Oral abrocitinib in the treatment of granuloma annulare: a case report.

Aim: To evaluate the therapeutic efficacy and safety of JAK inhibitor abrocitinib in patients with localized granuloma annulare (GA) and to review the available cases documented in English.Methods: We presented a patient who had a persistent, localized granuloma anulare (GA) for one year and did not respond to traditional therapies. This patient was treated with oral abrocitinib at a dosage of 150 mg daily.Results: After 6 weeks of treatment with abrocitinib, the patient exhibited notable symptom improvement with no new lesions. No adverse events or recurrences were reported during the 5-month follow-up period.Conclusions: Abrocitinib may be a promising and safe treatment option for patients with localized GA who do not respond to traditional therapies.

Predicting cancer-specific mortality in T1/2 hepatocellular carcinoma after radiofrequency ablation by competing risk nomogram: A population-based analysis.

BACKGROUND: Radiofrequency ablation (RFA) is one of the primary treatment methods for T1/2 hepatocellular carcinoma (HCC), but the risk factors after RFA remain controversial. This study aims to identify the key factors associated with cancer-specific mortality (CSM) in patients with T1/2 HCC after RFA using competing risk analysis and to establish a prognostic nomogram for improved clinical management. METHODS: A total of 2,135 T1/2 HCC patients treated with RFA were obtained from the Surveillance, Epidemiology, and End Results (SEER) database and randomly categorized into training and validation sets. Univariate and multivariable competing risk analyses were performed to identify risk factors associated with CSM and construct a competing risk nomogram. Receiver operating characteristic (ROC) curves, concordance indices (C-indexes), calibration plots, and decision curve analysis (DCA) were conducted to evaluate the predictive efficiency and clinical applicability of the nomogram in the training and validation sets. Patients were stratified according to their nomogram score, and the different risk groups were compared using cumulative incidence function (CIF) curves and Gray's validation . RESULTS: The 5-year CSM rate for HCC patients treated with RFA was 30.1 %. Grade, tumor size, tumor number, cirrhosis, and AFP level were identified as independent risk factors for CSM. A prognostic nomogram was developed based on these risk factors. The time-dependent C-indexes (0.65) were greater than those of the AJCC stage model (0.55) during the 12 to 60 months of follow-up. The calibration plots of the competing risk nomograms demonstrated excellent consistency between actual survival and nomogram predictions. ROC analyses showed that the 1-, 3-, and 5-year AUC values in both the training and validation cohorts were all greater than 0.63 and exceeded those of the AJCC stage model. DCA demonstrated the clinical usefulness of the nomogram. Patients were classified into low-, moderate-, and high-risk groups based on the nomogram scores, with the high-risk group showing significantly higher CSM rates after RFA compared to the other two groups. CONCLUSIONS: We identified Grade, AFP, cirrhosis, tumor size, and tumor number as independent risk factors associated with CSM. The competing risk nomogram exhibited high performance in predicting the probability of CSM for HCC patients undergoing RFA.

Sanguinarine, similar to the MICs of spectinomycin, exhibits good anti-Neisseria gonorrhoeae activity in vitro.

The increasing antibiotic resistance of Neisseria gonorrhoeae (NG) is an urgent need to explore new and effective drugs. The antibacterial activities of spectinomycin and sanguinarine against 117 clinical NG isolates and time-kill curve of sanguinarine were evaluated. Almost all isolates were resistant to penicillin (91.5%) and ciprofloxacin (96.5%), 8.5% showed resistance to azithromycin, 10.3% and 10.3% had decreased susceptibility/resistance to ceftriaxone and cefixime, respectively, whereas 100% were susceptible to spectinomycin. The minimum inhibitory concentration (MIC) ranges, MIC50, MIC90 and MICmean values of sanguinarine were 2-64 µg/ml, 16 µg/ml, 32 µg/ml and 16.9 µg/ml, respectively, and time-kill curve showed killing of bacteria in a dose-dependent manner during the assay time of 6h, very similar to spectinomycin. Sanguinarine has great potential as an effective and novel anti-NG agent.

RIPK1-dependent necroptosis promotes vasculogenic mimicry formation via eIF4E in triple-negative breast cancer.

Necroptosis is a caspase-independent form of programmed cell death. Receptor interacting protein kinase 1 (RIPK1) is a key molecule in the initiation of necroptosis and the formation of the necrotic complex. Vasculogenic mimicry (VM) provides a blood supply to tumor cells that is not dependent on endothelial cells. However, the relationship between necroptosis and VM in triple-negative breast cancer (TNBC) is not fully understood. In this study, we found that RIPK1-dependent necroptosis promoted VM formation in TNBC. Knockdown of RIPK1 significantly suppressed the number of necroptotic cells and VM formation. Moreover, RIPK1 activated the p-AKT/eIF4E signaling pathway during necroptosis in TNBC. eIF4E was blocked by knockdown of RIPK1 or AKT inhibitors. Furthermore, we found that eIF4E promoted VM formation by promoting epithelial-mesenchymal transition (EMT) and the expression and activity of MMP2. In addition to its critical role in necroptosis-mediated VM, eIF4E was essential for VM formation. Knockdown of eIF4E significantly suppressed VM formation during necroptosis. Finally, through clinical significance, the results found that eIF4E expression in TNBC was positively correlated with the mesenchymal marker vimentin, the VM marker MMP2, and the necroptosis markers MLKL and AKT. In conclusion, RIPK1-dependent necroptosis promotes VM formation in TNBC. Necroptosis promotes VM formation by activating RIPK1/p-AKT/eIF4E signaling in TNBC. eIF4E promotes EMT and MMP2 expression and activity, leading to VM formation. Our study provides a rationale for necroptosis-mediated VM and also providing a potential therapeutic target for TNBC.

A successful endovascular intervention for massive hemorrhage due to a ruptured gastric artery aneurysm in a patient with microscopic polyangiitis: A case report.

The formation of left gastric artery aneurysms (LGAAs) is a very rare complication of microscopic polyangiitis (MPA). Hemorrhage due to ruptured LGAAs is life threatening. In this case report, an 81-year-old female patient diagnosed with MPA developed massive bleeding from a ruptured LGAA and hemorrhagic shock during hospitalization. The patient underwent endovascular therapy to successfully embolize the aneurysm with microcoils and recovered postoperatively.

LC-MS metabolomics reveal skin metabolic signature of psoriasis vulgaris.

Recent metabolic studies have indicated that several metabolites in blood and urine of psoriasis functionally involved in the pathogenesis of psoriasis, but the skin metabonomics research of psoriasis is limited. We aimed to investigate the metabolic profiling of lesional and nonlesional skin and screen out potential biomarkers for psoriasis. We performed liquid chromatography-mass spectrometry (LC-MS)-based nontargeted metabolomic analysis to compare metabolic profile between lesional and nonlesional skin from 12 patients with psoriasis vulgaris. A total of 3463 metabolites were detected, of which 769 (346 named and 423 unnamed) in positive ion mode and 179 (80 named and 99 unnamed) in negative ion mode were significantly different between lesional and nonlesional skin. These different metabolites were mainly derived from amino acid, lipid and nucleotide metabolism, and involved in cell proliferation and apoptosis regulation. Fourteen metabolites (10 upregulated and 4 downregulated) were identified as the most potentially significant biomarkers. Interestingly, seven of them were positively (l-gamma-glutamyl-l-leucine, 2-methylcitric acid, l-palmitoylcarnitine, inosine, eicosapentaenoic acid and 13-hydroxy-octadecaenoic acid) or negatively (l-serine) correlated with disease severity. Significant differences of metabolic characteristics were found between lesional and nonlesional skin, which may contribute to assess the severity of psoriasis and therapeutic responses.

Tofacitinib combined with melanocyte protector α-MSH to treat vitiligo through dextran based hydrogel microneedles.

Vitiligo can cause serious damage to the appearance of patients and affect physical and mental health, but there is currently no simple and effective treatment. According to the theory of autoimmune disorder, the separable hydrogel microneedles delivering alpha-melanocyte-stimulating hormone (α-MSH) and tofacitinib were designed to treat vitiligo. This hydrogel microneedles were formed by dextran methacrylate (DexMA) and cyclodextrin-adamantane based host-guest supramolecules (HGSM) through CC double bond polymerization and host-guest assembly. The microneedle tips formed by the double cross-linked hydrogel can pierce the stratum corneum and deliver melanocyte protector α-MSH and JAK inhibitor tofacitinib directly to the epidermis and dermis. Under the treatment of α-MSH/tofacitinib microneedles, massive deposition of melanin in epidermis and hair follicles significantly accelerated skin and hair pigmentation.

A systematic review and meta-analysis on the efficacy and safety of transcatheter arterial chemoembolization combined with radiofrequency ablation in the treatment of primary liver cancer.

Background: Transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) intervention in prolonging the long-term survival and prognosis of patients with liver cancer are still controversy compared with the traditional interventional therapy of RFA alone. This meta-analysis aimed to compare the efficacy and safety of combination therapy versus RFA alone. Methods: The related articles were searched in PubMed, Embase, MEDLINE, Science Direct, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Science and Technology Journal Database, and China Biomedical Literature Database (CBM). The Chinese and English search keywords included transcatheter arterial chemoembolization, TACE, radiofrequency ablation, RFA, primary liver cancer, and liver tumor. The five evaluation criteria of randomized controlled trials (RCTs) in Cochrane RoB 2.0 repeatedly independently evaluated the bias risks involved in the study and cross-checked the results. Results: A total of 7 articles were included, and the results of bias risk assessment show that 6 articles described the generation of random sequences in detail; There were 3 articles describing allocation concealment in detail; Operator blindness was used in 4 articles; The outcome indicators of 7 documents were complete. The 3-year overall survival rate of the RFA combined with TACE group was significantly better than that of the RFA group [odds ratio (OR) =1.97, 95% confidence interval (CI): 1.42-2.74, Z=4.05, P<0.0001]. The 1-year and 3-year tumor recurrence-free survival rates in the RFA combined with TACE group were significantly better than those in the RFA group (OR =1.88, 95% CI: 1.28-2.76, Z=3.23, P=0.001; OR =2.11, 95% CI: 1.37-3.24, Z=3.38, P=0.0007). There was no significant difference in the complication rate of patients with primary liver cancer between the RFA combined with TACE group and the RFA group (OR =0.79, 95% CI: 0.45-1.39, Z=0.81, P=0.42). Discussion: Meta-analysis results confirmed that TACE combined with RFA was safe and effective in the treatment of primary liver cancer, and can improve the overall survival and recurrence-free survival of patients with primary liver cancer.

Review of secukinumab-induced adverse events of special interest and its potential pathogenesis.

Although secukinumab has demonstrated high efficacy and favorable safety in moderate-to-severe psoriasis and psoriatic arthritis, patients developing adverse events of special interest (AESI) were reported increasingly in real-world practice. A systematic literature search of the PubMed database was conducted to identify clinical studies or case reports on secukinumab-induced AESI. More than 1077 patients (aged 18-74 years) from 55 studies were reported to have 24 AESI 3 days to 96 weeks after secukinumab treatment. The four most common AESI was inflammatory bowel disease (n > 1000), eczematous drug eruption (n > 30), drug-associated vasculitis (n = 8), and drug-induced lupus erythematosus (n = 4). Most of these AESI were only mild to moderately severe and resolved after secukinumab discontinuation without or with symptomatic treatment. Secukinumab has the potential to develop a number of AESI by probably dysregulating the different expression of polar T-cell axes (Th1, Th2, Th17, Th22, and/or Treg) and driving various cytokines in some patients. Physicians should be aware of these AESI for timely diagnosis and proper treatment.

LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Improves Cardiac Hypertrophy and Fibrosis and Cardiac Lymphatic Remodeling in Transverse Aortic Constriction Model Mice.

Cardiac hypertrophy and ventricular remodeling following heart failure are important causes of high mortality in heart disease patients. The cardiac lymphatic system has been associated with limited research, but it plays an important role in the improvement of myocardial edema and the promotion of fluid balance. LCZ696 is a novel combination of angiotensin and neprilysin inhibitors. Here, we studied the role played by LCZ696 during transverse aortic constriction (TAC) induced cardiac hypertrophy and changes in the lymphatic system. Mice undergoing aortic coarctation were constructed to represent a cardiac hypertrophy model and then divided into random groups that either received treatment with LCZ696 (60 mg/kg/d) or no treatment. Cardiac ultrasonography was used to detect cardiac function, and hematoxylin and eosin (H&E) and Masson staining were used to detect myocardial hypertrophy and fibrosis. The proinflammatory factors interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) were detected in the blood and heart tissues of mice. The protein expression levels of lymphatic-specific markers, such as vascular endothelial growth factor C (VEGF-C), VEGF receptor 3 (VEGFR3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) were detected in mouse heart tissues. We also examined the colocalization of lymphatic vessels and macrophages by immunofluorescence. The results showed that LCZ696 significantly improved heart dysfunction, cardiac hypertrophy, and fibrosis and inhibited the expression of proinflammatory factors IL-6, IL-1ß, and TNF-α in the circulating blood and heart tissues of mice. LCZ696 also decreased the protein expression levels of VEGF-C, VEGFR3, and LYVE-1 in mouse heart tissues, ameliorated the transport load of lymphatic vessels to macrophages, and improved the remodeling of the lymphatic system in the hypertrophic cardiomyopathy model induced by TAC.

Ivabradine improved left ventricular function and pressure overload-induced cardiomyocyte apoptosis in a transverse aortic constriction mouse model.

This study aimed to investigate the effects and molecular mechanisms of ivabradine in preventing cardiac hypertrophy in an established transverse aortic constriction (TAC) mouse model. A total of 56 male C57BL/6 mice were randomly assigned into the following seven groups (8 mice per group): sham, TAC model, Iva-10 (10 mg/kg/day ivabradine), Iva-20 (20 mg/kg/day ivabradine), Iva-40 (40 mg/kg/day ivabradine), Iva-80 (80 mg/kg/day ivabradine), and Rap (rapamycin, a positive control). Echocardiography and left ventricular hemodynamics were performed. Hematoxylin-eosin (H&E), Masson's trichome staining, and TUNEL assays were conducted to evaluate cardiac hypertrophy, fibrosis, and apoptosis, respectively. Western blotting was performed to detect the expression of proteins related to the PI3K/Akt/mTOR/p70S6K pathway. Ivabradine could effectively improve left ventricular dysfunction and hypertrophy induced by TAC in a dose-independent manner. Moreover, no obvious change in heart rate (HR) was observed in the TAC and Rap groups, whereas a significant decrease in HR was found after ivabradine treatment (P < 0.05). Cardiac hypertrophy, fibrosis, and apoptosis induced by TAC were notably suppressed after either rapamycin or ivabradine treatment (P < 0.05). Ivabradine and rapamycin also decreased the expression of PI3K/Akt and mTOR induced by TAC. Ivabradine improved cardiac hypertrophy and fibrosis as well as reduced cardiomyocyte apoptosis via the PI3K/Akt/mTOR/p70S6K pathway in TAC model mice.

Distal tibial fracture: An ideal indication for external fixation using locking plate.

OBJECTIVE: To evaluate the feasibility and efficiency of one-stage external fixation by using locking plate in distal tibial fractures. METHODS: In this non-control prospective study, 28 patients with distal tibial fractures were included and underwent one-stage external fixation by using locking plate. There were 21 males and 7 females, with a mean age of 43 years (19-63). According to AO/OTA fracture classification, there were 9 cases of Type A1, 9 of Type A2, 10 of Type A3 fractures. There were 21 close and 7 open fractures. The locking plate was placed on the anteromedial aspect of the tibia with 4-5 bicortical screws inserted in both distal met- aphysis and diaphysis. The radiographic and clinic results were evaluated. RESULTS: All patients were followed up for the average of 16 months (ranging from 12 to 21 months). The average surgery duration was 38 (25-60) minutes. The mean time to fracture healing were 14.6 ± 2.67, 17.5 ± 3.66, and 18.4 ± 3.37 (p < 0.05) weeks in type A1, A2, and A3 fractures respectively. By the end of the follow-ups, the mean AOFAS score were 96.11 ± 2.32, 92.67 ± 1.80 and 92.00 ± 2.06 (p > 0.05) in type A1, A2, and A3 fractures respectively. None of nonunion, deep infection, or breakage of screw or plate were observed. CONCLUSIONS: Distal tibial fracture was the ideal indication for external fixation using locking plate. The external plating is characterized by ease of performance, less invasive, fewer soft tissue impingement, improved cosmesis, and convenient for removal.

Improvement of cardiac dysfunction by bilateral surgical renal denervation in animals with diabetes induced by high fructose and high fat diet.

AIMS: Insulin resistance (IR) and sympathetic over-activation play a critical role in diabetic cardiomyopathy (DCM). Percutaneous renal sympathetic denervation (RDN) was tested to treat refractory hypertension. However, the benefits of RDN for DCM and IR still remain unknown. The present study aimed to investigate the effect and associated mechanisms of bilateral surgical RDN (bsRDN) on cardiac function and glucose metabolism in animals with diabetes. METHODS: Thirty-two male New Zealand white rabbits were randomly assigned to Chow (n=8, normal diet) and TEST (n=24, high-fructose fat diet [HFD]) groups. At 48 weeks after HFD feeding, animals in the TEST group were randomized to the Sham, HFD, and RDN subgroups and were fed a HFD for an additional 8 weeks. Repeated measurements of cardiac function, IR, apoptosis/autophagy, and histopathological assessment were performed at 48 and 56 weeks. RESULTS: HFD feeding for 56 weeks induced IR and diastolic cardiac dysfunction with hypertrophy in septum but well preserved eject fraction in the animals. Impaired IR further deteriorated over the time in the RDN group, featured by a more profound reduction in GLUT4 mRNA and its translocation to the plasma membrane. Successful denervation was associated with improvement of cardiac function via preventing myocardial fibrosis and over-expression of procollagen III, mammalian target of rapamycin, and cardiac apoptosis. Cardiac autophagy, assessed by either electron microscopy or Western blot, was enhanced by bsRDN. CONCLUSIONS: Renal sympathetic denervation led to a significant improvement of HFD-induced cardiac dysfunction by shifting the cardiac apoptosis to autophagy, but worsening IR. Further study is required to identify the clinical benefits of RDN.

External Fixation Using a Locking Plate: A Reliable Way in Treating Distal Tibial Fractures.

The surgical treatment of distal tibial fractures is still challenging. The purpose of this study was to evaluate the clinical and radiographic results associated with the use of a precontoured distal femoral locking plate as an external fixator in treating distal tibial fractures. From August 2011 to October 2012, 28 patients with distal tibial fractures were consecutively enrolled in this study. There were 9 OTA 43.A1, 9 43.A2, and 10 43.A3, including 21 closed and 7 open fractures. The precontoured distal femoral locking plate was placed on the anteromedial aspect of the tibia as an external fixator. All patients were followed for an average of 16 months. The mean surgical duration was 38 (25-60) minutes. The mean time until fracture healing was 16.7 (12-24) weeks. At final follow-up, the mean American Orthopaedic Foot and Ankle Society score was 93 (88-100). There were no nonunions, deep infections, or implant fractures. Three patients had transient superficial pin site infection, but these did not change the clinical outcome. External fixation using a precontoured distal femoral locking plate is a reliable option in treating distal tibial fracture. The procedure is easy to perform, is less invasive, and the low profile plate can be concealed under stockings and can be conveniently removed.

Cardiac hypertrophy is positively regulated by long non-coding RNA PVT1.

The aim of this study was to determine whether long non-coding RNA PVT1 can participate in the regulation of cardiac hypertrophy. A C57BL/6 mouse cardiac hypertrophic model was established using transverse aortic constriction (TAC). The animals subjected to sham operation were used as controls. Transcripts of PVT1 were analyzed in hearts of model and sham control groups after TAC for 4 weeks using quantitative real-time PCR (qRT-PCR). Additionally, to investigate whether PVT1 was involved in cardiac hypertrophy, 1 µM angiotensin II (Ang II) was used to induce hypertrophy and PVT1 siRNA was performed in the cultured neonatal mouse cardiac cardiomyocytes. Cell size was measured by cell surface area and total protein content analyses in response to Ang II treatment. Moreover, some hypertrophic markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and beta-myosin heavy chain (ß-MHC) were also quantified using qRT-PCR. As a result, PVT1 was up-regulated by 2.5-fold (P<0.05) in hypertrophic hearts after TAC for 4 weeks as compared to sham group. In addition, siRNA of endogenous PVT1 in cardiomyocytes significantly reduced (P<0.05) Ang II-induced increase of cell size in terms of cell surface area (by 5.6-fold) and total protein content (by 23.0%). PVT1 siRNA also obviously attenuated Ang II-induced ANP and ß-MHC expression by 40.9% and 41.5%, respectively (P<0.05), but had no effect on BNP mRNA expression. Our results demonstrated that PVT1 was essential for the maintenance of cell size of cardiomyocytes and might play a role in the regulation of cardiac hypertrophy.

External fixation using femoral less invasive stabilization system plate in tibial proximal metaphyseal fracture.

BACKGROUND: The locking plates are often used for internal fixation of closed tibial fractures. The use of a locking plate as an external fixator is still controversial, particularly for closed fractures. The purpose of this study is to evaluate the results of external fixation using the femoral less invasive stabilization system (LISS) plate in proximal metaphyseal fractures of the tibia. METHODS: We prospectively evaluated 35 patients (26 males and 9 females) with a mean age of 42 years (range, 21 to 62 years) who presented with fresh tibial proximal metaphyseal fractures. According to the AO Foundation and Orthopaedic Trauma Association (AO/OTA) classification, the fractures were identified as type 41-A2 in 18 cases and type 41-A3 in 17 cases, including 25 closed fractures and 10 open fractures. The femoral LISS plate was used to fix these fractures, which was placed on the anteromedial aspect of the tibia as an external fixator. The mean follow-up period was 18 months (range, 13 to 22 months). RESULTS: All fractures healed in a mean time of 14 weeks (range, 10 to 20 weeks). There was no case of nonunion, deep infection, and loosening of screws and plates. One month after the appearance of cortical bridging on biplanar radiographs, the locking plate was removed within 3 minutes in the clinic without any difficulty. According to the Hospital for Special Surgery (HSS) knee scoring system and American Orthopaedic Foot & Ankle Society (AOFAS) ankle scoring system, the mean HSS score was 91 (range, 85 to 100) and 98 (range, 93 to 100), and the mean AOFAS score was 94 (range, 90 to 100) and 98 (range, 95 to 100) at 4 weeks postoperatively and final follow-up, respectively. CONCLUSIONS: For proximal metaphyseal fracture of the tibia, external fixation using the femoral LISS plate is a safe and reliable technique with minimal complications and excellent outcomes. Its advantages include ease of performing the surgery, use of a less invasive technique, and convenience of plate removal after fracture healing.

Surgical treatment of extra-articular or simple intra-articular distal tibial fractures: MIPO versus supercutaneous plating.

Minimally invasive plate osteosynthesis (MIPO) has become a widely accepted technique to treat distal tibial fractures. Recently, the novel application of a locking plate used as an external fixator (supercutaneous plating) was introduced for the management of open fractures and infected nonunions and even as an adjunct in distraction osteogenesis, which is considered another less invasive method. The aim of this study was to compare the results of supercutaneous plating with closed reduction and minimally invasive plating in the treatment of distal tibial fractures. Forty-eight matched patients were divided according to age, sex, Injury Severity Score, and fracture pattern into the MIPO group and the supercutaneous plating group. Minimum follow-up was 12 months (mean, 18.5 months; range, 12-26 months). No patient had nonunion, hardware breakdown, or deep infection. Patients in the supercutaneous plating group had a significantly shorter mean operative time (65.6±13.2 vs 85.9±14.0 minutes; P=.000), hospital stay (7.5±2.0 vs 13.0±4.4 days; P=.000), and union time (15.2±2.4 vs 17.0±2.8 weeks; P=.000). In the MIPO group, 15 (62.5%) patients reported implant impingement or discomfort and there was 1 incidence of stripping of 15.6% at the time of locking screw removal, whereas in the supercutaneous plating group, no patient reported skin irritation, and removal of the supercutaneous plate was easily performed in clinic without anesthesia. Distal tibial fractures may be treated successfully with MIPO or supercutaneous plating. However, the supercutaneous plating technique may represent a superior surgical option because it offers advantages in terms of mean operative time, hospital stay, and union time; skin irritation; and implant removal.