Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Loss of Direct Vascular Contact to Astrocytes in the Hippocampus as an Initial Event in Alzheimer's Disease. Evidence from Patients, In Vivo and In Vitro Experimental Models.

Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus-a complex brain structure with a pivotal role in learning and memory-is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice-a model of AD-and to determine the impact of Aß40 and Aß42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood-brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aß40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aß42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer's disease.

Atypical presentation of invasive meningococcal disease caused by serogroup W meningococci.

Neisseria meningitidis, a gram-negative diplococcus, is typically an asymptomatic coloniser of the oropharynx and nasopharynx. Passage of N. meningitidis into the bloodstream can cause invasive meningococcal disease (IMD), a potentially life-threatening illness with rapid onset that generally presents as meningitis, septicemia or both. Serogroup W IMD has been increasing in prevalence in recent years, and observations suggest that it may present with atypical signs and symptoms. Herein, a literature search was performed to identify trends in atypical serogroup W IMD presentation in order to review those that are most prevalent. Findings indicate that the most prevalent atypical presentations of serogroup W IMD include acute gastrointestinal (GI) symptoms, septic arthritis and bacteremic pneumonia or severe upper respiratory tract infection, notably epiglottitis. Atypical clinical presentation is associated with higher case fatality rates and can lead to misdiagnoses. Such risks highlight the need for clinicians to consider IMD in their differential diagnoses of patients with acute GI symptoms, septic arthritis or bacteremic pneumonia, primarily in regions where serogroup W is prevalent.

Autecology, feeding preferences and reproductive biology of Chorthippus (Glyptobothrus) vagans (Eversmann, 1848) (Orthoptera: Gomphocerinae) in Mediterranean ecosystems.

Chorthippus vagans is a common species of Gomphocerinae (Orthoptera) on the Iberian Peninsula. It is endangered in Central Europe where information about its ecological requirements is available; however, aspects of its biology are almost unknown in Mediterranean ecosystems, where it is widespread and common. The focus of this study was to determine how C. vagans adjusts its biology to environmental features of this ecosystem and to interpret how it may be affected by the ecological changes related to the re-vegetation programme linked to the construction of the Breña dam (SW Spain). The research parameters included the autoecology, feeding response and some aspects of reproduction of this species in the Southern Iberian Peninsula. To determine the local distribution and phenology of C. vagans, monthly samplings were conducted (2007-2010) in 12 sampling plots. For the food selection tests, ten nymphs and ten adults were placed individually in insectaries under controlled conditions. Grasses (Lolium sp.) and shrubs (Cistus sp.) were supplied ad libitum in two types of tests, monospecific and mixed diet. The reproductive biology was analysed by both observations of anatomical structures (integument, bristles, tibial spines, tarsal claws and mandibles) and ovarian dissections of 29 females and in laboratory rearing experiments with 15 pairs of adults. The results indicate that C. vagans shows an extended activity period which peaks at the end of summer. It is a polyphagous grasshopper, although adults show a slight preference for grasses. In addition, it is a univoltine species with spring-summer breeding activity.

Estrogen-related genes and postmenopausal osteoporosis risk.

BACKGROUND: To date, more than 150 candidate genes related to osteoporosis have been described, but osteoporosis has increasingly been considered a polygenic disease modulated by environmental factors. It is thought that osteoporosis predisposition, pathology, and treatment response depend on the interaction between different genes or between genes and environmental factors. OBJECTIVE: The aim of this study was to evaluate the relationship between the presence of single nucleotide polymorphisms (SNPs) in the estrogen metabolic pathway and the development of osteoporosis and to determine whether this relationship is monogenic or whether interactions between genes exist. MATERIALS AND METHODS: A multicentric study with 1980 postmenopausal Spanish women in five Spanish communities was conducted. The women completed a specific questionnaire that inquired about risk factors for osteoporosis. Data on participants' bone mineral density were obtained with dual-energy X-ray densitometers, and genetic data were obtained from frozen peripheral blood. RESULTS: The digenic protection combinations indicated involvement of the wild-type genotype (WT) of the 3'UTR marker for the CYP19A1 gene, the IVS4 marker of the same gene, and the BMP15 and FSHR genes. Among patients who carried two or more of the genotypes considered 'risky', the triple combination among markers of the ESR2 and NRIP1 genes with any of the two mutations of the analyzed markers of the BMP15 gene gave a mean T-score value of -2.32±0.91 (p = 0.02). CONCLUSION: Variants of the new candidate genes (NRIP and BMP15) can predispose patients to osteoporosis.

Development of a web-based support system for both homogeneous and heterogeneous air quality control networks: process and product.

The Environmental Laboratories Automation Software System or PALMA (Spanish abbreviation) was developed by a multidisciplinary team in order to support the main tasks of heterogeneous air quality control networks. The software process for PALMA development, which can be perfectly applied to similar multidisciplinary projects, was (a) well-defined, (b) arranged between environmental technicians and informatics, (c) based on quality guides, and (d) clearly user-centred. Moreover, it introduces some interesting advantages with regard to the classical step-by-step approaches. PALMA is a web-based system that allows 'off-line' and automated telematic data acquisition from distributed inmission stations belonging not only to homogeneous but also to heterogeneous air quality control networks. It provides graphic and tabular representations for a comprehensive and centralised analysis of acquired data, and considers the daily work that is associated with such networks: validation of the acquired data, alerts with regard to (periodical) tasks (e.g., analysers verification), downloading of files with environmental information (e.g., dust forecasts), etc. The implantation of PALMA has provided qualitative and quantitative improvements in the work performed by the people in charge of the considered control network.

[Laparoscopic adrenalectomy in adrenal carcinoma]. / Adrenalectomía laparoscópica por patología maligna.

There is general agreement on the suitability of the laparoscopic approach for benign adrenal lesions against open procedures because of the efficacy and less morbidity. For suspected adrenal malignancies laparoscopic use is controversial. We report our experience in 6 cases of laparoscopic adrenalectomy in patients with the suspicion of adrenal malignancy confined in the gland. In medium a follow up of 24 months (range 12 to 48 months) we observed no recurrences. We concluded that in a suspected adrenal malignancy organ confined laparoscopic adrenalectomy presents the advantage compared with open surgery of reduced morbidity and similar results in the follow up of the patient.

Estimation of postmortem interval in real cases based on experimentally obtained entomological evidence.

Using the entomological evidence obtained in several forensic cases analyzed in our laboratory for comparison, we evaluated the results of an experimental study carried out in a semiurban setting to determine the structure of the sarcosaprophagous fauna from a Mediterranean region of SE Spain. In all, 18 orders of arthropods were collected. The summarized experimental results refer to the most important taxa for estimating the postmortem interval. Thus, the seasonal character of certain Diptera species, such as Phaenicia sericata, Calliphora vicina, Chrysomya albiceps and Musca domestica, is cited. Among the Coleoptera, the role of Dermestidae as a necrophagous species, and of Staphylinidae and Histeridae as necrophilous, or Cleridae, Tenebrionidae and Nitidulidae as omnivorous, as well as their appearance on the corpse, is described. Among the Hymenoptera, Formicidae were as the most abundant group, acting as omnivores and not apparently related to any particular decomposition stage. The real cases are discussed using data from the literature and the experimentally obtained results. In every case, the most relevant factors for estimating PMI are briefly discussed, mentioning, when possible, the relation with the experimental results. We confirm the significance of the experimental results because they seem to be applicable to actual forensic cases, the details of which enlarge our very little knowledge on the subject in the Iberian Peninsula. The importance of regional faunistic studies of the sarcosaprophagous arthropod community, the results of which may be applied to forensic practice, is mentioned.

Studies on seasonal arthropod succession on carrion in the southeastern Iberian Peninsula.

A global study of the sarcosaprophagous community that occurs in the southeastern Iberian Peninsula during all four seasons is made for the first time, and its diversity is described with reference to biological indices. A total of 18,179 adults and, additionally, a number of preimaginal states were collected. The results for the main arthropod groups, and their diversity are discussed in relation to the season and decompositional stages. The results provide an extensive inventory of carrion-associated arthropods. An association between decomposition stages and more representative arthropod groups is established. With respect to the biological indices applied, Margalef's index shows that the diversity of the community increases as the state of decomposition advances, while Sorenson's quantitative index shows that the greatest similarities are between spring and summer on the one hand, and fall and winter, on the other.