Tissue Reaction Research Articles

Towards Personalized Radiotherapy in Pelvic Cancer: Patient-Related Risk Factors for Late Radiation Toxicity

Normal tissue reactions vary significantly among patients receiving the same radiation treatment regimen, reflecting the multifactorial etiology of late radiation toxicity. Predicting late radiation toxicity is crucial, as it aids in the initial decision-making process regarding the treatment modalities. For patients undergoing radiotherapy, anticipating late toxicity allows for planning adjustments to optimize individualized care. Various dosimetric parameters have been shown to influence the incidence of late toxicity, and the literature available on this topic is extensive. This narrative review examines patient-related determinants of late toxicity following external beam radiotherapy for pelvic tumors, with a focus on prostate and cervical cancer patients. In Part I, we address various methods for quantifying radiation toxicity, providing context for interpreting toxicity data. Part II examines the current insights into the clinical risk factors for late toxicity. While certain factors—such as previous abdominal surgery, smoking behavior, and severe acute toxicity—have consistently been reported, most of the others show inconsistent associations. In Part III, we explore the influence of genetic factors and discuss promising predictive assays. Single-nucleotide polymorphisms (SNPs) likely elevate the risk in specific combinations. Advances in artificial intelligence now allow for the identification of SNP patterns from large datasets, supporting the development of polygenic risk scores. These innovations hold promise for improving personalized treatment strategies and reducing the burden of late toxicity in cancer survivors.

Inflammasome activation in melanoma progression: the latest update concerning pathological role and therapeutic value.

The progression of melanoma is a complex process influenced by both internal and external cues which encourage the transition of tumour cells, uncontrolled growth, migration, and metastasis. Additionally, inflammation allows tumours to evade the immune system, contributing to cancer development. The inflammasome, a complex of many proteins, is crucial in enhancing immune responses to external and internal triggers. As a critical inflammatory mechanism, it contributes to the development of melanoma. These mechanisms may be triggered via various internal and external stimuli, causing the induction of specific enzymes such as caspase-1, caspase-11, or caspase-8. This, in turn, leads to the release of interleukin (IL)-1β and IL-18 and cell death by apoptosis and pyroptosis. Proper inflammasome stimulation is crucial for the host to deal with invading pathogens or tissue injury. However, inappropriate inflammasome stimulation can result in unregulated tissue reactions, thus easing many diseases, including melanoma. Hence, keeping a delicate equilibrium between the stimulation and prohibition of inflammasomes is crucial, necessitating meticulous control of the assembly and functional aspects of inflammasomes. This review examines the latest advancements in inflammasome studies, specifically focusing on the molecular processes that control inflammasome formation, signalling, and modulation in melanoma.

Individual Sensitivity for Radiotherapy-related Adverse Tissue Reactions in Patients Treated Twice for Metachronous Cancers.

The role of genetics in susceptibility to radiotherapy-induced toxicities is unclear. A strong impact of genetics should cause correlated toxicities in patients with metachronous double radiotherapy. We ascertained information about demographics, lifestyle, radiotherapy and early toxicities in irradiated tissues for a retrospective cohort of 98 patients from 2 hospitals who underwent two metachronous radiotherapeutic treatments (2007-2022) of different anatomical regions. European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scores per organ system were combined to a single mean score. We considered as genetic component the variation of toxicity not explained by radiation dose to the tumor, age at radiotherapy, sex, smoking status, and surgery. Variance components of toxicity were evaluated by ordinal logistic regression with random intercept. Common site combinations were breast/contralateral breast (N = 16), breast/endometrium (N = 6), and cervix/breast (N = 5). Mean toxicity over exposed tissues was 0.70 (range, 0-3). Prescribed radiation dose was significantly associated with mean toxicity, with a 5% (95% CI 3-8) increase of the odds for a higher toxicity level per Gy. Sex, surgery, age and smoking were not. There was no genetic contribution to risk of toxicities after adjustment. Toxicity levels were not more similar within patients than between patients, suggesting a negligible impact of genotype on radiotherapy-related toxicities.

Differential Expression and Distribution of Slco4a1 and Slco1b2 in an Internal Environment Disorder-induced Hepatocellular Carcinoma Mouse Model.

This study aims to enhance the understanding of underlying mechanisms and potential therapies of the solute carrier organic anion (SLCO) transporter family in internal environment disorder (IED)-induced hepatocellular carcinoma (HCC). This could lead to new therapeutic strategies and offer new directions for the creation of new patents for HCC treatment products. The orthotopic transplantation (OT), IED and IED-based OT (IED-OT) mouse models were established. Expression patterns of Slco4a1 and Slco1b2 were determined using reverse transcriptionquantitative polymerase chain reaction (RT-qPCR), western blotting (WB) and immunohistochemistry (IHC) in various tissues, including lung, stomach, liver, spleen, kidney, colon, small intestine, HCC tissues and adjacent non-cancerous tissues. Animals exhibited symptoms, including weight loss, lethargy, chills, dyspnea, altered hair texture, and gastrointestinal disturbances, confirming the successful establishment of the IED model. The analysis demonstrated differential expression and tissue-specific distribution of Slco4a1 and Slco1b2, which are associated with IED-induced changes. These alterations potentially disrupt organ transport functions, thereby promoting the development of HCC. Additionally, they suggest a role in rebalancing the tumor microenvironment and mitigating damage resulting from abnormal substance accumulation. Changes in SLCO expression and distribution induced by IED may play pivotal roles in the development of HCC. These findings contribute insights that could inform novel therapeutic strategies against HCC.

Investigation of natural infection of BALB C mice by Bartonella henselae

Specific Pathogen-Free (SPF) animals are bred and maintained to exclude pathogens associated with significant morbidity or mortality, which may pose a risk to research replicability. The BALB/c strain is distributed globally and is among the most commonly used inbred strains in immunology and infectious disease research. Despite being a widely distributed bacterium that causes chronic infection, Bartonella henselae infection has not been investigated in any protocol that characterizes SPF animals. The objective of this study was to investigate the potential natural infection of laboratory animals of the BALB/c lineage by B. henselae. To achieve this, ten immunocompetent BALB/c mice were obtained directly from the bioterium and euthanized for collection of samples, including blood, skin, spleen, liver, heart, eye, kidney, intestine, esophagus, and brain. DNA was extracted using a commercial kit and tested via nested PCR for the ftsZ gene, as well as conventional PCR and qualitative real-time PCR using Sybr® Green for the citrate synthase gene (gltA), all specific reactions for B. henselae. All animals showed detection of B. henselae DNA in at least two different reactions in different tissues. The sequenced amplicons showed 100% similarity to B. henselae. The use of mice infected by B. henselae in experiments is undesirable, as the bacteria can affect several aspects of the animal's physiology and consequently influence the results of the project, especially when subjected to immunosuppression. More studies are needed to understand and confirm the natural infection in experimental animals by Bartonella spp. To date, no additional published reports of contamination of experimental animals by these bacteria have been identified.

Incidence of mycobacteria in pulmonary granulomatous lesions.

Mycobacteria infections are caused by species of the Mycobacterium tuberculosis complex (MTB) and other species called Non-Tuberculosis Mycobacteria (NTM). Identification of mycobacteria species is very important to define treatment and it can be achieved by direct culture. However, the lack of clear protocols regarding the use of culture or molecular tests on specimens diagnosed with granulomatous lesions causes delays in the diagnosis of the etiological agents and, consequently, the definition of the right treatment. This work aimed to characterize the incidence of mycobacteria species in pulmonary granulomatous lesions and the contribution of Polymerase Chain Reaction (PCR) in Formalin-Fixed Paraffin-Embedded Tissue (FFPE), direct culture, and Ziehl-Neelsen histological stain to the diagnosis. The authors performed an observational, centralized, and retrospective study in a cohort of 336 cases with pulmonary granulomatous lesions. Mycobacteria were detected by ZNS in 54/323 (16.72 %) and by direct culture in 40/198 (20.20 %). MTB DNA was detected by PCR in 10/57 (17.54 %). Mycobacterial culture results revealed MTB in 26/40 (65.00 %), whereas NTM was detected in 13/40 (32.50 %). NTM was represented by M. avium (n = 4), M. intracellulare (n = 3), M. kansasii (n = 3), M. colombiense (n = 1), M. paraffinicum (n = 1), and M. abscessus subsp. massiliense (n = 1). In conclusion, this study demonstrated that mycobacteria are detected in 16.72 % to 20.20 % of pulmonary granulomatous lesions. Moreover, MTB and NTM were detected in these lesions. The use of different methods for mycobacteria detection, in addition to culture, is complementary and contributes to fastening and increasing the detection of mycobacteria in these lesions.

A Comparative Study on Absorbable and Non-Absorbable Suture Materials for the Closure of Skin in Rabbit Model

Skin closure is a critical component of surgical procedures, and the selection of suture material has a significant impact on wound healing outcomes. This investigation aims to compare the effectiveness of absorbable and non-absorbable sutures for skin closure in rabbits. An experimental study was conducted on thirty (n=30) male rabbits aged 9.78+0.46 weeks and with an average weight of 1186.94+69.93 gms. Rabbits were divided into two groups, with one receiving absorbable sutures while the other received non-absorbable sutures. Wound healing parameters such as wound closure time, tensile strength, tissue reaction, and histological evaluation were evaluated over a specified period. Our findings suggest that both types of suture materials are effective in closing skin wounds in rabbits. However, absorbable sutures exhibited faster wound closure times and less tissue reaction compared to non-absorbable sutures. Conversely, non-absorbable sutures demonstrated higher tensile strength and better histological evaluations at the wound site. The results indicated significantly better wound healing with non-absorbable suture material than with absorbable suture material; indeed, there was an outstandingly high (++++) wound healing score when using non-absorbable suture material compared to that obtained from using absorbables. Moreover, rabbits recovered excellently from wounds treated with non-absorbables; thus demonstrating that choosing a specific type of suture material should be based on individual patient factors and requirements for each surgical procedure. Further studies are required to confirm these findings across larger animal models or human patients conclusively. In conclusion, it is evident that opting for non-absorbent materials results in expedited skin wound healing with superior outcomes when compared to their absorbent counterparts.

Reducing DNA extraction costs through factorial design for the DNAdvance Kit

Abstract Objective Extracting DNA is essential in wildlife genetic studies, and numerous methods are available. However, the process is costly and time-consuming for non-model organisms, including most wildlife species. Therefore, we optimized a cost-efficient protocol to extract DNA from the muscle tissue of White-tailed Deer using the DNAdvance kit (Beckman Coulter), a magnetic-bead-based approach. We devised a 3 × 3 factorial design using combinations of tissue mass (10 mg, 50 mg, or 100 mg) and reaction volume (25%, 33%, and 50% of the manufacturer's recommended volumes). DNA was extracted for N = 81 tissue sub-samples (9 replicates/treatment). Results Our target yield was 500 ng of genomic DNA per sample, sufficient for population genetic assessments. A combination of 50 mg tissue and 25% reaction volume yielded enough DNA at the lowest cost. The factorial design revealed that varying tissue mass and reagent volume significantly affected extracted DNA yield. Our study demonstrates that sufficient DNA can be extracted at 75% lower costs than the manufacturer's standard protocol. Other researchers can directly use our modified DNAdvance protocol to perform cost-effective DNA extractions.

In English

In recent years, significant progress has been made in both the synthesis of metal nanoparticles and the creation of hydrogel platforms. It is assumed that their synergistic combination will allow to create the advanced hydrogel nanocomposites for the repair of anatomical and functional disorders of the human body, as well as for the needs of reconstructive surgery. The aim of the study is to develop a porous polymeric material based on polyvinylformal with incorporated functional hydrogels and gold nanoparticles, the study of its physicochemical properties and biocompatibility in vitro and in vivo. The developed hybrid hydrogel material is intended for use in reconstructive surgery of the oculo-orbital area and for filling postoperative cavities with simultaneous prevention of recurrence. The morphology of the synthesized hybrid hydrogel composites with gold nanoparticles was investigated by means of electron microscopy (SEM), while their thermal stability was studied by TGA and DSC methods. It was proved that the synthesized hybrid hydrogel materials demonstrate thermal stability in a wide temperature range, which significantly exceeds the range of their application, and can withstand steam sterilization (121 °C) without significant changes. The synthesized hybrid hydrogels were characterized as biocompatible in vitro according to the parameters of cytotoxicity, genotoxicity and biochemical markers (ATPase and LDHase activity) using L929 cell line. The study of the soft tissue reaction to implantation in vivo demonstrated the formation of fibrous tissue on the periphery and inside the implant, and a marked decrease in macrophage-histiocyte reaction and inflammatory infiltration in favor of fibroblastic proliferation and the absence of resorption, which creates the prerequisites for a stable clinical result. Thus, the developed spongy hybrid hydrogel material can be used in reconstructive surgery of the maxillofacial and ophthalmic-orbital areas.

Cytotoxicity and Bone Biocompatibility of the C-Root SP Experimental Root Canal Sealer.

This study evaluated the cytotoxicity and biocompatibility of a new strontium silicate-based root canal sealer (C-Root SP), in comparison with those of iRoot SP and AH plus. The sealer extract was diluted to the concentrations of 100%, 75%, 50%, and 25%. L929 cells were cultured for 24 h, and the absorbance value was determined. Two-way analysis of variance (two-way ANOVA) and sealers were implanted in the tibia of Sprague-Dawley (SD) rats, At 2, 6, and 12 weeks, rats were euthanised. The tissue reaction was evaluated by HE staining. The least significant difference (LSD) t-test and Kruskal-Wallis test were used. The cytotoxicity of C-Root SP and iRoot SP was found to be less than that of AH plus. At 12 weeks, new bone formation was induced around C-Root SP and iRoot SP sealer, but minimal evidence of bone formation was found in AH plus. C-Root SP has low cytotoxicity and superior biocompatibility.

Functional Morphology of the Bronchial Epithelium of Rats after Exposure to Chronic Low-Intensity γ Radiation

Revealing the reactions of cells and tissues to chronic low-intensity radiation exposure plays an important role in assessing the possible biological effects of man-made radiation effects on the body. The purpose of the study was to quantitatively study the microscopic structure and motor activity of the bronchial epithelium in rats under experimental exposure to chronic low-intensity ү-radiation. Materials and methods. Using the digital technology for intravital registration of motor activity indicators of the ciliary apparatus in combination with the methods of light and transmission electron microscopy, the main, lobular and segmental bronchi of 18 male Wistar rats subjected to experimental chronic gamma irradiation for 21 days (total absorbed doses – 5 cGy and 50 cGy) and 9 control animals were studied. In conditions of natural radiation background. The frequency was measured in the layer of the main types of epithelial cells and cells with Ki-67 expression, and the size characteristics of ciliated cells were determined as well. Research results. Chronic ү-irradiation in small doses causes a decrease in the frequency of cilia beating by 17–26% due to elongation of the recovery shock phase, an increase by 23–29% in the content of differentiated cell forms in the epithelium and a decrease in the frequency of basal (cambial) cells by 2–2.5 times. Electron microscopy revealed the emergence of cells with impaired ultrastructure, areas of intercellular edema, extrusion from the epithelial cell layer or their fragments. Irradiation at a dose of 50 cGy causes a decrease in the frequency of Ki-67 expressing epithelial cells by 3–3.8 times in all types of bronchi. In the subpopulation of basal cells, a pronounced dose-dependent inhibition of their proliferation in the main and lobar bronchi and complete blockade of cellular reproduction in segmental bronchi were found. Conclusions. Chronic low-intensity ү-radiation is a potential risk factor that can cause disturbance in the structure and function of the epithelial lining in the airways. Intravital assessing the frequency of cilia beating in combination with determining the content of Ki-67-positive epithelial cells can serve as an informative method for bioindicating the effects of low-dosed ionizing radiation on the body.

3D analysis of soft tissue dimensional changes after dental implant placement with butt-joint vs. conical connection: a 12-month randomized control trial

Purposeto quantify the soft tissue dimensional changes after single-gap implant placement, during healing abutment and crown delivery phase for butt-joint and conical implant-abutment connection type.Methodsforty patients were enrolled in the study and received randomly allocated implants with butt-joint and conical implant-abutment connection type. A standard healing abutment was placed after 6 months for two weeks. The definitive screw retained full-ceramic crowns were manufactured in a digital workflow. The soft tissue profile was digitized using IOS on following stages: pre-op, immediately, two, 7 and 14 days post-op, pre-exposure, immediately after exposure, two weeks after exposure (pre-delivery), immediately after crown delivery, 6 and 12 months after delivery. The intraoral scans were matched in the metrology software (Geomagic Control X). The mean maximum and mean average differences in mm were gathered to assess the soft tissues change. Various anamnesis parameters have been taken into account.Resultsthe conical connection implant system exhibited more soft tissue gain and less recession, compared to the butt-joint connection type within the 12 months follow-up period. A higher loss of soft tissue was observed in the distal papilla than in the mesial one.Conclusionsthe implant-abutment connection type may influence the reaction of peri-implant soft tissue within the 12 months follow-up period.

Prediction of normal tissue complication probability for rat spinal cord tolerance following ion irradiations

Objective.Currently, treatment planning in cancer hadrontherapy relies on dose-volume criteria and physical quantities constraints. However, incorporating biologically related models of tumor control probability and of normal tissue complication probability (NTCP) would help further minimizing adverse tissue reactions, and would allow achieving a more patient-specific strategy. The aim of this work was therefore the development of a mechanistic approach to predict NTCP for late tissue reactions following ion irradiation.Approach.A dataset on the tolerance of the rat spinal cord was considered, providing NTCP (for paresis of at least grade II) experimental data following irradiation by photons, protons, helium and carbon ions, under different fractionation schemes. The photon data were fit by a mechanistic NTCP model with four parameters, called Critical Element Model; this allowed fixing the two parameters that only depend on the tissue features. Afterwards, the two parameters depending on radiation quality were predicted by applying the BIophysical ANalysis of Cell death and chromosome Aberrations biophysical model, for each ion type and dose-averaged linear energy transfer value.Main results.The predicted NTCP curves for ion irradiation were tested against the ion experimental data, by Chi-Square andp-value calculations. The model passed a significance test at 1% for all the datasets, and 5% for 13 out of 16 datasets, thus showing a good predictive power. The Relative biological effectiveness (RBE) was also calculated and compared with the data for the endpoint of NTCP equal to 50%, and a considerable discrepancy with the commonly calculated RBE for cell survival was shown.Significance.This study highlights the importance of considering the endpoint of interest when computing the RBE, through the application of a NTCP model, and it represents a first step towards the development of an approach to improve treatment plan optimization in therapy. To this aim, the approach needs to be extended to other endpoints and to be applied to patients' data.

Histologic Reaction Patterns of Lymph Node Involvement in Ovarian Serous Borderline Tumors.

Lymph node (LN) involvement (LNI) is not infrequently observed in ovarian serous borderline tumors (SBTs) but is not considered equivalent to malignant tumor metastasis, as it reportedly does not impact recurrence or survival in patients with SBT. However, the reasons underlying the insignificant clinical impact of LNI remain unclear. To determine whether histologic reaction patterns (HRPs) are associated with SBT prognosis. We compared HRPs around tumor cell clusters in LNs of patients with SBT and low-grade serous carcinoma. HRPs were classified into 4 categories (HRP 1-HRP 4) based on tumor cell location in LNs, the presence of their adhesion to surrounding lymphoid tissue, or pericellular desmoplastic reactions. Although LNI itself was linked to reduced recurrence-free survival (RFS), no recurrence was observed in patients with HRP 1 or 2, characterized by freely floating tumor cells in the lumens of afferent/efferent lymphatics or intranodal sinus with surrounding free spaces. Conversely, HRP 3 or higher, characterized by firm tumor cell adhesion to lymphoid tissue (HRP 3) or peritumoral desmoplastic reaction (HRP 4), independently impacted RFS, albeit not overall survival. The prognosis of SBT with LNI is not uniformly favorable, and HRPs around the LNI significantly influence patient outcomes. Patients with firm tumor cell adhesion to surrounding tissue, with or without peritumoral desmoplastic reaction (HRP ≥3), independently experience decreased RFS, although this does not correlate with reduced overall survival.

Tissue Reaction Elicited by Neosealer Flo, AH 26, and CC Sealer in Rats

Background: Since root canal sealers are in contact with periradicular tissues, biocompatibility is one of their most important features .There is no available study about the biocompatibility of NSF and CC Sealer that are newly made bioceramic-based sealers. This study aimed to compare the tissue reaction elicited by NeoSealer Flo (NSF), AH26, and ColdCeramic Sealer (CC sealer) in rats. Material and Methods: The sealers were mixed and applied in molds to fabricate sealer discs, which were then implanted in the subcutaneous tissue of the backs of 30 healthy adult Albino Wistar rats. Each rat received three sealer discs and the fourth incision site remained empty as a control group. After 7, 30, and 90 days, the rats were sacrificed. Biopsy samples were evaluated regarding the extent and severity of inflammation, angiogenesis, fibroplasia, and infiltration. Data were analyzed in SPSS software using Kruskal-Wallis and Mann-Whitney U tests. Results: Tissue reaction to NSF was generally severe and increased up to day 30, but slightly decreased at three months, although it was still severe, and significantly greater than the tissue reaction to other sealer types. After one month, all rats in the NSF group showed foreign body reaction and giant cells around sealer particles; while, foreign body reaction was not seen in other groups. Tissue reaction to CC Sealer and AH26 was not significantly different at any point in time (P>0.05) and was the highest on day seven and then decreased up to month three. Conclusion: According to the present results, the CC Sealer appears to be a biocompatible material; however, NSF showed higher severity and extent of inflammation and triggered higher tissue reaction.

Cross-species single-cell RNA-seq analysis reveals disparate and conserved cardiac and extracardiac inflammatory responses upon heart injury

The immune system coordinates the response to cardiac injury and controls regenerative and fibrotic scar outcomes in the heart and subsequent chronic low-grade inflammation associated with heart failure. Adult mice and humans lack the ability to fully recover while adult zebrafish spontaneously regenerate after heart injury. Here we profile the inflammatory response to heart cryoinjury in zebrafish and coronary artery ligation in mouse using single cell transcriptomics. We interrogate the extracardiac reaction to cardiomyocyte necrosis to assess the specific peripheral tissue and immune cell reaction to chronic stress. Cardiac macrophages play a critical role in determining tissue homeostasis by healing versus scarring. We identify distinct transcriptional clusters of monocytes/macrophages (mono/Mϕ) in each species and find analogous pairs in zebrafish and mice. However, the reaction to myocardial injury is largely disparate between mice and zebrafish. The dichotomous response to heart damage between the murine and zebrafish mono/Mϕ and/or the presence of distinct zebrafish mono/Mϕ subtypes may underlie the impaired regenerative process in adult mammals and humans. Our study furnishes a direct cross-species comparison of immune responses between regenerative and profibrotic myocardial injury models, providing a useful resource to the fields of regenerative biology and cardiovascular research.

Degradation Pattern of a Biodegradable and Photocurable Sealants Based on Hyaluronic Acid : A Serial Magnetic Resonance Imaging Observational Study in Rat Craniectomy Model.

The aim of this study is evaluating in vivo degradation of photocrosslinkable hyaluronic acid (HA)-based dural sealant (HA photosealant) using magnetic resonance imaging (MRI) and histopathological analysis to assess its biodegradability and effectiveness in preventing cerebrospinal fluid (CSF) leakage. HA photosealants were applied to the incised dura in a rat craniectomy and durotomy. The HA photosealant quickly seal the wound upon low-energy visible light exposure (405 nm, < 5 s, < 1 J/cm2). The degradation of HA photosealants was tracked through serial MRI scans at 1, 2, and 4 weeks post-application. The remaining area of HA photosealants on the dura was measured using image processing program for volumetric analysis. Additionally, histopathological analyses were performed to evaluate the biocompatibility and effectiveness of the dural repair. The MRI and histopathological analyses showed that the HA photosealants achieved progressive degradation while successfully preventing CSF leakage without any adverse tissue reactions. The residual area of HA photosealants measured at 2 weeks ranged from 41.36% to 94.88%, with an average of 66.57%. At 4 weeks, a more distinct degradation pattern was observed compared to 2 weeks, showing a residual area of 10.28% to 56.12%. The HA photosealants maintained structural integrity until dural regeneration was complete. HA photosealant showed gradual degradation in vivo while maintaining mechanical strength until the dura was repaired for preventing CSF leakage without inflammation and toxicity. HA photosealant has great potentials for clinical application for dural repair with biodegradable properties and biocompatibility.

A stable rat model of high altitude pulmonary edema established by hypobaric hypoxia combined diurnal temperature fluctuation and exercise.

Hypobaric hypoxia (HH) is regarded as the main cause of high-altitude pulmonary edema (HAPE), however, the effect of diurnal temperature fluctuation and exercise has been overlooked. The aim of current study was to elucidate the role of diurnal temperature fluctuation and exercise in the development of HAPE and establish a reliable experimental rat model. Male SPF Wistar rats were assigned to control group (1400m, 25°C) and five model groups: Model Ⅰ group (6000m, 25°C), Model Ⅱ group (6000m, 2°C), Model Ⅲ group (6000m, 12°C/2°C light/dark cycle), Model IV group (6000m, 2°C, and exercise) and Model V group (6000m, 12°C/2°C light/dark cycle, and exercise). After exposure for 72h, the blood and lung tissues were collected for further research. The rats in Model I group did not show signs of HAPE. Compared with Model I group, the rats in Model II and Model III groups were suffered from more damage, evidence by enhanced oxidative stress and inflammatory reaction, but still did not show signs of HAPE. Model IV and Model V could induce HAPE, display the obvious pathological changes and edema, more serious oxidative stress and inflammatory reaction in lung tissues, suggesting that the key role of exercise in the development of HAPE. The rats in the Model V group showed the best performance in terms of modeling indicators, indicating that diurnal temperature fluctuation could further aggravate the degree of lung edema. In summary, HH combined with diurnal temperature fluctuation and exercise is a stable and reliable modeling method for HAPE, which can be used for subsequent research on the prevention and treatment of HAPE.

Neurohistopathological findings of the brain parenchyma after long-term deep brain stimulation: Case series and systematic literature review.

Efficacy of deep brain stimulation (DBS) is established for several movement and psychiatric disorders. However, the mechanism of action and local tissue changes are incompletely described. We describe neurohistopathological findings of 9 patients who underwent DBS for parkinsonism and performed a systematic literature review on postmortem pathologic reports post-DBS. We performed a retrospective study of patients who underwent DBS for Parkinsonism between 2000 and 2023 and had postmortem neurohistopathological assessments. Demographics and clinical features were collected. Levodopa equivalent daily dose (LEDD) and total electrical energy delivered (TEED) were calculated. A systematic literature review was conducted. Postmortem assessment of 9 DBS patients was performed (7 Parkinson's disease [PD], 1 Parkinsonism, 1 Multiple System Atrophy with pre-DBS clinical diagnosis of PD). Median age at DBS was 65 years (range, 54-69), 8 were male. Subthalamic nucleus was targeted in 8 patients, globus pallidus in 1. Median DBS duration was 65 months (range, 7-264). Post-DBS LEDD reduction was found in 7/9 patients and TEED increased over time in all cases. There were no DBS-related deaths. Neurohistopathological assessment showed gliosis in 7 patients and activated microglial infiltration in 1. In the literature (between 1977 and 2021), 59 patients with postmortem post-DBS findings were identified: 26 (44%) PD, 20 (34%) pain, and 13 (22%) other conditions. Findings confirm presence of a local tissue reaction (gliosis and activated microglia) around the implanted leads. The effect of local changes on the clinical efficacy of DBS is not established. Further DBS postmortem studies and standardization of tissue processing are needed.

NELL1 variant protein (NV1) modulates hyper-inflammation, Th-1 mediated immune response, and the HIF-1α hypoxia pathway to promote healing in viral-induced lung injury.

Research underscores the urgent need for technological innovations to treat lung tissue damage from viral infections and the lasting impact of COVID-19. Our study demonstrates the effectiveness of recombinant human NV1 protein in promoting a pro-healing extracellular matrix that regulates homeostasis in response to excessive tissue reactions caused by infection and injury. NV1 achieves this by calibrating multiple biological mechanisms, including reducing hyperinflammatory cytokine levels (e.g., IFN-γ, TNF-α, IL-10, and IP-10), enhancing the production of proteins involved in viral inactivation and clearance through endocytosis and phagocytosis (e.g., IL-9, IL-1α), regulating pro-clotting and thrombolytic pathways (e.g., downregulates SERPINE 1 and I-TAC during Th1-mediated inflammation), maintaining cell survival under hypoxic conditions via HIF-1α regulation through the M3K5-JNK-AP-1 and TSC2-mTOR pathways, and promoting blood vessel formation. Our findings reveal NV1 as a potential therapeutic candidate for treating severe lung injuries caused by inflammatory and hypoxic conditions from viral infections and related diseases.