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The redclaw crayfish, Cherax quadricarinatus, was introduced to Martinique Island for aquaculture purposes in 2004, in an attempt to revitalize the freshwater crustacean aquaculture sector. In 2015, three wild populations were discovered during an electrofishing survey on fish diversity. In 2018, a specific crayfish survey was performed at night using spotlighting and baited traps at 34 sites throughout the island. The species was mostly found in the center and northern part of the island, specifically, a total of 105 specimens were captured in eight streams and five closed water bodies. We sequenced a 491 base-pair fragment of the COI gene to understand the invasion history and pathway from the presumed source population at the Mangatal hatchery. Among the eight haplotypes found, three were dominant, of which, two occurred in the Mangatal hatchery. As crayfish are sold alive, there is a high risk of further human-mediated introductions across the island hydrographic basins. Thus, the distribution of this species could rapidly expand throughout Martinique freshwater ecosystems, with ecological impacts on native communities yet to be determined and requiring urgent investigation.

The redclaw crayfish, Cherax quadricarinatus, was introduced to Martinique Island for aquaculture purposes at the beginning of the 21st century, in an attempt to revitalize the freshwater crustacean aquaculture sector. Mainly due to its high economical value, it was intentionally released in the wild and was caught and sold by fishermen. Martinican rivers are polluted by chlordecone, considered as one of the worst Persistant Organic Pollutants (POP). Despite its dangerousness, it was used until 1993 in the French West Indies against a banana pest and was always found in the ecosystems. This study aimed to investigate the level of contamination in the muscle of crayfish caught in the wild, as well as the potential of bioconcentration and depuration in the C. quadricarinatus muscle. This study could allow us to quantify the risk for consumers but also, to evaluate a depuration process to reduce the risk related to its consumption. Using both in-vitro and in-situ experiments, results highlighted the importance of the chlordecone concentration in the water and the time of exposure to the pollutant. The bioconcentration seems to be very quick and continuous in crayfish muscle, as chlordecone can be detectable as early as 6 h of exposure, whatever the concentration tested. Finally, it appears that, even after 20 days of depuration in chlordecone-free water, chlordecone concentrations remained higher to the residual maximum limit (i.e. 20 ng/g wet weight), concluding that the decontamination of the muscle seems not very efficient, and the risk for the Martinican people could be serious.

The combination of existing technologies is necessary for innovation. An important aspect of technology exchange between firms is that it generates both business creation and, possibly, business stealing. These countervailing effects generate potentially misaligned interests between technology adopters and providers. We propose an empirical framework for studying the prevalence of business creation and business stealing in technology transfers from the effect of technological proximity and market proximity. We estimate the model on a new dataset that tracks interactions in the market for technology across a broad range of exchange modes between publicly held US companies. We obtain two main findings. First, technological proximity has a very robust positive effect on business creation and matching patterns. Second, market proximity has a negative but relatively small effect on matching patterns that is suggestive of business stealing effects. We use our results to assess the relevance of IP rights in deterring undesirable technology adoptions and discuss the suitability of alternative strategies of technology exchange.

Background Acute coronary syndrome (ACS) is a major cause of death and closely related with obstructive sleep apnea (OSA). Our hypothesis is that several cardiovascular-related biomarkers could have a differential prognostic value for ACS severity in patients with OSA, and could also help (individually or combined) in the detection of OSA in patients after a coronary event. Methods Up to 361 consecutive individuals admitted due to ACS were included in the study. All of them were evaluated for ACS severity (Killip score, number of diseased vessels, ejection fraction) and further classified as OSA or non-OSA. Medical records were registered and eleven blood biomarkers were measured, including heart-type fatty acid-binding globulin, N-terminal pro-brain natriuretic peptide, matrix metalloproteinase-9 (MMP9), placental growth factor (PlGF) and high-sensitivity C-reactive protein. Odds ratios of every biomarker for ACS severity-related parameters were calculated and adjusted for age, gender, body-mass index (BMI), hypertension, diabetes, smoking and drinking. The use of clinical measures and biomarkers for the diagnosis of OSA in ACS patients was evaluated both alone and combined using ROC curves. Results Several biomarkers showed a significant association with ACS severity, which remained after adjusting for OSA and other potentially confounding variables. The mathematical combination of age, BMI, PlGF and MMP9 showed an area under the ROC curve (AUC) for OSA identification of 0.741, which was greater than any individual parameter or combination assessed: AUC(BMI):0.687, AUC(age):0.576, AUC(PlGF):0.584, AUC(MMP9):0.555. Conclusions The usefulness of biomarkers in the assessment of ACS severity was independent of OSA and the other variables evaluated. In patients admitted after a coronary event, the combination of clinical measures and biomarkers showed a significant discriminating power for the detection of OSA. Clinical trial registration: NCT01335087 ( clinicaltrials.gov ).

Entrepreneurial innovation involves turning embryonic inventions into marketable innovations through costly technology development. Do venture capitalists (VCs) target their funding and managerial efforts to technology development or do they support later stages of the innovation cycle involving mostly commercialization? To answer this question we merge a list of first-round venture capital (VC) investments with an innovation survey of Spanish companies. We document changes in the innovative activity of VC-backed firms around first round VC investments which suggest that VCs fund technology development. First, the composition of R&D shifts from basic research to technology development. Second, the financing structure of R&D shows a greater reliance of external funds. Third, improved access to external funds reduces the intensity of financial constraints as an obstacle to innovation. Fourth, there is a slowdown in patenting and invention. Fifth, there is a substantial increase in the share of innovative sales.

Obstructive sleep apnoea is a risk factor for pulmonary embolism. Elevated D-dimer levels and other biomarkers are associated with recurrent pulmonary embolism. The objectives were to compare the frequency of elevated D-dimer levels (>500 ng·mL−1) and further coagulation biomarkers after oral anticoagulation withdrawal in pulmonary embolism patients, with and without obstructive sleep apnoea, including two control groups without pulmonary embolism. We performed home respiratory polygraphy. We also measured basic biochemical profile and haemogram, and coagulation biomarkers (D-dimer, prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor 1, and soluble P-selectin). 64 (74.4%) of the pulmonary embolism cases and 41 (46.11%) of the controls without pulmonary embolism had obstructive sleep apnoea. Plasmatic D-dimer was higher in PE patients with OSA than in those without obstructive sleep apnoea. D-dimer levels were significantly correlated with apnoea–hypopnoea index, and nocturnal hypoxia. There were more patients with high D-dimer after stopping anticoagulants in those with pulmonary embolism and obstructive sleep apnoea compared with PE without obstructive sleep apnoea (35.4% versus 19.0%, p=0.003). Apnoea–hypopnoea index was independently associated with high D-dimer. Pulmonary embolism patients with obstructive sleep apnoea had higher rates of elevated D-dimer levels after anticoagulation discontinuation for pulmonary embolism than in patients without obstructive sleep apnoea and, therefore, higher procoagulant state that might increase the risk of pulmonary embolism recurrence. Pulmonary embolism patients with sleep apnoea are more likely to have elevated post-anticoagulation plasma D-dimer

The concept that anatomical variations in the coronary artery tree might be influenced by genes is relatively old. However, empirical evidence on the effect of genotype on the coronary morphology is still scarce. In the Syrian hamster, there is a septal coronary artery which arises from the left or from the right coronary artery and supplies most of the interventricular septum. The aim was to decide whether the anatomical origin of the septal artery is subject to inheritance factors. Overall, 483 internal casts of the heart and coronary arteries were examined. All the hamsters included in this study had normal coronary arteries. The results of 74 crosses were compared statistically to seek for any significant difference between the phenotypes of the offspring and the phenotypes of the parents. The left septal artery was over-represented in the offspring of crosses between parents having both a left septal artery (p < .01), while the right septal artery was over-represented in the offspring of crosses between parents, one with a right and the other with a left septal artery (p < .001), and, more markedly, in the offspring of crosses between parents both with a right septal artery (p < .001). These results are the first to reveal that the coronary artery pattern is influenced by genetic factors, at least in its proximal portion with regard to the aorta.

The ongoing academization of gastronomic studies indicates the necessity for a commonly accepted classification system for cooks that does not contradict scientific approaches. This work discusses the fundamentals used by chefs and scientists to classify unelaborated food products; proposes taxonomic gastronomy as a new interdisciplinary framework that studies the taxonomy surrounding gastronomy; and presents a categorization of unelaborated food products that follows commonly accepted culinary criteria yet avoids contradiction by scientific knowledge. As little literature focuses on these issues, and similar experiences are scarce, it is concluded that further cross-disciplinary endeavors such as this will continue to be greatly fruitful., This work was carried out in the framework of the agreement between the Universitat de Barcelona and elBulliFoundation signed on 23 October 2012 and was subsidized by the Catalan government (grant number 2009SGR0403, 2014SGR1241, 2014SGR7, 2014SGR514, 2014SGR1315, 2014SGR1208, 2014SGR1480 and 2014SGR623).

Uterine fibroids are the most common benign tumours that affect women of reproductive age and they represent the main indication for surgery for benign uterine pathology. In 25% of cases, they become clinically apparent, causing heavy menstrual bleeding, pelvic pain and/or infertility. Therefore, fibroids have a notable impact on the economic costs for the health system and also on the quality of life of the women they afflict. Although MRI is the most precise technique to diagnose fibroids, ultrasound remains the most cost-effective method. Surgery has been the treatment of choice for years, and several minimally invasive procedures have recently been developed. There are a wide variety of conservative medical treatment options, which are continually expanding. Research on the biology of these tumours can lead to new therapeutic options for the management of fibroids as we better understand the role that growth factors and genetic mutations play in them.

Introduction: The prevalence of sleep apnoea-hypopnoea syndrome (SAHS) defined by an apnoea-hypopnoea index (AHI) ≥5 / hour in reproductive-age women is only 1-3.4%. Several authors suggest that this ratio increases during pregnancy due to hormonal, physiological and physical changes (specially during the third trimester). However, the prevalence of SAHSdiagnosed by polysomnography (PSG) in pregnant women is still unknown. Aims and Objectives: To assess the prevalence of SAHS (AHI≥5 h -1 ) in uncomplicated singleton pregnant women in the third trimester. Methods: We studied women in the third trimester of pregnancy in a prospective multicenter observational study. Anthropometry data, sleep apnoea symptoms, Epworth scale and the hospital PSG results were analyzed. Exclusion criteria were: steroids treatment, twin pregnancy, SAHS treated with CPAP and Diabetes Mellitus. Results: 84 women were included. They were 31± 2 years old. When the PSG was performed the mean gestational age was 33.4 ± 2.9 weeks and the BMI 27.3 ± 3.7 Kg/m 2 . Although snoring problems were reported in half of the women (51.9%), only 8 pregnant women (9.5%) had an AHI > 5h -1 on PSG. The PSG data are shown in Table 1. Conclusions: Our data show that prevalence of SAHS in late uncomplicated third trimester pregnancy is 9.5%, which it is at least 3 times higher than in non-pregnant reproductive-age women.

Introduction: Increasing evidence suggests that sleep apnoea-hypopnoea syndrome (SAHS) is prevalent in pregnancy and is associated with adverse gestational and perinatal outcomes. Polysomnography (PSG) is the gold standard diagnostic test, however, simple screening devices for SAHS have not been validated in this population. Aims and Objectives: To determine the relationship between diagnostic test characteristics and its associations with key variables obtained from PSG and a type 3 portable sleep monitoring system (Alice PDx) in pregnancy. Methods: We included women in the third trimester of pregnancy in a multicentre observational study. All women were studied with a 22-channel PSG and simultaneously a respiratory polygraphy (PR) (Alice PDx). PSG and Alice PDx raw data were blinded scored by experienced technologists using AASM 2007 criteria. Exclusion criteria were: steroid treatment, twin pregnancy, SAHS treated with CPAP and Diabetes Mellitus. Results: 157 singleton pregnant women were studied. They were 34.6 ± 4.3 years old. Mean gestational age was 34 ± 2.9 weeks. 8.6% of the women had an AHI > 5 h-1 on PSG, however PR correctly classified as SAHS 4.7% of the pregnant women. The correlation coefficient between the AHI by PSG and manual PR was 0.459 (p Conclusions: The respiratory polygraphy Alice PDx is not an appropriate tool to screen for SAHS in pregnant women.

What are the benefits of lifting structural impediments to banking the unbanked? We address this question by studying the Spanish Banking Expansion Plan 1964-1974, a program aimed at extending banking services into unbanked municipalities after decades of banking status quo. We exploit the quasi-experimental nature of the program to identify its effects. Selected municipalities experienced a 9% increase in the number of workers per inhabitant. This effect was driven by the lending channel, primarily through the provision of liquidity and working capital, though not through the savings channel.

Background: Vitamin D insufficiency and high levels of parathyroid hormone (PTH) appear to be emerging risk factors for metabolic syndrome (MS), diabetes and cardiovascular disease, conditions that occur frequently in patients with obstructive sleep apnea syndrome (OSAS). Objectives: This study examined whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] and PTH were associated with the presence of MS, diabetes and hypertension among an OSAS population. Methods: A total of 826 patients (635 men and 191 women) with newly diagnosed OSAS were studied. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III clinical criteria. Serum levels of 25(OH)D, PTH, glucose, triglycerides, cholesterol, HDL cholesterol, creatinine and uric acid were determined. Results: In 55.3% of the men and in 63.2% of the women, the serum 25(OH)D level was less than 30 ng/ml (insufficient status). After adjusting for age, sex and seasonality, there was a significant trend of decreasing odds for diabetes [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.33-0.94, ptrend = 0.038] and MS (OR 0.34, 95% CI 0.21-0.56, ptrend < 0.001) with increasing vitamin D levels. Higher PTH levels were associated with a higher prevalence of obesity (OR 2.05, 95% CI 1.06-3.09, ptrend < 0.001) and hypertension (OR 1.83, 95% CI 1.01-3.05, ptrend = 0.049). Conclusions: These data suggest an inverse association of 25(OH)D with diabetes and MS and a positive association of PTH with obesity and hypertension among patients with OSAS. Based on our observational study, the causative nature of the associations cannot be established. These findings require further examination in prospective studies including clinical trials.

An ectopic origin of the coronary artery from the aorta beyond the sinotubular junction, a condition commonly referred to as 'coronary artery high take-off', has been described in man and C57BL/6 mice. The present paper reports this congenital coronary artery anomaly in the Syrian hamster (Mesocricetus auratus). Hearts from 14 individuals, aged 53-350 days, were examined by means of a corrosion-cast technique, scanning electron microscopy or histological and immunohistochemical techniques. In 11 hamsters, the right coronary artery was the ectopic vessel. In the other three animals there was a solitary coronary ostium in the aorta. In all cases, the ectopic coronary artery originated at an acute angle and a valve-like ridge was in front of the coronary artery ostium. The ectopic arteries examined microscopically showed an intramural trajectory within the aortic wall. In the hearts with a solitary ostium in the aorta, the left main coronary artery coursed between the aorta and the pulmonary artery. In man, all of these anomalous conditions place the individual at risk of myocardial ischaemia and sudden death. However, none of the affected hamsters had clinical signs of disease. Intimal thickenings of increasing size with age were present in the intramural coronary artery segment of eight hamsters aged 106 days or older, examined histologically. The present findings fit with the notion that coronary arteries with acute angle take-off and an intramural course are subjected to unusual wear and tear, leading to tissue changes in the vessel wall.

Objectives The aim of this study was to decide whether bicuspid aortic valves (BAVs) with fused right and noncoronary leaflets (R-N) and BAVs with fused right and left leaflets (R-L) have different etiologies or are the product of a single diathesis. Background The BAV is the most common congenital cardiac malformation. The R-N and R-L BAVs are the most frequent BAV subtypes. Methods The study was carried out in adult and embryonic hearts of endothelium nitric oxide synthase knock-out mice and inbred Syrian hamsters with a high incidence of R-N and R-L BAVs, respectively. The techniques used were histochemistry, immunohistochemistry, and scanning electron microscopy. Results The R-N BAVs result from a defective development of the cardiac outflow tract (OT) endocardial cushions that generates a morphologically anomalous right leaflet. The left leaflet develops normally. The R-L BAVs are the outcome of an extrafusion of the septal and parietal OT ridges that thereby engenders a sole anterior leaflet. The noncoronary leaflet forms normally. Conclusions The R-N and R-L BAVs are different etiological entities. The R-N BAVs are the product of a morphogenetic defect that happens before the OT septation and that probably relies on an exacerbated nitric oxide–dependent epithelial-to-mesenchymal transformation. The R-L BAVs result from the anomalous septation of the proximal portion of the OT, likely caused by a distorted behavior of neural crest cells. Care should be taken in further work on BAV genetics because R-N and R-L BAVs might rely on different genotypes. Detailed screening for R-N and R-L BAVs should be performed for a better understanding of the relationships between these BAV morphologic phenotypes and other heart disease.

Summary This study describes a rare congenital coronary artery anomaly in the Syrian hamster; namely, the separate origin of the obtuse marginal and left circumflex arteries which are the main components of the left coronary artery. The hearts of nine affected animals were examined by means of a corrosion-cast technique and histology. The hamsters belonged to a laboratory inbred family with a high incidence of coronary artery anomalies and bicuspid aortic valve. The aortic valve was tricuspid in three hamsters and bicuspid in the other six hamsters. In all cases, the right coronary artery was normal, whereas the left coronary artery main trunk was absent. The present anomalous coronary artery patterns could be classified into two main entities: (i) ectopic origin of the obtuse marginal artery from the right aortic sinus or from the right coronary artery, with the left circumflex artery arising from the left side of the aortic valve; and (ii) ectopic origin of both the obtuse marginal artery from the right aortic sinus or from the right coronary artery and left circumflex artery from the dorsal aortic sinus. In all cases, the obtuse marginal artery coursed to the right side of the heart through the ventral wall of the right ventricular outflow tract. When the left circumflex artery arose from the dorsal aortic sinus, it formed an acute angle with the aortic wall. This report seems to be the first to describe the separate origin of the main components of the left coronary artery in a non-human mammalian species. In man, the congenital coronary artery and aortic valve defects reported herein may entail the risk of clinical complications. However, none of the affected hamsters showed signs of disease.

Background Compliance with continuous positive airway pressure (CPAP) therapy is essential in patients with obstructive sleep apnoea (OSA), but adequate control is not always possible. This is clinically important because CPAP can reverse the morbidity and mortality associated with OSA. Telemedicine, with support provided via a web platform and video conferences, could represent a cost-effective alternative to standard care management. Aim To assess the telemedicine impact on treatment compliance, cost-effectiveness and improvement in quality of life (QoL) when compared with traditional face-to-face follow-up. Methods A randomised controlled trial was performed to compare a telemedicine-based CPAP follow-up strategy with standard face-to-face management. Consecutive OSA patients requiring CPAP treatment, with sufficient internet skills and who agreed to participate, were enrolled. They were followed-up at 1, 3 and 6 months and answered surveys about sleep, CPAP side effects and lifestyle. We compared CPAP compliance, cost-effectiveness and QoL between the beginning and the end of the study. A Bayesian cost-effectiveness analysis with non-informative priors was performed. Results We randomised 139 patients. At 6 months, we found similar levels of CPAP compliance, and improved daytime sleepiness, QoL, side effects and degree of satisfaction in both groups. Despite requiring more visits, the telemedicine group was more cost-effective: costs were lower and differences in effectiveness were not relevant. Conclusions A telemedicine-based strategy for the follow-up of CPAP treatment in patients with OSA was as effective as standard hospital-based care in terms of CPAP compliance and symptom improvement, with comparable side effects and satisfaction rates. The telemedicine-based strategy had lower total costs due to savings on transport and less lost productivity (indirect costs). Trial register number NCT01716676.

Portuguese and Spanish universities have adopted well-defined royalty sharing schedules during the last fifteen years. We investigate whether these inventor royalty shares have been effective at stimulating inventors’ efforts and ultimately improving university outcomes. We base our empirical analysis on university-level data as well as on new self-collected surveys completed by inventors and Technology Transfer Offices (TTOs). Econometric evidence from the university-level dataset indicates that royalty shares have no impact on patenting or licensing income. The same result emerges from the inventors’ survey, with most respondents claiming to be largely unaffected by royalty sharing. Evidence from both the TTO and inventors’ surveys suggests that inventors do not react to royalty sharing because of the poor commercial prospects of their inventions, which means there is little income to be shared. These poor prospects appear to reflect the fact that the TTOs do not focus sufficiently on commercializing inventions and inventors are unable to produce potentially licensable inventions.

Background Solitary coronary ostium in the aorta (SCOA) is a rare anomaly, the pathogenesis of which remains uncertain. The lack of an animal model is one of the reasons why little understanding of this question has been gained. The aim was to examine the coronary distribution patterns associated with SCOA in laboratory inbred Syrian hamsters. Methods The study concerns 130 cases detected in a database consisting of 1202 internal casts of the heart, great arterial trunks, and coronary arteries. Results In 21 (16.2%) cases, the solitary ostium was located in the left aortic sinus. In a further 58 (44.6%) cases, it was in the right aortic sinus. In the remaining 51 (39.2%) cases, the ostium was in the right side of the ventral aortic sinus of a bicuspid aortic valve. The distribution patterns were classified according to the location of the solitary ostium and the presence, or absence, and course of the main coronary arterial vessels. Overall, 14 categories were established, 10 of which had their counterpart in man. Conclusions The findings reported substantiate the use of the present inbred Syrian hamsters for further studying the morphogenesis of the SCOA. The results of a statistical analysis indicate that when a sole coronary ostium becomes established in the aortic root, the development of the resultant anomalous coronary arterial tree tends to happen through preferential pathways. In addition, they indicate that the branching mode of the coronary tree and the condition of the aortic valve are independent traits.

The formation of cartilage in aortic valves of Syrian hamsters was studied using histological, histochemical and immunohistochemical techniques. The sample consisted of 281 specimens aged 0-363 days, all of which had a normal (tricuspid) aortic valve. The first sign of valvular chondrogenesis is the presence of small groups of cells embedded in a type II collagen-positive matrix. These groups of cells, which can appear as early as one day after birth, increase in size and differentiate into hyaline cartilage or fibrocartilage. From the fourth day of life, all hamsters examined displayed cartilaginous foci in the aortic valve. They were located along the fibrous attachments of the valve leaflets to their respective sinuses, including the valve commissures. A considerable proportion (76%) of cartilages formed within the first 40 days of life, that is during the period of time in which the histogenesis of the valve takes place. The present observations are consistent with the assumption that in mammals, the precursors of the aortic valve chondrocytes are neural crest-derived cells. Results of a statistical analysis substantiate that the incidence is significantly higher in (1) the territory that comprises the collagenous condensation of the ventral commissure and the ventro-lateral and proximal fibrous attachments of the right leaflet to its sinus, and (2) the proximal fibrous attachment of dorsal leaflet to its sinus. These findings together with data in the literature concerning the distribution of stress in each leaflet-sinus assembly of the valve during the cardiac cycle, suggest that mechanical action might play an inductive role in the formation of the cartilaginous tissue in the aortic valve of mammals. In addition, they point to the possibility that locally intense mechanical stimulation is responsible for the differentiation of the anticipated cartilaginous tissue into hyaline cartilage.

To the Editors: Obstructive sleep apnoea syndrome (OSAS) has been increasingly linked to cardiovascular disease. fetuin-A is an inhibitor of vascular calcification and an anti-inflammatory cytokine. We tested the hypothesis that plasma levels of fetuin-A are decreased in patients with OSAS. We studied 119 patients with OSAS and 35 controls. Participants were recruited and studied at the sleep unit at Hospital Universitari Son Espases, Palma de Mallorca, Spain. Serum levels of fetuin-A, glucose, triglycerides, cholesterol, high-density lipoprotein (HDL) cholesterol, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) were determined. Plasma fetuin-A levels were significantly lower in patients with OSAS than in controls (mean±sd 368±66 versus 445±53 ng·mL−1, p=0.015). In multivariate analysis, fetuin-A levels were independently associated with OSAS (p=0.034). OSAS is associated with reduced levels of fetuin-A and fetuin-A could be one of the contributing factors for the development of cardiovascular complications in OSAS patients. There is evidence that patients with OSAS have an increased risk for cardiovascular diseases [1]. The mechanisms underlying this association are unclear but candidate mechanisms include endothelial dysfunction, oxidative stress, systemic inflammation and metabolic dysregulation [2]. Vascular calcification has recently received much attention because of its relationship with cardiovascular disease [3, 4]. Chronic inflammation may promote vascular calcification and recent studies have demonstrated a relationship between vascular calcification and endothelial dysfunction [5, 6]. Fetuin-A is a circulating protein mostly synthesised in the liver [7, 8] that is known to be an important inhibitor of vascular calcification and a potent anti-inflammatory cytokine [8–10]. Fetuin-A is considered to be a mediator that links chronic inflammation to cardiovascular diseases [11]. However, previous studies investigating the role of fetuin-A in patients with cardiovascular disease …

Background: Metabolic syndrome (MS) occurs frequently in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We hypothesized that aldosterone levels are elevated in OSAHS and associated with the presence of MS. Methods: We studied 66 patients with OSAHS (33 with MS and 33 without MS) and 35 controls. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) clinical criteria. Measurements of plasma renin activity (PRA), aldosterone, aldosterone: PRA ratio, creatinine, glucose, triglycerides, cholesterol and HDL cholesterol were obtained at baseline and after CPAP treatment. Results: Aldosterone levels were associated with the severity of OSAHS and higher than controls (p = 0.046). Significant differences in aldosterone levels were detected between OSAHS patients with and without MS (p = 0.041). A significant reduction was observed in the aldosterone levels in patients under CPAP treatment (p = 0.012). Conclusion: This study shows that aldosterone levels are elevated in OSAHS in comparison to controls, and that CPAP therapy reduces aldosterone levels. It also shows that aldosterone levels are associated with the presence of metabolic syndrome, suggesting that aldosterone excess might predispose or aggravate the metabolic and cardiovascular complications of OSAHS., This work was supported in part by a grant from the Hospital Universitari Son Espases (Proyectos piloto HUSE-2011. No additional external funding received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

During the period 1965-1987 Spain was an emerging market in full transition from developing to developed status. During the same period the Spanish banking system underwent an unprecedented episode of expansion growing from 5,000 to over 30,000 bank branches. We examine whether the latter process partly caused the former by focusing on the relationship between branch expansion and entrepreneurship in the wholesale and retail trade industries. To address the non-random allocation of bank branches we exploit changes in branching policies that induced a plausibly exogenous time-varying pattern in the relationship between a municipality’s initial financial development and branch expansion. Our estimates, based on a panel data-set of over 2,000 Spanish municipalities, reveal that branch expansion had a strong positive impact on entrepreneurship. This effect was essentially driven by the savings banks, which have stronger regional development objectives than those held by the commercial banks, and which expanded more intensely into municipalities with more precarious financial services.

Background Bicuspid aortic valve is the most frequent congenital cardiac malformation in humans. However, the morphogenesis of the defect is still unknown. Previous work showed that, in the Syrian hamster, congenital bicuspid aortic valves with the aortic sinuses arranged in ventrodorsal orientation are expressions of a trait the variation of which takes the form of a continuous phenotypic spectrum, ranging from a tricuspid aortic valve with no fusion of the ventral commissure to a bicuspid aortic valve devoid of any raphe. The present study was designed to elucidate the mechanism involved in the formation of bicuspid aortic valves in Syrian hamsters as a possible starting point for further investigation of this process in humans. Methods The sample examined consisted of 80 embryos, aged between 10 days, 16 hours and 13 days, 1 hour postcoitum. Most (n = 59) of the embryos belonged to a laboratory-inbred family of Syrian hamsters with a high incidence of bicuspid aortic valves. The study was carried out using scanning electron microscopy and histological techniques for light microscopy. Results Twenty-three embryos showed a still undivided conotruncus. In all of these cases there were six mesenchymal semilunar valve primordia protruding into the lumen of the conotruncus. In a further 29 embryos, the conotruncus had just divided into the aortic and pulmonary channels; the embryos were at the beginning of the valvulogenesis. In 13 of these 29 embryos there were three well-defined aortic valve cushions, right, left, and dorsal, whereas in the other 16, the right and left valve cushions were more or less fused toward the lumen of the aorta; when they were completely fused, only two aortic valve cushions, a ventral and a dorsal, could be identified. In the remaining 28 embryos, the aortic valve cushions showed a marked degree of excavation. In 23 of these cases, the valve exhibited a basically tricuspid architecture, whereas it was unequivocally bicuspid in the other five. Conclusions All variants of the aortic valve morphologic spectrum occurring in the Syrian hamster develop from three mesenchymal valve cushions, right, left, and dorsal, after normal septation of the conotruncus. The bicuspid condition of the aortic valve is not the consequence of improper development of the conotruncal ridges, conotruncal malseptation, valve cushion agenesis, or lesions acquired after a normal valvulogenesis. Fusion of the right and left valve cushions at the beginning of the valvulogenesis appears to be a key factor in the formation of bicuspid aortic valves. Each aortic valve acquires its specific morphology prior to the end of the valvulogenetic process. © 1996 Wiley-Liss, Inc.

Summary The condition of the aortic valve and the origin of the coronary arteries were examined in 2413 Syrian hamsters aged between 1 and 823 days, belonging to nine inbred laboratory families. The specimens were studied with either a stereomicroscope, a corrosion-cast technique, or histological techniques (light microscopy). The aortic valve was tricuspid in 1823 (75-5%) cases, and bicuspid in the remaining 590 (24"5%). In all bicuspid aortic valves there were two aortic sinuses, a ventral and a dorsal, each supporting one cusp. The left coronary artery arose from the dorsal aortic sinus in 71 (2"9%) hamsters, eight of which died unexpectedly between ages 1 and 622 days. In 29 (40"8%) of the 71 cases, the aortic valve was tricuspid and the right coronary artery originated from the right aortic sinus. In the remaining 42 (59'2%) cases, the aortic valve was bicuspid and the right coronary artery arose from the right side of the ventral aortic sinus. Results ofa )~2 contingency test demonstrated that the frequency of left coronary artery arising from the dorsal aortic sinus significantly increased when the aortic valve was bicuspid. This fact, together with previously reported data on coronary artery anomalies in the Syrian hamster, suggests that the left coronary artery arising from the dorsal aortic sinus may be an expression of a single morphogenetic defect which is expressed as bicuspid aortic valve in some cases, anomalous origin of the left coronary artery in others, or in the simultaneous occurrence of these two cardiac abnormalities.

A histological study was made of the aortic valves of 141 Syrian hamsters aged between 35 and 657 days, belonging to an inbred laboratory colony with a high incidence of congenital bicuspid aortic valves. A tricuspid aortic valve was found in 81 specimens, whereas the remaining 60 possessed a bicuspid aortic valve. In all bicuspid valves there were two aortic sinuses, a ventral and a dorsal, each supporting one cusp. Thirty-three (23.4%) of the 141 specimens showed mucoid dysplasia of the aortic valve. The defect was characterized by thickening of the valve cusps and disruption of the fibrosa layer accompanied by an increased amount of glycosaminoglycans. Ten (12.3%) of the 81 tricuspid aortic valves and 23 (38.3%) of the 60 bicuspid aortic valves were dysplastic. This difference was statistically significant (P < 0.001). The findings indicate that, in the Syrian hamster, the simultaneous occurrence of bicuspid aortic valve and aortic valve dysplasia is not a random event. However, the fact that these valve defects also occur independently suggests that there is no primary morphogenetic dependence between them, but that some other cause predisposes to their concurrence.

Congenital underdevelopment of one or more main branches of the coronary arteries has been reported in man, but not in non-human mammals. In man, this defective coronary artery arrangement may cause myocardial ischaemia and even sudden death. The main goal of this study was to describe the coronary artery distribution patterns associated with the presence of a markedly underdeveloped (rudimentary) coronary artery in Syrian hamsters. Moreover, an attempt was made to explain the morphogenesis of these patterns, according to current knowledge on coronary artery development. Eleven affected hamsters belonging to a laboratory inbred family were examined by means of internal casts of the heart, great arterial trunks and coronary arteries. The aortic valve was tricuspid (normal) in seven hamsters and bicuspid in the other four. A rudimentary coronary artery arose from the right side of the aortic valve in four specimens, from the left side of the aortic valve in a further three, and from the dorsal aortic sinus in the remaining four. In all cases, a second, well-developed coronary artery provided for all the coronary blood flow. Except for the existence of a rudimentary coronary artery, the present anomalous coronary artery distribution patterns are similar to coronary artery patterns reported in Syrian hamsters, dogs and humans in association with a solitary coronary ostium in aorta. We suggest that an unusual prolonged time interval in the development of the embryonic coronary stems might be a key factor in the formation of coronary arteries displaying significantly dissimilar developmental degrees.

The condition of coronary arteries and aortic valves was studied in 552 Syrian hamsters belonging to a single family subjected to high endogamous pressure. The study was carried out using a corrosion-cast technique. In 178 hamsters the aortic valve was bicuspid. In 138 specimens, 54 of them with normal aortic valves and 84 with bicuspid aortic valves, anomalies in the origin of the coronary arteries could be classified in three morphologic types: left coronary artery from the pulmonary trunk (36 cases); single right coronary artery (84 cases); left coronary artery from the dorsal aortic sinus (18 cases). Results of a chi 2 contingency test show that the frequency of left coronary artery from the pulmonary trunk and single right coronary artery significantly increases when the aortic valve is bicuspid. The present findings suggest that there is a developmental complex consisting of biscuspid aortic valve and anomalous origin of the coronary arteries.

Summary Little attention is being paid to the presence of accessory coronary artery ostia in man and non-human mammals due to their limited clinical relevance. However, information about their frequency and the cardiac territories irrigated by the vessels arising from them is of interest to obtain an accurate survey of the establishment of the coronary artery system in each species. The aim here was to compare the incidence and significance of the accessory coronary ostia in Syrian hamsters with normal coronary arteries and several coronary anomalies characterized by the absence of a left coronary artery originating from the left aortic sinus. The hearts from 2829 hamsters were examined using a corrosion-cast technique, micro-dissection, histochemical techniques, and scanning electron microscopy. Overall, 148 specimens displayed accessory ostia. A limited number of them belonged to the conal artery which supplies the wall of the right ventricular outflow tract. The other accessory ostia led to the septal artery, a vessel which irrigates the most part of the interventricular septum. The incidence of accessory ostia in normal and anomalous coronary artery patterns was quite similar. This suggests that the morphogenetic deviations producing the coronary artery anomalies reported in this study do not alter the connections of the septal and conal arteries to the aorta. The present observations lead to the notion that in the Syrian hamster, the septal artery should be regarded as a third coronary artery.

La modificación genética de organismos vivos ha generado interrogantes éticos de difícil solución. La búsqueda de marcos conceptuales lleva a plantear si ha habido una modificación del estatuto ontológico de los organismos alterados por la biotecnología. Este artículo realiza una aproximación al organismo biotecnológico a partir del pensamiento de los filósofos José Ortega y Gasset y Xavier Zubiri acerca del hombre y de la técnica, conceptualizando el objeto artificial biotecnológico como "organismo artificial", con la particularidad de ser el primer objeto producido por el hombre que se reproduce independientemente The possibility of genetic modification of living organisms has generated ethical questions of difficult solution. The searching for conceptual frames has put into question whether the ontological status of organisms altered by biotechnology has been changed. This paper approaches the biotechnological organism following the thinking of philosophers Ortega y Gasset and Xavier Zubiri, based on their view on anthropology and technology conceptualizing the biotechnological artificial object as an "artificial organism" with the particularity that it is the first object produced by human beings which reproduces independently A modificação genética de organismos vivos gerou interrogativos éticos de difícil solução. A busca de marcos conceituais leva a questionar se ocorreu uma modificação do estatuto ontológico dos organismos modificados pela biotecnologia. Este artigo realiza uma aproximação ao organismo biotecnológico a partir do pensamento dos filósofos José Ortega y Gasset e Xavier Zubiri a respeito do homem e da técnica. Conceptualiza o objeto artificial biotecnológico como um "organismo artificial", com a particularidade de ser o primeiro objeto produzido pelo homem que se reproduz independentemente

The aim of this paper is to analyse empirically entry decisions by generic firms into markets with tough regulation. Generic drugs might be a key driver of competition and cost containment in pharmaceutical markets. The dynamics of reforms of patents and pricing across drug markets in Spain are useful to identify the impact of regulations on generic entry. Estimates from a count data model using a panel of 86 active ingredients during the 1999–2005 period show that the drivers of generic entry in markets with price regulations are similar to less regulated markets: generic firms entries are positively affected by the market size and time trend, and negatively affected by the number of incumbent laboratories and the number of substitutes active ingredients. We also find that contrary to what policy makers expected, the system of reference pricing restrains considerably the generic entry. Short run brand name drug price reductions are obtained by governments at the cost of long run benefits from fostering generic entry and post-patent competition into the markets.

The objective of the research is to know the factors that in Spain influence in the election of banking organization. The obtained results indicate that the dimension of the network of branches is the reason more valued. In spite of the increasing symmetry of the Spanish banking market, the preferences of the clients of the savings banks and those of the banks are not absolutely coincident, being the proximity - the main reason for election- much more valued by the former than by the latter. The existence of divergences in the preferences has also been detected according to the region and the typology of city of residence.

Summary This study describes the coronary artery distribution patterns associated with the anomalous origin of the left coronary artery from the right side of the aortic valve in Syrian hamsters. The hearts of 15 aiected animals were examined by means of a corrosion-cast technique, histology and scanning electron microscopy. The hamsters belonged to a laboratory inbred colony with a high incidence of coronary artery anomalies and bicuspid aortic valves. The aortic valve was tricuspid in eight hamsters and bicuspid in the other seven. In all cases, the right coronary artery was normal, whereas the left main coronary artery trunk arose from the right aortic sinus or from the right side of the ventral aortic sinus when the aortic valve was bicuspid. In 12 specimens, the left main trunk crossed the infundibular septum and then divided into the left circum£ex branch and the obtuse marginal branch. In another specimen, the course of the left main trunk was ventral to the right ventricular out£ow tract; in the remaining two, it surrounded the aorta dorsally. In man, some of these distribution patterns may cause myocardial ischaemia and sudden death. The present ¢ndings prove that the origin of the left coronary artery from the right aortic sinus occurs in primitive mammals such as the Syrian hamster, suggesting that the defect may occur in other mammalian species. Its possible occurrence should be borne in mind in domestic animals, especially in those with signs of myocardial ischaemia after strenuous activity. r 2006 Elsevier Ltd. All rights reserved.

This book provides a complete approach to the economics of financing medicines and policy implications for the efficiency and equity of health systems. In all health systems with majority public financing, pharmaceutical reimbursement is one of the key factors in policies of change and transformation of health services in order to face the future with guarantees of financial sustainability.

Summary The formation, topographical location and calcification of cartilage in congenital bicuspid aortic valves of 235 Syrian hamsters aged 0‐173 days were studied by histological, histochemical and immunohistochemical techniques. In all animals the aortic valve was bicuspid; it had two leaflets, ventral and dorsal, each supported by its own aortic sinus. In 141 valves, a more or less developed raphe was located in the ventral sinus. The remaining 94 valves were devoid of any raphe. The first sign of valvular chondrogenesis was the presence of small groups of cells embedded in a type II collagen-positive extracellular matrix. These cellular groups, which appeared as early as 2 days after birth, became converted into hyaline cartilage or fibrocartilage. A considerable proportion (67%) of the valvular cartilages developed within the first 6 weeks of life. The cartilaginous tissue was capable of forming anywhere along the attachments of the valve leaflets to their supporting sinuses. However, statistical analyses substantiated the observation that the bases of the sinuses and raphes were the valvular regions particularly prone to the development of cartilage. At these sites, the cartilage was usually hyaline and often became calcified. The findings were consistent with the assumption that intense mechanical stimulation plays an important role in the formation of the valvular cartilage. Moreover, these findings supplied new evidence that in the cardiac semilunar valves of Syrian hamsters, cartilage formation does not involve the aggregation of large numbers of cells before their differentiation into chondrocytes. The valvular hyaline cartilages appear to act as competent pivots, resisting mechanical tensions generated during the cardiac cycle. Deposition of calcium in the matrix can be regarded as a reinforcement process of the cartilaginous tissue. Finally, it is hypothesized that the formation of cartilage in the aortic valves of hamsters prevents dystrophic calcification of the valve, a pathological change that causes aortic stenosis in man, especially in patients with a bicuspid aortic valve. q 2005 Published by Elsevier Ltd.

This work starts stating the great increase of pharmacological studies associated with pharmacogenetic studies without clear knowledge of their consequences. The first challenge is to find out whether pharmacogenetic studies have greater implications than the determination of routine parameters. We cannot obviate that genetics engenders special worries due to several factors, such as: technical language, lack of information, media simplifications and complexity. The second goal is to define which property rights researchers or sponsor companies have on biological samples and genetic data in pharmacogenetic studies.

El incesante avance de la tecnociencia y, más concretamente, de la biotecnología, abre un mundo de nuevas posibilidades no exentas de riesgos. El objetivo del presente trabajo es analizar el conflicto social y ecológico que está generando el desarrollo biotecnológico en el continente latinoamericano y dilucidar cuáles son los posibles espacios y actores claves para que el desarrollo biotecnológico no se convierta en un asunto tecnocrático, sino en un espacio de participación social, donde la biotecnología sea una posibilidad "apropiada" por la sociedad. Para realizar esta tarea es necesario identificar cuál es la situación real, los peligros y los discursos de las instituciones y qué ámbitos existen donde los diferentes actores puedan interactuar, de modo que la bioética ejerza no sólo un papel mediador sino también hermenéutico. Ello no ha de situar a la Bioética en un espacio académico, sino que ha de buscar o crear los mecanismos para la generación de una praxis bioética

The conditions of the aortic and pulmonary valves and the arrangement in the origin of the coronary arteries were studied in 247 Syrian hamsters belonging to a single family subjected to high endogamous pressure. Most specimens (n = 216) were examined using a stereomicroscope. The remaining 31 were studied histologically. In 110 specimens both cardiac semilunar valves were normal. The aortic valve was bicuspid and the pulmonary valve was normal in 79 animals, while a normal aortic valve and a bicuspid pulmonary valve occurred in 37. In the remaining 21 specimens both semilunar valves were bicuspid. In 34 cases, the left coronary artery originated from the pulmonary trunk. Statistical analyses indicate that there is no significant relationship between the bicuspid condition of the pulmonary valve and the fact that a coronary artery arises from the pulmonary trunk. On the other hand, they substantiate that the frequency of this coronary artery anomaly significantly increases when the aortic valve is bicuspid. The present findings agree with the hypothesis that abnormal migration of the neural crest cells may be responsible for the combined occurrence of bicuspid aortic valve and anomalous origin of the left coronary artery from the pulmonary trunk. In addition, they suggest that the neural crest cells involved in the formation of the pulmonary valve diverge from those migrating into the aortic valve and those imposing spatial order upon the development of the proximal coronary arteries.

Summary Bearing in mind that the Syrian hamster provides an animal model for the study of congenital coronary artery anomalies, we decided to undertake a definition of its normal coronary artery pattern. The sample examined consisted of 1204 specimens. They were studied both histologically and by means of a corrosion-cast technique. The course of the coronary arteries in this species is intramyocardial. The right coronary artery has two principal branches: the right circumflex branch and the dorsal interventricular branch. The conal branch usually originates from the main trunk of the right coronary artery. The main branches of the left coronary artery are the obtuse marginal branch, the left circumflex branch, and usually a dorsal ventricular branch as well. The ventral interventricular branch is often absent. When it is present, it always originates from the left coronary artery and seldom reaches the apex of the heart. The interventricular septum is principally supplied by one, or rarely two, septal arteries arising from the right and/or left coronary arteries. According to the number and origin of these vessels, three septal coronary artery patterns were established; namely, the right, the left, and the right-left septal patterns. In the Syrian hamster, the left septal pattern is the most frequent (70.4%). The right septal pattern occurred in 28.1 % of the specimens studied, whereas the right-left septal pattern was only found in 1.5% of them.

A coronary artery that arises from the nonfacing (posterior or dorsal) aortic sinus is regarded as having an anomalous origin. We studied 34 Syrian hamsters in which the left coronary artery originated from the nonfacing aortic sinus. All hamsters belonged to a single family subjected to high endogamous pressure in our laboratory. Twenty-four specimens were examined using a corrosion-cast technique and scanning electron microscopy, whereas the remaining 10 were studied histologically. The aortic valve was normal in 15 cases, whereas it was bicuspid in the other 19 cases. In each specimen of our series, the left coronary artery arose with an acute angle with respect to the aortic valve. Moreover, when the coronary ostium was located in the center of the nonfacing aortic sinus, the proximal coronary artery had an intramural aortic course. These left coronary artery arrangements might underlie an unfavorable coronary circulation physiology. Our morphologic findings agree with the morphogenetic hypothesis that each aortic sinus has the potential to develop coronary artery buds, which hollow out from the aorta to become coronary artery trunks.

We studied the conditions of the aortic and pulmonary valves of 153 Syrian hamsters belonging to a single family subjected to high endogamous pressure. Semilunar valves of 143 specimens were examined using a stereomicroscope, and in 5 of these cases a histologic study was also performed. The remaining 10 specimens were studied by means of scanning electron microscopy. In 77 specimens both semilunar valves were normal. The aortic valve was bicuspid and the pulmonary valve was normal in 46 animals, while a normal aortic valve and a bicuspid pulmonary valve occurred in 24. In the remaining 6 specimens both semilunar valves were bicuspid. All bicuspid semilunar valves detected herein showed the same morphotype, namely with the leaflets oriented ventrodorsally. The incidence of these anomalous valves did not significantly differ between sexes. Results of a chi 2-test substantiate that conditions of both outflow tract semilunar valves are independent traits. Thus, concurrence of a bicuspid aortic valve and a bicuspid pulmonary valve in an individual is a random event. The present findings support the assumption that bicuspid aortic and pulmonary valves have different morphogenetic origin, although factors producing a bicuspid aortic valve and those leading to a bicuspid pulmonary valve are not mutually exclusive.

In the Syrian hamster, anomalies in the origin of the left coronary artery are significantly associated with the bicuspid condition of the aortic valve. In this species, bicuspid aortic valves are expressions of a trait, the variation of which takes the form of a phenotypic continuum, ranging from a tricuspid aortic valve with no commissural fusion to a bicuspid aortic valve with the aortic sinuses located in ventrodorsal orientation and devoid of any raphe. The intermediate stages of the continuum are represented by tricuspid aortic valves with a more or less extensive fusion of the ventral commissure and bicuspid aortic valves with a more or less developed raphe located in the ventral aortic sinus. The present study was designed to decide whether there is a gap between tricuspid and bicuspid aortic valves regarding the incidence of coronary artery anomalies, or whether this incidence varies according to the different tricuspid and bicuspid morpho types of the continuum. The study was carried out in Syrian hamsters belonging to a single inbred family with a high incidence of tricuspid aortic valves with fusion of the ventral commissure, bicuspid aortic valves, and anomalies in the origin of the left coronary artery, i.e. single right coronary artery ostium in aorta, anomalous origin of the left coronary artery from the pulmonary artery, and anomalous origin of the left coronary artery from the dorsal aortic sinus. The specimens were examined by means of a stereomicroscope and, in several cases; scanning electron microscopy was also used. The relationships between anomalous coronary artery patterns and aortic valve morphologies were tested using a logistic regression model. The results obtained indicate that there is no discontinuity between tricuspid and bicuspid aortic valves regarding the incidence of coronary artery anomalies. The probability of occurrence of anomalous coronary artery patterns increases continuously according to the deviation degree of the aortic valve from its normal (tricuspid) design. The present findings suggest that in the Syrian hamster, the morphogenetic mechanisms involved in the formation of congenital anomalous aortic valves and anomalies in the origin of the left coronary artery, respectively, are strongly related from an aetiological viewpoint.

We conducted a light-microscopic histologic study of the aortic valves of 224 Syrian hamsters aged between 1 and 771 days. Most of the hamsters examined belonged to a single laboratory-inbred family with a high incidence of bicuspid aortic valves (BAVs). In 146 specimens the aortic valve was tricuspid, and in 107 of them the ventral commissure was more or less fused. The remaining 78 specimens showed a BAV with the aortic sinuses oriented ventrodorsally. In 33 BAVs a raphe was located in the ventral aortic sinus. Cartilaginous foci were present in the aortic valves of 86 specimens, 40-771 days old. The foci were located at two different sites, namely in the ventral wall of the valve and/or in the dorsal aortic sinus. Statistical analyses substantiate that (1) chondrogenesis begins earlier in BAVs, and especially in those having a raphe, than in tricuspid aortic valves and (2) the location of the cartilaginous foci is significantly associated with the morphology of the aortic valve. The present findings support the hypothesis that, in the Syrian hamster, cartilage forms in the aortic valve as a response to locally intense mechanical stimulation.