A dense ring of the trans-Neptunian object Quaoar outside its Roche limit.

Planetary rings are observed not only around giant planets1, but also around small bodies such as the Centaur Chariklo2 and the dwarf planet Haumea3. Up to now, all known dense rings were located close enough to their parent bodies, being inside the Roche limit, where tidal forces prevent material with reasonable densities from aggregating into a satellite. Here we report observations of an inhomogeneous ring around the trans-Neptunian body (50000) Quaoar. This trans-Neptunian object has an estimated radius4 of 555 km and possesses a roughly 80-km satellite5 (Weywot) that orbits at 24 Quaoar radii6,7. The detected ring orbits at 7.4 radii from the central body, which is well outside Quaoar's classical Roche limit, thus indicating that this limit does not always determine where ring material can survive. Our local collisional simulations show that elastic collisions, based on laboratory experiments8, can maintain a ring far away from the body. Moreover, Quaoar's ring orbits close to the 1/3 spin-orbit resonance9 with Quaoar, a property shared by Chariklo's2,10,11 and Haumea's3 rings, suggesting that this resonance plays a key role in ring confinement for small bodies.

The influence of inhibitors of apoptosis proteins (IAPs) on chronic rhinosinusitis with nasal polyps.

BACKGROUND: Inhibitors of apoptosis proteins (IAPs) modulate the inflammatory process, and may facilitate the formation of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to observe if IAPs were differently expressed between patients with CRSwNP and controls, and to correlate the expression of IAPs with some inflammatory markers, as with the response to nasal corticosteroids in patients with CRSwNP. METHODOLOGY: We obtained nasal biopsies from patients with CRSwNP (n=27) and controls (n=16). qRT-PCR measured the expression of IAPs and caspases, while Luminex assay measured the concentration of cytokines. Unpaired parametric tests and Principal Component Analysis (PCA) were used for statistical analysis. RESULTS: We observed lower expression of IAP genes (XIAP, BIRC2/IAP1, and BIRC3/IAP2) in CRSwNP patients compared to controls, and we identified that patients with bad response to corticosteroids presented lower levels of BIRC2/IAP1, XIAP, BCL2, CASP9, and IL-17, and higher levels of CASP7 and TGF-B. CONCLUSIONS: IAPs expression was downregulated in CRSwNP, and was associated with poorer response to nasal corticosteroids. The present findings suggest the importance of IAPs as a link between environment and the host inflammatory responses, and this pathway could be explored as a potential new target therapy for patients with CRSwNP.

Smell loss associated with SARS-CoV-2 is not clinically different from other viruses: a multicenter cohort study.

BACKGROUND: Although the COVID-19 pandemic has increased the prevalence of cases with olfactory loss, other respiratory viruses can also cause this condition. We aimed to compare the prevalence of acute SARS-CoV-2 infection and other respiratory viruses in patients with sudden smell loss, and to assess the impact of SARS-CoV-2 viral load and co-infection on olfactory symptoms. METHODS: Patients with sudden smell loss were recruited in a multicenter prospective cohort study in 15 hospitals in Brazil. Clinical questionnaire, Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test and nasopharyngeal swab to perform a PCR-based respiratory viral panel were collected at first visit (day 0) and 30 and 60 days after recruitment. RESULTS: 188 of 213 patients presented positive test result for SARS-CoV-2, among which 65 were co-infected with other respiratory viruses (e.g., rhinovirus, enterovirus, and parainfluenza). 25 had negative test results for SARS-CoV-2. Patients in both SARSCoV-2 and non-SARS-CoV-2 groups had objective anosmia (less than 2 points according to the psychophysical olfactory CCCRC) at day 0, with no significant difference between them. Both groups had significant smell scores improvement after 30 and 60 days, with no difference between them. Co-infection with other respiratory viruses, and SARS-CoV-2 viral load did not impact olfactory scores. CONCLUSION: Patients with sudden smell loss associated with SARS-CoV-2 and other respiratory viruses had similar presentation, with most participants initiating with anosmia, and total or near total recovery after 60 days. SARS-CoV-2 viral load and co-infections with other respiratory viruses were not associated with poorer olfactory outcomes.

The size, shape, density and ring of the dwarf planet Haumea from a stellar occultation.

Haumea-one of the four known trans-Neptunian dwarf planets-is a very elongated and rapidly rotating body. In contrast to other dwarf planets, its size, shape, albedo and density are not well constrained. The Centaur Chariklo was the first body other than a giant planet known to have a ring system, and the Centaur Chiron was later found to possess something similar to Chariklo's rings. Here we report observations from multiple Earth-based observatories of Haumea passing in front of a distant star (a multi-chord stellar occultation). Secondary events observed around the main body of Haumea are consistent with the presence of a ring with an opacity of 0.5, width of 70 kilometres and radius of about 2,287 kilometres. The ring is coplanar with both Haumea's equator and the orbit of its satellite Hi'iaka. The radius of the ring places it close to the 3:1 mean-motion resonance with Haumea's spin period-that is, Haumea rotates three times on its axis in the time that a ring particle completes one revolution. The occultation by the main body provides an instantaneous elliptical projected shape with axes of about 1,704 kilometres and 1,138 kilometres. Combined with rotational light curves, the occultation constrains the three-dimensional orientation of Haumea and its triaxial shape, which is inconsistent with a homogeneous body in hydrostatic equilibrium. Haumea's largest axis is at least 2,322 kilometres, larger than previously thought, implying an upper limit for its density of 1,885 kilograms per cubic metre and a geometric albedo of 0.51, both smaller than previous estimates. In addition, this estimate of the density of Haumea is closer to that of Pluto than are previous estimates, in line with expectations. No global nitrogen- or methane-dominated atmosphere was detected.

Evaluation of a battery of biotests to improve waste ecotoxicity assessment (HP 14), using incineration bottom ash as a case study.

The assessment of waste ecotoxicity (hazardous property HP14 in the European Union) is fundamental for proper waste classification and safe application/disposal. Biotests are relevant for evaluating waste complex matrices, but their efficiency is crucial to encourage their adoption at the industrial level. This work aims at evaluating possibilities of improving the efficiency of a biotest battery previously suggested in the literature, regarding test selection, duration, and/or laboratory resources optimization. Fresh incineration bottom ash (IBA) was the case study. The test battery analysed included standard aquatic (bacteria, microalgae, macrophytes, daphnids, rotifers, fairy shrimp) and terrestrial (bacteria, plants, earthworms, collembolans) organisms. The assessment followed an Extended Limit Test design (three dilutions of eluate or solid IBA) and the Lowest Ineffective Dilution (LID-approach) for ecotoxicity classification. The results emphasize the importance of testing different species. It was also evidenced that tests with daphnids and earthworms may be shortened to 24 h; the miniaturization of tests is suitable as e.g. differential sensitivity of microalgae and macrophytes was captured with low variability; alternative testing kits can be used when methodological difficulties are found. Microalgae were more sensitive than macrophytes. Similar results were found for the Thamnotoxkit and daphnids test for eluates with natural pH, so the former may be used as an alternative. B. rapa was the most sensitive organism, suggesting that it may be tested as the only terrestrial plant species and that minimum test duration is appropriate. F. candida does not appear to add information to the battery. The differences in sensitivity of A. fischeri and E. fetida compared to the remaining species were not significant enough to exclude them from the battery. Thus, this work suggests a biotest battery to test IBA comprising aquatic tests - Aliivibrio fischeri, Raphidocelis subcapitata (miniaturised test), and Daphnia magna (24 h when clear deleterious effects are observed) or Thamnocephalus platyurus (toxkit) - and terrestrial tests - Arthrobacter globiformis, Brassica rapa (14 d), and Eisenia fetida (24 h). Testing waste with natural pH is also recommended. The Extended Limit Test design considering the LID-approach seems useful in waste testing, particularly for the industry, involving low effort, test material requirements, and few laboratory resources. The LID-approach allowed for differentiating ecotoxic from non-ecotoxic effects and captured different sensitivities between species. Ecotoxicological assessment of other waste may benefit from these recommendations, but caution should be taken given the properties of each waste type.

Beta-blockers for the treatment of arrhythmias: Bisoprolol - a systematic review.

OBJECTIVES: Beta-blockers have long been successfully used for the treatment of both supraventricular and ventricular arrhythmias. However, differences exist between their chemical structure, pharmacokinetic and pharmacodynamic properties (absorption, bioavailability, metabolism, hydrophilic or lipophilic character, selective or non-selective nature, the presence or absence of intrinsic sympathomimetic activity), which may confer different antiarrhythmic properties to different beta-blockers. The aim of this study was to analyze the current existing evidence for bisoprolol for the treatment of both supraventricular and ventricular arrhythmias. MATERIAL AND METHODS: Using the keywords "bisoprolol" and "arrhythmias" or "atrial fibrillation" or "ventricular tachycardia" or "premature ventricular complexes" or "ventricular fibrillation", the Medline database was searched for articles in English or French until April 2020 assessing the role of bisoprolol in the treatment of arrhythmias. Data was then analyzed according to the type of arrhythmia treated and the quality of evidence using the GRADE approach. RESULTS: A total of 325 studies were identified, of which 28 were considered relevant to the current topic. Among these studies, 19 assessed the role of bisoprolol for the treatment of supraventricular arrhythmias, 8 its role in treating ventricular arrhythmias and 1 its role in supraventricular and ventricular arrhythmias. The quality of evidence varied from low (7 studies) to high (5 studies). CONCLUSION: Current evidence exists supporting the use of bisoprolol for the treatment of supraventricular arrhythmias, especially for rate control during atrial fibrillation. Evidence also exists for its efficacy in the treatment of ventricular arrhythmias, both in primary and in secondary prevention.

Spatial dynamics of the COVID-19 pandemic in Brazil.

The objective of this study was to analyse the dynamics of spatial dispersion of the coronavirus disease 2019 (COVID-19) in Brazil by correlating them to socioeconomic indicators. This is an ecological study of COVID-19 cases and deaths between 26 February and 31 July 2020. All Brazilian counties were used as units of analysis. The incidence, mortality, Bayesian incidence and mortality rates, global and local Moran indices were calculated. A geographic weighted regression analysis was conducted to assess the relationship between incidence and mortality due to COVID-19 and socioeconomic indicators (independent variables). There were confirmed 2 662 485 cases of COVID-19 reported in Brazil from February to July 2020 with higher rates of incidence in the north and northeast. The Moran global index of incidence rate (0.50, P = 0.01) and mortality (0.45 with P = 0.01) indicate a positive spatial autocorrelation with high standards in the north, northeast and in the largest urban centres between cities in the southeast region. In the same period, there were 92 475 deaths from COVID-19, with higher mortality rates in the northern states of Brazil, mainly Amazonas, Pará and Amapá. The results show that there is a geospatial correlation of COVID-19 in large urban centres and regions with the lowest human development index in the country. In the geographic weighted regression, it was possible to identify that the percentage of people living in residences with density higher than 2 per dormitory, the municipality human development index (MHDI) and the social vulnerability index were the indicators that most contributed to explaining incidence, social development index and the municipality human development index contributed the most to the mortality model. We hope that the findings will contribute to reorienting public health responses to combat COVID-19 in Brazil, the new epicentre of the disease in South America, as well as in other countries that have similar epidemiological and health characteristics to those in Brazil.

The predictive value of serial serum estradiol and serial endometrial volume on endometrial receptivity on assisted reproductive technology cycles.

BACKGROUND: Diagnosis of endometrial receptivity is still unclear and conflicting. Despite advances in embryo development during assisted reproductive technologies (ART) cycles, the intricate process of implantation is still matter for debate and research. MATERIALS AND METHODS: Prospective case control of 169 subjects during ovarian controlled stimulation for ART. Endometrial receptivity assessment to predict clinical pregnancy with serial continuous biochemical (serum estradiol) and biophysical (endometrial volume and adjusted endometrial volume) parameters were used. Both parameters were compared between negative and positive outcome in terms of clinical pregnancy. RESULTS: No statistical difference was noted between the two groups in terms of demographics and ART procedures and scores. Serum estradiol was significantly higher in the positive group from day 8 after ovarian controlled stimulation. Endometrial volume and adjusted endometrial volume were significantly higher in the positive group as soon as day 6 of ovarian controlled stimulation. CONCLUSIONS: Continuous serum estradiol and 3D endometrial volume and adjusted endometrial volumes may reflect endometrial changes during ART procedures and provide a useful real time tool for clinicians in predicting endometrial receptivity.

Genome-wide association study and pathway analysis for carcass fatness in Nellore cattle measured by ultrasound.

Identifying genes or genomic regions influencing carcass-quality traits such as fatness (FTN) is essential to optimize the genetic selection processes in beef cattle. The aim of this study was to identify genomic regions associated with FTN in Nellore cattle as well as to elucidate the metabolic pathways related to the phenotypic expression. Ultrasound-based measurements of FTN were collected in 11 750 animals, with 39 903 animals in the pedigree file. Additionally, 1440 animals were genotyped using the GGP-indicus 35K SNP panel, which contained 33 623 SNPs after quality control. Twenty genes related to FTN were found on 11 chromosomes, explaining 12.96% of the total additive genetic variance. Gene ontology revealed seven genes: NR1L2, PKD2, GSK3ß, EXT1, RAD51B, SORCS1 and DPH6, associated with important processes related to FTN. In addition, novel candidate genes (MAATS1, LYPD1, CDK5RAP2, RAD51B, c13H2Oorf96 and TRAPPC11) were detected and could provide further knowledge to uncover genetic regions associated to carcass fatness in beef cattle.

Nerve transfers for acute flaccid myelitis: a case series.

BACKGROUND: Acute flaccid myelitis (AFM) syndrome consists of loss of lower motor neurons following a viral infection, with preserved sensory function. It usually affects the upper limbs asymmetrically, with proximal more than distal muscle involvement. METHODS: Five cases were surgically treated with nerve transfers: spinal accessory to suprascapular nerve transfer (4 patients), branch of radial nerve to axillary nerve transfer (Somsak's procedure) (2 patients), and transfer of a fascicle of the ulnar nerve to the motor branch to the biceps (Oberlin's procedure) (1 patient). RESULTS: Motor improvement was seen in three cases. Widespread motor involvement was associated with poor outcome. CONCLUSION: This small series of cases reinforces that nerve transfers are a reliable option for treatment of selected children with AFM.

Developing a social prescribing local system in a European Mediterranean country: a feasibility study to promote active and healthy aging.

BACKGROUND: Social Prescribing (SP) is an innovative strategy to respond to the non-clinical health needs of the population. A Social Prescribing Local System (SPLS) can be defined as a set of joined community, health, and social organizations to foster SP-oriented activities. This study aimed to develop and assess the feasibility of an SPLS implemented in a Mediterranean country, to promote health and wellbeing and contribute to active and healthy aging. METHODS: A mixed-methods approach was followed, including three sequential components: 1) Cross-sectional online survey targeting health professionals (HP) working in a primary health care cluster, Portugal's southern region; 2) Pilot study implementing an on-the-job training program for HP, designed to meet identified training needs in the survey; 3) Focus group (FG) with the HP who participated in the pilot study, two individual interviews, with an elderly patient and a community provider for assessing the satisfaction with the pilot test. RESULTS: Sixty-five HP completed the survey; of these, 13 completed the theoretical part of the on-the-job training program; and six (out of these 13) completed the full program. Five HP participated in the FG, one patient and one community provider were interviewed. The surveyed HP perceived as facilitators to implement SP: an automatic system of notifications to prompt the use of SP, contribute to patient satisfaction, human and community resources' stability. The survey also highlighted barriers to SP implementation: length of appointments, shortage of human resources, data records confidentiality, low patient adherence rates, bureaucratic issues, time constraints, and financial costs. Participants were satisfied with the training. Identified SPLS implementation benefits were grouped into four dimensions (from the qualitative approach): gains for patients' health and wellbeing, support for the health services, sustainability of the community resources, and HP' professional satisfaction. CONCLUSIONS: Our study took the first steps towards the implementation of an SPLS. Findings reinforce that training HP in SP and on-the-job training seems feasible. This approach was well received and appears to represent a suitable and sustainable strategy. It can promote professional satisfaction, support health services, contribute to the stability of community resources, improve health and promote active and healthy aging.

miRNA-205-5p can be related to T2-polarity in Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: microRNAs (miRNAs) are directly associated with inflammatory response, but their direct role in CRSwNP (chronic rhinosinusitis with nasal polyps) remains evasive. This study aimed to compare the expression of several miRNAs in tissue samples obtained from patients with CRSwNP and controls and to evaluate if miRNAs correlate to a specific inflammatory pattern (T1, T2, T17, and Treg) or intensity of symptoms in CRSwNP. METHODS: nasal polyps (from patients with CRSwNP - n=36) and middle turbinate mucosa (from control patients - n=41) were collected. Microarray determined human mature miRNA expression, and the results obtained were validated by qPCR. miRNAs that were differentially expressed were then correlated to cytokine proteins (by Luminex), tissue eosinophilia, and SNOT-22. RESULTS: After microarray and qPCR analyses, six microRNAs were up-regulated in CRSwNP samples when compared with controls: miR-205-5p, miR-221-3p, miR-222-3p, miR-378a-3p, miR-449a and miR-449b-5p. All these miRNAs are directly implicated with cell cycle regulation and apoptosis, and to a minor extent, with inflammation. Importantly, miR-205-5p showed a significantly positive correlation with IL-5 concentration and eosinophil count at the tissue and with the worst SNOT-22 score. CONCLUSIONS: miRNA 205-5p was increased in CRSwNP compared to controls, and it was especially expressed in CRSwNP patients with higher T2 inflammation (measured by both IL-5 levels and local eosinophilia) and worst clinical presentation. This miRNA may be an interesting target to be explored in patients with CRSwNP.

A ring system detected around the Centaur (10199) Chariklo.

Hitherto, rings have been found exclusively around the four giant planets in the Solar System. Rings are natural laboratories in which to study dynamical processes analogous to those that take place during the formation of planetary systems and galaxies. Their presence also tells us about the origin and evolution of the body they encircle. Here we report observations of a multichord stellar occultation that revealed the presence of a ring system around (10199) Chariklo, which is a Centaur--that is, one of a class of small objects orbiting primarily between Jupiter and Neptune--with an equivalent radius of 124 ± 9 kilometres (ref. 2). There are two dense rings, with respective widths of about 7 and 3 kilometres, optical depths of 0.4 and 0.06, and orbital radii of 391 and 405 kilometres. The present orientation of the ring is consistent with an edge-on geometry in 2008, which provides a simple explanation for the dimming of the Chariklo system between 1997 and 2008, and for the gradual disappearance of ice and other absorption features in its spectrum over the same period. This implies that the rings are partly composed of water ice. They may be the remnants of a debris disk, possibly confined by embedded, kilometre-sized satellites.

Subendometrial resistence and pulsatility index assessment of endometrial receptivity in assisted reproductive technology cycles.

OBJECTIVE: To evaluate Subendometrial and Uterine artery resistance and pulsatility index continuous analysis as a predictor of Endometrial receptivity in Assisted Reproductive Technology (ART) Cycles. DESIGN: Serial 2D transvaginal coloured power doppler ultrasound performed in women on ART cycle to evaluate a pattern that better predicts implantation rates. One hundred sixty-nine subjects on a prospective case control study were assessed. Uterine artery and Subendometrial resistance and pulsatility index was performed to all subjects at baseline (prior to ovarian controlled stimulation), at day 6, 8 and 10 of controlled ovarian stimulation, at trigger day and at embryo transfer day. Also the ratio of fluxometric parameters between Subendometrial blood flow and uterine artery was measured. RESULTS: No statistical difference was noted between two groups in terms of demographics and ART procedures and scores. Uterine artery resistance and pulsatility index showed statistical difference between the two groups (implantation versus non-implantation group). Also statistical significance was obtained between two groups in terms of Subendometrial vascularization. Ratio between Subendometrial and Uterine artery showed lower values of fluxometric parameters in all range for the Subendometrial territory. CONCLUSIONS: Serial Subendometrial and Uterine artery fluxometry may be a useful tool for clinicians in predicting endometrial receptivity enhancing elective embryo transfers in the same ART cycle.

Elevated plasma ferritin in elderly individuals with high neocortical amyloid-ß load.

Ferritin, an iron storage and regulation protein, has been associated with Alzheimer's disease (AD); however, it has not been investigated in preclinical AD, detected by neocortical amyloid-ß load (NAL), before cognitive impairment. Cross-sectional analyses were carried out for plasma and serum ferritin in participants in the Kerr Anglican Retirement Village Initiative in Aging Health cohort. Subjects were aged 65-90 years and were categorized into high and low NAL groups via positron emission tomography using a standard uptake value ratio cutoff=1.35. Ferritin was significantly elevated in participants with high NAL compared with those with low NAL, adjusted for covariates age, sex, apolipoprotein E ɛ4 carriage and levels of C-reactive protein (an inflammation marker). Ferritin was also observed to correlate positively with NAL. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve (AUC)=0.766), but was outperformed when plasma ferritin was added to the base model (AUC=0.810), such that at 75% sensitivity, the specificity increased from 62 to 71% on adding ferritin to the base model, indicating that ferritin is a statistically significant additional predictor of NAL over and above the base model. However, ferritin's contribution alone is relatively minor compared with the base model. The current findings suggest that impaired iron mobilization is an early event in AD pathogenesis. Observations from the present study highlight ferritin's potential to contribute to a blood biomarker panel for preclinical AD.

Vertebrate SLRP family evolution and the subfunctionalization of osteoglycin gene duplicates in teleost fish.

BACKGROUND: Osteoglycin (OGN, a.k.a. mimecan) belongs to cluster III of the small leucine-rich proteoglycans (SLRP) of the extracellular matrix (ECM). In vertebrates OGN is a characteristic ECM protein of bone. In the present study we explore the evolution of SLRP III and OGN in teleosts that have a skeleton adapted to an aquatic environment. RESULTS: The SLRP gene family has been conserved since the separation of chondrichthyes and osteichthyes. Few gene duplicates of the SLRP III family exist even in the teleosts that experienced a specific whole genome duplication. One exception is ogn for which duplicate copies were identified in fish genomes. The ogn promoter sequence and in vitro mesenchymal stem cell (MSC) cultures suggest the duplicate ogn genes acquired divergent functions. In gilthead sea bream (Sparus aurata) ogn1 was up-regulated during osteoblast and myocyte differentiation in vitro, while ogn2 was severely down-regulated during bone-derived MSCs differentiation into adipocytes in vitro. CONCLUSIONS: Overall, the phylogenetic analysis indicates that the SLRP III family in vertebrates has been under conservative evolutionary pressure. The retention of the ogn gene duplicates in teleosts was linked with the acquisition of different functions. The acquisition by OGN of functions other than that of a bone ECM protein occurred early in the vertebrate lineage.

A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location.

The search for antiprion compounds has been encouraged by the fact that transmissible spongiform encephalopathies (TSEs) share molecular mechanisms with more prevalent neurodegenerative pathologies, such as Parkinson's and Alzheimer's diseases. Cellular prion protein (PrPC) conversion into protease-resistant forms (protease-resistant PrP [PrPRes] or the scrapie form of PrP [PrPSc]) is a critical step in the development of TSEs and is thus one of the main targets in the screening for antiprion compounds. In this work, three trimethoxychalcones (compounds J1, J8, and J20) and one oxadiazole (compound Y17), previously identified in vitro to be potential antiprion compounds, were evaluated through different approaches in order to gain inferences about their mechanisms of action. None of them changed PrPC mRNA levels in N2a cells, as shown by reverse transcription-quantitative real-time PCR. Among them, J8 and Y17 were effective in real-time quaking-induced conversion reactions using rodent recombinant PrP (rPrP) from residues 23 to 231 (rPrP23-231) as the substrate and PrPSc seeds from hamster and human brain. However, when rPrP from residues 90 to 231 (rPrP90-231), which lacks the N-terminal domain, was used as the substrate, only J8 remained effective, indicating that this region is important for Y17 activity, while J8 seems to interact with the PrPC globular domain. J8 also reduced the fibrillation of mouse rPrP23-231 seeded with in vitro-produced fibrils. Furthermore, most of the compounds decreased the amount of PrPC on the N2a cell surface by trapping this protein in the endoplasmic reticulum. On the basis of these results, we hypothesize that J8, a nontoxic compound previously shown to be a promising antiprion agent, may act by different mechanisms, since its efficacy is attributable not only to PrP conversion inhibition but also to a reduction of the PrPC content on the cell surface.

Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. There is no test for its definitive diagnosis in routine clinical practice. Although phase III clinical trials have failed, only symptomatic treatment is currently available; a possible reason for these failed trials is that intervention commenced at an advanced stage of the disease. The hallmarks of an AD brain include plaques comprising of extracellular beta-amyloid (Aß) protein aggregates and intracellular hyperphosphorylated neurofibrillary tangles of tau. Research into the preclinical diagnosis of AD has provided considerable evidence regarding early neuropathological changes using brain Aß imaging and the cerebrospinal fluid biomarkers, Aß and tau. Both these approaches have limitations that are expensive, invasive or time consuming and thus preclude them from screening at-risk population. Recent studies have demonstrated the presence of Aß plaques in the eyes of AD subjects, which is positively associated with their brain Aß burden. Thus ocular biomarkers point to a potential avenue for an earlier, relatively low-cost diagnosis in order for therapeutic interventions to be effective. Here we review the literature that spans the investigation for the presence of Aß in aging eyes and the significance of its deposition in relation to AD pathology. We discuss clinical studies investigating in vivo imaging of Aß in the eye and its association with brain Aß burden and therapies that target ocular Aß. Finally, we focus on the need to characterize AD-specific retinal Aß to differentiate Aß found in some eye diseases. Based on the current evidence, we conclude that integration of ocular biomarkers that can correctly predict brain Aß burden would have an important role as a non-invasive, yet economical surrogate marker in the diagnostic process of AD.

Osseointegration of zirconia and titanium implants in a rabbit tibiae model evaluated by microtomography, histomorphometry and fluorochrome labeling analyses.

OBJECTIVES: This study compares the osseointegration of machined-zirconia implants containing yttria (M-Y-TZP) with machined (M-Ti) and resorbable blast media (RBM-Ti) titanium implants. MATERIAL AND METHODS: M-Y-TZP, M-Ti and RBM-Ti implants were randomly placed in rabbit tibiae. Fluorochrome bone labels (tetracycline, alizarin and calcein) were administered at different time periods. After 8 weeks, osseointegration was evaluated in terms of bone-to-implant contact (BIC), new bone area (nBA), remaining cortical bone area (rBA) and temporal quantification of fluorochromes, using micro-CT and histomorphometric analyses. RESULTS: RBM-Ti implants showed higher resorption of the remaining cortical bone and bone formation (rBA = 36.9% and nBA = 38.8%) than M-Y-TZP implants (rBA = 48% and nBA = 26.5%). The BIC values showed no differences among the groups in the cortical region (mean = 52.2%) but in the medullary region, they were 0.45-fold higher in the RBM-Ti group (51.2%) than in the M-Y-TZP group (35.2%). In all groups, high incorporation of tetracycline was observed (2nd to 4th weeks), followed by alizarin (4th to 6th weeks) and calcein (6th to 8th weeks). In the cortical region, incorporation of tetracycline was similar between RBM-Ti (49.8%) and M-Y-TZP (35.9%) implants, but higher than M-Ti (28.2%) implants. Subsequently, alizarin and calcein were 1.1-fold higher in RBM-Ti implants than in the other implants. In the medullary region, no significant differences were observed for all fluorochromes. CONCLUSION: All implants favored bone formation and consequently promoted primary stability. Bone formation around the threads was faster in RBM-Ti and M-Y-TZP implants than in M-Ti implants, but limited bone remodeling with M-Y-TZP implants over time can have significant effects on secondary stability, suggesting caution for its use as an alternative substitute for titanium implants.