Interaction time with conspecifics induces food preference or aversion in the wild Algerian mouse.

The social transmission of a novel food preference can avoid unnecessary costs arising from tasting nonedible foods. This type of social learning has been demonstrated in laboratory rats and mice. However, among wild animals, there may be several constraints that make it less effective. Using wild Algerian mice (Mus spretus) tested in the laboratory, we demonstrate that a preference for a novel food can be transmitted between Observer and Demonstrator individuals and that it is maintained for at least 30 days. However, only half of the Observers acquired a preference for the same food as the Demonstrators, and only when the duration of oronasal investigation was above a certain threshold (≥122 s); below this threshold (<122 s), Observers acquired a preference for the alternative food offered, which was maintained for a shorter time. Sex, size, and identity of individuals did not influence the transmission of social information. The results show that different interaction times will result in animals copying or avoiding the food choices of others. This suggests that the transmission of social information among wild animals is complex and probably influenced by many factors (e.g., dominance, familiarity, and health condition), ultimately conditioning the type of interaction between individuals and its outcome. Testing wild animals and the ecological and social constraints they face is, therefore, an important step in our understanding of how effectively social information is transmitted in nature.

Sex differences in social buffering and social contagion of alarm responses in zebrafish.

The alarm substance in fish is a pheromone released by injured individuals after a predator attack. When detected by other fish, it triggers fear/defensive responses, such as freezing and erratic movement behaviours. Such responses can also help other fish in the shoal to modulate their own behaviours: decreasing a fear response if conspecifics have not detected the alarm substance (social buffering) or triggering a fear response if conspecifics detected the alarm substance (social contagion). Response variation to these social phenomena is likely to depend on sex. Because males have higher-risk life-history strategies than females, they may respond more to social buffering where they risk not responding to a real predator attack, while females should respond more to social contagion because they only risk responding to a false alarm. Using zebrafish, we explored how the response of males and females to the presence/absence of the alarm substance is modified by the alarmed/unalarmed behaviour of an adjacent shoal of conspecifics. We found that, in social buffering, males decreased freezing more than females as expected, but in social contagion males also responded more than females by freezing at a higher intensity. Males were, therefore, more sensitive to visual information, while females responded more to the alarm substance itself. Because visual information updates faster than chemical information, males took more risks but potentially more benefits as well, because a quicker adjustment of a fear response allows to save energy to other activities. These sex differences provide insight into the modifying effect of life-history strategies on the use of social information.

The role of intrasexual competition on the evolution of male-male courtship display: a systematic review.

Background: Evidence of male-male courtship display is widespread across the animal kingdom. Yet, its function and evolutionary origin remain unclear. Here, we hypothesise that male-male courtship display evolved in response to selection pressure exerted by intrasexual competition during male-female courtship interactions. Intrasexual competition can be caused by bystander male pressure through eavesdropping and exploiting on displayer male's courtship interactions with females. This bystander pressure can lead to an audience effect by the displayer, who will change their courtship behaviour in the presence of bystanders and display directly towards them, even in the absence of females, as an intimidation strategy. In species where this selection pressure has taken place, we predict that the male courtship display will have a dual function: attract females and deter competitors. Therefore, we expected to find more evidence of bystander-related behaviours in species for which male-male courtship display is linked to intrasexual competition compared to species for which other explanatory hypotheses are more plausible (e.g., mistaken identity or courtship practice). Methodology: We conducted two systematic reviews to test this hypothesis. First, we conducted a search for studies of species with courtship display between males and of the hypotheses provided to explain this behaviour. Our goal was to identify the species with male-male courtship display and evidence of intrasexual competition. Second, among the species with male-male courtship display, we searched for evidence of bystander-related behaviours, i.e., articles referring to eavesdropping, exploitation, and audience effect during male-female courtship interactions. Our goal was to test whether species with intrasexual competition are also more likely to show bystander-related behaviours. Results: Although most studies reporting male courtship display towards other males do not suggest any explanatory hypothesis for this behaviour, the intrasexual competition hypothesis was largely mentioned and supported by some studies reviewed. Additionally, there is more evidence of eavesdropping and of all three bystander-related behaviours combined in species for which the intrasexual competition hypothesis was suggested. Conclusions: Overall, our review supports the hypothesis that intrasexual competition can play a key role in male courtship display evolution, namely that male-male courtship display may have evolved as a secondary function of male-female courtship interactions via bystander male pressure. However, our review also shows that despite the increasing interest in same-sex sexual behaviours, and male-male courtship display in particular, most studies were found to be merely descriptive, and the hypotheses they suggested to explain courtship display between males mostly speculative. This highlights an important gap in the literature. To clarify both the evolution and the function of male-male courtship display, this behaviour needs to be empirically studied more often. Our review can help advancing this research area, as it makes the 20 species with male-male courtship display for which the intrasexual competition hypothesis was suggested excellent candidates for empirical research.

Phenotypic architecture of sociality and its associated genetic polymorphisms in zebrafish.

Sociality relies on motivational and cognitive components that may have evolved independently, or may have been linked by phenotypic correlations driven by a shared selective pressure for increased social competence. Furthermore, these components may be domain-specific or of general-domain across social and non-social contexts. Here, we used zebrafish to test if the motivational and cognitive components of social behavior are phenotypically linked and if they are domain specific or of general domain. The behavioral phenotyping of zebrafish in social and equivalent non-social tests shows that the motivational (preference) and cognitive (memory) components of sociality: (1) are independent from each other, hence not supporting the occurrence of a sociality syndrome; and (2) are phenotypically linked to non-social traits, forming two general behavioral modules, suggesting that sociality traits have been co-opted from general-domain motivational and cognitive traits. Moreover, the study of the association between single nucleotide polymorphisms (SNPs) and each behavioral module further supports this view, since several SNPs from a list of candidate "social" genes, are statistically associated with the motivational, but not with the cognitive, behavioral module. Together, these results support the occurrence of general-domain motivational and cognitive behavioral modules in zebrafish, which have been co-opted for the social domain.

Optimal surgical timing after post-infarction ventricular septal rupture.

BACKGROUND: Ventricular septal rupture (VSR) following acute myocardial infarction (AMI) is a dangerous condition. Surgical VSR closure is the definitive therapy, but there is controversy regarding the surgical timing and the bridging therapy between diagnosis and intervention. The objective of this study is to analyze the ideal time of surgical repair and to establish the contribution of mechanical circulatory support (MCS) devices on the prognosis. METHODS: We designed an observational, retrospective, multicenter study, selecting all consecutive patients with post-AMI VSR between January 1, 2008 and December 31, 2018, with non-exclusion criteria. The main objective of this study was to analyze the optimal timing for surgical repair of post-AMI VSR. Secondary endpoints were to determine which factors could influence mortality in the patients of the surgical group. RESULTS: A total of 141 patients were included. We identified lower mortality rates with an odds ratio of 0.3 (0.1-0.9) in patients operated on from day 4 compared with the surgical mortality in the first 24 hours after VSR diagnosis. The use of MCS was more frequent in patients treated with surgery, particularly for intra-aortic balloon pump (IABP; 79.6% vs. 37.8%, p < 0.001), but also for veno-arterial extracorporeal membrane oxygenation (VA-ECMO; 18.2% vs. 6.4%, p = 0.134). Total mortality was 91.5% for conservative management and 52.3% with surgical repair (p < 0.001). CONCLUSIONS: In our study, we observed that the lowest mortality rates in patients with surgical repair of post-AMI VSR were observed in patients operated on from day 4 after diagnosis of VSR, compared to earlier interventions.

Angioedema Due to Acquired Deficiency of C1-Inhibitor: A Cohort Study in Spain and a Comparison With Other Series.

BACKGROUND: Data on acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) from 4 European countries (France, Italy, Germany, and Hungary) were recently published. OBJECTIVE: To report data from a group of 50 patients with acquired C1-INH deficiency from Spain, of whom 46 had angioedema, and compare them with other European series. METHODS: We performed a retrospective observational study of 46 patients with C1-INH-AAE and 4 asymptomatic patients. Clinical and biological characteristics and associated diseases were assessed and compared with other European series. RESULTS: Women accounted for 73.9% of cases. The prevalence of C1-INH-AAE related to hereditary forms was 1/10.1. Overall, 8.7% patients were aged <40 years. Diagnostic delay was 1.1 years. Angioedema mainly affected the face (91.3%), followed by the oropharynx (63%), extremities (50%), and abdomen (37%). Only 1 patient underwent orotracheal intubation. Erythema marginatum was present in 1 patient. A hematologic disorder was recorded in 50% of patients. Angioedema preceded all benign conditions, mostly monoclonal gammopathy of undetermined significance, but appeared very close to or after malignant hematologic diseases (median, 2.2 and 0.29 years). Autoimmune diseases were associated in 50% (autoimmune thyroiditis, 21.5%; systemic lupus erythematosus, 10.9%). Half of them coexisted with hematologic disorders. Anti-C1-INH antibodies were found in 67% of tested patients and were not related to the associated disease. Long-term prophylaxis was necessary in 52.2%, most of whom responded to tranexamic acid. CONCLUSIONS: This study emphasizes the possibility of C1-INH-AAE in patients younger than 40 and in autoimmune diseases other than systemic lupus erythematosus such as autoimmune thyroiditis.

Developmental Effects of Oxytocin Neurons on Social Affiliation and Processing of Social Information.

Hormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders (ASDs); however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naive state and in response to social stimulus and became less social. We propose that OXT neurons have an organizational role, namely, to shape forebrain neuroarchitecture during development and to acquire an affiliative response toward conspecifics.SIGNIFICANCE STATEMENT Social behavior is developed over the lifetime of an organism and the neuropeptide oxytocin (OXT) modulates social behaviors across vertebrate species, and is associated with neuro-developmental social deficits such as autism. However, whether OXT plays a role in the developmental maturation of neural systems that are necessary for social behavior remains poorly explored. We show that proper behavioral and neural response to social stimuli depends on a developmental process orchestrated by OXT neurons. Animals whose OXT system is ablated in early life show blunted neuronal and behavioral responses to social stimuli as well as wide ranging disruptions in the functional connectivity of the social brain. We provide a window into the mechanisms underlying OXT-dependent developmental processes that implement adult sociality.

Temporal trends in postinfarction ventricular septal rupture: the CIVIAM Registry.

INTRODUCTION AND OBJECTIVES: Postinfarction ventricular septal rupture is a rare but severe complication of myocardial infarction with high mortality rates. Our goal was to analyze which factors could have an impact on mortality due to this entity over the past decade, including those related to mechanical circulatory support. METHODS: The CIVIAM registry is an observational, retrospective, multicenter study carried out in Spain. We designed a comparative analysis, focused on description of in-hospital management and in-hospital and 1-year total mortality as the primary endpoints, dividing the total observation time into 2 equal temporal periods (January 2008 to June2013 and July 2013 to December 2018). RESULTS: We included 120 consecutive patients. Total mortality during this period was 61.7% at 1-year follow-up. Patients in the second period were younger. One-year mortality was significantly reduced in the second period (75.6% vs 52.7%, P=.01), and this result was confirmed after adjustment by confounding factors (OR, 0.40; 95%CI, 0.17-0.98). Surgical repair was attempted in 58.7% vs 70.3%, (P=.194), and percutaneous closure in 8.7% and 6.8%, respectively (P=.476). Heart transplant was performed in 1 vs 5 patients (2.2% vs 6.8%, P=.405). The main difference in the clinical management between the 2 periods was the greater use of venoarterial extracorporeal membrane oxygenatiom in the second half of the study period (4.4% vs 27%; P=.001). CONCLUSIONS: Postinfarction ventricular septal rupture still carries a very high mortality risk. There has been a progressive trend to increased support with venoarterial extracorporeal membrane oxygenatiom and greater access to available corrective treatments, with higher survival rates.

Are in vitro and in silico approaches used appropriately for animal-based major depressive disorder research?

The current paradigm for biomedical research and drug testing postulates that in vitro and in silico data inform animal studies that will subsequently inform human studies. Recent evidence points out that animal studies have made a poor contribution to current knowledge of Major Depressive Disorder, whereas the contribution of in vitro and in silico studies to animal studies- within this research area- is yet to be properly quantified. This quantification is important since biomedical research and drug discovery and development includes two steps of knowledge transferability and we need to evaluate the effectiveness of both in order to properly implement 3R principles (Replacement, Reduction and Refinement). Here, we used the citation tracking facility within Web of Science to locate citations of original research papers on in vitro and in silico related to MDD published identified in PubMed by relevant search terms. 67 publications describing target papers were located. Both in vitro and in silico papers are more cited by human medical papers than by animal papers. The results suggest that, at least concerning MDD research, the current two steps of knowledge transferability are not being followed, indicating a poor compliance with the 3R principles.

The Relevance of In Silico, In Vitro and Non-human Primate Based Approaches to Clinical Research on Major Depressive Disorder.

Major depressive disorder (MDD) is the most severe form of depression and the leading cause of disability worldwide. When considering research approaches aimed at understanding MDD, it is important that their effectiveness is evaluated. Here, we assessed the effectiveness of original studies on MDD by rating their contributions to subsequent medical papers on the subject, and we compared the respective contribution of findings from non-human primate (NHP) studies and from human-based in vitro or in silico research approaches. For each publication, we conducted a quantitative citation analysis and a systematic qualitative analysis of the citations. In the majority of cases, human-based research approaches (both in silico and in vitro) received more citations in subsequent human research papers than did NHP studies. In addition, the human-based approaches were considered to be more relevant to the hypotheses and/or to the methods featured in the citing papers. The results of this study suggest that studies based on in silico and in vitro approaches are taken into account by medical researchers more often than are NHP-based approaches. In addition, these human-based approaches are usually cheaper and less ethically contentious than NHP studies. Therefore, we suggest that the traditional animal-based approach for testing medical hypotheses should be revised, and more opportunities created for further developing human-relevant innovative techniques.

The social evolution of sleep: sex differences, intragenomic conflicts and clinical pathologies.

Sleep appears to be essential for most animals, including humans. Accordingly, individuals who sacrifice sleep are expected to incur costs and so should only be evolutionarily favoured to do this when these costs are offset by other benefits. For instance, a social group might benefit from having some level of wakefulness during the sleeping period if this guards against possible threats. Alternatively, individuals might sacrifice sleep in order to gain an advantage over mate competitors. Here, we perform a theoretical analysis of the social evolutionary pressures that drive investment into sleep versus wakefulness. Specifically, we: investigate how relatedness between social partners may modulate sleeping strategies, depending upon whether sleep sacrifice is selfish or altruistic; determine the conditions under which the sexes are favoured to adopt different sleeping strategies; identify the potential for intragenomic conflict between maternal-origin versus paternal-origin genes regarding an individual's sleeping behaviour; translate this conflict into novel and readily testable predictions concerning patterns of gene expression; and explore the concomitant effects of different kinds of mutations, epimutations, and uniparental disomies in relation to sleep disorders and other clinical pathologies. Our aim is to provide a theoretical framework for future empirical data and stimulate further research on this neglected topic.

The role of mate-choice copying in speciation and hybridization.

Mate-choice copying, a social, non-genetic mechanism of mate choice, occurs when an individual (typically a female) copies the mate choice of other individuals via a process of social learning. Over the past 20 years, mate-choice copying has consistently been shown to affect mate choice in several species, by altering the genetically based expression of mating preferences. This behaviour has been claimed by several authors to have a significant role in evolution. Because it can cause or increase skews in male mating success, it seems to have the potential to induce a rapid change of the directionality and rate of sexual selection, possibly leading to divergent evolution and speciation. Theoretical work has, however, been challenging this view, showing that copying may decelerate sexual selection and that linkage disequilibrium cannot be established between the copied preference and the male trait, because females copy from unrelated individuals in the population, making an invasion of new and potentially fitter male traits difficult. Given this controversy, it is timely to ask about the real impact of mate-choice copying in speciation. We propose that a solution to this impasse may be the existence of some degree of habitat selection, which would create a spatial structure, causing scenarios of micro-allopatry and thus overcoming the problem of the lack of linkage disequilibrium. As far as we are aware, the potential role of mate-choice copying on fostering speciation in micro-allopatry has not been tackled. Also important is that the role of mate-choice copying has generally been discussed as being a barrier to gene flow. However, in our view, mate-choice copying may actually play a key role in facilitating gene flow, thereby fostering hybridization. Yet, the role of mate-choice copying in hybridization has so far been overlooked, although the conditions under which it might occur are more likely, or less restricted, than those favouring speciation. Hence, a conceptual framework is needed to identify the exact mechanisms and the conditions under which speciation or hybridization are expected. Here, we develop such a framework to be used as a roadmap for future research at the intersection of these research areas.

Mate-choice copying: A fitness-enhancing behavior that evolves by indirect selection.

A spatially explicit, individual-based simulation model is used to study the spread of an allele for mate-choice copying (MCC) through horizontal cultural transmission when female innate preferences do or do not coevolve with a male viability-increasing trait. Evolution of MCC is unlikely when innate female preferences coevolve with the trait, as copier females cannot express a higher preference than noncopier females for high-fitness males. However, if a genetic polymorphism for innate preference persists in the population, MCC can evolve by indirect selection through hitchhiking: the copying allele hitchhikes on the male trait. MCC can be an adaptive behavior-that is, a behavior that increases a population's average fitness relative to populations without MCC-even though the copying allele itself may be neutral or mildly deleterious.

Male spider mites use chemical cues, but not the female mating interval, to choose between mates.

The choice of the partner an individual will mate with is expected to strongly impact its fitness. Hence, natural selection has favoured the evolution of cues to distinguish among mates that will provide different fitness benefits to the individual that is choosing. In species with first-male sperm precedence, this is particularly important for males, as mating with mated females will result in no offspring. In the spider mite Tetranychus urticae only the first mating is effective, except if the interval between first and second copulations is shorter than 24 h. In line with this, males prefer to mate with virgin over mated females. They do not, however, choose between females that have mated at different time intervals. Here, we tested which type of cues males use to distinguish between females with different mating status (virgin versus mated). To do so, we firstly confirmed that males prefer virgins over mated females and that they do not select females on the basis of their age or mating interval. Next, we tested whether contact and volatile compounds or chemical trails affected male discrimination between mated and virgin females, by systematically varying the exposure of males to these cues. We found that volatile compounds and chemical trails were sufficient to induce discrimination between virgin and mated females in males. Direct contact with females, however, does not seem to play a role in this discrimination. The composition of such chemical cues (trails and volatiles) remains to be identified.

Sexual selection modulates genetic conflicts and patterns of genomic imprinting.

Recent years have seen a surge of interest in linking the theories of kin selection and sexual selection. In particular, there is a growing appreciation that kin selection, arising through demographic factors such as sex-biased dispersal, may modulate sexual conflicts, including in the context of male-female arms races characterized by coevolutionary cycles. However, evolutionary conflicts of interest need not only occur between individuals, but may also occur within individuals, and sex-specific demography is known to foment such intragenomic conflict in relation to social behavior. Whether and how this logic holds in the context of sexual conflict-and, in particular, in relation to coevolutionary cycles-remains obscure. We develop a kin-selection model to investigate the interests of different genes involved in sexual and intragenomic conflict, and we show that consideration of these conflicting interests yields novel predictions concerning parent-of-origin specific patterns of gene expression and the detrimental effects of different classes of mutation and epimutation at loci underpinning sexually selected phenotypes.

Sex-biased dispersal, kin selection and the evolution of sexual conflict.

There is growing interest in resolving the curious disconnect between the fields of kin selection and sexual selection. Rankin's (2011, J. Evol. Biol. 24, 71-81) theoretical study of the impact of kin selection on the evolution of sexual conflict in viscous populations has been particularly valuable in stimulating empirical research in this area. An important goal of that study was to understand the impact of sex-specific rates of dispersal upon the coevolution of male-harm and female-resistance behaviours. But the fitness functions derived in Rankin's study do not flow from his model's assumptions and, in particular, are not consistent with sex-biased dispersal. Here, we develop new fitness functions that do logically flow from the model's assumptions, to determine the impact of sex-specific patterns of dispersal on the evolution of sexual conflict. Although Rankin's study suggested that increasing male dispersal always promotes the evolution of male harm and that increasing female dispersal always inhibits the evolution of male harm, we find that the opposite can also be true, depending upon parameter values.

Evolution of mating behavior between two populations adapting to common environmental conditions.

Populations from the same species may be differentiated across contrasting environments, potentially affecting reproductive isolation among them. When such populations meet in a novel common environment, this isolation may be modified by biotic or abiotic factors. Curiously, the latter have been overlooked. We filled this gap by performing experimental evolution of three replicates of two populations of Drosophila subobscura adapting to a common laboratorial environment, and simulated encounters at three time points during this process. Previous studies showed that these populations were highly differentiated for several life-history traits and chromosomal inversions. First, we show initial differentiation for some mating traits, such as assortative mating and male mating rate, but not others (e.g., female mating latency). Mating frequency increased during experimental evolution in both sets of populations. The assortative mating found in one population remained constant throughout the adaptation process, while disassortative mating of the other population diminished across generations. Additionally, differences in male mating rate were sustained across generations. This study shows that mating behavior evolves rapidly in response to adaptation to a common abiotic environment, although with a complex pattern that does not correspond to the quick convergence seen for life-history traits.

Negative public information in mate choice copying helps the spread of a novel trait.

Numerous field and laboratory experiments have shown that many species have the capacity for social learning, including mate choice decisions that can be influenced by witnessing the mating decisions of others. Here we develop a numerical model of mate choice copying that follows the population genetics tradition, consisting in tracking allele frequencies in a population over time under various scenarios. In contrast to previous evolutionary models, we consider both positive social information and negative social information because many mating systems are driven by males in pursuit of a mate and female refusal of copulation may provide negative social information. The inclusion of negative social information to mate choice copying helps the spread of a novel trait, even if female innate mate choice preference is biased toward the common male type. We argue that the presence or absence of copying might simply mirror the associated cost-benefit relationship of the mating system of a given species and suggest how to test this prediction.

Medicinal use of fauna by a traditional community in the Brazilian Amazonia.

BACKGROUND: Zootherapy inventories are important as they contribute to the world documentation of the prevalence, importance and diversity of the medicinal use of animals in traditional human communities. The present study aims to contribute with a more valuable example of the zootherapy practices of a traditional community in the Brazilian Amazonia - the "Riozinho do Anfrísio" Extractive Reserve, in Northern Brazil. METHODS: We used the methods of participant observation and semi-structured interviews, applied to 25 informants. We employed the combined properties of two indices to measure the medicinal importance of each cited species to the studied community, as well as their versatility in the treatment of diseases: the well known Use Value (UV) and the Medicinal Applications Value (MAV) that we developed. RESULTS: We recorded 31 species of medicinal animals from six taxonomic categories, seven of which are new to science. The species are used for the treatment of 28 diseases and one species is used as an amulet against snakebites. The five species with the highest UV indices are the most popular and valued by the studied community. Their contrasting MAV indices indicate that they have different therapeutic properties: specific (used for the treatment of few diseases; low versatility) and all-purpose (several diseases; high versatility). Similarly, the most cited diseases were also those that could be treated with a larger number of animal species. Ten species are listed in the CITES appendices and 21 are present in the IUCN Red List. The knowledge about the medicinal use of the local fauna is distributed evenly among the different age groups of the informants. CONCLUSIONS: This study shows that the local fauna represents an important medicinal resource for the inhabitants of the protected area. The combined use of the UV and MAV indices allowed identifying the species with the highest therapeutic potential. This type of information about a species may be of interest to pharmacological research, and is crucial to its conservation, since it helps signaling the species that may undergo higher hunting pressures. Data on zootherapy can also be of interesting to ecologists by contributing to indicators of local biodiversity richness.

Clinical, biochemical, and genetic characterization of type III hereditary angioedema in 13 Northwest Spanish families.

BACKGROUND: A new variant of hereditary angioedema has been reported during the last decade. Three main characteristics distinguish it from classic hereditary angioedema: normal C1 inhibitor activity, predominance in women, and different genetic alterations. OBJECTIVE: To assess the symptoms, laboratory findings, and treatment of a population with type III hereditary angioedema from Northwest Spain. METHODS: We studied 29 patients (26 female and 3 male) from 13 different families. RESULTS: The 26 female patients showed a similar clinical pattern to the classic forms of hereditary angioedema, and 22 of these patients had the estrogen-dependent phenotype. Three patients had a negative family history, and 1 of the parents was confirmed as an asymptomatic carrier in 2 of them. All had functional C1 inhibitor activity within the normal range in periods without high estrogen levels, but during attacks (in female patients) and pregnancy, activity decreased to below 50%. One male patient had normal C1 inhibitor activity during attacks, and he was initially diagnosed as having idiopathic angioedema. The C4 and antigenic C1 inhibitor levels were always normal. All studied patients had the c.1032C>A, Thr309Lys mutation in the factor XII gene. The mutation was also found in asymptomatic relatives: 5 of 6 men studied and 1 of 8 women studied. CONCLUSION: Positive family history is a diagnosis criterion, but it could be lacking because there may be asymptomatic relatives, primarily males.