Right Ventricular Longitudinal Strain Predicts Survival in Patients With Functional Tricuspid Regurgitation

BackgroundFunctional tricuspid regurgitation (TR) is a frequent finding in echocardiography. Despite general consent that right ventricular (RV) dysfunction impacts outcome of patients with TR, it is still unknown which echocardiographic parameters most accurately reflect prognosis. In this study we aimed to evaluate the prevalence of RV dysfunction and its prognostic value in patients with TR.MethodsData from 1089 consecutive patients were analysed. Tricuspid annular plane systolic excursion (TAPSE), fractional area change, and right ventricular free wall longitudinal strain (RV strain) were used to define RV dysfunction. Patients were followed for 2-year all-cause mortality. For prediction of survival, reclassification and C statistics of RV functional parameters using TR grade as reference model were performed.ResultsAmong the patients studied, 13.9% showed no TR, 61.2% had mild TR, 19.6% had moderate TR, and 5.3% had severe TR. The TR grade was associated with increased mortality (log rank, P < 0.001). Impaired RV strain and TAPSE were independent predictors for mortality (RV: hazard ratio [HR], 1.130; 95% confidence interval [CI], 1.099-1.160; P < 0.001; TAPSE: HR, 1.131; 95% CI, 1.085-1.175; P < 0.001). Both RV strain and TAPSE improved the reference model for survival prediction (RV: integrated discrimination improvement [IDI], 0.184; 95% CI, 0.146-0.221; P < 0.001; TAPSE: IDI, 0.057; 95% CI, 0.037-0.077; P < 0.001).ConclusionsEchocardiographic evaluation of RV function appears to useful for patients with TR. Assessment of RV strain provides additional value for prediction of 2-year mortality.     

Development of a Brief Cognitive and Behavioral Intervention for the Management of Episodic Breathlessness—A Delphi Survey With International Experts

ContextEpisodic breathlessness is characterized by a severe worsening of breathlessness intensity that goes beyond usual fluctuations. Episodes are usually short; therefore, nonpharmacological strategies (cognitive and behavioral) seem most promising to be beneficial. Which strategies—delivered separately or in combination—might be most effective and feasible remains unclear.ObjectivesThe Delphi survey selects and determines different nonpharmacological strategies for coping with episodic breathlessness to develop a brief cognitive and behavioral intervention for the management of episodic breathlessness.MethodsUsing an online Delphi survey comprising three rounds, international, multidisciplinary experts in breathlessness summarized and determined cognitive and behavioral strategies. The a priori target agreement for close-ended questions was 70%.ResultsExperts (n = 41/87; n = 45/85; n = 36/85) agreed on 15 of the 31 cognitive and behavioral strategies. Based on the panellists' opinion, the final version of the cognitive and behavioral intervention comprised the following characteristics: individually tailored intervention, a high proportion of communication, short duration, the involvement of carers, and use of the Breathing, Thinking, Functioning Model of Spathis et al. Consensus upon the delivery of the subsequent strategies within the intervention was reached: handheld fan, forward lean, diaphragmatic breathing, distraction, pursed lips breathing, long breaths out, and relaxation training.ConclusionUsing the consented nonpharmacological strategies, a brief cognitive and behavioral intervention was developed that balances between individualization and standardization of the intervention.     

Myopodin is an F-actin bundling protein with multiple independent actin-binding regions

The assembly of striated muscle myofibrils is a multistep process in which a variety of proteins is involved. One of the first and most important steps in myofibrillogenesis is the arrangement of thin myofilaments into ordered I-Z-I brushes, requiring the coordinated activity of numerous actin binding proteins. The early expression of myopodin prior to sarcomeric α-actinin, as well as its binding to actin, α-actinin and filamin indicate an important role for this protein in actin cytoskeleton remodelling with the precise function of myopodin in this process yet remaining to be resolved. While myopodin was previously described as a protein capable of cross-linking actin filaments into thick bundles upon transient transfections, it has remained unclear whether myopodin alone is capable of bundling actin, or if additional proteins are involved. We have therefore investigated the in vitro actin binding properties of myopodin. High speed cosedimentation assays with skeletal muscle actin confirmed direct binding of myopodin to F-actin and showed that this interaction is mediated by at least two independent actin binding sites, found in all myopodin isoforms identified to date. Furthermore, low-speed cosedimentation assays revealed that not only full length myopodin, but also the fragment containing only the second binding site, bundles microfilaments in the absence of accessory proteins. Ultrastructural analysis demonstrated that this bundling activity resembled that of α-actinin. Biochemical experiments revealed that bundling was not achieved by myopodin’s ability to dimerize, indicating the presence of two individual F-actin binding sites within the second binding segment. Thus full length myopodin contains at least three F-actin binding sites. These data provide further understanding of the mechanisms by which myopodin contributes to actin reorganization during myofibril assembly.

     

Sex determination in skeletal remains from the medieval Eastern Adriatic coast – discriminant function analysis of humeri

Aim

To investigate the usefulness of humerus measurement for sex determination in a sample of medieval skeletons from the Eastern Adriatic Coast. Additional aim was to compare the results with contemporary female population.

Methods

Five humerus measurements (maximum length, epicondylar width, maximum vertical diameter of the head, maximum and minimum diameter of the humerus at midshaft) for 80 male and 35 female medieval and 19 female contemporary humeri were recorded. Only sufficiently preserved skeletons and those with no obvious pathological or traumatic changes that could affect the measurements were included. For ten samples, analysis of DNA was performed in order to determine sex using amelogenin.

Results

The initial comparison of men and women indicated significant differences in all five measures (P < 0.001). Discriminant function for sex determination indicated that as much as 85% of cases could be properly categorized, with better results in men (86%) than women (80%). Furthermore, the comparison of the medieval and contemporary women did not show significant difference in any of the measured features. Sex results obtained by anthropological and DNA analysis matched in all 10 cases.

Conclusion

The results indicate that humerus measurement in Croatian medieval population may be sufficient to determine the sex of the skeleton. Furthermore, it seems that secular changes have not substantially affected contemporary population, suggesting that the results of this study are transferable to contemporary population as well.Once the skeletal remains are uncovered, anthropologists initially aim to reconstruct the biological profile of the person, which includes sex, age, and height estimation. During the reconstruction process, numerous issues may arise, including bone fragmentation and poor preservation of skeletal remains, coupled with the complexity of human skeleton (1,2). Sex determination is one of the first and basic steps of assessing the biological profile. Although the analysis of DNA is the most reliable method for sex determination (3), it is also the most expensive and time consuming method, which can also be hindered by local conditions. This may especially be true in cases of poor preservation of the remains, inhibitors effects, or a small amount of extracted DNA from the sample.In absence of DNA results, skeletal remains can be used to infer subject’s sex via two methods, morphological and anthropometric. The morphological approach is based on the examination of the bones that show the strongest sexual dimorphism, principally the skull and the pelvis (4). However, this method is not always reliable, especially if the skull is fragmented or incomplete. Age can also affect the results, especially in elderly women, in which morphological characteristics of the skull tend to resemble those of men (5). Although morphological methods are very important for a preliminary sex assessment, they additionally rely on the experience of the examiner and are therefore rather subjective and unreliable.The second approach is based on anthropometric analysis, which relies on the bone measurements. The main analytic approach is based on discriminant function analysis, which attempts to classify subjects into each of the sexes, by using either one or more bones (6). This kind of analysis is a very important quantitative method (7) for sex determination as it reduces the subjectivity of the examiner (2,4,8). So far, only a few such studies have been published using Croatian bone samples. These include medieval and contemporary femurs and tibias (8-11) and medieval and contemporary mandibles and teeth (6,12). Such studies are important, since clear differences were observed in different populations (13-15), making this a locally-specific feature that requires the development of regional standards, applicable for local population (16).Besides already used femurs and tibias, humerus is another long bone from the body that is presumably informative for sex determination. This idea was initially derived from the empirical investigations of the skeletal remains, and further supported by the previously reported sexual dimorphism of humeri (7,17), even in cases of severe bone fragmentation (18). Furthermore, such location-specific results may be of interest in modern forensics as well, since observed changes in the skeleton marked predominantly by the increase in height (19), appear to be proportional, with no indication of sexual dimorphism in ancient and modern samples (20). Therefore, the aim of this study was to investigate the possibility to determine the sex of the subject based on anthropometric analysis of humeri measures.     

G-protein-coupled receptor kinase activity in human heart failure: effects of beta-adrenoceptor blockade

OBJECTIVES: In human end-stage heart failure as well as in experimental animal models of heart failure, G-protein-coupled receptor kinase activity (GRK) is increased while beta-adrenoceptor responsiveness is diminished. In animal studies, beta-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial beta-adrenoceptors. The aim of this study was to investigate whether alterations in GRK activity are an early or late accompaniment of human heart failure and whether also in humans beta-adrenoceptor blocker treatment is able to influence myocardial GRK activity. METHODS: We assessed in right atria, obtained from patients at different stages of heart failure, treated with or not treated with beta-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, beta-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and GRK activity (by an in vitro rhodopsin phosphorylation assay). RESULTS: With increasing severity of heart failure, plasma noradrenaline levels increased while myocardial beta-adrenoceptor density decreased with a maximum in GRK activity in end-stage heart failure. However, in relation to the progression of heart failure, we found that GRK activity transiently increased at an early stage of heart failure (NYHA I and II) but decreased back to control values in patients at NYHA III and IV. beta-Adrenoceptor blockers were able to reduce the early increase in GRK activity at NYHA I and II to control levels, whereas in those patients who did not have increased GRK activity (NYHA III and IV), they had only a marginal effect. CONCLUSION: According to our results, an increase in GRK activity is an early and transient event in the course of heart failure that can be prevented by beta-adrenoceptor blocker treatment.     

Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid–Resistant Nephrotic Syndrome

Background and objectives

Treatment of congenital nephrotic syndrome (CNS) and steroid–resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in SRNS that affect the renal podocyte. In the era of high–throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease.

Design, setting, participants, & measurements

Cross–sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50–178). Genotyping was performed systematically in all patients.

Results

The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA–induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy.

Conclusions

The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients.