DRD3 Predicts Cognitive Impairment and Anxiety in Parkinson's Disease: Susceptibility and Protective Effects.

Background: A possible genetic contribution of dopamine D3 receptor (DRD3) to cognitive impairment in Parkinson's disease (PD) has yet to be investigated. Objective: To explore the effects of rs6280 (Ser9Gly) genotype on PD patients' cognitive performance and to clarify possible interactions with psychopathology. Methods: Two hundred and fifty-three consecutive PD patients underwent neurological and neuropsychological evaluations, which included: Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Dementia Rating Scale-2 (DRS-2), and Hospital Anxiety and Depression Scale (HADS). rs6280 polymorphism was genotyped for all PD patients and for 270 ethnically matched healthy volunteers (HC). Non-parametric group comparisons and logistic regressions were used for data analyses. Results: rs6280 genotype did not differ between PD and HC groups. PD patients with rs6280 CC genotype had more impaired cognitive performance (i.e., <1st percentile of demographically adjusted norms) on DRS-2 subscales Initiation/Perseveration and Construction than those with TT genotype. These associations remained statistically significant when other covariates (e.g., demographic features, disease duration, severity of motor symptoms in OFF and ON states, anti-parkinsonian medication, and psychopathology symptoms) were taken into consideration. PD patients with rs6280 TC had less anxiety (i.e., HADS Anxiety≥11) than those with TT (p = 0.012). This association was also independent of other covariates. Conclusions: Study findings suggest that rs6280 CC genotype predisposes to executive dysfunction and visuoconstructional deficits, whereas the heterozygous genotype protects from anxiety in PD. These effects do not appear to be dependent of one another. rs6280 is not a genotypic susceptibility factor for PD.

Device innovation in cardiovascular medicine: a report from the European Society of Cardiology Cardiovascular Round Table.

Research performed in Europe has driven cardiovascular device innovation. This includes, but is not limited to, percutaneous coronary intervention, cardiac imaging, transcatheter heart valve implantation, and device therapy of cardiac arrhythmias and heart failure. An important part of future medical progress involves the evolution of medical technology and the ongoing development of artificial intelligence and machine learning. There is a need to foster an environment conducive to medical technology development and validation so that Europe can continue to play a major role in device innovation while providing high standards of safety. This paper summarizes viewpoints on the topic of device innovation in cardiovascular medicine at the European Society of Cardiology Cardiovascular Round Table, a strategic forum for high-level dialogue to discuss issues related to the future of cardiovascular health in Europe. Devices are developed and improved through an iterative process throughout their lifecycle. Early feasibility studies demonstrate proof of concept and help to optimize the design of a device. If successful, this should ideally be followed by randomized clinical trials comparing novel devices vs. accepted standards of care when available and the collection of post-market real-world evidence through registries. Unfortunately, standardized procedures for feasibility studies across various device categories have not yet been implemented in Europe. Cardiovascular imaging can be used to diagnose and characterize patients for interventions to improve procedural results and to monitor devices long term after implantation. Randomized clinical trials often use cardiac imaging-based inclusion criteria, while less frequently trials randomize patients to compare the diagnostic or prognostic value of different modalities. Applications using machine learning are increasingly important, but specific regulatory standards and pathways remain in development in both Europe and the USA. Standards are also needed for smart devices and digital technologies that support device-driven biomonitoring. Changes in device regulation introduced by the European Union aim to improve clinical evidence, transparency, and safety, but they may impact the speed of innovation, access, and availability. Device development programmes including dialogue on unmet needs and advice on study designs must be driven by a community of physicians, trialists, patients, regulators, payers, and industry to ensure that patients have access to innovative care.

New perspectives for hypertension management: progress in methodological and technological developments.

Hypertension is the most common and preventable risk factor for cardiovascular disease (CVD), accounting for 20% of deaths worldwide. However, 2/3 of people with hypertension are undiagnosed, untreated, or under treated. A multi-pronged approach is needed to improve hypertension management. Elevated blood pressure (BP) in childhood is a predictor of hypertension and CVD in adulthood; therefore, screening and education programmes should start early and continue throughout the lifespan. Home BP monitoring can be used to engage patients and improve BP control rates. Progress in imaging technology allows for the detection of preclinical disease, which may help identify patients who are at greatest risk of CV events. There is a need to optimize the use of current BP control strategies including lifestyle modifications, antihypertensive agents, and devices. Reducing the complexity of pharmacological therapy using single-pill combinations can improve patient adherence and BP control and may reduce physician inertia. Other strategies that can improve patient adherence include education and reassurance to address misconceptions, engaging patients in management decisions, and using digital tools. Strategies to improve physician therapeutic inertia, such as reminders, education, physician-peer visits, and task-sharing may improve BP control rates. Digital health technologies, such as telemonitoring, wearables, and other mobile health platforms, are becoming frequently adopted tools in hypertension management, particularly those that have undergone regulatory approval. Finally, to fight the consequences of hypertension on a global scale, healthcare system approaches to cardiovascular risk factor management are needed. Government policies should promote routine BP screening, salt-, sugar-, and alcohol reduction programmes, encourage physical activity, and target obesity control.

Carbon-based materials for water disinfection and heavy metals removal.

The presence of heavy metals and/or harmful bacteria in drinking water represents significant risks to human health. This study aimed to develop a low-cost water treatment technology using synthesized nanocomposites with metal nanoparticles supported on activated carbon (AC) for bacteria and heavy metal removal. In addition, the performance of the developed nanomaterials was compared with that of commercial materials - carbon fibers of three different typologies. The chemical and textural properties of all tested materials were characterized. To simulate a technology to be applied in a water outlet point, removal tests were carried out in a continuous system using suspensions of Escherichia coli and/or Staphylococcus aureus, wherein the contact time with the two phases was minimal (1 min). The obtained results revealed that iron and copper oxides supported on AC with a calcination treatment (CuFeO/AC-C) was the nanocomposite with the best performance, achieving a 6 log reduction for both bacteria in the same suspension up to 9 h operation. A mix of bacteria and heavy metals, simulating a real water, was treated with CuFeO/AC-C obtaining a 6 log reduction of bacteria, a Pb2+ removal >99.9% and Cd2+ removal between 97 and 98% over 180 passage times.

Auditory verbal learning test can lateralize hippocampal sclerosis.

The ability of the Auditory Verbal Learning Test (AVLT) to lateralize hippocampal sclerosis (HS) in mesial temporal lobe epilepsy (MTLE) was explored in a sample of 50 patients with MTLE-HS (23 right and 27 left). Patients' AVLT scores were adjusted to the demographic characteristics of each individual in accordance with the Portuguese normative data. The laterality of the HS was determined by consensus by two neuroradiologists. ROC curves were used to identify the best AVLT cutoff scores to differentiate right vs. left HS. Diagnostic statistics were applied to different AVLT measures. The study results revealed that four AVLT scores can correctly classify the laterality of HS in the total sample and a sub-group of 39 right-handed patients (Edinburgh Laterality Inventory +100): delayed recall trial (76 and 80%, respectively), delayed recognition trial (64 and 67%, respectively), learning over trials index (64 and 74%, respectively), and long-term percent retention index (68 and 72%, respectively). In right-handed patients, the diagnostic capability of the delayed recall trial was improved by pairing it with the learning over trials index (accuracy of 85%). In sum, AVLT measures of verbal memory differentiate left from right HS in MTLE. The delayed recall trial demonstrated good diagnostic capacity.

Left Atrial Remodeling and Stroke in Patients With Sinus Rhythm and Normal Ejection Fraction: ARIC-NCS.

Background Age-related left atrial (LA) structural and functional abnormalities may be related to subclinical cerebral infarcts (SCIs) and stroke. We evaluated the association of 3-dimensional echocardiographic LA contractility parameters with SCIs and stroke across the spectrum of tertiles of age increment in elderly patients with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation. Methods and Results We enrolled 407 participants (mean age, 76±8 years; 40% men) from ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study) undergoing a brain magnetic resonance imaging and 3-dimensional echocardiographic examinations in 2011 to 2013. The sample was analyzed among age tertiles and subgroups: no cerebral magnetic resonance imaging-detectable infarcts (n=315), magnetic resonance imaging-diagnosed SCIs (n=58), and clinically diagnosed stroke (n=34). The frequency of SCIs significantly increased over age tertiles (P trend 0.023). LA global longitudinal strain-a 3-dimensional echocardiographic index of LA reservoir function-and E/e' divided by LA global longitudinal strain-an index of LA stiffness-worsened across age tertiles (P trend 0.014 and 0.001, respectively), and only in the categories of SCIs (P trend <0.001 and 0.045, respectively) and stroke (P trend 0.001 and 0.011, respectively). LA global longitudinal strain was negatively associated with increased odds of SCIs (P=0.036, P=0.008, and P=0.001, respectively) and strokes (P=0.043, P=0.015, and P=0.001, respectively) over age tertiles, with a significant interaction between age tertiles (interaction P=0.043 and P=0.010, respectively). E/e' divided by LA global longitudinal strain was positively associated with the presence of SCIs (P=0.037, P=0.007, and P=0.001, respectively) and strokes (P=0.045, P=0.007, and P=0.003, respectively) over age tertiles, with a significant interaction only for SCIs (interaction P=0.040) and not for clinical stroke. Conclusions In a large cohort study of elderly patients, among participants with sinus rhythm, normal ejection fraction, and no history of atrial fibrillation, measures of worse age-related LA reservoir function and stiffness are associated with higher odds of SCIs and stroke.

Poisoning by Nierembergia veitchii: Effects on vascular smooth muscle cells in the pathogenesis of enzootic calcinosis.

Vascular mineralization is a hallmark of enzootic calcinosis. Histopathological, ultrastructural, and immunohistochemical investigations were performed on the external carotid arteries of seven sheep naturally poisoned by Nierembergia veitchii. Histologically, moderate to marked hyperplasia of the tunica intima was observed without mineralization. The tunica media exhibited mild to severe mineralization and osteochondroid metaplasia. Sheep with enzootic calcinosis showed arterial overexpression of osteopontin and tissue-nonspecific alkaline phosphatase and immunolabeling for osteonectin and osteocalcin in both intima and media layers of the tested arteries. The main ultrastructural finding in the tunica media was a marked phenotypic change of vascular smooth muscle cells from a contractile phenotype (VSMC-C) into a synthetic phenotype (VSMC-S). In the tunica media, VSMC-S produced matrix and extracellular vesicles, forming mineralizable granules associated with arterial mineralization. VSMC-S were also present in the tunica intima, but matrix and extracellular vesicles and mineralization were not observed. The absence of matrix and extracellular vesicles in the intimal hyperplasia, even in the presence of noncollagenous bone proteins, tissue-nonspecific alkaline phosphatase, and vitamin D receptors, reinforces the hypothesis that the presence of matrix and extracellular vesicles are crucial for the development of vascular mineralization in enzootic calcinosis. It is proposed that the two different VSMC-S phenotypes in calcinosis are due to the expression of at least two genetically different types of these cells induced by the action of 1,25(OH)2D3.

Association of Left Atrial Structure and Function With Heart Failure in Older Adults.

BACKGROUND: Limited data exist to characterize novel measures of left atrial (LA) structure and function in older adults without prevalent heart failure (HF). OBJECTIVES: The aim was to assess reference range of LA measures, their associations with N-terminal pro-B-type natriuretic-peptide (NT-proBNP) and the related risk for incident HF or death. METHODS: We analyzed LA structure (LA maximal [LAViMax] and minimal volume indexed by body surface area) and function (LA emptying fraction, LA reservoir, conduit, and contraction strain) in 4,901 participants from the ARIC (Atherosclerosis Risk In Communities) study (mean age 75 ± 5 years, 40% male, and 19% Black) without prevalent HF. We assessed sex-specific 10th and 90th percentile ARIC-based reference limits in 301 participants free of prevalent cardiovascular disease, and related LA measures to NT-proBNP and incident HF or death (median follow-up of 5.5 years) in the whole ARIC cohort. RESULTS: Approximately 20% of the overall population had LA abnormalities according to the ARIC-based reference limit. Each LA measure was associated with NT-proBNP and, except for LAViMax, with incident HF or death after multivariable adjustment (including left ventricular function and NT-proBNP). Results were consistent in participants with normal LAViMax (P for interaction > 0.05). LA measures were prognostic for both incident HF with preserved ejection fraction or death and incident HF with reduced ejection fraction or death. When added to HF risk factors and NT-proBNP (baseline C-statistics = 0.74) all LA measures, except for LAViMax, significantly enhanced the prognostic accuracy. CONCLUSIONS: Novel measures of LA structure and function, but not standard assessment by LAViMax, are associated with increased risk of incident HF or death regardless of measures of left ventricular function and NT-proBNP.

Bioconversion of Terephthalic Acid and Ethylene Glycol Into Bacterial Cellulose by Komagataeibacter xylinus DSM 2004 and DSM 46604.

Komagataeibacter xylinus strains DSM 2004 and DSM 46604 were evaluated for their ability to grow and produce bacterial cellulose (BC) upon cultivation on terephthalic acid (TA) and ethylene glycol (EG), which are monomers of the petrochemical-derived plastic polyethylene terephthalate (PET). Both strains were able to utilize TA, EG, and their mixtures for BC synthesis, with different performances. K. xylinus DSM 2004 achieved higher BC production from TA (0.81 ± 0.01 g/L), EG (0.64 ± 0.02 g/L), and TA + EG mixtures (0.6 ± 0.1 g/L) than strain DSM 46604. The latter was unable to utilize EG as the sole carbon source and reached a BC production of 0.16 ± 0.01 g/L and 0.23 ± 0.1 g/L from TA alone or TA + EG mixtures, respectively. Further supplementing the media with glucose enhanced BC production by both strains. During cultivation on media containing TA and EG, rapid pH drop due to metabolization of EG into acidic compounds led to some precipitation of TA that was impregnated into the BC pellicles. An adaptation of the downstream procedure involving BC dissolution in NaOH was used for the recovery of pure BC. The different medium composition tested, as well as the downstream procedure, impacted the BC pellicles' physical properties. Although no variation in terms of the chemical structure were observed, differences in crystallinity degree and microstructure of the produced BC were observed. The BC produced by K. xylinus DSM 2004 had a higher crystallinity (19-64%) than that of the strain DSM 46604 (17-53%). Moreover, the scanning electron microscopy analysis showed a higher fiber diameter for K. xylinus DSM 2004 BC (46-56 nm) than for K. xylinus DSM 46604 (37-49 nm). Dissolution of BC in NaOH did not influence the chemical structure; however, it led to BC conversion from type I to type II, as well as a decrease in crystallinity. These results demonstrate that PET monomers, TA and EG, can be upcycled into a value-added product, BC, presenting an approach that will contribute to lessening the environmental burden caused by plastic disposal in the environment.

Fatal Human Alphaherpesvirus 1 Infection in Free-Ranging Black-Tufted Marmosets in Anthropized Environments, Brazil, 2012-2019.

Human alphaherpesvirus 1 (HuAHV1) causes fatal neurologic infections in captive New World primates. To determine risks for interspecies transmission, we examined data for 13 free-ranging, black-tufted marmosets (Callithrix penicillata) that died of HuAHV1 infection and had been in close contact with humans in anthropized areas in Brazil during 2012-2019. We evaluated pathologic changes in the marmosets, localized virus and antigen, and assessed epidemiologic features. The main clinical findings were neurologic signs, necrotizing meningoencephalitis, and ulcerative glossitis; 1 animal had necrotizing hepatitis. Transmission electron microscopy revealed intranuclear herpetic inclusions, and immunostaining revealed HuAHV1 and herpesvirus particles in neurons, glial cells, tongue mucosal epithelium, and hepatocytes. PCR confirmed HuAHV1 infection. These findings illustrate how disruption of the One Health equilibrium in anthropized environments poses risks for interspecies virus transmission with potential spillover not only from animals to humans but also from humans to free-ranging nonhuman primates or other animals.

Non-invasive imaging as the cornerstone of cardiovascular precision medicine.

AIMS: To provide an overview of the role of cardiovascular (CV) imaging in facilitating and advancing the field of precision medicine in CV disease. METHODS AND RESULTS: Non-invasive CV imaging is essential to accurately and efficiently phenotype patients with heart disease, including coronary artery disease (CAD) and heart failure (HF). Various modalities, such as echocardiography, nuclear cardiology, cardiac computed tomography (CT), cardiovascular magnetic resonance (CMR), and invasive coronary angiography, and in some cases a combination, can be required to provide sufficient information for diagnosis and management. Taking CAD as an example, imaging is essential for the detection and functional assessment of coronary stenoses, as well as for the quantification of cardiac function and ischaemic myocardial damage. Furthermore, imaging may detect and quantify coronary atherosclerosis, potentially identify plaques at increased risk of rupture, and guide coronary interventions. In patients with HF, imaging helps identify specific aetiologies, quantify damage, and assess its impact on cardiac function. Imaging plays a central role in individualizing diagnosis and management and to determine the optimal treatment for each patient to increase the likelihood of response and improve patient outcomes. CONCLUSIONS: Advances in all imaging techniques continue to improve accuracy, sensitivity, and standardization of functional and prognostic assessments, and identify established and novel therapeutic targets. Combining imaging with artificial intelligence, machine learning and computer algorithms, as well as with genomic, transcriptomic, proteomic, and metabolomic approaches, will become state of the art in the future to understand pathologies of CAD and HF, and in the development of new, targeted therapies.

Pathology and One Health implications of fatal Leptospira interrogans infection in an urbanized, free-ranging, black-tufted marmoset (Callithrix penicillata) in Brazil.

Leptospirosis is a zoonotic neglected disease of worldwide public health concern. Leptospira species can infect a wide range of wild and domestic mammals and lead to a spectrum of disease, including severe and fatal forms. Herein, we report for the first time a fatal Leptospira interrogans infection in a free-ranging nonhuman primate (NHP), a black-tufted marmoset. Icterus, pulmonary haemorrhage, interstitial nephritis, and hepatocellular dissociation were the main findings raising the suspicion of leptospirosis. Diagnostic confirmation was based on specific immunohistochemical and PCR assays for Leptospira species. Immunolocalization of leptospiral antigens and identification of pathogenic species (L. interrogans species) were important for better understanding the pathogenesis of the disease. One Health-related implications of free-ranging NHPs in anthropized areas and transmission dynamics of human and animal leptospirosis are discussed.

Feasibility of using magnetic nanoparticles in water disinfection.

Disinfection is a crucial step during the water treatment process due to the significant risks of water contamination with human and animal excreta. The development of innovative disinfection technologies that can be applied at water point of use, avoiding contamination problems in water distribution systems and reservoirs, are needed. Thus, the present work aimed at assessing the disinfection efficiency of iron oxide magnetic nanoparticles (MNPs) modified with different compounds, such as carbon nanotubes, copper and silver, in water solutions contaminated with bacteria. Kinetic and influence of nanoparticles concentration experiments, performed with Escherichia coli, allowed to define the optimal reaction conditions to apply in batch experiments (1 min of contact time and 50 mg/mL of MNPs). During these experiments, CuFeO/CNT, C-FeO@CVD750 and 5% Ag/FeO were selected as the most efficient presenting log reduction values of 2.99, 1.50 and 2.11, respectively; however, experiments performed with Staphylococcus aureus suspension and a mixed bacterial suspension (E. coli + S. aureus) allowed to observe a slight decrease in nanomaterials efficiency, which was more evident for C-FeO@CVD750 and 5% Ag/FeO materials achieving efficiencies of 94 and 83% (corresponding log reductions of 1.26 and 0.77, respectively). CuFeO/CNT nanoparticles proved to be the most efficient material for both bacteria removal presenting an efficiency of 99% (corresponding log reduction of 1.99) for the mixed bacterial suspension. These nanoparticles proved to have great stability over successive experiments, and the low leaching values of the metals present in their composition after reaction proved the resistance and efficiency of these magnetic nanoparticles.

Long-term impact of early initiation of enzyme replacement therapy in 34 MPS VI patients: A resurvey study.

Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT.

Immune System Efficiency in Cancer and the Microbiota Influence.

The immune system plays a critical role in preventing cancer development and progression. However, the complex network of cells and soluble factor that form the tumor microenvironment (TME) can dictate the differentiation of tumor-infiltrating leukocytes and shift the antitumor immune response into promoting tumor growth. With the advent of cancer immunotherapy, there has been a reinvigorated interest in defining how the TME shapes the antitumor immune response. This interest brought to light the microbiome as a novel player in shaping cancer immunosurveillance. Indeed, accumulating evidence now suggests that the microbiome may confer susceptibility or resistance to certain cancers and may influence response to therapeutics, particularly immune checkpoint inhibitors. As we move forward into the age of precision medicine, it is vital that we define the factors that influence the interplay between the triad immune system-microbiota-cancer. This knowledge will contribute to improve the therapeutic response to current approaches and will unravel novel targets for immunotherapy.

Past appendectomy may be related to early cognitive dysfunction in Parkinson's disease.

INTRODUCTION: The vermiform appendix is a potential site of initiation of Parkinson's disease (PD) pathology. We hypothesized that the appendectomy earlier in life may alter the clinical expression of PD. OBJECTIVE: To explore the effects of appendectomy prior to onset of PD motor symptoms on patients' symptoms, in particular on cognitive dysfunction. METHODS: Two hundred and sixty-two consecutive PD patients were asked about past history of appendectomy and underwent an evaluation, which included the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Schwab & England Independence Scale (S&E), Dementia Rating Scale-2 (DRS-2), Apathy Evaluation Scale, Hospital Anxiety and Depression Scale, and Brief Smell Identification Test. Motor symptoms were evaluated in OFF and ON states. Non-parametric group comparisons and logistic regressions were used for data analyses. RESULTS: Thirty-one patients (11.8%) had history of appendectomy prior to PD onset. These patients had more severe motor symptoms (UPDRS-III and H&Y) and lower functional independence (S&E) in ON and had higher frequency of cognitive dysfunction (DRS-2 Initiation/Perseveration, Conceptualization, and Memory subscales) (p < 0.05). The association between history of appendectomy and cognitive dysfunction was evident only in patients with late onset PD (≥ 55 years) and with disease duration ≤ 5 years. History of appendectomy remained statistically associated with impairment on DRS-2 Conceptualization and Memory subscales, when demographic and clinical variables were considered. CONCLUSION: History of appendectomy appears to alter the clinical expression of late onset PD, with early cognitive impairment, more severe motor symptoms in ON, and poorer functional independence under anti-parkinsonian medication.

Uraemic Encephalopathy in a Persian Cat with Chronic Kidney Disease.

Uraemic encephalopathy (UE) is rarely associated with acute kidney injury or chronic kidney disease in domestic animals, and we now report the first case in a cat. The animal presented with hypothermia, apathy, lethargy, depression, severe dehydration, uraemic breath, elevated serum urea nitrogen and creatine concentrations, and eventual seizures and coma prior to death. Gross necropsy findings included severe bilateral renal scarring, ulcerative stomatitis and glossitis, and uraemic gastropathy. Microscopic lesions of diffuse interstitial fibrosis, multifocal mineralization and lymphoplasmacytic interstitial nephritis were seen in the kidneys. There was symmetrical, bilateral spongy vacuolation of the white matter of the basal nuclei and cerebellum and Alzheimer type II astrocytes in the cerebral cortex and hippocampus. Glial fibrillary acid protein immunolabelling was absent or faint in astrocytes of the cerebral grey matter. UE should be included in the differential diagnosis in animals with chronic kidney disease and neurological signs.

Profiling the participants in creative tourism activities: Case studies from small and medium sized cities and rural areas from Continental Portugal.

Although cultural tourists increasingly seek to experience cultural events actively and to directly engage in creative activities, empirical knowledge about the creative tourist remains limited. This study aims to characterize the motivations and profile of creative tourists. The data was collected through a survey of participants in creative tourism activities in Portugal developed by 40 pilot institutions of the CREATOUR project during 2017 and 2018, with 814 usable questionnaires collected and validated. The questionnaire had 30 questions and marked the first time this kind of research was conducted in Portugal. The questionnaire included questions on: the composition of their travel companions, their previous participation in a creative tourism experience, reasons for visiting the destination, their characterization of the creative tourism experience, an evaluation of their creative tourism experience, and their socio-demographic profile. Using a cluster analysis to analyse the data, three clusters were found: Novelty-Seekers, Knowledge and Skills Learners, and Leisure Creative-Seekers.

Transcriptional responses of Candida glabrata biofilm cells to fluconazole are modulated by the carbon source.

Candida glabrata is an important human fungal pathogen known to trigger serious infections in immune-compromised individuals. Its ability to form biofilms, which exhibit high tolerance to antifungal treatments, has been considered as an important virulence factor. However, the mechanisms involving antifungal resistance in biofilms and the impact of host niche environments on these processes are still poorly defined. In this study, we performed a whole-transcriptome analysis of C. glabrata biofilm cells exposed to different environmental conditions and constraints in order to identify the molecular pathways involved in fluconazole resistance and understand how acidic pH niches, associated with the presence of acetic acid, are able to modulate these responses. We show that fluconazole treatment induces gene expression reprogramming in a carbon source and pH-dependent manner. This is particularly relevant for a set of genes involved in DNA replication, ergosterol, and ubiquinone biosynthesis. We also provide additional evidence that the loss of mitochondrial function is associated with fluconazole resistance, independently of the growth condition. Lastly, we propose that C. glabrata Mge1, a cochaperone involved in iron metabolism and protein import into the mitochondria, is a key regulator of fluconazole susceptibility during carbon and pH adaptation by reducing the metabolic flux towards toxic sterol formation. These new findings suggest that different host microenvironments influence directly the physiology of C. glabrata, with implications on how this pathogen responds to antifungal treatment. Our analyses identify several pathways that can be targeted and will potentially prove to be useful for developing new antifungals to treat biofilm-based infections.