Emerging Hyalomma lusitanicum: From identification to vectorial role and integrated control.

In the Mediterranean basin, the tick species Hyalomma lusitanicum Koch stands out among other species of the Hyalomma genus due to its wide distribution, and there is great concern about its potential role as a vector and/or reservoir and its continuous expansion to new areas because of climate warming and human and other animal movements. This review aims to consolidate all the information on H. lusitanicum, including taxonomy and evolution, morphological and molecular identification, life cycle, sampling methods, rearing under laboratory conditions, ecology, hosts, geographical distribution, seasonality, vector role and control methods. The availability of adequate data is extremely relevant to the development of appropriate control strategies in areas where this tick is currently distributed as well as in new areas where it could become established in the near future.

Decreased mortality among patients with catheter-related bloodstream infections at Catalan hospitals (2010-2019).

BACKGROUND: The incidence of catheter-related bloodstream infections (CRBSIs) has fallen over the last decade, especially in intensive care units (ICUs). AIM: To assess the existence of concomitant trends in outcomes and to analyse the current risk factors for mortality. METHODS: A multicentre retrospective cohort study was conducted at 24 Catalan hospitals participating in the Surveillance of healthcare-associated infections in Catalonia (VINCat). All hospital-acquired CRBSI episodes diagnosed from January 2010 to December 2019 were included. A common protocol including epidemiological, clinical, and microbiological data was prospectively completed. Mortality at 30 days after bacteraemia onset was analysed using the Cox regression model. FINDINGS: Over the study period, 4795 episodes of CRBSI were diagnosed. Among them, 75% were acquired in conventional wards and central venous catheters were the most frequently involved (61%). The 30-day mortality rate was 13.8%, presenting a significant downward trend over the study period: from 17.9% in 2010 to 10.6% in 2019 (hazard ratio (HR): 0.95; 95% confidence interval (CI): 0.92-0.98). The multivariate analysis identified age (HR: 1.03; 95% CI: 1.02-1.04), femoral catheter (1.78; 1.33-2.38), medical ward acquisition (2.07; 1.62-2.65), ICU acquisition (3.45; 2.7-4.41), S. aureus (1.59; 1.27-1.99) and Candida sp. (2.19; 1.64-2.94) as risk factors for mortality, whereas the mortality rate associated with episodes originating in peripheral catheters was significantly lower (0.69; 0.54-0.88). CONCLUSION: Mortality associated with CRBSI has fallen in recent years but remains high. Intervention programmes should focus especially on ICUs and medical wards, where incidence and mortality rates are highest.

Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene.

BACKGROUND: Alport syndrome is an inherited renal disorder characterized by glomerular basement membrane lesions with hematuria, proteinuria and frequent hearing defects and ocular abnormalities. The disease is associated with mutations in genes encoding α3, α4, or α5 chains of type IV collagen, namely COL4A3 and COL4A4 in chromosome 2 and COL4A5 in chromosome X. In contrast to the well-known X-linked and autosomal recessive phenotypes, there is very little information about the autosomal dominant. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. METHODS: We investigated a Spanish family with variable phenotype of autosomal dominant Alport syndrome using clinical, histological, and genetic analysis. RESULTS: Mutational analysis of COL4A3 and COL4A4 genes showed a novel heterozygous mutation (c. 998G > A; p.G333E) in exon 18 of the COL4A3 gene. Among relatives carrying the novel mutation, the clinical phenotype was variable. Two additional COL4A3 mutations were found, a Pro-Leu substitution in exon 48 (p.P1461L) and a Ser-Cys substitution in exon 49 (p.S1492C), non-pathogenics alone. CONCLUSION: Carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3 gene appear to be more severely affected than carriers of only p.G333E mutation, and the clinical findings has an earlier onset. In this way, we could speculate on a synergistic effect of compound heterozygosity that could explain the different phenotype observed in this family.

Biocidal effects of Piper hispidinervum (Piperaceae) essential oil and synergism among its main components.

In this study we evaluated the effect of a pressure gradient (1-2 atm) in the extraction and composition of the essential oil (EO) of Piper hispidinervum by steam distillation. We also evaluated the insect antifeedant effects (Spodoptera littoralis, Leptinotarsa decemlineata, Myzus persicae and Rhopalosiphum padi) and nematicidal activity (Meloidogyne javanica) of the oils, their major components and their synergistic interactions. Safrole was the major component (78-81%) followed by terpinolene (5-9%). The EOs tested were effective insect antifeedants. Safrole, explained most of the insect antifeedant action of P. hispidinervum EOs. When safrole and terpinolene were tested in binary combinations, low ratios of safrole improved the antifeedant effects of terpinolene. P. hispidinervum EOs caused higher mortality of M. javanica juveniles than their major components. In binary combinations, low ratios of terpinolene increased the nematicidal effects of safrole. The EO treatment strongly suppressed nematode egg hatching and juvenile infectivity. P. hispidinervum EOs affected the germination of S. lycopersicum and L. sativa mostly at 24 h of treatment, being L. sativa the most sensitive. Safrole moderately affected germination and root growth of L. sativa, S. lycopersicum and L. perenne. Terpinolene only affected S. lycopersicum root growth.

Relationship Between Vitamin D Blood Levels and Cancer Development in Renal Transplant Patients: A Case-Control Study.

BACKGROUND: Malignancy is one of the most common long-term complications in renal transplant patients, often related to immunosuppressive treatment although other factors could be considered. Vitamin D plays an important role in reducing cancer risk. After kidney transplantation (KT), 25-hydroxyvitamin D (25OH-D, or calcidiol) insufficiency concerns >85%. The main aim of the present study was to determine the relationship between calcidiol blood levels and cancer development in KT recipients. METHODS: This was a retrospective observational case-control study including patients who received transplants in our hospital from 2003 to 2009 with a follow-up period to 2015. A total of 738 patients were included; 94 of them developed malignancy process, 80 of whose tumor data were analyzed in the cancer group, and the rest composed the control group. At the moment of cancer presentation, age, sex, primary kidney disease, time after surgery, immunosuppressant schedule, and 25OH-D blood levels were collected. RESULTS: The mean patient age was 57 years. The percentages of man and women were 59.5% and 41.5%. The predominant etiology of kidney disease was chronic glomerulonephritis in 31.9%. There were no significant differences between sex, primary kidney disease, immunosuppressant schedule, or incidence of neoplasm in each group of patients. There were no significant differences in 25OH-D blood levels. The incidence of cancer was 7.1%-13.7% per year. The mean time between the graft surgery and the event was 5.6 years. CONCLUSIONS: In patients with functioning KT, we found no correlation between blood levels of calcidiol and the incidence of cancer.

Indole alkaloids from Geissospermum reticulatum.

Ten indole alkaloids were isolated from Geissospermum reticulatum, seven (1-7) from the leaves and three (8-10) from the bark. Seven were aspidospermatan-type alkaloids (1-3, 5-9), including four (5-8) with a 1-oxa-3-cyclopentene group in their molecule, which we named geissospermidine subtype. Compounds 1-3, 5-8, and 10 had not been reported previously as natural products, while 4 and 9 were the known alkaloids O-demethylaspidospermine and flavopereirine. Their structures were determined by spectroscopic techniques including 1D and 2D NMR experiments (COSY, NOESY, HSQC, HMBC). Additionally, X-ray crystallographic analyses of 1, 2, and 6 were performed. Antiparasitic activities of the ethanolic and alkaloidal extracts and of the pure alkaloids were tested against Trypanosoma cruzi and Leishmania infantum. In general, the extracts exhibited selective action and were more active against Leishmania than against Trypanosoma. Alkaloid 4 was also very active against L. infantum.

Diterpenoid alkaloids from Delphinium gracile.

Two highly oxygenated hetisine-type diterpenoid alkaloids, delphigraciline (1), 14-hydroxyhetisinone N-oxide (2), and the norditerpenoid alkaloid 8-methoxykarakoline (3), were isolated from a neutral extract of Delphinium gracile. Their structures were elucidated on the basis of spectroscopic data and by comparison with previously reported spectroscopic data of similar alkaloids. Their antiparasitic and insecticidal activities are also discussed.

Factores genéticos de riesgo microvascular y macrovascular en la diabetes mellitus

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Heliotropium huascoense resin exudate: chemical constituents and defensive properties.

From the resinous exudate of Heliotropium huascoense a new compound, rel-(8R,9R)-carrizaloic acid, (1) (3-[rel-(8R,9R-9-hydroxy-9,13,13-trimethyl-12-oxo-10-cyclohexenyl)methyl]-4-methoxybenzoic acid), and three known flavonoids, [3-methylgalangin, 3,7-dimethylgalangin, and (-)-alpinone] have been isolated. The structure of 1 was determined by spectral and chemical methods. Several plant defensive properties of 1 (insecticidal and antifungal) have been evaluated.

Minor diterpenes from Persea indica: their antifeedant activity.

The new diterpenes anhydrocinnzeylanone, garajonone and 2,3-didehydrocinnzeylanone, and the known anhydrocinnzeylanine, have been isolated from Persea indica. The antifeedant activity of these compounds has been evaluated showing the importance of the 11-hemiketal group for the antifeedant effects of ryanodane diterpenes.

Defensive chemistry of Senecio miser.

Three eremophilanolides, 1alpha-acetoxy-8beta-methoxy-10betaH-eremophil-7(11)-en-8alpha,12-olide (1); 1alpha-angeloyloxy-6beta-hydroxy-8beta-methoxy-10betaH-eremophil-7(11)-en-8alpha,12-olide (2); and 1alpha-angeloyloxy-8betaH,10betaH-eremophil-7(11)-en-8alpha,12-olide (3), and two pyrrolizidine alkaloids, integerrimine (4) and its N-oxide (5), were isolated from bioactive fractions of Senecio miser. The structures of the new compounds 1 and 2 were established by NMR spectroscopic analysis and chemical transformation. The X-ray analysis of compound 1 was also performed. Eremophilanolides 1 and 2 and alkaloids 4 and 5 were found to be strong insect antifeedants, further supporting a proposed defensive role for these classes of compounds.

Structure- and species-dependent insecticidal effects of neo-clerodane diterpenes.

Several natural neo-clerodane diterpenoids isolated from Linaria saxatilis and some semisynthetic derivatives were tested against several insect species with different feeding adaptations. The antifeedant tests showed that the oliphagous Leptinotarsa decemlineata was the most sensitive insect, followed by the aphid Myzus persicae. The polyphagous Spodoptera littoralis was not deterred by these diterpenoids; however, following oral administration, some of these compounds did have postingestive antifeedant effects on this insect. In general terms, the antifeedant effects of these compounds were species-dependent and more selective than their toxic/postingestive effects. The study of their structure-activity relationships showed that both the decalin moiety and the chain at C-9 determined their bioactivity. Furthermore, the presence of a 4,18-epoxy/diol moiety was an important feature for both the antifeedant and the toxic/postingestive effects.

Insecticidal and mutagenic evaluation of two annonaceous acetogenins.

Annonaceous acetogenins represent a new class of bioactive compounds whose primary mode of action is the inhibition of NADH-ubiquinone oxidoreductase. Given the potential pesticidal use of such a class of compounds, we have further evaluated the antifeedant and insecticidal effects of squamocin and annonacin, two annonaceous acetogenins, on Spodoptera littoralis, Leptinotarsa decemlineata, and Myzus persicae. Additionally, to partially assess their environmental risk, we have also tested their mutagenicity in Salmonella typhimurium strains TA98, TA100, and TA102 in the presence and absence of a metabolic activation system. Among the test compounds, annonacin showed antifeedant effects on L. decemlineata, while squamocin was toxic to L. decemlineata and M. persicae. Neither acetogenin was mutagenic, although both were toxic in the absence of a metabolic activation system. We compared these results with those obtained with rotenone, a well-known respiratory inhibitor that was highly toxic to L. decemlineata and M. persicae and showed no mutagenicity/toxicity in the S. typhimurium strains tested up to a concentration of 1000 microg per plate.

Selective insect antifeedant and toxic action of ryanoid diterpenes.

In this work, we have studied the antifeedant and insecticidal effects of several natural ryanoid diterpenes. These compounds can be classified in two groups according to their chemical structures: ryanodol/isoryanodol-type (nonalkaloidal type) and ryanodine-type (alkaloidal type) ryanoids. The nonalkaloidal ryanoids were isolated from Persea indica (Lauraceae) while the alkaloidal ryanoids (ryanodines and spiganthines) were isolated from Spigelia anthelmia (Loganiaceae). The effects of these compounds on the feeding behavior and performance (with and without piperonyl butoxide pretreatment) of Spodoptera littoralis larvae and Leptinotarsa decemlineata adults indicate that some strongly deterred these insects, L. decemlineata being less sensitive than S. littoralis. Their antifeedant effects did not parallel their toxic action. Additionally, more than 60% of the nonalkaloidal ryanoids were antifeedants and/or toxic in contrast to 30% of active alkaloidal ones, supporting the hypothesis of a ryanodol-specific mode of action in insects.

Development of a new bioluminescent mutagenicity assay based on the Ames test.

A newly developed rapid mutagenicity assay based on the adenosine triphosphate (ATP)-bioluminescence technique and the Ames test is described. Salmonella typhimurium strains TA98 and TA100 were exposed in an appropriate liquid medium to the direct mutagens 4-nitroquinoline-N-oxide and methyl methanesulphonate, respectively, and to the indirect mutagen 2-aminoanthracene. Both auxotrophic and prototrophic growth were monitored throughout the incubation period as variations in the intracellular ATP levels by means of the luciferin-luciferase assay. After 9-12 h of incubation a dose-response increase in the levels of ATP was readily detected. In order to demonstrate that this increase was due to the growth of revertant bacteria, aliquots from each culture were plated on minimal agar plates. A very good correlation between the changes in ATP levels and the appearance of revertant colonies on the plates was found. Given the rapidity of this method as compared with conventional mutagenicity assays, it has potential for industrial and environmental applications. Other potential applications are also discussed.

Identification of a human homolog of the Drosophila rotated abdomen gene (POMT1) encoding a putative protein O-mannosyl-transferase, and assignment to human chromosome 9q34.1.

We have isolated a human gene homologous to Drosophila melanogaster rotated abdomen, rt, a poorly viable recessive mutation causing a clockwise twisted abdomen in affected flies due to defects in embryonic muscle development. The human gene, like rt, encodes a protein with high homology to the yeast mannosyl-transferases (Pmts) and has been named POMT1. POMT1 is expressed as a 3.1-kb transcript in all tissues tested, with highest levels in testis and fetal brain. Alternative splicing of several exons in all tissues predicts the generation of several protein isoforms. The most common mRNA variant encodes a 725-aa protein with 40% identity and 62.5% similarity to rt, as well as 30.5% identity and 54% similarity to yeast Pmts. Computer prediction of protein sorting suggests that the POMT1 product could be an integral protein of the endoplasmic reticulum membrane. Given the strong conservation of protein motifs between POMT1 and the yeast Pmts, POMT1 may function as a mannosyl-transferase involved in O-mannosylation of proteins, being the first of such a class found in mammals. The POMT1 locus has been assigned to human chromosome 9q34.1 by somatic cell hybrids, radiation hybrids, and linkage analysis. On the basis of the rt phenotype, POMT1 could be a candidate for uncharacterized genetic disorders of the muscular system, such as some forms of congenital muscular dystrophy or congenital myopathy.

The human RC3 gene homolog, NRGN contains a thyroid hormone-responsive element located in the first intron.

NRGN is the human homolog of the neuron-specific rat RC3/neurogranin gene. This gene encodes a postsynaptic 78-amino acid protein kinase substrate that binds calmodulin in the absence of calcium, and that has been implicated in dendritic spine formation and synaptic plasticity. In the rat brain RC3 is under thyroid hormone control in specific neuronal subsets in both developing and adult animals. To evaluate whether the human gene is also a target of thyroid hormone we have searched for T3-responsive elements in NRGN cloned genomic fragments spanning the whole gene. Labeled DNA fragments were incubated with T3 receptors (T3R) and 9-cis-retinoic acid receptors and immunoprecipitated using an anti T3R antibody. A receptor-binding site was localized in the first intron, 3000 bp downstream from the origin of transcription. Footprinting analysis revealed the sequence GGATTAAATGAGGTAA, closely related to the consensus T3-responsive element of the direct repeat (DR4) type. This sequence binds the T3R-9-cis-retinoic acid receptors heterodimers, but not T3R monomers or homodimers, and is able to confer regulation by T3R and T3 when fused upstream of the NRGN or thymidine kinase promoters. The data reported in this work suggest that NRGN is a direct target of thyroid hormone in human brain, and that control of expression of this gene could underlay many of the consequences ofhypothyroidism on mental states during development as well as in adult subjects.

Identification of a cis-acting element that interferes with thyroid hormone induction of the neurogranin (NRGN) gene.

The neuron-specific RC3/neurogranin gene is regulated by thyroid hormone at the transcriptional level in brain and in cultured neuronal cells. Regulation in vivo displays exquisite regional selectivity which is not due to differential distribution of thyroid receptors and is most probably related to region-specific trans-acting elements. We have previously identified an intronic thyroid hormone responsive element in the human RC3 gene homolog, NRGN. In a search for cis-acting elements that might contribute to the specificity of thyroid regulation, we have identified a novel sequence, TTCCAAAATGG, which binds to a developmentally regulated protein, and interferes with T3 transactivation.

Pyrrolizidine alkaloids from Heliotropium megalanthum.

Two pyrrolizidine alkaloids, megalanthonine (1) and lycopsamine (2), have been isolated from Heliotropium megalanthum. The structure of the novel compound 1 was determined by spectroscopic methods. The insecticidal, antifeedant, and antifungal effects of compounds 1 and 2 have been evaluated.