The Role of Programmed Cell Death Ligand 1 Expression in Pituitary Tumours: Lessons from the Current Literature.

BACKGROUND: Programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) expression predict the biological behaviour, aggressiveness, and response to immune checkpoint inhibitors in different cancers. We reviewed the published data on PD-L1 expression in pituitary tumours from the perspective of its biological role and prognostic usefulness. SUMMARY: A literature review focused on PD-L1 expression in pituitary tumours was performed. Six immunohistochemistry-based studies which assessed PD-L1 positivity in pituitary tumours were included, encompassing 704 patients. The cohort consisted of 384 (54.5%) nonfunctioning tumours and 320 (43.5%) functioning pituitary tumours. PD-L1 expression was positive in 248 cases (35.2%). PD-L1 positivity rate was higher in functioning than in nonfunctioning tumours (46.3% vs. 26.0%; p < 0.001) but also higher in growth hormone-secreting tumours (56.7%) and prolactinomas (53.6%) than in thyrotroph (33.3%) or corticotroph tumours (20.6%). While proliferative pituitary tumours showed higher rate of PD-L1 positivity than non-proliferative tumours (p < 0.001), no association with invasion or recurrence was found. KEY MESSAGES: PD-L1 is expressed in a substantial number of pituitary tumours, predominantly in the functioning ones. PD-L1 positivity rates were significantly higher in proliferative pituitary tumours in comparison to non-proliferative tumours, but no differences were found concerning invasive or recurrent pituitary tumours. More studies following homogeneous and standardised methodologies are needed to fully elucidate the role and usefulness of PD-L1 expression in pituitary tumours.

Intrahepatic clear cell cholangiocarcinoma - An uncommon histologic subtype: case report and literature review.

Clear-cell cholangiocarcinoma is a very uncommon variant of cholangiocarcinoma with a largely unknown natural history and prognosis. We report a case of a 51-year-old previously healthy woman presenting with a large liver nodule found on routine imaging. Needle biopsy of the lesion suggested a non-hepatocellular carcinoma. After extensive workup for other primary neoplasms, the patient underwent a partial hepatectomy. Histopathology was compatible with a moderately differentiated clear-cell cholangiocarcinoma. There was no evidence of liver disease in the remaining tissue. The patient underwent chemotherapy and remains in clinical remission after two years.

Epithelioid angiomyolipoma of the liver: Clinicopathological correlation in a series of 4 cases.

Hepatic angiomyolipoma is a rare neoplasm that can be difficult to diagnose in cases of ecoguide biopsy. We studied 4 cases of female patients with a mean age of 51 years. None of the patients presented specific abdominal symptoms, or other tumour masses detected by chance. One of them had relevant personal history: Renal cell carcinoma. This same patient was diagnosed with a contralateral renal angiomyolipoma. None of the patients showed evidence of tuberous sclerosis. Three tumours have been diagnosed by biopsy and only in one patient was decided to completely remove the tumour surgically. None of the patients had evidence of recurrence of disease or an increase in tumour size over an average period of 45 months. Histologically, the tumours have been sub classified into angiomyolipomas epithelioid. In 50% of the cases, extramedullary haematopoiesis was observed. The first diagnostic impression using imaging methods included: Focal nodular hyperplasia, hepatocellular adenoma, hepatocellular carcinoma and metastasis. By immunohistochemistry, it has been demonstrated that all tumours expressing melanocytic markers (HMB45 and Melan A) and markers of smooth muscle cells (smooth muscle actin). The diagnosis of these tumours is increasing due to programmes for early detection of hepatocellular carcinoma in patients with liver cirrhosis. It must be taken into account their broad spectrum of morphological diversity to avoid incorrect diagnosis of a malignant neoplasm.

Psychotropic drugs and driving: prevalence and types.

BACKGROUND: Some psychotropic medications (e.g., benzodiazepines, sedative antidepressants, etc.) may impair cognitive and psychomotor functions and, therefore, endanger traffic safety (Ravera, Br J Clin Pharmacol, 72(3):505-513, 2011). They affect detection, registration, and information processing, problem solving, and decision-making processes, and they also affect emotional and social aspects. The objective of this research was to clarify three closely related issues that are significant for traffic safety: the prevalence of psychotropic drugs on driving, the most frequently used psychotropic drugs to treat depression, anxiety, insomnia, or any tranquilizers (whether it is a medical prescription or self-medication), and finally, provide a further understanding of the socio-demographic and psycho-social characteristics of drivers related to the psychotropic drugs consumption in Spain. METHODS: A sample of 1,200 Spanish drivers ranging from 18 to 64 years was used, 666 men and 534 women were asked to answer a questionnaire composed by a set of questions structured in different sections. The only selection criteria were to be in possession of any type of driving license for vehicles other than motorcycles and drive frequently. RESULTS: The results showed that 15% of the participants were consuming psychotropic drugs to treat depressive disorders, anxiety disorders, insomnia, or tranquilizers; 13.5% were using drugs to treat one of these disorders; while 1.5% used them for several of these disorders. A 2.5% of drivers were using medicines to treat depression, 2.6% to treat anxiety, and 3.7% to treat insomnia. The 8.3% of those drivers who were not using any drugs to treat these three disorders were occasionally using some type of tranquilizers. Benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) were the most used type of medicines among drivers. Benzodiazepines were the most used medicines to treat anxiety, while SSRIs were the most used to treat depression, 56.5% and 43.5%, respectively. CONCLUSIONS: Measures can be developed to reduce traffic accidents caused by the effects of these drugs; however, this will only be possible once the drivers and the use of these drugs are understood. Health care professionals and patients should be properly informed about the potential effects of some psychotropic medications on driving abilities considering individual and group differences.

Multidisciplinary Team Care in Pituitary Tumours.

The optimal care for patients with pituitary tumours is best provided in a multidisciplinary and collaborative environment, which requires the contribution of multiple medical specialties working together. The benefits and advantages of the pituitary multidisciplinary team (MDT) are broad, and all relevant international consensus and guidelines in the field recommend that patients with pituitary tumours should always be managed in a MDT. Endocrinologists and neurosurgeons are normally the leading specialties within the pituitary MDT, supported by many other specialties with significant contributions to the diagnosis and management of pituitary tumours, including neuropathology, neuroradiology, neuro-ophthalmology, and otorhinolaryngology, among others. Here, we review the literature concerning the concepts of Pituitary MDT/Pituitary Tumour Centre of Excellence (PTCOE) in terms of their mission, goals, benefits, structure, proposed models of function, and barriers, and we also provide the views of different specialists involved in our Pituitary MDT.

Evaluation of Psychophysical Fitness in Drivers over 65 Years of Age.

BACKGROUND: The deterioration of cognitive and psychophysical ability associated with aging has an effect on road safety, especially in the driving of vehicles. The current study's main objective is to evaluate the psychophysical aptitudes in drivers over 65 years of age in a sample of drivers in Spain. METHODS: The sample was formed of a total of 1663 drivers who attended a Driver Recognition Center. The evaluation of their psychophysical aptitudes was carried out following the Medical-Psychological Exploration Protocol for Driver Recognition Centers, edited by the Ministry of Health and the General Directorate of Traffic. RESULTS: The results show increased restrictions in the evaluation of driving ability with age, which are especially significant after 75 years of age. Regarding sex, 70.1% of women have an approved evaluation, compared to men aged between 65-69, although from 69 onwards, the percentage of approved women decreases significantly. The loss of visual capabilities and poor performance in psycho-technical tests are the main causes associated with an evaluation with restrictions, with the number of restrictive conditions increasing with age. CONCLUSIONS: There is an increase in the number of cases with age-related restrictions, especially in the case of women and ophthalmologic-related problems, although the majority of drivers over 65 years old continue driving, thus continuing with a practice that has been related to the well-being and quality of life of older adults.

Effects of Cannabis Legalization on Road Safety: A Literature Review.

BACKGROUND: Legalizing medical and recreational cannabis and decriminalizing this substance may have unanticipated effects on traffic safety. The present study aimed to assess the impact of cannabis legalization on traffic accidents. METHODS: A systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) declaration of the articles included in the Web of Science (WoS) and Scopus databases. The number of papers included in the review was 29. RESULTS: The results show that in 15 papers, there is a relationship between the legalization of medical and/or recreational cannabis and the number of traffic accidents, while in 5 papers, no such relationship is observed. In addition, nine articles indicate a greater number of risk behaviors related to driving after consumption, identifying young, male, and alcohol consumption together with cannabis as the risk profile. CONCLUSIONS: It can be concluded that the legalization of medical and/or recreational cannabis has negative effects on road safety when considering the number of jobs that affect the number of fatalities.

Changing human hair fibre colour and shape from the follicle.

INTRODUCTION: Natural hair curvature and colour are genetically determined human traits, that we intentionally change by applying thermal and chemical treatments to the fibre. Presently, those cosmetic methodologies act externally and their recurrent use is quite detrimental to hair fibre quality and even to our health. OBJECTIVES: This work represents a disruptive concept to modify natural hair colour and curvature. We aim to model the fibre phenotype as it is actively produced in the follicle through the topical delivery of specific bioactive molecules to the scalp. METHODS: Transcriptome differences between curly and straight hairs were identified by microarray. In scalp samples, the most variable transcripts were mapped by in situ hybridization. Then, by using appropriate cellular models, we screened a chemical library of 1200 generic drugs, searching for molecules that could lead to changes in either fibre colour or curvature. A pilot-scale, single-centre, investigator-initiated, prospective, blind, bilateral (split-scalp) placebo-controlled clinical study with the intervention of cosmetics was conducted to obtain a proof of concept (RNEC n.92938). RESULTS: We found 85 genes transcribed significantly different between curly and straight hair, not previously associated with this human trait. Next, we mapped some of the most variable genes to the inner root sheath of follicles, reinforcing the role of this cell layer in fibre shape moulding. From the drug library screening, we selected 3 and 4 hits as modulators of melanin synthesis and gene transcription, respectively, to be further tested in 33 volunteers. The intentional specific hair change occurred: 8 of 14 volunteers exhibited colour changes, and 16 of 19 volunteers presented curvature modifications, by the end of the study. CONCLUSION: The promising results obtained are the first step towards future cosmetics, complementary or alternative to current methodologies, taking hair styling to a new level: changing hair from the inside out.

Natural and anthropogenic-induced stressors affecting the composition of fish communities on the rocky reefs of Ecuador.

Natural and human-induced stressors have threatened the sustainability of the fish communities of coral-rocky reefs worldwide in the last decades. The composition of the fish communities on the reefs of Ecuador and the factors affecting spatiotemporal changes are unknown. We studied the influence of the descriptors of structural complexity, the current status of coral and human-induced variables over fish communities. A video transect method was used to assess fish communities in three zones (slope, crest, and bottom) of two reefs during two seasons (rainy and dry). The structure of fish communities was highly influenced by the zones and season; rugosity and live coral affected the fish composition on the crest and slope zones. The fractured coral and derelict fishing gear on coral produced an adverse effect on fish composition over the crest. A multifactorial process causing loss of structural complexity and affecting fish composition was identified, however, periodical assessment is required for a greater understanding of this process.

Environmental challenges of intensive woody crops: The case of super high-density olive groves.

Super high-density olive groves (>800 trees ha-1) are rapidly expanding in olive oil producer countries, which entails a strong modification of the olive growing system with important agronomic, economic, sociocultural, and environmental consequences. Among them, the latter is particularly unknown. The aim of this paper is to bring the attention on the environmental impacts of super high-density olive groves, by systematically reviewing the current evidence and identifying knowledge gaps yet to be filled. As a result, we can argue that new super high-density olive plantations reduce habitat heterogeneity and complexity, and the younger trees of these plantations impoverish habitat quality for farmland biodiversity. In addition, the high input use (e.g. phytosanitary treatments, fertilisers and water supply) may entail ecological impacts as well. Therefore, we conclude that i) new highly intensive olive groves should be limited to areas with lower ecological value; ii) consumers should have more information concerning how is produced the olive oil they buy, including the environmental impacts produced; iii) agricultural policies should be reformulated following the provider-gets principle; iv) input use (fertilisers, pesticides, water, etc.) should be gradually optimised to reduce the environmental impact; and finally, v) more research is necessary to foster decisions based on science.

High-intensity infrasound effects on glucose metabolism in rats.

Recent focus has been given on the effects of high-intensity infrasound (HII) exposure, and whether it induces changes in pancreatic morphology and glucose metabolism is still unknown. As such, we have studied the impact of HII exposure on glucose tolerance, insulin sensitivity, pancreatic islet morphology, muscle GLUT4 and plasma insulin and corticosterone levels. Normal and glucose intolerant wild-type Wistar rats were randomly divided in two groups: one group not exposed to HII and the other continuously exposed to HII. Animals were sacrificed at three timepoints of exposure (1, 6 or 12 weeks). An intraperitoneal glucose tolerance test was performed, blood samples were collected and the pancreas and the quadriceps femoris muscle were excised. Circulating insulin and corticosterone levels were determined and pancreatic and muscular tissue were routinely processed for histochemistry and immunohistochemistry with an anti-GLUT4 antibody. Animals exposed to HII had higher corticosterone levels than animals not exposed. No differences were found on insulin concerning HII exposure or glucose intolerance. Glucose intolerant animals had pancreatic islet fibrosis and no differences were found in GLUT4 ratio concerning HII exposure. In conclusion, we found that continuous exposure to HII increases stress hormone levels without inducing glucose intolerance in rats.

Levelling profiles and a GPS network to monitor the active folding and faulting deformation in the Campo de Dalias (Betic Cordillera, southeastern Spain).

The Campo de Dalias is an area with relevant seismicity associated to the active tectonic deformations of the southern boundary of the Betic Cordillera. A non-permanent GPS network was installed to monitor, for the first time, the fault- and fold-related activity. In addition, two high precision levelling profiles were measured twice over a one-year period across the Balanegra Fault, one of the most active faults recognized in the area. The absence of significant movement of the main fault surface suggests seismogenic behaviour. The possible recurrence interval may be between 100 and 300 y. The repetitive GPS and high precision levelling monitoring of the fault surface during a long time period may help us to determine future fault behaviour with regard to the existence (or not) of a creep component, the accumulation of elastic deformation before faulting, and implications of the fold-fault relationship.

General Microbiota of the Soft Tick Ornithodoros turicata Parasitizing the Bolson Tortoise (Gopherus flavomarginatus) in the Mapimi Biosphere Reserve, Mexico.

The general bacterial microbiota of the soft tick Ornithodoros turicata found on Bolson tortoises (Gopherus flavomarginatus) were analyzed using next generation sequencing. The main aims of the study were to establish the relative abundance of bacterial taxa in the tick, and to document the presence of potentially pathogenic species for this tortoise, other animals, and humans. The study was carried-out in the Mapimi Biosphere Reserve in the northern-arid part of Mexico. Bolson tortoises (n = 45) were inspected for the presence of soft ticks, from which 11 tortoises (24.4%) had ticks in low loads (1-3 ticks per individual). Tick pools (five adult ticks each) were analyzed through 16S rRNA V3-V4 region amplification in a MiSeq Illumina, using EzBioCloud as a taxonomical reference. The operational taxonomic units (OTUs) revealed 28 phyla, 84 classes, 165 orders, 342 families, 1013 genera, and 1326 species. The high number of taxa registered for O. turicata may be the result of the variety of hosts that this tick parasitizes as they live inside G. flavomarginatus burrows. While the most abundant phyla were Proteobacteria, Actinobacteria, and Firmicutes, the most abundant species were two endosymbionts of ticks (Midichloria-like and Coxiella-like). Two bacteria documented as pathogenic to Gopherus spp. were registered (Mycoplasma spp. and Pasteurella testudinis). The bovine and ovine tick-borne pathogens A. marginale and A. ovis, respectively, were recorded, as well as the zoonotic bacteria A. phagocytophilum,Coxiella burnetii, and Neoehrlichia sp. Tortoises parasitized with O. turicata did not show evident signs of disease, which could indicate a possible ecological role as a reservoir that has yet to be demonstrated. In fact, the defense mechanisms of this tortoise against the microorganisms transmitted by ticks during their feeding process are still unknown. Future studies on soft ticks should expand our knowledge about what components of the microbiota are notable across multiple host-microbe dynamics. Likewise, studies are required to better understand the host competence of this tortoise, considered the largest terrestrial reptile in North America distributed throughout the Chihuahuan Desert since the late Pleistocene.

Antitumour and Toxicity Evaluation of a Ru(II)-Cyclopentadienyl Complex in a Prostate Cancer Model by Imaging Tools.

BACKGROUND: Ruthenium complexes have been extensively investigated for their prospective value as alternatives to cisplatin. Recently, we reported the in vitro anticancer properties of a family of organometallic ruthenium( II)-cyclopentadienyl complexes and have explored their mechanism of action. OBJECTIVE: The purpose of this study was to evaluate the in vivo antitumour efficacy and toxicity of one of these Ru(II) compounds, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO2] (TM85) which displayed an interesting spectrum of activity against several cancer cells. METHODS: Studies to assess the antitumour activity and toxicity were performed in a metastatic prostate (PC3) mice model using ICP-MS, nuclear microscopy, elemental analysis and Transmission Electron Microscopy (TEM). RESULTS: TM85 showed low systemic toxicity but no significant tumour reduction, when administered at tolerated dose (20mg/kg) over 10 days. Ru was mainly retained in the liver and less in kidneys, with low accumulation in tumour. Increased bilirubin levels, anomalous Ca and Fe concentrations in liver and mitochondria alterations were indicative of liver injury. The hepatotoxicity observed was less severe than that of cisplatin and no nephrotoxicity was found. CONCLUSION: Under the experimental conditions of this study, TM85 is less toxic than cisplatin, induces similar tumour reduction and avoids the formation of metastatic foci. No renal toxicity was observed by the analysis of creatinine levels and the effective renal plasma flow by 99mTc-MAG3 clearance. Hence, it can be considered a valuable compound for further studies in the field of Ru-based anticancer drugs.

Does gender really matter? A structural equation model to explain risky and positive cycling behaviors.

INTRODUCTION: While the use of bicycles as mean of transport is growing worldwide, the increasing rates of traffic crashes involving cyclists have turned into a relevant scientific, public health, and road safety concern. According to several studies, and despite the fact that some countries are taking part in preventive actions, the data indicate that the problem of cycling injuries implies high costs for the community welfare, for the economy, and for healthcare systems, thus proving a clear need for solutions. In this regard, and considering the available empirical evidence, risky and positive riding behaviors have gained significant weight in terms of explaining, intervening in, and preventing traffic crashes of cyclists, and some evidence suggests that gender may influence the road behavior of users. OBJECTIVE: The objective of this study was to examine the effect of gender on cyclists' risky and positive riding behavior, considering a set of demographic, psychosocial and bike-use-related variables as potential predictors. METHOD: For this cross-sectional study, data from 1064 cyclists (61.2% males and 38.8% females, aged between 17 and 80) from 20 countries, responding an electronic survey, were analyzed through a multi-group structural equation modeling approach. RESULTS: Although hourly intensity, psychological distress and level of knowledge of traffic rules similarly predict the risky road behaviors of both genders, age and risk perception are significant behavioral predictors only in the case of male cyclists. On the other hand, positive behaviors of men are predicted by cycling intensity, knowledge of traffic rules and risk perception, while in the case of women psychological distress predicts -to a significant extent- positive behaviors. Age had no significant effect on the explanation of positive behaviors. CONCLUSION: The findings of this study support the influence of gender in the statistical explanation of risky and protective behaviors, and they also reveal differentiating variables predicting the riding behavior of male and female cyclists.

Novel aspects in histopathology of the pituitary gland. / Aspectos novedosos en histopatología de la hipófisis.

The sellar and parasellar region is a complex anatomical area in which several diseases may develop. The pituitary gland may be affected by a wide range of conditions having similar clinical characteristics. Diagnosis of these lesions requires a multidisciplinary approach including, in addition to clinical, laboratory, imaging, and surgical findings, histological diagnosis of pituitary adenomas to guide therapeutic management. As the result of development in recent years of new immunohistochemical techniques, histopathological classification has become more complex and wide, and not only continues to be the gold standard in diagnosis, but also has prognostic implications. The aim of this review is to provide a clear and simple update of the main concepts of histological diagnosis of the most common pituitary conditions, especially for professionals in direct contact with such diseases.

In Vivo Performance of a Ruthenium-cyclopentadienyl Compound in an Orthotopic Triple Negative Breast Cancer Model.

BACKGROUND: Ruthenium-based anti-cancer compounds are proposed as viable alternatives that might circumvent the disadvantages of platinum-based drugs, the only metallodrugs in clinical use for chemotherapy. Organometallic complexes in particular hold great potential as alternative therapeutic agents since their cytotoxicity involves different modes of action and present reduced toxicity profiles. OBJECTIVE: During the last few years our research group has been reporting on a series of organometallic ruthenium(II)- cyclopentadienyl complexes with important cytotoxicity against several cancer cell lines, surpassing cisplatin in activity. We report herein preliminary in vivo studies with one representative compound of this family, with exceptional activity against several human cancer cell lines, including the glycolytic and highly metastatic MDAMB231 cell line used in this study. METHOD: The anti-tumor activity of our compound was studied in vivo on N:NIH(S)II-nu/nu nude female mice bearing triple negative breast cancer (TNBC) orthotopic tumors. Administration of 2.5 mg/kg/day during ten days caused cell death mostly by necrosis (in vitro and in vivo), inducing tumor growth suppression of about 50% in treated animals when compared to controls. RESULTS: The most remarkable result supporting the effectiveness and potential of this drug was the absence of metastases in the main organs of treated animals, while metastases were present in the lungs of all control mice, as revealed by histopathological and immunohistochemical analysis. CONCLUSION: These in vivo studies suggest a dual effect for our drug not only by suppressing growth at the primary tumor tissue but also by inhibiting its metastatic behavior. Altogether, these results represent a benchmark and a solid starting point for future studies.

Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine.

The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.