Essential oil of oregano (Origanum vulgare L.) reduces infection and proliferation of Toxoplasma gondii in BeWo cells with induction of autophagy and death of tachyzoites through a mechanism similar to necrosis.

Toxoplasmosis poses a global health threat, ranging from asymptomatic cases to severe, potentially fatal manifestations, especially in immunocompromised individuals and congenital transmission. Prior research suggests that oregano essential oil (OEO) exhibits diverse biological effects, including antiparasitic activity against Toxoplasma gondii. Given concerns about current treatments, exploring new compounds is important. This study was to assess the toxicity of OEO on BeWo cells and T. gondii tachyzoites, as well as to evaluate its effectiveness in in vitro infection models and determine its direct action on free tachyzoites. OEO toxicity on BeWo cells and T. gondii tachyzoites was assessed by MTT and trypan blue methods, determining cytotoxic concentration (CC50), inhibitory concentration (IC50), and selectivity index (SI). Infection and proliferation indices were analyzed. Direct assessments of the parasite included reactive oxygen species (ROS) levels, mitochondrial membrane potential, necrosis, and apoptosis, as well as electron microscopy. Oregano oil exhibited low cytotoxicity on BeWo cells (CC50: 114.8 µg/mL ± 0.01) and reduced parasite viability (IC50 12.5 ± 0.06 µg/mL), demonstrating 9.18 times greater selectivity for parasites than BeWo cells. OEO treatment significantly decreased intracellular proliferation in infected cells by 84% after 24 h with 50 µg/mL. Mechanistic investigations revealed increased ROS levels, mitochondrial depolarization, and lipid droplet formation, linked to autophagy induction and plasma membrane permeabilization. These alterations, observed through electron microscopy, suggested a necrotic process confirmed by propidium iodide labeling. OEO treatment demonstrated anti-T. gondii action through cellular and metabolic change while maintaining low toxicity to trophoblastic cells.

IL-10 and TGF-ß1 may weaken the efficacy of preoperative anti-tuberculosis therapy in older patients with spinal tuberculosis.

Spinal tuberculosis is a common extrapulmonary type that is often secondary to pulmonary or systemic infections. Mycobacterium tuberculosis infection often leads to the balance of immune control and bacterial persistence. In this study, 64 patients were enrolled and the clinicopathological and immunological characteristics of different age groups were analyzed. Anatomically, spinal tuberculosis in each group mostly occurred in the thoracic and lumbar vertebrae. Imaging before preoperative anti-tuberculosis therapy showed that the proportion of abscesses in the older group was significantly lower than that in the younger and middle-aged groups. However, pathological examination of surgical specimens showed that the proportion of abscesses in the older group was significantly higher than that in the other groups, and there was no difference in the granulomatous inflammation, caseous necrosis, inflammatory necrosis, acute inflammation, exudation, granulation tissue formation, and fibrous tissue hyperplasia. B cell number was significantly lower in the middle-aged and older groups compared to the younger group, while the number of T cells, CD4+ T cells, CD8+ T cells, macrophages, lymphocytes, plasma cells, and NK cells did not differ. Meaningfully, we found that the proportion of IL-10 high expression and TGF-ß1 positive in the older group was significantly higher than that in the younger group. TNF-α, CD66b, IFN-γ, and IL-6 expressions were not different among the three groups. In conclusion, there are some differences in imaging, pathological, and immune features of spinal tuberculosis in different age groups. The high expression of IL-10 and TGF-ß1 in older patients may weaken their anti-tuberculosis immunity and treatment effectiveness.

Nafamostat mesylate decreases skin flap necrosis in a mouse model of type 2 diabetes by protecting the endothelial glycocalyx.

The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.

Nanoemulsion containing Jatropha gossypiifolia leaf extract reduces dermonecrosis induced by Bothrops erythromelas venom and accelerates wound closure.

ETHNOPHARMACOLOGICAL RELEVANCE: The species Jatropha gossypiifolia, popularly known as "pinhão-roxo", is distributed throughout Brazil, is commonly employed for topical or oral administration in treating wounds, inflammations, and snake bites. Given the significant impact of snakebites on public health and the limitations of antivenom, coupled with the diverse molecular composition of this plant species, investigating its healing and antidermonecrotic capacities is relevant. AIM OF THE STUDY: This study aimed to develop a topical nanoemulsion incorporating the hydroethanolic extract of J. gossypiifolia leaves, to evaluate its therapeutic potential, particularly in terms of its efficacy in wound healing and inhibition of dermonecrosis induced by B. erythromelas venom (BeV). MATERIAL AND METHODS: The extract of J. gossypiifolia (JgE) leaves was obtained by maceration and remaceration. The phytochemical analysis was conducted and J. gossypiifolia nanoemulsion (JgNe) was obtained, characterized and assessed for stability. The cytotoxicity was determined in normal cells (erythrocytes and 3T3) using hemolytic assay and cell viability assay using crystal violet staining. The antioxidant activity was evaluated by the reduction of ABTS and DPPH radicals. The evaluation of wound healing was conducted in vivo following treatment with JgNe, wherein the percentage of wound closure and inflammatory mediators. The skin irritation test was assessed in vivo by applying JgNe directly to the animal's skin. In vitro, the antivenom capacity was evaluated through enzymatic inhibition assays (phospholipase A2 and hyaluronidase) of BeV. Additionally, the in vivo antidermonecrotic activity of JgNe was evaluated by measuring the reduction of the dermonecrotic halo. RESULTS: The HPLC-DAD analysis identified flavonoids, specifically vitexin, luteolin derivatives and apigenin derivatives. In addition, 95.08 ± 5.46 mg of gallic acid/g of extract and 137.92 ± 0.99 mg quercetin/g extract, was quantified. JgNe maintained stability over a 4-week period. Moreover, JgE and JgNe demonstrated no cytotoxicity in human erythrocytes and murine fibroblasts at tested concentrations (32.25-250 µg/mL). Additionally, exhibited significant antioxidant activity by reducing ABTS and DPPH radicals. The treatment with JgNe did not induce skin irritation and accelerated wound healing, with significant wound closure observed from 5th day and reduction in nitrite levels, myeloperoxidase activity, and cytokine. Both JgE and JgNe demonstrated in vitro inhibition of the phospholipase and hyaluronidase enzymes of BeV. Moreover, JgNe exhibited antidermonecrotic activity by reducing the dermonecrotic halo caused by BeV after 24 h. CONCLUSIONS: JgNe and JgE exhibited no cytotoxicity at the tested concentrations. Additionally, our findings demonstrate that JgNe has the ability to accelerate wound closure and reduce dermonecrosis caused by BeV, indicating to be promising formulation for complementary therapy to antivenom treatment.

Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.11) [corrected] higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD.

UDCA for Drug-Induced Liver Disease: Clinical and Pathophysiological Basis.

Drug-induced liver injury (DILI) is an adverse reaction to medications and other xenobiotics that leads to liver dysfunction. Based on differential clinical patterns of injury, DILI is classified into hepatocellular, cholestatic, and mixed types; although hepatocellular DILI is associated with inflammation, necrosis, and apoptosis, cholestatic DILI is associated with bile plugs and bile duct paucity. Ursodeoxycholic acid (UDCA) has been empirically used as a supportive drug mainly in cholestatic DILI, but both curative and prophylactic beneficial effects have been observed for hepatocellular DILI as well, according to preliminary clinical studies. This could reflect the fact that UDCA has a plethora of beneficial effects potentially useful to treat the wide range of injuries with different etiologies and pathomechanisms occurring in both types of DILI, including anticholestatic, antioxidant, anti-inflammatory, antiapoptotic, antinecrotic, mitoprotective, endoplasmic reticulum stress alleviating, and immunomodulatory properties. In this review, a revision of the literature has been performed to evaluate the efficacy of UDCA across the whole DILI spectrum, and these findings were associated with the multiple mechanisms of UDCA hepatoprotection. This should help better rationalize and systematize the use of this versatile and safe hepatoprotector in each type of DILI scenarios.

Long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha treatment for patients with Behcet's uveitis: A systematic review and meta-analysis.

AIM: This study aims to evaluate the long-term efficacy, safety, and cumulative retention rate of antitumor necrosis factor-alpha (anti-TNF-α) therapy for patients with Behcet's uveitis (BU) using meta-analysis. METHODS: We searched the Web of Science and PubMed databases for eligible studies up to December 1, 2022. The quality of each identified study was assessed using the Joanna Briggs Institute's case series literature quality assessment tool. Statistical analysis was conducted using Stata 16.0 software with a random-effects model. RESULTS: Twelve studies comprising 1156 patients with BU were included in our analysis. We found that 85.0% of patients achieved ocular inflammation remission after receiving anti-TNF-α treatment, with a 95% confidence interval (CI) ranging from 78.7% to 90.5%. Additionally, 77.4% (95% CI: 57.5%-92.5%) experienced an improvement in visual acuity (VA). Moreover, the pooled dose reduction of glucocorticoids (GCs) was 11.08 mg (95% CI: -13.34 mg to -8.83 mg). Throughout the follow-up period, the cumulative retention rate of the medication was 67.3% (95% CI: 53.7%-79.6%). Serious adverse events occurred in 5.8% (95% CI: 3.1%-8.9%) of cases, with the three most common types being severe infusion or injection reactions (2.7%; 95% CI: 0.8%-5.4%), tuberculosis (1.3%; 95% CI: 0.0%-3.9%), and bacterial pneumonia (1.3%; 95% CI: 0.1%-3.4%). Subgroup analysis revealed that ocular inflammation remission rates were 89.3% (95% CI: 81.2%-95.5%) for adalimumab treatment and 83.7% (95% CI: 75.3%-90.8%) for infliximab treatment. The drug retention rate after adalimumab therapy was 70.3% (95% CI: 62.0%-78.0%) compared to 66.4% (95% CI: 48.6%-82.2%) for infliximab treatment. Furthermore, the incidence of severe infusion or injection reactions was 2.2% (95% CI: 0.1%-5.8%) following adalimumab treatment and 3.5% (95% CI: 0.7%-7.7%) following infliximab treatment. CONCLUSIONS: Anti-TNF-α therapy represents an effective treatment for BU patients with favorable safety profile and high drug retention rate and a potential advantage of adalimumab over infliximab in terms of ocular inflammation remission, drug retention, and the incidence of severe infusion or injection reactions.

Splanchnic vein thrombosis in necrotizing pancreatitis: a post-hoc analysis of a nationwide prospective cohort.

BACKGROUND: Treatment guidelines for splanchnic vein thrombosis in necrotizing pancreatitis are lacking due to insufficient data on the full clinical spectrum. METHODS: We performed a post-hoc analysis of a nationwide prospective necrotizing pancreatitis cohort. Multivariable analyses were used to identify risk factors and compare the clinical course of patients with and without SVT. RESULTS: SVT was detected in 97 of the 432 included patients (22%) (median onset: 4 days). Risk factors were left, central, or subtotal necrosis (OR 28.52; 95% CI 20.11-40.45), right or diffuse necrosis (OR 5.76; 95% CI 3.89-8.51), and younger age (OR 0.94; 95% CI 0.90-0.97). Patients with SVT had higher rates of bleeding (n = 10,11%) and bowel ischemia (n = 4,4%) compared to patients without SVT (n = 14,4% and n = 2,0.6%; OR 3.24; 95% CI 1.27-8.23 and OR 7.29; 95% CI 1.31-40.4, respectively), and were independently associated with ICU admission (adjusted OR 2.53; 95% CI 1.37-4.68). Spontaneous recanalization occurred in 62% of patients (n = 40/71). Radiological and clinical outcomes did not differ between patients treated with and without anticoagulants. DISCUSSION: SVT is a common and early complication of necrotizing pancreatitis, associated with parenchymal necrosis and younger age. SVT is associated with increased complications and a worse clinical course, whereas anticoagulant use does not appear to affect outcomes.

[Inhibitory Effect of Ginsenoside Rg3 Combined With 5-Fluorouracil on Tumor Angiogenesis and Tumor Growth of Colon Cancer in Mice: An Experimental Study]. / 人参皂苷Rg3与5-æ°Ÿå°¿å˜§å•¶è”ç”¨å¯¹ç»“è‚ ç™Œå°é¼ è‚¿ç˜¤çš„è¡€ç®¡ç”Ÿæˆä¸Žè‚¿ç˜¤ç”Ÿé•¿æŠ‘åˆ¶æ•ˆæžœçš„å®žéªŒç ”ç©¶.

Objective: To evaluate the inhibitory effect of ginsenoside Rg3 combined with 5-fluorouracil (5-FU) on tumor angiogenesis and tumor growth in colon cancer in mice. Methods: CT26 mouse model of colon cancer was established and the mice were randomly assigned to the control group, the ginsenoside Rg3 group, the 5-FU group, and the Rg3 combined with 5-FU group. The 5-FU group was injected intraperitoneally at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 10 days. Treatment for the Rg3 group was given at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 21 days via gastric gavage. The dose and the mode of treatment for the Rg3+5-FU combination group were the same as those for the 5-FU and the Rg3 group. The control group was intraperitoneally injected with 0.2 mL/d of normal saline for 10 days. The expression of vascular endothelial growth factor (VEGF) and CD31 and the microvascular density (MVD) of the tumor tissues were examined by immunohistochemistry. The blood flow signals and tumor necrosis were examined by color Doppler flow imaging (CDFI). The quality of life, survival rate, tumor volume, tumor mass, and tumor inhibition rate of the mice were monitored. Results: After 21 days of treatment, the tumor volume and the tumor mass of all treatment groups were significantly decreased compared with those the control group, with the combination treatment group exhibiting the most significant decrease. The tumor inhibition rates of the Rg3 group, the 5-FU group, and the combination group were 29.96%, 68.78%, and 73.42%, respectively. Rg3 treatment alone had inhibitory effect on tumor growth to a certain degree, while 5-FU treatment alone or 5-FU combined with Rg3 had a stronger inhibitory effect on tumor growth. The tumor inhibition rate of the combination group was higher than that of the 5-FU group, but the difference was not statistically significant (P>0.05). Color Doppler ultrasound showed that there were multiple localized and large tumor necrotic areas that were obvious and observable in the Rg3 group and the combination group, and that there were only small tumor necrotic areas in the 5-FU group and the control group. The tumor necrosis rate of the combination group was (55.63±3.12)%, which was significantly higher than those of the other groups (P<0.05). CDFI examination of the blood flow inside of the tumor of the mice showed that the blood flow signals in the combination group were mostly grade 0-Ⅰ, and that the blood flow signals in the control group were the most abundant, being mostly grade Ⅱ-Ⅲ. The abundance of the blood flow signals in the Rg3 and 5-FU groups were between those of the control group and the combination group. Compared with those of the control group, the expression levels of MVD and VEGF in the tumor tissues of the Rg3 group, the 5-FU group, and the combination group were significantly decreased, with the combination group showing the most significant decrease (P<0.05). HE staining results indicated that there was significant tumor necrosis in mice in the control group and that there were more blood vessels. In contrast, in the tumor of the Rg3 group and the 5-FU group, there were fewer blood vessels and necrotic gaps appeared within the tumors. In the combination group, the tumor tissues had the fewest blood vessels and rope-like necrosis was observed. The mice started dying on the 18th day after treatment started, and all the mice in the control group died on the 42nd day. By this time, there were 3, 5, and 7 mice still alive in the Rg3 group, the 5-FU group, and the combination group, respectively, presenting a survival rate of 30%, 50%, and 70%, respectively. All mice in all the groups died on day 60 after treatment started. Conclusion: Ginsenoside Rg3 combined with 5-FU can significantly inhibit tumor angiogenesis and tumor growth of colon cancer in mice and improve the survival and quality of life of tumor-bearing mice.

Management of Tacrolimus-Induced Toxicity With Normal Serum Levels After Liver Transplant.

Drug-induced liver injury after liver transplant occurs in 1.7% of patients. Tacrolimus is an effective immunosuppressant that is used to treat acute rejection. Although rare, it can cause toxicity, which is demonstrated by cholestatic liver injury. Here, we present a case of a young male patient who was diagnosed with Wilson disease, had penicillaminechelating therapy, and underwent living related liver transplant. Within 1 month posttransplant, he developed deranged, predominantly cholestatic pattern liver function tests. Laboratory parameters showed total bilirubin of 1.12 mg/ dL, alanine aminotransferase of 553 IU/L, gammaglutamyltransferase of 624 IU/L, and tacrolimus level of 10.2 ng/mL. After thorough evaluation, a liver biopsy was performed. Liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. However, with normal level of tacrolimus, the biopsy was suggestive of drug-induced liver injury. Thus, tacrolimus dose was reduced, resulting in improved liver function tests and patient discharge from the hospital. Tacrolimus is an effective immunosuppressant after liver transplant and has the ability to treat early acute rejection. The patient's liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. Cholestatic liver injury after tacrolimus usually resolves after dose reduction or by switching to another agent. With demonstrated tacrolimus-induced toxicity in liver transplant recipients, despite normal serum levels, transplant physicians should keep high index of suspicion regarding toxicity in the posttransplant setting.

Pharmacological and cell-based treatments to increase local skin flap viability in animal models.

Local skin flaps are frequently employed for wound closure to address surgical, traumatic, congenital, or oncologic defects. (1) Despite their clinical utility, skin flaps may fail due to inadequate perfusion, ischemia/reperfusion injury (IRI), excessive cell death, and associated inflammatory response. (2) All of these factors contribute to skin flap necrosis in 10-15% of cases and represent a significant surgical challenge. (3, 4) Once flap necrosis occurs, it may require additional surgeries to remove the entire flap or repair the damage and secondary treatments for infection and disfiguration, which can be costly and painful. (5) In addition to employing appropriate surgical techniques and identifying healthy, well-vascularized tissue to mitigate the occurrence of these complications, there is growing interest in exploring cell-based and pharmacologic augmentation options. (6) These agents typically focus on preventing thrombosis and increasing vasodilation and angiogenesis while reducing inflammation and oxidative stress. Agents that modulate cell death pathways such as apoptosis and autophagy have also been investigated. (7) Implementation of drugs and cell lines with potentially beneficial properties have been proposed through various delivery techniques including systemic treatment, direct wound bed or flap injection, and topical application. This review summarizes pharmacologic- and cell-based interventions to augment skin flap viability in animal models, and discusses both translatability challenges facing these therapies and future directions in the field of skin flap augmentation.

A rare case of gingival necrosis following an extraoral injection of dermal filler.

BACKGROUND: The utilization of dermal fillers for cosmetic procedures has increased dramatically in the past several years, and so is the number of reported adverse events and complications. Most of these reports are centered on extraoral facial structures such as skin, nose, forehead, and eyes. However, as this report illustrates, intraoral complications are also possible and require appropriate management. Our extensive search of the medical and dental literature has failed to yield any such report. METHODS AND RESULTS: An injection of dermal filler composed of hyaluronic acid for managing a deep nasolabial fold resulting in an arterial occlusion is presented. Patient exhibited facial skin necrosis, with ecchymoses and crusting, extending to the right eye. Transient diplopia and vision changes were also present. Additionally, intraoral necrosis of the palatal mucosa extending from the right central incisor to the molars and approaching the midline was noted. Patient was managed palliatively until complete re-epithelization was noted, with no further loss of periodontal attachment. CONCLUSION: This case illustrates a rare oral complication of extraoral injection of a dermal filler, and its management. The clinicians should be aware of the potential risks of these cosmetic procedures. Early detection and timely management may prevent lasting damage and discomfort. Additionally, some of these complications may require a well-coordinated multidisciplinary involvement to restore health and functions (plastic surgeon, dermatologist, ophthalmologist, and a periodontist). KEY POINTS: Why is this case new information? Previous reports of adverse effects linked to dermal fillers were limited to extraoral structures such as the facial skin, nose, forehead, and eye. To the authors' best knowledge, this is the first and only documented case of intraoral necrosis following dermal filler injection What are the keys to successful management of this case? The most important step in managing intra-arterial filler injection and occlusion is the immediate injection of hyaluronidase enzyme to minimize the extent of tissue necrosis. In the case of ocular involvement, immediate referral to an ophthalmologist is required What are the primary limitations to success in this case? Success of managing the adverse effects of vascular occlusion following filler injection depends on several factors, including the anatomical area of occlusion, its extend, along with timely treatment.

Successful Treatment with Steroids in a Patient with Vanishing Bile Duct Syndrome and Acute Tubular Necrosis.

Vanishing bile duct syndrome (VBDS) is a rare but potentially serious cholestatic liver disease caused by various etiologies, including drugs. We herein report a complicated case of VBDS with acute tubular necrosis (ATN) that improved significantly with steroid treatment. An Asian man in his 30s was admitted with the acute onset of severe jaundice and a decline in the renal function. Although initial treatment with ursodeoxycholic acid did not reduce jaundice or renal dysfunction, steroid treatment remarkably improved the VBDS and ATN to within the respective normal ranges. Steroid treatment can be considered in cases of VBDS that appear to have an immune-mediated cause.

Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN.

BACKGROUND: Current data on dual biologic therapy in children are limited. This multicenter study aimed to evaluate the effectiveness and safety of dual therapy in pediatric patients with inflammatory bowel disease (IBD). METHODS: A retrospective study from 14 centers affiliated with the Pediatric IBD Interest and Porto Groups of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Included were children with IBD who underwent combinations of biologic agents or biologic and small molecule therapy for at least 3 months. Demographic, clinical, laboratory, endoscopic, and imaging data were collected. Adverse events were recorded. RESULTS: Sixty-two children (35 Crohn's disease, 27 ulcerative colitis; median age 15.5 [interquartile range, 13.1-16.8] years) were included. They had all failed previous biologic therapies, and 47 (76%) failed at least 2 biologic agents. The dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Normalization of C-reactive protein and decrease in fecal calprotectin to <250 µg/g were achieved in 75% and 64%, respectively, at 12 months of follow-up. Twenty-nine (47%) children sustained adverse events, 8 of which were regarded as serious and led to discontinuation of therapy in 6. CONCLUSIONS: Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events.

This multicenter study describes 62 children with refractory inflammatory bowel disease who received dual biologic therapy. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Several serious adverse events were reported.

Sex Differences in Organophosphate Model of Benzodiazepine-Refractory Status Epilepticus and Neuronal Damage.

Sex differences are common in human epilepsy. Although men are more susceptible to seizure than women, the mechanisms underlying sex-specific vulnerabilities to seizure are unclear. The organophosphate (OP) diisopropylfluorophosphate (DFP) is known to cause neurotoxicity and status epilepticus (SE), a serious neurologic condition that causes prolonged seizures and brain damage. Current therapies for OP poisoning and SE do not consider neuronal variations between male and female brains. Therefore, we investigated sex-dependent differences in electrographic seizure activity and neuronal injury using the DFP model of refractory SE in rats. Electroencephalogram recordings were used to monitor DFP-induced SE, and the extent of brain injury was determined using fluoro-jade-B staining to detect cellular necrosis. After DFP exposure, we observed striking sex-dependent differences in SE and seizure activity patterns as well as protective responses to midazolam treatment. Following acute DFP exposure, male animals displayed more severe SE with intense epileptiform spiking and greater mortality than females. In contrast, we observed significantly more injured cells and cellular necrosis in the hippocampus and other brain regions in females than in males. We also observed extensive neuronal injury in the somatosensory cortex of males. The anticonvulsant effect of midazolam against SE was limited in this model and found to be similar in males and females. However, unlike males, females exhibited substantially more protection against neuronal damage after midazolam treatment. Overall, these results demonstrate significant sex-dependent differences in DFP-induced refractory SE and neuronal damage patterns, suggesting that it may be possible to develop sex-specific neuroprotective strategies for OP intoxication and refractory SE. SIGNIFICANCE STATEMENT: Sex-dependent differences in neurotoxicity and status epilepticus (SE) are key biological variables after organophosphate (OP) exposure. Here, we investigated sex-dependent differences in SE and brain injury after acute diisopropylfluorophosphate exposure. Male rats had more severe SE and less survival than females, while females had more neuronal damage. Females had more neuroprotection to midazolam than males, while both sexes had similar but partial anticonvulsant effects. These findings suggest that a sex-specific therapeutic approach may prevent neurological complications of OP-induced SE.

Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: Prospective phase 2 MARCIE trial.

BACKGROUND: Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). METHODS: A total of 33 patients were enrolled from July 2012 until July 2020. The study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was the 3-year progression-free survival (PFS), and the secondary endpoints included overall survival, safety and treatment toxicities. RESULTS: With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7%, and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in 1 patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. CONCLUSIONS: Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve a superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.

Osimertinib-induced Keratitis and Secondary Toxic Epidermal Necrotic Drug Eruption- A Case Report and Literature Review.

BACKGROUND: Osimertinib is a third-generation Tyrosine Kinase inhibitor, mainly used in non-small cell lung cancer with EGFR mutation. Its efficacy and safety have been confirmed by clinical practice. Toxic epidermolysis necrotizing disease (TEN) is a severe drug eruption that is rare in clinics and has a high mortality rate. Toxic epidermal necrotic drug rash caused by Osimeritinib is even rarer. OBJECTIVE: To investigate the rare side effects of Osimertinib through a case of toxic Epidermal necrosis. CASE PRESENTATION: A 63-year-old female patient was diagnosed with lung adenocarcinoma with brain metastases, and genetic testing revealed an EGFR21 exon mutation. The disease progressed 24 days after the administration of gefitinib, then the patient switched to Osimertinib (80 mg QD) and, resulting in keratitis and secondary systemic toxic epidermolysis necrotizing disease (TEN). Finally, the patient died. CONCLUSION: Although the clinical use of osimertinib is becoming widespread, the side effects may not be fully understood. Clinicians should pay more attention to the occurrence of the side reaction and deal with it in time.

Calpain as a Therapeutic Target for Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a complex pathophysiological process with multiple links and factors. It involves the interaction of inflammation, oxidative stress, and glucose metabolism, and results in acute and even long-term brain damage and impairment of brain function. Calpain is a family of Ca2+-dependent cysteine proteases that regulate cellular function. Calpain activation is involved in cerebral ischemic injury, and this involvement is achieved by the interaction among Ca2+, substrates, organelles, and multiple proteases in the neuronal necrosis and apoptosis pathways after cerebral ischemia. Many calpain inhibitors have been developed and tested in the biochemical and biomedical fields. This study reviewed the potential role of calpain in the treatment of HIE and related mechanism, providing new insights for future research on HIE.

Persistent pain and its predictors after starting anti-tumour necrosis factor therapy in psoriatic arthritis: what is the role of inflammation control?

OBJECTIVE: While considerable focus has been placed on pain due to inflammation in psoriatic arthritis (PsA), less is reported on pain despite inflammation control. Here, we aimed to investigate the occurrence/predictors of persistent pain, including non-inflammatory components, after starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Bionaïve PsA patients starting a first anti-TNF therapy 2004-2010 were identified (South Swedish Arthritis Treatment Group register; N = 351). Outcomes included unacceptable pain [visual analogue scale (VAS) pain > 40 mm], and unacceptable pain despite inflammation control (refractory pain; VAS pain > 40 mm + C-reactive protein < 10 mg/L + ≤ 1 swollen joint of 28), assessed at 0, 3, 6, and 12 months. Baseline predictors were estimated by logistic regression. RESULTS: Upon starting anti-TNF therapy, 85% of patients reported unacceptable pain, falling to 43% at 3 months and then remaining stable. After 12 months, refractory pain constituted 63% of all unacceptable pain. Higher baseline VAS pain/global, worse physical function and lower health-related quality-of-life were associated with a higher risk of unacceptable/refractory pain at 12 months. More swollen joints and higher evaluator's global assessment were associated with a lower risk of 12-month refractory pain. CONCLUSIONS: A substantial proportion of PsA patients reported unacceptable pain throughout the first anti-TNF treatment year. At 12 months, refractory pain constituted about two-thirds of this remaining pain load. More objective signs of inflammation at anti-TNF initiation were associated with less future refractory pain. This highlights insufficient effect of biologics in patients with inflammation-independent pain, warranting alternative treatments.

Hepatoprotective actions of melatonin by mainly modulating oxidative status and apoptosis rate in lipopolysaccharide-induced liver damage.

AIM: One of the serious complications of sepsis is liver damage and liver failure. This study aimed to evaluate the protective and therapeutic potential of melatonin in rats with lipopolysaccharide-induced sepsis. MAIN METHODS: Female Spraque-Dawley rats received single a dose of 7.5 mg/kg lipopolysaccharide in saline to create a 24-h sepsis model. One of the other groups received melatonin at a dose of 10 mg/kg/day beginning 1 week before sepsis induction to the end of the experiment. The melatonin group received the same doses of melatonin for the same duration but not lipopolysaccharide. The vehicle group received the same doses of saline, the vehicle of melatonin, for the same duration. Twenty-four hours after the last injection, the rats were decapitated. By appropriate histochemical, immunohistochemical, biochemical, and molecular techniques, anti-necrotic, anti-apoptotic, anti-necroptotic, anti-inflammatory, and antioxidant effects of melatonin were assessed. KEY FINDINGS: Lipopolysaccharide has disrupted liver functions by inducing oxidative stress, inflammation, necrotic, apoptotic, and necroptotic cell death, thus disrupting liver functions. Melatonin was found to be beneficial in terms of inhibiting the intrinsic pathway of apoptosis and tissue oxidant levels, stimulating tissue antioxidant enzyme levels, and restoring hepatocyte functions. SIGNIFICANCE: Melatonin, at those doses and duration, was found to be hepatoprotective by mainly modulating oxidative status and apoptosis rate, however, failed to significantly reduce histopathological damage. We suggest that longer-term melatonin administration may produce anti-inflammatory and anti-necrotic effects as well.