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Introduction: Laryngeal Mask Airway(LMA) insertion requires a certain depth of anaesthesia to blunt the airway reflexes. Propofol alone causes undesirable hemodynamics effects and suboptimal LMA insertion condition. So this study was designed to compare the hemodynamics and insertion conditions when Ketamine or Fentanyl was combined with Propofol for induction. Methods: In this study, sixty ASA PSI(American Society of Anesthesiologists Physical Status) patients undergoing various surgical procedures under LMA were assigned to three groups; Group K, Group F and Group S who received 0.5 mg/kg of Ketamine, 1 μg/kg Fentanyl and Normal saline respectively before receiving Propofol 2.5 mg/kg after which LMA insertion was done. Arterial blood pressure and heart rate were measured at various intervals. LMA insertion conditions were graded under different parameters to calculate LMA insertion summation score. Result: Significant difference in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MAP) was seen between Gr K and Gr S after successful LMA insertion and after 2 mins of insertion. Significant difference in SBP was seen in between Group K and Group F (p=0.01) after successful LMA insertion. The median summed score describing the LMA insertion condition was significantly better in Ketamine [7.0 (6.0-7.5)] and Fentanyl [7.0 (6.0-7.0)J in comparison to Saline [ 8.5 (8.0-11.0)] Conclusion: During LMA insertion, adding Ketamine to Propofol provides stable hemodynamics in comparison to using Propofol. Addition of either Ketamine or Fentanyl to Propofol provides equally good conditions during LMA insertion than using Propofol alone. [ABSTRACT FROM AUTHOR]

Xeroderma Pigmentosum (XP) is a rare autosomal recessive disease, caused by a molecular defect in nucleotide excision repair (NER) genes. These patients present with many perioperative anaesthetic challenges like difficult venous cannulation, difficult intubation due to facial and oropharyngeal changes, difficult extubation due to epiglottis subsidence, prolonged action of neuromuscular blocking agents and increased sensitivity to opioids. Harmful effects of inhalational anaesthetic agents on nucleotide excision repair has been proposed. Planned airway management is necessary, short acting opioids with the use of multimodal analgesia is preferred and total intravenous anaesthesia (TIVA) is preferred to inhalational anesthetics. The novel anaesthetic agent Dexmedetomidine, alpha-2 agonist could be a valuable anaesthetic adjunct to TIVA. Besides, it also reduces the induction and maintenance dose of propofol, blunts the airway reflex during intubation and extubation, decreases the requirement of opioids and also helps to enhance the recovery. We present 3 cases of XP, who underwent surgery using propofol and dexmedetomidine infusion, without the use of muscle relaxants and inhalational agents. [ABSTRACT FROM AUTHOR]

Introduction: Scaphoid fracture is the commonest carpal bone fracture. Various radiographic views have been proposed for diagnosing it. This study was conducted to determine which radiographic view/s among five different views showed scaphoid fracture consistently. Methods: This prospective study was carried out in Department of Orthopedics, IOM, TUTH from February 2012 to June 2013. Twenty six patients with scaphoid fracture were included in the study who had five scaphoid views done viz. postero-anterior, ulnar deviated PA, pronation oblique, supination oblique and lateral. Each view was assessed with respect to demonstrating a fracture and the clarity of demonstration. Statistical analysis of data obtained was done using SPSS 17.0 version. Results: This study included 26 patients, 18 to 54 years of age (27.5±9.5 years). Average duration after injury was 6.73± 8.64 days. Out of five different views, pronation oblique showed fracture in 69.2% of patients followed by ulnar deviated PA in 61.5% patients. Pronation oblique showed fracture in all patients who had demonstrated fracture in supination oblique and lateral views also. Pronation oblique and ulnar deviated PA were the only views to show fracture in 5 patients each. Fracture in middle 1/3rd of the scaphoid was present in 53.8% patients while no patients had proximal 1/3rd fracture. Conclusion: Pronation oblique and ulnar deviated PA are the most important views among the other views of scaphoid series. Supination oblique and lateral views are the least important views to detect a scaphoid fracture. [ABSTRACT FROM AUTHOR]

Abstract Background Microglia are resident macrophage-like cells in the central nervous system (CNS) and cause innate immune responses via the LPS receptors, Toll-like receptor (TLR) 4 and CD14, in a variety of neuroinflammatory disorders including bacterial infection, Alzheimer’s disease, and amyotrophic lateral sclerosis. Granulocyte macrophage-colony stimulating factor (GM-CSF) activates microglia and induces inflammatory responses via binding to GM-CSF receptor complex composed of two different subunit GM-CSF receptor α (GM-CSFRα) and common β chain (βc). GM-CSF has been shown to be associated with neuroinflammatory responses in multiple sclerosis and Alzheimer’s disease. However, the mechanisms how GM-CSF promotes neuroinflammation still remain unclear. Methods Microglia were stimulated with 20 ng/ml GM-CSF and the levels of TLR4 and CD14 expression were evaluated by RT-PCR and flowcytometry. LPS binding was analyzed by flowcytometry. GM-CSF receptor complex was analyzed by immunocytechemistry. The levels of IL-1β, IL-6 and TNF-α in culture supernatant of GM-CSF-stimulated microglia and NF-κB nuclear translocation were determined by ELISA. Production of nitric oxide (NO) was measured by the Griess method. The levels of p-ERK1/2, ERK1/2, p-p38 and p38 were assessed by Western blotting. Statistically significant differences between experimental groups were determined by one-way ANOVA followed by Tukey test for multiple comparisons. Results GM-CSF receptor complex was expressed in microglia. GM-CSF enhanced TLR4 and CD14 expressions in microglia and subsequent LPS-binding to the cell surface. In addition, GM-CSF priming increased LPS-induced NF-κB nuclear translocation and production of IL-1β, IL-6, TNF-α and NO by microglia. GM-CSF upregulated the levels of p-ERK1/2 and p-p38, suggesting that induction of TLR4 and CD14 expression by GM-CSF was mediated through ERK1/2 and p38, respectively. Conclusions These results suggest that GM-CSF upregulates TLR4 and CD14 expression in microglia through ERK1/2 and p38, respectively, and thus promotes the LPS receptor-mediated inflammation in the CNS.

Abstract Background Phosphatidylserine receptor is a key molecule that mediates the phagocytosis of apoptotic cells. Milk fat globule-EGF factor 8 (MFG-E8) is a phosphatidylserine receptor that is expressed on various macrophage lineage cells, including microglia in the central nervous system (CNS). Targeted clearance of degenerated neurons by microglia is essential to maintain healthy neural networks. We previously showed that the CX3C chemokine fractalkine is secreted from degenerated neurons and accelerates microglial clearance of neuronal debris via inducing the release of MFG-E8. However, the mechanisms by which microglia produce MFG-E8 and the precise functions of MFG-E8 are unknown. Methods The release of MFG-E8 from microglia treated with conditioned medium from neurons exposed to neurotoxic substances, glutamate or oligomeric amyloid β (oAβ) was measured by ELISA. The neuroprotective effects of MFG-E8 and MFG-E8 − induced microglial phagocytosis of oAβ were assessed by immunocytochemistry. The effects of MFG-E8 on the production of the anti-oxidative enzyme hemeoxygenase-1 (HO-1) were determined by ELISA and immunocytochemisty. Results MFG-E8 was induced in microglia treated with conditioned medium from neurons that had been exposed to neurotoxicants, glutamate or oAβ. MFG-E8 significantly attenuated oAβ-induced neuronal cell death in a primary neuron − microglia coculture system. Microglial phagocytosis of oAβ was accelerated by MFG-E8 treatment due to increased CD47 expression in the absence of neurotoxic molecule production, such as tumor necrosis factor-α, nitric oxide, and glutamate. MFG-E8 − treated microglia induced nuclear factor E(2) − related factor 2 (Nrf2) − mediated HO-1 production, which also contributed to neuroprotection. Conclusions These results suggest that microglia release MFG-E8 in response to signals from degenerated neurons and that MFG-E8 protects oAβ-induced neuronal cell death by promoting microglial phagocytic activity and activating the Nrf2-HO-1 pathway. Thus, MFG-E8 may have novel roles as a neuroprotectant in neurodegenerative conditions.

Background. Prolonged cold storage (CS) of kidneys is associated with poor renal outcome after transplantation (Tx). We recently showed that in rats (Lewis), proteasome and renal function were severely compromised in kidney transplants subjected to CS (CS/Tx) as compared with those without CS exposure (autotransplanted [ATx]). Methods. Evaluation of whole-kidney extracts from our rat kidney transplant model showed a subset of proteins induced after CS/Tx when compared with ATx or sham groups; this study examined those proteins using mass spectrometry, western blotting, immunoprecipitation, and immunohistochemistry. Results. Mass spectrometry identified basal albumin levels in sham kidney extracts; western blots and immunohistochemistry confirmed this. Western blotting showed exceptionally higher albumin levels in both soluble and insoluble fractions of CS/Tx renal extracts when compared with ATx and sham groups. Surprisingly, levels of advanced glycation-end products (AGE) were higher in CS/Tx renal extracts. Furthermore, immunoprecipitation of albumin followed by western blotting for AGE revealed AGE-albumin in all 3 extracts; its levels were highest in CS/Tx extracts. Immunohistochemistry analysis of kidney sections revealed higher albumin or AGE levels in the CS/Tx group, and the protein was detected all over (within glomeruli, and intratubular and extratubular compartments) when compared with ATx and sham groups, which show confinement of these proteins to the extratubular compartment and within glomeruli. As expected, kidneys of the ATx group showed evidence of more macrophages, which was exacerbated in the CS/Tx group. Conclusions. These results suggested that CS/Tx increased AGE-albumin, which was correlated with increased inflammation and renal damage.

Competing Interests: Declarations Ethics approval This article does not contain any studies with human participants or animals performed by the authors. Informed consent Not applicable. Competing interests The authors declare no competing interests.

Alexander disease (AxD) is an intractable neurodegenerative disease caused by mutations in glial fibrillary acidic protein ( GFAP ), which is predominantly expressed in astrocytes. Thus, AxD is a primary astrocyte disease. However, it remains unclear how GFAP mutations affect astrocytes and cause AxD pathology. Three features are characteristic of AxD astrocytes in vivo : (1) Rosenthal fibers (RFs), the hallmark of AxD; (2) aberrant Ca 2+ signals (AxCa); and (3) upregulation of disease-associated genes (AxGen). We established a primary culture system for astrocytes from an AxD transgenic mouse model, and used it to analyze the above features of AxD pathogenesis in astrocytes in vitro . We observed the formation of RFs in AxD primary cultures. The abundance of RFs was greater in AxD-transgene-homozygous compared with -hemizygous astrocytes, indicating a gene dosage effect, and this abundance increased with time in culture, indicating a developmental process effect. However, cultured AxD astrocytes did not exhibit changes in either AxCa or AxGen. We therefore conclude that RFs in astrocytes form via a cell-autonomous mechanism, whereas AxCa and AxGen are likely to occur via a non-cell-autonomous mechanism through interactions with other cells, such as neurons, microglia, and vascular cells. Although primary cultured AxD astrocytes are suitable for elucidating the mechanisms of RFs formation and for intervention studies, it should be noted that they cannot reflect the pathophysiology of non-cell-autonomous events in astrocytes.

Abstract: Both abdominal radiotherapy and a nuclear event can result in gastrointestinal symptoms, including acute radiation syndrome (GI-ARS). GI-ARS is characterized by compromised intestinal barrier integrity increasing the risk for infectious complications. Physiologically relevant animal models are crucial for elucidating host responses and therapeutic targets. We aimed to determine the radiation dose requirements for creating GI-ARS in the Sinclair minipig. Male, sexually mature swine were randomly divided into sham (n = 6) and three lower hemibody radiation dosage groups of 8, 10, and 12 Gy (n = 5/group) delivered using linear accelerator-derived x-rays (1.9 Gy/min). Animals were monitored for GI-ARS symptoms for 14 days with rectal swab and blood collection at days 0-3, 7, 10, and 14 followed by necropsy for western blotting and histology. Dose-dependent increases in weight loss, diarrhea severity, and mortality (log-rank test, P = 0.041) were seen. Villi length was significantly reduced in all irradiated animals compared to controls ( P < 0.001). Serum citrulline decreased and bacterial translocation increased after irradiation compared to controls. Increased NLRP3 levels in post-mortem jejunum were seen ( P = 0.0043) as well as increased IL-1β levels in the 12 Gy group ( P = 0.041). Radiation dose and survival were associated with significant gut microbial community shifts in beta diversity. Moreover, decedents had increased Porphyromonas, Campylobacter, Bacteroides , Parvimonas , and decreased Fusobacterium and decreased Aerococcus, Lactobacillus, Prevotella, and Streptococcus . Our novel Sinclair minipig model showed dose-dependent clinical symptoms of GI-ARS. These findings provide invaluable insights into the intricate interplay between GI-ARS, intestinal inflammation, and gut microbiota alterations offering potential targets for therapeutic and diagnostic interventions after radiation exposure., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government"œ for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Introduction Bronchiolitis is a leading cause of respiratory distress and hospitalizations among infants and young children worldwide. Despite its prevalence, predicting the severity and outcomes of bronchiolitis remains challenging. Standardized criteria for severity assessment are essential for improving patient care and resource allocation. The modified Tal score is a reliable tool for assessing the severity of bronchiolitis. This study examines the relationship between the modified Tal score at presentation and key clinical outcomes in children with bronchiolitis. Methods This cross-sectional study classified children with bronchiolitis into mild, moderate, and severe groups using the modified Tal score at presentation. Patients were followed to record the length of hospital stay, duration of oxygen therapy, and the need for pediatric intensive care unit (PICU) or escalated care. Results Of the 121 children analyzed, the majority (71.9%) were aged three to 11 months, with a mean age of 9.09 months, and 73.6% were male. Oxygen supplementation was required by 60.3% of participants, 10.7% needed PICU admission, and 2.5% required escalated care. The mean duration of oxygen therapy was significantly longer in the severe group compared to the mild and moderate groups (p<0.001). Hospital stays also increased with severity (p<0.001). Linear regression showed that each unit increase in the modified Tal score resulted in a 0.746-day rise in hospital stay, a 10.19-hour increase in oxygen requirement, and a 0.35-day increase in PICU stay (all p<0.001). The score accounted for 66.1% of the variability in hospital stay, 63.0% in oxygen requirement, and 53.3% in PICU stay, but only 9.5% in escalated care. Conclusion A higher modified Tal score at admission was associated with prolonged hospitalization, increased oxygen requirement duration, and greater need for PICU admission in bronchiolitis. However, the modified Tal score was not a strong determinant of the requirement for escalated care., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Committee (IRC), Kist Medical College issued approval Ref. No 078/079/28. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Timalsena et al.)

This study describes the outcome of supracondylar humerus fractures in children using crossed K-wires after closed or open reduction with the medial, lateral or bilateral approach. Patients treated between January 2000 and December 2019 were classified according to the Von Laer classification, complications were classified according to the Sink classification and clinical outcomes were classified according to modified Flynn criteria. In total, 364 patients with a mean age of 5.23 ± 2.45 years were included. The majority were type IV fractures (156; 42.9%) and 94 (60.3%) needed an open reduction for which the medial approach (53; 56.4%) was predominantly used. Overall, of 50 complications (31 using closed reduction, 19 open reduction), 17/50 (34%) needed revision surgery. An excellent clinical outcome was achieved in 348/364 (95.6%) patients. The approach used for open reduction as such had no influence on the complication rate or clinical outcome. For severely displaced fractures, the data showed that an open approach for crossed K-wires tended to result in fewer complications and better clinical outcomes than a closed reduction. If an open reduction is indicated, the required approach (medial, lateral or bilateral) should be primarily selected according to the requirements of the fracture pattern and eventual cosmetic considerations.

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune modulating effects. To facilitate delivery of CO, we have designed hyaluronic acid-based CO-gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N 2 -GEMs and untreated controls.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to control noncompressible hemorrhage not addressed with traditional tourniquets. However, REBOA is associated with acute kidney injury (AKI) and subsequent mortality in severely injured trauma patients. Here, we investigated how the degree of aortic occlusion altered the extent of AKI in a porcine model. Female Yorkshire-cross swine ( n = 16, 68.1 ± 0.7 kg) were anesthetized and had carotid and bilateral femoral arteries accessed for REBOA insertion and distal and proximal blood pressure monitoring. Through a laparotomy, a 6-cm liver laceration was performed and balloon inflation was performed in zone 1 of the aorta for 90 min, during which animals were randomized to target distal mean arterial pressures of 25 or 45 mmHg via balloon volume adjustment. Blood draws were taken at baseline, end of occlusion, and time of death, at which point renal tissues were harvested 6 h after balloon deflation for histological and molecular analyses. Renal blood flow was lower in the 25-mmHg group (48.5 ± 18.3 mL/min) than in the 45-mmHg group (177.9 ± 27.2 mL/min) during the occlusion phase, which recovered and was not different after balloon deflation. AKI was more severe in the 25-mmHg group, as evidenced by circulating creatinine, blood urea nitrogen, and urinary neutrophil gelatinase-associated lipocalin. The 25-mmHg group had increased tubular necrosis, lower renal citrate synthase activity, increased tissue and circulating syndecan-1, and elevated systemic inflammatory cytokines. The extent of renal ischemia-induced AKI is associated with the magnitude of mitochondrial biomass and systemic inflammation, highlighting potential mechanistic targets to combine with partial REBOA strategies to prevent AKI. NEW & NOTEWORTHY Large animal models of ischemia-reperfusion acute kidney injury (IR-AKI) are lacking. This report establishes a titratable IR-AKI model in swine in which a balloon catheter can be used to alter distal pressures experienced by the kidney, thus controlling renal blood flow. Lower blood flow results in greater renal dysfunction and structural damage, as well as lower mitochondrial biomass, elevated systemic inflammation, and vascular dysfunction.

Introduction: Seizures are the most common neurological emergency and one of the most common reasons for paediatrics hospital admissions. This study aimed to identify the etiology, clinical profile, and immediate outcome of children with the first episode of seizure in Eastern Nepal., Methods: This was a prospective descriptive study carried out in the Tertiary Care Centre from September 2022 to August 2023. Ethical clearance was taken from the Institutional Review Committee (Ref no:654/2022). Convenience sampling was done to include 170 children presenting with the first episode of seizure at age 6 months to 15 years. Variables collected were demographics, clinical presentations, family history, trauma history, laboratory tests, neuroimaging, EEG, final diagnosis, and immediate outcome., Results: A total of 170 patients were admitted with the first episode of seizure with 123 (72.36%) males and 47 (27.64%) females. The mean age of the patients was 5.13±2.95 years with 104 (61.18%) patients under 5 years of age. The most common seizure was generalized tonic-clonic type in 132 (77.64%) patients. The most common associated symptom was fever in 150 (88.23%) children. Neuroimaging was abnormal in 52 (30.59%) patients, with neurocysticercosis seen in 27 (15.88%). The most common etiology was febrile seizure in 92 (54.17%) patients, neurocysticercosis in 27 (15.88%), and meningitis in 12 (7.05%)., Conclusions: Febrile seizures, neurocysticercosis, infection, and trauma were the major causes of seizures in children. When simple febrile seizures were unlikely, lumbar puncture, neuroimaging, and laboratory tests were useful tools for diagnosing etiologies of seizures.

Winter cover crop performance metrics (i.e., vegetative biomass quantity and quality) affect ecosystem services provisions, but they vary widely due to differences in agronomic practices, soil properties, and climate. Cereal rye (Secale cereale) is the most common winter cover crop in the United States due to its winter hardiness, low seed cost, and high biomass production. We compiled data on cereal rye winter cover crop performance metrics, agronomic practices, and soil properties across the eastern half of the United States. The dataset includes a total of 5,695 cereal rye biomass observations across 208 site-years between 2001-2022 and encompasses a wide range of agronomic, soils, and climate conditions. Cereal rye biomass values had a mean of 3,428 kg ha -1 , a median of 2,458 kg ha -1 , and a standard deviation of 3,163 kg ha -1 . The data can be used for empirical analyses, to calibrate, validate, and evaluate process-based models, and to develop decision support tools for management and policy decisions., (© 2024. The Author(s).)

Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. It is a primary astrocyte disease with a pathological hallmark of Rosenthal fibres within astrocytes. AxD astrocytes show several abnormal phenotypes. Our previous study showed that AxD astrocytes in model mice exhibit aberrant Ca2+ signals that induce AxD aetiology. Here, we show that microglia have unique phenotypes with morphological and functional alterations, which are related to the pathogenesis of AxD. Immunohistochemical studies of 60TM mice (AxD model) showed that AxD microglia exhibited highly ramified morphology. Functional changes in microglia were assessed by Ca2+ imaging using hippocampal brain slices from Iba1-GCaMP6-60TM mice and two-photon microscopy. We found that AxD microglia showed aberrant Ca2+ signals, with high frequency Ca2+ signals in both the processes and cell bodies. These microglial Ca2+ signals were inhibited by pharmacological blockade or genetic knockdown of P2Y12 receptors but not by tetrodotoxin, indicating that these signals are independent of neuronal activity but dependent on extracellular ATP from non-neuronal cells. Our single-cell RNA sequencing data showed that the expression level of Entpd2, an astrocyte-specific gene encoding the ATP-degrading enzyme NTPDase2, was lower in AxD astrocytes than in wild-type astrocytes. In situ ATP imaging using the adeno-associated virus vector GfaABC1D ATP1.0 showed that exogenously applied ATP was present longer in 60TM mice than in wild-type mice. Thus, the increased ATP level caused by the decrease in its metabolizing enzyme in astrocytes could be responsible for the enhancement of microglial Ca2+ signals. To determine whether these P2Y12 receptor-mediated Ca2+ signals in AxD microglia play a significant role in the pathological mechanism, a P2Y12 receptor antagonist, clopidogrel, was administered. Clopidogrel significantly exacerbated pathological markers in AxD model mice and attenuated the morphological features of microglia, suggesting that microglia play a protective role against AxD pathology via P2Y12 receptors. Taken together, we demonstrated that microglia sense AxD astrocyte dysfunction via P2Y12 receptors as an increase in extracellular ATP and alter their morphology and Ca2+ signalling, thereby protecting against AxD pathology. Although AxD is a primary astrocyte disease, our study may facilitate understanding of the role of microglia as a disease modifier, which may contribute to the clinical diversity of AxD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Peripheral infection induces inflammation in peripheral tissues and the brain, impacting brain function. Glial cells are key players in this process. However, the effects of peripheral infection on glial activation and brain function remain unknown. Here, we showed that varying degrees of peripheral infection had different effects on the regulation of brain functions by microglia-dependent and -independent mechanisms. Acute mild infection (one-day LPS challenge: 1LPS) exacerbated middle cerebral artery occlusion (MCAO) injury, and severe infection (four-day LPS challenge: 4LPS) for one week suppressed it. MCAO injury was assessed by triphenyltetrazolium chloride staining. We observed early activation of microglia in the 1LPS and 4LPS groups. Depleting microglia with a colony-stimulating factor-1 receptor (CSF1R) antagonist had no effect on 1LPS-induced brain injury exacerbation but abolished 4LPS-induced protection, indicating microglial independence and dependence, respectively. Microglia-independent exacerbation caused by 1LPS involved peripheral immune cells including macrophages. RNA sequencing analysis of 4LPS-treated microglia revealed increased factors related to anti-inflammatory and neuronal tissue repair, suggesting their association with the protective effect. In conclusion, varying degrees of peripheral inflammation had contradictory effects (exacerbation vs. protection) on MCAO, which may be attributed to microglial dependence. Our findings highlight the significant impact of peripheral infection on brain function, particularly in relation to glial cells.

Classical Hodgkin lymphoma (cHL) has achieved high cure rates as a result of recent advancements in treatment. However, recurring or relapsed illness still poses a therapeutic challenge. Immune checkpoint inhibitor pembrolizumab, which targets PD-1, is now being commonly used as part of immunotherapy for recurrent and relapsed cHL. We found eight appropriate articles through systematic search and conducted in-depth analysis to find insights into the effectiveness and safety profiles of pembrolizumab by analyzing clinical trial data in patients with recurrent and relapsed cHL. Analysis of the studies shows that response rates, progression-free survival, and patient-reported quality of life have all significantly improved. However, immune-related consequences are among the adverse outcomes. The necessity for continued study is highlighted by the variation in reported adverse events and follow-up times. Clinicians, researchers, and other healthcare professionals can use this study as a resource to provide knowledgeable and individualized patient care in cHL., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Hossain et al.)

Bacteroidales use type VI secretion systems (T6SS) to competitively colonize and persist in the colon. We identify a horizontally transferred T6SS with Ntox15 family nuclease effector (Tde1) that mediates interbacterial antagonism among Bacteroidales, including several derived from a single human donor. Expression of cognate (Tdi1) or orphan immunity proteins in acquired interbacterial defense systems protects against Tde1-dependent attack. We find that immunity protein interaction induces a large effector conformational change in Tde nucleases, disrupting the active site and altering the DNA-binding site. Crystallographic snapshots of isolated Tde1, the Tde1/Tdi1 complex, and homologs from Phocaeicola vulgatus (Tde2/Tdi2) illustrate a conserved mechanism of immunity inserting into the central core of Tde, splitting the nuclease fold into two subdomains. The Tde/Tdi interface and immunity mechanism are distinct from all other polymorphic toxin-immunity interactions of known structure. Bacteroidales abundance has been linked to inflammatory bowel disease activity in prior studies, and we demonstrate that Tde and T6SS structural genes are each enriched in fecal metagenomes from ulcerative colitis subjects. Genetically mobile Tde1-encoding T6SS in Bacteroidales mediate competitive growth and may be involved in inflammatory bowel disease. Broad immunity is conferred by Tdi1 homologs through a fold-disrupting mechanism unique among polymorphic effector-immunity pairs of known structure. IMPORTANCE Bacteroidales are related to inflammatory bowel disease severity and progression. We identify type VI secretion system (T6SS) nuclease effectors (Tde) which are enriched in ulcerative colitis and horizontally transferred on mobile genetic elements. Tde-encoding T6SSs mediate interbacterial competition. Orphan and cognate immunity proteins (Tdi) prevent intoxication by multiple Tde through a new mechanism among polymorphic toxin systems. Tdi inserts into the effector central core, splitting Ntox15 into two subdomains and disrupting the active site. This mechanism may allow for evolutionary diversification of the Tde/Tdi interface as observed in colicin nuclease-immunity interactions, promoting broad neutralization of Tde by orphan Tdi. Tde-dependent T6SS interbacterial antagonism may contribute to Bacteroidales diversity in the context of ulcerative colitis., Competing Interests: The authors declare no conflict of interest.

While urinary output (UOP) remains the primary endpoint for titration of intravenous fluid resuscitation, it is an insufficient indicator of fluid responsiveness. Although advanced hemodynamic monitoring (including arterial pulse wave analysis [PWA]) is of recent interest, the validity of PWA-derived indices in burn resuscitation extremes has not been established. The goal of this paper is to test the hypothesis that PWA-derived cardiac output (CO) and stroke volume (SV) indices as well as pulse pressure variation (PPV) and systolic pressure variation (SPV) can play a complementary role to UOP in burn resuscitation. Swine were instrumented with a Swan-Ganz catheter for reference CO and underwent a 40% TBSA burns with varying resuscitation paradigms, and were monitored for 24 hours in an ICU setting under mechanical ventilation. The longitudinal changes in PWA-derived indices were investigated, and resuscitation adequacy was compared as determined by UOP vs PWA indices. The results indicated that PWA-derived indices exhibited trends consistent with reference CO and SV measurements: CO and SV indices were proportional to reference CO and SV, respectively (CO: postcalibration limits of agreement [LoA] = ±24.7 [ml/min/kg], SV: postcalibration LoA = ±0.30 [ml/kg]) while PPV and SPV were inversely proportional to reference SV (PPV: postcalibration LoA = ±0.32 [ml/kg], SPV: postcalibration LoA = ±0.31 [ml/kg]). The results also indicated that PWA-derived indices exhibited notable discrepancies from UOP in determining adequate burn resuscitation. Hence, it was concluded that the PWA-derived indices may have complementary value to UOP in assessing and guiding burn resuscitation., (Published by Oxford University Press on behalf of the American Burn Association 2022.)

There exists extensive variation in eye size. Much work has provided a connection between light availability and differences in eye size across taxa. Experimental tests of the role of the light environment on the evolution of eye size are lacking. Here, we performed a selection experiment that examined the influence of light availability on shifts in eye size and the connection between eye size and phototactic (anti-predator) behaviour in Daphnia. We set-up replicate experimental populations of Daphnia, repeatedly evaluated phenotypic shifts in eye size during the ~50-day experiment, and performed a common garden experiment at the end of the experiment to test for evolutionary shifts in eye size and behaviour. Our phenotypic analyses showed that eye size rapidly diverged between the light treatments; relative eye size was consistently larger in the low versus high light treatments. Selection on eye size was also modified by variation in density as increases in Daphnia density favoured a larger eye. However, we did not observe differences in eye size between the light treatments following two generations of common garden rearing at the end of the experiment. We instead observed strong shifts in anti-predator behaviour. Daphnia from the low light treatment exhibited decreased phototactic responses to light. Our results show that decreased light relaxes selection on anti-predator behaviour. Such trends provide new insights into selection on eye size and behaviour., (© 2023 European Society for Evolutionary Biology.)

Study Design: Cross-sectional study OBJECTIVES: To identify the prevalence of posttraumatic stress disorder (PTSD) among the individuals with traumatic spinal cord injury (TSCI) and to examine the relationships between demographic and clinical characteristics, and PTSD., Setting: Spinal Injury Rehabilitation Center (SIRC) and Dhulikhel Hospital, Kathmandu University Hospital (DH, KUH), Kavrepalanchowk, Nepal., Methods: Individuals above 18 years of age with TSCI of at least one month from trauma and admitted to SIRC and DH, KUH from June 2019 to May 2021 were included. The specific stress version of the PostTraumatic Stress Disorder Checklist (PCL), was utilized. To classify the neurological status of TSCI individuals, International Standard for Neurological Classification of Spinal Cord Injury (ISNCSCI) was used. Hierarchical multiple regression analysis between independent variables and normalized PCL score was done to evaluate the predictors of PTSD., Results: Among 163 patients, the overall prevalence of PTSD was 27%, and the mean PCL score was 36 ± 13.9. Factors predictive of PTSD included gender, family type, ethnicity, and literacy rate. No significant association was found between the clinical characteristics and PTSD., Conclusions: PTSD appears to be considerably prevalent among individuals with TSCI in Nepal. Females, individuals from nuclear families, individuals with lower literacy, and individuals from lower caste are significantly vulnerable to developing PTSD. However, clinical characteristics do not appear to be influential in the development of PTSD., (© 2023. The Author(s), under exclusive licence to International Spinal Cord Society.)

Microglia are the specialized macrophages of the central nervous system and play an important role in neural circuit development, modulating neurotransmission, and maintaining brain homeostasis. Microglia in normal brain is quiescent and show ramified morphology with numerous branching processes. They constantly survey their surrounding microenvironment through the extension and retraction of their processes and interact with neurons, astrocytes, and blood vessels using these processes. Microglia respond quickly to any pathological event in the brain by assuming ameboid morphology devoid of branching processes and restore homeostasis. However, when there is chronic inflammation, microglia may lose their homeostatic functions and secrete various proinflammatory cytokines and mediators that initiate neural dysfunction and neurodegeneration. In this article, we review the role of microglia in the normal brain and in various pathological brain conditions, such as Alzheimer's disease and multiple sclerosis. We describe strategies to manipulate microglia, focusing on depletion, repopulation, and replacement, and we discuss their therapeutic potential., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)