Multiscale modeling of glioma pseudopalisades: contributions from the tumor microenvironment.

Gliomas are primary brain tumors with a high invasive potential and infiltrative spread. Among them, glioblastoma multiforme (GBM) exhibits microvascular hyperplasia and pronounced necrosis triggered by hypoxia. Histological samples showing garland-like hypercellular structures (so-called pseudopalisades) centered around the occlusion site of a capillary are typical for GBM and hint on poor prognosis of patient survival. We propose a multiscale modeling approach in the kinetic theory of active particles framework and deduce by an upscaling process a reaction-diffusion model with repellent pH-taxis. We prove existence of a unique global bounded classical solution for a version of the obtained macroscopic system and investigate the asymptotic behavior of the solution. Moreover, we study two different types of scaling and compare the behavior of the obtained macroscopic PDEs by way of simulations. These show that patterns (not necessarily of Turing type), including pseudopalisades, can be formed for some parameter ranges, in accordance with the tumor grade. This is true when the PDEs are obtained via parabolic scaling (undirected tissue), while no such patterns are observed for the PDEs arising by a hyperbolic limit (directed tissue). This suggests that brain tissue might be undirected - at least as far as glioma migration is concerned. We also investigate two different ways of including cell level descriptions of response to hypoxia and the way they are related .

Mitochondrial Ca2+ regulation in the etiology of heart failure: physiological and pathophysiological implications.

Heart failure (HF) represents one of the leading causes of cardiovascular diseases with high rates of hospitalization, morbidity and mortality worldwide. Ample evidence has consolidated a crucial role for mitochondrial injury in the progression of HF. It is well established that mitochondrial Ca2+ participates in the regulation of a wide variety of biological processes, including oxidative phosphorylation, ATP synthesis, reactive oxygen species (ROS) generation, mitochondrial dynamics and mitophagy. Nonetheless, mitochondrial Ca2+ overload stimulates mitochondrial permeability transition pore (mPTP) opening and mitochondrial swelling, resulting in mitochondrial injury, apoptosis, cardiac remodeling, and ultimately development of HF. Moreover, mitochondria possess a series of Ca2+ transport influx and efflux channels, to buffer Ca2+ in the cytoplasm. Interaction at mitochondria-associated endoplasmic reticulum membranes (MAMs) may also participate in the regulation of mitochondrial Ca2+ homeostasis and plays an essential role in the progression of HF. Here, we provide an overview of regulation of mitochondrial Ca2+ homeostasis in maintenance of cardiac function, in an effort to identify novel therapeutic strategies for the management of HF.

Cocaine Use and Levamisole-Induced Vasculitis: A Multiple Case Study.

BACKGROUND: Levamisole is an immunomodulatory medication previously used to treat rheumatoid arthritis and some types of cancers; it was banned for use in humans in 2000 owing to its harmful side effects. Use of levamisole-laced cocaine is associated with a life-threatening syndrome characterized by a necrotizing purpuric rash leading to tissue destruction and necrotic wounds. This Clinical Challenges article summarizes our experience with the care of 2 adult women diagnosed with levamisole-related vasculitis. CASE: Case 1 is a 46-year-old woman who presented with joint pain in her hands and legs, along with bilateral ear pain, swelling, and bleeding. She was initially diagnosed with vasculitis and possible systemic lupus erythematosus. She experienced multiple recurrences and exacerbation of her condition over a period of months. She was ultimately diagnosed with levamisole-related vasculitis from recurrent cocaine use resulting in bilateral above the knee amputations. The second case is a 50-year-old woman who presented to our emergency department with redness and swelling of her bilateral lower extremities. She developed blisters and pustules that rapidly evolved into abscesses and red lesions over the course of several months. Her wounds also deteriorated despite topical therapy that occurred in a context of recurring use of cocaine. CONCLUSIONS: Our experience with these cases suggests that WOC nurses should consider levamisole-induced vasculitis in all patients presenting with unexplained vasculitis-type lesions, and particularly when these lesions occur in the context of known or suspected use of illicit substances such as cocaine. Given the absence of clinical guidelines for this increasingly prevalent condition, we recommend wound care based on principles of moist wound healing, combined with judicious use of therapies with antimicrobial activity and nonadherent dressings to reduce pain. Finally, we strongly recommend that care of these patients occurs as one part of a multidisciplinary care approach that focuses on cessation of the use of cocaine and all other illicit substances.

Dexamethasone promotes mesenchymal stem cell apoptosis and inhibits osteogenesis by disrupting mitochondrial dynamics.

Long-term or heavy use of glucocorticoids can cause severe necrosis of the femoral head, but the underlying mechanisms are still unclear. Recent studies have found that mitochondrial dynamics play an important role in femoral head necrosis. Here, we investigated the effect of dexamethasone on the mitochondrial function of mesenchymal stem cells. We observed that high concentrations of dexamethasone (10-6  mol·L-1 ) decreased cell activity, promoted apoptosis, elevated levels of reactive oxygen species and disrupted mitochondrial dynamics. Furthermore, dexamethasone (10-6  mol·L-1 ) inhibited osteogenesis of stem cells and promoted adipogenesis. These findings may facilitate greater understanding of the adverse effects of dexamethasone on the femoral head.

[Treatment of necrotizing infection in patients with chronic arterial insufficiency of the lower extremities]. / Rezul'taty lecheniia nekrotiziruiushchei infektsii u patsientov s khronicheskoi arterial'noi nedostatochnost'iu nizhnikh konechnostei.

OBJECTIVE: To analyze the effectiveness of complex therapy of necrotizing infection using the original method of stimulation of angiogenesis in patients with chronic arterial insufficiency of the lower extremities. MATERIAL AND METHODS: In 53 patients, operations were performed using the proposed technologies for stimulation of angiogenesis. A control group consisting of 56 patients was formed to compare the results of treatment. They had standard vascular therapy for the correction of ischemia. Morphological studies of the muscles of the lower extremities included assessment of capillary bed density and spatial orientation of the capillaries before and after treatment. Computed angiography of the lower extremities followed by calculation of perfusion index was performed to assess changes in the microvasculature. Clinical evaluation of the results was carried out using R. Rutherford scale. RESULTS: Revascularization resulted significant augmentation of capillary bed density and the number of functioning capillaries in muscular tissue. This was accompanied by increased perfusion index and TcPO2 values. The effect of treatment is observed in 12-14 days after surgery and persists for a long time. The best outcomes are found in patients with ischemia grade IIb-III. Incidence of lower limb amputations was more than 2 times lower in the main group compared with the control group. CONCLUSION: Combined stimulation of angiogenesis including mechanical tunneling of the muscles of the affected limb and administration of platelet rich plasma is effective procedure. This method does not require complex equipment and may be used in the treatment of patients with complications of chronic lower limb ischemia and contraindicated direct arterial reconstruction.

The AMPK-Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome.

The receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 play important roles in necroptosis that are closely linked to the inflammatory response. Although the activation of necroptosis is well characterized, the mechanism that tunes down necroptosis is largely unknown. Here we find that Parkin (also known as PARK2), an E3 ubiquitin ligase implicated in Parkinson's disease and as a tumour suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation and necroptosis. Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis by inhibiting RIPK1-RIPK3 complex formation; this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.

CellSaic, A Cell Aggregate-Like Technology Using Recombinant Peptide Pieces for MSC Transplantation.

In the field of stem cell therapy, research on the application of mesenchymal stem cells (MSCs) has flourished because of the various functions. On the other hand, research on the method of cell transplantation has developed from the administration of cell suspensions to cell-sheet engineering and 3D technology. In the trend, a cell transplantation platform named CellSaic, which is a combination of xeno-free recombinant scaffolds in a cell aggregate-like shape, was developed. CellSaic is the cell transplantation platform that can prevent the central necrosis within cell aggregates by arranging the cells and petaloid pieces of recombinant peptide (RCP) in a mosaic. The prevention of central necrosis is the most significant advantage over other 3D culture systems. This review details the unique characteristics of CellSaic including safety examination results and describes its future application for MSC transplantation. Particularly, in the application of MSCs, it has been reported that the MSC CellSaics increased the effect on improving various symptoms compared with MSCs only in the application of the therapy to inflammatory bowel disease (IBD), cerebral infarction, bone cartilage regeneration in joints, and islet transplantation. In accordance with the "One Health" concept, it is anticipated that this technology is expected to contribute to companion animal therapy and human therapy in the future.

Paving the way for precision medicine v2.0 in intensive care by profiling necroinflammation in biofluids.

Current clinical diagnosis is typically based on a combination of approaches including clinical examination of the patient, clinical experience, physiologic and/or genetic parameters, high-tech diagnostic medical imaging, and an extended list of laboratory values mostly determined in biofluids such as blood and urine. One could consider this as precision medicine v1.0. However, recent advances in technology and better understanding of molecular mechanisms underlying disease will allow us to better characterize patients in the future. These improvements will enable us to distinguish patients who have similar clinical presentations but different cellular and molecular responses. Treatments will be able to be chosen more "precisely", resulting in more appropriate therapy, precision medicine v2.0. In this review, we will reflect on the potential added value of recent advances in technology and a better molecular understanding of necrosis and inflammation for improving diagnosis and treatment of critically ill patients. We give a brief overview on the mutual interplay between necrosis and inflammation, which are two crucial detrimental factors in organ and/or systemic dysfunction. One of the challenges for the future will thus be the cellular and molecular profiling of necroinflammation in biofluids. The huge amount of data generated by profiling biomolecules and single cells through, for example, different omic-approaches is needed for data mining methods to allow patient-clustering and identify novel biomarkers. The real-time monitoring of biomarkers will allow continuous (re)evaluation of treatment strategies using machine learning models. Ultimately, we may be able to offer precision therapies specifically designed to target the molecular set-up of an individual patient, as has begun to be done in cancer therapeutics.

[Is Oxygen Deficiency Always Harmful?] / Ist Sauerstoffmangel immer nur schädlich?

Is Oxygen Deficiency Always Harmful? Abstract. The role of the cardiovascular circulation is to supply tissue with oxygen and nutrients. Oxygen deficiency (hypoxia) is considered life-threatening, since cells die, either through apoptotic or necrotic processes. Tissue tries to counteract this by means of evolutionary signalling pathways, such as the nuclear hypoxia-inducible factor, which protects the tissue by promoting cell survival strategies and simultaneously intervening in angiogenesis, haematogenesis and metabolic processes. Recent findings indicate that these conserved signalling pathways can also function as therapeutic approaches in wound healing of bones and skin, as well as in the regeneration of tissues, e.g. in the liver, and in the hematopoietic system.

The Role of Negative Pressure Wound Therapy in Managing Chinese Patients With Wound-derived Acute Severe Illness.

INTRODUCTION: Resulting mostly from major injury or infection, severe acute wounds are often accompanied by septic shock or multiple organ failure and associated with high disability and mortality rates. In managing Chinese patients with wound-derived acute severe illnesses, salvage treatment in the emergency department has traditionally prioritized life support and protection of vital organs before wound repair. OBJECTIVE: This retrospective review evaluated the outcomes of patients with wound-derived acute severe illness who were treated with a new salvage protocol that combined proactive wound care with simultaneous life-support measures. MATERIALS AND METHODS: Records from 2011 to 2013 at Peking Union Medical College Hospital (PUMCH) in Beijing, China, were reviewed to identify patients with wound-derived acute severe illness treated with the new protocol. The plastic surgery department, emergency department, and intensive care unit developed the protocol, which included proactive wound treatment with negative pressure wound therapy (NPWT), interdepartmental cooperation, and comprehensive patient treatment. RESULTS: Fifty-six patients were managed with the new protocol. At presentation, all patients were in septic shock and 29 of 56 (51.8%) required mechanical ventilation. Of the treated patients, 21 (37.5%) fully recovered and 29 (51.8%) improved sufficiently enough for transfer to a general ward. Six patients (10.7%) died of causes unrelated to NPWT. CONCLUSIONS: At PUMCH, the new collaborative salvage protocol with proactive use of NPWT with simultaneous life- support methods resulted in greater therapeutic effects than traditional salvage treatment could offer.

The Pathogenesis of Necroptosis-Dependent Signaling Pathway in Cerebral Ischemic Disease.

Necroptosis is the best-described form of regulated necrosis at present, which is widely recognized as a component of caspase-independent cell death mediated by the concerted action of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3). Mixed-lineage kinase domain-like (MLKL) was phosphorylated by RIPK3 at the threonine 357 and serine 358 residues and then formed tetramers and translocated onto the plasma membrane, which destabilizes plasma membrane integrity leading to cell swelling and membrane rupture. Necroptosis is downstream of the tumor necrosis factor (TNF) receptor family, and also interaction with NOD-like receptor pyrin 3 (NLRP3) induced inflammasome activation. Multiple inhibitors of RIPK1 and MLKL have been developed to block the cascade of signal pathways for procedural necrosis and represent potential leads for drug development. In this review, we highlight recent progress in the study of roles for necroptosis in cerebral ischemic disease and discuss how these modifications delicately control necroptosis.

Receptor-Interacting Protein 3/Caspase-8 May Regulate Inflammatory Response and Promote Tissue Regeneration in the Periodontal Microenvironment.

BACKGROUND Periodontal ligament stem cells (PDLSCs) possess characteristics of multi-potential differentiation and immuno-modulation, and PDLSCs-mediated periodontal tissue regeneration is regarded as a hopeful method for periodontitis treatment. Recent studies demonstrated that RIP3 and caspase8 regulate bacteria-induced innate immune response and programmed necrosis, which is also called necroptosis. This study aimed to determine the role of the RIP3/Caspase8 signal pathway on necroptosis of PDLSCs under the inflammatory microenvironment, both [i]in vitro[/i] and [i]in vivo[/i]. MATERIAL AND METHODS PDLSCs were cultured, and transmission electron microscopy and flow cytometry were used to detect necroptosis. PCR, ALP, and Alizarin Red S staining were used to assess the effect of necroptosis on osteogenesis differentiation of PDLSCs [i]in vitro[/i], while HE and Masson staining were taken after the nude mouse subcutaneous transplant experiment. RESULTS Our research indicates that RIP3/caspase8 can regulate the immune response of PDLSCs, and blockade of RIP3/caspase8 can protect the biological characteristics of the PDLSCs, effectively promoting periodontal tissue regeneration in the inflammatory microenvironment. CONCLUSIONS Inhibiting RIP3/caspase8 can effectively promote periodontal tissue regeneration in the inflammatory microenvironment.

A rare cause of proximal muscle weakness: immune necrotising myopathy.

Background Immune-mediated necrotising myopathies are characterised clinically by the subacute onset of proximal limb weakness, accompanied by elevated creatinine kinase levels. They are distinguished from other myopathies by the absence of prominent infiltration of the muscle with inflammatory cells in the biopsies. Case presentation A 44-year-old man presented with upper extremity weakness and dysphagia. Laboratory tests included a creatinine kinase level of 4362 U/L (normal: 52-336 U/L). Rheumatological markers were all negative. A muscle biopsy showed multiple necrotic fibres with minimal inflammatory infiltration. One gram of methylprednisolone (IV) was given, followed by 1 mg/kg of methylprednisolone daily by the oral route. Intravenous immunoglobulin (0.4 mg/kg/day) was given for five days. Muscle weakness regressed and dysphagia disappeared with treatment. The patient remains well in the 23rd month of treatment, taking 5 mg/day prednisolone and monthly intravenous immunoglobulin. Conclusion Treatment of immune-mediated necrotising myopathy can be challenging as evidence-based therapeutic options are limited. It is generally accepted that early and extensive immunosuppression, including glucocorticoids as first-line agents, may be required.

Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics.

Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infections. In this study, UPEC strains harboring hemolysin A (HlyA) did not induce programmed cell death pathways by the activation of caspases. Instead, the UPEC pore-forming toxin HlyA triggered an increase in mitochondrial Ca2+ levels and manipulated mitochondrial dynamics by causing fragmentation of the mitochondrial network. Alterations in mitochondrial dynamics resulted in severe impairment of mitochondrial functions by loss of membrane potential, increase in reactive oxygen species production, and ATP depletion. Moreover, HlyA caused disruption of plasma membrane integrity that was accompanied by extracellular release of the danger-associated molecules high-mobility group box 1 (HMGB1) and histone 3 (H3). Our results indicate that UPEC induced programmed cell necrosis by irreversibly impairing mitochondrial function. This finding suggests a strategy devised by UPEC at the onset of infection to escape early innate immune response and silently propagate inside host cells.-Lu, Y., Rafiq, A., Zhang, Z., Aslani, F., Fijak, M., Lei, T., Wang, M., Kumar, S., Klug, J., Bergmann, M., Chakraborty, T., Meinhardt, A., Bhushan, S. Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics.

PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors.

Necroptosis, a form of regulated necrotic cell death, is governed by RIP1/RIP3-mediated activation of MLKL. However, the signaling process leading to necroptotic death remains to be elucidated. In this study, we found that PUMA, a proapoptotic BH3-only Bcl-2 family member, is transcriptionally activated in an RIP3/MLKL-dependent manner following induction of necroptosis. The induction of PUMA, which is mediated by autocrine TNF-α and enhanced NF-κB activity, contributes to necroptotic death in RIP3-expressing cells with caspases inhibited. On induction, PUMA promotes the cytosolic release of mitochondrial DNA and activation of the DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. Furthermore, deletion of PUMA partially rescues necroptosis-mediated developmental defects in FADD-deficient embryos. Collectively, our results reveal a signal amplification mechanism mediated by PUMA and cytosolic DNA sensors that is involved in TNF-driven necroptotic death in vitro and in vivo.

Dorsal thermal necrosis in dogs: a retrospective analysis of 16 cases in the southwestern USA (2009-2016).

BACKGROUND: Prolonged sun exposure in high ambient temperatures has been recognized as a cause of thermal burns on the dorsal skin of dogs, termed dorsal thermal necrosis (DTN). HYPOTHESES/OBJECTIVES: To characterize the clinical presentation, histopathology and outcomes of 16 dogs diagnosed with DTN and to identify associated risk factors. ANIMALS: Sixteen dogs diagnosed with DTN. METHODS: Medical records from 2009 to 2016 were reviewed retrospectively. Inclusion criteria included: (i) historical solar exposure; (ii) dorsal burn injuries and (iii) histopathological findings consistent with DTN. RESULTS: The majority of cases (15 of 16) occurred during warmer months (May-September) in the southwestern USA. Affected dogs had predominantly dark, short hair coats, whereas four of 16 dogs had lighter coat colours. Five dogs had naturally longer hair, but two hair coats had been recently clipped. Signs consistent with heat exhaustion or heatstroke were reported prior to the development of cutaneous lesions in four of 16 dogs. The most common skin lesions were alopecia, erythema, ulcerations, eschars/necrosis and crusts. Histological findings were consistent with other types of partial and full-thickness thermal burns, and included coagulation necrosis in the majority of cases. Most dogs were treated supportively with analgesics and antimicrobial therapies. The majority of DTN wounds healed via second intention, although surgery was performed on two dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Dorsal thermal necrosis should be considered as a differential diagnosis for dogs with dorsal cutaneous burns and a history of sun exposure in high external temperatures. Dogs with dark, short hair coats may be at an increased risk.

Digital Ischemia After Application of Self-Adherent Elastic Wrap Dressing: A Case Series.

Self-adherent elastic wrap dressings are a convenient option to manage pediatric hand and finger injuries. However, when improperly applied, they have the potential to cause devastating complications. We detail in this report 5 cases of dressing-induced ischemic injury to the hand in pediatric patients with a review of the literature. All patients were treated by the senior author between 2007 and 2015 and were retrospectively reviewed for initial injury, frequency of dressing changes, presence of pain, time to evaluation by the orthopedic hand team, treatment, and outcome. Patients' families were contacted for clinical updates and to obtain current photographs. Age at injury ranged from 11 months to 3 years with 2 girls and 3 boys. Only 1 of 5 patients complained of pain or discomfort during the onset of their ischemic injury. Treatment of the ischemic injury included local wound care without surgery in 3 cases (including sympathetic block in 1) and surgical intervention with partial or complete digital amputation in 2 cases. At final follow-up, 2 of the 5 patients reported currently being bothered by the appearance of the injured hand; however, none had persistent pain or difficulty using the hand. Through these examples, health care professionals can be educated on the potentially disastrous complications of improper dressing application in the pediatric population and can be encouraged to share this information with patients' families.

Role of Periapical Diseases in Medication-Related Osteonecrosis of the Jaws.

OBJECTIVE: The present study aimed to investigate the role of periapical diseases in inducing medication-related osteonecrosis of the jaws (MRONJ) using an ovariectomized (OVX) mice model. MATERIALS AND METHODS: Twenty C57BL/6N female mice were randomly assigned to two groups. All mice were subjected to bilateral ovariectomy and then treated with oncologic dose of zoledronic acid (ZA) or vehicle for twelve weeks. Eight weeks after commence of drug administration, a pulpal exposure (PE) operation was performed on the first right lower molar to induce periapical periodontitis; the contralateral non-PE tooth was used as control. All animals were sacrificed four weeks after pulpal exposure, and the mandibles were harvested for radiological and histomorphometrical analysis. RESULTS: Micro computed tomography (µ-CT) examination demonstrated that periapical diseases significantly increased alveolar bone resorption, and the resorption was greatly attenuated by ZA treatment. Concurrent ZA therapy significantly increased bone density and histological osteocyte necrosis in the presence of periapical lesions. CONCLUSION: ZA treatment reduced bone absorption resulting from periapical disease but increased the risk of developing MRONJ in the ovariectomized mouse model.