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Prior to ~1 million years ago (Ma), variations in global ice volume were dominated by changes in obliquity; however, the role of precession remains unresolved. Using a record of North Atlantic ice rafting spanning the past 1.7 million years, we find that the onset of ice rafting within a given glacial cycle (reflecting ice sheet expansion) consistently occurred during times of decreasing obliquity whereas mass ice wasting (ablation) events were consistently tied to minima in precession. Furthermore, our results suggest that the ubiquitous association between precession-driven mass wasting events and glacial termination is a distinct feature of the mid to late Pleistocene. Before then (increasing), obliquity alone was sufficient to end a glacial cycle, before losing its dominant grip on deglaciation with the southward extension of Northern Hemisphere ice sheets since ~1 Ma.

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The biogeochemistry of hypersaline environments is strongly influenced by changes in biological processes and physicochemical parameters. Although massive evaporation events have occurred repeatedly throughout Earth history, their biogeochemical cycles and global impact remain poorly understood. Here, we provide the first nitrogen isotopic data for nutrients and chloropigments from modern shallow hypersaline environments (solar salterns, Trapani, Italy) and apply the obtained insights to δ15N signatures of the Messinian salinity crisis (MSC) in the late Miocene. Concentrations and δ15N of chlorophyll a, bacteriochlorophyll a, nitrate, and ammonium in benthic microbial mats indicate that inhibition of nitrification suppresses denitrification and anammox, resulting in efficient ammonium recycling within the mats and high primary productivity. We also suggest that the release of 15N-depleted NH3(gas) with increasing salinity enriches ammonium 15N in surface brine (≈34.0‰). Such elevated δ15N is also recorded in geoporphyrins isolated from sediments of the MSC peak (≈20‰), reflecting ammonium supply sufficient for sustaining phototrophic primary production. We propose that efficient nutrient supply combined with frequent bottom-water anoxia and capping of organic-rich sediments by evaporites of the Mediterranean MSC could have contributed to atmospheric CO2 reduction during the late Miocene.

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of malignant arrhythmia and sudden death particularly in young people. Although it is considered a desmosomal disease, mutations in non-desmosomal genes have also been identified. We report on a family where a mutation in LDB3 is associated with this condition. The index case and first and second degree relatives underwent a complete clinical evaluation: physical examination, electrocardiography (ECG), signal-averaged ECG, 2D echocardiogram, cardiac magnetic resonance and 24-h monitoring. After ruling out mutations in the five desmosomal genes, genetic testing by means of Next Generation Sequencing was carried out on the proband. A heterozygous missense mutation in LDB3 c.1051A>G was identified. This result was confirmed by subsequent Sanger DNA sequencing. Another six carriers were identified amongst her relatives. Three subjects fulfilled the criteria for a definitive diagnosis of ARVC and one reached a borderline diagnosis. In conclusion, this is the first family with ARVC where a mutation in LDB3 is associated with ARVC. Next generation sequencing arises as a particular useful tool to point to new causative genes in ARVC.

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Present day lead pollution is an environmental hazard of global proportions. A correct determination of natural lead levels is very important in order to evaluate anthropogenic lead contributions. In this paper, the anthropogenic signature of early metallurgy in Southern Iberia during the Holocene, more specifically during the Late Prehistory, was assessed by mean of a multiproxy approach: comparison of atmospheric lead pollution, fire regimes, deforestation, mass sediment transport, and archeological data. Although the onset of metallurgy in Southern Iberia is a matter of controversy, here we show the oldest lead pollution record from Western Europe in a continuous paleoenvironmental sequence, which suggests clear lead pollution caused by metallurgical activities since ~3900 cal BP (Early Bronze Age). This lead pollution was especially important during Late Bronze and Early Iron ages. At the same time, since ~4000 cal BP, an increase in fire activity is observed in this area, which is also coupled with deforestation and increased erosion rates. This study also shows that the lead pollution record locally reached near present-day values many times in the past, suggesting intensive use and manipulation of lead during those periods in this area.

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We aim to study the SCN5A gene in a cohort of Brugada syndrome (BS) patients and evaluate the genotype-phenotype correlation. BS is caused by mutations in up to 10 different genes, SCN5A being the most frequently involved. Large genomic rearrangements in SCN5A have been associated with conduction disease, but its prevalence in BS is unknown. Seventy-six non-related patients with BS were studied. Clinical characteristics and family risk profile were recorded. Direct sequencing and multiplex ligation-dependent probe amplification (MLPA) of the SCN5A gene for identification of mutations and larger rearrangements were performed, respectively. Eight patients (10.5%) had point mutations (R27H, E901K, G1743R (detected in three families), V728I, N1443S and E1152X). Patients with mutations had a trend toward a higher proportion of spontaneous type I Brugada electrocardiogram (ECG) (87.5% vs 52.9%, p = 0.06) and had evidence of familial disease (62.5%, vs 23.5%, p = 0.03). The symptoms and risk profile of the carriers were not different from wild-type probands. There were non-significant differences in the prevalence of type I ECG, syncope and history of arrhythmia in carriers of selected polymorphisms. None of the patients had any deletion/duplication in the SCN5A gene. In conclusion, 10.5% of our patients had mutations in the SCN5A gene. Patients with mutations seemed to have more spontaneous type I ECG, but no differences in syncope or arrhythmic events compared with patients without mutations. Larger studies are needed to evaluate the role of polymorphisms in the SCN5A in the expression of the phenotype and prognosis. Large rearrangements were not identified in the SCN5A gene using the MLPA technique.

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The aberrations of cholinesterase (ChE) genes and the variation of ChE activity in cancerous tissues prompted us to investigate the expression of ChEs in colorectal carcinoma. The study of 55 paired specimens of healthy (HG) and cancerous gut (CG) showed that acetylcholinesterase (AChE) activity fell by 32% and butyrylcholinesterase (BuChE) activity by 58% in CG. Abundant AChE-H, fewer AChE-T, and even fewer AChE-R and BuChE mRNAs were observed in HG, and their content was greatly diminished in CG. The high level of the AChE-H mRNA explains the abundance of AChE-H subunits in HG, which as glycosylphosphatidylinositol (GPI)-anchored amphiphilic AChE dimers (G2(A)) and monomers (G1(A)) account for 69% of AChE activity. The identification of AChE-T and BuChE mRNAs justifies the occurrence in gut of A12, G4(H) and PRiMA-containing G4(A) AChE forms, besides G4(H), G4(A) and G1(H) BuChE. The down-regulation of ChEs might contribute to gut carcinogenesis by increasing acetylcholine availability and over-stimulating muscarinic receptors.

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An anti-malarial vaccine is urgently needed, especially against P. falciparum which causes 2 to 3 million deaths each year, mostly in Sub-Saharan African children. This vaccine should contain molecules from the parasite's different developmental stages due to the parasite's remarkable complexity and genetic variability. The first approach using synthetic peptides from different parasite stage molecules (the SPf66 malaria vaccine) conferred limited protective efficacy in Aotus monkeys and in large field-trials carried out in different parts of the world SPf66 contains red blood cell (RBC) binding merozoite peptides for which immune responses against them are genetically controlled by HLA-DR region. Therefore, a systematic search of conserved high activity binding peptides (HABP) was undertaken aimed at using them as immunogens. However, these peptides were poorly immunogenic and had poor protection-inducing capacity against experimental challenge with a P. falciparum strain highly infective for Aotus monkeys an experimental model with an immune system quite similar to humans. Modifications were thus made to key residues to render them immunogenic and protection-inducing. These native and modified HABPs' three-dimensional structure was determined by (1)H-NMR studies and their ability in forming stable Major Histocompatibility Class II - peptide (MHCII-peptide) complexes was correlated with their ability to bind in vitro to purified HLA-DR beta1* molecules. Our experimental data suggests a correlation between modified HABPs' three-dimensional structure, HLA-DR beta1* binding preferences and their protection-inducing capacity in monkeys. Furthermore, the data presented here indicates that a synthetic peptide vaccine's three-dimensional structural features dictate both HLA-DR beta1* allele binding preference (imposing genetic restriction on the immune response) and on these vaccines' protection-inducing value. Basic knowledge of a parasite's functionally active peptides, their 3D structure and their interaction for forming the MHC II- peptide-TCR complex will thus contribute towards designing fully effective multi-component, multi-stage subunit-based malarial vaccines.

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BACKGROUND AND METHODS: In the search for new factors of cardiovascular risk associated to diabetes mellitus (DM), special attention has been paid in recent years to hyperhomocysteinaemia. Therefore, we have established the concentration of homocysteine (Hcy) and other biochemical parameters in the plasma of a group of 57 type 1 and 32 type 2 diabetic patients and 54 control subjects and studied whether plasmatic homocysteinaemia was related to macroangiopathy, nephropathy, retinopathy and neuropathy. Because of significant differences for plasma Hcy values between men and women in the control group, we distinguished between both groups throughout the study. RESULTS: Patients with DM had higher Hcy than control subjects (11.7+/-5.4 vs. 10.1+/-2.4 micromol/l, p<0.05). Fasting hyperhomocysteinaemia was considered as the mean of the plasma Hcy for control subjects+2 SD (14.9 micromol/l in total group, 15.6 micromol/l in males and 13.9 micromol/l in females). In the studied groups with complications, we found significant differences between normohomocysteinaemic type 1 diabetic patients and those considered hyperhomocysteinaemic by us. On the other hand, patients having type 1 DM and complications had higher plasmatic Hcy concentration than those with no complications. CONCLUSIONS: We have found a relationship between high Hcy levels and prevalence of macroangiopathy, retinopathy and nephropathy in the type 1 diabetic patients, which was not been observed in the type 2 diabetic patients of our study. As a result, we consider plasmatic Hcy a complication-risk indicator in type 1 DM, and we recommend its use together with already established biochemical parameters in the control of the evolution of the disease.

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Objetivo: Testar a análise discriminante como um método de transformar a informaçäo obtida num inquérito de satisfaçäo dos usuários de rotina numa acurada ferramenta de tomada de decisäo. Métodos: Utilizou-se um questionário auto-aplicável com sete questöes de dez opçöes numa amostra dos pacientes atendidos em duas unidades ambulatórias públicas, em Valparaíso, Chile, sendo uma de cuidados primários (n=100) e a outra de atençäo secundária (n=249). Utilizaram-se dois pontos de corte na variável dependente (índice final de satisfaçäo): satisfeitos vs insatisfeitos e muito satisfeitos vs os demais. Os resultados foram comparados com medidas empíricas habitualmente utilizadas (proporçäo de satisfeitos, proporçäo de insatisfeitos e dimensäo da mediana). Resultados: O nivel de resposta foi muito elevado (sempre acima de 97,0 por cento). Uma variável adicional revelou-se (atendimento médico), explicando a satisfaçäo com o atendimento na unidade primária. Ao comparar satisfeitos com insatisfeitos, a proporçäo total da variabilidade explicada pelo modelo foi muito elevada (acima de 99.4 por cento) em ambas unidades. Ao comparar muito satisfeitos com os demais, observou-se uma relaçäo significativa apenas no caso da unidade primária. Explicou-se uma baixa proporçäo da variabilidade (41,9 por cento). Conclusöes: A análise discriminante revelou relaçöes näo percebidas pela análise empírica e indicou a proporçäo exata da variabilidade explicada pelo modelo utilizado. A técnica afastou como näo significativas relaçöes sugeridas pela análise empírica (por exemplo: muito satisfeitos vs os demais no caso da unidade secundária). A mesma permitiu medir a intensidade da contribuiçäo de cada variável na explicaçäo da variaçäo da satisfaçäo

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OBJECTIVE: To test discriminant analysis as a method of turning the information of a routine customer satisfaction survey (CSS) into a more accurate decision-making tool. METHODS: A 7-question, 10-multiple choice, self-applied questionnaire was used to study a sample of patients seen in two outpatient care units in Valparaíso, Chile, one of primary care (n=100) and the other of secondary care (n=249). Two cutting points were considered in the dependent variable (final satisfaction score): satisfied versus unsatisfied, and very satisfied versus all others. Results were compared with empirical measures (proportion of satisfied individuals, proportion of unsatisfied individuals and size of the median). RESULTS: The response rate was very high, over 97.0% in both units. A new variable, medical attention, was revealed, as explaining satisfaction at the primary care unit. The proportion of the total variability explained by the model was very high (over 99.4%) in both units, when comparing satisfied with unsatisfied customers. In the analysis of very satisfied versus all other customers, significant relationship was identified only in the case of the primary care unit, which explained a small proportion of the variability (41.9%). CONCLUSIONS: Discriminant analysis identified relationships not revealed by the previous analysis. It provided information about the proportion of the variability explained by the model. It identified non-significant relationships suggested by empirical analysis (e.g. the case of the relation very satisfied versus others in the secondary care unit). It measured the contribution of each independent variable to the explanation of the variation of the dependent one.

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BACKGROUND: There is little information about the real prevalence of hypertension in Chile. AIM: To assess the adjusted prevalence of hypertension and its main therapeutic measures among adults living in Valparaiso, Chile. MATERIALS AND METHODS: A random sample of dwellings in Valparaiso was chosen. Among these, an individual of 25 to 64 years old was randomly surveyed for risk factors for chronic diseases and sociodemographic parameters. Blood pressure, weight, height, oral glucose tolerance test, fasting cholesterol and triglycerides were also measured. Prevalence was pondered according to age, sex, and probability of selection in the dwelling interior. RESULTS: Three thousand one hundred twelve individuals were studied. The adjusted prevalence of hypertension was 11.4% (11.6% among females and 10.6% among men). The prevalence increased along with age from 3 and 1.9% in men and women of 25 to 34 years old respectively, to 18.2 and 27.4% among men and women of 55 to 64 years old (p < 0.01). People of low socioeconomic level had a higher prevalence of hypertension than those of high socioeconomic level (14.2 and 9.3% respectively, P < 0.05). Diabetes, obesity and hypercholesterolemia were significantly more frequent in subjects with hypertension than in the general population. Forty-four percent of diagnosed hypertensives were receiving medications (angiotensin converting enzyme inhibitors 40%, calcium antagonists 34%, beta blockers 22%). Twenty five percent of patients were treated with a combination of medications. Of those treated, only 22% had normal blood pressure levels at the moment of examination. CONCLUSIONS: High blood pressure is an important public health problem that requires more efficient detection and treatment programs.

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BACKGROUND: In the last decades, chronic non communicable diseases are becoming the main cause of disability and mortality among adults. The risk factor surveillance and management is the most efficient mean of reducing the impact of these diseases. AIM: To report the results of a non communicable disease risk factor surveillance program in Valparaiso, Chile. MATERIAL AND METHODS: A random samples of people aged 25 to 64 years old living in Valparaiso, Chile was studied. Subjects were questioned about smoking and physical activity habits. Blood pressure, height and weight were measured using standardized techniques at their homes and blood samples were obtained to measure serum lipid levels and oral glucose tolerance test at the nearest outpatient clinic. RESULTS: Of the initial 3852 homes selected, 752 individuals did no agree to answer the inquiry, therefore 3120 subjects were finally interviewed. Of these, 40.6% were smokers, 15% drank alcohol in two or more occasions per month, 84.6% were physically inactive, 19.7% had a body mass index over 30 kg/m2, 11.1% had high blood pressure, 3.9% were diabetic and 46.9% had high serum cholesterol levels. CONCLUSIONS: The basal survey for the CARMEN program shows a high prevalence of cardiovascular risk factors among Chileans.

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A psi[CH2NH] isoster bond was introduced by replacing one peptide bond at a time within the 1513 malaria peptide KEKMV motif to obtain a set of five pseudopeptides. The motif belongs to a Plasmodium falciparum malarial peptide coded 1513, derived from the MSP-1 protein. This high-binding motif included in the 1513 peptide is involved in the attachment of the malarial parasite to human erythrocytes. The novel malaria 1513 psi[CH2NH] surrogates were analyzed using RP-HPLC and MALDI-TOF mass spectrometry techniques. Nuclear magnetic resonance experiments allowed definition of the five pseudopeptide analogues' secondary structural features. Such structures are present in only a very few molecules in the 1513 parent peptide. A molecular model demonstrating the solution of the three-dimensional structure of the 1 513 peptide Pse-437 analogue was constructed on the basis of 1H-NMR spectral parameters. Monoclonal antibodies were generated to the five 1513 malaria peptide pseudopeptide analogues. These antibodies not only recognize the native MSP-1 (195 kDa) and its 83 kDa and 42 kDa proteolytic processing proteins but also different SPf(66)n malaria vaccine batches containing the native sequence. In addition, the mAbs were able to modify the kinetics of Plasmodium falciparum parasites' intraerythrocytic development and their ability to invade new RBCs. The presented evidence suggests that peptide bond-modified peptides could reproduce a transient state in 1513's native sequence and represent useful candidates in the development of a second generation of effective malarial vaccines.

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This paper reports the results of the first field study performed to assess the safety, immunogenicity and protectivity of the synthetic malaria vaccine SPf66 directed against the asexual blood stages of Plasmodium falciparum. Clinical and laboratory tests were performed on all volunteers prior to and after each immunization, demonstrating that no detectable alteration was induced by the immunization process. The vaccines were grouped as high, intermediate or low responders according to their antibody titres directed against the SPf66 molecule. Two of the 185 (1.08%) SPf66-vaccinated and nine of the 214 (4.20%) placebo-vaccinated volunteers developed P. falciparum malaria. The efficacy of the vaccine was calculated as 82.3% against P. falciparum and 60.6% against Plasmodium vivax.

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Two independent vaccination trials using a hybrid synthetic polypeptide containing epitopes from four proteins of Plasmodium falciparum were performed. In the first trial 63 and in the second 122 volunteers were vaccinated, using different immunization schedules. The analysis of the humoral response to the vaccine, measured by IgG antibody titres to the polypeptide showed a bimodal distribution in both cases suggesting genetic control of the immune response to this protein. There was a small group of low or non-responders and a large group of good responders. HLA phenotyping of the two groups disclosed an association of the low responders to HLA-DR4 antigens with chi-square P value of 0.00039 when compared with the good responders group. These findings provide evidence for the genetic control of the immune response to the synthetic vaccine by the association of this response with particular alleles of the HLA class II antigens; such findings may lead to an explanation of the mechanism involved in disease susceptibility and need to be used in the design of a totally effective vaccine.

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The calibers and microtubular content of axons were studied in normal and regenerating fibers of the sural nerve from 17 to 122 days after a lesion of the sciatic nerve of young adult rats. During this period (70-175 days of age), the cross-sectional area of control myelinated axons almost doubled but that of nonmedullated axons did not change. In regenerating nerves, after 122 days of recovery, the cross-sectional area of myelinated fibers was still 38% below that of the normal side. In contrast, the regenerating nonmedullated population was richer in fine (less than 0.2 micron2) and in coarse (greater than 0.9 micron2) fibers than on the control side; the cross-sectional area averages were 0.50 and 0.54-0.70 micron 2 for the normal and regenerating populations, respectively. The microtubular density of normal 3-micron myelinated fibers averaged 24.0 microtubules/micron2. In regenerating fibers of the same size the density varied between 19.2 and 23.2 microtubules/micron2. Microtubular density values of normal and regenerating fibers were not statistically different. In nonmedullated fibers, the microtubular content (expressed as microtubular density or number of microtubules per axon) correlated with the caliber of the fiber. In these correlations, only minor differences were observed between regenerating and uninjured fibers. Our results indicate that nonmedullated fibers terminate their radial growth well before myelinated fibers do, and that axonal microtubular content correlates with the local size of the fiber and is largely insensitive to regeneration.

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The density of microtubules in sympathetic postganglionic fibres of the cat was studied with the electron-microscope before and after administration of reserpine. The microtubule density was 56 microtubules per square micron under basal conditions. Six hours after reserpine administration, the density rose by 46%. This change was still present 55 h later. At least 31% of the total microtubular protein in the axoplasm of sympathetic fibres of the unrestrained cat was estimated to be in the soluble form. The increase in microtubule density was prevented by a section of the preganglionic fibres. Microtubules of the unmyelinated fibres of the cutaneous sural nerve were unaffected by reserpine treatment. Since reserpine is known to produce hyperactivity of sympathetic nerves, it is concluded that this hyperactivity is instrumental in the increase of the number of axonal microtubules. It is proposed that the electrical activity of nerves regulates axonal microtubules in the living animal.

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