Adrenomedullin as a potential biomarker involved in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Adrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity.  The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. METHODS: Serum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group. RESULTS: Forty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1-80.6] pg/mL in the HHT group and 47.7 [43.2-53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies. CONCLUSIONS: We detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.

Orthotopic Liver Transplantation With Elderly Donors (Over 80 Years of Age): A Prospective Evaluation.

BACKGROUND: Our main objective was to assess the clinical outcomes obtained in a single orthotopic liver transplant (OLT) hospital with donors ≥80 years of age compared to a control group of patients subjected to OLT during the same period of time with donors who were under 65 years of age. METHODS: A prospective analysis was carried out on all the OLTs performed using liver grafts from donors in a state of brain death and with an age of ≥80 years (study group) between April 2007 and January 2015. The results of the study group (n = 36) were compared with those of a control group of patients less than 65 years of age receiving transplants with grafts. RESULTS: A total of 51 potential donors ≥80 years were assessed, with a total of 36 liver transplants being carried out and their results were compared with a control group of 283 patients receiving transplants. The median follow-up time of the patients in the series was 36 months (range: 24-120 months). Graft survival at 1, 2, and 3 years was 77%, 72%, and 62%, respectively, among the patients in the study group and 79%, 73%, and 65% among the patients in the control group, and there were no statistically significant differences. Patient survival at 1, 2, and 3 years was 86%, 82%, and 75%, respectively, among the patients in the study group and 82%, 76%, and 72% among the patients in the control group, also without there being any statistically significant differences. CONCLUSIONS: There is no age limit for liver transplant donors. The use of octogenarian donors makes it possible to increase the pool of donors while providing enough safety for the recipient.

Molecular Adsorbent Recirculating System Treatment Can Reduce Blood Levels of N-Acetylcysteine in Patients With Acetaminophen Overdose: Case Reports.

BACKGROUND: Acetaminophen poisoning continues to be a major cause of liver failure that can lead to liver transplantation. N-acetylcysteine (NAC) is the cornerstone of treatment. Some authors use a Molecular Adsorbent Recirculating System (MARS) system in acetaminophen poisoning. It is reported that the MARS system eliminates acetaminophen more efficiently than conventional dialysis. It is theoretically possible that treatment with MARS administered after NAC will increase the effectiveness of treatment. CASE REPORTS: The first patient, a woman of 14 years old, presented blood levels of 112 mg/dL 12 hours after ingestion of 15 g of acetaminophen. Treatment with NAC was initiated. At 17 and 23 hours after ingestion, blood levels were 23.5 µg/mL and 5.9 µg/mL, respectively. The second patient, a woman of 28 years old, presented blood levels of 115 mg/dL 4 hours after ingestion of 40 g of acetaminophen. Treatment with NAC was initiated. At 14 and 23 hours after ingestion, blood levels were 15.8 µg/mL and <2 µg/mL, respectively. In both patients, we performed MARS after completing treatment with NAC, and after the first session, blood levels were below the lower limit of detection (≤2 µg/mL). DISCUSSION: The correct timing of MARS to avoid interactions with the administered dose of NAC in acetaminophen overdose is essential so as to not impair the effectiveness of this treatment. These considerations in the management of this entity help in the resolution of liver failure, thus avoiding the need for a liver transplant.

Under-reporting bicycle accidents to police in the COST TU1101 international survey: Cross-country comparisons and associated factors.

Police crash reports are often the main source for official data in many countries. However, with the exception of fatal crashes, crashes are often underreported in a biased manner. Consequently, the countermeasures adopted according to them may be inefficient. In the case of bicycle crashes, this bias is most acute and it probably varies across countries, with some of them being more prone to reporting accidents to police than others. Assessing if this bias occurs and the size of it can be of great importance for evaluating the risks associated with bicycling. This study utilized data collected in the COST TU1101 action "Towards safer bicycling through optimization of bicycle helmets and usage". The data came from an online survey that included questions related to bicyclists' attitudes, behaviour, cycling habits, accidents, and patterns of use of helmets. The survey was filled by 8655 bicyclists from 30 different countries. After applying various exclusion factors, 7015 questionnaires filled by adult cyclists from 17 countries, each with at least 100 valid responses, remained in our sample. The results showed that across all countries, an average of only 10% of all crashes were reported to the police, with a wide range among countries: from a minimum of 0.0% (Israel) and 2.6% (Croatia) to a maximum of a 35.0% (Germany). Some factors associated with the reporting levels were type of crash, type of vehicle involved, and injury severity. No relation was found between the likelihood of reporting and the cyclist's gender, age, educational level, marital status, being a parent, use of helmet, and type of bicycle. The significant under-reporting - including injury crashes that do not lead to hospitalization - justifies the use of self-report survey data for assessment of bicycling crash patterns as they relate to (1) crash risk issues such as location, infrastructure, cyclists' characteristics, and use of helmet and (2) strategic approaches to bicycle crash prevention and injury reduction.

Multiscalar cellular automaton simulates in-vivo tumour-stroma patterns calibrated from in-vitro assay data.

BACKGROUND: The tumour stroma -or tumour microenvironment- is an important constituent of solid cancers and it is thought to be one of the main obstacles to quantitative translation of drug activity between the preclinical and clinical phases of drug development. The tumour-stroma relationship has been described as being both pro- and antitumour in multiple studies. However, the causality of this complex biological relationship between the tumour and stroma has not yet been explored in a quantitative manner in complex tumour morphologies. METHODS: To understand how these stromal and microenvironmental factors contribute to tumour physiology and how oxygen distributes within them, we have developed a lattice-based multiscalar cellular automaton model. This model uses principles of cytokine and oxygen diffusion as well as cell motility and plasticity to describe tumour-stroma landscapes. Furthermore, to calibrate the model, we propose an innovative modelling platform to extract model parameters from multiple in-vitro assays. This platform provides a novel way to extract meta-data that can be used to complement in-vivo studies and can be further applied in other contexts. RESULTS: Here we show the necessity of the tumour-stroma opposing relationship for the model simulations to successfully describe the in-vivo stromal patterns of the human lung cancer cell lines Calu3 and Calu6, as models of clinical and preclinical tumour-stromal topologies. This is especially relevant to drugs that target the tumour microenvironment, such as antiangiogenics, compounds targeting the hedgehog pathway or immune checkpoint inhibitors, and is potentially a key platform to understand the mechanistic drivers for these drugs. CONCLUSION: The tumour-stroma automaton model presented here enables the interpretation of complex in-vitro data and uses it to parametrise a model for in-vivo tumour-stromal relationships.

Evidence of plastic probing behavior in a 'superclone' of the grain aphid Sitobion avenae.

Asexual reproduction is very common in invasive insect pest. In the recent years, increasing evidences have shown that some invasive asexual lineages display an outstanding capacity to predominate in space and persist on time (superclones). However, little is known about the host-use behavior of these superclones. The English grain aphid Sitobion avenae (Fabricius) (Hemiptera: Aphididae) is one of the major pests of cereals worldwide. Chilean populations of the grain aphid are characterized by a high degree of heterozygosity and low genotypic variability across regions and years, with only four predominant superclone genotypes representing nearly 90% of populations. In this study, (1) the reproductive performance and (2) the probing behavior followed a host shift of one superclone and one non-superclone of S. avenae, were compared. The host plant in the superclone did not affect the reproductive performance, while in the non-superclone was lower on highly defended wheat seedling. The experimental switching of the host plants from barley (without chemical defenses) to two wheat species with low and high levels of chemical defenses, revealed that superclone exhibited a flexible probing activities related to access of sieve elements, while the non-superclone exhibited rigid responses. These findings are consistent with the pattern of occurrence of these genotypes in the field on cereals with different plant defenses (e.g. benzoxazinoids). These responses are discussed on the view of developing new strategies for the management in invasive populations of aphid pest species.

Distribution and molecular detection of Theileria and Babesia in questing ticks from northern Spain.

A total of 562 questing adult ixodid ticks, collected during 2003-05 in 10 recreational mountain areas in northern Spain, were analysed for piroplasm infection. Reverse line blot (RLB) analysis using a panel of probes for 23 piroplasm species identified 16 different piroplasms, with an overall prevalence of 9.3%. Most were Theileria spp.-positive (7.7%), 3.0% were positive for Babesia spp. and 1.4% of ticks harboured both genera. Ixodes ricinus (Linnaeus, 1758), the most abundant tick in the vegetation, ranked third with regard to piroplasm infection prevalence (11.4%) after Rhipicephalus bursa (Canestrini & Fanzago, 1878) (16.0%) and Haemaphysalis punctata (Canestrini & Fanzago, 1878) (13.5%). Infection was detected in 6.2% of Dermacentor reticulatus (Fabricius, 1794) and in 1.1% of Haemaphysalis inermis (Birula, 1895), but was absent from Haemaphysalis concinna (Koch, 1844). Ixodes ricinus carried more piroplasm species (13), followed by H. punctata (10), D. reticulatus (8), R. bursa (3) and H. inermis (1). Although most of the positive ticks harboured a single infection (76.9%), mixed infections with two or three different piroplasm species were also detected (23.1%). The various tick-pathogen associations found are discussed and prevalences of infection in ticks are compared with previous results on piroplasms infecting animals in the same region.

Molecular detection and characterization of piroplasms infecting cervids and chamois in Northern Spain.

Wildlife can act as reservoir of different tick-borne pathogens of veterinary and zoonotic importance. To investigate the role of wild ruminants as reservoir of piroplasm infection, 28 red deer, 69 roe deer and 38 chamois from Northern Spain were examined by reverse line blot (RLB) hybridization. The survey detected a prevalence of 85.7% in red deer, 62.3% in roe deer and 28.9% in chamois. Four different piroplasms were identified: Theileria sp. OT3 (previously described in sheep) as the most prevalent (85.7% in red deer, 46.4% in roe deer and 26.3% in chamois); Theileria sp. 3185/02 (previously described in a red deer in Central Spain) more abundant in red deer (53.6%) than in roe deer (10.1%) but absent from chamois; Babesia divergens detected in 6 roe deer; Theileria ovis present in 1 chamois. Mixed infections (Theileria sp. OT3 and Theileria sp. 3185/02) were only found in red and roe deer. Sequencing analysis of the 18S rRNA gene confirmed the RLB results and showed 99.7% identity between Theileria sp. 3185/02 and T. capreoli, suggesting that they are the same species. Tick distribution and contact of wild ruminants with domestic animals are discussed in terms of piroplasm infection. The results suggest that a considerable number of wildlife ruminants are asymptomatic carriers that may serve as reservoirs of the infection posing a serious concern in terms of piroplasmosis control.

Sodium 2-oxo-3-semicarbazono-2,3-dihydro-1H-indole-5-sulfonate dihydrate.

The title compound, Na+.C9H7N4O5S-.2H2O, presents a Z configuration around the imine C=N bond and an E configuration around the C(O)NH2 group, stabilized by two intramolecular hydrogen bonds. The packing is governed by ionic interactions between the Na+ cation and the surrounding O atoms. The ionic unit, Na+ and 2-oxo-3-semicarbazono-2,3-dihydro-1H-indole-5-sulfonate, forms layers extending in the bc plane. The layers are connected by hydrogen bonds involving the water molecules.

Isatin 3-semicarbazone and 1-methylisatin 3-semicarbazone.

The two title semicarbazones, namely 2,3-dihydro-1H-indole-2,3-dione 3-semicarbazone, C9H8N4O2, (I), and 1-methyl-2,3-dihydro-1H-indole-2,3-dione 3-semicarbazone, C10H10N4O2, (II), show the same configuration, viz. Z around the imine C=N bond and E around the C(O)-NH2 bond, stabilized by two intramolecular hydrogen bonds. The presence of a methyl group on the isatin N atom determines the difference in the packing; in (I), the molecules are linked into chains which lie in the crystallographic (102) plane and run perpendicular to the b axis, while in (II), the molecules are arranged to form helices running parallel to a crystallographic screw axis in the a direction.

[Tuberculosis control in the Central Health Region of Catalonia during the period 1986-2000]. / El control de la tuberculosis en la Región Sanitaria Centro de Cataluña durante el período 1986-2000.

OBJECTIVE: To assess tuberculosis control in the Central Health Region, Catalonia, Spain, from the implementation of the area's Tuberculosis Control Program in 1986 until the year 2000. METHOD: To study the epidemiological profile of tuberculosis and the outcome of the following control measures in sputum smear-positive patients: final outcome of treatment and monitoring, and the percentage of patients for whom a contact investigation (CI) was carried out. Tuberculosis control is considered effective if the sum of noncompliant patients, plus the cases in which treatment failed, plus the patients transferred out remains below 10% of the cohort of patients studied, and if a CI has been conducted in at least 80% of this cohort. RESULTS: The number of cases reported was 6326, of which 7% were retreatments. A total of 5865 new cases was detected. Of these, 5652 (96%) were patients born in Spain. The number of cases reported annually peaked in 1990 (474) and then declined continuously until 2000, when it was 54% lower (220). Foreign-born patients numbered 213 (4%), and 95% of them came from countries with a high prevalence of tuberculosis. In the cohort of patients studied between 1997 and 2000, the sum of noncompliant patients, plus cases in which treatment failed, plus the patients transferred out came to 11%. Since 1994, a CI has been carried out for over 80% of patients, and this figure reached 92% in 2000. CONCLUSIONS: We consider that a substantial degree of tuberculosis control has been achieved given the decline in tuberculosis morbidity among people born in Spain, the fact that the percentage of noncompliant patients, treatment failures and transfers was only slightly over 10%, and that a CI has been conducted for over 80% of patients since 1994 (92% in 2000).

Análisis comparativo de los factores asociados a la mortalidad de las bacteriemas / Comparison of factors associated with mortality from bacteraemias in individuals aged 60-70 years old and in those aged more than 70 years

INTRODUCCIÓN: El objetivo de este estudio ha sido determinar los factores asociados, en relación con la evolución mortal, de las bacteriemias-fungemias ocurridas en un año, y comparar los resultados en la población con edades comprendidas entre 60 y 70 años y la población mayor de 70 años. PACIENTES Y MÉTODOS: Estudio descriptivo, prospectivo de todos los episodios de bacteriemias-fungemias producidos en el Hospital Universitario de la Princesa de Madrid, entre el 16 de mayo de 1996 y el 14 de mayo de1997. Se utilizaron las mismas definiciones en los dos grupos de estudio. El análisis univariado de los resultados se realizó con el test de la 2 y las variables con más de dos categorías mediante regresión logística, considerándose significación estadística un valor de p < 0,05. RESULTADOS: Un total de 250 episodios han sido analizados, 158 en personas mayores de 70 años frente a 92 episodios en el grupo de pacientes con edades comprendidas entre 60 y 70 años. Globalmente, no existe diferencia en cuanto a la mortalidad en ambos grupos (odds ratio [OR] = 1,22; intervalo, 0,662,24). El servicio que más episodios recibe en ambos grupos es el médico. Los microorganismos más frecuentes asociados a bacteriemia son los gramnegativos. La adquisición extrahospitalaria es la más habitual. El origen más frecuente es el vascular en el grupo de 60-70 años, y el genitourinario en el grupo de los mayores de 70 años. Hay un alto porcentaje de tratamientos quirúrgicos adecuados en ambos grupos. Las variables con significación clínica y estadística en cuanto a la evolución mortal en el grupo de 60-70 años son: adquisición intrahospitalaria (OR = 6,28 [1,9-20,7]); hipotensión (OR = 4,46 [1,14-17,4]); coagulación intravascular diseminada (OR = 4,93 [3,14-7,75]). Sin embargo, se asocia a menor evolución mortal la realización de un tratamiento quirúrgico adecuado (OR = 10,76 [2,017-57,05]).En el grupo de más de 70 años son factores asociados a mal pronóstico en cuanto a evolución a muerte: uso previo de antibióticos (OR = 2,71 [1,25-6,13]); hipotensión (OR = 3,35 [1,34-8,36]); trombopenia (OR = 2,7 [0,97-7,69]); coagulación intravascular diseminada (OR = 7,51 [0,65-83]). Sin embargo, también el tratamiento quirúrgico adecuado es un factor asociado a mejor pronóstico (OR = 6,03 [1,62-22,35]). CONCLUSIONES: No existen diferencias en cuanto a mortalidad en las personas con edades comprendidas entre 60 y 70 años y en los mayores de 70 años. Muchas de las variables se mantienen constantes en ambos grupos, lo que indica la potencia de dichas variables independientemente de la edad, siendo llamativa la asociación a mejor pronóstico del tratamiento quirúrgico adecuado, lo que debe favorecer dicho tipo de intervención terapéutica en caso necesario, independientemente de la edad (AU)

Cholesterol regulates membrane binding and aggregation by annexin 2 at submicromolar Ca(2+) concentration.

Annexin 2 is a member of the annexin family which has been implicated in calcium-regulated exocytosis. This contention is largely based on Ca(2+)-dependent binding of the protein to anionic phospholipids. However, annexin 2 was shown to be associated with chromaffin granules in the presence of EGTA. A fraction of this bound annexin 2 was released by methyl-beta-cyclodextrin, a reagent which depletes cholesterol from membranes. Restoration of the cholesterol content of chromaffin granule membranes with cholesterol/methyl-beta-cyclodextrin complexes restored the Ca(2+)-independent binding of annexin 2. The binding of both, monomeric and tetrameric forms of annexin 2 was also tested on liposomes of different composition. In the absence of Ca(2+), annexin 2, especially in its tetrameric form, bound to liposomes containing phosphatidylserine, and the addition of cholesterol to these liposomes increased the binding. Consistent with this observation, liposomes containing phosphatidylserine and cholesterol were aggregated by the tetrameric form of annexin 2 at submicromolar Ca(2+) concentrations. These results indicate that the lipid composition of membranes, and especially their cholesterol content, is important in the control of the subcellular localization of annexin 2 in resting cells, at low Ca(2+) concentration. Annexin 2 might be associated with membrane domains enriched in phosphatidylserine and cholesterol.

Cholesterol enhances phospholipid binding and aggregation of annexins by their core domain.

Annexins are Ca(2+)-dependent phospholipid-binding proteins composed of two domains: A conserved core that is responsible for Ca(2+)- and phospholipid-binding, and a variable N-terminal tail. A Ca(2+)-independent annexin 2-membrane association has been shown to be modulated by the presence of cholesterol in the membranes. Herein, the roles of the core and the N-terminal tail on the cholesterol-enhancement of annexin 2 membrane binding and aggregation were studied. The results show that (i) the cholesterol-mediated increase in membrane binding and in the Ca(2+) sensitivity for membrane aggregation were not modified by a N-terminal peptide (residues 15-26), and were conserved in mutants of the N-terminal end (S11 and S25 substitutions); (ii) cholesterol induced an increase in the Ca(2+)-dependent membrane binding and aggregation of the N-terminally truncated protein (Delta 1-29); and (iii) annexins 5 and 6, two proteins with unrelated N-terminal tails and homologous core domains showed a cholesterol-mediated enhancement of the Ca(2+)-dependent binding to membranes. These data indicate that the core domain is responsible for the cholesterol-mediated effects. A model for the cholesterol effect in membrane organisation, annexin binding and aggregation is discussed.

[Adult congenital anomalies of the coronary arteries described over 31 years of angiographic studies in the Asturias Principality: main angiographic and clinical characteristics]. / Anomalías congénitas de las arterias coronarias del adulto descritas en 31 años de estudios coronariográficos en el Principado de Asturias: principales características angiográficas y clínicas.

OBJECTIVE: The aim of this study was to determine the incidence of adult congenital anomalies of the coronary arteries over 31 years of angiographic studies, describing their angiographic and clinical characteristics. The results have been compared with the main series published. METHODS: The diagnostic angiographic reports done in the Principado de Asturias from 1968 to 1999 are reviewed. In those in which a congenital anomaly was diagnosed, the clinical report and the angiography were studied. The initial course of the anomaly was defined following angiographic criteria. RESULTS: Thirteen thousand five hundred reports were reviewed describing 75 patients with 75 anomalies (0.5%) including: anomalous origin of the left circumflex coronary artery (n = 24), coronary artery fistulae (n = 21), both coronary arteries arising from the left coronary sinus (n = 15), single coronary arteries (n = 6), both coronary arteries arising from the right coronary sinus (n = 2), separated origin of anterior descending and left circumflex coronary arteries (n = 3), anterior descending artery arising from the right coronary sinus (n = 2), and others (n = 1). Angiographic studies were done because of: angina (59%), dysnea (25%), atypical chest pain (7%), syncope (3%), dizziness (3%) and palpitations (3%). The initial course was retroaortic in all the circumflex arteries, interarterial in the right coronaries, anterior in the anterior descending arteries and retroaortic, septal and combined, in the left coronaries. CONCLUSIONS: Adult congenital anomalies of the coronary arteries are not very common and are usually casual findings of diagnostic angiographic studies. Left circumflex coronary artery anomalies are the most frequently diagnosed.