Asprosin levels in patients with type 2 diabetes mellitus, metabolic syndrome and obesity: A systematic review and meta-analysis.

BACKGROUND & AIMS: Asprosin is a promising candidate for novel treatments for metabolic-endocrine disorders. The objective of this systematic review and meta-analysis was to consolidate the existing evidence regarding asprosin levels in patients diagnosed with type 2 diabetes (T2D), metabolic syndrome (MetS), and obesity. METHODS: Scopus, Embase, PubMed, Ovid/Medline, and Web of Science were systematically searched without restrictions. We only used the standardized mean differences (SMD) with their 95 % confidence intervals (95 % CI) as the effect measure. A random-effects model (DerSimonian and Laird method) was used for the meta-analysis. Risk of bias was assessed with the Newcastle-Ottawa Scale and Newcastle-Ottawa Scale for Cross-Sectional Studies. RESULTS: Twenty-six studies (n = 3,787) were included in the meta-analysis. Participants with T2D had higher asprosin values than those without T2D (SMD: 1.64; 95 % CI: 1.08-2.21; I2 = 97 %). Patients with MetS had higher asprosin levels compared to those without MetS (SMD: 0.99; 95 % CI: 0.34-1.64; I2 = 96 %). Patients with obesity had higher asprosin levels than participants without obesity (SMD: 1.49; 95 % CI: 0.23-2.76; I2 = 98 %). CONCLUSIONS: Asprosin is significantly higher in patients with either T2D, MetS, or obesity, compared with controls.

Associations of alcohol and tobacco use with psychotic, depressive and developmental disorders revealed via multimodal neuroimaging.

People affected by psychotic, depressive and developmental disorders are at a higher risk for alcohol and tobacco use. However, the further associations between alcohol/tobacco use and symptoms/cognition in these disorders remain unexplored. We identified multimodal brain networks involving alcohol use (n = 707) and tobacco use (n = 281) via supervised multimodal fusion and evaluated if these networks affected symptoms and cognition in people with psychotic (schizophrenia/schizoaffective disorder/bipolar, n = 178/134/143), depressive (major depressive disorder, n = 260) and developmental (autism spectrum disorder/attention deficit hyperactivity disorder, n = 421/346) disorders. Alcohol and tobacco use scores were used as references to guide functional and structural imaging fusion to identify alcohol/tobacco use associated multimodal patterns. Correlation analyses between the extracted brain features and symptoms or cognition were performed to evaluate the relationships between alcohol/tobacco use with symptoms/cognition in 6 psychiatric disorders. Results showed that (1) the default mode network (DMN) and salience network (SN) were associated with alcohol use, whereas the DMN and fronto-limbic network (FLN) were associated with tobacco use; (2) the DMN and fronto-basal ganglia (FBG) related to alcohol/tobacco use were correlated with symptom and cognition in psychosis; (3) the middle temporal cortex related to alcohol/tobacco use was associated with cognition in depression; (4) the DMN related to alcohol/tobacco use was related to symptom, whereas the SN and limbic system (LB) were related to cognition in developmental disorders. In summary, alcohol and tobacco use were associated with structural and functional abnormalities in DMN, SN and FLN and had significant associations with cognition and symptoms in psychotic, depressive and developmental disorders likely via different brain networks. Further understanding of these relationships may assist clinicians in the development of future approaches to improve symptoms and cognition among psychotic, depressive and developmental disorders.

Calculating Within-Pair Difference Scores in the Co-twin Control Design. Effects of Alternative Strategies.

Co-twin studies are an elegant and powerful design that allows controlling for the effect of confounding variables, including genetic and a range of environmental factors. There are several approaches to carry out this design. One of the methods commonly used, when contrasting continuous variables, is to calculate difference scores between members of a twin pair on two associated variables, in order to analyse the covariation of such differences. However, information regarding whether and how the different ways of estimating within-pair difference scores may impact the results is scant. This study aimed to compare the results obtained by different methods of data transformation when performing a co-twin study and test how the magnitude of the association changes using each of those approaches. Data was simulated using a direction of causation model and by fixing the effect size of causal path to low, medium, and high values. Within-pair difference scores were calculated as relative scores for diverse within-pair ordering conditions or absolute scores. Pearson's correlations using relative difference scores vary across the established scenarios (how twins were ordered within pairs) and these discrepancies become larger as the within-twin correlation increases. Absolute difference scores tended to produce the lowest correlation in every condition. Our results show that both using absolute difference scores or ordering twins within pairs, may produce an artificial decrease in the magnitude of the studied association, obscuring the ability to detect patterns compatible with causation, which could lead to discrepancies across studies and erroneous conclusions.

Optimization of indirect wastewater characterization using led spectrophotometry: a comparative analysis of regression, scaling, and dimensionality reduction methods.

LED spectrophotometry is a robust technique for the indirect characterization of wastewater pollutant load through correlation modeling. To tackle this issue, a dataset with 1300 samples was collected, from both raw and treated wastewater from 45 wastewater treatment plants in Spain and Chile collected over 4 years. The type of regressor, scaling, and dimensionality reduction technique and nature of the data play crucial roles in the performance of the processing pipeline. Eighty-four pipelines were tested through exhaustive experimentation resulting from the combination of 7 regression techniques, 3 scaling methods, and 4 possible dimensional reductions. Those combinations were tested on the prediction of chemical oxygen demand (COD) and total suspended solids (TSS). Each pipeline underwent a tenfold cross-validation on 15 sub-datasets derived from the original dataset, accounting for variations in plants and wastewater types. The results point to the normalization of the data followed by a conversion through the PCA to finally apply a Random Forest Regressor as the combination which stood out These results highlight the importance of modeling strategies in wastewater management using techniques such as LED spectrophotometry.

Characterization of acute effects of football competition on hamstring muscles by muscle functional MRI techniques.

Muscle functional MRI identifies changes in metabolic activity in each muscle and provides a quantitative index of muscle activation and damage. No previous studies have analyzed the hamstrings activation over a football match. This study aimed at detecting different patterns of hamstring muscles activation after a football game, and to examine inter- and intramuscular differences (proximal-middle-distal) in hamstring muscles activation using transverse relaxation time (T2)-weighted magnetic resonance images. Eleven healthy football players were recruited for this study. T2 relaxation time mapping-MRI was performed before (2 hours) and immediately after a match (on average 13 min). The T2 values of each hamstring muscle at the distal, middle, and proximal portions were measured. The primary outcome measure was the increase in T2 relaxation time value after a match. Linear mixed models were used to detect differences pre and postmatch. MRI examination showed that there was no obvious abnormality in the shape and the conventional T2 weighted signal of the hamstring muscles after a match. On the other hand, muscle functional MRI T2 analysis revealed that T2 relaxation time significantly increased at distal and middle portions of the semitendinosus muscle (p = 0.0003 in both cases). By employing T2 relaxation time mapping, we have identified alterations within the hamstring muscles being the semitendinosus as the most engaged muscle, particularly within its middle and distal thirds. This investigation underscores the utility of T2 relaxation time mapping in evaluating muscle activation patterns during football matches, facilitating the detection of anomalous activation patterns that may warrant injury reduction interventions.

Breast segmentation in infrared thermography from characteristical inframammary shape.

Infrared thermography is gaining relevance in breast cancer assessment. For this purpose, breast segmentation in thermograms is an important task for performing automatic image analysis and detecting possible temperature changes that indicate the presence of malignancy. However, it is not a simple task since the breast limit borders, especially the top borders, often have low contrast, making it difficult to isolate the breast area. Several algorithms have been proposed for breast segmentation, but these highly depend on the contrast at the lower breast borders and on filtering algorithms to remove false edges. This work focuses on taking advantage of the distinctive inframammary shape to simplify the definition of the lower breast border, regardless of the contrast level, which indeed also provides a strong anatomical reference to support the definition of the poorly marked upper boundary of the breasts, which has been one of the major challenges in the literature. In order to demonstrate viability of the proposed technique for an automatic breast segmentation, we applied it to a database with 180 thermograms and compared their results with those reported by others in the literature. We found that our approach achieved a high performance, in terms of Intersection over Union of 0.934, even higher than that reported by artificial intelligence algorithms. The performance is invariant to breast sizes and thermal contrast of the images.

Description of the local hemodynamic environment in intracranial aneurysm wall subdivisions.

Intracranial aneurysms (IAs) pose severe health risks influenced by hemodynamics. This study focuses on the intricate characterization of hemodynamic conditions within the IA walls and their influence on bleb development, aiming to enhance understanding of aneurysm stability and the risk of rupture. The methods emphasized utilizing a comprehensive dataset of 359 IAs and 213 IA blebs from 268 patients to reconstruct patient-specific vascular models, analyzing blood flow using finite element methods to solve the unsteady Navier-Stokes equations, the segmentation of aneurysm wall subregions and the hemodynamic metrics wall shear stress (WSS), its metrics, and the critical points in WSS fields were computed and analyzed across different aneurysm subregions defined by saccular, streamwise, and topographical divisions. The results revealed significant variations in these metrics, correlating distinct hemodynamic environments with wall features on the aneurysm walls, such as bleb formation. Critical findings indicated that regions with low WSS and high OSI, particularly in the body and central regions of aneurysms, are prone to conditions that promote bleb formation. Conversely, areas exposed to high WSS and positive divergence, like the aneurysm neck, inflow, and outflow regions, exhibited a different but substantial risk profile for bleb development, influenced by flow impingements and convergences. These insights highlight the complexity of aneurysm behavior, suggesting that both high and low-shear environments can contribute to aneurysm pathology through distinct mechanisms.

Effect of different Volumes of exercise on skin temperature responses over the following 24 hours.

Skin temperature responses have been advocated to indicate exercise-induced muscle soreness and recovery status. While the evidence is contradictory, we hypothesize that the presence of muscle damage and the time window of measurement are confounding factors in the skin temperature response. The objective was to determine whether skin temperature is influenced by different workloads and the time course of temperature measurements over the following 24 h. 24 trained male military were assigned to one of three groups: GC group (n = 8) serving as control not performing exercises, GE group (n = 8) performing a simulated military combat protocol in an exercise track with different obstacles but designed not to elicit muscle damage, and the GEMD group (n = 8) performing the simulated military combat protocol plus 5 sets of 20 drop jumps, with 10-sec between repetitions and with 2-min of rest between sets aiming to induce muscle damage. Skin temperature was measured using infrared thermography before exercise (Pre) and 4 (Post4h), 8 (Post8h) and 24h (Post24h) post-exercise. Perception of pain (DOMS) was evaluated Pre, Post24h, and Post48h, and countermovement jump height was evaluated at Pre and Post24h. DOMS did not differ between groups in the Pre and Post24h measures but GEMD presented higher DOMS than the other groups at Post48h (p < 0.001 and large effect size). Jump height did not differ for GEMD and GC, and GE presented higher jump height at Post24h than GC (p = 0.02 and large effect size). Skin temperature responses of GEMD and GG were similar in all measurement moments (p > 0.22), and GE presented higher skin temperature than the GC and the GEMD groups at Post24h (p < 0.01 and large effect sizes). In conclusion, although physical exercise elicits higher skin temperature that lasts up to 24 h following the efforts, muscle soreness depresses this response.

Protective effects of mesenchymal stromal cell-derived secretome on dermonecrosis induced in rabbits by Loxosceles intermedia spider venom.

Background: Loxoscelism refers to a set of clinical manifestations caused by the bite of spiders from the Loxosceles genus. The classic clinical symptoms are characterized by an intense inflammatory reaction at the bite site followed by local necrosis and can be classified as cutaneous loxoscelism. This cutaneous form presents difficult healing, and the proposed treatments are not specific or effective. This study aimed to evaluate the protective effect of mesenchymal stromal cells-derived secretome on dermonecrosis induced by Loxosceles intermedia spider venom in rabbits. Methods: Sixteen rabbits were distributed into four groups (n = 4). Except for group 1 (G1), which received only PBS, the other three groups (G2, G3, and G4) were initially challenged with 10 µg of L. intermedia venom, diluted in 100 µL of NaCl 0.9%, by intradermic injection in the interscapular region. Thirty minutes after the challenge all groups were treated with secretome, except for group 2. Group 1 (G1-control group) received intradermal injection (ID) of 60 µg of secretome in 0.15 M PBS; Group 2 (G2) received 0.9% NaCl via ID; Group 3 (G3) received 60 µg of secretome, via ID and Group 4 (G4), received 60 µg of secretome by intravenous route. Rabbits were evaluated daily and after 15 days were euthanized, necropsied and skin samples around the necrotic lesions were collected for histological analysis. Results: Rabbits of G1 did not present edema, erythema, hemorrhagic halo, or necrosis. In animals from G2, G3, and G4, edema appeared after 6h. However, minor edema was observed in the animals of G2 and G3. Hemorrhagic halo was observed in animals, six hours and three days after, on G2, G3, and G4. Macroscopically, in G4, only one animal out of four had a lesion that evolved into a dermonecrotic wound. No changes were observed in the skin of the animals of G1, by microscopic evaluation. All animals challenged with L. intermedia venom showed similar alterations, such as necrosis and heterophilic infiltration. However, animals from G4 showed fibroblast activation, early development of connective tissue, neovascularization, and tissue re-epithelialization, indicating a more prominent healing process. Conclusion: These results suggest that secretome from mesenchymal stromal cells cultured in a xeno-free and human component-free culture media can be promising to treat dermonecrosis caused after Loxosceles spiders bite envenoming.

The epileptic blip syndrome.

We report on the case of an adolescent with juvenile myoclonic epilepsy exhibiting compulsory sporadic voluntary movement. These movements entailed the deliberate act of touching her forehead with her hand and were triggered by a short and indefinable cephalic sensation. Upon inquiry regarding the nature of this movement, the patient reported a sudden perception of a peculiar event localized "inside her head". In the course of a prolonged video-electroencephalographic recording, it appeared that the movements consistently followed the occurrence of diffuse Generalized Spike-and-Wave Bursts (GSWBs), lasting one to three seconds. This observation suggests that the impact of the GSWBs on the patient's stream of consciousness could be detected by the patient herself, who attributed it to an internal sensation, like a "blip on a screen". This clinical observation echoes the "blip syndrome", as described by the neurologist James W. Lance thirty years ago. These findings give some support that "blips" could be of an epileptic origin and lend weight to the notion that some patients could perceive their own EEG discharges. Moreover, this observation should be added to the perennial debate on the cognitive impact of intercritical discharges.

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Iron accumulation in tumors contributes to disease progression and chemoresistance. While targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (NK) cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T cell-centric modalities.

Surgical outcomes of novel retroperitoneal low anterior vs posterior and transperitoneal access in single-port partial nephrectomy.

PURPOSE: Single-Port Robot-Assisted Partial Nephrectomy (SP-RAPN) can be performed by transperitoneal and retroperitoneal approaches. However, there is a lack of surgical outcomes for novel Retroperitoneal Low Anterior Access (LAA) in SP-RAPN. The study compared outcomes of the standard approach (SA), considering transperitoneal (TP) and posterior retroperitoneal (RP) access vs LAA in SP-RAPN series. METHODS: 102 consecutive patients underwent SP-RAPN between 2019 and 2023 at a tertiary referral robotic center were identified. Baseline characteristics, peri- and post-operative outcomes were collected. Patients were stratified according to surgical approach into standard (RP or TP) vs LAA and, subsequently, RP vs LAA. Multivariable logistic regression analysis was used to test the probability of the same-day discharge adjusting for comorbidity indexes. RESULTS: Overall, 102 consecutive patients were included in this study (68 SA - 26 TP and 42 posterior RP vs 34 LAA). Median age was 60 (IQR 51.5-66) years and median BMI was 31 (IQR 26.3-37.6). No baseline differences were observed. LAA exhibited significantly shorter length of stay (LOS) (median 10 [IQR 8-12] vs 24 [IQR 12-30.2.] hours, p < .0001), reduced post-operative pain (p < .0001) and decreased narcotic use on 0-1 PO Day (p < .001) compared to SA and RP only. Multivariate analysis, adjusting for comorbidities, identified LAA as a strong predictor for Same-Day Discharge. CONCLUSION: LAA is an effective approach as well as RP and TP, regardless of the renal mass location, whether it is anterior or posterior, upper/mid or lower pole, yielding favorable outcomes in LOS, post-operative pain and decreased narcotics use compared to SA in SP-RAPN.

Recognition of anion-water clusters by peptide-based supramolecular capsules.

The biological and technological importance of anion-mediated processes has made the development of improved methods for the selective recognition of anions one of the most relevant research topics today. The hydration sphere of anions plays an important role in the functions performed by anions by forming a variety of cluster complexes. Here we describe a supramolecular capsule that recognizes hydrated anion clusters. These clusters are most likely composed of three ions that form hydrated C3 symmetry complexes that are entrapped within the supramolecular capsule of the same symmetry. The capsule is made of self-assembled α,γ-cyclic peptide containing amino acid with by five-membered rings and equipped with a tris(triazolylethyl)amine cap. To recognise the hydrated anion clusters, the hexapeptide capsule must disassemble to entrap them between its two subunits.

Static and Dynamic Cross-Network Functional Connectivity Shows Elevated Entropy in Schizophrenia Patients.

Schizophrenia (SZ) patients exhibit abnormal static and dynamic functional connectivity across various brain domains. We present a novel approach based on static and dynamic inter-network connectivity entropy (ICE), which represents the entropy of a given network's connectivity to all the other brain networks. This novel approach enables the investigation of how connectivity strength is heterogeneously distributed across available targets in both SZ patients and healthy controls. We analyzed fMRI data from 151 schizophrenia patients and demographically matched 160 healthy controls. Our assessment encompassed both static and dynamic ICE, revealing significant differences in the heterogeneity of connectivity levels across available brain networks between SZ patients and healthy controls (HC). These networks are associated with subcortical (SC), auditory (AUD), sensorimotor (SM), visual (VIS), cognitive control (CC), default mode network (DMN) and cerebellar (CB) functional brain domains. Elevated ICE observed in individuals with SZ suggests that patients exhibit significantly higher randomness in the distribution of time-varying connectivity strength across functional regions from each source network, compared to healthy control group. C-means fuzzy clustering analysis of functional ICE correlation matrices revealed that SZ patients exhibit significantly higher occupancy weights in clusters with weak, low-scale functional entropy correlation, while the control group shows greater occupancy weights in clusters with strong, large-scale functional entropy correlation. k-means clustering analysis on time-indexed ICE vectors revealed that cluster with highest ICE have higher occupancy rates in SZ patients whereas clusters characterized by lowest ICE have larger occupancy rates for control group. Furthermore, our dynamic ICE approach revealed that it appears healthy for a brain to primarily circulate through complex, less structured connectivity patterns, with occasional transitions into more focused patterns. However, individuals with SZ seem to struggle with transiently attaining these more focused and structured connectivity patterns. Proposed ICE measure presents a novel framework for gaining deeper insights into understanding mechanisms of healthy and disease brain states and a substantial step forward in the developing advanced methods of diagnostics of mental health conditions.

Immunoregulatory properties of melatonin in the humoral immune system: A narrative review.

Melatonin is the major product both synthesized and secreted by the pineal gland during the night period and it is the principal chronobiotic hormone that regulates the circadian rhythms and seasonal changes in vertebrate biology. Moreover, melatonin shows both a broad distribution along the phylogenetically distant organisms and a high functional versatility. At the present time, a significant amount of experimental evidence has been reported in scientific literature and has clearly shown a functional relationship between the endocrine, nervous, and immune systems. The biochemistry basis of the functional communication between these systems is the utilization of a common chemicals signals. In this framework, at present melatonin is considered to be a relevant member of the so-called neuro-endocrine-immunological network. Thus, both in vivo and in vitro investigations conducted in both experimental animals and humans, have clearly documented that melatonin has an important immunomodulatory role. However, most of the published results refer to information on T lymphocytes, i.e., cell-mediated immunity. On the contrary, fewer studies have been carried out on B lymphocytes, the cells responsible for the so-called humoral immunity. In this review, we have focused on the biological role of melatonin in the humoral immunity. More precisely, we report the actions of melatonin on B lymphocytes biology and on the production of different types of antibodies.

Building a framework for fake news detection in the health domain.

Disinformation in the medical field is a growing problem that carries a significant risk. Therefore, it is crucial to detect and combat it effectively. In this article, we provide three elements to aid in this fight: 1) a new framework that collects health-related articles from verification entities and facilitates their check-worthiness and fact-checking annotation at the sentence level; 2) a corpus generated using this framework, composed of 10335 sentences annotated in these two concepts and grouped into 327 articles, which we call KEANE (faKe nEws At seNtence lEvel); and 3) a new model for verifying fake news that combines specific identifiers of the medical domain with triplets subject-predicate-object, using Transformers and feedforward neural networks at the sentence level. This model predicts the fact-checking of sentences and evaluates the veracity of the entire article. After training this model on our corpus, we achieved remarkable results in the binary classification of sentences (check-worthiness F1: 0.749, fact-checking F1: 0.698) and in the final classification of complete articles (F1: 0.703). We also tested its performance against another public dataset and found that it performed better than most systems evaluated on that dataset. Moreover, the corpus we provide differs from other existing corpora in its duality of sentence-article annotation, which can provide an additional level of justification of the prediction of truth or untruth made by the model.

CYCLOPEp Builder: Facilitating cyclic peptide and nanotube research through a user-friendly web platform.

The study of cyclic peptides (CPs) and self-assembling cyclic peptide nanotubes (SCPNs) is pivotal in advancing applications in diverse fields such as biomedicine, nanoelectronics, and catalysis. Recognizing the limitations in the experimental study of these molecules, this article introduces CYCLOPEp Builder, a comprehensive web-based application designed to facilitate the design, simulation, and visualization of CPs and SCPNs. The tool is engineered to generate molecular topologies, essential for conducting Molecular Dynamics simulations that span All-Atom to Coarse-Grain resolutions. CYCLOPEp Builder's user-friendly interface simplifies the complex process of molecular modeling, providing researchers with the ability to readily construct CPs and SCPNs. The platform is versatile, equipped with various force fields, and capable of producing structures ranging from individual CPs to complex SCPNs with different sequences, offering parallel and antiparallel orientations among them. By enhancing the capacity for detailed visualization of molecular assemblies, CYCLOPEp Builder improves the understanding of CP and SCPN molecular interactions. This tool is a step forward in democratizing access to sophisticated simulations, offering an invaluable resource to the scientific community engaged in the exploration of supramolecular structures. CYCLOPEp is accessible at http://cyclopep.com/.

Lipid Metabolism in Insect Vectors of Diseases.

According to the World Health Organization vector-borne diseases account for more than 17% of all infectious diseases, causing more than 700,000 deaths annually. Vectors are organisms that are able to transmit infectious pathogens between humans, or from animals to humans. Many of these vectors are hematophagous insects, which ingest the pathogen from an infected host during a blood meal, and later transmit it into a new host. Malaria, dengue, African trypanosomiasis, yellow fever, leishmaniasis, Chagas disease, and many others are examples of diseases transmitted by insects.Both the diet and the infection with pathogens trigger changes in many metabolic pathways, including lipid metabolism, compared to other insects. Blood contains mostly proteins and is very poor in lipids and carbohydrates. Thus, hematophagous insects attempt to efficiently digest and absorb diet lipids and also rely on a large de novo lipid biosynthesis based on utilization of proteins and carbohydrates as carbon source. Blood meal triggers essential physiological processes as molting, excretion, and oogenesis; therefore, lipid metabolism and utilization of lipid storage should be finely synchronized and regulated regarding that, in order to provide the necessary energy source for these events. Also, pathogens have evolved mechanisms to hijack essential lipids from the insect host by interfering in the biosynthesis, catabolism, and transport of lipids, which pose challenges to reproduction, survival, fitness, and other insect traits.In this chapter, we have tried to collect and highlight the current knowledge and recent discoveries on the metabolism of lipids in insect vectors of diseases related to the hematophagous diet and pathogen infection.

In vitro evaluation of flow diverter performance using a human fibrinogen-based flow model.

OBJECTIVE: Fibrin deposition represents a key step in aneurysm occlusion, promoting endothelization of implants and connective tissue organization as part of the aneurysm-healing mechanism. In this study, the authors introduce a novel in vitro testing platform for flow diverters based on human fibrinogen. METHODS: A flow diverter was deployed in 4 different glass models. The glass models had the same internal parent artery (4 mm) and aneurysm (8 mm) diameters with varying parent artery angulations (paraophthalmic, sidewall, bifurcation, and slightly curved models). The neck size and area were 4 mm and 25 mm2, respectively. Human fibrinogen (330 mg/dl) was circulated within the glass models at varying flow rates (0, 3, 4, and 5 ml/sec) with or without heparin, calcium chloride, and thrombin for as long as 6 hours or until complete fibrin coverage of the flow diverter's neck was achieved. Aneurysm neck coverage was defined as macroscopic fibrin deposition occluding the flow diverters' pores. Flow characteristics after flow diverter deployment were assessed with computational fluid dynamics analysis. The effects of flow rates, heparin, calcium chloride, and thrombin on fibrin deposition rates were tested using 1-way ANOVA and the Tukey test. RESULTS: A total of 84 replicates were performed. Human fibrin did not accumulate on the flow diverter stents under static conditions. The fibrin deposition rate on the aneurysm neck was significantly greater with the 5 ml/sec flow rate as compared to 3 ml/sec for all models. The paraophthalmic model had the highest inflow velocity of 48.7 cm/sec. The bifurcation model had the highest maximum shear stress (SS) and maximum normalized shear stress values at the device cells at 843.3 dyne/cm2 and 35.1 SS/SSinflow, respectively. The fibrin deposition rates of the paraophthalmic and bifurcation models were significantly higher than those of sidewall and slightly curved models for all additive or flow rate comparisons (p = 0.001 for all comparisons). The incorporation of thrombin significantly increased the fibrin deposition rates across all models (p = 0.001 for all models). CONCLUSIONS: Rates of fibrin deposition varied widely across different configurations and additive conditions in this novel in vitro model system. Fibrin accumulation started at the aneurysm inflow zone where flow velocity and shear stress were the highest. The primary factors influencing fibrin deposition included flow velocities, shear stress, and the addition of thrombin at a physiological concentration. Further research is needed to test the clinical utility of fibrinogen-based models for patient-specific aneurysms.

Selective Assembly of TRPC Channels in the Rat Retina during Photoreceptor Degeneration.

Transient receptor potential canonical (TRPC) channels are calcium channels with diverse expression profiles and physiological implications in the retina. Neurons and glial cells of rat retinas with photoreceptor degeneration caused by retinitis pigmentosa (RP) exhibit basal calcium levels that are above those detected in healthy retinas. Inner retinal cells are the last to degenerate and are responsible for maintaining the activity of the visual cortex, even after complete loss of photoreceptors. We considered the possibility that TRPC1 and TRPC5 channels might be associated with both the high calcium levels and the delay in inner retinal degeneration. TRPC1 is known to mediate protective effects in neurodegenerative processes while TRPC5 promotes cell death. In order to comprehend the implications of these channels in RP, the co-localization and subsequent physical interaction between TRPC1 and TRPC5 in healthy retina (Sprague-Dawley rats) and degenerating (P23H-1, a model of RP) retina were detected by immunofluorescence and proximity ligation assays. There was an overlapping signal in the innermost retina of all animals where TRPC1 and TRPC5 physically interacted. This interaction increased significantly as photoreceptor loss progressed. Both channels function as TRPC1/5 heteromers in the healthy and damaged retina, with a marked function of TRPC1 in response to retinal degenerative mechanisms. Furthermore, our findings support that TRPC5 channels also function in partnership with STIM1 in Müller and retinal ganglion cells. These results suggest that an increase in TRPC1/5 heteromers may contribute to the slowing of the degeneration of the inner retina during the outer retinal degeneration.