Suppression by central adenosine A3 receptors of the cholinergic defense against cardiovascular aberrations of sepsis: role of PI3K/MAPKs/NFκB signaling.

Introduction: Despite the established role of peripheral adenosine receptors in sepsis-induced organ dysfunction, little or no data is available on the interaction of central adenosine receptors with sepsis. The current study tested the hypothesis that central adenosine A3 receptors (A3ARs) modulate the cardiovascular aberrations and neuroinflammation triggered by sepsis and their counteraction by the cholinergic antiinflammatory pathway. Methods: Sepsis was induced by cecal ligation and puncture (CLP) in rats pre-instrumented with femoral and intracisternal (i.c.) catheters for hemodynamic monitoring and central drug administration, respectively. Results: The CLP-induced hypotension, reduction in overall heart rate variability (HRV) and sympathovagal imbalance towards parasympathetic predominance were abolished by i.v. nicotine (100 µg/kg) or i.c. VUF5574 (A3AR antagonist, 2 µg/rat). In addition, the selective A3AR agonist, 3-iodobenzyl-5'-N-methylcarboxamidoadenosine IB-MECA, 4 µg/rat, i.c.) exaggerated the hypotension and cardiac autonomic dysfunction induced by sepsis and opposed the favorable nicotine actions against these septic manifestations. Immunohistochemically, IB-MECA abolished the nicotine-mediated downregulation of NFκB and NOX2 expression in rostral ventrolateral medullary areas (RVLM) of brainstem of septic rats. The inhibitory actions of IB-MECA on nicotine responses disappeared after i.c. administration of PD98059 (MAPK-ERK inhibitor), SP600125 (MAPK-JNK inhibitor) or wortmannin (PI3K inhibitor). Moreover, infliximab (TNFα inhibitor) eliminated the IB-MECA-induced rises in RVLM-NFκB expression and falls in HRV, but not blood pressure. Conclusion: Central PI3K/MAPKs pathway mediates the A3AR counteraction of cholinergic defenses against cardiovascular and neuroinflammatory aberrations in sepsis.

Korean Mint (Agastache rugosa) Extract and Its Bioactive Compound Tilianin Alleviate Muscle Atrophy via the PI3K/Akt/FoxO3 Pathway in C2C12 Myotubes.

Skeletal muscle atrophy, which is characterized by diminished muscle mass, strength, and function, is caused by malnutrition, physical inactivity, aging, and diseases. Korean mint (Agastache rugosa Kuntze) possesses various biological functions, including anti-inflammatory, antioxidant, anticancer, and antiosteoporosis activities. Moreover, it contains tilianin, which is a glycosylated flavone that exerts antioxidant, anti-inflammatory, antidiabetic, and neuroprotective activities. However, no studies have analyzed the inhibitory activity of A. rugosa extract (ARE) and tilianin on muscle atrophy. Thus, the present study investigated the potential of ARE and tilianin on muscle atrophy and their underlying mechanisms of action in C2C12 myotubes treated with tumor necrosis factor-α (TNF-α). The results showed that ARE and tilianin promoted the phosphatidylinositol 3-kinase/protein kinase B pathway, thereby activating mammalian target of rapamycin (a protein anabolism-related factor) and its downstream factors. Moreover, ARE and tilianin inhibited the mRNA expression of muscle RING-finger protein-1 and atrogin-1 (protein catabolism-related factors) by blocking Forkhead box class O3 translocation. ARE and tilianin also mitigated inflammatory responses by downregulating nuclear factor-kappa B expression levels, thereby diminishing the expression levels of inflammatory cytokines, including TNF-α and interleukin-6. Additionally, ARE and tilianin enhanced the expression levels of antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Overall, these results suggest that ARE and tilianin are potential functional ingredients for preventing or improving muscle atrophy.

The "Halo Appearance" of Shear Wave Elastography in the Setting of Fat Necrosis: A Potentially Useful Sonographic Discriminator.

OBJECTIVE: To describe the morphologic sonographic appearances and frequency of the "halo sign" in the setting of fat necrosis on shear wave elastography (SWE). METHODS: Patients with clinically suspected fat necrosis were prospectively scanned using SWE in addition to standard gray-scale and Doppler images. Cases were qualitatively grouped into one of three sonographic appearances: focal hypoechoic lesion with increased internal tissue stiffness ("focal stiffness"), focal hypoechoic lesion with isoechoic or hyperechoic periphery demonstrating increased tissue stiffness relative to the central hypoechoic lesion ("halo stiffness"), heterogeneously echogenic lesion with diffusely increased stiffness ("heterogeneous stiffness"). RESULTS: Exactly 19 patients met inclusion criteria (female n = 14; male n = 5). Shear wave velocities were recorded and retrospectively evaluated. The mean clinical follow-up was 11.4 months (range 3.0-25.5). Lesions demonstrated higher average tissue stiffness than background tissue (overall mass shear wave velocity 3.26 m/s, background 1.42 m/s, P < .001; lesion Young's modulus 40.85 kPa vs background 7.22 kPa, P < .001). The halo sign was identified in 10/19 (55%) patients. CONCLUSION: The halo sign is a potentially useful sign in the setting of fat necrosis seen in the majority of clinically suspected cases.

Tenofovir-Associated Kidney Dysfunction and Bone Fracture: A Case Report and Literature Review.

Tenofovir is an integral part of antiretroviral therapy used to treat HIV. Long-term use of tenofovir has been associated with decreased glomerular filtration rate, leading to chronic kidney disease, as well as acidosis, electrolyte imbalances, and tubular dysfunction. Tenofovir can also disrupt bone health by decreasing renal phosphate absorption, contributing to osteomalacia. This leads to disruption in mineral metabolism, elevated parathyroid hormone levels, and ultimately, low bone mineral density. Replacing tenofovir with alternative antiretroviral therapy can improve kidney function if done early in the course of the disease. Here, we discuss a case of a 65-year-old woman with HIV who presented with advanced renal failure and hypophosphatemia-induced bone fracture attributed to long-term use of tenofovir. We conclude monitoring kidney function and considering alternative antiretroviral therapy is important to prevent and manage these side effects in patients on long-term tenofovir therapy.

Exposure to golimumab during pregnancy: Results from the Company's global safety database.

Data on the use of golimumab (GLM) during pregnancy are limited. This study evaluated pregnancy outcomes in women treated with GLM during pregnancy. Cumulative data on GLM-exposed pregnancies from the Company's global safety database (GSD) are summarized. Cases were medically confirmed maternal exposures to GLM during pregnancy or within 3 months prior to conception with a reported pregnancy outcome. Pregnancy outcomes (e.g., live births) and congenital anomalies in prospectively reported cases (i.e., pregnancy outcome not known when first reported to the company) are presented in a descriptive manner. As of May 31, 2022, 261 prospectively reported pregnancies exposed to GLM were reported in the GSD: 214 (82.0%) live births (including six sets of twins), 31 (11.9%) spontaneous abortions (including one set of twins), 13 (5.0%) induced/elective abortions, 2 (0.8%) reported intrauterine death/still birth, and 1 (0.4%) fetal adverse event in an ongoing pregnancy. The majority of pregnancies had exposure to GLM at least in the first trimester of pregnancy. In total, seven congenital anomalies (7/261; 2.7%) were reported. Of these seven congenital anomalies, five were considered major according to EUROCAT classification version 1.4. Among the five prospectively reported congenital anomalies noted in live births (5/214; 2.3%), four were classified as major (4/214; 1.8%). The rates of adverse pregnancy outcomes and major congenital anomalies in prospectively reported pregnancy cases with exposure to GLM in the Company's GSD were consistent with published background rates for the general population.

Minimally invasive surgery compared to endoscopic intervention for treating infected pancreatic necrosis. A meta-analysis.

Introduction: The current study aimed to compare the outcomes of endoscopic and minimally invasive surgical treatment for infected necrotizing pancreatitis. Material and methods: A meta-analysis of clinical studies on minimally invasive operations for necrotic infection was conducted. A systematic review and study inclusion were done on multiple databases. English-language prospective comparison studies were included. Random design was used to analyze research with continuous and dichotomous variables. Results: Ten studies were included in the current study. When compared to minimally invasive surgery, endoscopic procedures showed significant beneficial outcomes regarding low post-operative complication rates (p = 0.006), new onset organ failure (p < 0.001), and pancreatic fistula (p < 0.001). However, there was no significant difference between the two interventions regarding hospital stay, postoperative bleeding, incisional hernia, endocrine insufficiency, and perforation of a visceral organ. Conclusions: Endoscopic therapy appears to have potential advantages over minimally invasive surgery. However, there is no difference between interventions regarding several parameters.

The effectiveness of tumor necrosis factor-α blocker therapy in patients with axial spondyloarthritis who failed conventional treatment: a comparative study focused on improvement in ASAS Health Index.

Objective: The purpose of this study is to evaluate the impact of tumor necrosis factor (TNF)-α blocker therapy on the Assessment of SpondyloArthritis international Society Health Index (ASAS-HI) among patients who have failed conventional nonsteroidal anti-inflammatory drugs. Methods: A comparative study was conducted involving axial spondyloarthritis (axSpA) patients treated with either TNF-α blocker or conventional therapy. Patient data, including demographics, disease characteristics, and ASAS-HI scores, were collected before and after treatment. Statistical analysis was performed to compare changes in ASAS-HI scores between the TNF-α blocker and the conventional therapy group. Results: The study population consisted of patients with axSpA, with a mean age of 38.3 years in conventional treatment group and 29.3 years in TNF-α blocker group. Most variables, including C-reactive protein levels, other comorbidities, and disease assessment scores showed no significant difference between groups. Longitudinal analysis within each treatment group from Week 0 to 12 showed no significant change in the conventional treatment group, whereas the TNF-α blocker group experienced a significant reduction in ASAS-HI scores, demonstrating the effectiveness of the treatment. The TNF-α blocker group exhibited a significantly greater improvement in ASAS-HI scores compared to the conventional therapy group. The Bath Ankylosing Spondylitis Functional Index and the Bath Ankylosing Spondylitis Disease Activity Index demonstrated strong positive correlations with ASAS-HI scores, indicating higher disease activity and functional limitation are associated with worse health outcomes in patients. Conclusion: The research demonstrates that ASAS-HI scores significantly improve with TNF-α blocker therapy in axSpA patients, underscoring ASAS-HI's effectiveness as a tool for evaluating drug responses.

The ß2-adrenergic receptor agonist formoterol attenuates necrosis and apoptosis in the rat myocardium under experimental stress-induced cardiac injury.

BACKGROUND: Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that ß2-adrenergic receptor (ß2-AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome. OBJECTIVES: The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy. METHODS: Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours. RESULTS: The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6 hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of ß2-AR agonist formoterol (50 µg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels. CONCLUSION: Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the ß2-AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress.

The role of TNF-α as a potential marker for acute cutaneous lupus erythematosus in patients with systemic lupus erythematosus.

Acute cutaneous lupus erythematosus (ACLE) is closely associated with systemic symptoms in systemic lupus erythematosus (SLE). This study aimed to identify potential biomarkers for ACLE and explore their association with SLE to enable early prediction of ACLE and identify potential treatment targets for the future. In total, 185 SLE-diagnosed patients were enrolled and categorized into two groups: those with ACLE and those without cutaneous involvement. After conducting logistic regression analysis of the differentiating factors, we concluded that tumor necrosis factor-alpha (TNF-α) is an independent risk factor for ACLE. Analysis of the receiver operating characteristic revealed an area under the curve of 0.716 for TNF-α. Additionally, both TNF-α and ACLE are positively correlated with disease activity. TNF-α shows promise as a biomarker for ACLE, and in SLE patients, ACLE may serve as a clear indicator of moderate-to-severe disease activity.

Paracetamol overdose causing acute kidney injury without hepatotoxicity: a case report.

BACKGROUND: Paracetamol is a widely used analgesic and antipyretic. Paracetamol-induced hepatotoxicity is well known, but nephrotoxicity without hepatotoxicity is rarely seen. CASE PRESENTATION: We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48 h after she had taken 10 g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20 mg/dL on admission, with a peak at 3.67 mg/dL 3 days later. The liver blood tests and blood paracetamol level were negative. She did not receive N-acetyl cysteine and was treated with intravenous fluid (crystalloid). The ultrasonography of the kidneys was normal. Her renal function returned almost to baseline 7 days after admission. It was concluded that the diagnosis was an acute kidney injury caused by acute tubular necrosis due to paracetamol overdose. CONCLUSION: This case shows that nephrotoxicity can occur without hepatotoxicity in paracetamol overdose.

Comparative evaluation of thermal impact of 980nm diode laser on soft tissue using irrigation and non-irrigation systems: A histomorphometric study.

Background: Diode laser is one of the most captivating technologies in dental practice. In periodontics, when used at appropriate settings, it possesses the best properties for selective surgical and nonsurgical procedures such as subgingival calculus removal without a thermal change of the root surface, and also provides tissue surface sterilization. However, lasers always produce a certain amount of thermal damage to the soft tissues. Therefore, this study aimed to comparatively evaluate the thermal impact of 980-nm diode laser incisions, when used with irrigation versus nonirrigation systems. Materials and Methods: The study was conducted on 24 gingival tissue samples obtained from the goat's mandible and maxilla. The samples were divided into two groups of 12 samples each, and laser incisions were given in 4 power settings, using 980-nm diode laser in super short pulse mode, with and without saline irrigation. Martius Scarlet Blue staining technique was used to prepare the histological slides. Then, slides were examined under a research microscope (Olympus CX 21), and the pictures of the slides were taken by mounting the camera onto the microscope mobile mount. The microscopic images hence obtained were analyzed for the depth and width of the incisions, area of carbonization, necrosis, and reversible damage, using the Digimizer image analysis software. Results: The results of this study demonstrated that the mean incision depth was higher (592.49 ± 180.97, P < 0.05), with less carbonization (25.52 ± 29.21, P = 0.00) and less necrosis (311.63 ± 156.441, P < 0.05) in the laser incisions with irrigation, as compared to the laser incisions given without irrigation system. Conclusion: Within the limitations of this study, it can be concluded that using an irrigation system causes less collateral damage while maintaining the incising efficiency of the diode laser. Further studies with a higher sample size, controlled irrigation systems, and incision techniques are needed to evaluate the efficiency of diode lasers for the clinical explanation of the results.

Early detection of necrosis in low-enhanced pancreatic parenchyma using contrast-enhanced computed tomography was a better predictor of clinical outcomes than pancreatic inflammation: A multicentric cohort study of severe acute pancreatitis.

OBJECTIVES: We aim to assess the early use of contrast-enhanced computed tomography (CECT) of patients with severe acute pancreatitis (SAP) using the computed tomography severity index (CTSI) in prognosis prediction. The CTSI combines quantification of pancreatic and extrapancreatic inflammation with the extent of pancreatic necrosis. METHODS: Post-hoc retrospective analysis of a large, multicentric database (44 institutions) of SAP patients in Japan. The area under the curve (AUC) of the CTSI for predicting mortality and the odds ratio (OR) of the extent of pancreatic inflammation and necrosis were calculated using multivariable analysis. RESULTS: In total, 1097 patients were included. The AUC of the CTSI for mortality was 0.65 (95 % confidence interval [CI:] [0.59-0.70]; p < 0.001). In multivariable analysis, necrosis 30-50 % and >50 % in low-enhanced pancreatic parenchyma (LEPP) was independently associated with a significant increase in mortality, with OR 2.04 and 95 % CI 1.01-4.12 (P < 0.05) and OR 3.88 and 95 % CI 2.04-7.40 (P < 0.001), respectively. However, the extent of pancreatic inflammation was not associated with mortality, regardless of severity. CONCLUSIONS: The degree of necrosis in LEPP assessed using early CECT of SAP was a better predictor of mortality than the extent of pancreatic inflammation.

Cysts of the ligamentum flavum are often linked to ischemic conditions: A morphological study.

"Cysts of the ligamentum flavum (cysts-LF)" is the term for non-neoplastic cystic lesion involving LF. The aim of the present study was to elucidate the histopathological characteristics and pathogenesis of "cysts-LF". Herein, we defined cysts-LF as spinal cysts containing degenerative LF components. From archival cases, we investigated 18 symptomatic cysts-LF surgically removed from 18 patients (13 males and five females; median age 68.5 years [range, 42-86 years]). The elastic fibers of LF components in the wall were separated and/or torn, and cyst walls were accompanied by chondroid metaplasia (17 cases), myxoid changes (13 cases), ossification (11 cases), amyloid deposits (14 cases), hemosiderosis (six cases), granular/smudgy calcification (four cases), synovial cell linings (three cases), and severe inflammatory infiltrates (one case). These histologic features of our cysts-LF were shared by previously reported "cysts-LF." Fourteen cysts-LF demonstrated vascular stenosis/occlusion, and eight showed thick hyalinized vessels, suggesting local circulatory insufficiency. Eight cases (44%) exhibited lipomembranous fat necrosis, accompanied by hyalinized vascular changes (p = 0.003). Ischemic conditions were observed in nearly half of the present cysts-LF, and may be one of the main contributing factors for the formation of cysts-LF, via degeneration and cystic changes in the LF.

The power of trans-sodium crocetinate: exploring its renoprotective effects in a rat model of colistin-induced nephrotoxicity.

Colistin, a multidrug-resistant gram-negative bacterial infection medication, has been associated with renal impairment and failure. Trans-sodium crocetinate (TSC), a saffron-derived chemical recognized for its antioxidant and nephroprotective properties, was studied in this study to determine its potential to alleviate the nephrotoxic effects of colistin. Forty-two male Wistar rats were randomly classified into seven groups (n = 6): (1) control (normal saline, 12 days, i.p.), (2) colistin (22 mg/kg, 7 days, i.p.), (3-5) colistin + TSC (25, 50, and 100 mg/kg, 12 days, i.p., starting from 5 days before colistin), (6) TSC (100 mg/kg, 12 days, i.p.), (7) colistin + vitamin E (100 IU/kg, 12 days, i.p). On day 13, the rats were euthanized and the serum content of creatinine, BUN, Na+, and K+, as well as oxidative stress (GSH, MDA, SOD, CAT), inflammatory (IL-1ß), apoptotic (Bax, Bcl-2, caspase-3, 8, 9), and autophagy (Beclin-1, LC3) markers, NGAL, and histopathological changes in the kidney were measured. Colistin significantly increased serum creatinine, BUN, MDA, IL-1ß, caspase-3,8,9, Bax, Beclin-1, LC3, and NGAL levels in kidney tissue. It also caused inflammation, focal necrosis of tubular epithelial cells, protein cast, and acute tubular necrosis. Furthermore, colistin decreased SOD, CAT, GSH, and Bcl-2 levels. TSC and vitamin E administration along with colistin restored most of the alterations induced by colistin. Overall, it could be concluded that colistin induces oxidative stress, inflammation, autophagy, and apoptosis, which can cause kidney injury. However, TSC can also be used as a therapeutic agent to reduce injuries caused by colistin.

Does the site, size, and number of necrotic collections affect the outcome of necrotizing pancreatitis? - a prospective analysis.

PURPOSE: In patients with acute necrotizing pancreatitis (ANP), the site, size, and the number of acute necrotic collections (ANC) may determine the outcome of patients. The current study aimed to correlate the nature of ANC with the adverse outcomes in ANP patients. METHODS: This was a single-center, prospective study (August 2019-August 2022) recruiting patients with ANP, correlating the site, size, and number of ANC with the length of hospital stay, intensive care unit (ICU) stays, development of organ failure and infection, need for intervention, and mortality. RESULTS: A total of 114 patients (mean age: 37.3 ± 13.4 years, 85.1% males) with ANP were included in the study. The number and maximum diameter of collections significantly correlated with the length of the hospital and ICU stay and the need for intervention. Taking a cut-off size of 8 cm, the sensitivity and specificity for predicting the need for intervention were 82.7% and 74.2%, respectively. ANCs located in the perinephric, paracolic, subhepatic, and epigastric regions had a significant correlation with two or more adverse outcomes. Additional points were added to the modified CT severity index (mCTSI) based on the present study's findings. The new score had significantly higher AUROC than mCTSI for predicting infection, need for intervention, ICU stay > 1 week, and mortality. CONCLUSION: The site, size, and number of EPNs have a significant correlation with adverse clinical outcomes in patients with ANP. The inclusion of these parameters, along with present scoring systems, will help further improve the prognostication of patients.

Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway.

Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.

Ammonia and urea metabolism in acute liver failure: A multicentre cohort study.

BACKGROUND & AIMS: Ammonia is metabolized into urea in the liver. In acute liver failure (ALF), ammonia has been associated with survival. However, urea variation has been poorly studied. METHODS: Observational cohort including ALF patients from Curry Cabral Hospital (Lisbon, Portugal) and Clinic Hospital (Barcelona, Spain) between 10/2010 and 01/2023. The United States ALF Study Group cohort was used for external validation. Primary exposures were serum ammonia and urea on ICU admission. Primary endpoint was 30-day transplant-free survival (TFS). Secondary endpoint was explanted liver weight. RESULTS: Among 191 ALF patients, median (IQR) age was 46 (32; 57) years and 85 (44.5%) were males. Overall, 86 (45.0%) patients were transplanted and 75 (39.3%) died. Among all ALF patients, following adjustment for age, sex, body weight, and aetiology, higher ammonia or lower urea was independently associated with higher INR on ICU admission (p < .009). Among all ALF patients, following adjustment for sex, aetiology, and lactate, higher ammonia was independently associated with lower TFS (adjusted odds ratio (95% confidence interval [CI]) = 0.991 (0.985; 0.997); p = .004). This model predicted TFS with good discrimination (area under receiver operating curve [95% CI] = 0.78 [0.75; 0.82]) and reasonable calibration (R2 of 0.43 and Brier score of 0.20) after external validation. Among transplanted patients, following adjustment for age, sex, actual body weight, and aetiology, higher ammonia (p = .024) or lower (p < .001) urea was independently associated with lower explanted liver weight. CONCLUSIONS: Among ALF patients, serum ammonia and urea were associated with ALF severity. A score incorporating serum ammonia predicted TFS reasonably well.

A Single-Center Case Series of Acute Retinal Necrosis at Teikyo University: Clinical Characteristics and Treatment Outcomes.

Aim To evaluate the clinical characteristics, treatment course, and prognosis of patients with acute retinal necrosis (ARN), which can rapidly progress and cause severe vision loss. Design Single-center retrospective case series. Subjects and methods Six patients and seven eyes diagnosed with ARN at Teikyo University Hospital were included in this study. The clinical presentation and treatment prognosis were investigated based on data obtained from medical records. Results The mean age of the patients at the initial diagnosis was 63.6 years. Although the mean Logarithm of the Minimum Angle of Resolution (LogMAR) visual acuity tended to decrease from 0.77 at the first visit to 1.29 at the last visit, the difference was not statistically significant. Intraocular manifestations observed during the study period included ocular hypertension (14.3%), anterior uveitis (100.0%), retinal hemorrhage (71.4%), vitreous opacity (100.0%), retinal exudative vasculitis (85.7%), optic nerve atrophy (85.7%), retinal vascular occlusion (85.7%), choroidal atrophy (85.7%), macular edema (100.0%), subretinal fluid in the macula (71.4%), and retinal detachment (85.7%). Treatment modalities included oral and intravitreal antivirals (85.7%), antiplatelet medications (85.7%), steroid eye drops (85.7%), subcapsular (57.1%) and vitreous (42.9%) steroid injections, oral steroids (71.4%), and surgical intervention (85.7%). Vitrectomy led to retinal recovery in all five eyes that underwent the procedure. Conclusions The visual prognosis of patients with ARN is poor, particularly in those with preexisting visual impairment. Early detection coupled with antiviral therapy and prompt surgical intervention have been identified as potential factors that influence visual outcomes. Given the severity of ARN, collecting data from multiple centers could aid in devising future diagnostic and therapeutic strategies.

Paradoxical Psoriasis in Patients Receiving Therapy with Tumor Necrosis Factor Inhibitors: Potential Pathogenic Mechanisms and the Role of Genetic Factors.

TNF inhibitors (TNFi) have revolutionized the therapeutic management of various chronic immune-mediated inflammatory diseases. Despite their known benefits, these therapies are related to paradoxical adverse effects (PAEs), including paradoxical psoriasis (PP). Although the underlying mechanism remains somewhat unclear, some theories suggest that genetic factors, particularly certain single-nucleotide polymorphisms (SNPs), may play an important role. The present review aimed to research and analyze recent findings regarding the pathomechanisms involved in the appearance of PP and the association between various genetic factors and PP in individuals treated with TNFi. We performed a literature search and found that certain genes (IL23R, TNF, FBXL19, CTLA4, SLC12A8, TAP1) are strongly associated with the occurrence of PP in pediatric and adult patients during therapy with TNFi. The identification of the specific SNPs involved in the appearance of PP and other PAEs in patients treated with TNFi for various diseases and in different populations may later favor the recognition of those patients at a high risk of developing such adverse effects and could guide personalized therapeutic strategies in future years.

Inflammatory response of leptomeninges to a single cortical spreading depolarization.

BACKGROUND: Neurogenic meningeal inflammation is regarded as a key driver of migraine headache. Multiple evidence show importance of inflammatory processes in the dura mater for pain generation but contribution of the leptomeninges is less clear. We assessed effects of cortical spreading depolarization (CSD), the pathophysiological mechanism of migraine aura, on expression of inflammatory mediators in the leptomeninges. METHODS: A single CSD event was produced by a focal unilateral microdamage of the cortex in freely behaving rats. Three hours later intact cortical leptomeninges and parenchyma of ipsi-lesional (invaded by CSD) and sham-treated contra-lesional (unaffected by CSD) hemispheres were collected and mRNA levels of genes associated with inflammation (Il1b, Tnf, Ccl2; Cx3cl1, Zc3h12a) and endocannabinoid CB2 receptors (Cnr2) were measured using qPCR. RESULTS: Three hours after a single unilateral CSD, most inflammatory factors changed their expression levels in the leptomeninges, mainly on the side of CSD. The meninges overlying affected cortex increased mRNA expression of all proinflammatory cytokines (Il1b, Tnf, Ccl2) and anti-inflammatory factors Zc3h12a and Cx3cl1. Upregulation of proinflammatory cytokines was found in both meninges and parenchyma while anti-inflammatory markers increased only meningeal expression. CONCLUSION: A single CSD is sufficient to produce pronounced leptomeningeal inflammation that lasts for at least three hours and involves mostly meninges overlying the cortex affected by CSD. The prolonged post-CSD inflammation of the leptomeninges can contribute to mechanisms of headache generation following aura phase of migraine attack.