Irreversible Tissue Research Articles

The Effects of Hypoxia-Reoxygenation in Mouse Digital Flexor Tendon-Derived Cells.

Objective Ischemia-reperfusion injury refers to the exacerbated and irreversible tissue damage caused by blood flow restoration after a period of ischemia. The hypoxia-reoxygenation (H/R) model in vitro is ideal for studying ischemia-reperfusion injury at the cellular level. We employed this model and investigated the effects of cobalt chloride- (CoCl2-) induced H/R in cells derived from mouse digital flexor tendons. Materials and Methods Various H/R conditions were simulated via treatment of tendon-derived cells with different concentrations of CoCl2 for 24 h, followed by removal of CoCl2 to restore a normal oxygen state for up to 96 h. Cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay. Cell growth was determined via observation of cell morphology and proliferation. Oxidative stress markers and mitochondrial activity were detected. The expression levels of hypoxia-inducible factor- (HIF-) 1α, vascular endothelial growth factor-A (VEGF-A), collagen I, and collagen III were determined using Western blot (WB), real-time PCR, and immunofluorescence staining. Cellular apoptosis was analyzed via flow cytometry, and the expression of apoptosis-related proteins Bax and bcl-2 was examined using WB. Results The cells treated with low concentrations of CoCl2 showed significantly increased cell viability after reoxygenation. The increase in cell viability was even more pronounced in cells that had been treated with high concentrations of CoCl2. Under H/R conditions, cell morphology and growth were unchanged, while oxidative stress reaction was induced and mitochondrial activity was increased. H/R exerted opposite effects on the expression of HIF-1α mRNA and protein. Meanwhile, the expression of VEGF-A was upregulated, whereas collagen type I and type III were significantly downregulated. The level of cellular apoptosis did not show significant changes during H/R, despite the significantly increased Bax protein and reduced bcl-2 protein levels that led to an increase in the Bax/bcl-2 ratio during reoxygenation. Conclusions Tendon-derived cells were highly tolerant to the hypoxic environments induced by CoCl2. Reoxygenation after hypoxia preconditioning promoted cell viability, especially in cells treated with high concentrations of CoCl2. H/R conditions caused oxidative stress responses but did not affect cell growth. The H/R process had a notable impact on collagen production and expression of apoptosis-related proteins by tendon-derived cells, while the level of cellular apoptosis remained unchanged.

Impaired host response and the presence of Acinetobacter baumannii in the serum microbiome of type-II diabetic patients.

SummaryType II diabetes (T2D) affects over 10% of the US population and is a growing disease worldwide that manifests with numerous comorbidities and defects in inflammation. This dysbiotic host response allows for infection of the host by numerous microorganisms. In the course of T2D disease, individuals can develop chronic infections including foot ulcers and periodontitis, which lead to further complications and opportunistic infections in multiple body sites. In this study, we investigated the serum of healthy subjects and patients with T2D with (T2DP) or without periodontitis for both microbiome signatures in addition to cytokine profiles. Surprisingly, we detected the presence of Acinetobacter baumanii in the serum of 23% individuals with T2D/T2DP tested. In T2DP, IL-1β, TNF-α, MCP-1, IL-6, IL-8, and IFN-γ were significantly elevated in ABC-positive subjects. As an emerging pathogen, A. baumanii infection represents a risk for impaired inflammation and the development of comorbidities in subjects with T2D.

Triggers, Timescales, and Treatments for Cytokine-Mediated Tissue Damage.

Inflammation is an essential cytokine-mediated process for generating a neutralizing immune response against pathogens and is generally protective. However, aberrant or excessive production of pro-inflammatory cytokines is associated with uncontrolled local and systemic inflammation, resulting in cell death and often irreversible tissue damage. Uncontrolled inflammation can manifest over timescales spanning hours to years and is primarily dependent on the triggering event. Rapid and potentially lethal increase in cytokine production, or a 'cytokine storm,' develops in hours to days and is associated with cancer cell-based immunotherapies, such as CAR-T cell therapy. On the other hand, some bacterial and viral infections with high microbial replication or highly potent antigens elicit immune responses that result in supraphysiological systemic cytokine concentrations which manifest over days to weeks. Immune dysregulation in autoimmune diseases can lead to chronic cytokine-mediated tissue damage spanning months to years, which often occurs episodically. While the initiating events and cellular participants may differ in these disease processes, many of the cytokines that drive disease progression are shared. For example, upregulation of IL-1, IL-6, IFN-γ, TNF, and GM-CSF frequently coincides with cytokine storm, sepsis, and autoimmune disease. Targeted inhibition of these pro-inflammatory molecules via antagonist monoclonal antibodies has improved clinical outcomes, but the complexity of the underlying immune dysregulation results in high variability. Rather than a "one size fits all" treatment approach, an identification of disease endotypes may permit the development of effective therapeutic strategies that address the contributors of disease progression. Here, we present a literature review of the cytokine-associated etiology of acute and chronic cytokine-mediated tissue damage, describe successes and challenges in developing clinical treatments, and highlight advancements in preclinical therapeutic strategies for mitigating pathological cytokine production.

The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

Classifying white matter hyperintensities according to intensity and spatial localisation reveals specific association with cognition

AbstractBackgroundWhite matter hyperintensities (WMH) on T2‐weighted images are imaging biomarkers of brain small vessel disease. When classified according to location (periventricular/deep), they have shown different associations with cognition. WMH can also appear hypointense on T1‐weighted (T1w) images as a possible sign of irreversible tissue damage. We hypothesise that sub‐classifying WMH combining intensity information and spatial localisation may provide better insight into the association with cognition, not detectable for the total WMH burden.MethodWe analysed data from 684 subjects of the Whitehall II imaging sub‐study. A supervised machine learning method (BIANCA) was used to segment WMH. An automatic method based on cluster localisation and image intensity was then applied to classify WMH into 4 categories according to adjacency to the ventricles (periventricular/deep) and appearance on T1w images (either T1w‐hypointense or not) (Figure 1). Derived volumes were entered into a general linear model as predictors of the participants’ cognitive scores on neuropsychological tests.ResultPeriventricular T1w‐hypointense WMH were significantly related to worse performance in the trail‐making test A (p = 0.011), digit‐symbol (p = 0.028), and digit‐coding (p = 0.009) tests. When including only the total WMH burden in the model, we could not find any associations between WMH and cognition. Age, gender, years of education, systolic and diastolic blood pressure were used as covarietes in the statistical models.ConclusionSub‐classifying WMH according to both location and appearance on T1w images provided added value compared to total WMH burden alone. These are promising findings for WMH interpretation in the clinical practice and for the development of methods for analysing imaging biomarkers related to cognition.

Grafted human induced pluripotent stem cells improve the outcome of spinal cord injury: modulation of the lesion microenvironment

Spinal cord injury results in irreversible tissue damage followed by a very limited recovery of function. In this study we investigated whether transplantation of undifferentiated human induced pluripotent stem cells (hiPSCs) into the injured rat spinal cord is able to induce morphological and functional improvement. hiPSCs were grafted intraspinally or intravenously one week after a thoracic (T11) spinal cord contusion injury performed in Fischer 344 rats. Grafted animals showed significantly better functional recovery than the control rats which received only contusion injury. Morphologically, the contusion cavity was significantly smaller, and the amount of spared tissue was significantly greater in grafted animals than in controls. Retrograde tracing studies showed a statistically significant increase in the number of FB-labeled neurons in different segments of the spinal cord, the brainstem and the sensorimotor cortex. The extent of functional improvement was inversely related to the amount of chondroitin-sulphate around the cavity and the astrocytic and microglial reactions in the injured segment. The grafts produced GDNF, IL-10 and MIP1-alpha for at least one week. These data suggest that grafted undifferentiated hiPSCs are able to induce morphological and functional recovery after spinal cord contusion injury.

Two-phase amputation among critically ill patients with ischemic gangrene of lower limbs as a way to improve treatment outcome. Cohort study

BackgroundThe results of lower limb amputation, especially in critically ill patients with severe endogenous intoxication, sepsis, multi-organ failure and severe concomitant diseases are still unsatisfactory. Guillotine amputation is a method routinely used to reduce wound complications associated with wet gangrene and severe cases of diabetic foot, however, it is unclear how well it could help to decrease mortality and improve functional outcome when dealing with critically ill patients. The objectiveof the study was to estimate the effectiveness of two-phase method of urgent low limb amputation among critically ill patients with high risk of complications. The effectiveness was evaluated in terms of perioperative mortality, frequency of early complications and ultimate level of limb loss. Materials and methodsTwo cohort groups of patients with acute lower limb gangrene were retrospectively matched. Approximately 25.8% of patients from the comparison (control) group (N = 240) died without surgery due to severity of their condition and ineffective pre-operative treatment. The remaining patients underwent one-phase high-level amputation after 48–72 h of pre-operative intensive care. The experimental group consisted of 153 patients who underwent guillotine amputation at the lower part of tibia (34.6%), knee disarticulation (32.0%), or open thigh amputation (33.3%), depending on the level of irreversible soft tissue necrosis. The reamputation with the stump shaping was performed later when their health status improved. ResultsThe assessment of treatment outcomes showed that the two-phase amputation in critically ill patients (i) decreased the mortality from 48.7 to 37.9%, (ii) reduced the risk of wound complications from 20.9 to 11.1%, and (iii) improved functional results by saving the knee joint in 34.6 versus 4.5% in comparison/control group. ConclusionThe method of two-phase amputation is recommended for critically ill patients.

Спосіб фасціотомії кістково-фасціальних футлярів при компартмент-синдромі внаслідок вогнепальних поліструктурних ушкоджень кінцівки

SummaryRationale. Compartment syndrome (CS) of bone-fascial cases (BFC) is the mostsevere complication of gunshot or traumatic limb injuries. The only pathogeneticallydetermined method of CS treatment is fasciotomy, which is one of the elements ofprimary surgical treatment.Classical open or closed fasciotomy, which involves dissection along the axis of theskin limb with underlying tissues and fascia, reduces intramuscular pressure andimproves tissue perfusion, but may not provide a sufficient decompression effect in allcases.The aim of the study was to develop and evaluate the effectiveness of the step-bystep fasciotomy, which provides adequate decompression effect and reduces the risk ofprogression of irreversible ischemic tissue changes regardless of the severity of gunshotwounds to the limb.Results and discussion. A method of fasciotomy for CS in victims with gunshotpolystructural injuries of the limb has been developed, tested and implemented. Theproposed method is a kind of open fasciotomy, which allows to achieve maximumdecompression of the BFC due to a change in the direction of dissection of the skin withthe underlying tissues and fascia relative to the axis of the limb. A step-by-stepfasciotomy is proposed: the first step is a cross-section of both layers of the fascia of thecompromised muscle relative to the axis of the limb, the second step is a longitudinalincision of both layers of the fascia in both directions from the cross-section.The expediency of the primary cross-section is due to the fact that against thebackground of increased subfascial pressure dissection of the fascia across its lines offorce is guaranteed to lead to the dilution of its edges and clear identification ofsuperficial and deep layers of the fascia, which allows the next step to perform areliable longitudinal fascia dissection.Conclusions. The proposed method of open stepwise fasciotomy can effectivelyreduce intramuscular pressure in patients due to gunshot or traumatic injury of theextremities and reduce the risk of progression of irreversible ischemic tissue changesregardless of the severity of the lesion. The use of this method allows to reduce thenumber of repeated surgical treatment of wounds by (3.4±1.4) cases and to speed up thebed-day by (2.8±1.1) days.

Treatable lysosomal storage diseases in the advent of disease-specific therapy.

Lysosomal storage diseases (LSD) comprise a rare and heterogeneous group of nearly 50 heritable metabolic disorders caused by mutations in proteins critical for cellular lysosomal function. Defects in the activity of these proteins in multiple organs leads to progressive intra-lysosomal accumulation of specific substrates, resulting in disruption of cellular functions, extracellular inflammatory responses, tissue damage and organ dysfunction. The classification and clinical presentation of different LSD are dependent on the type of accumulated substrate. Some clinical signs and symptoms are common across multiple LSD, while others are more specific to a particular syndrome. Due to the rarity and wide clinical diversity of LSD, identification and diagnosis can be challenging, and in many cases diagnosis is delayed for months or years. Treatments, such as enzyme replacement therapy, haemopoietic stem cell transplantation and substrate reduction therapy, are now available for some of the LSD. For maximum effect, therapy must be initiated prior to the occurrence of irreversible tissue damage, highlighting the importance of prompt diagnosis. Herein, we discuss the clinical presentation, diagnosis and treatment of four of the treatable LSD: Gaucher disease, Fabry disease, Pompe disease, and two of the mucopolysaccharidoses (I and II). For each disease, we present illustrative case studies to help increase awareness of their clinical presentation and possible treatment outcomes.

Living with Salt

Living with Salt

Neural stem cells induce M2 polarization of macrophages through the upregulation of interleukin-4.

Macrophages are divided into two types: M1- and M2-type macrophages. Both types of macrophages serve important roles during the process of inflammation. M1-type macrophages release various pro-inflammatory cytokines, such as IL-1, IFN-γ and other inflammatory mediators, such as nitric oxide, glutamate and reactive oxygen species to generate inflammation. In contrast, M2-type macrophages counteract the pro-inflammatory M1 conditions and promote tissue repair by secreting anti-inflammatory cytokines, such as IL-10. In spinal cord injury (SCI), an imbalance in M1/M2 macrophages leads to irreversible tissue destruction. Thus, it is crucial to increase the number of M2-type macrophages and promote M2 polarization of macrophages in SCI. Accordingly, in this study an in vitro co-culture system was established to investigate the effect of neural stem cells (NSCs) on macrophages. The results of the present study demonstrated that NSCs induced M2 polarization and suppressed M1 polarization of macrophages in an interleukin (IL)-4-dependent manner. Furthermore, the nuclear factor (NF)-κB/p65 signaling pathway was involved in the M1 polarization of macrophages and NSCs suppressed the activation of the NF-κB/p65 pathway in an IL-4-dependent manner to induce M2 macrophage polarization. These findings provide more insight into SCI and help to identify novel treatment strategies.

Production of hydrogen peroxide in formulated beverages is associated with the presence of ascorbic acid combined with selected redox-active functional ingredients

Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) that mediates essential signaling in vivo but may cause irreversible tissue damage under dysregulated or acute exposure conditions. Beverages containing redox-active compounds might produce H2O2 during shelf storage and potentially be consumed. Concentrations of H2O2 in selected ‘functional’ (including energy, E, n = 28), ‘non-functional’ flavored, (S, n = 6) and mineral water (W, n = 6) drinks were measured under ambient (i.e., produced in situ) and ‘potentiated’ conditions (i.e., H2O2 production enhanced by addition of a reducing agent, to simulate availability of reducible substrates in vivo). Under air-saturated conditions, mean H2O2 contents were: 15.60 ± 15.84; 1.39 ± 2.06 and 0.30 ± 0.21 µM in E, S and W drinks, respectively. Under air-saturated, potentiated conditions, mean rates of H2O2 production were 21.7 ± 33.3, 0.98 ± 2.84, and −0.38 ± 1.18 µM/h for E, S and W drinks, respectively. Using multivariate statistics, the ingredient significantly associated with H2O2 production in combination with other ingredients was found to be ascorbic acid.

Live In Vivo Imaging of Plasmodium Invasion of the Mosquito Midgut.

The mosquito midgut is a critical barrier that Plasmodium parasites must overcome to complete their developmental cycle and be transmitted to a new vertebrate host. Previous confocal studies with fixed infected midguts showed that ookinetes traverse midgut epithelial cells and cause irreversible tissue damage. Here, we investigated the spatiotemporal dynamics of ookinete midgut traversal and the response of midgut cells to invasion. A novel mounting strategy was established, suitable fluorescent dye combinations were identified and protocols optimized to label mosquito tissues in vivo, and live imaging protocols using confocal microscopy were developed. Tracking data showed that ookinetes gliding on the midgut surface travel faster and farther than those that remain in the lumen or those that have invaded the epithelium. Image analysis confirmed that parasite invasion and cell traversal occur within a couple of minutes, while caspase activity in damaged cells, indicative of cellular apoptosis, and F-actin cytoskeletal rearrangements in cells extruded into the gut lumen persist for several hours. This temporal difference highlights the importance of hemocyte-mediated cellular immunity and the mosquito complement system to mount a coordinated and effective antiplasmodial response. This novel in vivo imaging protocol allowed us to continuously observe individual ookinetes in live mosquitoes within the gut lumen and during cell traversal and to capture the subsequent cellular responses to invasion in real time for several hours, without loss of tissue integrity.IMPORTANCE Malaria is one of the most devastating parasitic diseases in humans and is transmitted by anopheline mosquitoes. The mosquito midgut is a critical barrier that Plasmodium parasites must overcome to complete their developmental cycle and be transmitted to a new host. Here, we developed a new strategy to visualize Plasmodium ookinetes as they traverse the mosquito midgut and to follow the response of damaged epithelial cells by imaging live mosquitoes. Understanding the spatial and temporal aspects of these interactions is critical when developing novel strategies to disrupt disease transmission.

Heating and cooling stages using a doubly conjugate thermal and electric asymptotic analysis between a gel and the stratum corneum

We study by using perturbation techniques, a conjugate formulation for the heating and cooling stages related with the skin electroporation phenomenon. The fundamental idea is very simple: to analyze simultaneously the thermal and electric effects in a thin layer of gel in contact with the stratum corneum, a situation that results of the application of a uniform electric pulse in the external surface of the gel with very short duration to avoid a temperature rise induced by the Joule heating effect, which can cause irreversible tissue damage. After the application of this short time, needed to characterize the first heating stage, enters in operation a second stage where both layers are cooled because the external electric field is interrupted and the external convective ambient is sufficient to cause it.We have used perturbation techniques to solve the governing equations, identifying a dimensionless parameter denoted by γ that measures the ratio of the electrical conductivities of the two media affected by the pulse. This parameter has a direct influence on the process. Due to that the electrical conductivity of the stratum corneum is very small, γ can assume finite or usually very large values compared with unity and the theoretical predictions show the relevance that this parameter has on the increment of the temperature in both media. Therefore, we consider that this parameter guides the performance of this class of medical treatments based on electric signals and can serve to delimit under transient conditions up to where the thermal effects control the skin electroporation.We demonstrate that to achieve thermodynamic equilibrium, the cooling stage must have a much longer duration than the heating stage, in such a way that it prevents the accumulation of thermal energy in the stratum corneum and thereby prevents the formation of possible damage to the skin.

Engineered immunological niches to monitor disease activity and treatment efficacy in relapsing multiple sclerosis

Relapses in multiple sclerosis can result in irreversible nervous system tissue injury. If these events could be detected early, targeted immunotherapy could potentially slow disease progression. We describe the use of engineered biomaterial-based immunological niches amenable to biopsy to provide insights into the phenotype of innate immune cells that control disease activity in a mouse model of multiple sclerosis. Differential gene expression in cells from these niches allow monitoring of disease dynamics and gauging the effectiveness of treatment. A proactive treatment regimen, given in response to signal within the niche but before symptoms appeared, substantially reduced disease. This technology offers a new approach to monitor organ-specific autoimmunity, and represents a platform to analyze immune dysfunction within otherwise inaccessible target tissues.

An Integrated Theranostic Nanomaterial for Targeted Photodynamic Therapy of Infectious Endophthalmitis

Infectious endophthalmitis is a growing concern that causes irreversible intraocular tissue and optic nerve damage. Here, we report a theranostic nanoplatform based on UiO-66-NH2 to combine photodynamic therapy (PDT) and lipopolysaccharide (LPS) targeting through polypeptide (YVLWKRKRKFCFI-NH2) modification. Toluidine blue (TB), serving as a photosensitizer (PS), is loaded into UiO-66-NH2 nanoparticles (NPs) for both self-imaging and PDT functions. The accelerated TB release at pH 5.5 compared to pH 7.4 demonstrates the responsive drug release feature. In vitro antibacterial tests, including contact incubation-agar plate counting, bacterial live/dead staining, and scanning electron microscopy observations, confirm the utility of the [email protected]2@PEP&PEG NPs (UTPP NPs) in biofilms removal and sterilization of Pseudomonas aeruginosa and Staphylococcus epidermidis. Furthermore, the UTPP NPs also show good biocompatibility toward human retinal pigment epithelial cells, as well as in situ self-imaging property. Finally, an in vivo infectious endophthalmitis model supports the application of the UTPP NPs in infectious endophthalmitis treatment.

Small RNA Deep Sequencing Identifies a Unique miRNA Signature Released in Serum Exosomes in a Mouse Model of Sjögren's Syndrome.

Sjögren's Syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and loss of function of moisture-producing exocrine glands as well as systemic inflammation. SS diagnosis is cumbersome, subjective and complicated by manifestation of symptoms that overlap with those of other rheumatic and ocular diseases. Definitive diagnosis averages 4–5 years and this delay may lead to irreversible tissue damage. Thus, there is an urgent need for diagnostic biomarkers for earlier detection of SS. Extracellular vesicles called exosomes carry functional small non-coding RNAs which play a critical role in maintaining cellular homeostasis via transcriptional and translational regulation of mRNA. Alterations in levels of specific exosomal miRNAs may be predictive of disease status. Here, we have assessed serum exosomal RNA using next generation sequencing in a discovery cohort of the NOD mouse, a model of early-intermediate SS, to identify dysregulated miRNAs that may be indicative of SS. We found five miRNAs upregulated in serum exosomes of NOD mice with an adjusted p < 0.05—miRNA-127-3p, miRNA-409-3p, miRNA-410-3p, miRNA-541-5p, and miRNA-540-5p. miRNAs 127-3p and 541-5p were also statistically significantly upregulated in a validation cohort of NOD mice. Pathway analysis and existing literature indicates that differential expression of these miRNAs may dysregulate pathways involved in inflammation. Future studies will apply these findings in a human cohort to understand how they are correlated with manifestations of SS as well as understanding their functional role in systemic autoimmunity specific to SS.

A simulated model for fluid and tissue heating during pediatric laser lithotripsy

Laser lithotripsy (LL) is a common modality for treatment of children and adolescents with nephrolithiasis. Recent introduction of higher-powered lasers may result in more efficacious "dusting" of urinary calculi. However, invivo animal studies and computational simulations have demonstrated rapid and sustained rise of fluid temperatures with LL, possibly resulting in irreversible tissue damage. How fluid and tissue heating during LL vary with pediatric urinary tract development, however, is unknown. We hypothesize that kidneys of younger children will be more susceptible to changes in fluid temperature and therefore tissue damage than those of older children. Computational simulations were developed for LL in children utilizing COMSOL Multiphysics finite-element modeling software. Simulation parameters were varied, including the child's age (3, 8, and 12 years), flow of irrigation fluid (gravity - 5mL/min or continuous pressure flow - 40mL/min), treatment location (renal pelvis, ureter, calyx), and power settings (5W - 40W). Using a simplified axisymmetric geometry to represent the collecting space, the model accounted for heat transfer via diffusion, convection, perfusion, and heat sourcing as well as tissue properties and blood flow of the urothelium and renal parenchyma. Laminar and heat-induced convection flow were simulated, assuming room-temperature ureteroscopic irrigation. Renal size was varied by age, based on normative values. The maximum fluid temperature after 60s of simulated LL was captured. Thermal dose was calculated using the t43 equivalence of 240min as a threshold for tissue damage, as was tissue volume at risk for irreversible cellular damage. Simulation with gravity flow irrigation revealed generation of thermal doses sufficient to cause tissue injury for all ages at 20W and 40W power settings. Higher temperatures were seen in younger ages across all power settings. Temperature increases were dampened with intermittent laser activity and continuous pressure flow irrigation. Smaller renal size is more susceptible to thermal changes induced by LL. However, power settings equal to or greater than 20W can result in temperatures high enough for tissue damage at any age. Continuous pressure flow and intermittent laser activity may mitigate the potential thermal damage from high power LL.

P53 is Subjected to Lipoteichoic Acid-Induced Phosphorylation in the Lungs.

P53 is a transcription factor protecting the cells against malignancies via modulation of multifarious regulatory signaling cascades. Those activities may result to either cellular repair, or to the elimination of the irreversible damaged tissue components. Recent evidence suggest that this endothelium defender (P53) exerts strong anti-inflammatory activities in the lungs.[1] P53 protects the endothelium cells against the lipopolysaccharide (LPS)-induced endothelial hyperpermeability by reducing the generation of the reactive oxygen species,[2] by suppressing the inflammatory RhoA/MLC2 pathway,[3] and by inducing the repairing activities of the unfolded protein response in the lungs.[4] [5]

CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond.

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare systemic disease characterized by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils, causing irreversible tissue damage. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells (PCs) are undoubtedly involved in monoclonal LC production.CD38 is a pleiotropic molecule detectable on the surface of PCs and maintained during the neoplastic transformation in multiple myeloma (MM). CD38 is expressed on T, B and NK cell populations as well, though at a lower cell surface density. CD38 is an ideal target in the management of PC dyscrasia, including AL amyloidosis, and indeed anti-CD38 monoclonal antibodies (MoAbs) have promising therapeutic potential. Anti-CD38 MoAbs act both as PC-depleting agents and as modulators of the balance of the immune cells. These aspects, together with their interaction with Fc receptors (FcRs) and neonatal FcRs, are specifically addressed in this paper. Moreover, the initiallyavailable experiences with the anti-CD38 MoAb DARA in AL amyloidosis are reviewed.