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Variations in colouration patterns have been reported in numerous wildlife species, particularly birds. However, the increased use of camera traps for wildlife monitoring has enabled the detection of elusive species and phenotypic variations that might otherwise go undetected. Here, we compiled records of unusual colouration patterns in terrestrial mammals, documented through camera-trap studies over a 12-year period in the Llanganates-Sangay Connectivity Corridor, in the Tropical Andes of Ecuador. We identified colour variations in seven species of terrestrial mammals, including disorders, such as melanism, white spotting/ piebaldism, xanthocromism and progressive greying. Notably, we reported a high prevalence of melanism in wild populations of the clouded oncilla, along with observations on the species' activity patterns. Approximately half of the recorded clouded oncillas were melanistic. We detected significant differences in activty patterns between melanistic and non-melanistc clouded oncilla, with melanistic morphs showing a peak of activity between 3 a.m. and before dawn. The proportion of melanistic individuals suggests that melanism is widespread throughout the corridor. However, its impact on the species' fitness remains unclear., Competing Interests: No conflict of interest to declare Disclaimer: This article is (co-)authored by any of the Editors-in-Chief, Managing Editors or their deputies in this journal., (Elias Viteri-Basso, Juan Pablo Reyes Puig, Carolina Reyes-Puig, Gorky Ríos-Alvear.)

In Spain, 33% of adults aged 30 to 79 years (10 million) were hypertensive in 2019. Among them, 68% were diagnosed, 57% received drug therapy, and effective therapeutic coverage (control) reached 33%. Both diagnosis and control show geographical and social disparities. Approximately 46 000 cardiovascular deaths per year are attributable to hypertension. In recent decades, the control of hypertension has increased, due to improvements in lifestyle measures and increased use of polytherapy, coinciding with a reduction in stroke mortality. There are several modifiable determinants of the lack of hypertension control: a) white-coat phenomenon affects 22% to 33% of treated individuals, partly due to the limited availability of ambulatory blood pressure monitoring (ABPM) (49%) and self-measured BP (SMBP) (78%); b) inadequate patient adherence to medication and healthy lifestyles (weight loss, the most effective measure, is the least used, ≈40%); and c) insufficient use of polytherapy (≈55%). The remaining challenges include: a) technological aspects, such as measuring BP with more accurate techniques (ABPM, SMBP) and using cardiovascular-risk estimation tools (eg, SCORE); b) clinical challenges, such as reducing therapeutic inertia (≈59%), involving patients in their own management (medication adherence, ≈62%) and effectively implementing clinical guidelines); and c) public health challenges, such as reducing the burden of obesity (≈24%), monitoring progress with updated surveys, and setting national BP control targets., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Centrolenidae is a Neotropical family widely distributed in Central and South America, with its species richness concentrated in the tropical Andes. Several taxonomic problems have been identified within this family, mostly related to species with broad geographic distributions. In this study, we assessed and redefined the species boundaries of the Centrolene buckleyi species complex, and formally described two new species from the Andes of Ecuador. These new taxa are recognized by a combination of morphometric, osteological, acoustic, and genetic data. Following IUCN criteria, we propose that the two new species should to be considered as Endangered (EN), mainly because of their small distributions and habitat loss. The C. buckleyi complex provides insights into the biogeography of closely related Andean species. As in other glassfrogs, speciation in Centrolene seems to be mediated by the linearity of the Andes, where gene flow can be restricted by topography and, also, local extinctions., Competing Interests: The authors declare that they have no competing interests., (© 2024 Franco-Mena et al.)

The explosive diversity of rainfrogs ( Pristimantis spp) reaches its highest levels in the mountains of the Tropical Andes, with remarkable cryptic species mainly in unexplored areas of Ecuador. Based on phylogenetics, morphometric traits, skull osteology and bioacoustics, we describe two new species of Pristimantis , previously confused with Pristimantisgladiator , that belong to the subgenus Trachyphrynus traditionally known as the Pristimantismyersi species group. The two new taxa are closely related, but have allopatric distributions. We discuss the importance of the Quijos and Pastaza River valleys in the diversification along Amazonian slopes of the Ecuadorian Andes., Competing Interests: The authors have declared that no competing interests exist., (Juan Pablo Reyes-Puig, Miguel Urgilés-Merchán, Daniela Franco-Mena, Juan M. Guayasamin, Diego Batallas, Carolina Reyes-Puig.)

Habitat disturbance leads to biodiversity decline and modifications in the landscape structure and composition, affecting both dispersal movements and ecological processes at different temporal and spatial scales. The Ecuadorian Tropical Andes harbour suitable habitats for the distribution of a wide variety of species; however, there is a lack of studies focused on mammal diversity and its association with the habitat attributes in the central-eastern slopes. Here, we reported the diversity of terrestrial mammals recorded between 2019 and 2021 in a camera-trap monitoring study in the Candelaria and Machay reserves in the upper basin of the Pastaza River, Ecuador. We performed site-occupancy probability analysis to assess the influence of spatial variables in the species' occurrence and also, based on natural marks, we reported preliminary findings in Andean bear individual identification. We detected 22 species of terrestrial mammals. Alpha diversity was similar between reserves with slightly higher species richness in Machay. Evenness indices showed unequal species distribution, with the Andean bear and domestic dogs exhibiting greater dominance. In addition, species composition was dissimilar between reserves, where the species turnover mostly explained the beta diversity. We observed that Andean bear and puma detections increased according to the natural vegetation cover. Conversely, domestic dogs were frequently detected in cells with an increasing proportion of pastures and crops. Additionally, we identified 26 Andean bears and six individuals recaptured during our study. Our results caution about the disturbance derived from human activities since we recorded unprecedented detections of domestic dogs in wild habitats. Nonetheless, it highlights the importance of private conservation areas (e.g. Candelaria, Machay and others) for supporting the occurrence and dispersal of terrestrial mammal species between larger areas in the upper basin of the Pastaza River., (Juan Pablo Reyes-Puig, Carolina Reyes-Puig, Jessica Pacheco-Esquivel, Santiago Recalde, Fausto Recalde, Darwin Recalde, Jordy Salazar, Eduardo Peña, Silvia Paredes, Marina Robalino, Fernanda Flores, Vladimir Paredes, Edelina Sailema, Gorky Ríos-Alvear.)

We have discovered a spectacular new species of frog in the genus Hyloscirtus , belonging to the H. larinopygion species group. The adult female is characterized by a mostly black body with large bright red spots on the dorsal and ventral surface, extremities, and toe pads. The adult male is unknown. Small juveniles are characterized by a yellow body with variable black markings on the flanks; while one larger juvenile displayed irregular orange or yellow marks on a black background color, with light orange or yellow toe pads. Additional distinctive external morphological features such as cloacal ornamentation are described, and some osteological details are imaged and analyzed. The performed phylogeny places the new species as the sister to a clade consisting of ten taxa, all of which are part of the H. larinopygion group. We use genetic distances to fit the new species into a published time-calibrated phylogeny of this group; our analysis based on the published chronology suggests that the divergence of the new species from its known congeners pre-dates the Quaternary period. The new species is currently only known only from Cerro Mayordomo, in Fundación EcoMinga´s Machay Reserve, at 2,900 m in the eastern Andes of Tungurahua province, Ecuador, near the southern edge of Los Llanganates National Park, but its real distribution may be larger., Competing Interests: The authors declare that they have no competing interests., (© 2022 Reyes-Puig et al.)

The control of the pandemic caused by SARS-CoV-2 is a challenge for governments all around the globe. To manage this situation, countries have adopted a bundle of measures, including restrictions to population mobility. As a consequence, drivers face with the problem of obtaining fast routes to reach their destinations. In this context, some recent works combine Intelligent Transportation Systems (ITS) with big data processing technologies taking the traffic information into account. However, there are no proposals able to gather the COVID-19 health information, assist in the decision-making process, and compute fast routes in an all-in-one solution. In this paper, we propose a Pandemic Intelligent Transportation System (PITS) based on Complex Event Processing (CEP), Fuzzy Logic (FL) and Colored Petri Nets (CPN). CEP is used to process the COVID-19 health indicators and FL to provide recommendations about city areas that should not be crossed. CPNs are then used to create map models of health areas with the mobility restriction information and obtain fast routes for drivers to reach their destinations. The application of PITS to Madrid region (Spain) demonstrates that this system provides support for authorities in the decision-making process about mobility restrictions and obtain fast routes for drivers. PITS is a versatile proposal which can easily be adapted to other scenarios in order to tackle different emergency situations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Lesch-Nyhan disease (LND) is a disease of purine metabolism linked to chromosome X due to the absence or near-absence of enzyme hypoxanthine-guanine phosphoribosyltransferase. Patients with LND have a compulsive autoaggressive behavior that consists of self-mutilation by biting., Methods: The objective of this study was to explore the safety and efficacy of botulinum toxin (BoNT) injected into the masticatory muscles and biceps brachii to reduce self-mutilation in patients with LND. We retrospectively analyzed six patients with LND who were treated with BoNT to prevent automutilatory behavior., Results: The patient ages when started on treatment with BoNT were 4, 4.5, 6.6, 7.9, 13.9, and 32.3 years. Patients received a mean number of injections of 20, ranging from 3 to 29, over a period that ranged from 1.5 to 7.1 years. The maximum total dose of Botox was 21.3 units/kg mean and the maximum total dose of Dysport was 37.5 units/kg mean. A total of 119 injections were performed. Of these 113 (95%) were partially or completely effective. Only three of 119 injections (2.5%) produced adverse effects., Conclusions: Botulinum toxin is useful and safe for the treatment of self-biting behavior in patients with LND., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We present the results of herpetological surveys in two adjacent mountains where the EcoMinga Foundation protects the cloud forest in the Upper Rio Pastaza watershed, in the Llanganates Sangay Ecological Corridor in Ecuador. A rapid assessment of the amphibian communities of the study sites reveals a diverse and heterogeneous composition, dominated by terrestrial frogs from the genus Pristimantis . We also identify a cryptic diversity with a significant number of candidate new species. We describe two new species of terrestrial frogs of the genus Pristimantis . Pristimantismaryanneae sp. nov. is characterised by not having tympanum externally visible and having 2-3 subconical tubercles in the upper eyelid; and Pristimantisburtoniorum sp. nov. is characterised by the presence of red colouration in hidden surfaces of the hind-limbs, tubercles on the upper eyelid, interorbital tubercle and a row of rounded tubercles along the snout to the tip and a pale red venter with dark brown mottled pattern. Our samples from the two Reserves do not share species between them, so the proportion of shared species seems to be relatively low. In addition, we highlight the importance of updating the knowledge of amphibians that are restricted to this important conservation region and comment about the threats and composition of the amphibian communities on the eastern slopes of the Upper Rio Pastaza watershed., (Juan Pablo Reyes-Puig, Carolina Reyes-Puig, Daniela Franco-Mena, Lou Jost, Mario H. Yánez-Muñoz.)

We describe a new species of Neotropical spiny-lizard of the genus Echinosaura from the Imbabura and Carchi Provinces on the western slopes of the Andes in northwestern Ecuador. The new species mostly resembles E. horrida . However, it can be distinguished from all congeners by having keeled enlarged dorsal scales forming a paired vertebral row, two paravertebral series of short oblique rows of projecting scales, and a pair of spine-like scales on temporal and nuchal regions. We also provide a detailed description of the osteology of the skull and pectoral girdle of the new species and present a phylogenetic hypothesis for Echinosaura based on three mitochondrial genes (12S, 16S, ND4) and one nuclear gene (c-mos)., Competing Interests: The authors declare there are no competing interests., (©2021 Yánez-Muñoz et al.)

The Internet of Things (IoT) paradigm keeps growing, and many different IoT devices, such as smartphones and smart appliances, are extensively used in smart industries and smart cities. The benefits of this paradigm are obvious, but these IoT environments have brought with them new challenges, such as detecting and combating cybersecurity attacks against cyber-physical systems. This paper addresses the real-time detection of security attacks in these IoT systems through the combined used of Machine Learning (ML) techniques and Complex Event Processing (CEP). In this regard, in the past we proposed an intelligent architecture that integrates ML with CEP, and which permits the definition of event patterns for the real-time detection of not only specific IoT security attacks, but also novel attacks that have not previously been defined. Our current concern, and the main objective of this paper, is to ensure that the architecture is not necessarily linked to specific vendor technologies and that it can be implemented with other vendor technologies while maintaining its correct functionality. We also set out to evaluate and compare the performance and benefits of alternative implementations. This is why the proposed architecture has been implemented by using technologies from different vendors: firstly, the Mule Enterprise Service Bus (ESB) together with the Esper CEP engine; and secondly, the WSO2 ESB with the Siddhi CEP engine. Both implementations have been tested in terms of performance and stress, and they are compared and discussed in this paper. The results obtained demonstrate that both implementations are suitable and effective, but also that there are notable differences between them: the Mule-based architecture is faster when the architecture makes use of two message broker topics and compares different types of events, while the WSO2-based one is faster when there is a single topic and one event type, and the system has a heavy workload., Competing Interests: The authors declare that they have no competing interests., (© 2021 Roldán-Gómez et al.)

Cell-free gene expression systems have emerged as a promising platform for field-deployed biosensing and diagnostics. When combined with programmable toehold switch-based RNA sensors, these systems can be used to detect arbitrary RNAs and freeze-dried for room temperature transport to the point-of-need. These sensors, however, have been mainly implemented using reconstituted PURE cell-free protein expression systems that are difficult to source in the Global South due to their high commercial cost and cold-chain shipping requirements. Based on preliminary demonstrations of toehold sensors working on lysates, we describe the fast prototyping of RNA toehold switch-based sensors that can be produced locally and reduce the cost of sensors by two orders of magnitude. We demonstrate that these in-house cell lysates provide sensor performance comparable to commercial PURE cell-free systems. We further optimize these lysates with a CRISPRi strategy to enhance the stability of linear DNAs by knocking-down genes responsible for linear DNA degradation. This enables the direct use of PCR products for fast screening of new designs. As a proof-of-concept, we develop novel toehold sensors for the plant pathogen Potato Virus Y (PVY), which dramatically reduces the yield of this important staple crop. The local implementation of low-cost cell-free toehold sensors could enable biosensing capacity at the regional level and lead to more decentralized models for global surveillance of infectious disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Arce, Guzman Chavez, Gandini, Puig, Matute, Haseloff, Dalchau, Molloy, Pardee and Federici.)

We provide several lines of evidence to delimit a new species of Hyloscirtus and define its phylogenetic position inside the Hyloscirtus bogotensis group. The new species is the sister taxon to Hyloscirtus mashpi and is related to a clade formed by H. alytolylax and a putative new species from the province of El Oro in, southwestern Ecuador. Hyloscirtus conscientia sp. nov. is described from the montane forests of the Mira River basin in the extreme northwestern Ecuador. The new species is characterized as follows: tympanic annulus conspicuous, tip of snout in dorsal view subacuminate, middorsal stripe formed by melanophores larger and less dense, dorsal skin with individual iridophores forming dots, scarcely distributed across dorsum. Our study also highlights the importance of the Mira River Valley as a biogeographic barrier; suggesting research efforts north and south of the valley are likely to reveal additional endemic cryptic diversity. Finally, our partnership with Reserva: The Youth Land Trust, Rainforest Trust and EcoMinga Foundation has produced a novel and meaningful way to connect young people with biodiversity discovery and habitat conservation., Competing Interests: The authors declare they do not have any competing interests., (© 2021 Yánez-Muñoz et al.)

Ecuador is one of the most biodiverse countries in the world, but faces severe pressures and threats to its natural ecosystems. Numerous species have declined and require to be objectively evaluated and quantified, as a step towards the development of conservation strategies. Herein, we present an updated National Red List Assessment for amphibian species of Ecuador, with one of the most detailed and complete coverages for any Ecuadorian taxonomic group to date. Based on standardized methodologies that integrate taxonomic work, spatial analyses, and ecological niche modeling, we assessed the extinction risk and identified the main threats for all Ecuadorian native amphibians (635 species), using the IUCN Red List Categories and Criteria. Our evaluation reveals that 57% (363 species) are categorized as Threatened, 12% (78 species) as Near Threatened, 4% (26 species) as Data Deficient, and 27% (168 species) as Least Concern. Our assessment almost doubles the number of threatened species in comparison with previous evaluations. In addition to habitat loss, the expansion of the agricultural/cattle raising frontier and other anthropogenic threats (roads, human settlements, and mining/oil activities) amplify the incidence of other pressures as relevant predictors of ecological integrity. Potential synergic effects with climate change and emergent diseases (apparently responsible for the sudden declines), had particular importance amongst the threats sustained by Ecuadorian amphibians. Most threatened species are distributed in montane forests and paramo habitats of the Andes, with nearly 10% of them occurring outside the National System of Protected Areas of the Ecuadorian government. Based on our results, we recommend the following actions: (i) An increase of the National System of Protected Areas to include threatened species. (ii) Supporting the ex/in-situ conservation programs to protect species considered like Critically Endangered and Endangered. (iii) Focalizing research efforts towards the description of new species, as well as species currently categorized as Data Deficient (DD) that may turn out to be threatened. The implementation of the described actions is challenging, but urgent, given the current conservation crisis faced by amphibians., Competing Interests: The authors have declared that no competing interests exist.

We describe a new species of terrestrial frog of the genus Noblella from the eastern versants of the Ecuadorian Andes in the upper Pastaza watershed. Noblella naturetrekii sp. n. differs from its Ecuadorian congeners by the presence of a differentiated tympanic membrane and a weakly defined tympanic annulus, and eyelids with rounded tubercles. In addition, the new species is characterized by its blackish-dark brown ventral coloration scattered with little white dots and the absence of papillae at the tip of the fingers and toes. We provide a detailed description of the call and osteology of the new species. Finally, we present the most complete phylogeny of the genus, which confirms that Noblella is a non-monophyletic group., Competing Interests: Juan Pablo Reyes-Puig and Fausto Recalde are employed by the non-profit organization Fundación EcoMinga; José Vieira is employed by Tropical Herping.

United States and European guidelines have recommended new treatment goals for office blood pressure (BP). We examined 9784 hypertensives of the Spanish Ambulatory BP Monitoring (ABPM) registry with office BP treated to the prior goal (<140/90 mm Hg); and evaluated the frequency and all-cause mortality of 4 BP strata depending on whether or not they attained more conservative or new office BP goal (130-139/80-89 and <130/80 mm Hg, respectively) and whether or not BP was controlled according to ABPM criteria in the European and US guidelines (24-hour ambulatory BP <130/80 and <125/75 mm Hg, respectively). Whether achieving or not the new office BP goal, the total-mortality risk during a 5-year follow-up was only significantly higher than the reference (normal office BP and ABPM) when 24-hour ambulatory BP was above goal (hazard ratio from multivariable Cox models was in the range of 2.4-2.9; P<0.001). The frequency of patients achieving the new office BP goal was 34.4%, and the frequencies of those not achieving the ABPM goal were 31.6% and 53.7% using the 130/80 or the 125/75 ABPM goal, respectively. Mean office systolic BP was 129 mm Hg for patients not achieving the ABPM goal. In hypertensive patients controlled under prior office BP goal, the frequency of those achieving new office BP goal <130/80 was high, suggesting this goal can be attained. In addition, patients had a higher mortality risk only when ABPM was above goal despite having mean office systolic BP under control, a condition that was also common.

We describe a new species of Pristimantis from the montane forest of the Río Zuñag Ecological Reserve, upper basin of the Pastaza River, Ecuador. Pristimantismallii sp. n. is characterized by a snout-vent length of 11.6-21.3 mm in adult males ( n = 12), 22.6-34.3 mm in adult females ( n = 8), and is compared morphologically and genetically with Pristimantismiktos and with other relevant species of Pristimantis . The new species is characterized by having skin on dorsum and flanks shagreen, distinctive scapular folds, snout broadly rounded in dorsal view, upper eyelid bearing one or two subconical tubercles and some rounded tubercles, dorsum and flanks light brown to brown, with irregular dark brown marks bounded by dirty cream and groin with irregular yellowish marks.

Purpose: Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was  to describe macrocytic erythrocytes as another common aspect of the phenotype., Methods: The results of 257 complete blood counts from 65 patients over a 23-year period were collected from 2 reference centers where many patients are seen regularly., Results: Macrocytic erythrocytes occurred in 81-92% of subjects with Lesch-Nyhan disease or its neurological variants. After excluding cases with iron deficiency because it might pseudonormalize erythrocyte volumes, macrocytosis occurred in 97% of subjects. Macrocytic erythrocytes were sometimes accompanied by mild anemia, and rarely by severe anemia., Conclusion: These results establish macrocytic erythrocytes as a very common aspect of the clinical phenotype of Lesch-Nyhan disease and its neurological variants. Macrocytosis is so characteristic that its absence should prompt suspicion of a secondary process, such as iron deficiency. Because macrocytosis is uncommon in unaffected children, it can also be used as a clue for early diagnosis in children with neurodevelopmental delay. Better recognition of this characteristic feature of the disorder will also help to prevent unnecessary diagnostic testing and unnecessary attempts to treat it with folate or B12 supplements.

A new species of Anolis lizard from the Andean slopes of southwestern Colombia and northwestern Ecuador, from between 1187 and 2353 m in elevation, is described. The new species can be distinguished from other Anolis in squamation, cranial osteology, hemipenial morphology, and nuclear and mitochondrial DNA. The new species is sister to Anolisaequatorialis , and it is suggested that previous records of A.aequatorialis in Colombia correspond to the new species described herein.

Bakground and Objective: To compare the efficacy of two strategies of blood pressure (BP) measurement-based follow-up in hypertension and albuminuria control., Patients and Methods: Multicentre, prospective, randomised, open trial with a parallel-group design. Nineteen primary care centres and a hospital clinic participated. Adult type 2 diabetics with systolic BP ≥140mmHg without relevant renal disease were randomised to one of two follow-up strategies: 1) standard follow up, with a clinic BP target <140/90mmHg and 2) self-monitoring home BP (SMHBP)-based follow up, with a BP target <135/85mmHg. Biochemical standard blood variables, albuminuria, and 24-h ambulatory BP monitoring were performed at entry, 12 and 24 months. The main outcome measurement was 24-h ambulatory systolic BP variation. Albuminuria change was analysed as a secondary outcome., Results: 116 patients were analysed (mean age: 66.8 years). Mean systolic ambulatory 24- h BP change in two years was 3.9mmHg (95% CI 1.8-6.1). We did not find significant differences between both groups (p=0.706). Similarly, no differences were found when we compared other ambulatory BP values. Initial albuminuria was similar in both groups and did not significantly changed throughout the follow-up period., Conclusion: In type 2 diabetics without relevant nephropathy a SMHBP- based follow up was equivalent to a standard clinic-based BP follow up in BP and albuminuria control., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

Background: Patients with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity present hyperuricemia and/or hyperuricosuria, with a variable degree of neurological manifestations. Hyperuricemia in HPRT deficiency is due to uric acid overproduction and is frequently treated with allopurinol. Renal uric acid excretion is sharply increased in these patients. In recent years, several renal tubular urate transporter single nucleotide polymorphisms (SNPs), including those of the GLUT9, ABCG2 and URAT1 genes, have been described that influence the renal handling of uric acid and modulate serum urate levels. In the present study, we analyzed whether GLUT9, ABCG2 and URAT1 gene SNPs are able to influence uric acid levels and allopurinol response in patients with HPRT deficiency., Methods: Three SNPs, URAT1 rs11231825, GLUT9 rs16890979 and ABCG2 rs2231142, previously associated in our population with hyperuricemia and gout, were analyzed in 27 patients with HPRT deficiency treated with allopurinol for at least 5 years., Results: Patients with HPRT deficiency having allele A of rs16890979 in the GLUT9 gene present with a lower serum urate concentration at diagnosis, before allopurinol treatment is instituted, and need lower allopurinol doses to maintain serum urate levels between 268 and 446 μmol/L (4.5 and 7.5 mg/dL). No relationship between rs2231142 in the ABCG2 gene or rs11231825 in the URAT1 gene and serum urate levels or allopurinol response was found in our patients with HPRT deficiency., Conclusions: GLUT9 SNPs influence the renal handling of uric acid and modulate serum urate levels and the response to treatment in patients with uric acid overproduction due to HPRT deficiency., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: To explore whether the increase in the intima-media thickness (IMT) in arteriosclerotic disease correlates with the increase in the IMT in temporal arteries (TAs) and if that could mimic the US GCA halo sign., Methods: Consecutive patients ⩾50 years old with high vascular risk and without signs or symptoms of GCA were included. The carotid US IMT measurements were obtained using a standardized software radiofrequency-tracking technology. Colour Doppler US and grey-scale measurements of the IMT in the branches of both TAs were performed by a second sonographer using a 22 MHz probe., Results: Forty patients were studied (28 men) with a mean age of 70.6 years. The carotid IMT exhibited significant correlation with the TA IMT. A carotid IMT >0.9 mm was associated with a temporal IMT >0.3 mm. Only one patient had an IMT >0.34 mm in two branches., Conclusions: Atherosclerotic disease with a carotid IMT >0.9 mm increases the TA IMT and might mimic the halo sign. As atherosclerosis is common in this age group, we propose a cut-off of TA IMT >0.34 mm in at least two branches to minimize false positives in a GCA diagnosis., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

The neurological manifestations of Lesch-Nyhan disease (LND) have been attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on nervous system development. An increase has been reported in the levels of 5-aminoimidazole-4-carboxamide-1-β-D-ribotide (AICAR) and its triphosphate form ZTP in the red blood cells of patients with LND. AICAR accumulation in the brain has been hypothesized as the cause of some of the neurological symptoms of patients with LND. In this study, we examined the effect of AICAR on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells were differentiated along neuroectodermal lineages after exposure to 10-µM retinoic acid (RA), with or without the addition of 25-µM AICAR to the culture medium. The effect of AICAR on RA differentiation were examined through changes in the expression of genes essential to neuronal differentiation, as well as genes from the Wnt/β-catenin, transforming growth factor beta (TGFβ) and sonic hedgehog (SHH) pathways. Results: RA-induced differentiation in the NT2/D1 cells significantly increased the expression of MAP2, NRG1, NRP1, NRP2, NEUROG1 and EN1 genes (genes linked to neural differentiation) compared with undifferentiated NT2/D1 cells. We found that AICAR increased the expression of the SHH gene and the WNT2 and WNT7B genes but did not influence the expression of genes whose overexpression characterize early neurodevelopmental processes. Conclusion: The relevance of the AICAR related changes in the SHH and Wnt/β-catenin pathway genes expression in the physiopathology of LND warrants further exploration.

X chromosome inactivation (XCI) ratios of normal females can range from a highly skewed ratio of 0:100 to a 50:50 ratio. In several X-linked disorders, female carriers present skewed X inactivation. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked disorder. Males are affected and present with the complete Lesch-Nyhan disease (LND) or with a partial phenotype (Lesch-Nyhan variant, LNV). Female carriers are usually asymptomatic. The aim of the present study was to analyze the XCI pattern of HPRT-deficiency carrier females. As a group, 75% of HPRT-deficiency carrier females presented skewed XCI. Moreover, skewed XCI is significantly more frequent in LND carriers (83%) than in LNV (0-50%, depending on the phenotype severity). The ratios of the preferentially inactivated allele of carrier females were significantly higher than the ratios of the preferentially inactivated allele of noncarrier females (89.4±15, n=52 vs 65.2±12, n=52; P<0.0001). For carrier diagnosis, the presence of skewed XCI presents a sensitivity of 75% with a specificity of 85%. In LND families, the presence of skewed XCI is more sensitive for carrier diagnosis than in LNV families; however, we believe that this test is not accurate for carrier diagnostic purposes.

Clinic blood pressure (BP) is usually higher than daytime ambulatory BP in hypertensive patients, but some recent studies have challenged this view, suggesting that this relationship is strongly influenced by age. We used the Spanish ambulatory BP monitoring cohort to examine differences between clinic and daytime BP by age among 104 639 adult hypertensive patients (office systolic/diastolic BP ≥140/90 mm Hg or treated) in usual primary-care practice, across the wide age spectrum. To assess the impact of age, cardiovascular variables, and clinic BP on the clinic-daytime BP differences, we built multivariable regression models of the average BP differences, white-coat hypertension (high clinic BP and normal daytime BP), and masked hypertension (normal clinic BP and high daytime BP). In most patients, mean clinic BP values were higher than daytime BP at all ages. Some 36.7% of patients had white-coat hypertension (amounting to 50% at clinic systolic BP of 140-159 mm Hg) and 3.9% had masked hypertension (amounting to 18% at clinic systolic BP of 130-139 mm Hg). Age explained 0.1% to 1.7% of the variance of quantitative or categorical BP differences (P<0.001). Cardiovascular variables explained an additional 1.6% to 3.4% of the variance (P<0.001). Finally, clinic BP generally explained ≥20% more of the variance (P<0.01). In this large study in usual clinical practice, clinic BP misclassified hypertension status in >40% of patients. This misclassification was not importantly influenced by age but was more evident in patients with borderline/grade 1 hypertension. These findings reinforce the importance of ambulatory BP monitoring for defining BP status in routine clinical practice., (© 2017 American Heart Association, Inc.)

We report two Lesch-Nyhan Disease (LND) patients who developed new forms of self-injurious behavior following total dental extraction. Patients 1 and 2 were submitted to total teeth extraction at the age of 13 and 8 years, respectively, due to continuous self-biting, not prevented by mouth guards. Severity of dystonia was markedly reduced and quality of life improved. After 12 and 17 months, respectively, patient 1 started rubbing one foot against other and scratching toenails with his hands, and patient 2 stuck his legs and feet against hard objects. These forms of self-injury behavior could be easily prevented with protective materials, according to the mothers.

Lesch-Nyhan disease (LND) is a genetic disorder that has characteristic metabolic, neurologic, and behavioral features. There are multiple behavioral problems including impulsivity, aggressiveness, and severe recurrent self-injurious behavior (SIB). This last behavior varies considerably across subjects and may encompass self-biting, self-hitting, scratching, head banging, and other injurious actions. Current treatments for SIB involve behavioral extinction, sedatives, physical restraints, and removal of teeth. Because these interventions do not reliably control SIB, better treatments are urgently needed. Animal studies have suggested that D1-dopamine receptor antagonists such as ecopipam may suppress SIB. These observations have led to proposals that such drugs might provide effective treatment for in LND. The current study describes the results of a double-blind, three-period, crossover trial of a single dose of ecopipam in subjects with LND. The study was designed for 20 patients, but it was terminated after recruitment of only 10 patients, because interim analysis revealed unanticipated side effects. These side effects were most likely related to starting with a single large dose without any titration phase. Despite the limited data due to early termination, the drug appeared to reduce SIB in most cases. Subjects who completed the trial were eligible to continue the drug in an open-label extension phase lasting a year, and one patient who elected to continue has maintained a striking reduction in SIB for more than a year with no apparent side effects. These results suggest ecopipam could be a useful treatment for SIB in, but further studies are needed to establish an appropriate dosing regimen., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: An international double-blind, parallel-group, randomized controlled trial was performed to determine the efficacy and safety of a new first-line strategy in mild to moderate hypertension based on a single-pill combination of perindopril/amlodipine versus a validated stepped-care strategy (initiation with valsartan monotherapy, up-titrating to valsartan/amlodipine after 2 months)., Methods: At inclusion, patients received perindopril/amlodipine 3.5/2.5 mg or valsartan 80 mg. At 1, 2, and 3 months, patients were up-titrated if they had uncontrolled hypertension (≥140/90 mmHg). The up-titration steps were: perindopril/amlodipine 7/5 mg, 14/10 mg, and 14/10 mg + indapamide sustained release 1.5 mg; or valsartan 160 mg, valsartan/amlodipine 160/5 mg, and 160/10 mg. The two groups were similar at baseline (55.5 years, 53% men, blood pressure 163.5/100.2 mmHg); 881 perindopril/amlodipine and 876 valsartan/amlodipine patients were analyzed for efficacy., Results: After 1 month, the rate of controlled hypertension was 33% with perindopril/amlodipine versus 27% with valsartan/amlodipine (estimate of difference, +6.1%; P = 0.005); this between-strategy difference remained significant at every visit (P < 0.05). After 3 months, blood pressure was 137.8 ± 12.4/83.3 ± 8.7 and 139.7 ± 13.3/84.8 ± 9.0 mmHg, respectively, with greater reductions from baseline with perindopril/amlodipine (primary endpoint -2.0/-1.5 mmHg; both P < 0.001). Similar results were observed at all other visits (all P ≤ 0.001). The safety of the two strategies was equivalent., Conclusions: The three-step strategy of initiation with single-pill perindopril/amlodipine produces greater reductions in blood pressure, and better and quicker rates of control of hypertension. This can be expected to be associated with benefits beyond blood pressure control, notably improved compliance and better cardioprotection.

Patients infected with the human immunodeficiency virus (HIV) have an increased cardiovascular risk. Although initially this increased risk was attributed to metabolic alterations associated with antiretroviral treatment, in recent years, the attention has been focused on the HIV disease itself. Inflammation, immune system activation, and endothelial dysfunction facilitated by HIV infection have been identified as key factors in the development and progression of atherosclerosis. In this review, we describe the epidemiology and pathogenesis of cardiovascular disease in patients with HIV infection and summarize the latest knowledge on the relationship between traditional and novel inflammatory, immune activation, and endothelial dysfunction biomarkers on the cardiovascular risk associated with HIV infection.

Introduction: An adequate certification of causes of death is essential for Public Health. The objective of this work is to improve the professional competence of medicine students and family doctors with regard to the certification of causes of death according to the international regulations of the WHO., Methods: Intervention-formation, before and after design, addressed to students of Medicine in their last year (6th year), and Family Doctors and Interns. The blended learning or b-learning program consisted in an on-site seminar-workshop, plus basic information/documentation stored in an on-line platform, together with the preparation of Certificates of Causes of Death based on Clinical Histories of real cases., Results: 308 students participated in the program. We observed an individual improvement in the professional competence in all certifications of death, which was significant in 3 out of 5 cases (it was not significant in a medical-legal case of violent death and the case of a pluripathological chronic patient). The intermediate causes improved in all cases. Most formal aspects of the certification improved with significant changes. In the group of 62 Family Doctors and interns who took part in the program there were improvements in the basic or underlying causes in 4 of the 5 cases and improvements in the formal quality of the assessment, although less significantly than in students, because they started with better basal indexes in their certificates in the Before stage of the study., Conclusions: Blended learning training has shown to be effective in improving the professional competence, both in students of the Degree of Medicine and in practicing Family Doctors and Interns., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Phosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation., Methods: Whole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation., Results: A novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency., Conclusions: These results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts.

Aim: There are limited data on the quality of treated blood pressure (BP) control during normal daily life, and in particular, the prevalence of 'masked uncontrolled hypertension' (MUCH) in people with treated and seemingly well-controlled BP is unknown. This is important because masked hypertension in 'treatment naïve' patients is associated with a high risk of cardiovascular events. We therefore conducted the first study to define the prevalence and characteristics of MUCH among a large sample of hypertensive patients in routine clinical practice in whom BP was treated and controlled to recommended clinic BP goals., Methods and Results: We analysed data from the Spanish Society of Hypertension ambulatory blood pressure monitoring (ABPM) Registry and identified patients with treated and controlled BP according to current international guidelines (clinic BP <140/90 mmHg). Masked uncontrolled hypertension was diagnosed in these patients if despite controlled clinic BP, the mean 24-h ABPM average remained elevated (24-h systolic BP ≥130 mmHg and/or 24-h diastolic BP ≥80 mmHg). From 62 788 patients with treated BP in the Spanish registry, we identified 14 840 with treated and controlled clinic BP, of whom 4608 patients (31.1%) had MUCH according to 24-h ABPM criteria (mean age 59.4 years, 59.7% men). The prevalence of MUCH was significantly higher in males, patients with borderline clinic BP (130-9/80-9 mmHg), and patients at high cardiovascular risk (smokers, diabetes, obesity). Masked uncontrolled hypertension was most often because of poor control of nocturnal BP, with the proportion of patients in whom MUCH was solely attributable to an elevated nocturnal BP almost double that solely attributable to daytime BP elevation (24.3 vs. 12.9%, P < 0.001)., Conclusion: The prevalence of masked suboptimal BP control in patients with treated and well-controlled clinic BP is high. Clinic BP monitoring alone is thus inadequate to optimize BP control because many patients have an elevated nocturnal BP. These findings suggest that ABPM should become more routine to confirm BP control, especially in higher risk groups and/or those with borderline control of clinic BP., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Objective: Primary gout has been associated with single-nucleotide polymorphisms (SNP) in several tubular urate transporter genes. No study has assessed the association of reabsorption and secretion urate transporter gene SNP with gout in a single cohort of documented primary patients with gout carefully subclassified as normoexcretors or underexcretors., Methods: Three reabsorption SNP (SLC22A12/URAT1, SLC2A9/GLUT9, and SLC22A11/OAT4) and 2 secretion transporter SNP (SLC17A1/NPT1 and ABCG2/BRCP) were studied in 104 patients with primary gout and in 300 control subjects. The patients were subclassified into normoexcretors and underexcretors according to their serum and 24-h urinary uric acid levels under strict conditions of dietary control., Results: Compared with control subjects, patients with gout showed different allele distributions of the 5 SNP analyzed. However, the diagnosis of underexcretor was only positively associated with the presence of the T allele of URAT1 rs11231825, the G allele of GLUT9 rs16890979, and the A allele of ABCG2 rs2231142. The association of the A allele of ABCG2 rs2231142 in normoexcretors was 10 times higher than in underexcretors. The C allele of NPT1 rs1165196 was only significantly associated with gout in patients with normal uric acid excretion., Conclusion: Gout with uric acid underexcretion is associated with transporter gene SNP related mainly to tubular reabsorption, whereas uric acid normoexcretion is associated only with tubular secretion SNP. This finding supports the concept of distinctive mechanisms to account for hyperuricemia in patients with gout with reduced or normal uric acid excretion.

Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.

Background and Objectives: Pharmacologic urate lowering therapy (ULT), at full maintenance doses, has been associated with acute gout arthritis (in up to 80% of patients). The American College of Rheumatology has recently advocated gradually titrating the maintenance dose upward to chosen serum urate target. Few studies have examined the efficacy and safety of a ULT in primary gout., Patients and Methods: The ULT regimen examined included allopurinol (50 mg/day, with increases of 50 mg/month up to 300 mg/day) and colchicine, as prophylaxis to prevent acute gouty attacks. The efficacy and safety of this regimen was examined in 42 patients in whom allopurinol was withheld for ≥3 months and restarted after this assessment and followed up for 12 months. The efficacy and safety of the ULT regimen was related to the serum urate decrease and to the incidence of acute gout flares, respectively., Results: Fifty-nine patients (mean age 59 years, 56 men) with primary gout received the gradually titrated ULT regimen. Baseline serum urate was (mean±SD) 8.4±0.8 mg/dL. At 3, 6, 9, and 12 months serum urate fell by a mean of 1.8, 2.5, 2.7, and 2.5 mg/dL, respectively (p<0.001). A serum urate level<6.0 mg/dL was achieved by 38/59 (64%) patients. During the 12 months following the start of the ULT we documented 10 acute arthritis episodes (17% of patients)., Conclusions: A gradually titrated hypouricemic regimen for 6 months in patients with primary gout appears to be effective and safe.

Background and Objectives: Primary gout has traditionally been associated with obesity, arterial hypertension, and abnormal lipid and glucose homeostasis, but we do not know the prevalence of these vascular risk factors in patients with primary gout from a Mediterranean country., Patients and Method: All patients with primary gout and 2 or more acute arthritis episodes documented by a physician were selected for the study. The diagnosis of MS required ≥3 criteria (ATP III). Patients were classified in two groups: decreased (underexcretors) and normal (normoexcretors) uric acid excretion related to serum urate levels., Results: One hundred and four patients (mean age, 59 years; 100 males) with primary gout were included in the study. MS was diagnosed in 38 subjects (37%). The most frequent triad defining MS was an increased waist circumference, blood pressure, and trygliceride levels. The prevalence of type 2 diabetes mellitus (T2D) was significantly higher in patients with the MS (21/38, 55%) as compared with subjects without the MS (3/66, 5%; p<0.001). Mean serum urate level in patients with and without MS was identical (8.1 mg/dL), but mean 24-hour uric acid excretion was significantly lower in the former than in the latter (444±110 mg/24-hour/1,73 m2 versus 546±221 mg/day/1,73 m2; p=0.009)., Conclusions: The condition of the MS occurs in about one-third of the patients with primary gout. Increased waist circumference, blood pressure, and triglycerides levels is the most frequent MS triad. Diminished urinary uric acid excretion is more severe in gout patients with the MS.

The biennial 15th symposium on Purine and Pyrimidine metabolism was held in Madrid, June 2013 (PP13). During the meeting, several novel developments on the diagnosis, pathophysiology, and treatment of several inborn errors of purine and pyrimidine metabolism were presented. These ranged from new drugs for gout to enzyme replacement therapies for mitochondrial diseases. A relatively novel aspect in this meeting was the interest in purine and pyrimidine metabolism in nonmammalian systems, such as parasites, mycoplasms, and bacteria. Development of novel analogs for parasite infections, cardiovascular diseases, inflammatory diseases, and cancer were also discussed.

Background: Extended-spectrum β-lactamase (ESBL)- producing Klebsiella pneumonia is more the frequently implied bacterium infections nosocomiales in the Neonatal High Risk Unit (NHRU), and adult intensive care unit (aICU) in the The Andes University Hospital Autonomy Institute., Aim: To determine the microbiological and molecular characteristics associated with infections caused by this bacterium., Material and Methods: 17 strains of K. pneumoniae isolated from neonates from NHRU with nosocomial infections and 11 isolates from patients hospitalized in the aICU between June to November 2009 were characterized by in vitro agar diffusion test and MIC, the production of β-lactamase, the presence of blaTEM blaSHV y blaCTX-M genes and genotyping., Results: A high percentage of resistance to β-lactams and the presence of ESβL TEM, SHV and CTX-M in 41.2 y 82% of strains obtained at HRNU and at aICU respectively were detected. BLEE (+) phenotype was detected in 17,6% of HRNU strains and 91% of aICU strains. Genotypic analysis by REP-PCR detected several clones suggesting that resistant clones of ESBL-producing K. pneumoniae are endemic not only specific circulation and transmission of a single common among patients., Conclusion: K. pneumoniae strains that produce β-lactamases circulate in these critical units studied representing a therapeutic challenge that is necessary to fight against.

Cardiovascular diseases are the leading cause of death in the Spanish population and may be a relationship between the prevalence of these and excessive sugar consumption. In recent years, researchers have focused on the properties of these nutrients. Although there are many studies examining this association, the results are not unanimous. In any case there is sufficient basis for designing public health strategies in order to reduce the consumption of sugary drinks as part of a healthy lifestyle. Therefore, the question we address is: sugar intake in abundant amounts, is associated with a higher risk of cardiovascular disease? We use as the focus of the discussion SAFO analysis model., (Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.)

Lesch-Nyhan disease (LND) is caused by lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. Mutations in HPRT1 gene show variability in type and location within the gene, and in certain patients the HPRT coding sequence is normal and the molecular defect cannot be found. These patients presented a decreased HPRT1 expression of unknown cause. This is the first report of a carrier and prenatal diagnosis of LND due to a defect in HPRT gene expression regulation., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Combination antihypertensive therapies are recommended to attain blood pressure (BP) targets especially in high-risk patients in whom rapid and pronounced BP control is essential. This 28- to 54-week, open-label, multicenter study evaluated the safety and efficacy of a triple combination, aliskiren with amlodipine and hydrochlorothiazide (HCTZ), in patients with moderate to severe hypertension. Following a washout period of up to 4 weeks, patients received aliskiren/HCTZ 300/12.5 mg for 1 week, followed by add-on amlodipine 5 mg for 1 week. Thereafter, the doses of amlodipine and HCTZ were doubled. The first 206 of 564 patients who completed 28 weeks of study continued for an additional 26 weeks. Safety was assessed by recording all adverse events. Efficacy variables included changes in BP from baseline to endpoint and BP control rate. Of 564 patients, 493 completed the study. Peripheral edema (9.4%), headache (5.7%), nasopharyngitis (4.1%), and bronchitis (3.7%) were reported frequently. Clinically significant reductions in mean sitting systolic BP/mean sitting diastolic BP from baseline (-34.2/-20.3 mm Hg and -37.3/-21.8 mm Hg at weeks 28 and 54, respectively) were observed. Corresponding BP control rates were 69.1% and 77.1%. The aliskiren/amlodipine/HCTZ combination in patients with moderate to severe hypertension was well tolerated and provided clinically significant BP reductions and effective BP control., (© 2012 Wiley Periodicals, Inc.)