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1.
Artigo em Inglês | MEDLINE | ID: mdl-34506942

RESUMO

OBJECTIVE: To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). METHODS: Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2-/- mice. Half of the DMM-WT mice and all other cohorts (n = 6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n = 6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033 mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4-6-day-old WT and Camkk2-/- mice, and treated with 10 ng/ml interleukin-1ß (IL)-1ß for 24 or 48 h to investigate gene and protein expression. RESULTS: CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1ß treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1ß, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1ß-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. CONCLUSIONS: Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.

2.
Ann Oncol ; 32(9): 1178-1187, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34139273

RESUMO

BACKGROUND: Clinical management of soft tissue sarcoma (STS) is particularly challenging. Here, we used digital pathology and deep learning (DL) for diagnosis and prognosis prediction of STS. PATIENTS AND METHODS: Our retrospective, multicenter study included a total of 506 histopathological slides from 291 patients with STS. The Cancer Genome Atlas cohort (240 patients) served as training and validation set. A second, multicenter cohort (51 patients) served as an additional test set. The use of the DL model (DLM) as a clinical decision support system was evaluated by nine pathologists with different levels of expertise. For prognosis prediction, 139 slides from 85 patients with leiomyosarcoma (LMS) were used. Area under the receiver operating characteristic (AUROC) and accuracy served as main outcome measures. RESULTS: The DLM achieved a mean AUROC of 0.97 (±0.01) and an accuracy of 79.9% (±6.1%) in diagnosing the five most common STS subtypes. The DLM significantly improved the accuracy of the pathologists from 46.3% (±15.5%) to 87.1% (±11.1%). Furthermore, they were significantly faster and more certain in their diagnosis. In LMS, the mean AUROC in predicting the disease-specific survival status was 0.91 (±0.1) and the accuracy was 88.9% (±9.9%). Cox regression showed the DLM's prediction to be a significant independent prognostic factor (P = 0.008, hazard ratio 5.5, 95% confidence interval 1.56-19.7) in these patients, outperforming other risk factors. CONCLUSIONS: DL can be used to accurately diagnose frequent subtypes of STS from conventional histopathological slides. It might be used for prognosis prediction in LMS, the most prevalent STS subtype in our cohort. It can also help pathologists to make faster and more accurate diagnoses. This could substantially improve the clinical management of STS patients.


Assuntos
Aprendizado Profundo , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Prognóstico , Estudos Retrospectivos , Sarcoma/diagnóstico
3.
J Orthop Surg Res ; 16(1): 378, 2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34120628

RESUMO

BACKGROUND: Patellar instability has a high incidence and occurs particularly in young and female patients. If the patella dislocates for the first time, treatment is usually conservative. However, this cautious approach carries the risk of recurrence and of secondary pathologies such as osteochondral fractures. Moreover, there is also risk of continuous symptoms apparent, as recurrent patella dislocation is related to patellofemoral osteoarthritis as well. An initial surgical treatment could possibly avoid these consequences of recurrent patella dislocation. METHODS: A prospective, randomized-controlled trial design is applied. Patients with unilateral first-time patella dislocation will be considered for participation. Study participants will be randomized to either conservative treatment or to a tailored patella stabilizing treatment. In the conservative group, patients will use a knee brace and will be prescribed outpatient physical therapy. The surgical treatment will be performed in a tailored manner, addressing the pathologic anatomy that predisposes to patella dislocation. The Banff Patellofemoral Instability-Instrument 2.0, recurrence rate, apprehension test, joint degeneration, and the Patella Instability Severity Score will serve as outcome parameters. The main analysis will focus on the difference in change of the scores between the two groups within a 2-year follow-up. Statistical analysis will use linear mixed models. Power analysis was done for the comparison of the two study arms at 2-year follow-up with regard to the BPII Score. A sample size of N = 64 per study arm (128 overall) provides 80% power (alpha = 0.05, two-tailed) to detect a difference of 0.5 standard deviations in a t-test for independent samples. DISCUSSION: Although several studies have already dealt with this issue, there is still no consensus on the ideal treatment concept for primary patellar dislocation. Moreover, most of these studies show a unified surgical group, which means that all patients were treated with the same surgical procedure. This is regarded as a major limitation as surgical treatment of patella dislocation should depend on the patient's anatomic pathologies leading to patellar instability. To our knowledge, this is the first study investigating whether patients with primary patella dislocation are better treated conservatively or operatively with tailored surgery to stabilize the patella. TRIAL REGISTRATION: The study will be prospectively registered in the publicly accessible database www.ClinicalTrials.gov .


Assuntos
Tratamento Conservador/métodos , Procedimentos Ortopédicos/métodos , Osteoartrite do Joelho/cirurgia , Patela/cirurgia , Luxação Patelar/cirurgia , Articulação Patelofemoral/cirurgia , Medicamentos Biossimilares , Braquetes , Feminino , Humanos , Masculino , Modalidades de Fisioterapia , Estudos Prospectivos , Recidiva , Prevenção Secundária , Fatores de Tempo , Resultado do Tratamento
4.
Skeletal Radiol ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33851252

RESUMO

OBJECTIVE: During the COVID-19 pandemic, the number of patients presenting in hospitals because of emergency conditions decreased. Radiology is thus confronted with the effects of the pandemic. The aim of this study was to use natural language processing (NLP) to automatically analyze the number and distribution of fractures during the pandemic and in the 5 years before the pandemic. MATERIALS AND METHODS: We used a pre-trained commercially available NLP engine to automatically categorize 5397 radiological reports of radiographs (hand/wrist, elbow, shoulder, ankle, knee, pelvis/hip) within a 6-week period from March to April in 2015-2020 into "fracture affirmed" or "fracture not affirmed." The NLP engine achieved an F1 score of 0.81 compared to human annotators. RESULTS: In 2020, we found a significant decrease of fractures in general (p < 0.001); the average number of fractures in 2015-2019 was 295, whereas it was 233 in 2020. In children and adolescents (p < 0.001), and in adults up to 65 years (p = 0.006), significantly fewer fractures were reported in 2020. The number of fractures in the elderly did not change (p = 0.15). The number of hand/wrist fractures (p < 0.001) and fractures of the elbow (p < 0.001) was significantly lower in 2020 compared with the average in the years 2015-2019. CONCLUSION: NLP can be used to identify relevant changes in the number of pathologies as shown here for the use case fracture detection. This may trigger root cause analysis and enable automated real-time monitoring in radiology.

6.
Pneumologie ; 74(11): 773-779, 2020 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-33202438

RESUMO

The new ATS/ERS/ESCMID/IDSA guideline answers 22 PICO questions on the treatment of lung diseases caused by Mycobacterium avium complex (MAC), M. kansasii, M. xenopi and M. abscessus. NON-TUBERCULOUS MYCOBACTERIA (NTM) LUNG DISEASE: Especially in patients with microscopic detection of acid-fast bacteria in sputum or with cavernous disease manifestation, the start of treatment should not be delayed. Treatment should be based on species-specific resistance testing (according to the CLSI guidelines). In selected patients, adjuvant surgical resection after consultation with an expert is recommended. MAC LUNG DISEASE: Therapy is based on a regimen with at least three drugs including a macrolide (rather azithromycin than clarithromycin) and ethambutol. For patients with cavitation, with pronounced nodular bronchiectatic disease or with macrolide resistance, daily oral therapy should be expanded by parenteral amikacin or streptomycin. Liposomally encapsulated amikacin for inhalation is recommended in patients with treatment failure. Patients with nodular-bronchiectatic disease manifestation should receive oral macrolide-based therapy, which - depending on the extent - can be given 3 times a week. The recommended duration is 12 months after conversion of the sputum culture. M. KANSASII LUNG DISEASE: The triple combination of rifampicin, ethambutol and macrolide (or isoniazid) is recommended for at least 12 months. In patients with rifampicin resistance or intolerance, moxifloxacin is recommended as a replacement. M. XENOPI LUNG DISEASE: The combination of rifampicin, ethambutol and macrolide (and/or moxifloxacin) is recommended for at least 12 months after conversion of the sputum culture. For patients with cavernous disease manifestation, it is recommended to add at least parenteral amikacin and to consult experts. M. ABSCESSUS LUNG DISEASE: At least 3, in the beginning rather 4 drugs are recommended for therapy. The choice of substance should be based on a in vitro resistance test. Macrolides are the basis, but should not be counted in patients with strains with inducible macrolide resistance. Due to the lack of data, no explicit recommendations are made regarding the duration of therapy; a consultation of experts is recommended.


Assuntos
Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas/isolamento & purificação , Guias de Prática Clínica como Assunto , Escarro/microbiologia , Quimioterapia Combinada , Humanos , Macrolídeos/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Micobactérias não Tuberculosas/efeitos dos fármacos
7.
Pneumologie ; 74(9): 615-620, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32916744

RESUMO

PATIENT HISTORY AND CLINICAL FINDINGS: A 46-year old construction worker presented at the emergency department with two orthostatic syncopes. The patient complained of prolonged fever and coughs for 7 days which had not improved after oral treatment with sultamicillin for 5 days, prescribed by the patient's general practitioner. Physical examination showed high blood pressure due to previously known hypertension. Other vital signs without pathological findings. Pulmonary auscultation showed basal soft crackling noises of the left lung. FINDINGS AND DIAGNOSIS: Laboratory examination showed increased values for LDH, pro-BNP and CRP and normal values for leucocytes and procalcitonin. Conventional X-Ray of the chest showed bipulmonal lateral atypical infiltrates. After the first PCR turned in negative another PCR-analysis for SARS-CoV-2 of a deep oral swab-sample was performed since the clinical, laboratory and radiological findings were typical for COVID-19. Again, SARS-CoV-2-RNA was not detected. A CT-scan of the chest showed bipulmonal lateral ground-glass attenuation, again typical for COVID-19 associated pneumonia. After a third attempt for a PCR-analysis of a deep oral swab-sample was negative, analysis of a sputum was performed which finally confirmed the diagnosis of COVID-19 associated pneumonia. THERAPY AND COURSE OF EVENTS: The patient was admitted for evaluation of syncopes and suspect of COVID-19 associated pneumonia. The patient was prophylactically isolated while the result of SARS-CoV-2-PCR from a deep oral swab was pending. Suspecting a possible secondary bacterial infection at the beginning, intravenous antibiotic treatment with ampicillin/sulbactam was initiated. While further examinations showed no indication for bacterial infection, antibiotics were discontinued after 3 days. Due to clinical recovery antiviral therapy was not performed after confirming the diagnosis. The patient was discharged 17 days after onset of first symptoms without any requirements for further isolation. CONCLUSION: This casuistic describes a case of COVID-19 associated pneumonia presenting with typical clinical features, laboratory and radiological findings. Detection of viral RNA was not successful from deep oral swab-samples despite repeated attempts. Finally, PCR-analysis of sputum confirmed the diagnosis. Analysis of deeper airway samples (sputum, bronchoalveolar lavage, tracheal secretions) or stool for SARS-CoV-2 should be performed in cases of evident clinical suspicion of COVID-19 and negative PCR results from deep oral swabs.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Betacoronavirus/isolamento & purificação , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Humanos , Pulmão/diagnóstico por imagem , Pessoa de Meia-Idade , Orofaringe/virologia , Pandemias , Reação em Cadeia da Polimerase , RNA Viral/isolamento & purificação , Radiografia Torácica , SARS-CoV-2
8.
Nanotechnology ; 31(45): 455403, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-32698167

RESUMO

Numerical optimization has been used to determine the optimum junction design for core-shell nanowires used in betavoltaic generators. A genetic algorithm has been used to calculate the relative thickness, height, and doping of each segment within silicon, gallium arsenide, and gallium phosphide nanowires. Using the simulated spectra and energy deposition of nickel-63, nickel citrate, tritium, and tritiated butyl, devices with power output and overall efficiency up to 8 µW.cm-2 and 12%, respectively, have been predicted. Compared to previously investigated axial nanowires, the core-shell structures simulated here have realized drastic improvements by reducing surface recombination for longer nanowires. In addition, core-shell nanowires are shown to be capable of nearly matching the ideal performance predicted for this device structure. A new approach for calculating the practical upper limit of betavoltaic performance is presented and additional methods for improvement are discussed.

10.
J Hosp Infect ; 104(2): 214-235, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31715282

RESUMO

Mycobacterial infection-related morbidity and mortality in patients following cardiopulmonary bypass surgery is high and there is a growing need for a consensus-based expert opinion to provide international guidance for diagnosing, preventing and treating in these patients. In this document the International Society for Cardiovascular Infectious Diseases (ISCVID) covers aspects of prevention (field of hospital epidemiology), clinical management (infectious disease specialists, cardiac surgeons, ophthalmologists, others), laboratory diagnostics (microbiologists, molecular diagnostics), device management (perfusionists, cardiac surgeons) and public health aspects.


Assuntos
Infecção Hospitalar , Infecções por Mycobacterium não Tuberculosas , Mycobacterium , Antibacterianos/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiologia , Ponte Cardiopulmonar , Doenças Transmissíveis , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Infecção Hospitalar/prevenção & controle , Contaminação de Equipamentos , Humanos , Mycobacterium/isolamento & purificação , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/prevenção & controle , Fatores de Risco , Sociedades Médicas , Reino Unido
11.
Injury ; 50(11): 1966-1973, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31492514

RESUMO

Fragility fractures of the pelvis (FFP) are an increasing entity among elderly persons. Characteristics are different from high-energy pelvic trauma. Little is known about the natural course of FFP in conservative and after operative treatment. MATERIALS AND METHODS: Medical charts and radiologic data of 148 patients with an FFP, who were admitted in a 3-year period, were analysed retrospectively. Incidence and characteristics of fracture progression (FP) were noted. RESULTS: Patients presenting early after a traumatic event had more often non-displaced fractures, fractures with lower FFP Type classification and were more frequently treated conservatively. FP was observed in 21 cases (14.2%), twenty times after conservative and once after operative treatment. FP under conservative treatment occurred in female patients only. Patients with FP were younger than patients without. FP occurred in all fracture types, most frequently in FFP Type I. A second CT scan was positive for FP in 39.2% of patients with prolonged pain or restricted mobility. CONCLUSION: FP is a real phenomenon, occurring in a minority of FFP patients. Female patients are at highest risk. Repeated CT scan is positive in nearly 40% of patients with continuing pain or restricted mobility. Operative treatment is a good preventive measure of FP as FP does only exceptionally occur after operative fixation of FFP.


Assuntos
Tratamento Conservador , Fixação Interna de Fraturas , Fraturas por Osteoporose/fisiopatologia , Ossos Pélvicos/lesões , Idoso , Conservadores da Densidade Óssea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/terapia , Ossos Pélvicos/diagnóstico por imagem , Ossos Pélvicos/cirurgia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
J Hum Nutr Diet ; 32(6): 781-788, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31334579

RESUMO

BACKGROUND: Novel and innovative imaging methods that rapidly estimate body fat percentage (%BF) are publicly available, yet little is known about their accuracy. The present study evaluated the test-retest reliability of a two-dimensional iPad (Apple, Inc., Cupertino, CA, USA) application (2D APP) and a three-dimensional body scanner (3D SCAN) for estimating %BF and compared both imaging methods with air displacement plethysmography (Bod Pod; Cosmed USA, Inc., Concord, CA, USA). METHODS: Seventy-nine adults (37 female, 42 male) varying widely in age [mean (SD), range] [32.9 (12.4), 18-65 years] and body mass index [25.0 (4.9), 18.2-41.8 kg m-2 ] were measured with the Bod Pod and twice with the 3D SCAN and the 2D APP in a repeated-measures design. RESULTS: Test-retest reliability was excellent for both the 2D APP (intraclass correlation = 0.993) and the 3D SCAN (intraclass correlation = 0.993) with the SEM <1% BF for both methods. Although the three methods were highly correlated with each other (r = 0.857-0.923), the mean %BF estimations were significantly different (P = 0.001). The 2D APP [19.9 (8.2)%BF] underestimated the Bod Pod value [21.9 (9.4)%BF] and the 3D SCAN [24.0 (6.8)%BF] overestimated. Additionally, the SE of estimate and total error exceeded 4% BF for both 2D APP and 3D SCAN, and both methods tended to overestimate lean participants and underestimate fat participants. CONCLUSIONS: Although highly reliable, neither the 2D APP, nor the 3D SCAN provided valid estimates of %BFB od Pod .


Assuntos
Composição Corporal , Diagnóstico por Imagem/instrumentação , Diagnóstico por Imagem/métodos , Pletismografia/métodos , Adiposidade , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Computadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fotografação/instrumentação , Fotografação/métodos , Reprodutibilidade dos Testes , Adulto Jovem
13.
Meat Sci ; 155: 109-114, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31103942

RESUMO

The purpose of this study was to determine the effect of captive bolt lengths on penetration hole characteristics, brain damage, and specified risk material (SRM) dispersal. Cattle were stunned with a pneumatic captive bolt stunner using: standard (15.2 cm; STRD), medium (16.5 cm; MED), or long (17.8 cm; LON) bolts. Heads (N = 293) and exsanguination blood (N = 103) were collected for analyses. Penetration hole diameter and depth differed by treatment (P ≤ 0.004); both parameters were greatest for LON (P < 0.05). Presence of damage in frontal, parietal, and occipital lobes, olfactory bulb, and collective area including the corpus callosum, fornix and thalamus were impacted by treatment (P < 0.003). Treatment did not impact SRM dispersal (P = 0.33), determined by presence of glial acidic fibrillary protein. Data suggest that bolt length affects both the extent of brain damage and the specific structures damaged but all bolt lengths are successful in causing substantial brain damage and subsequent insensibility.


Assuntos
Matadouros , Lesões Encefálicas Traumáticas/patologia , Imobilização/métodos , Bem-Estar do Animal , Animais , Bovinos , Proteína Glial Fibrilar Ácida/sangue , Traumatismos Cranianos Penetrantes/veterinária , Imobilização/instrumentação
14.
Pesqui. vet. bras ; 39(5): 348-354, May 2019. tab, graf
Artigo em Inglês | ID: biblio-1012752

RESUMO

Pelvis is an osteoligamentous complex, which is classified as dolichopellic in ruminants. Impairments linked to incompatibility of pelvic canal and fetal size is directly related to pelvic anatomy and disposition. Heritability of pelvic area characteristics varies from moderate to high, demonstrating its importance for animal selection. Pelvimetry can be performed through direct and indirect methods that were accessed in this study aiming to establish a correlation between internal and external pelvic dimensions in multiparous Nellore cows (26 animals) at cycling and early puerperal (up to 30 days postpartum) reproductive stages. Pelvic dimensions measured by descriptive analysis were higher at early puerperal stage. Strong Pearson's correlation was determined between internal and external pelvic dimensions, between reproductive stages, and between pelvic girdle area and internal pelvic area. Significant Tukey's test differences between animals in internal and external dimensions were also found. According to the results, the pelvic anatomy of Nellore cows varies according to their reproductive stage. We detach that and provide data regarding the use of internal pelvic area for animal selection studies on this breed is determined and should be measured using the proposed formula, since it can confirm statistical differences in the areas of pelvic components between animals in the cycling and early puerperal stages.(AU)


A pelve é considerada um complexo osteoligamentoso, classificada como dolicopélvica em ruminantes. Prejuízos ligados à incompatibilidade canal pélvico/tamanho fetal relacionam-se diretamente à anatomia e disposição pélvica. A característica de área pélvica apresenta herdabilidade variando de moderada a alta, indicando sua importância na seleção animal. A pelvimetria inclui formas direta e indireta. Neste estudo utilizaram-se vinte e seis vacas multíparas, da raça Nelore, agrupadas de acordo com o estágio reprodutivo, cíclico e em início de estágio puerperal (até 30 dias pós-parto). Através deste, objetivou-se evidenciar a relação das medidas pélvicas internas e externas nos diferentes períodos reprodutivos e coletar obter dados referentes a utilização da área interna do hexágono no estudo pelvimétrico dessa espécie em estágio cíclico ou puerperal. Para tanto, realizou-se, a pelvimetria direta e indireta. Os resultados obtidos, pela análise descritiva, foram maiores para animais em início de estágio puerperal. Por meio da correlação de Pearson podem-se observar fortes correlações entre mensurações pélvicas internas e externas, também entre os grupos propostos, e forte correlação entre elipse pélvica e área interna do hexágono. Pelo teste Tukey diferenças significativas tanto em medidas internas e externas puderam ser demonstradas. Conclui-se que as condições anatômicas da pelve variam de acordo com o estágio reprodutivo do animal, que aferição da área pélvica utilizando a formula proposta para área do hexágono interno é relevante pois foi possível comprovar a diferenças estatísticas de áreas nas fases cíclica e puerperal.(AU)


Assuntos
Animais , Feminino , Bovinos , Pelvimetria/veterinária , Bovinos/anatomia & histologia , Período Pós-Parto
15.
Clin Immunol ; 203: 45-52, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30974290

RESUMO

OBJECTIVE: To determine the role of the NLRP3 inflammasome by using the selective NLRP3 inhibitor MCC950 in patients with NLRP3 low penetrance variants and clinical symptoms suggestive for an autoinflammatory syndrome including central nervous system (CNS) involvement. METHODS: Nineteen symptomatic patients with low penetrance NLRP3 variants (Q703K n = 17, V198M n = 2) recruited between 2011 and 2017 were included in this monocentric study. A functional inflammasome activation assay was performed in patients in comparison to healthy controls (HC), including the determination of interleukin-1beta (IL-1ß), interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α) secretion in the presence of the NLRP3 selective small-molecule inhibitor MCC950. Detailed clinical features were assessed and anti-IL-1 treatment response was determined. RESULTS: Peripheral blood mononuclear cells (PBMC) from patients with low penetrance NLRP3 variants displayed enhanced IL-1ß levels following inflammasome activation compared to HC. Furthermore, IL-1ß release was NLRP3-dependent as it was blocked by MCC950. The production of IL-6 and TNF-α was also increased in patients with low penetrance NLRP3 variants. Clinically, they presented with a heterogenous spectrum of neurological manifestations, while cranial nerve inflammation was the most common feature. Overall inflammasome activation did not correlate with disease severity. Eight of ten treated patients responded to anti IL-1 treatment, however a complete response was only documented in four patients. CONCLUSION: PBMC of several patients with NLRP3 low penetrance variants and CNS manifestation showed increased NLRP3-specific IL-1ß release upon stimulation and elevated NLRP3-independent IL-6 and TNF-α levels as those were not suppressed by MCC950. Our data suggest that beside the possible causal involvement of the NLRP3 inflammasome additional, yet unidentified genetic or environmental factors may contribute to the multi-organ inflammation in our patients and explain the partial response to IL-1 targeting therapies.


Assuntos
Nervos Cranianos/imunologia , Doenças Hereditárias Autoinflamatórias/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças do Sistema Nervoso/imunologia , Adulto , Células Cultivadas , Feminino , Seguimentos , Furanos/farmacologia , Doenças Hereditárias Autoinflamatórias/genética , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Indenos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças do Sistema Nervoso/genética , Penetrância , Sulfonamidas/farmacologia , Sulfonas , Fator de Necrose Tumoral alfa/metabolismo
16.
J Cell Biochem ; 120(6): 9608-9623, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30525230

RESUMO

Several molecules extracted from natural products exhibit different biological activities, such as ion channel modulation, activation of signaling pathways, and anti-inflammatory or antitumor activity. In this study, we tested the antitumor ability of natural compounds extracted from the Raputia praetermissa plant. Among the compounds tested, an alkaloid, here called compound S4 (4-Deoxyraputindole C), showed antitumor effects against human tumor lineages. Compound S4 was the most active against Raji, a lymphoma lineage, promoting cell death with characteristics that including membrane permeabilization, dissipation of the mitochondrial potential, increased superoxide production, and lysosomal membrane permeabilization. The use of cell death inhibitors such as Z-VAD-FMK (caspase inhibitor), necrostatin-1 (receptor-interacting serine/threonine-protein kinase 1 inhibitor), E-64 (cysteine peptidases inhibitor), and N-acetyl- L-cysteine (antioxidant) did not decrease compound S4-dependent cell death. Additionally, we tested the effect of cellular activity on adherent human tumor cells. The highest reduction of cellular activity was observed in A549 cells, a lung carcinoma lineage. In this lineage, the effect on the reduction of the cellular activity was due to cell cycle arrest, without plasma membrane permeabilization, loss of the mitochondrial potential or lysosomal membrane permeabilization. Compound S4 was able to inhibit cathepsin B and L by a nonlinear competitive (negative co-operativity) and simple-linear competitive inhibitions, respectively. The potency of inhibition was higher against cathepsin L. Compound S4 promoted cell cycle arrest at G 0 and G 2 phase, and increase the expression of p16 and p21 proteins. In conclusion, compound S4 is an interesting molecule against cancer, promoting cell death in the human lymphoma lineage Raji and cell cycle arrest in the human lung carcinoma lineage A549.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Alcaloides/química , Alcaloides/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Catepsina B/metabolismo , Catepsina L/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Cinética , Leucemia/patologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Necrose , Rutaceae/química
17.
Infection ; 47(3): 483-487, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30417214

RESUMO

INTRODUCTION: Broncho-esophageal fistula formation is a rare complication of tuberculosis, most often seen in immunocompromised patients. METHODS AND RESULTS: In this paper, we report the case of a young non-immunocompromised refugee from Somalia diagnosed with open pulmonary tuberculosis complicated by extensive osseous involvement and a broncho-esophageal fistula with consecutive aspiration of gastric contents. The patient rapidly developed a severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (ECMO) therapy for nearly 2 months. The fistula was initially treated by standard antituberculous combination therapy and implantation of an esophageal and a bronchial stent. Long-term antibiotic treatment was instituted for pneumonia and mediastinitis. 7 months later, discontinuity resection of the esophagus was performed and the bronchial fistula covered by an intercostal muscle flap. DISCUSSION: This case illustrates that tuberculosis should always be suspected in patients from high-incidence countries in case of lung involvement and that an interdisciplinary approach including long-term intensive care management can enable successful treatment of tuberculosis with severe, near-fatal complications.


Assuntos
Fístula Brônquica/tratamento farmacológico , Fístula Esofágica/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Tuberculose/complicações , Adulto , Fístula Brônquica/diagnóstico , Fístula Brônquica/etiologia , Fístula Brônquica/cirurgia , Fístula Esofágica/diagnóstico , Fístula Esofágica/etiologia , Fístula Esofágica/cirurgia , Oxigenação por Membrana Extracorpórea , Alemanha , Humanos , Masculino , Mediastinite/tratamento farmacológico , Pneumonia/tratamento farmacológico , Refugiados , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Somália/etnologia , Tuberculose/diagnóstico
18.
Sci Total Environ ; 657: 351-364, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30550900

RESUMO

Landslides are common in high-latitude forest ecosystems that have developed on permafrost. The most vulnerable areas in the permafrost territories of Siberia occur on the south-facing slopes of northern rivers, where they are observed on about 20% of the total area of river slopes. Landslide disturbances will likely increase with climate change especially due to increasing summer-autumn precipitation. These processes are the most destructive natural disturbance agent and lead to the complete removal of pre-slide forest ecosystems (vegetation cover and soil). To evaluate postsliding ecosystem succession, we undertook integrated ecological research at landslides of different age classes along the Nizhnyaya Tunguska River and the Kochechum River (Tura, Krasnoyarsk region, Russia). Just after the event (at the one-year-old site), we registered a drop in soil respiration, a threefold lower microbial respiration rate, and a fourfold smaller mineral soil carbon and nitrogen stock at bare soil (melkozem) plots at the middle location of the site as compared with the non-affected control site. The recovery of disturbed areas began with the re-establishment of plant cover and the following accumulation of an organic soil layer. During the 35-year succession (L1972), the accumulated layer (O-layer) at the oldest site contained similar C- and N stocks to those found at the control sites. However, the mineral soil C- and N stocks and the microbial biomass - even of the oldest landslide area - did not reach the value of these parameters in control plots. Later, the soil respiration level and the eco-physiological status of soil microbiota also recovered due to these changes. This study demonstrates that the recovery after landslides in permafrost forests takes several decades. In addition, the degradation of permafrost due to landslides clearly hinders the accumulation of soil organic matter in the mineral soil.


Assuntos
Poluentes Atmosféricos/análise , Dióxido de Carbono/análise , Sequestro de Carbono , Deslizamentos de Terra , Pergelissolo , Solo/química , Carbono/metabolismo , Sibéria
19.
Pathologe ; 39(6): 532-538, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30350175

RESUMO

BACKGROUND: The quantity, distribution, activation status, cytokine profile, and spatial distribution of tumor-infiltrating immune cells have prognostic value and may be predictive of response to immunotherapies. OBJECTIVES: A survey of relevant immune cell populations including their prognostic significance in the most common types of tumors. METHODS: Nonsystematic assessment and a discussion of studies that were conducted to estimate the prognostic significance of certain immune cell subsets and the methodical approaches used. RESULTS: For many tumor entities, prognostically favorable and unfavorable immune cell populations can be differentiated. However, nonspecific cell markers that may partly summarize antithetic immune cell subsets can be employed. Differences in sampling procedures and the determination of cut-off levels further limit the comparability of the studies carried out so far. CONCLUSION: The phenotypic and functional heterogeneity of tumor-infiltrating immune cells requires the use of cell subset-specific antibodies and antibody combinations. Furthermore, harmonized assessment routines, validation studies, and meta-analyses are important prerequisites for potential diagnostic implementation.


Assuntos
Linfócitos do Interstício Tumoral , Neoplasias , Biomarcadores , Humanos , Prognóstico
20.
Epidemiol Infect ; 147: e11, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30236166

RESUMO

Typhoid fever is an illness caused by Salmonella enterica serotype Typhi. In developing regions, it affects an estimated 20 million people annually, causing 200 000 deaths. Although uncommon, cases occur in the USA each year, predominantly due to international travel. During February 2015, the Oklahoma State Department of Health (OSDH) detected an outbreak of typhoid fever among residents of northwestern Oklahoma. OSDH conducted case-patient interviews to identify the source and symptomatic contacts. Whole genome sequencing (WGS) was performed to characterise the genetic relatedness of isolates among the four outbreak-associated pulsed-field gel electrophoresis (PFGE) patterns. We identified 38 cases, 25 confirmed and 13 probable, in two states. WGS revealed a 0-10 single-nucleotide polymorphism variation between isolates. Although we were unable to determine the source, almost all case-patients were members of the Marshallese community that attended a common event in Oklahoma, or were contacts to a confirmed case. This is the largest outbreak of typhoid fever in the USA since 1989, and first to apply WGS to complement interpretation of PFGE results during a typhoid fever outbreak investigation. This investigation illustrates the potential risk of outbreaks among communities comprised of international populations from regions where typhoid fever remains endemic.

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