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A central characteristic of Bayesian statistics is the ability to consistently incorporate prior knowledge into various modeling processes. In this paper, we focus on translating domain expert knowledge into corresponding prior distributions over model parameters, a process known as prior elicitation. Expert knowledge can manifest itself in diverse formats, including information about raw data, summary statistics, or model parameters. A major challenge for existing elicitation methods is how to effectively utilize all of these different formats in order to formulate prior distributions that align with the expert's expectations, regardless of the model structure. To address these challenges, we develop a simulation-based elicitation method that can learn the hyperparameters of potentially any parametric prior distribution from a wide spectrum of expert knowledge using stochastic gradient descent. We validate the effectiveness and robustness of our elicitation method in four representative simulation studies covering linear models, generalized linear models, and hierarchical models. Our results support the claim that our method is largely independent of the underlying model structure and adaptable to various elicitation techniques, including quantile-based, moment-based, and histogram-based methods.
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Although stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1+ cardiac stromal cells (CSCs) for myocardial injury. The overexpression of HAX1 significantly increased cell proliferation and conferred enhanced resistance to hypoxia-induced cell death in CSCs. Mechanistically, HAX1 can interact with Mst1 (a prominent conductor of Hippo signal transduction) and inhibit its kinase activity for protein phosphorylation. This inhibition led to enhanced nuclear translocation of Yes-associated protein (YAP) and activation of downstream therapeutic-related genes. Notably, HAX1 overexpression significantly increased the pro-angiogenic potential of CSCs, as demonstrated by elevated expression of vascular endothelial growth factors. Importantly, implantation of HAX1-overexpressing CSCs promoted neovascularization, protected against functional deterioration, and ameliorated cardiac fibrosis in ischemic mouse hearts. In conclusion, HAX1 emerges as a valuable and efficient inducer for enhancing the effectiveness of cardiac stem or progenitor cell therapeutics.
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Proteínas Adaptadoras Transductoras de Señales , Proliferación Celular , Vía de Señalización Hippo , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Proteínas Señalizadoras YAP , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ratones , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Proliferación Celular/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Humanos , Infarto del Miocardio/terapia , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/genética , Neovascularización Fisiológica , Células Madre/metabolismo , Células Madre/citología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Trasplante de Células Madre , Factor de Crecimiento de Hepatocito/metabolismo , Factor de Crecimiento de Hepatocito/genética , Proteínas Proto-OncogénicasRESUMEN
Bayesian model comparison (BMC) offers a principled approach to assessing the relative merits of competing computational models and propagating uncertainty into model selection decisions. However, BMC is often intractable for the popular class of hierarchical models due to their high-dimensional nested parameter structure. To address this intractability, we propose a deep learning method for performing BMC on any set of hierarchical models which can be instantiated as probabilistic programs. Since our method enables amortized inference, it allows efficient re-estimation of posterior model probabilities and fast performance validation prior to any real-data application. In a series of extensive validation studies, we benchmark the performance of our method against the state-of-the-art bridge sampling method and demonstrate excellent amortized inference across all BMC settings. We then showcase our method by comparing four hierarchical evidence accumulation models that have previously been deemed intractable for BMC due to partly implicit likelihoods. Additionally, we demonstrate how transfer learning can be leveraged to enhance training efficiency. We provide reproducible code for all analyses and an open-source implementation of our method. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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OBJECTIVE: Rumination is a major risk factor for the onset and recurrence of depressive episodes and has been associated with deficits in updating working memory content. This randomized controlled trial examines whether training updating-specific cognitive control processes reduces daily ruminative thoughts in clinically depressed individuals. METHODS: Sixty-five individuals with a current major depressive episode were randomized to 10 sessions of either cognitive control training (N = 31) or placebo training (N = 34). The frequency and negativity of individuals' daily ruminative thoughts were assessed for seven days before training, after training, and at a 3-month follow-up using experience sampling methodology. Secondary outcomes were depressive symptoms, depressed mood, and level of disability. RESULTS: Cognitive control training led to stronger improvements in the trained task than placebo training. However, cognitive control training did not lead to greater reductions in the frequency or negativity of daily ruminative thoughts than placebo training. There were no training-specific effects on participants' depressive symptoms or level of disability. CONCLUSIONS: The robustness of the present null-findings, combined with the methodological strengths of the study, suggest that training currently depressed individuals to update emotional content in working memory does not affect the frequency or negativity of their daily ruminative thoughts.
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Terapia Cognitivo-Conductual , Trastorno Depresivo Mayor , Memoria a Corto Plazo , Rumiación Cognitiva , Humanos , Femenino , Masculino , Trastorno Depresivo Mayor/psicología , Trastorno Depresivo Mayor/terapia , Adulto , Rumiación Cognitiva/fisiología , Terapia Cognitivo-Conductual/métodos , Persona de Mediana Edad , Terapia Asistida por Computador/métodos , Adulto Joven , Resultado del TratamientoRESUMEN
Gut microbes shape many aspects of organismal biology, yet how these key bacteria transmit among hosts in natural populations remains poorly understood. Recent work in mammals has emphasized either transmission through social contacts or indirect transmission through environmental contact, but the relative importance of different routes has not been directly assessed. Here we used a novel radio-frequency identification-based tracking system to collect long-term high-resolution data on social relationships, space use and microhabitat in a wild population of mice (Apodemus sylvaticus), while regularly characterizing their gut microbiota with 16S ribosomal RNA profiling. Through probabilistic modelling of the resulting data, we identify positive and statistically distinct signals of social and environmental transmission, captured by social networks and overlap in home ranges, respectively. Strikingly, microorganisms with distinct biological attributes drove these different transmission signals. While the social network effect on microbiota was driven by anaerobic bacteria, the effect of shared space was most influenced by aerotolerant spore-forming bacteria. These findings support the prediction that social contact is important for the transfer of microorganisms with low oxygen tolerance, while those that can tolerate oxygen or form spores may be able to transmit indirectly through the environment. Overall, these results suggest social and environmental transmission routes can spread biologically distinct members of the mammalian gut microbiota.
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Microbioma Gastrointestinal , Animales , ARN Ribosómico 16S/análisis , Murinae/microbiología , Conducta Social , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Masculino , Femenino , RatonesRESUMEN
The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.
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Importance: There are concerns about the safety of medications for treatment of attention-deficit/hyperactivity disorder (ADHD), with mixed evidence on possible cardiovascular risk. Objective: To assess whether short-term methylphenidate use is associated with risk of cardiovascular events. Design, Setting, and Participants: This retrospective, population-based cohort study was based on national Swedish registry data. Participants were individuals with ADHD aged 12 to 60 years with dispensed prescriptions of methylphenidate between January 1, 2007, and June 30, 2012. Each person receiving methylphenidate (n = 26â¯710) was matched on birth date, sex, and county to up to 10 nonusers without ADHD (n = 225â¯672). Statistical analyses were performed from September 13, 2022, to May 16, 2023. Main Outcomes and Measures: Rates of cardiovascular events, including ischemic heart disease, venous thromboembolism, heart failure, or tachyarrhythmias, 1 year before methylphenidate treatment and 6 months after treatment initiation were compared between individuals receiving methylphenidate and matched controls using a bayesian within-individual design. Analyses were stratified by history of cardiovascular events. Results: The cohort included 252â¯382 individuals (15â¯442 [57.8% men]; median age, 20 (IQR, 15-31) years). The overall incidence of cardiovascular events was 1.51 per 10â¯000 person-weeks (95% highest density interval [HDI], 1.35-1.69) for individuals receiving methylphenidate and 0.77 (95% HDI, 0.73-0.82) for the matched controls. Individuals treated with methylphenidate had an 87% posterior probability of having a higher rate of cardiovascular events after treatment initiation (incidence rate ratio [IRR], 1.41; 95% HDI, 1.09-1.88) compared with matched controls (IRR, 1.18; 95% HDI, 1.02-1.37). The posterior probabilities were 70% for at least a 10% increased risk of cardiovascular events in individuals receiving methylphenidate vs 49% in matched controls. No difference was found in this risk between individuals with and without a history of cardiovascular disease (IRR, 1.11; 95% HDI, 0.58-2.13). Conclusions and Relevance: In this cohort study, individuals receiving methylphenidate had a small increased cardiovascular risk vs matched controls in the 6 months after treatment initiation. However, there was little evidence for an increased risk of 20% or higher and for differences in risk increase between people with and without a history of cardiovascular disease. Therefore, before treatment initiation, careful consideration of the risk-benefit trade-off of methylphenidate would be useful, regardless of cardiovascular history.
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Enfermedades Cardiovasculares , Metilfenidato , Masculino , Humanos , Adulto Joven , Adulto , Femenino , Metilfenidato/efectos adversos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Teorema de Bayes , Estudios de Cohortes , Estudios Retrospectivos , Factores de Riesgo , Factores de Riesgo de Enfermedad CardiacaRESUMEN
Background and Objectives: Burn surgery on the hands is a difficult procedure due to the complex anatomy and fragility of the area. Enzymatic debridement has been shown to effectively remove burn eschar while minimizing damage to the surrounding tissue and has therefore become a standard procedure in many burn centers worldwide over the past decade. However, surprisingly, our recent literature review showed limited valid data on the long-term scarring after the enzymatic debridement of the hands. Therefore, we decided to present our study on this topic to fill this gap. Materials and Methods: This study analyzed partial-thickness to deep dermal burns on the hands that had undergone enzymatic debridement at least 12 months prior. Objective measures, like flexibility, trans-epidermal water loss, erythema, pigmentation, and microcirculation, were recorded and compared intraindividually to the uninjured skin in the same area of the other hand to assess the regenerative potential of the skin after EDNX. The subjective scar quality was evaluated using the patient and observer scar assessment scale (POSAS), the Vancouver Scar Scale (VSS), and the "Disabilities of the Arm, Shoulder, and Hand" (DASH) questionnaire and compared interindividually to a control group of 15 patients who had received traditional surgical debridement for hand burns of the same depth. Results: Between January 2014 and December 2015, 31 hand burns in 28 male and 3 female patients were treated with enzymatic debridement. After 12 months, the treated wounds showed no significant differences compared to the untreated skin in terms of flexibility, trans-epidermal water loss, pigmentation, and skin surface. However, the treated wounds still exhibited significantly increased blood circulation and erythema compared to the untreated areas. In comparison to the control group who received traditional surgical debridement, scarring was rated as significantly superior. Conclusions: In summary, it can be concluded that the objective skin quality following enzymatic debridement is comparable to that of healthy skin after 12 months and subjectively fares better than that after tangential excision. This confirms the superiority of enzymatic debridement in the treatment of deep dermal burns of the hand and solidifies its position as the gold standard.
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Quemaduras , Cicatriz , Humanos , Masculino , Femenino , Cicatriz/cirugía , Cicatrización de Heridas , Desbridamiento/métodos , Bromelaínas , Quemaduras/complicaciones , Quemaduras/cirugía , Eritema , AguaRESUMEN
Smoking has multiple detrimental effects on health, and is a major preventable cause of premature death and chronic disease. Despite the well-described effect of inhaled substances from tobacco smoke on cell toxicity, the association between smoking and suicidal erythrocyte death, termed eryptosis, is virtually unknown. Therefore, the blood samples of 2023 participants of the German National Cohort Study (NAKO) were analyzed using flow cytometry analysis to determine eryptosis from fluorescent annexin V-FITC-binding to phosphatidylserine-exposing erythrocytes. Blood analyses were complemented by the measurement of hematologic parameters including red blood cell count, hematocrit, hemoglobin, mean corpuscular cell volume (MCV) and mean corpuscular hemoglobin (MCH). Eryptosis was higher in smokers than in non- and ex-smokers, and positively associated with the number of cigarettes smoked daily (r = 0.08, 95% CI [0.03, 0.12]). Interestingly, despite increased eryptosis, smokers had higher red blood cell indices than non-smokers. To conclude, smokers were characterized by higher eryptosis than non-smokers, without showing any obvious detrimental effect on classic hematological parameters.
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Eriptosis , Humanos , Especies Reactivas de Oxígeno/metabolismo , Estudios de Cohortes , Eritrocitos/metabolismo , Fumar , Calcio/metabolismo , Fosfatidilserinas/metabolismo , Ceramidas/metabolismo , Tamaño de la CélulaRESUMEN
BACKGROUND: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of all CS cases. Nevertheless, there is a lack of evidence on sex-related differences in HF-CS, especially regarding use of treatment and mortality risk in women vs. men. This study aimed to investigate potential differences in clinical presentation, use of treatments, and mortality between women and men with HF-CS. METHODS: In this international observational study, patients with HF-CS (without acute myocardial infarction) from 16 tertiary-care centers in five countries were enrolled between 2010 and 2021. Logistic and Cox regression models were used to assess differences in clinical presentation, use of treatments, and 30-day mortality in women vs. men with HF-CS. RESULTS: N = 1030 patients with HF-CS were analyzed, of whom 290 (28.2%) were women. Compared to men, women were more likely to be older, less likely to have a known history of heart failure or cardiovascular risk factors, and lower rates of highly depressed left ventricular ejection fraction and renal dysfunction. Nevertheless, CS severity as well as use of treatments were comparable, and female sex was not independently associated with 30-day mortality (53.0% vs. 50.8%; adjusted HR 0.94, 95% CI 0.75-1.19). CONCLUSIONS: In this large HF-CS registry, sex disparities in risk factors and clinical presentation were observed. Despite these differences, the use of treatments was comparable, and both sexes exhibited similarly high mortality rates. Further research is necessary to evaluate if sex-tailored treatment, accounting for the differences in cardiovascular risk factors and clinical presentation, might improve outcomes in HF-CS.
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Insuficiencia Cardíaca , Choque Cardiogénico , Masculino , Humanos , Femenino , Choque Cardiogénico/diagnóstico , Choque Cardiogénico/epidemiología , Choque Cardiogénico/etiología , Volumen Sistólico , Función Ventricular Izquierda , Factores Sexuales , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Mortalidad HospitalariaRESUMEN
Cardiovascular diseases remain a leading cause of hospitalization affecting approximately 38 million people worldwide. While pharmacological and revascularization techniques can improve the patient's survival and quality of life, they cannot help reversing myocardial infarction injury and heart failure. Direct reprogramming of somatic cells to cardiomyocyte and cardiac progenitor cells offers a new approach to cellular reprogramming and paves the way for translational regenerative medicine. Direct reprogramming can bypass the pluripotent stage with the potential advantage of non-immunogenic cell products, reduced carcinogenic risk, and no requirement for embryonic tissue. The process of directly reprogramming cardiac cells was first achieved through the overexpression of transcription factors such as GATA4, MEF2C, and TBX5. However, over the past decade, significant work has been focused on enhancing direct reprogramming using a mixture of transcription factors, microRNAs, and small molecules to achieve cardiac cell fate. This review discusses the evolution of direct reprogramming, recent progress in achieving efficient cardiac cell fate conversion, and describes the reprogramming mechanisms at a molecular level. We also explore various viral and non-viral delivery methods currently being used to aid in the delivery of reprogramming factors to improve efficiency. However, further studies will be needed to overcome molecular and epigenetic barriers to successfully achieve translational cardiac regenerative therapeutics.
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Técnicas de Reprogramación Celular , Calidad de Vida , Humanos , Técnicas de Reprogramación Celular/métodos , Miocitos Cardíacos , Reprogramación Celular , Factores de Transcripción/genética , Medicina Regenerativa/métodos , FibroblastosRESUMEN
AIMS: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in CS differ in clinical characteristics and outcome remains unclear. The aim of this study was to evaluate differences in clinical presentation and mortality between patients with de novo and acute-on-chronic HF-CS. METHODS AND RESULTS: In this international observational study, patients with HF-CS from 16 tertiary care centres in five countries were enrolled between 2010 and 2021. To investigate differences in clinical presentation and 30-day mortality, adjusted logistic/Cox regression models were fitted. Patients (n = 1030) with HF-CS were analysed, of whom 486 (47.2%) presented with de novo HF-CS and 544 (52.8%) with acute-on-chronic HF-CS. Traditional markers of CS severity (e.g. blood pressure, heart rate and lactate) as well as use of treatments were comparable between groups. However, patients with acute-on-chronic HF-CS were more likely to have a higher CS severity and also a higher mortality risk, after adjusting for relevant confounders (de novo HF 45.5%, acute-on-chronic HF 55.9%, adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.72, p = 0.005). CONCLUSION: In this large HF-CS cohort, acute-on-chronic HF-CS was associated with more severe CS and higher mortality risk compared to de novo HF-CS, although traditional markers of CS severity and use of treatments were comparable. These findings highlight the vast heterogeneity of patients with HF-CS, emphasize that HF chronicity is a relevant disease modifier in CS, and indicate that future clinical trials should account for this.
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Insuficiencia Cardíaca , Choque Cardiogénico , Humanos , Mortalidad Hospitalaria , Pronóstico , Choque Cardiogénico/etiologíaRESUMEN
BACKGROUND: Currently, use of mechanical circulatory support (MCS) in non-ischaemic cardiogenic shock (CS) is predominantly guided by shock-specific markers, and not by markers of cardiac function. We hypothesise that left ventricular ejection fraction (LVEF) can identify patients with a higher likelihood to benefit from MCS and thus help to optimise their expected benefit. METHODS: Patients with non-ischaemic CS and available data on LVEF from 16 tertiary-care centres in five countries were analysed. Cox regression models were fitted to evaluate the association between LVEF and mortality, as well as the interaction between LVEF, MCS use and mortality. RESULTS: N = 807 patients were analysed: mean age 63 [interquartile range (IQR) 51.5-72.0] years, 601 (74.5%) male, lactate 4.9 (IQR 2.6-8.5) mmol/l, LVEF 20 (IQR 15-30) %. Lower LVEF was more frequent amongst patients with more severe CS, and MCS was more likely used in patients with lower LVEF. There was no association between LVEF and 30-day mortality risk in the overall study cohort. However, there was a significant interaction between MCS use and LVEF, indicating a lower 30-day mortality risk with MCS use in patients with LVEF ≤ 20% (hazard ratio 0.72, 95% confidence interval 0.51-1.02 for LVEF ≤ 20% vs. hazard ratio 1.31, 95% confidence interval 0.85-2.01 for LVEF > 20%, interaction-p = 0.017). CONCLUSION: This retrospective study may indicate a lower mortality risk with MCS use only in patients with severely reduced LVEF. This may propose the inclusion of LVEF as an adjunctive parameter for MCS decision-making in non-ischaemic CS, aiming to optimise the benefit-risk ratio.
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Corazón Auxiliar , Choque Cardiogénico , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Choque Cardiogénico/diagnóstico , Choque Cardiogénico/terapia , Volumen Sistólico , Función Ventricular Izquierda , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
An essential step in the life cycle of malaria parasites is their egress from hepatocytes, which enables the transition from the asymptomatic liver stage to the pathogenic blood stage of infection. To exit the liver, Plasmodium parasites first disrupt the parasitophorous vacuole membrane that surrounds them during their intracellular replication. Subsequently, parasite-filled structures called merosomes emerge from the infected cell. Shrouded by host plasma membrane, like in a Trojan horse, parasites enter the vasculature undetected by the host immune system and travel to the lung where merosomes rupture, parasites are released, and the blood infection stage begins. This complex, multi-step process must be carefully orchestrated by the parasite and requires extensive manipulation of the infected host cell. This review aims to outline the known signaling pathways that trigger exit, highlight Plasmodium proteins that contribute to the release of liver-stage merozoites, and summarize the accompanying changes to the hepatic host cell.
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Malaria , Parásitos , Plasmodium , Animales , Humanos , Parásitos/metabolismo , Hígado/parasitología , Hepatocitos/parasitología , Plasmodium/metabolismo , Malaria/parasitología , Eritrocitos/parasitología , Proteínas Protozoarias/metabolismoRESUMEN
The exponential growth of COVID-19 cases in early 2020 presented a massive challenge for healthcare systems and called for the adaptation of emergency care routines and intensive care capacities. We, therefore, analyzed a possible impact of the COVID-19 pandemic on the general structure and emergency preparedness of burn centers in German-speaking countries through a cross-sectional descriptive survey questionnaire. The survey was conducted for the first time in January 2019 by Al-Shamsi et al. before the beginning of the COVID-19 pandemic. It was performed for a second time in November 2020 during the second wave of COVID-19 infections in German-speaking countries. We noticed a pronounced increase in the preparation for a great number of patients in need of intensive care including the enlargement of overall capacity when necessary. We also showed a notable decrease in the specific preparation for burn disasters and also reduced communication with first responders and other burn centers. To what extent these alterations were caused by the impact the pandemic had on healthcare systems could not be determined in this study and should be the subject of future research.
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Quemaduras , COVID-19 , Humanos , Unidades de Quemados , COVID-19/epidemiología , Pandemias , Estudios Transversales , Quemaduras/epidemiología , Quemaduras/terapiaRESUMEN
Transmission of malaria parasites to the mosquito is mediated by sexual precursor cells, the gametocytes. Upon entering the mosquito midgut, the gametocytes egress from the enveloping erythrocyte while passing through gametogenesis. Egress follows an inside-out mode during which the membrane of the parasitophorous vacuole (PV) ruptures prior to the erythrocyte membrane. Membrane rupture requires exocytosis of specialized egress vesicles of the parasites; that is, osmiophilic bodies (OBs) involved in rupturing the PV membrane, and vesicles that harbor the perforin-like protein PPLP2 (here termed P-EVs) required for erythrocyte lysis. While some OB proteins have been identified, like G377 and MDV1/Peg3, the majority of egress vesicle-resident proteins is yet unknown. Here, we used high-resolution imaging and BioID methods to study the two egress vesicle types in Plasmodium falciparum gametocytes. We show that OB exocytosis precedes discharge of the P-EVs and that exocytosis of the P-EVs, but not of the OBs, is calcium sensitive. Both vesicle types exhibit distinct proteomes with the majority of proteins located in the OBs. In addition to known egress-related proteins, we identified novel components of OBs and P-EVs, including vesicle-trafficking proteins. Our data provide insight into the immense molecular machinery required for the inside-out egress of P. falciparum gametocytes.
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Malaria Falciparum , Plasmodium falciparum , Animales , Plasmodium falciparum/metabolismo , Proteómica/métodos , Proteínas Protozoarias/metabolismo , Eritrocitos/parasitología , Malaria Falciparum/parasitologíaRESUMEN
An essential process in transmission of the malaria parasite to the Anopheles vector is the conversion of mature gametocytes into gametes within the mosquito gut, where they egress from the red blood cell (RBC). During egress, male gametocytes undergo exflagellation, leading to the formation of eight haploid motile microgametes, while female gametes retain their spherical shape. Gametocyte egress depends on sequential disruption of the parasitophorous vacuole membrane and the host cell membrane. In other life cycle stages of the malaria parasite, phospholipases have been implicated in membrane disruption processes during egress, however their importance for gametocyte egress is relatively unknown. Here, we performed comprehensive functional analyses of six putative phospholipases for their role during development and egress of Plasmodium falciparum gametocytes. We localize two of them, the prodrug activation and resistance esterase (PF3D7_0709700) and the lysophospholipase 1 (PF3D7_1476700), to the parasite plasma membrane. Subsequently, we show that disruption of most of the studied phospholipase genes does neither affect gametocyte development nor egress. The exception is the putative patatin-like phospholipase 3 (PF3D7_0924000), whose gene deletion leads to a delay in male gametocyte exflagellation, indicating an important, albeit not essential, role of this enzyme in male gametogenesis.
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Malaria , Plasmodium falciparum , Animales , Masculino , Femenino , Fosfolipasas/genética , Mosquitos Vectores , Eritrocitos/parasitologíaRESUMEN
Following the enzymatic debridement of deep dermal burns, the choice of wound dressing is crucial for providing an adequate environment and suitable conditions for rapid wound healing. As Suprathel® and fatty gauze (Jelonet®) are the most commonly used dressings in burn centers, the aim of this study is to compare Suprathel® and Jelonet® in the treatment of deep dermal burns after enzymatic debridement with respect to wound healing, patient comfort, and pain. A total of 23 patients with deep dermal burns of the hand or foot (mean total body surface area of 4.31%) were included in this prospective, unicentric, open, comparative, and intra-individual clinical study. After enzymatic debridement, wounds were divided into two areas: one was treated with Suprathel® and the other with Jelonet®. Suprathel® remained on the wounds without dressing changes while Jelonet® was regularly changed. Wound healing, infection, bleeding, exudation, time for dressing changes, and pain were documented (from days 2 to 48) after injury. Satisfactory results were obtained in 22 cases; only one patient had to undergo a second debridement followed by skin grafting. No significant difference in time to final wound healing could be observed (18-19 d). Patients reported significantly less pain during the dressing changes for Suprathel® compared to Jelonet®. Furthermore, the wound areas treated with Suprathel® showed significantly less exudation and bleeding. Wound infections rarely occurred in both groups. In conclusion, the authors found that both wound dressings could be used to achieve safe and rapid wound healing after the enzymatic debridement of deep dermal burns of the hands and feet. However, compared to Jelonet®, Suprathel® showed superior results in terms of patient comfort and pain reduction.
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Processing properties of PMMA bone cements can be divided into four phases: 1. mixing, 2. waiting, 3. processing and 4. curing. Each of these phases is subject to several external influencing factors, such as temperature and humidity, which must be considered during application. Instructions for use provided by the manufacturers of PMMA bone cements and mixing and application systems contain important information on correct application. The processing properties of PMMA bone cements and possible factors influencing the curing process are of great importance for safe procedures in the operating room. Knowledge of the viscosity and consistency of the PMMA bone cement from the dough phase to complete curing facilitates preparation and application, which in the long term significantly improves the requirements placed on PMMA cements regarding the function and service life of the implant.