(43): 8990-3, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25932702

RESUMO

A 7-step synthesis of pharbinilic acid, a member of the gibberellin family of natural products and the first naturally occurring allogibberic acid, is reported. An efficient decarboxylative aromatization reaction enables the synthesis of pharbinilic acid and related analogs for evaluation as modulators of NF-κB activity. Remarkably, one analog displays a 2 µM IC50 in an NF-κB activity assay and inhibits an endogenous NF-κB-regulated pathway.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/química , NF-kappa B/antagonistas & inibidores , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Catálise , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Interleucina-1beta/farmacologia , NF-kappa B/genética , NF-kappa B/metabolismo , Paládio/química , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos
14.
Clin Neurophysiol ; 126(2): 268-74, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24996926

RESUMO

OBJECTIVE: To compare the reliability of a newly developed Matlab® toolbox for the fully automated, pre- and post-processing of resting state EEG (automated analysis, AA) with the reliability of analysis involving visually controlled pre- and post-processing (VA). METHODS: 34 healthy volunteers (age: median 38.2 (20-49), 82% female) had three consecutive 256-channel resting-state EEG at one year intervals. Results of frequency analysis of AA and VA were compared with Pearson correlation coefficients, and reliability over time was assessed with intraclass correlation coefficients (ICC). RESULTS: Mean correlation coefficient between AA and VA was 0.94±0.07, mean ICC for AA 0.83±0.05 and for VA 0.84±0.07. CONCLUSION: AA and VA yield very similar results for spectral EEG analysis and are equally reliable. AA is less time-consuming, completely standardized, and independent of raters and their training. SIGNIFICANCE: Automated processing of EEG facilitates workflow in quantitative EEG analysis.


Assuntos
Eletroencefalografia/métodos , Eletroencefalografia/normas , Potenciais Evocados Visuais/fisiologia , Descanso/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
15.
Neuroscience ; 269: 35-42, 2014 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-24662847

RESUMO

The islet-antigens IA-2 and IA-2ß are major autoantigens in type-1 diabetes and transmembrane proteins in dense core vesicles (DCV). Recently we showed that deletion of both IA-2 and IA-2ß alters the secretion of hormones and neurotransmitters and impairs behavior and learning. The present study was designed to evaluate the contribution to learning of each of these genes by using single knockout (SKO) and double knockout (DKO) mice in an active avoidance test. After 5 days of training, wild-type (WT) mice showed 60-70% active avoidance responses, whereas the DKO mice showed only 10-15% active avoidance responses. The degree of active avoidance responses in the IA-2 SKO mice was similar to that of the DKO mice, but in contrast, the IA-2ß SKO mice behaved like WT mice showing 60-70% active avoidance responses. Molecular studies revealed a marked decrease in the phosphorylation of the cAMP response element-binding protein (CREB) and Ca(2+)/calmodulin-dependent protein kinase II (CAMKII) in the striatum and hippocampus of the IA-2 SKO and DKO mice, but not in the IA-2ß SKO mice. To evaluate the role of CREB and CAMKII in the SKO and DKO mice, GBR-12909, which selectively blocks the dopamine uptake transporter and increases CREB and CAMKII phosphorylation, was administered. GBR-12909 restored the phosphorylation of CREB and CAMKII and increased active avoidance learning in the DKO and IA-2 SKO to near the normal levels found in the WT and IA-2ß SKO mice. We conclude that in the absence of the DCV protein IA-2, active avoidance learning is impaired.


Assuntos
Aprendizagem da Esquiva/fisiologia , Corpo Estriado/fisiologia , Hipocampo/fisiologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Western Blotting , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Corpo Estriado/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Heterozigoto , Hipocampo/efeitos dos fármacos , Homozigoto , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Piperazinas/farmacologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/genética , Especificidade da Espécie
16.
Clin Neurophysiol ; 125(9): 1889-92, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24555924

RESUMO

OBJECTIVE: Little is known about optimal timing of multimodal evoked potential (EP)-investigations regarding prediction of MS disability. The aim of this study was to investigate whether timing of EP-investigations during a relapse or in the relapse-free interval influences prediction of MS disability. METHODS: Two groups of MS patients with similar age and gender distributions received visual, motor and somatosensory EPs either during a relapse (Group 1) or in the relapse-free interval (Group 2). Expanded Disability Status Score (EDSS) was obtained at baseline (T0) and year 3 (T2). Linear regression analysis was performed to examine the association between EDSS(T2) and a baseline EP compound measure (s-EP-Q(T0)) for each group. RESULTS: Median EDSS(T0) was 3.0 for Group 1 and 1.5 for Group 2. Mean disease durations were 2.0 and 2.8 years, respectively. Median EDSS(T2) was 2.0 for both groups. The s-EP-Q(T0) significantly predicted EDSS(T2) (R(2)=0.47) for patients in Group 2, but not for patients in Group 1 (R(2)=0.07). CONCLUSION: In early MS the functional remnants of relapses are a better predictor for development of medium-term disability than is the extent of impulse propagation impairment measured during relapse. SIGNIFICANCE: This suggests a role of multimodal EPs in prediction of MS disability if performed in the relapse-free interval.


Assuntos
Avaliação da Deficiência , Potenciais Evocados/fisiologia , Esclerose Múltipla/fisiopatologia , Adulto , Pessoas com Deficiência , Eletroencefalografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva
18.
Occup Environ Med ; 71(4): 234-40, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24213563

RESUMO

OBJECTIVES: We evaluated interactions between SERPINA1 PiMZ genotype, associated with intermediate α1-antitrysin deficiency, with outdoor particulate matter ≤10 µm (PM10), and occupational exposure to vapours, dusts, gases and fumes (VGDF), and their effects on annual change in lung function. METHODS: Pre-bronchodilator spirometry was performed in 3739 adults of the Swiss Cohort Study on Air Pollution and Lung Disease in Adults (SAPALDIA) for whom SERPINA1 genotypes were available. At baseline in 1991, participants were aged 18-62 years; follow-up measurements were conducted from 2001 to 2003. In linear mixed regression models of annual change in lung function, multiplicative interactions were evaluated between PiMZ genotype (PiMM as reference) and change in PM10 (µg/m(3)), and VGDF exposure (high-level, low-level or no exposure as reference) during follow-up. RESULTS: Annual declines in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%) (-82 mL/s, 95% CI -125 to -39) and forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC) (-0.3%, 95% CI -0.6% to 0.0%) in association with VGDF exposure were observed only in PiMZ carriers (Pinteraction<0.0001 and Pinteraction=0.03, respectively). A three-way interaction between PiMZ genotype, smoking and VGDF exposure was identified such that VGDF-associated FEF25-75% decline was observed only in ever smoking PiMZ carriers (Pinteraction=0.01). No interactions were identified between PiMZ genotype and outdoor PM10. CONCLUSIONS: SERPINA1 PiMZ genotype, in combination with smoking, modified the association between occupational VGDF exposure and longitudinal change in lung function, suggesting that interactions between these factors are relevant for lung function decline. These novel findings warrant replication in larger studies.


Assuntos
Genótipo , Pneumopatias/genética , Pulmão/fisiopatologia , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Material Particulado/efeitos adversos , alfa 1-Antitripsina/genética , Adolescente , Adulto , Poluição do Ar/efeitos adversos , Estudos de Coortes , Poeira , Feminino , Seguimentos , Volume Expiratório Forçado , Gases , Predisposição Genética para Doença , Humanos , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/etiologia , Doenças Profissionais/fisiopatologia , Fumar/efeitos adversos , Espirometria , Suíça , Capacidade Vital , Adulto Jovem , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genética
19.
Eur J Nucl Med Mol Imaging ; 41(2): 214-22, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24085501

RESUMO

PURPOSE: Somatostatin-based radiopeptide treatment is generally performed using the ß-emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. METHODS: In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y-DOTA]-TOC or [(177)Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. RESULTS: Overall, 910 patients underwent 1,804 cycles of [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(90)Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [(177)Lu-DOTA]-TOC over [(90)Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [(177)Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). CONCLUSION: The present results revealed no difference in median overall survival after [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.


Assuntos
Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Adolescente , Adulto , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Resultado do Tratamento
20.
Anaesthesist ; 62(8): 632-8, 2013 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-23925461

RESUMO

INTRODUCTION: Most surgery of the lumbar spine is performed with the patient under general anesthesia (GA); however, qualitative benefits of spinal anesthesia (SA) have been reported. The goal of this study was to compare time efficiency between these two anesthesia methods in lumbar spine surgery. To test the hypothesis that the use of SA leads to significant time saving compared to GA for lumbar spine surgery, key points in the preoperative, intraoperative and postoperative anesthesiology care times were analyzed. The focus was on anesthesia time excluding surgery time. MATERIALS AND METHODS: Electronically based data of 473 anesthesia procedures (368 SA, 105 GA) for lumbar spine interventions performed in the prone position (i. e. decompression, discectomy and transpedicular instrumentation) were analyzed retrospectively. Patient population data including gender, age, American Society of Anesthesiologists (ASA) classification and body mass index (BMI) were analyzed. The focus was on the documented perioperative key time points which are defined as follows: (1) induction, (2) positioning (turning into prone position), (3) scrubbing and covering, (4) surgery time (knife to skin closure), (5) closing (end of surgery until leaving operating room) and (6) handing over to recovery. Differences in the amount of time for each perioperative period were calculated for SA and GA. RESULTS: In 7 out of the 368 SA patients SA failed and had to be converted to GA. There were no significant differences in BMI, ASA prevalence and gender between SA and GA patients but SA patients were significantly older (median 61.7 ± 15.4 years) than GA patients (median 56.1 ± 14.6 years). However, SA required significantly less time for induction (SA: 17.7 ± 7.0 min, GA: 21.6 ± 7.2 min), preoperative preparation (SA: 9.7 ± 3.6 min, GA: 13.3 ± 5.4 min) and closing period (SA: 4.9 ± 1.1 min, GA: 15.3 ± 5.7 min) compared to GA. Total anesthesia time with exclusion of the surgery time revealed a significant time reduction using SA of 19 min (95 % confidence interval: range 13.6-24.4 min, median in SA: 56.7 min, median in GA: 75.7 min, p < 0.0001). CONCLUSIONS: This study showed that in lumbar spine surgery 19 min of anesthesia time can be saved using SA compared to GA which could have an impact on economic aspects. Gender, BMI and ASA had no statistically detectable influence on the choice between the two anesthesia methods. The fact that time-intensive complex instrumentation is mainly performed in younger patients may explain why GA patients were younger than SA patients.


Assuntos
Anestesia por Inalação , Raquianestesia , Região Lombossacral/cirurgia , Assistência Perioperatória/métodos , Coluna Vertebral/cirurgia , Adulto , Fatores Etários , Idoso , Período de Recuperação da Anestesia , Anestesia por Inalação/efeitos adversos , Raquianestesia/efeitos adversos , Índice de Massa Corporal , Feminino , Humanos , Intubação Intratraqueal , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Transferência da Responsabilidade pelo Paciente , Assistência Perioperatória/estatística & dados numéricos , Decúbito Ventral , Estudos Retrospectivos , Fatores Sexuais , Fatores de Tempo
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