RESUMO
Soft tissue sarcomas harboring EWSR1::PATZ1 are a recently recognized entity with variable morphology and a heterogeneous immunohistochemical profile. We studied 17 such tumors. The tumors occurred in 12 men and 5 women (median age, 50 years; range, 15-71 years), involved the thoracoabdominal soft tissues (14 cases; 82%), lower extremities (2 cases; 12%), and tongue (1 case; 6%), and ranged from 0.7 to 11.3 cm (median, 4.7 cm). All but 1 patient received complete surgical resection; 7 were also treated with neoadjuvant chemo/radiotherapy. All cases showed typical features of EWSR1::PATZ1 sarcoma, including uniform round to spindled cells, fibromyxoid matrix, fibrous bands, hyalinized vessels, and pseudoalveolar/microcystic spaces. Unusual features, seen in a subset of cases, included degenerative-appearing nuclear atypia, epithelioid cytomorphology, mature fat, abundant rhabdomyoblasts, high mitotic activity, and foci with increased cellularity and nuclear atypia. Positive immunohistochemical results were desmin (16/17, 94%), MyoD1 (13/14, 93%), myogenin (6/14, 43%), GFAP (10/10, 100%), S100 protein (15/17, 88%), SOX10 (7/13, 54%), keratin (10/17, 59%), CD99 (4/11, 36%), H3K27me3 (retained expression 9/9, 100%), p16 (absent expression 1/4, 25%), and p53 (wild type 3/3, 100%). Fusion events included EWSR1 exon 8::PATZ1 exon 1 (14/17, 82%), EWSR1 exon 9::PATZ1 exon 1 (2/17, 12%), and EWSR1 exon 7::PATZ1 exon 1 (1/17, 6%). No evaluated tumor had alterations of CDKN2A/B and/or TP53, or MDM2 amplification. Clinical follow-up (16 patients: median, 13.5 months; range, 1-77 months) showed distant metastases in 3 patients (1/3 at time of presentation) and no local recurrences. At the time of last follow-up, 14 patients were disease free, 1 was alive with disease, 1 was dead of disease (at 13 months), and 1 had an indeterminant pulmonary nodule. We conclude that the morphologic spectrum of EWSR1::PATZ1 is broader than has been previously appreciated. Although more long-term follow-up is needed, the prognosis of these very rare sarcomas may be more favorable than previously reported.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Sarcoma/genética , Sarcoma/terapia , Sarcoma/patologia , Fatores de Transcrição , Proteína EWS de Ligação a RNA/genética , Proteínas S100 , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/terapia , Neoplasias de Tecidos Moles/patologia , Prognóstico , Biomarcadores Tumorais/genética , Proteínas Repressoras/genética , Fatores de Transcrição Kruppel-LikeRESUMO
Phosphodiesterase (PDE) inhibitors - such as vardenafil - are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform. A sustained rise in cGMP in photoreceptors is known to be toxic; therefore, we hypothesized that long-term vardenafil treatment might result in retinotoxicity. The hypothesis was tested in a clinically relevant animal model of type 2 diabetes mellitus. Histological experiments were performed on lean and diabetic Zucker Diabetic Fatty rats. Half of the animals were treated with vardenafil for six months, and the retinal effects were evaluated. Vardenafil treatment alleviated rod outer segment degeneration but decreased rod numbers in some positions and induced changes in the interphotoreceptor matrix, even in control animals. Vardenafil treatment decreased total retinal thickness in the control and diabetic groups and reduced the number of nuclei in the outer nuclear layer. Müller cell activation was detectable even in the vardenafil-treated control animals, and vardenafil did not improve gliosis in the diabetic group. Vardenafil-treated animals showed complex retinal alterations with improvements in some parameters while deterioration in others. Our results point towards the retinotoxicity of vardenafil, even without diabetes, which raises doubts about the retinal safety of long-term continuous vardenafil administration. This effect needs to be considered when approving PDE inhibitors for alternative indications.
Assuntos
Diabetes Mellitus Experimental , Inibidores da Fosfodiesterase 5 , Ratos Zucker , Dicloridrato de Vardenafila , Dicloridrato de Vardenafila/farmacologia , Dicloridrato de Vardenafila/toxicidade , Animais , Ratos , Inibidores da Fosfodiesterase 5/farmacologia , Masculino , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Retina/efeitos dos fármacos , Retina/patologia , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/patologia , Células Ependimogliais/metabolismoRESUMO
INTRODUCTION: Estrogen hormones and their metabolites are implicated in the maintenance of healthy pregnancy and adequate fetal development. Abnormal levels were related to increased risk of pregnancy complications, particularly preeclampsia. Our aims were (1) to develop a methodological platform for the comprehensive assessment of estrogen metabolome in pregnancy; (2) to collect healthy reference data for relevant elements of estrogen metabolome in each trimester; (3) to assess unconjugated fractions of the estrogen metabolome, (4) to assess the dominant metabolic pathways of estrogen compounds. METHODS: We enrolled healthy pregnant mothers between gestational week 5-15 (on the confirmation of pregnancy; 79 samples), gestational weeks 19-27 (70 samples), and gestational week 34-39 (54 samples). A method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to assess estrone, 17-beta-estradiol, estriol levels, and their metabolites as conjugated and unconjugated forms. Descriptive statistics were used to characterize the level of compounds in each trimester. RESULTS: Estrone, 17-beta-estradiol and estriol levels are dramatically increasing with the advancement of pregnancy. Measured levels were in a very wide range. 17-beta-estradiol is neither glucuronated nor sulphated. To the contrary, estriol and estrone are significantly conjugated; unconjugated fraction is <15% of total hormone levels in any trimester. Regarding metabolism, 4-methoxy-estradiol and 17-epiestriol were not detected. CONCLUSION: We concluded that (1) the levels of estrogen compounds and metabolites increase with advancing gestational age; (2) the wide ranges of levels challenge the establishment of a healthy reference range for clinical purposes; (3) 17-beta-estradiol is not conjugated significantly; (4) 4-methylation and 17-epimerization pathways of estrogens are negligible with our LC-MS/MS method.
Assuntos
Estrona , Espectrometria de Massas em Tandem , Gravidez , Feminino , Humanos , Estrona/metabolismo , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Estrogênios/análise , Estrogênios/metabolismo , Estradiol/metabolismo , Estriol , MetabolomaRESUMO
BACKGROUND: Frozen shoulder is a common medical condition, but the ideal therapeutic method is yet to be determined. Our aim was to analyze the pain-relieving effect of different treatment options used for the management of this disease. METHODS: Medical records of 59 patients (22 male, 37 female, average age: 55.5 years ±9.9) with early stage primary frozen shoulder were evaluated, their demographic data, physical examination, concomitant diseases and treatment specific data were registered. Life quality and the level of pain were assessed using the Oxford Shoulder Score (OSS) and Numeric Rating Scale (NRS). Different treatment modalities and their effect on pain relief were recorded. Any existing correlation between life quality, pain and demographic data, concomitant diseases or the therapeutic method used was investigated. RESULTS: The level of pain measured on NRS improved from 7.9 ± 1.6 to 1.9 ± 2.2. The most effective therapeutic method in terms of pain relief was surgery, followed by physiotherapy and intraarticular steroid injection (NRS score after treatment: 2 - p < 0.0001; 3.3 - p < 0.0001; 4.9 - p < 0.0001, respectively). Non-steroidal anti-inflammatory drugs (NSAIDs) did not reduce pain significantly. OSS improved from 24 to 43.6 and was not affected by the investigated variables, time to recovery was not influenced by the demographic data, the type of treatment or concomitant diseases. CONCLUSIONS: Arthroscopic capsular release, physiotherapy and intraarticular steroid injection outperformed physical therapy and NSAID treatment in terms of pain relief. Despite of slight but persistent post-therapeutic pain found in half of the cases, treatment was considered satisfactory by the patients. Nor patient specific neither therapy specific data had a significant effect on the course of the disease.
Assuntos
Bursite , Articulação do Ombro , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Liberação da Cápsula Articular , Artroscopia/métodos , Tratamento Conservador , Bursite/cirurgia , Dor , Esteroides , Articulação do Ombro/cirurgia , Resultado do Tratamento , Amplitude de Movimento Articular , Dor de Ombro/diagnóstico , Dor de Ombro/etiologia , Dor de Ombro/terapiaRESUMO
BACKGROUND: Numerous surgical approaches are being used to perform total knee arthroplasty (TKA). This systematic review and network meta-analysis aimed to compare surgical approaches used in TKA regarding postoperative outcomesat different time points. METHODS: We performed a literature search from medical database inception until October 2, 2021. We searched for randomized controlled trials (RCTs) investigating patients undergoing TKA and comparing at least 2 surgical approaches regarding early postsurgical clinical outcomes (range of motion [ROM], pain on a visual analog scale, and Knee Society Score [KSS]). We included 33 RCTs in our networks. Using paired and network meta-analysis, we calculated pooled mean differences (MDs) with 95% CIs by comparing surgical approaches to the medial parapatellar method. RESULTS: The subvastus (SV) method performed the best on days 1 (MD = 6.99; CI: 1.08; 12.89), 3 (MD = 8.00; CI: 2.08; 13.92), 4 (MD = 27.01; CI: 18.09; 35.92), and 6 (MD = 27.22; CI: 18.38; 36.07) for ROM improvement. Regarding the decrease in pain, the mini SV approach offered significantly lower pain values on days 1 (MD = -1.98; CI: -2.93; -1.03), 3 (MD = -0.85; CI: -1.49; -0.22), and 7 (MD = -1.90; CI: -2.23; -1.57). The differences decreased as time passed. Furthermore, the SV and mini-SV methods performed the best regarding total, knee and function KSS. CONCLUSION: Quadriceps-sparing approaches, especially the SV and mini-SV, are superior to the other approaches in the early postsurgical period, but the differences decrease as time passes.
Assuntos
Artroplastia do Joelho , Osteoartrite do Joelho , Humanos , Artroplastia do Joelho/métodos , Metanálise em Rede , Resultado do Tratamento , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia , Amplitude de Movimento Articular , Dor/cirurgiaRESUMO
Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB1Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB1R knockout (CB1R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-ß) were performed. Conjugated E2 levels were higher in CB1R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB1R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB1R KO. Effects of indomethacin on E2-relaxation in CB1R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-ß density in CB1R KO than in WT mice. CB1R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB1Rs may have beneficial vascular effects.
Assuntos
Receptores de Canabinoides , Remodelação Vascular , Animais , Feminino , Camundongos , Acetilcolina/metabolismo , Aorta Abdominal/metabolismo , Ciclo-Oxigenase 2/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Indometacina/farmacologia , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores de Canabinoides/metabolismo , VasodilataçãoRESUMO
BACKGROUND: Ischemic stroke is a leading cause of mortality worldwide, largely due to the inflammatory response to brain ischemia during post-stroke reperfusion. Despite ongoing intensive research, there have not been any clinically approved drugs targeting the inflammatory component to stroke. Preclinical studies have identified T cells as pro-inflammatory mediators of ischemic brain damage, yet mechanisms that regulate the infiltration and phenotype of these cells are lacking. Further understanding of how T cells migrate to the ischemic brain and facilitate neuronal death during brain ischemia can reveal novel targets for post-stroke intervention. METHODS: To identify the population of T cells that produce IL-21 and contribute to stroke, we performed transient middle cerebral artery occlusion (tMCAO) in mice and performed flow cytometry on brain tissue. We also utilized immunohistochemistry in both mouse and human brain sections to identify cell types and inflammatory mediators related to stroke-induced IL-21 signaling. To mechanistically demonstrate our findings, we employed pharmacological inhibitor anti-CXCL13 and performed histological analyses to evaluate its effects on brain infarct damage. Finally, to evaluate cellular mechanisms of stroke, we exposed mouse primary neurons to oxygen glucose deprivation (OGD) conditions with or without IL-21 and measured cell viability, caspase activity and JAK/STAT signaling. RESULTS: Flow cytometry on brains from mice following tMCAO identified a novel population of cells IL-21 producing CXCR5+ CD4+ ICOS-1+ T follicular helper cells (TFH) in the ischemic brain early after injury. We observed augmented expression of CXCL13 on inflamed brain vascular cells and demonstrated that inhibition of CXCL13 protects mice from tMCAO by restricting the migration and influence of IL-21 producing TFH cells in the ischemic brain. We also illustrate that neurons express IL-21R in the peri-infarct regions of both mice and human stroke tissue in vivo. Lastly, we found that IL-21 acts on mouse primary ischemic neurons to activate the JAK/STAT pathway and induce caspase 3/7-mediated apoptosis in vitro. CONCLUSION: These findings identify a novel mechanism for how pro-inflammatory T cells are recruited to the ischemic brain to propagate stroke damage and provide a potential new therapeutic target for stroke.
Assuntos
Lesões Encefálicas , Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Quimiocina CXCL13/metabolismo , Humanos , Infarto da Artéria Cerebral Média/patologia , Mediadores da Inflamação/metabolismo , Interleucinas , Isquemia/patologia , Janus Quinases/metabolismo , Camundongos , Neurônios/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/patologiaRESUMO
BACKGROUND: Reduced cardiovascular risk in premenopausal women has been the focus of research in recent decades. Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling pathways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach. METHODS: Ischemia was induced in male (M-Isch) and female (F-Isch) rats with sc. injection of isoproterenol (85 mg/kg) daily for 2 days, while controls (M-Co, F-Co) received sc. saline solution. At 48 h after the first injection pressure-volume analysis was carried out to assess left ventricular function. FFPE tissue slides were scanned and analyzed digitally, while myocardial proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using isobaric labeling. Concentrations of circulating steroid hormones were measured with LC-MS/MS. Feature selection (PLS and PLS-DA) was used to examine associations among functional, proteomic and hormonal datasets. RESULTS: Induction of ischemia resulted in 38% vs 17% mortality in M-Isch and F-Isch respectively. The extent of ischemic damage to surviving rats was comparable between the sexes. Systolic dysfunction was more pronounced in males, while females developed a more severe impairment of diastolic function. 2224 proteins were quantified, with 520 showing sex-specific differential regulation. Our analysis identified transcriptional, cytoskeletal, contractile, and mitochondrial proteins, molecular chaperones and the extracellular matrix as sources of disparity between the sexes. Bioinformatics highlighted possible associations of estrogens and their metabolites with early functional and proteomic alterations. CONCLUSIONS: Our study has highlighted sex-specific alterations in systolic and diastolic function shortly after ischemia, and provided a comprehensive look at the underlying proteomic changes and the influence of estrogens and their metabolites. According to our bioinformatic analysis, inflammatory, mitochondrial, chaperone, cytoskeletal, extracellular and matricellular proteins are major sources of intersex disparity, and may be promising targets for early sex-specific pharmacologic interventions.
Assuntos
Isquemia Miocárdica , Proteômica , Animais , Cromatografia Líquida , Feminino , Coração , Humanos , Masculino , Isquemia Miocárdica/metabolismo , Ratos , Espectrometria de Massas em TandemRESUMO
The medial temporal lobe memory system has long been identified as the brain region showing the first histopathological changes in early Alzheimer's disease (AD), and the functional decline observed in patients also points to a loss of function in this brain area. Nonetheless, the exact identity of the neurons and networks that undergo deterioration has not been determined so far. A recent study has identified the entorhinal and hippocampal neural circuits responsible for encoding new episodic memories. Using this novel model we describe the elements of the episodic memory network that are especially vulnerable in early AD. We provide a hypothesis of how reduced reelin signaling within such a network can promote AD-related changes. Establishing novel associations and creating a temporal structure for new episodic memories are both affected in AD. Here, we furnish a reasonable explanation for both of these previous observations.
Assuntos
Doença de Alzheimer/fisiopatologia , Memória Episódica , Hipocampo/fisiopatologia , Humanos , Lobo Temporal/fisiopatologiaRESUMO
BACKGROUND: Recent data suggest that gene expression profiles of peripheral white blood cells can reflect changes in the brain. We aimed to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) and changes of plasma metabolite levels of migraineurs in a self-controlled manner during and between attacks. METHODS: Twenty-four patients with migraine were recruited and blood samples were collected in a headache-free (interictal) period and during headache (ictal) to investigate disease- and headache-specific alterations. Control samples were collected from 13 age- and sex-matched healthy volunteers. RNA was isolated from PBMCs and single-end 75 bp RNA sequencing was performed using Illumina NextSeq 550 instrument followed by gene-level differential expression analysis. Functional analysis was carried out on information related to the role of genes, such as signaling pathways and biological processes. Plasma metabolomic measurement was performed with the Biocrates MxP Quant 500 Kit. RESULTS: We identified 144 differentially-expressed genes in PBMCs between headache and headache-free samples and 163 between symptom-free patients and controls. Network analysis revealed that enriched pathways included inflammation, cytokine activity and mitochondrial dysfunction in both headache and headache-free samples compared to controls. Plasma lactate, succinate and methionine sulfoxide levels were higher in migraineurs while spermine, spermidine and aconitate were decreased during attacks. CONCLUSIONS: It is concluded that enhanced inflammatory and immune cell activity, and oxidative stress can play a role in migraine susceptibility and headache generation.
Assuntos
Transtornos de Enxaqueca , Transcriptoma , Cefaleia , Humanos , Leucócitos Mononucleares , Transtornos de Enxaqueca/genéticaRESUMO
BACKGROUND: The systematic evaluation of the clinical concordance of various 25-hydroxyvitamin D (25OHD) testing methods is presented. The need for this approach is raised by the discrepancies in the analytical performance of the available assays. METHODS: The analytical and clinical performance of six automated 25OHD assays and an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was investigated. Leftover serum samples (n=162, SA: n=114) were analyzed and all 21 assay combinations were evaluated. The utility of Cohen's κ values was assessed by transforming them into minimum percentage agreement (MPA). McNemar's hypothesis test was employed for testing the symmetry of the disagreeing classification outcomes within each method pair. RESULTS: Depending on the assay method, the ratio of results classified as positive (<20 ng/mL) was 13.5%-40.0%. The percentage agreement (PA) was 74.1%-92.6%. Compared to other methods, significantly more hypovitaminosis cases were delivered by DiaSorin Liaison® 25 OH vitamin D Total (DL) and significantly fewer by IDS-iSYS 25-Hydroxy Vitamin DS (II). The strongest clinical concordance was exerted by II vs. LC-MS/MS. The κ-derived MPA showed close similarity to the PA scores. McNemar's tests confirmed the asymmetry of the disagreement in the classification in 14 method combinations. CONCLUSIONS: The presented approach allows the prediction of the clinical consequences of a 25OHD method transfer. Differences in the clinical classification of assay results are likely encountered when transferring to a new method, even between assays standardized according to the Vitamin D Standardization Program (VDSP) Reference Method Procedure (RMP).
Assuntos
Bioensaio/métodos , Modelos Lineares , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromatografia Líquida/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem/métodos , Vitamina D/sangue , Adulto JovemRESUMO
Considerable knowledge has been gathered on the physiological role of estrogens. However, fairly little information is available on the role of compounds produced in the breakdown process of estrone and estradiol wich may play a role in various diseases associated with estrogen impact. To date, approximately 15 extragonadal estrogen-related compounds have been identified. These metabolites may exert protective, or, instead, pro-inflammatory and/or pro-oncogenic activity in a tissue-specific manner. Systemic and local estrogen metabolite levels are not necesserily correlated, which may promote the diagnostic significance of the locally produced estrogen metabolites in the future. The aim of the present study is a bibliographic review of the extragonadal metabolome in peripheral tissues, and to highlight the role of the peripheral tissue homeostasis of estrogens as well as the non-hormonal biological activity and clinical significance of the estrogen metabolome. Orv Hetil. 2017; 158(24): 929-937.
Assuntos
Estrogênios/metabolismo , Receptores de Estrogênio/metabolismo , Estradiol/metabolismo , Estrogênios/fisiologia , Estrogênios de Catecol/metabolismo , Estrona/metabolismo , HumanosRESUMO
Our aim was to investigate the rare malignant soft tissue sarcomas responsible for 1.5% of all malignant tumors, to compare our epidemiological data from the patient population of the Department of Orthopaedics, Semmelweis University, to data described in the international literature for soft tissue tumors. We reviewed 595 cases of primary soft tissue sarcomas treated between 1994 and 2014 and compared results to international data from the literature. Our results were similar to those found in the international literature: mean age, mild male predominance, the most common sarcoma subgroups, the superficial and deep sarcoma ratio, low and high grade sarcoma ratio, the ratio of patients with a primary lung metastasis. Compared to other European data we found significantly longer patient referral to centers (3.6 months in case of superficial sarcomas, 8 months in case of deep localization) which surprisingly had no substantial effect on average tumor size (superficial: 5 cm, deep: 10.5 cm). This corresponds with data from the literature. The long delay period in patients' request of medical service draws attention to difficulties in differential diagnosis in this rare type of tumor, delays in referring patients to a center, and the lack of consultation. We recommend that the required investigations be performed in a musculoskeletal oncology center where this type of cancer is treated.
Assuntos
Diagnóstico Tardio/estatística & dados numéricos , Sistema de Registros , Sarcoma/epidemiologia , Sarcoma/patologia , Neoplasias de Tecidos Moles/epidemiologia , Neoplasias de Tecidos Moles/patologia , Centros Médicos Acadêmicos , Adulto , Distribuição por Idade , Idoso , Causas de Morte , Intervalo Livre de Doença , Feminino , Hospitais Universitários , Humanos , Hungria , Masculino , Pessoa de Meia-Idade , Ortopedia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Sarcoma/terapia , Distribuição por Sexo , Neoplasias de Tecidos Moles/terapia , Análise de Sobrevida , Reino UnidoRESUMO
Native and designer cationic antimicrobial peptides are increasingly acknowledged as host defense molecules rather than true antimicrobials. Due to their ability to activate the innate immune system, these structures are used to treat uninfected and bacterially-infected wounds, including those harboring Acinetobacter baumannii. Previously we documented that when administered intramuscularly or topically in liquid formulations, the proline-rich host defense peptide dimer A3-APO accelerates uninfected wound re-epithelization and eliminates systemic and local A. baumannii, methicillin-resistant Staphylococcus aureus and other pathogen load from infected lesions better than conventional antibiotics. In the current study we sought to produce and characterize a novel delivery system, suitable for immediate and convenient application in non-hospital environments. The APO monomer was incorporated into polyvinyl alcohol nanofibers and the complex was polymerized into a solid patch dressing. Mice were subjected to skin abrasion where the wounds were either left uninfected or were inoculated with a near lethal dose of multidrug resistant A. baumannii strain. Analyzed after 3 days, APO monomer-containing patches improved wound appearance significantly better than polymer patches without antibiotics. When compared to colistin, the APO patches accelerated wound healing, and statistically significantly reduced wound size and wound bacterial load. The in vivo antimicrobial effect was more extensive than after intramuscular administration of the peptide drug, by using only one tenth of the active pharmaceutical ingredient. These data suggest that the APO monomer-impregnated nanofiber dressing can be developed as an economical first-line treatment option to skin injuries in general and battlefield burn and blast injuries in particular.
Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Portadores de Fármacos/química , Nanofibras/química , Álcool de Polivinil/química , Pele/microbiologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/crescimento & desenvolvimento , Animais , Peptídeos Catiônicos Antimicrobianos/química , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pele/lesõesRESUMO
The application of high-speed rotary spinning can offer a useful mean for either preparation of fibrous intermediate for conventional dosage forms or drug delivery systems. Polyvinylpyrrolidone (PVP) and poly(vinylpyrrolidone-vinylacetate) (PVP VA) micro- and nanofibers of different polymer concentrations and solvent ratios were prepared with a high-speed rotary spinning technique. In order to study the influence of parameters that enable successful fiber production from polymeric viscous solutions, a complex micro- and macrostructural screening method was implemented. The obtained fiber mats were subjected to detailed morphological analysis using scanning electron microscope (SEM), and rheological measurements while the microstructural changes of fiber samples, based on the free volume changes, was analyzed by positron annihilation lifetime spectroscopy (PALS) and compared with their mechanical characteristics. The plasticizing effect of water tracked by ortho-positronium lifetime changes in relation to the mechanical properties of fibers. A concentration range of polyvinylpyrrolidone solutions was defined for the preparation of fibers of optimum fiber morphology and mechanical properties. The method enabled fiber formulation of advantageous functionality-related properties for further formulation of solid dosage forms.
Assuntos
Nanofibras , Polímeros/química , Povidona/química , Pirrolidinas/química , Compostos de Vinila/química , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Microscopia Eletrônica de Varredura , Reologia , Solventes/química , Água/químicaRESUMO
A ten-year-long examination of macroinvertebrate community recovery was conducted following a catastrophic spill of highly alkaline red sludge (pH >13) into lowland streams. Our primary objective was to compare recovery patterns after coarse- and fine-grain disturbances, focusing on two aspects: i) trend analysis to reveal long-term changes of six community parameters, and ii) variation analyses to assess parameter changes over time. We conducted statistical analysis on long-term data series of macroinvertebrates obtained from quantitative samples collected at four sections with varying degrees of disturbance along the impacted stream sections. We developed a comprehensive theoretical framework comprising a series of sequential phases: Ramp-up, Overshoot, and Oscillation Phases. i) A trend analysis revealed that disturbances show a gradual recovery pattern, while variance analyses showed an asymptotic convergence to an equilibrium. ii) Evaluating these trends across phases unveiled that the initial recovery phase exhibited a steep trajectory, lasting 4-9 months, irrespective of disturbance severity. Coarse-grain disturbances induced a remarkable Overshoot phenomenon across all community metrics. The more severe the disturbance, the greater the height and duration of the Overshoot. Our results suggest that the presence or absence of Overshoot can serve as an indicator for coarse-grain disturbances in the context of large and infrequent disturbances (LID). The entire recovery process lasts for 2.5-3 years irrespective of the severity of the LID. In conclusion, a minimum survey duration of two and half years is deemed imperative to capture the phases of recovery, and changes associated with LID are not expected to extend beyond the three-year threshold. The theoretical framework, including Overshoot parameters, may assist future studies in comparing recovery patterns of different LID types. Furthermore, our theoretical framework is likely to be applicable to other groups of organisms given a sufficiently long monitoring of recovery, influenced also by the length of reproductive cycles.
Assuntos
Desastres , Invertebrados , Animais , Esgotos , Hungria , Rios/química , EcossistemaRESUMO
Background: Despite the continuously rising rate of pediatric-onset inflammatory bowel diseases (PIBD), there are no consensus transitional guidelines or standardized practices. Objectives: We aimed to examine: (1) the determinants of a successful transfer, (2) the effects of the transfer versus transition on the disease course and patient compliance, (3) the unique characteristics of PIBD patients, that need special attention in adult care. Design: Longitudinal, follow-up, controlled study conducted between 2001 and 2022, with retrospective data collection until 2018, thence prospective. Methods: Three hundred fifty-one PIBD patients enrolled in the study, of whom 152 were moved to adult care, with a mean post-transfer follow-up time of 3 years. Seventy-three patients took part in structured transition, whereas 79 self-transferred to adult care. The main outcome measures were disease activity (defined by PCDAI, PUCAI, CDAI, and Mayo-scores) and course, hospitalizations, surgeries, IBD-related complications, including anthropometry and bone density, patient compliance, medication adherence, and continuation of medical care. Results: Patients who underwent structured transition spent significantly more time in remission (83.6% ± 28.5% versus 77.5% ± 29.7%, p = 0.0339) and had better adherence to their medications (31.9% versus 16.4% non-adherence rate, p = 0.0455) in adult care, with self-transferred patients having a 1.59-fold increased risk of discontinuing their medical care and a 1.88-fold increased risk of experiencing a relapse. Post-transfer the compliance of patients deteriorated (38.5% versus 29%, p = 0.0002), with the highest lost-to-follow-up rate during the changing period between the healthcare systems (12.7%), in which female gender was a risk factor (p = 0.010). PIBD patients had experienced IBD-related complications (23.4%) and former surgeries (15%) upon arriving at adult care, with high rates of malnutrition, growth impairment, and poor bone health. Conclusion: Structured transition plays a key role in ensuring the best disease course and lowering the lost-to-follow-up rate among PIBD patients. Brief summary: Structured transition plays a key role in ensuring the best disease outcome among PIBD patients, as in our study it was associated with lower disease activity, fewer relapses, better medication adherence, and lower lost-to-follow-up rate as opposed to self-transfer.
RESUMO
INTRODUCTION: During the pandemic years in Hungary, the completed suicide rates have risen significantly. Violent suicide attempts represent the majority of completed suicides. OBJECTIVE: In our study, we analyzed the change of the number of inpatients treated in Dr. Manninger Jeno National Traumatology Center between 2016 and 2021 due to violent suicide attempts, focusing on the trend in the first two years of the pandemic outbreak. METHOD: We used an interrupted time-series analysis with Prais-Winsten regression, controlling autoagressive and seasonal effects, to estimate the effect of the pandemic on the violent suicide attempt rates in our sample. RESULTS: In the first two pandemic years, the number of inpatients treated in Dr. Manninger Jeno National Traumatology Center due to violent suicide attempts rose significantly, compared to the previous years. After the rapid rise observed in 2020, decreasing numbers were seen in 2021. DISCUSSION AND CONCLUSION: Analyzing the numbers of violent suicide attempts between 2016 and 2021, an increase in the number of attempts was observed during the first two pandemic years. Orv Hetil. 2023; 164(26): 1003-1011.
Assuntos
COVID-19 , Traumatologia , Humanos , Tentativa de Suicídio , Pandemias , Hungria/epidemiologia , Violência , COVID-19/epidemiologiaRESUMO
BACKGROUND: Asparaginase is a key component of chemotherapy protocols for the treatment of lymphoblastic malignancies among children. Adequate asparagine depletion is an important factor to achieve optimal therapeutic outcomes. METHODS: Over a 3.5 year period, 106 patients were monitored for asparaginase activity (329 samples) in a single center of the Hungarian Pediatric Oncology-Hematology Group. In Hungary, three asparaginase products are available: native E. coli ASNase (Kidrolase), a pegylated form of this enzyme (Pegaspargase) and another native product from Erwinia chrysanthemi (Erwinase). A retrospective data analysis was performed. RESULTS: In 81% (268/329) of our patients, AEA levels were in the optimal therapeutic range of over 100 IU/L. Of 106 patients, 13 (12%) were diagnosed with 'silent inactivation'. CONCLUSIONS: Monitoring of AEA can help to identify patients with 'silent inactivation' and their asparaginase therapy can thus be optimized.
RESUMO
The importance of finite element analysis (FEA) is growing in orthopedic research, especially in implant design. However, Young's modulus (E) values, one of the most fundamental parameters, can range across a wide scale. Therefore, our study aimed to identify factors influencing E values in human bone specimens. We report our systematic review and meta-analysis based on the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline. We conducted the analysis on November 21, 2021. We included studies investigating healthy human bone specimens and reported on E values regarding demographic data, specimen characteristics, and measurement specifics. In addition, we included study types reporting individual specimen measurements. From the acquired data, we created a cohort in which we performed an exploratory data analysis that included the explanatory variables selected by random forest and regression trees methods, and the comparison of groups using independent samples Welch's t test. A total of 756 entries were included from 48 articles. Eleven different bones of the human body were included in these articles. The range of E values is between 0.008 and 33.7 GPa. The E values were most heavily influenced by the cortical or cancellous type of bone tested. Measuring method (compression, tension, bending, and nanoindentation), the anatomical region within a bone, the position of the bone within the skeleton, and the bone specimen size had a decreasing impact on the E values. Bone anisotropy, specimen condition, patient age, and sex were selected as important variables considering the value of E. On the basis of our results, E values of a bone change with bone characteristics, measurement techniques, and demographic variables. Therefore, the evaluation of FEA should be performed after the standardization of in vitro measurement protocol. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.