Side-specific factors for intraoperative hemodynamic instability in laparoscopic adrenalectomy for pheochromocytoma: a comparative study.

BACKGROUND: Adrenalectomy for pheochromocytoma (PHEO) is challenging because of the high risk of intraoperative hemodynamic instability (HDI). This study aimed to compare the incidence and risk factors of intraoperative HDI between laparoscopic left adrenalectomy (LLA) and laparoscopic right adrenalectomy (LRA). METHODS: We retrospectively analyzed two hundred and seventy-one patients aged > 18 years with unilateral benign PHEO of any size who underwent transperitoneal laparoscopic adrenalectomy at our hospitals between September 2016 and September 2023. Patients were divided into LRA (N = 122) and LLA (N = 149) groups. Univariate and multivariate logistic regression analyses were used to predict intraoperative HDI. In multivariate analysis for the prediction of HDI, right-sided PHEO, PHEO size, preoperative comorbidities, and preoperative systolic blood pressure were included. RESULTS: Intraoperative HDI was significantly higher in the LRA group than in the LLA (27% vs. 9.4%, p < 0.001). In the multivariate regression analysis, right-sided tumours showed a higher risk of intraoperative HDI (odds ratio [OR] 5.625, 95% confidence interval [CI], 1.147-27.577, p = 0.033). The tumor size (OR 11.019, 95% CI 3.996-30.38, p < 0.001), presence of preoperative comorbidities [diabetes mellitus, hypertension, and coronary heart disease] (OR 7.918, 95% CI 1.323-47.412, p = 0.023), and preoperative systolic blood pressure (OR 1.265, 95% CI 1.07-1.495, p = 0.006) were associated with a higher risk of HDI in both LRA and LLA, with no superiority of one side over the other. CONCLUSION: LRA was associated with a significantly higher intraoperative HDI than LLA. Right-sided PHEO was a risk factor for intraoperative HDI.

Outcome of cataract surgery in children with presumed trematode-induced granulomatous anterior uveitis.

PURPOSE: To examine the 6-month visual outcomes and complications following cataract surgery in patients with persumed trematode induced granulomatous anterior uveitis. SETTING: Assiut university hospital, Assiut, Egypt. DESIGN: This is a retrospective non comparative case series study. METHODS: Patients presenting with significant cataract secondary to uveitis caused by trematode induced anterior chamber granuloma were included in this study. Cases with active anterior uveitis, within the last 3 months preceding surgery, and those with a history of trauma, were excluded from this study. Data collected included demographic characteristics, history of the condition including when uveitis started, treatment received and history of other health conditions that may be relevant to uveitis.Complete opthalmologic examination including assessment of best corrected visual acuity (BCVA) and OCT macula, if possible, were done. These was repeated 1 week, 1 month, 3 months and 6 months after surgery. Specular microscopy was performed preoperatively and 3 months after surgery. Patients underwent cataract surgery with posterior chamber intra ocular lens and statistical analysis was performed to compare preoperative and postoperative BCVA and corneal endothelial cell counts. Postoperative complications were recorded. RESULTS: Five eyes of 5 patients were included in the study. All study eyes showed improvement in the post-operative visual acuity. A statistically significant improvement was observed in VA in the sixth postoperative month compared to the baseline measurements (p = 0.004). No statistically significant difference was observed between the preoperative and postoperative endothelial cell counts (p = 0.696). Cystoid macular edema did not occur as a postoperative complication. CONCLUSION: Visual outcomes of cataract surgery in eyes with persumed trematode induced granulametous anterior uveitis are favorable. No sight threatening complication was observed in our series.

A comparative evaluation of the sniffing, the simple head extension and the head hyperextension positions for laryngoscopic view and intubation difficulty in adults undergoing direct laryngoscopy.

OBJECTIVE: This work aimed to compare between the laryngoscopy positions; sniffing, simple head extension and head hyperextension positions to assess whether the laryngeal view, intubation time and intubation difficulty could improve with one of these positions than the others. DESIGN: Prospective randomized three arms clinical trial. SETTING: Operation room, the phoniatrics unit [removed for blind peer review]. PARTICIPANTS: The study included 75 cases with 25 cases in each group. Group "A" with head in the sniffing position, Group "B" with the head in simple extension position, Group "C" with head in hyperextension position. RESULTS: The three groups were compared regarding intubation time and laryngoscopic view time. Intubation time showed statistically significant difference between the three groups. Mean of sniffing group (No. = 25) was 13.19 s (± 3.35). Mean of simple extension group (No. = 25) was 11.29 s (± 3.14). Mean of Hyperextension group (No. = 25) was 14.39 s (± 4.14). Laryngoscopic view time showed statistically highly significant difference between the three groups. Mean of sniffing group (No. = 25) was 17.19 s (± 7.27). Mean of simple group (No. = 25) was 12.18 s (± 4.46). Mean of hyperextension group (No. = 25) was 17.08 s (± 6.51). CONCLUSION: Comparing the sniffing, the simple extension and the hyperextension positions, the simple extension position showed the best time regarding intubation time and laryngoscopic view time.

Secure Computing for Fog-Enabled Industrial IoT.

Smart cities are powered by several new technologies to enhance connectivity between devices and develop a network of connected objects which can lead to many smart industrial applications. This network known as the Industrial Internet of Things (IIoT) consists of sensor nodes that have limited computing capacity and are sometimes not able to execute intricate industrial tasks within their stipulated time frame. For faster execution, these tasks are offloaded to nearby fog nodes. Internet access and the diverse nature of network types make IIoT nodes vulnerable and are under serious malicious attacks. Malicious attacks can cause anomalies in the IIoT network by overloading complex tasks, which can compromise the fog processing capabilities. This results in an increased delay of task computation for trustworthy nodes. To improve the task execution capability of the fog computing node, it is important to avoid complex offloaded tasks due to malicious attacks. However, even after avoiding the malicious tasks, if the offloaded tasks are too complex for the fog node to execute, then the fog nodes may struggle to process all legitimate tasks within their stipulated time frame. To address these challenges, the Trust-based Efficient Execution of Offloaded IIoT Trusted tasks (EEOIT) is proposed for fog nodes. EEOIT proposes a mechanism to detect malicious nodes as well as manage the allocation of computing resources so that IIoT tasks can be completed in the specified time frame. Simulation results demonstrate that EEOIT outperforms other techniques in the literature in an IIoT setting with different task densities. Another significant feature of the proposed EEOIT technique is that it enhances the computation of trustable tasks in the network. The results show that EEOIT entertains more legitimate nodes in executing their offloaded tasks with more executed data, with reduced time and with increased mean trust values as compared to other schemes.

Endoscopic management of low output recurrent colonic fistula or leak after anterior resection for rectal cancer: a randomized controlled trial.

BACKGROUND: Colonic anastomotic leak and fistula following anterior resection surgery for rectal cancer are associated with high mortality rates. The incidence of occurrence varies from 2 to 25% and it is difficult to accurately calculate the incidence of fistula and leak post anterior resection, as most of them are asymptomatic. Endoscopic management of fistula and leak has become the first line of management after conservative management in many gastrointestinal surgical centers with the advantages of being less invasive, shorter length of post-operative hospital stay, effective and rapid recovery in comparison to revision surgery. Effective endoscopic management for colonic fistula or leak depends on the clinical status of the patient and fistula characters (time-to-occur and size and site of defect), and device availability. METHODS: This prospective randomized controlled clinical trial included all patients who developed the manifestations of low output recurrent colonic fistula or leak after colonic anterior resection for rectal cancer at Zagazig University Hospital between (December 2020 and August 2022). Sample size was 78 patients divided into two equal groups. Endoscopic group (EG): included 39 patients who underwent endoscopic management. Surgical group (SG): included 39 patients who underwent surgical management. RESULTS: The investigators randomized eligible 78 patients into two groups: 39 patients in SG and 39 patients in EG. The median size of the fistula or leak was nine (range: 7-14) mm in EG, versus ten (range: 7-12) mm in SG. Clipping and Endo-stitch device were used in 24 patients versus 15 patients, respectively, in EG while primary repair with ileostomy, and resection & anastomosis were used in 15 patients versus 24 patients, respectively, in SG. Recurrence, abdominal collection, and mortality were the post procedure's complications with incidence of occurrence of 10.3, 7.7 and 0%, respectively, in EG versus 20.5, 20.5 and 2.6%, respectively, in SG. Excellent, good, and poor were the parameters for quality of life with incidence of occurrence of 43.6, 54.6 and 0%, respectively, in EG versus 28.2, 33.3 and 38.5%, respectively, in SG. Median hospital stay was one (range: 1-2) day in endoscopic group, and seven (range: 6-8) days in SG. CONCLUSION: Endoscopic intervention may offer a successful modality in managing low output recurrent colonic fistula or leak after anterior resection for rectal cancer that did not respond to conservative measures in stable patients. CLINICALTRIALS: gov ID: NCT05659446.

Design and synthesis of novel rigid dibenzo[b,f]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators.

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).HighlightsTwo novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.5e was the most active anti-topo II congener (IC50 = 6.36 ± 0.36 µM).5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC50 = 13.05 ± 0.62 µM).In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm3 compared to doxorubicin treatment.

Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies.

Topoisomerase II (TOP-2) is a promising molecular target for cancer therapy. Numerous antibiotics could interact with biologically relevant macromolecules and provoke antitumor potential. Herein, molecular docking studies were used to investigate the binding interactions of 138 antibiotics against the human topoisomerase II-DNA complex. Followed by the MD simulations for 200 ns and MM-GBSA calculations. On the other hand, the antitumor activities of the most promising candidates were investigated against three cancer cell lines using doxorubicin (DOX) as a reference drug. Notably, spiramycin (SP) and clarithromycin (CL) showed promising anticancer potentials on the MCF-7 cell line. Moreover, azithromycin (AZ) and CL exhibited good anticancer potentials against the HCT-116 cell line. Finally, the TOP-2 enzyme inhibition assay was carried out to confirm the proposed rationale. Briefly, potent TOP-2 inhibitory potentials were recorded for erythromycin (ER) and roxithromycin (RO). Additionally, a SAR study opened eyes to promising anticancer pharmacophores encountered by these antibiotics.HighlightsMolecular docking studies of 139 antibiotics against the topoisomerase II-DNA complex.SP, RO, AZ, CL, and ER were the most promising and commercially available candidates.Molecular dynamics simulations for 200 ns for the most promising five complexes.MM-GBSA calculations for the frontier five complexes.SP and CL showed promising anticancer potentials on the MCF-7 cell line, besides, AZ and CL exhibited good anticancer potentials against the HCT-116 cell line.Potent TOP-2 inhibitory potentials were recorded for ER and RO.

Targeted Drug Administration onto Cancer Cells Using Hyaluronic Acid-Quercetin-Conjugated Silver Nanoparticles.

Quercetin (QtN) displays low systemic bioavailability caused by poor water solubility and instability. Consequently, it exerts limited anticancer action in vivo. One solution to increase the anticancer efficacy of QtN is the use of appropriate functionalized nanocarriers that preferentially target and deliver the drug to the tumor location. Herein, a direct advanced method was designed to develop water-soluble hyaluronic acid (HA)-QtN-conjugated silver nanoparticles (AgNPs). HA-QtN reduced silver nitrate (AgNO3) while acting as a stabilizing agent to produce AgNPs. Further, HA-QtN#AgNPs served as an anchor for folate/folic acid (FA) conjugated with polyethylene glycol (PEG). The resulting PEG-FA-HA-QtN#AgNPs (further abbreviated as PF/HA-QtN#AgNPs) were characterized both in vitro and ex vivo. Physical characterizations included UV-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), particle size (PS) and zeta potential (ZP) measurements, and biopharmaceutical evaluations. The biopharmaceutical evaluations included analyses of the cytotoxic effects on the HeLa and Caco-2 cancer cell lines using the MTT assay; cellular drug intake into cancer cells using flow cytometry and confocal microscopy; and blood compatibility using an automatic hematology analyzer, a diode array spectrophotometer, and an enzyme-linked immunosorbent assay (ELISA). The prepared hybrid delivery nanosystem was hemocompatible and more oncocytotoxic than the free, pure QtN. Therefore, PF/HA-QtN#AgNPs represent a smart nano-based drug delivery system (NDDS) and could be a promising oncotherapeutic option if the data are validated in vivo.

ß-cell Smad2 null mice have improved ß-cell function and are protected from diet-induced hyperglycemia.

Understanding signaling pathways that regulate pancreatic ß-cell function to produce, store, and release insulin, as well as pathways that control ß-cell proliferation, is vital to find new treatments for diabetes mellitus. Transforming growth factor-beta (TGF-ß) signaling is involved in a broad range of ß-cell functions. The canonical TGF-ß signaling pathway functions through intracellular smads, including smad2 and smad3, to regulate cell development, proliferation, differentiation, and function in many organs. Here, we demonstrate the role of TGF-ß/smad2 signaling in regulating mature ß-cell proliferation and function using ß-cell-specific smad2 null mutant mice. ß-cell-specific smad2-deficient mice exhibited improved glucose clearance as demonstrated by glucose tolerance testing, enhanced in vivo and ex vivo glucose-stimulated insulin secretion, and increased ß-cell mass and proliferation. Furthermore, when these mice were fed a high-fat diet to induce hyperglycemia, they again showed improved glucose tolerance, insulin secretion, and insulin sensitivity. In addition, ex vivo analysis of smad2-deficient islets showed that they displayed increased glucose-stimulated insulin secretion and upregulation of genes involved in insulin synthesis and insulin secretion. Thus, we conclude that smad2 could represent an attractive therapeutic target for type 2 diabetes mellitus.

Placental Invasion into the Small Bowel Intestine Through a Myomectomy Scar: A Case Report With Literature Review.

Although extremely rare, uterine damage after hysteroscopic myomectomy sets the precondition for various life-threatening placental attachment disorders like placenta percreta (PP) or scar pregnancy. Due to vast clinical similarities, these terms are often used interchangeably. We report a case of a 47-yr-old patient at 27 wk + 4 d of gestation who presented with rectal bleeding. Clinical history revealed a previous uterine posterior wall myomectomy. The patient received intensive diagnostic work-up including sonography and magnetic resonance imaging. Under the suspicion of a bleeding Meckel diverticulum, an emergency laparotomy was performed. Intraoperatively it was observed that the placental tissue infiltrated the small bowel intestine at the location of the previous myomectomy. The adjacent intestine and the infiltrating placenta were surgically removed. The placenta could be easily detached from the uterus, which is why no hysterectomy was performed. Retrospectively, no radiologic or clinical hints of PP or scar pregnancy were evident before the surgery. Moreover, the pathologic work-up carried out afterwards proved no histopathologic evidence for PP. Our case underlines several clinical and pathologic difficulties. First, invasive placenta disorders including infiltration of intestinal organs have to be considered even after minor surgical interventions such as myomectomy. Second, clinical presentation is extremely variable and sometimes misleading, depending on the localization and the type of invasion. Our case underlines the importance of histopathologic work-up for distinguishing between various placenta attachment disorders such as PP and scar pregnancy. Given the large overlap in clinical presentation, pathophysiology and definition, we propose that the current definitions for PP and scar pregnancy have to be carefully reevaluated and broadened.

Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies.

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.

Carnosic Acid Protects INS-1 ß-Cells against Streptozotocin-Induced Damage by Inhibiting Apoptosis and Improving Insulin Secretion and Glucose Uptake.

Carnosic acid (CA), a natural polyphenolic diterpene derived from Rosmarinus officinalis, has been proven to possess a broad spectrum of medicinal properties. Nevertheless, no studies on its impact on pancreatic ß-cells have been conducted to date. Herein, clonal rat INS-1 (832/13) cells were pretreated with CA for 24 h and then incubated with streptozotocin (STZ) for 3 h. Several functional experiments were performed to determine the effect of CA on STZ-induced pancreatic ß-cell damage, including cell viability assay, apoptosis analysis, and measurement of the level of insulin secretion, glucose uptake, malondialdehyde (MDA), reactive oxygen species (ROS), and proteins expression. STZ treatment decreased cell survival, insulin secretion, glucose uptake, and increased apoptosis, MDA, and ROS production in INS-1 cells. Furthermore, protein expression/phosphorylation analysis showed significant down-regulation in insulin, PDX-1, PI3K, AKT/p-AKT, and Bcl2. On the other hand, expression of BAX and BAD and cleaved PARP were significantly increased. Interestingly, preincubation with CA reversed the adverse impact of STZ at the cellular and protein expression levels. In conclusion, the data indicate that CA protects ß-cells against STZ-induced damage, presumably through its modulatory effect on the different pathways, including the Pi3K/AKT/PDX-1/insulin pathway and mitochondria-mediated apoptosis.

Topical application of indigo-plant leaves extract enhances healing of skin lesion in an excision wound model in rats.

OBJECTIVES: This study aims to evaluate the pharmacological role of indigo extract in accelerating the wound healing in a rat model. METHODS: Female Sprague-Dawley rats were anesthetized with ketamine (30 mg/kg, i.p.) and the full thickness of the marked skin was then cut carefully and wounds were left undressed. Indigo extract (5%) in PBS was applied topically twice daily until healing was complete. A control group of rats was treated with povidone-iodide (Betadine®). Rats treated with phosphate buffer saline were used as a negative control group. The rate of wound healing was assessed daily. Histopathological examination of skin sections were qualitatively assessed by independent evaluators. The inflammatory and apoptotic markers were assessed in skin tissue homogenates using ELISA. RESULTS: Histopathology data showed that applying indigo to skin wounds enhanced the healing process, resulting in a significant decrease in dermal inflammation in comparison to untreated rats. Topical application of indigo significantly increased antioxidant enzyme activities with reduced malondialdehyde (MDA) levels in wound tissues. The levels of matrix metalloproteases-2 and -9 were significantly lower with an accompanied increase in the level of TGF-ß1 in skin tissues from rats treated with indigo compared to the control group treated with PBS. CONCLUSIONS: The antioxidant and anti-inflammatory properties of indigo leaf extract accelerate the healing of skin injuries.

Phacoemulsification with double-in-bag intraocular lens implantation in nanophthalmic eyes with angle-closure glaucoma.

PURPOSE:  To report the outcomes of phacoemulsification with piggyback intraocular lens (IOL) implantation, with double-in-bag IOLs in the management of angle-closure glaucoma (ACG) in nanophthalmic eyes. METHODS: This is a retrospective case series on nanophthalmic eyes with variable presentations of ACG. Phacoemulsification with double-in-bag IOL implantation was done for the included eyes. Baseline and follow-up corrected distance visual acuity (CDVA), spherical equivalent (SE), intraocular pressure (IOP), and the number of glaucoma medications were evaluated. Surgical details were extracted, and complications were recorded. RESULTS: Six eyes of three patients were included. The mean axial length was 17.24 ± 1.02 mm. The mean preoperative IOP was 20 ± 2.7 mmHg with medical treatment. The mean preoperative CDVA (logMar) was 0.83 ± 0.37 with mean SE 12.7 ± 1.77 diopters. The mean postoperative IOP at 3-month and 1-year follow-ups was 14 ± 5.3 mmHg and 15.5 ± 4.1 mmHg, respectively. Postoperative CDVA was 0.78 ± 0.41, with mean SE -0.04 ± 2 diopters. No significant intraoperative or postoperative complications were reported. One eye developed posterior capsule opacification (PCO), and another eye developed visually insignificant inter-lenticular opacification (ILO). CONCLUSIONS: In the evaluated nanophthalmic eyes with ACG, lens extraction with double-in-bag IOL implantation showed promising results regarding the IOP control as well as the visual and refractive outcomes.

SMAD7 enhances adult ß-cell proliferation without significantly affecting ß-cell function in mice.

The interplay between the transforming growth factor ß (TGF-ß) signaling proteins, SMAD family member 2 (SMAD2) and 3 (SMAD3), and the TGF-ß-inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development and also in normal ß-cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice with SMAD7fx/fx mice. We also created a ß cell-specific SMAD7-overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed ß-cell function in adult islets when SMAD7 was either absent or overexpressed in ß cells. Loss of SMAD7 in ß cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression in ß cells. Our results show that both the absence and overexpression of SMAD7 affect TGF-ß signaling and modulates ß-cell proliferation but does not appear to alter ß-cell function. Reversible SMAD7 overexpression may represent an attractive therapeutic option to enhance ß-cell proliferation without negative effects on ß-cell function.

Loss of hepatocyte identity following aberrant YAP activation: A key mechanism in alcoholic hepatitis.

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration. METHOD: The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A. RESULTS: In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication. CONCLUSION: Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH. LAY SUMMARY: Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.

Alpha-to-beta cell trans-differentiation for treatment of diabetes.

Diabetes mellitus is a significant cause of morbidity and mortality in the United States and worldwide. According to the CDC, in 2017, ∼34.2 million of the American population had diabetes. Also, in 2017, diabetes was the seventh leading cause of death and has become the number one biomedical financial burden in the United States. Insulin replacement therapy and medications that increase insulin secretion and improve insulin sensitivity are the main therapies used to treat diabetes. Unfortunately, there is currently no radical cure for the different types of diabetes. Loss of ß cell mass is the end result that leads to both type 1 and type 2 diabetes. In the past decade, there has been an increased effort to develop therapeutic strategies to replace the lost ß cell mass and restore insulin secretion. α cells have recently become an attractive target for replacing the lost ß cell mass, which could eventually be a potential strategy to cure diabetes. This review highlights the advantages of using α cells as a source for generating new ß cells, the various investigative approaches to convert α cells into insulin-producing cells, and the future prospects and problems of this promising diabetes therapeutic strategy.

Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease.

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.

Surgical Interventions for Supratentorial Intracranial Hemorrhage: The Past, Present, and Future.

Spontaneous supratentorial intracranial hemorrhage is extremely disabling and is associated with high mortality. Primary treatment for patients with this disease process is maximal medical management with blood pressure control and correction of clotting disorders due to comorbid conditions or medications. Over the past decade, significant strides have been made in understanding the benefits of surgical intervention in the treatment of intracranial hemorrhage through multiple clinical trials. In this article, we review the evolution of surgical treatments beginning with the STICH trials, discuss new developments with minimally invasive surgical strategies, and provide a brief update regarding ongoing trials and future directions in the treatment of spontaneous supratentorial intracranial hemorrhage.

Imaging spectrum of acute invasive fungal rhino-orbital-cerebral sinusitis in COVID-19 patients: A case series and a review of literature.

BACKGROUND: The incidence of devastating opportunistic coinfections in patients with COVID-19 infection, their imaging features and their morbidity and mortality consequences need to be unraveled. METHODS: This is a case series presenting the radiologic features and clinical presentation of acute invasive fungal rhino-orbital-cerebral sinusitis (AIFS) in eight hospitalized patients with confirmed COVID-19 infection. RESULTS: Our patient cohort presented with symptoms of the invasive fungal disease within 12-35 days from their initial presentation with COVID-19 infection. The cross-sectional imaging features of AIFS associated with COVID-19 infection do not differ from those reported in the literature for AIFS associated with other risk factors, yet our patients had features of aggressive late-stage forms with high morbidity and mortality rate. CONCLUSION: AIFS is a possible encounter in patients with COVID-19 patients and radiologists should be familiar with its imaging features.