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1.
World J Urol ; 42(1): 168, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38492077

RESUMO

PURPOSE: To introduce and illustrate a novel urethral reconstruction technique-the 'urethral hammock-technique'-and to assess its impact on early postoperative continence following laparoscopic radical prostatectomy (LRP). METHODS: 119 patients who underwent LRP between January 2020 and May 2022 (hammock group: n = 43, control group: n = 76) were included in the study. The primary outcome was continence (zero pads or max. one security pad) at 1, 3, and 6 months following surgery. Secondary outcomes were operative time, complications, and histological findings. Univariate and multivariate regression analyses were performed to reveal predictors for continence. p values < 0.05 with a two-sided 95%-confidence interval were considered statistically significant. RESULTS: Baseline characteristics were comparable among both groups. The number of patients achieving complete continence in both the hammock and control groups at various time intervals was: 4 weeks 37.2% (16/43) vs. 19.2% (14/73) (p = 0.047); 3 months 60.5% (26/43) vs. 37.3% (28/75) (p = 0.021) and 6 months 72.1% (31/43) vs. 60.3% (44/73) (p = 0.23), respectively. Adjusting for bladder neck preservation status and age, the hammock technique was a significant predictor for continence for the 4-week (OR 0.33, 95% CI 0.13-0.83, p = 0.019) and 3-month (OR 0.28, 95% CI 0.12-0.66, p = 0.004) interval but not for the 6-month interval (OR 0.64, 95% CI 0.27-1.5, p = 0.31). Operative time, complication rates, time till catheter extraction and histological findings were comparable between both groups (all p > 0.05). CONCLUSIONS: The hammock technique is a simple and reproducible technique to improve early postoperative continence for at least 3 months following surgery. However, these promising results warrant confirmation through a randomized controlled trial.


Assuntos
Laparoscopia , Incontinência Urinária , Humanos , Masculino , Laparoscopia/métodos , Prostatectomia/métodos , Recuperação de Função Fisiológica , Uretra/cirurgia , Bexiga Urinária/cirurgia , Incontinência Urinária/epidemiologia , Incontinência Urinária/etiologia , Incontinência Urinária/prevenção & controle
2.
Neurocrit Care ; 36(3): 927-941, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34918214

RESUMO

BACKGROUND: Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, coagulation profiles beyond standard conventional coagulation assays were assessed in patients with isolated TBI within the very early hours of injury. METHODS: Results from blood samples (citrate/EDTA) obtained on hospital admission were matched with clinical and routine laboratory data of patients with TBI captured in the CENTER-TBI central database. To minimize confounding factors, patients with strictly isolated TBI (iTBI) (n = 88) were selected and stratified for coagulopathy by routine international normalized ratio (INR): (1) INR < 1.2 and (2) INR ≥ 1.2. An INR > 1.2 has been well adopted over time as a threshold to define trauma-related coagulopathy in general trauma populations. The following parameters were evaluated: quick's value, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin, coagulation factor activity of factors V, VIII, IX, and XIII, protein C and S, plasminogen, D-dimer, fibrinolysis-regulating parameters (thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1, antiplasmin), thrombin generation, and fibrin monomers. RESULTS: Patients with iTBI with INR ≥ 1.2 (n = 16) had a high incidence of progressive intracranial hemorrhage associated with increased mortality and unfavorable outcome compared with patients with INR < 1.2 (n = 72). Activity of coagulation factors V, VIII, IX, and XIII dropped on average by 15-20% between the groups whereas protein C and S levels dropped by 20%. With an elevated INR, thrombin generation decreased, as reflected by lower peak height and endogenous thrombin potential (ETP), whereas the amount of fibrin monomers increased. Plasminogen activity significantly decreased from 89% in patients with INR < 1.2 to 76% in patients with INR ≥ 1.2. Moreover, D-dimer levels significantly increased from a mean of 943 mg/L in patients with INR < 1.2 to 1,301 mg/L in patients with INR ≥ 1.2. CONCLUSIONS: This more in-depth analysis beyond routine conventional coagulation assays suggests a counterbalanced regulation of coagulation and fibrinolysis in patients with iTBI with hemostatic abnormalities. We observed distinct patterns involving key pathways of the highly complex and dynamic coagulation system that offer windows of opportunity for further research. Whether the changes observed on factor levels may be relevant and explain the worse outcome or the more severe brain injuries by themselves remains speculative.


Assuntos
Transtornos da Coagulação Sanguínea , Lesões Encefálicas Traumáticas , Lesões Encefálicas Traumáticas/epidemiologia , Humanos , Plasminogênio , Estudos Prospectivos , Proteína C , Trombina
3.
Neurocrit Care ; 35(1): 184-196, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33306177

RESUMO

BACKGROUND: Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the development of TBI-associated coagulopathy is poorly understood. METHODS: This analysis, embedded in the prospective, multi-centred, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) (n = 598) were selected for this analysis. RESULTS: Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to - 6, hypothermia and hypotension increased risk significantly. CONCLUSION: Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.


Assuntos
Transtornos da Coagulação Sanguínea , Lesões Encefálicas Traumáticas , Transtornos da Coagulação Sanguínea/epidemiologia , Transtornos da Coagulação Sanguínea/etiologia , Testes de Coagulação Sanguínea , Lesões Encefálicas Traumáticas/complicações , Escala de Coma de Glasgow , Humanos , Estudos Prospectivos
4.
BMC Urol ; 19(1): 93, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623590

RESUMO

BACKGROUND: A supernumerary kidney (SK) is an additional kidney with its own capsule and blood supply that is not fused with the ipsilateral kidney (IK). Because individual case reports indicate a high morbidity rate, the aim of this retrospective study was a detailed analysis of this rare anatomical variant. METHODS: Our systematic imaging-based search for SKs, conducted in the period from 2000 and to 2017, yielded 9 cases in total (5 men, 4 women; mean age: 51.8 ± 22.8 years). RESULTS: The SKs were observed on the right in six and on the left side in three cases. In six subjects (66%) they were located caudal and in three cases (33%) cranial to the ipsilateral kidney. Calculi were found in three (33%) of the renal collecting systems. Five (56%) of the SKs had hydronephrosis grade IV and one SK had recurrent pyelonephritis (11%). Two of the ureters opened into the ipsilateral seminal vesicle (22%). Two (22%) SKs were functional but atrophic. Clinically relevant findings were made in 33% of the IKs: atrophy (n = 2), calculi (n = 1), and reflux with recurrent pyelonephritis (n = 1); another 33% had anatomical anomalies without functional impairment. The correct diagnosis of a SK is possible using CT imaging in all subjects. The prevalence of SK based on CT imaging can be estimated to be 1:26750. CONCLUSIONS: CT is the method of choice for visualizing SKs. The correct diagnosis is crucial in preventing dispensable surgical procedures and for providing optimal patient treatment and outcome.


Assuntos
Rim/anormalidades , Rim/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Feminino , Humanos , Nefropatias/diagnóstico por imagem , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
Nervenarzt ; 90(5): 490-496, 2019 May.
Artigo em Alemão | MEDLINE | ID: mdl-30377732

RESUMO

OBJECTIVE: Collation of frequencies and clinical characteristics of autism spectrum disorders (ASD) in persons with intellectual disability (ID). METHODS: Cross-sectional analysis of a clinical psychiatric sample of 710 adults with ID and mental disorders. RESULTS: The frequency of ASD in an adult sample with ID was 19%. The occurrence of ASD was associated with a higher severity of ID, male gender (in mild to moderate ID), anticonvulsive therapy and reduced employment rates in workshops. CONCLUSION: The ASD are a frequent clinical diagnosis in adults with ID.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Adulto , Transtorno do Espectro Autista/complicações , Estudos Transversais , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino
6.
Fortschr Neurol Psychiatr ; 87(8): 437-443, 2019 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-30791059

RESUMO

OBJECTIVES: Analysis of the causes of challenging behavior in individuals with intellectual disability (ID). METHODS: The relatedness and the impact of cognitive and emotional functioning on challenging behavior was investigated by correlation and regression analyses in 262 individuals with ID and mental disorders / challenging behavior. RESULTS: Despite the high correlation between ID and emotional development, cognitive-emotional developmental discrepancies were found in every second patient. The severity of challenging behavior was associated with a lower level of emotional development, especially in the area of "aggression regulation". CONCLUSION: The level of emotional development should be ascertained in the context of an assessment of challenging behavior in individuals with ID.


Assuntos
Agressão , Emoções , Deficiência Intelectual/psicologia , Humanos , Transtornos Mentais/psicologia
7.
Wound Repair Regen ; 26(1): 27-35, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29363857

RESUMO

Treating infected acute and/or chronic wounds still represents a major challenge in medical care. Various interactions of antiseptic dressings with wound environments regarding antimicrobial efficacy remain unclear. Therefore, this work aimed to investigate the influence of human acute wound fluid (AWF) on the antimicrobial performance of different antiseptic foam dressings in vitro against typical bacterial wound pathogens. Eight antiseptic polyurethane foam dressings containing either a silver formulation or a polyhexamethylene-biguanide (PHMB) were assessed regarding their antimicrobial potency against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa using a modified time-kill assay based on ISO EN 20743. The antiseptic efficacy was evaluated standardly as well as under the influence of human AWF after 2, 4, 6, and 24 hours. The specific chemical formulation and concentration of the antiseptic substance (ionic or nanocrystalline silver, silver sulfadiazine, PHMB 0.1%/0.5%) embedded within the dressings seemed to play a key role. For certain dressings (two nanocrystalline and one ionic silver dressing), the antimicrobial efficacy was significantly reduced under the influence of AWF compared to unchallenged test series. Unchallenged the efficacy of PHMB was comparable to silver against P. aeruginosa and even significantly superior against S. aureus and E. coli. Challenged with AWF the reduction rates for silver adjusted or even exceeded (P. aeruginosa) those of PHMB. Within a challenging wound environment, especially some silver formulations demonstrated a reduced bacterial reduction. Regarding the presented in vitro results, the biomolecular interactions of antiseptic wound dressings with wound fluid should be part of more extensive investigations, considering varying factors such as bacterial species and wound (micro)environment to develop targeted therapeutic regimes for the individual.


Assuntos
Anti-Infecciosos Locais/farmacologia , Anti-Infecciosos/farmacologia , Bandagens , Poliuretanos/farmacologia , Infecção dos Ferimentos/prevenção & controle , Ferimentos e Lesões/terapia , Doença Aguda , Líquidos Corporais/microbiologia , Drenagem/métodos , Humanos , Técnicas In Vitro , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Sensibilidade e Especificidade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação
8.
Mol Microbiol ; 95(5): 859-74, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25521009

RESUMO

In heterothallic ascomycetes, mating is controlled by two nonallelic idiomorphs that determine the 'sex' of the corresponding strains. We recently discovered mating-type loci and a sexual life cycle in the penicillin-producing fungus, Penicillium chrysogenum. All industrial penicillin production strains worldwide are derived from a MAT1-1 isolate. No MAT1-2 strain has been investigated in detail until now. Here, we provide the first functional analysis of a MAT1-2 locus from a wild-type strain. Similar to MAT1-1, the MAT1-2 locus has functions beyond sexual development. Unlike MAT1-1, the MAT1-2 locus affects germination and surface properties of conidiospores and controls light-dependent asexual sporulation. Mating of the MAT1-2 wild type with a MAT1-1 high penicillin producer generated sexual spores. We determined the genomic sequences of parental and progeny strains using next-generation sequencing and found evidence for genome-wide recombination. SNP calling showed that derived industrial strains had an uneven distribution of point mutations compared with the wild type. We found evidence for meiotic recombination in all chromosomes. Our results point to a strategy combining the use of mating-type genes, genetics, and next-generation sequencing to optimize conventional strain improvement methods.


Assuntos
Genes Fúngicos Tipo Acasalamento , Penicilinas/biossíntese , Penicillium chrysogenum/genética , Recombinação Genética , Sequência de Bases , Mapeamento Cromossômico , Loci Gênicos/fisiologia , Dados de Sequência Molecular , Mutagênese , Filogenia , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Alinhamento de Sequência , Análise de Sequência de DNA , Esporos Fúngicos/genética
9.
Proc Natl Acad Sci U S A ; 110(4): 1476-81, 2013 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-23307807

RESUMO

Penicillium chrysogenum is a filamentous fungus of major medical and historical importance, being the original and present-day industrial source of the antibiotic penicillin. The species has been considered asexual for more than 100 y, and despite concerted efforts, it has not been possible to induce sexual reproduction, which has prevented sexual crosses being used for strain improvement. However, using knowledge of mating-type (MAT) gene organization, we now describe conditions under which a sexual cycle can be induced leading to production of meiotic ascospores. Evidence of recombination was obtained using both molecular and phenotypic markers. The identified heterothallic sexual cycle was used for strain development purposes, generating offspring with novel combinations of traits relevant to penicillin production. Furthermore, the MAT1-1-1 mating-type gene, known primarily for a role in governing sexual identity, was also found to control transcription of a wide range of genes with biotechnological relevance including those regulating penicillin production, hyphal morphology, and conidial formation. These discoveries of a sexual cycle and MAT gene function are likely to be of broad relevance for manipulation of other asexual fungi of economic importance.


Assuntos
Penicilinas/biossíntese , Penicillium chrysogenum/fisiologia , Sequência de Bases , Biotecnologia , Cruzamentos Genéticos , DNA Fúngico/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/fisiologia , Deleção de Genes , Expressão Gênica , Genes Fúngicos Tipo Acasalamento , Penicillium chrysogenum/genética , Penicillium chrysogenum/crescimento & desenvolvimento , Fenótipo , Feromônios/genética , Feromônios/fisiologia , Receptores de Feromônios/genética , Receptores de Feromônios/fisiologia , Recombinação Genética , Reprodução/genética , Esporos Fúngicos/genética , Esporos Fúngicos/fisiologia
10.
PLoS Genet ; 9(2): e1003250, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23408899

RESUMO

Aberrant CpG methylation is a universal epigenetic trait of cancer cell genomes. However, human cancer samples or cell lines preclude the investigation of epigenetic changes occurring early during tumour development. Here, we have used MeDIP-seq to analyse the DNA methylome of APC(Min) adenoma as a model for intestinal cancer initiation, and we present a list of more than 13,000 recurring differentially methylated regions (DMRs) characterizing intestinal adenoma of the mouse. We show that Polycomb Repressive Complex (PRC) targets are strongly enriched among hypermethylated DMRs, and several PRC2 components and DNA methyltransferases were up-regulated in adenoma. We further demonstrate by bisulfite pyrosequencing of purified cell populations that the DMR signature arises de novo in adenoma cells rather than by expansion of a pre-existing pattern in intestinal stem cells or undifferentiated crypt cells. We found that epigenetic silencing of tumour suppressors, which occurs frequently in colon cancer, was rare in adenoma. Quite strikingly, we identified a core set of DMRs, which is conserved between mouse adenoma and human colon cancer, thus possibly revealing a global panel of epigenetically modified genes for intestinal tumours. Our data allow a distinction between early conserved epigenetic alterations occurring in intestinal adenoma and late stochastic events promoting colon cancer progression, and may facilitate the selection of more specific clinical epigenetic biomarkers.


Assuntos
Adenoma/genética , Neoplasias do Colo/genética , Metilação de DNA/genética , Neoplasias Intestinais/genética , Proteínas do Grupo Polycomb/genética , Adenoma/patologia , Animais , Sequência de Bases , Ilhas de CpG/genética , Epigenômica , Genoma , Humanos , Neoplasias Intestinais/patologia , Camundongos , Sintenia
11.
Curr Genet ; 61(4): 679-83, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25993917

RESUMO

The recent discovery and functional characterization of opposite mating-type loci in the industrial penicillin producer Penicillium chrysogenum demonstrated their regulatory role in sexual as well as asexual development. Subsequent experiments further showed that a sexual life cycle can be induced in P. chrysogenum that was for long believed to reproduce exclusively by asexual propagation. Finally, crossing of wild type and production strains resulted in the generation of recombinant ascospore isolates. We predict from these recent findings that recombinant progeny for industrial applications can be obtained by sexual crossings and discuss experimental difficulties that occur when parental strains with karyotype heterogeneity are used for mating.


Assuntos
Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Microbiologia Industrial , Penicillium chrysogenum/genética , Feromônios/genética , Cruzamentos Genéticos , Proteínas Fúngicas/metabolismo , Genes Fúngicos Tipo Acasalamento/genética , Heterogeneidade Genética , Cariótipo , Penicilinas/biossíntese , Penicillium chrysogenum/metabolismo , Feromônios/metabolismo , Recombinação Genética , Esporos Fúngicos/genética , Esporos Fúngicos/metabolismo
12.
J Transl Med ; 13: 375, 2015 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-26620128

RESUMO

BACKGROUND: Due to demographical changes the number of elderly patients depending on oral anticoagulation is expected to rise. Prolonged bleeding times in case of traumatic injuries represent the drawback of these medications, not only in major trauma, but also in superficial wounds. Therefore, dressings capable of accelerating coagulation onset and shortening bleeding times are desirable for these patients. METHODS: The hemostatic potential and physical properties of different types of superficial wound dressings (standard wound pad, two alginates, chitosan, collagen (Lyostypt(®)), oxidized cellulose, and QuikClot(®)) were assessed in vitro. For this purpose the clotting times of blood under the influence of the named hemostatics from healthy volunteers were compared with Marcumar(®) or ASS(®) treated patients. For that, a newly developed coagulation assay based on spectrophotometric extinction measurements of thrombin activity was used. RESULTS: The fastest coagulation onset was observed for oxidized cellulose (Ø 2.47 min), Lantor alginate-L (Ø 2.50 min) and QuikClot(®) (Ø 3.01 min). Chitosan (Ø 5.32 min) and the collagen Lyostypt(®) (Ø 7.59 min) induced clotting comparatively late. Regarding physical parameters, QuikClot(®) showed the lowest absorption capacity and speed while chitosan and both alginates achieved the highest. While oxidized cellulose displayed the best clotting times, unfortunately it also revealed low absorption capacity. CONCLUSIONS: All tested specimens seem to induce clotting independently from the administered type of oral anticoagulant, providing the possibility to neglect the disadvantage in clotting times arising from anticoagulation on a local basis. QuikClot(®), oxidized cellulose and unexpectedly alginate-L were superior to chitosan and Lyostypt(®). Due to its additional well-known positive effect on wound healing alginate-L should be considered for further investigations.


Assuntos
Bandagens , Hemostáticos , Cicatrização/efeitos dos fármacos , Humanos
13.
Appl Microbiol Biotechnol ; 97(22): 9609-20, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24085397

RESUMO

A large number of molds serve as producer strains for the industrial production of pharmaceuticals, foods, or organic chemicals. To optimize strains for production processes, conventional strain development programs use random mutagenesis and, more recently, recombinant technologies to generate microbial strains with novel and advantageous properties. The recent detection of mating type genes in fungal production strains and the discovery of cryptic sexuality in presumably asexual fungi open up novel strategies for generating progeny with new, as yet unobserved properties. Mating type genes, which can be considered as "sex genes," not only direct sexual development but also regulate a broad range of fungal secondary metabolites. In addition, they control hyphal morphology, which has a direct impact on production processes that are often conducted in huge fermenter tanks. Here, we survey the occurrence and function of mating type genes that have been discovered in a wide range of industrial fungal producer strains. The possibility to obtain progeny from industrial producers by sexual mating provides an exciting alternative to conventional strain improvement programs aiming to generate optimized recombinant production strains.


Assuntos
Fungos/genética , Fungos/metabolismo , Genes Fúngicos Tipo Acasalamento , Microbiologia Industrial/métodos , Engenharia Metabólica/métodos , Biologia Molecular/métodos , Hibridização Genética , Hifas/crescimento & desenvolvimento , Hifas/metabolismo , Recombinação Genética , Metabolismo Secundário
15.
Psychiatr Prax ; 48(1): 37-43, 2021 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-32659791

RESUMO

OBJECTIVES: The study assesses the diagnostic validity of the Scale of Pervasive Developmental Disorder in Mentally Retarded Persons (PDD-MRS). METHODS: Unblinded conduct of PDD-MRS in a clinical psychiatric sample of adults with intellectual disability (ID; N = 109) and suspect of autism. RESULTS: For a cut-off-score of 10, sensitivity was 89 %, specificity 62 % and the Area Under the Curve (AUC) 0.83. The total score was independent of age, gender and level of ID. However the diagnostic validity was better balanced in adults with mild to moderate ID (sensitivity/specificity: 85 %/73 %) compared to those with severe to profound ID (93 %/42 %). The SEAS-M total score was correlated with various ASD screening measures (r = .3-.6), while no correlation was found for scales assessing challenging behavior. CONCLUSION: To conclude, the PDD-MRS is a screening instrument for diagnosing autism in adults with mild to moderate ID. Knowledge of the PDD-MRS results within the consensus conference may have led to an overestimation of its diagnostic validity.


Assuntos
Transtorno do Espectro Autista , Transtornos Globais do Desenvolvimento Infantil , Deficiência Intelectual , Adulto , Transtorno do Espectro Autista/diagnóstico , Criança , Alemanha , Humanos , Deficiência Intelectual/diagnóstico , Reprodutibilidade dos Testes
16.
Scand J Trauma Resusc Emerg Med ; 29(1): 38, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622398

RESUMO

BACKGROUND: Aggressive fluid management and other external factors may lead to hypothermia, acidosis and hemodilution (defined as Lethal Triad, LT) contributing to a trauma-induced coagulopathy (TIC) that worsens patients' outcomes. Procoagulant microparticles (MP) are crucial players at the interface of cellular and plasmatic coagulation. However, their functions remain largely unexplored. This study aimed to characterize effects of MP subtypes and concentrations on functional coagulation under in vitro simulated conditions. METHODS: Blood from eleven volunteers were collected to simulate in vitro conditions of hemodilution (HD) and LT, respectively. HD was induced by replacing a blood volume of 33% by crystalloids and for LT, samples were further processed by reducing the temperature to 32 °C and lowering the pH to 6.8. MP were obtained either from platelet concentrates (platelet-derived MP, PDMP) or from cell culture (ECV304 cells for endothelial-derived MP, EDMP) by targeted stimulation. After introducing MP to in vitro conditions, we measured their concentration-dependent effects (1.000, 10.000 and 15.000 MP/µl blood) on coagulation compared to whole blood (WB). For each condition, coagulation was characterized by flow cytometric platelet activation and by quantification of fibrin clot propagation using Thrombodynamics® technology. RESULTS: MP originated from platelets and endothelial cells affected blood coagulation in a concentration-dependent manner. Particularly, high PDMP quantities (10.000 and 15.000 PDMP/µl blood) significantly induced platelet activation and fibrin clot growth and size in HD conditions. In LT conditions as well, only high PDMP concentration induced platelet activation, clot growth and size. In contrast, EDMP did not induce platelet activation, but resulted in enhanced formation of spontaneous clots, irrespective of simulated condition. With increasing EDMP concentration, the time until the onset of spontaneous clotting decreased in both HD and LT conditions. DISCUSSION: The study demonstrates an essential role of MP within the coagulation process under simulated coagulopathic conditions. PDMP affected platelets promoting clot formation likely by providing a surface enlargement. EDMP presumably affected clotting factors of the plasmatic coagulation resulting in an increased formation of spontaneous clots. CONCLUSION: Under simulated conditions of a dilutional coagulopathy, MP from different cellular origin indicate a divergent but both procoagulant mechanism within the coagulation process.


Assuntos
Coagulação Sanguínea/fisiologia , Plaquetas , Micropartículas Derivadas de Células/fisiologia , Células Endoteliais , Hemodiluição , Acidose/fisiopatologia , Transtornos da Coagulação Sanguínea/etiologia , Testes de Coagulação Sanguínea , Feminino , Citometria de Fluxo , Humanos , Hipotermia/fisiopatologia , Técnicas In Vitro , Masculino , Plasma , Ferimentos e Lesões/sangue
17.
PLoS One ; 14(4): e0215474, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30998731

RESUMO

BACKGROUND: In persons with intellectual and developmental disabilities, not only cognitive brain functions, but also socio-emotional processing networks may be impaired. This study aims to validate the Scale of Emotional Development-Short (SED-S) to provide an instrument for the assessment of socio-emotional brain functions. METHOD: The SED-S was applied in 160 children aged 0-12 years. Criterion validity was investigated at item and scale level in terms of the agreement between the scale classification and the child's chronological age. Additionally, interrater reliability and internal consistency were assessed. RESULTS: For the majority of items, the expected response pattern emerged, showing the highest response probabilities in the respective target age groups. Agreement between the classification of the different SED-S domains and chronological age was high (κw = 0.95; exact agreement = 80.6%). Interrater reliability at domain level ranged from κw = .98 to 1.00 and internal consistency was high (α = .99). CONCLUSION: The study normed the SED-S in a sample of typically developing children and provides evidence for criterion validity on item, domain and scale level.


Assuntos
Desenvolvimento Infantil , Cognição , Deficiências do Desenvolvimento/fisiopatologia , Emoções , Deficiência Intelectual/fisiopatologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
18.
Cell Rep ; 29(6): 1675-1689.e9, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31693904

RESUMO

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neurofibromina 1/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Supressora de Tumor p53/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/metabolismo , Criança , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Genômica , Humanos , Camundongos , Mutação , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Recidiva , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento do Exoma , Tumor de Wilms/genética , Tumor de Wilms/metabolismo
19.
J Autism Dev Disord ; 48(2): 341-350, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28988347

RESUMO

The study assessed the diagnostic validity of the diagnostic behavioral assessment for autism spectrum disorders-revised (DiBAS-R; 19-item screening scale based on ratings by caregivers) in a clinical sample of 381 adults with ID. Analysis revealed a sensitivity of 0.82 and a specificity of 0.67 in the overall sample (70.3% agreement). Sensitivity (0.79) and specificity (0.84) were balanced in individuals with mild to moderate ID (83.3% agreement), while specificity was lower in individuals with severe to profound ID (sensitivity: 0.83, specificity: 0.34, 51% agreement). The level of ID as well as its interaction with ASD explained a significant proportion of the variance in the DiBAS-R scores. The DiBAS-R is an adequate screening tool, especially in individuals with mild to moderate ID.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Inquéritos e Questionários/normas , Adulto , Transtorno do Espectro Autista/psicologia , Cuidadores/psicologia , Cuidadores/normas , Estudos Transversais , Feminino , Humanos , Deficiência Intelectual/psicologia , Classificação Internacional de Doenças/normas , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
20.
Scand J Trauma Resusc Emerg Med ; 26(1): 33, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703240

RESUMO

BACKGROUND: After severe polytrauma the dynamic process of coagulation may deteriorate towards a trauma-induced coagulopathy (TIC) promoting a dramatic increase in morbidity and mortality. Recent evidence suggests that microparticles (MPs) play a pivotal role at the interface between cellular and plasmatic coagulation systems. However, the impact of MPs on functional coagulation has not been clarified yet in the setting of traumatic injuries. We assessed the temporal patterns of circulating MP concentrations including their cellular origin in the context of clinical presentation and global coagulation assays. METHODS: Blood samples from 22 consecutive polytrauma patients (ISS ≥16) from 2015 were collected at hospital admission, after 24 and 72 h and compared to those from healthy individuals and minor injured patients with isolated extremity fractures. Flow cytometry (BD Accuri C6; Heidelberg/Germany) was used to determine MP concentrations and cellular origin using cell-specific markers (platelet derived (PDMP): CD42b+, CD61+, CD62p+; endothelial cell derived (EDMP): CD144+, CD62e+, CD144+/62e+). Results were correlated with clinical data and results from viscoelastic testing (ROTEM). RESULTS: Twenty two polytrauma patients (17 males, agemedian 60 yrs) with a median ISS 26.5 (IQR 14.5) were assessed. PDMP and EDMP concentrations increased significantly in polytrauma patients as compared to healthy individuals and minor injured patients. MP concentrations correlated with injury severity (CD144+: ρsp = 0.79, p < 0.001; CD42b+: ρsp = 0.61, p < 0.001). EDMP displayed a negative correlation with aPTT (CD144/62e+, ρsp = - 0.55, p < 0.05), INR (CD144/62e+, ρsp = - 0.61, p < 0.05) and ROTEM-INTEM CT (CD144/62e+, ρsp = - 0.68, p < 0.05) reflecting increased dynamics of clot formation and an overall procoagulative effect. Additionally, EDMP showed a negative association with FIBTEM values (10 min amplitude, maximum clot firmness) indicating a fibrinolytic potential. DISCUSSION: In a small cohort, analysing most severly injured patients, the association of increased MP levels and altered coagulation parameters could be demonstrated. However, these findings are based on correlation analysis, which do not enable causel evidence. Therefore, further in-vitro studies are needed analysing the underlying pathomechanisms. CONCLUSION: In conclusion, this study could demonstrate that PDMP and EDMP levels increase significantly following polytrauma correlating with injury severity. Although severe coagulopathy was not observed, EDMP levels were associated with improved coagulation parameters suggesting their essential role for regulating blood coagulation after trauma.


Assuntos
Transtornos da Coagulação Sanguínea/sangue , Coagulação Sanguínea/fisiologia , Micropartículas Derivadas de Células/metabolismo , Traumatismo Múltiplo/complicações , Biomarcadores/sangue , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Testes de Coagulação Sanguínea , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismo Múltiplo/sangue , Tempo de Tromboplastina Parcial , Estudos Prospectivos , Tromboelastografia/métodos
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