Disease States Research Articles

Spectral Fingerprinting Coupled Machine Learning: An Optimized Tool for Cellular Phenotype Identification

Spectral fingerprinting has emerged as a powerful tool for unraveling intricate interactions between the intracellular environment and nanomaterials. This study leverages spectral fingerprinting to deepen our comprehension of the interplay between macrophages and nanotubes, utilizing their Near Infrared fluorescence to discern cellular characteristics. This study employs Raman microscopy to showcase significant differences in defect ratio and intracellular processing of nanotubes, among macrophage phenotypes. The near infrared features of DNA-SWCNTs serve as distinctive markers for identifying different macrophage phenotypes. Here we use a support vector machine learning model to accurately identify M1 and M2 macrophages, achieving an impressive accuracy of 95%. The implications of this research extend to the development of nanomaterial-based platforms for cellular identification, holding promise for potential applications in real time in-vivo cell differentiation monitoring.This study underlines the pivotal role of nanotubes in delineating the diverse micro-environments of distinct macrophage phenotypes for clinical research. It emphasizes the potential of short DNA sequences and machine learning in characterizing and classifying cell phenotypes, offering valuable insights into the intersection of nanotechnology and biomedical research.This innovative approach holds great promise in advancing our understanding of dynamic cellular processes, disease states, disease progression, and response to stimuli in-vivo. The platform’s sensitivity to minute changes in the Near Infrared spectrum positions it as a valuable tool for researchers and clinicians. It facilitates the real time monitoring of cellular behavior within living systems, offering insights that extend to both fundamental research and clinical applications. The implications of this research pave the way for future developments in nanotechnology and biomedicine, bridging the gap between spectral analysis and cellular dynamics for enhanced diagnostic and therapeutic interventions. Figure 1

ОТНОШЕНИЕ К ВАКЦИНАЦИИ ДЕТСКИХ ГАСТРОЭНТЕРОЛОГОВ И РЕВМАТОЛОГОВ ПО РЕЗУЛЬТАТАМ АНОНИМНОГО ОНЛАЙН-ОПРОСА

Vaccination of patients with immune-mediated diseases, such as inflammatory bowel diseases (IBD) and juvenile idiopathic arthritis (JIA), is an actual problem since these patients have an increased risk of developing infectious complications due to immunosuppressive therapy and features of the disease itself. The specialists’ attitude towards vaccination of patients with autoimmune inflammatory diseases has changed dramatically over the past decades: from complete refusal previously to almost complete implementation of the vaccine complex and the use of vaccines outside the national immunization schedule as of now. The purpose of this research was to assess the current attitude of pediatric gastroenterologists (PGs) and rheumatologists (PRs) towards vaccination of patients with IBD and JIA, to study their levels of knowledge and practical skills in this area using the anonymous online survey. Materials and methods used: an anonymous survey of 97 pediatric practitioners was conducted, of which 51 were PGs and 46 PRs. The questionnaire included questions about the physicians’ themselves (gender, experience, facility, academic degree) and their knowledge and approaches to vaccination of patients with IBD and JIA with live and inactivated vaccines during different stages of therapy. Results: most physicians believed that immune-inflammatory diseases are not provoked by vaccination (88% of PGs and 69.6% of PRs). A significant group of physicians (40.3% of PGs and 36.9% of PRs) consider vaccination with live vaccines safe for patients with IBD/JIA in remission while receiving immunosuppressive therapy. Most physicians consider vaccination with live vaccines unsafe in the state of active disease (80.4% of PGs and 71.8% of PRs). Outside of remission, physicians vaccinate such patients with live vaccines extremely rarely. A significant portion of physicians (32.0% of PGs and 21.7% of PRs) do not participate in vaccination considering it the responsibility of primary care pediatric practitioners/family physicians. Still, a significant portion of physicians (18.0% of PGs and 47.8% of PRs) actively discourage vaccination in general during the treatment of an immune-inflammatory disease. Determining antibodies to vaccines before starting immunosuppressive therapy/vaccination is considered appropriate by only 35.2%/47.0% of PGs and 32.5%/67.3% of PRs (р=0,885/0,110, respectively). Some physicians believe that vaccination can provoke an exacerbation of IBD/JIA (13.7%/21.6% of PGs and 21.7%/34.8% of PRs answered in affirmative or “rather yes than no,” respectively). Conclusion: the study revealed a differentiated attitude towards vaccination issues between PGs and PRs. Additional efforts needed in order to change the attitude of physicians of different specialties towards vaccination.

Comparison of Tenecteplase Versus Alteplase for the Treatment of Pulmonary Embolism and Cardiac Arrest with Suspected Pulmonary Embolism.

High-risk pulmonary embolism (PE) is a life-threatening disease state with current guidelines recommending reperfusion therapy with systemic thrombolytics in addition to anticoagulation. This was a prospective observational cohort study with a historical control group comparing tenecteplase to alteplase for the treatment of PE or cardiac arrest with suspected PE. The primary outcome was the incidence of institutional protocol deviations defined as incorrect thrombolytic dose administered or the incorrect product compounded. Secondary outcomes included any bleeding event, major bleeding event, all-cause mortality, and for patients with a cardiac arrest, successful return of spontaneous circulation (ROSC). Fifty-four patients were included in the study. Protocol deviations occurred in one patient receiving tenecteplase and one patient receiving alteplase (4.0% vs 3.4%; P = 1.0). There was no difference in all-cause mortality (80% vs 86.2%; P = .72), any bleed (12% vs 13.8%; P = 1.0), major bleed (8.0% vs 6.9%; P = 1.0), or ROSC achievement (22.2% vs 28.6%; P = .73) when comparing tenecteplase to alteplase. Our study demonstrates that tenecteplase may be an alternative thrombolytic to alteplase for treatment of PE or cardiac arrest with suspected PE. Further studies comparing the different systemic thrombolytic agents for PE or cardiac arrest with suspected PE are needed.

Comprehensive single-cell analysis deciphered microenvironmental dynamics and immune regulator olfactomedin 4 in pathogenesis of gallbladder cancer

ObjectiveElucidating complex ecosystems and molecular features of gallbladder cancer (GBC) and benign gallbladder diseases is pivotal to proactive cancer prevention and optimal therapeutic intervention.DesignWe performed single-cell transcriptome analysis on 230...

Treating infertility as a missing capability, not a disease: a capability approach

Infertility patients and patient advocates have long argued for classifying infertility as a disease, in the hopes that this recognition would improve coverage for and access to fertility treatment. However,...

Idiopathic intracranial hypertension pathogenesis: The jugular hypothesis.

In spite of expanding research, idiopathic intracranial hypertension (IIH) and its spectrum conditions remain challenging to treat. The failure to develop effective treatment strategies is largely due to poor agreement on a coherent disease pathogenesis model. Herein we provide a hypothesis of a unifying model centered around the internal jugular veins (IJV) to explain the development of IIH, which contends the following: (1) the IJV are prone to both physiological and pathological compression throughout their course, including compression near C1 and the styloid process, dynamic muscular/carotid compression from C3 to C6, and lymphatic compression; (2) severe dynamic IJV stenosis with developments of large cervical gradients is common in IIH-spectrum patients and significantly impacts intracranial venous and cerebrospinal fluid (CSF) pressures; (3) pre-existing IJV stenosis may be exacerbated by infectious/inflammatory etiologies that induce retromandibular cervical lymphatic hypertrophy; (4) extra-jugular venous collaterals dilate with chronic use but are insufficient resulting in impaired aggregate cerebral venous outflow; (5) poor IJV outflow initiates, or in conjunction with other factors, contributes to intracranial venous hypertension and congestion leading to higher CSF pressures and intracranial pressure (ICP); (6) glymphatic congestion occurs but is insufficient to compensate and this pathway becomes overwhelmed; and (7) elevated intracranial CSF pressures triggers extramural venous sinus stenosis in susceptible individuals that amplifies ICP elevation producing severe clinical manifestations. Future studies must focus on establishing norms for dynamic cerebral venous outflow and IJV physiology in the absence of disease so that we may better understand and define the diseased state.

Real-world study of the multimorbidity and health service utilisation among individuals with non-diabetic hyperglycemia and type 2 diabetes mellitus in North West London

IntroductionThe prevalence of non-diabetic hyperglycemia (NDH) and type 2 diabetes mellitus (T2DM) is increasing. While T2DM is recognised to be associated with multimorbidity and early mortality, people with NDH are...

Doxorubicin downregulates cell cycle regulatory hub genes in breast cancer cells.

Breast cancer (BC) is the leading commonly diagnosed cancer in the world, with complex mechanisms underlying its development. There is an urgent need to enlighten key genes as potential therapeutic targets crucial to advancing BC treatment. This study sought to investigate the influence of doxorubicin (DOX) on identified key genes consistent across numerous BC datasets obtained through bioinformatic analysis. To date, a meta-analysis of publicly available coding datasets for expression profiling by array from the Gene Expression Omnibus (GEO) has been carried out. Differentially Expressed Genes (DEGs) identified using GEO2R revealed a total of 23 common DEGs, including nine upregulated genes and 14 downregulated genes among the datasets of three platforms (GPL570, GPL6244, and GPL17586), and the commonly upregulated DEGs, showed significant enrichment in the cell cycle in KEGG analysis. The top nine genes, NUSAP1, CENPF, TPX2, PRC1, ANLN, BUB1B, AURKA, CCNB2, and CDK-1, with higher degree values and MCODE scores in the cytoscape program, were regarded as hub genes. The hub genes were activated in disease states commonly across all the subclasses of BC and correlated with the unfavorable overall survival of BC patients, as verified by the GEPIA and UALCAN databases. qRT-PCR confirmed that DOX treatment resulted in reduced expression of these genes in BC cell lines, which reinforces the evidence that DOX remains an effective drug for BC and suggests that developing modified formulations of doxorubicin to reduce toxicity and resistance, could enhance its efficacy as an effective therapeutic option for BC.

Lithium in the time of COVID: forever vigilant

BackgroundThere have been case reports of renal dysfunction with lithium toxicity among severely ill COVID-19 patients. Lithium levels may be affected by comorbid conditions and the presence of infective disease states like the SARS-CoV-2 which clearly adds systemic health burden. This study aimed to review the effect SARS-CoV-2 has on serum Li levels and the possible mechanism underlying it.MethodsRetrospective data from all clinical service encounters within the University of Michigan health system between September 2019 and September 2023 were reviewed. The study cohort included 98 patients with an average age of 45 years (62% female) who were diagnosed with any subtype of bipolar disorder, actively taking Li, and infected with SARS-CoV-2 during the study timeframe.ResultsThere was no overarching effect of a SARS-CoV-2 infection on Li chemistry in the overall sample. Higher serum Li levels were not significantly associated with SARS-CoV-2 infection nor total comorbidity index. However, higher Li levels were observed in males while infected with SARS-CoV-2 when compared with no infection. eGFR remained unassociated with serum Li level. Receiving COVID vaccination was associated with lower serum Li levels (Coeff. = − 0.88, p = 0.048).ConclusionsPatients with a diagnosis of BD, treated with Li, and infected with SARS-CoV-2 were not likely to present with elevated Li levels unless they are male or unvaccinated. Elevated serum Li level was not associated with significant renal dysfunction in this cohort. The case reports of severe renal complications and Li toxicity may be among cases of greater overall clinical severity of COVID-19. These findings are reassuring that Li may be used in the context of a COVID-19 illness but emphasize the ongoing need for clinical vigilance.

Fibrin Clot Degradation by Polyaniline-Coated AuNP Using Laser Photolysis

Fibrin clots are crucial for hemostasis and the healing of wounds; nevertheless, excessive blood clotting plays an important role in many chronic diseases, including cardiovascular disease. In this study, we demonstrated the effect of the prepared AuNPs@PANI core/shell on the formed fibrin network. The synthesis of nanoparticles combining electrically conducting polymers polyaniline (PANI) and gold nanoparticles (AuNPs) is an appealing field of research currently because of their physical features and prospective applications in biochemistry. AuNPs showed surface plasmonic resonance (SPR) properties in the visible region at 520 nm then, after coating with PANI, there was a dramatic red shift to 610 nm. The morphological conformation was confirmed by characterization at the microscopic (TEM, SEM, EDX). The PANI shell plays a crucial role in this system, first enhances the stability of AuNPs core; also, the surface of the PANI shell has positive charges (zeta potential = +17.8 mV), leading to electrostatic interactions with fibrin clots that have negatively charged surfaces. The synthesized core/shell AuNPs@PANI showed good efficiency for degrading fibrin networks under 1:30 h of irradiation by an external source of laser light, which is a result of AuNPs’ ability to absorb light at 520 nm. The degradation of fibrin was observed using a scanning electron microscope (SEM), which showed a clear change in the shape of the network. The appearance of fibrous endings and gaping indicates the beginning of the degradation and melting of the fibrin network in different sites of the clot. Overall, this method could have a major influence on disease states, for example, deep vein thrombosis, through a localized, catheter-based approach.

Serum Leucine Aminopeptidase Activity Patterns Across Various Disease States: Potential Implications for Bleeding and Thrombosis Risk.

Disruptions in the pathways for activating and deactivating proteases in the bloodstream can lead to thrombosis and bleeding issues. Leucine aminopeptidases (LAPs), which are exopeptidases essential for regulating protein and peptide activities, are recognized as clinical biomarkers for liver diseases. However, the relationship between serum LAP activity and the risks of bleeding or thrombosis, as well as the identification of the specific tissues or organs that control LAP levels, is not well understood. We performed a retrospective study to evaluate serum LAP activities in 149,360 patients with 47 different diseases and 9,449 healthy individuals. The analysis was conducted using SPSS V2.6, RStudio V.1.3.1073, and libraries in Python 3.8. Our research revealed that 21 of the 47 diseases studied showed increased median serum LAP activities, while 26 diseases were associated with significantly lower activities, especially those related to thrombosis. Furthermore, most diseases were found to have an increased risk of bleeding and thrombosis, indicated by higher Q25 and lower Q75 LAP activities compared to the control group. Receiver operating characteristic curve analysis confirmed the effectiveness of LAP activities as biomarkers for specific conditions like hepatic encephalopathy, liver cancer, pancreatitis, and pancreatic cancer. Diseases were categorized into clusters with similar bleeding or thrombotic tendencies through principal component analysis. This study highlighted regulatory influence of the liver and pancreas on LAP levels. The established link between serum LAP concentrations and the risk of bleeding or thrombosis paved the way for the development of diagnostic and preventative approaches for various medical conditions.

Systemic Juvenile Idiopathic Arthritis: The Challenges and Opportunities

Systemic juvenile idiopathic arthritis (SJIA), presently included under the broad taxonomy of Still’s disease along with ‘Adult-onset Stills disease’, is a unique disease entity, characterised predominantly by features of systemic inflammation at disease onset and running a heterogenous course, evolving into a disabling chronic, destructive arthritis in a sizable proportion of patients. With a better understanding of the disease biology, there has been a paradigm shift in therapeutic strategy targeting immunological remission. With the evolution of better biomarkers (to guide diagnosis, predict complications and predict treatment responses) and robust therapeutic options and treatment targets, newer challenges such as refractory disease states and SJIA-associated lung disease have risen to the fore, making disease management all the more challenging.

Exploring the link between dystrophic microglia and the spread of Alzheimer's neuropathology.

Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease (AD) progression, but details of microglia's disease-driving influence are poorly understood. Microglial cells can be parsed into subtypes based on their histologic appearance. One microglia subtype, termed dystrophic microglia, is characterised structurally by fragmented processes and cytoplasmic decay, and their presence has been associated with ageing and neurodegeneration. Recent studies suggest that the interaction between tau proteins and amyloid-β might induce dystrophic changes in microglia, potentially linking amyloid-β and tau pathologies to their effects on these microglia. We developed a study of human brains to test the hypothesis that dystrophic microglia are involved in AD progression. We speculated that if their presence is unique to AD neuropathologic change (ADNC), they would be substantially more common in ADNC than in neurodegenerative diseases characterised by other proteinopathies, e.g., α-synuclein or TDP-43 pathology. Our analyses used histologically stained sections from five human brain regions of 64 individuals across six disease states, from healthy controls to advanced AD stages, including comparative conditions such as Lewy Body Disease (LBD) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Using stereological sampling and digital pathology, we assessed ramified, hypertrophic, and dystrophic microglia populations. We found a significant increase in dystrophic microglia in areas early affected by ADNC, suggesting a disease-specific role in neuropathology. Mediation analysis and structural equation modelling suggest dystrophic microglia may impact the regional spread of ADNC. In the mediation model, tau was found to be the initiating factor leading to the development of dystrophic microglia, which then was associated with the spread of amyloid-β and tau. These results suggest that a loss of microglia's protective role could contribute to the spread of ADNC and indicate that further research into preserving microglial function may be warranted.

Multi-modal incomplete label information three-way bidirectional decision-making: Applications of disease assessment

Disease assessment involves two stages of decision-making process. The first process is to infer the development trend of the disease through the existing judgment conditions, which is to make a positive estimation (prediction) decision. The second process is to update the judgment conditions for different disease states and optimize the clinical assessment evidence by fusing disease progression data, that is, to make a reverse evaluation (optimization) decision by reviewing historical diagnostic and treatment data to summarize the best judgment conditions for the disease characteristics. Therefore, we construct a three-way bidirectional decision method for multi-modal incomplete labeling information, considering the mixed data features with no labels and labels, and the bidirectional decision features of positive prediction and reverse optimization. Specifically, the method first introduces semi-supervised learning (SSL) into the rough sets, constructs a rough sets model based on cosine similarity relation, generates pseudo-labels for incomplete information, and explains the positive prediction decision process principle. Second, the gradient space is constructed on the predictive information system by the three-way decision-making principle, the loss function formed by the combination of KL divergence and cross entropy loss function is used to find the direction of the fastest decline in attribute information value, and the optimal decision rule and the automatic updating strategy of the threshold value are obtained. At the same time, the principle of the reverse optimization decision process is explained. Finally, multimodal information from pathological tissue images is used to evaluate clinical progress problem. A pathological tissue images dataset includes 2000 colorectal cancer and 300 kidney disease cases used for simulation experiments. The proposed three-way bidirectional decision-making model can be widely applied to actual decision-making scenarios for evaluating clinical progress of different diseases. Compared with previous studies, this method can realize objective calculation and automatic update of threshold and loss values and effectively solve complex prediction and optimization decision-making problems.

An Experimental Protocol for the Boyden Chamber Invasion Assay With Absorbance Readout.

The phenomenon of cell invasion is an essential step in angiogenesis, embryonic development, immune responses, and cancer metastasis. In the course of cancer progression, the ability of neoplastic cells to degrade the basement membrane and penetrate neighboring tissue (or blood vessels and lymph nodes) is an early event of the metastatic cascade. The Boyden chamber assay is one of the most prevalent methods implemented to measure the pro- or anti-invasive effects of drugs, investigate signaling pathways that modulate cell invasion, and characterize the role of extracellular matrix proteins in metastasis. However, the traditional protocol of the Boyden chamber assay has some technical challenges and limitations. One such challenge is that the endpoint of the assay involves photographing and counting stained cells (in multiple fields) on porous filters. This process is very arduous, requires multiple observers, and is very time-consuming. Our improved protocol for the Boyden chamber assay involves lysis of the dye-stained cells and reading the absorbance using an ELISA reader to mitigate this challenge. We believe that our improved Boyden chamber methodology offers a standardized, high-throughput format to evaluate the efficacy of various drugs and test compounds in influencing cellular invasion in normal and diseased states. We believe that our protocol will be useful for researchers working in the fields of immunology, vascular biology, drug discovery, cancer biology, and developmental biology. Key features • Measurement of tumor invasion using human cancer cells. • Ability to measure the pro-invasive/anti-invasive activity of small molecules and biological modifiers. • Measurement of chemotaxis, chemokines, trafficking of immune cells, and proteolytic activity of matrix metalloproteinases, lysosomal hydrolysates, collagenases, and plasminogen activators in physiological and pathological conditions. • Investigation of the role of extracellular matrix proteins in the crosstalk between endothelial, epithelial, muscle, or neuronal cells and their adjacent stroma.

Senescence detection using reflected light.

Senescence is an important cellular program occurring in development, tissue repair, cancer, and aging. Increased senescence is also associated with disease states, including obesity and Type 2 diabetes (T2D). Characterizing and quantifying senescent cells at a single cell level has been challenging and particularly difficult in large primary cells, such as human adipocytes. In this study, we present a novel approach that utilizes reflected light for accurate senescence-associated beta-galactosidase (SABG) staining measurements, which can be integrated with immunofluorescence and is compatible with primary mature adipocytes from both human and mouse, as well as with differentiated 3T3-L1 cells. This technique provides a more comprehensive classification of a cell's senescent state by incorporating multiple criteria, including robust sample-specific pH controls. By leveraging the precision of confocal microscopy to detect X-gal crystals using reflected light, we achieved superior sensitivity over traditional brightfield techniques. This strategy allows for the capture of all X-gal precipitates in SABG-stained samples, revealing diverse X-gal staining patterns and improved detection sensitivity. Additionally, we demonstrate that reflected light outperforms western blot analysis for the detection and quantification of senescence in mature human adipocytes, as it offers a more accurate representation of SABG activity. This detection strategy enables a more thorough investigation of senescent cell characteristics and specifically a deeper look at the relationship between adipocyte senescence and obesity associated disorders, such as T2D.

Exploring the Utility of Long Non-Coding RNAs for Assessing the Health Consequences of Vaping.

Electronic cigarette (e-cig) use, otherwise known as "vaping", is widespread among adolescent never-smokers and adult smokers seeking a less-harmful alternative to combustible tobacco products. To date, however, the long-term health consequences of vaping are largely unknown. Many toxicants and carcinogens present in e-cig vapor and tobacco smoke exert their biological effects through epigenetic changes that can cause dysregulation of disease-related genes. Long non-coding RNAs (lncRNAs) have emerged as prime regulators of gene expression in health and disease states. A large body of research has shown that lncRNAs regulate genes involved in the pathogenesis of smoking-associated diseases; however, the utility of lncRNAs for assessing the disease-causing potential of vaping remains to be fully determined. A limited but growing number of studies has shown that lncRNAs mediate dysregulation of disease-related genes in cells and tissues of vapers as well as cells treated in vitro with e-cig aerosol extract. This review article provides an overview of the evolution of e-cig technology, trends in use, and controversies on the safety, efficacy, and health risks or potential benefits of vaping relative to smoking. While highlighting the importance of lncRNAs in cell biology and disease, it summarizes the current and ongoing research on the modulatory effects of lncRNAs on gene regulation and disease pathogenesis in e-cig users and in vitro experimental settings. The gaps in knowledge are identified, priorities for future research are highlighted, and the importance of empirical data for tobacco products regulation and public health is underscored.

Serum concentration of ferroportin in women of reproductive age.

Ferroportin (Fpn) is the only known iron exporter and plays an essential role in iron homeostasis. Serum concentrations of Fpn in health and/or diseased states are still mostly unknown. Therefore, the aim of this study was to determine the concentration of Fpn in the serum of women of reproductive age (WRA) for the first time, and to establish whether there is a difference in the concentration of Fpn according to ferritin status. This research included 100 WRA (18-45 years, C-reactive protein (CRP) < 5 mg/L, hemoglobin > 120 g/L). Serum Fpn was measured using Enzyme Linked Immunosorbent Assay (ELISA) method on the analyzer EZ Read 800 Plus (Biochrom, Cambridge, UK). Reference interval was calculated using the robust method. The median concentration of Fpn in the whole study group was 9.74 (5.84-15.69) µg/L. The subgroup with ferritin concentration > 15 µg/L had a median Fpn concentration 15.21 (10.34-21.93) µg/L, which significantly differed from Fpn concentration in the subgroup with ferritin concentration ≤ 15 µg/L (5.93 (4.84-8.36) µg/L, P < 0.001). The reference limits for the Fpn were 2.26-29.81 µg/L with 90% confidence intervals (CI) of 1.78 to 2.83 and 25.37 to 34.33, respectively. The proposed reference interval could help in the future research on iron homeostasis both in physiological conditions and in various disorders, because this is the first study that measured Fpn concentration in a certain gender and age group of a healthy population.

New perspectives on the high-density lipoprotein system and its role in the prevention and treatment of atherosclerotic cardiovascular disease.

The causal role of high-density lipoprotein (HDL) in atherosclerotic cardiovascular disease (CVD) remains debated. Considering recent evidence, the purpose of this review is to a provide a focused update and new perspectives on HDL and CVD. A Mendelian randomization study demonstrated an increased risk of CVD when HDL-cholesterol was predominantly transported in larger HDL particles and a decreased risk of CVD when HDL-cholesterol was predominantly transported in smaller HDL particles. Moreover, another Mendelian randomization study demonstrated that concentration and content of medium HDL particles is associated with CVD. A Mendelian randomization study that utilized stratified analyses demonstrated that individuals with HDL-cholesterol 50 mg/dl or less were at increased risk of CVD. Lastly, the AEGIS-II trial demonstrated that CSL112, a human apolipoprotein A-I that increases cholesterol efflux, did not significantly reduce cardiovascular events in patients at very high risk. Exploratory analyses showed that patients treated with CSL112 had numerically lower rates of cardiovascular events. Qualitative markers of HDL may be causally related to CVD. There is a need for ongoing research into HDL therapeutics that promote the biological properties of HDL. The optimal cohort or disease state that will benefit from these therapies needs to be identified.

Changes in Neuroimmunological Synapses During Cerebral Ischemia.

The direct interplay between the immune and nervous systems is now well established. Within the brain, these interactions take place between neurons and resident glial cells, i.e., microglia and astrocytes, or infiltrating immune cells, influenced by systemic factors. A special form of physical cell-cell interactions is the so-called "neuroimmunological (NI) synapse." There is compelling evidence that the same signaling pathways that regulate inflammatory responses to injury or ischemia also play potent roles in brain development, plasticity, and function. Proper synaptic wiring is as important during development as it is during disease states, as it is necessary for activity-dependent refinement of neuronal circuits. Since the process of forming synaptic connections in the brain is highly dynamic, with constant changes in strength and connectivity, the immune component is perfectly suited for the regulatory task as it is in constant turnover. Many cellular and molecular players in this interaction remain to be uncovered, especially in pathological states. In this review, we discuss and propose possible communication hubs between components of the adaptive and innate immune systems and the synaptic element in ischemic stroke pathology.