Hyponatraemia in imported malaria is common and associated with disease severity

<p>Abstract</p> <p>Background</p> <p>Hyponatraemia (serum sodium < 135 mmol/L) has long been recognized as a complication of malaria. However, few studies have been done in non-immune adult populations. It has not been investigated previously how hyponatraemia is distributed among the various <it>Plasmodium </it>species, and its association with malaria severity is unknown.</p> <p>The aim of this retrospective cohort study was to determine the prevalence of hyponatraemia and its association with malaria severity in a large cohort of patients with imported malaria caused by various <it>Plasmodium </it>species.</p> <p>Methods</p> <p>All patients that were diagnosed with malaria in the Harbour Hospital and Institute for Tropical Diseases in Rotterdam in the period 1999-2009 and who had available serum sodium on admission were included. Severe malaria was defined according to the modified WHO criteria. Prevalence of hyponatraemia and its association with malaria severity were investigated by univariate comparison, ROC analysis and multivariate logistic regression analysis.</p> <p>Results</p> <p>A total of 446 patients with malaria (severe falciparum malaria n = 35, non-severe falciparum malaria n = 280, non-falciparum malaria n = 131) was included. Hyponatraemia was present in 207 patients (46%). Prevalence and severity of hyponatraemia were greatest in severe falciparum malaria (77%, median serum sodium 129 mmol/L), followed by non-severe falciparum malaria (48%, median serum sodium 131 mmol/L), and non-falciparum malaria (34%, median serum sodium 132 mmol/L). Admission serum sodium < 133 mmol/L had a sensitivity of 0.69 and a specificity of 0.76 for predicting severe malaria. Multivariate logistic regression showed that serum sodium < 131 mmol/L was independently associated with severe falciparum malaria (odds ratio 10.4, 95% confidence interval 3.1-34.9). In patients with hyponatraemia, hypovolaemia did not appear to play a significant role in the development of hyponatraemia when prerenal azotaemia and haematocrit were considered as surrogate markers for hypovolaemia.</p> <p>Conclusions</p> <p>Hyponatraemia is common in imported malaria and is associated with severe falciparum malaria. From a clinical point of view, the predictive power of hyponatraemia for severe malaria is limited. The precise pathophysiological mechanisms of hyponatraemia in malaria require further study.</p

A lung function information system

Abstract A lung function information system (LFIS) was developed for the data analysis of pulmonary function tests at different locations. This system was connected to the hospital information system (HIS) for the retrieval of patient data and the storage of the lung function variables of patients to generate follow-up reports and to support financial and administrative management. The application programs were developed in such a way that high flexibility was obtained with respect to the patient-computer-technician interaction. The sampled data are stored on a disc to correct earlier decisions, perform recalculations and reanalyse the data for research purposes. When the measurements performed on a patient are authorized, the sampled data are deleted, except for when they are needed for future research. A distributed computer system was chosen to combine the benefits of a centralized system with those of several stand-alone systems. The main tasks of the central unit are to store collected data and computer programs, generate a final lung function report on laser printer and provide a connection to the HIS. In the satellite computers, which are located close to the lung function equipment, the signals and raw data are processed. Furthermore, the satellite computers were in use for program development and several research projects, and for the offline data processing of the lung function measurements from two other hospitals by means of a modem connection. The LFIS improved the quantity and quality of data acquisition. It resulted in an increased capacity of about 50% concerning spirometry, and facilitated time-consuming complex analyses. It also avoided miscalculations and mistakes in reports previously experienced with hand calculations

Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor

Recent studies have identified a series of estrogen receptor (ER)interacting peptides that recognize sites that are distinct from the classic coregulator recruitment (AF2) region. Here, we report the structural and functional characterization of an ER alpha-specific peptide that binds to the liganded receptor in an AF2-independent manner. The 2-angstrom crystal structure of the ER/peptide complex reveals a binding site that is centered on a shallow depression on the beta-hairpin face of the ligand-binding domain. The peptide binds in an unusual extended conformation and makes multiple contacts with the ligand-binding domain. The location and architecture of the binding site provides an insight into the peptide's ER subtype specificity and ligand interaction preferences. In vivo, an engineered coactivator containing the peptide motif is able to strongly enhance the transcriptional activity of liganded ER alpha, particularly in the presence of 4-hydroxytamoxifen. Furthermore, disruption of this binding surface alters ER's response to the coregulator TIF2. Together, these results indicate that this previously unknown interaction site represents a bona fide control surface involved in regulating receptor activity

Neural correlates of prosocial peer influence on public goods game donations during adolescence

A unique feature of adolescent social re-orientation is heightened sensitivity to peer influence when taking risks. However, positive peer influence effects are not yet well understood. The present fMRI study tested a novel hypothesis, by examining neural correlates of prosocial peer influence on donation decisions in adolescence. Participants (age 12–16 years; N ¼ 61) made decisions in anonymous groups about the allocation of tokens between themselves and the group in a public goods game. Two spectator groups of same-age peers—in fact youth actors—were allegedly online during some of the decisions.The task had a within-subjects design with three conditions: (1) Evaluation: spectators evaluated decisions with likes for large donations to the group, (2) Spectator: spectators were present but no evaluative feedback was displayed and (3) Alone: no spectators nor feedback. Results showed that prosocial behavior increased in the presence of peers, and even more when participants received evaluative feedback from peers. Peer presence resulted in enhanced activity in several social brain regions including medial prefrontal cortex, temporal parietal junction (TPJ), precuneus and superior temporal sulcus.TPJ activity correlated with donations, which suggests similar networks for prosocial behavior and sensitivity to peers.These findings highlight the importance of peers in fostering prosocial development throughout adolescence.Social decision makin

Copeptin does not accurately predict disease severity in imported malaria

<p>Abstract</p> <p>Background</p> <p>Copeptin has recently been identified to be a stable surrogate marker for the unstable hormone arginine vasopressin (AVP). Copeptin has been shown to correlate with disease severity in leptospirosis and bacterial sepsis. Hyponatraemia is common in severe imported malaria and dysregulation of AVP release has been hypothesized as an underlying pathophysiological mechanism. The aim of the present study was to evaluate the performance of copeptin as a predictor of disease severity in imported malaria.</p> <p>Methods</p> <p>Copeptin was measured in stored serum samples of 204 patients with imported malaria that were admitted to our Institute for Tropical Diseases in Rotterdam in the period 1999-2010. The occurrence of WHO defined severe malaria was the primary end-point. The diagnostic performance of copeptin was compared to that of previously evaluated biomarkers C-reactive protein, procalcitonin, lactate and sodium.</p> <p>Results</p> <p>Of the 204 patients (141 <it>Plasmodium falciparum</it>, 63 non-falciparum infection), 25 had severe malaria. The Area Under the ROC curve of copeptin for severe disease (0.66 [95% confidence interval 0.59-0.72]) was comparable to that of lactate, sodium and procalcitonin. C-reactive protein (0.84 [95% CI 0.79-0.89]) had a significantly better performance as a biomarker for severe malaria than the other biomarkers.</p> <p>Conclusions</p> <p>C-reactive protein but not copeptin was found to be an accurate predictor for disease severity in imported malaria. The applicability of copeptin as a marker for severe malaria in clinical practice is limited to exclusion of severe malaria.</p

Fetal and post-natal outcomes in offspring after intrauterine metformin exposure:A systematic review and meta-analysis of animal experiments

Aims: The impact of maternal metformin use during pregnancy on fetal, infant, childhood and adolescent growth, development, and health remains unclear. Our objective was to systematically review the available evidence from animal experiments on the effects of intrauterine metformin exposure on offspring's anthropometric, cardiovascular and metabolic outcomes. Methods: A systematic search was conducted in PUBMED and EMBASE from inception (searched on 12th April 2023). We extracted original, controlled animal studies that investigated the effects of maternal metformin use during pregnancy on offspring anthropometric, cardiovascular and metabolic measurements. Subsequently, risk of bias was assessed and meta-analyses using the standardized mean difference and a random effects model were conducted for all outcomes containing data from 3 or more studies. Subgroup analyses were planned for species, strain, sex and type of model in the case of 10 comparisons or more per subgroup. Results: We included 37 articles (n = 3133 offspring from n = 716 litters, containing n = 51 comparisons) in this review, mostly (95%) on rodent models and 5% pig models. Follow-up of offspring ranged from birth to 2 years of age. Thirty four of the included articles could be included in the meta-analysis. No significant effects in the overall meta-analysis of metformin on any of the anthropometric, cardiovascular and metabolic offspring outcome measures were identified. Between-studies heterogeneity was high, and risk of bias was unclear in most studies as a consequence of poor reporting of essential methodological details. Conclusion: This systematic review was unable to establish effects of metformin treatment during pregnancy on anthropometric, cardiovascular and metabolic outcomes in non-human offspring. Heterogeneity between studies was high and reporting of methodological details often limited. This highlights a need for additional high-quality research both in humans and model systems to allow firm conclusions to be established. Future research should include focus on the effects of metformin in older offspring age groups, and on outcomes which have gone uninvestigated to date.</p

Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the''Guard-Hypothesis,'' R proteins (the ``guards'') can sense modification of target molecules in the host (the ``guardees'') by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the ``guardee-effector'' interface for pathogen recognition, natural selection acts on the ``guard-guardee'' interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen