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Liver transplantation (LT) is the final step in a complex care cascade. Little is known about how race, gender, rural versus urban residence, or neighborhood socioeconomic indicators impact a patient's likelihood of LT waitlisting or risk of death during LT evaluation. We performed a retrospective cohort study of adults referred for LT to the Indiana University Academic Medical Center from 2011 to 2018. Neighborhood socioeconomic status indicators were obtained by linking patients' addresses to their census tract defined in the 2017 American Community Survey. Descriptive statistics were used to describe completion of steps in the LT evaluation cascade. Multivariable analyses were performed to assess the factors associated with waitlisting and death during LT evaluation. There were 3454 patients referred for LT during the study period; 25.3% of those referred were waitlisted for LT. There was no difference seen in the proportion of patients from vulnerable populations who progressed to the steps of financial approval or evaluation start. There were differences in waitlisting by insurance type (22.6% of Medicaid vs. 34.3% of those who were privately insured; p 0.01) and neighborhood poverty (quartile 1 29.6% vs. quartile 4 20.4%; p 0.01). On multivariable analysis, neighborhood poverty was independently associated with waitlisting (odds ratio 0.56, 95% confidence interval [CI] 0.38-0.82) and death during LT evaluation (hazard ratio 1.49, 95% CI 1.09-2.09). Patients from high-poverty neighborhoods are at risk of failing to be waitlisted and death during LT evaluation.

Very recently, we have developed a new generation of ligands targeting the cannabinoid receptor type 2 (CB2R), namely JR compounds, which combine the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both synthesized in our laboratories. The functional examination enabled us to identify JR14a, JR22a, and JR64a as the most promising compounds of the series. In the current study, we focused on the assessment of the bitopic (dualsteric) nature of these three compounds. Experiments in cAMP assays highlighted that only JR22a behaves as a CB2R bitopic (dualsteric) ligand. In parallel, computational studies helped us to clarify the binding mode of these three compounds at CB2R, confirming the bitopic (dualsteric) nature of JR22a. Finally, the potential of JR22a to prevent neuroinflammation was investigated on a human microglial cell inflammatory model.

Using laryngeal mask airways (LMAs) in laparoscopic surgery is still controversial because of the risk of insufficient ventilation and gastric overinflation. We investigated the use of BASKA LMA as an alternative to endotracheal intubation in low-risk females undergoing short-term gynecologic laparoscopic surgeries in Trendelenburg position under general anesthesia and positive pressure ventilation.Sixty-five females (19-43 years), ASA (I-II) were scheduled to receive endotracheal tube (ETT group, N.=32) or BASKA mask (BASKA group, N.=33) for airway management. Assessments included insertion time and score, intraoperative lung mechanics, oropharyngeal leak pressure (OLP), ventilatory score, leak fraction, perioperative lung spirometry, and adverse effects. Timepoints were after device insertion, pneumoperitoneum inflation, Trendelenburg position, at 15, 30, 45 minutes intraoperatively and at end of surgery.The median insertion time was shorter in BASKA group (21.0 [18-38] s), compared with ETT group (27.0 [24-33] s, P=0.000). First-time success rate for insertion of BASKA mask was 87.9% (29 patients). The peak inflation pressure, calculated dynamic compliance, ventilatory score and lung spirometry data showed no significant difference between the two groups. The median leak fraction was higher in BASKA group after insertion (P=0.012) and after Trendelenburg position (P=0.032), with no significant differences afterwards. The median OLP after insertion was 32.0 (29-35) cmH2O which decreased after pneumoperitoneum inflation (31.0 [27-33] cmH2O, P=0.000), and after Trendelenburg position (30.0 [27-32] cmH2O, P=0.000) and remained stable at this range.BASKA mask can be considered as a safe alternative to ETT with comparable ventilatory performance in low-risk females undergoing short-term gynecologic laparoscopic surgeries.

Background Colorectal Cancer is found one of the most profound type of cancer around globe, affecting men and women with different ethnic and racial groups. Insulin-like growth factor 1 is known as peptide growth factor found to increase the proliferation of cell and prevent apoptosis. Insulin pathway might have linked with progression of colorectal cancer. Methods This study conducted on total 160 subjects, including 80 patients with colorectal cancer with 80 age and gender match controls. Clinical parameters were compared between the control group and Colorectal cancer group. Blood serum IGF-1 was quantified by using ELISA and IGF-1 rs6214(C/T) variations were investigated using TaqMan allelic discrimination assay. Results Blood serum level of Insulin growth factor-I (ng/ml) showed substantial association concerning groups while IGF-1 rs6214(C/T) genotype distribution observed increased in colorectal cancer patients as compared to controls with significant association. The variant TT and CT genotype frequency observed more common in cases as compared to control. However, the wild type CC genotype were common in cases used to compared with controls. The Odds Ratio reveal the risk of variant IGF-1 rs6214 T allele to increase 3 times compared to wild type allele. Conclusion The homozygous TT genotypes and T variant allele of IGF-1 rs6214(C/T) showed association with high serum Insulin growth factor level 1, may increase susceptibility to the colorectal cancer. This work will use to investigate the associations between Insulin-like growth factor 1 and rs6214(C/T) gene variant and blood serum level with the vulnerability to treat Colorectal. In summary, we have investigated the relationship between Insulin growth factor level hormone and colorectal cancer. Further studies are required to understand the association between colorectal cancer and polymorphism. However, this study can be serve as an informative study to uncover mechanisms behind main cause of colon cancer. Therefore, the genomic profiling of Insulin-like growth factor-1 can be helpful to treat colorectal cancer patients.

The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric compound, our bitopic ligands selectively target CB2R versus CB1R and show a functional selectivity for the cAMP signaling pathway versus βarrestin2 recruitment. Moreover, the most promising bitopic ligand

Background: Skin tags (STs) are benign connective tissue neoplasms, in which insulin-like growth factor -1 (IGF-1) has a mitogenic and antiapoptotic activity. Purpose: We aimed to study for the first time, the possible role of IGF-1 (CA) 19 and rs6214 gene polymorphisms, and its tissue immunoreactivity in the pathogenesis of STs. Patients and methods: This case-control study included 40 ST patients and 20 controls. We searched for (CA) 19 single-nucleotide polymorphism (SNP) using conversional PCR and for rs6214 gene polymorphism using real-time PCR. IGF-1 tissue immunoreactivity was investigated using polyclonal IGF-1 antibody. Results: IGF-1 immunoreactivity showed significantly strong upregulation in epidermis (p=0.002) and dermal components (endothelial cells [p=0.038] and fibroblasts [p=0.004]) of excised STs than control skin. TT and CT rs6214 genotypes and its T allele were significantly associated with STs (p=0.006 and P=0.002, respectively). Also (

We previously reported the 2-oxopyridine-3-carboxamide derivative EC21a as the first small synthetic CB2R positive allosteric modulator which displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Herein, we extended the structure-activity relationships of EC21a through structural modifications regarding the p-fluoro benzyl moiety at position 1 and the amide group in position 3 of the central core. The characterization in vitro was assessed through radioligand binding experiments and functional assays (GTPγS, cAMP, βarrestin2). Among the new compounds, the derivatives A1 (SV-10a) and A5 (SB-13a) characterized respectively by fluorine atom or by chlorine atom in ortho position of the benzylic group at position 1 and by a cycloheptane-carboxamide at position 3 of the central core, showed positive allosteric behavior on CB2R. They enhanced the efficacy of CP55,940 in [35S]GTPγS assay, and modulated CP55,940-dependent βarrestin2 recruitment and cAMP inhibition. The obtained results extend our knowledge of the structural requirements for interaction with the allosteric site of CB2R.

The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the ‘high’ associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.

Cannabinoids are compounds that are structurally and/or functionally related to the primary psychoactive constituent of Cannabis sativa, [INCREMENT]-tetrahydrocannabinol (THC). Cannabinoids can be divided into three broad categories: endogenous cannabinoids, plant-derived cannabinoids, and synthetic cannabinoids (SCs). Recently, there has been an unprecedented surge of interest into the pharmacological and medicinal properties of cannabinoids for the treatment of epilepsies. This surge has been stimulated by an ongoing shift in societal opinions about cannabinoid-based medicines and evidence that cannabidiol, a nonintoxicating plant cannabinoid, has demonstrable anticonvulsant activity in children with treatment-refractory epilepsy. The major receptors of the endogenous cannabinoid system (ECS)-the type 1 and 2 cannabinoid receptors (CB1R, CB2R)-have critical roles in the modulation of neurotransmitter release and inflammation, respectively; so, it is not surprising therefore that the ECS is being considered as a target for the treatment of epilepsy. SCs were developed as potential new drug candidates and tool compounds for studying the ECS. Beyond the plant cannabinoids, an extensive research effort is underway to determine whether SCs that directly target CB1R, CB2R, or the enzymes that breakdown endogenous cannabinoids have anticonvulsant effects in preclinical rodent models of epilepsy and seizure. This research demonstrates that many SCs do reduce seizure severity in rodent models and may have both positive and negative pharmacodynamic and pharmacokinetic interactions with clinically used antiepilepsy drugs. Here, we provide a comprehensive review of the preclinical evidence for and against SC modulation of seizure and discuss the important questions that need to be addressed in future studies.

Background. Direct-acting antivirals (DAAs) made a drastic change in the management of HCV infection. Sofosbuvir is one of the highly potent DAAs, eliminated mainly through the kidney. But concerns about renal safety during treatment may limit its use. Neutrophil gelatinase-associated lipocalin (NGAL) has been proven as a predictor of renal tubular injury. Hence, the aim of this work was to assess serum neutrophil gelatinase-associated lipocalin (NGAL) in HCV-positive patients before and after treatment with the sofosbuvir-based antiviral regimen. Methods. This prospective study included 87 Egyptian patients with chronic HCV infection treated with sofosbuvir plus daclatasvir with or without ribavirin for 12 weeks. Serum NGAL was measured before and at the end of treatment (EOT). Analysis of NGAL and estimated glomerular filtration rate (eGFR) evolution was done. Results. Our results showed a statistically significant decrease in serum NGAL (P=0.02) with a nonsignificant reduction in eGFR (P=0.06). Moreover, changes in serum NGAL levels (baseline compared to EOT) in patients ranked by KDIGO-CKD classification showed a significant decrease in stages 1 and 2 (P=0.14 and 0.034, respectively) and a nonsignificant decrease in stage 3 (P=0.25). Also, eGFR changes after treatment in patients ranked by the same classifications showed a nonsignificant reduction in all stages (P>0.05). Conclusions. Sofosbuvir appears to have no nephrotoxic effects and is safe to treat patients with chronic HCV infection.

Azza Gaber Antar Farag,1 Azza Mohamed Kamel Abdu Allah,2 Hala Said El-Rebey,3 Kawthar Ibraheem Mohamed Ibraheem,4,5 Asmaa Shams El Dein Mohamed,3 Azza Zaghlol Labeeb,6 Ayman Elhussien Elgazzar,1 Magda Mostafa Haggag11Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufia University, ShibÄ«n al Kawm, Egypt; 2Department of Biochemistry and Molecular biology, Faculty of Medicine, Menoufia University, ShibÄ«n al Kawm, Egypt; 3Department of Pathology, Faculty of Medicine, Menoufia University, ShibÄ«n al Kawm, Egypt; 4Department of Medical Microbiology and Immunology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 5Microbiology Department, Taibah University, Medina, Kingdom of Saudi Arabia; 6Department of Microbiology, Faculty of Medicine, Menoufia University, ShibÄ«n al Kawm, EgyptBackground: Skin tags (STs) are benign connective tissue neoplasms, in which insulin-like growth factor −1 (IGF-1) has a mitogenic and antiapoptotic activity.Purpose: We aimed to study for the first time, the possible role of IGF-1 (CA) 19 and rs6214 gene polymorphisms, and its tissue immunoreactivity in the pathogenesis of STs.Patients and methods: This case–control study included 40 ST patients and 20 controls. We searched for (CA) 19 single-nucleotide polymorphism (SNP) using conversional PCR and for rs6214 gene polymorphism using real-time PCR. IGF-1 tissue immunoreactivity was investigated using polyclonal IGF-1 antibody.Results: IGF-1 immunoreactivity showed significantly strong upregulation in epidermis (p=0.002) and dermal components (endothelial cells [p=0.038] and fibroblasts [p=0.004]) of excised STs than control skin. TT and CT rs6214 genotypes and its T allele were significantly associated with STs (p=0.006 and P=0.002, respectively). Also (p=0.013). These 4 genotypes were significantly associated with development of multiple STs and epidermal IGF-1 tissue immunoreactivity in studied patients.Conclusions: IGF-1 (CA) 19 and rs6214 gene polymorphisms may contribute to a predisposition of STs in Egyptian patients, the role of which could be mediated through local upregulation of IGF-1 in cutaneous tissues.Keywords: skin tags, insulin growth factor-1, gene polymorphism, immunohistochemistry

Background: Skin tags (STs) are benign connective tissue neoplasms, in which insulin-like growth factor −1 (IGF-1) has a mitogenic and antiapoptotic activity. Purpose: We aimed to study for the first time, the possible role of IGF-1 (CA) 19 and rs6214 gene polymorphisms, and its tissue immunoreactivity in the pathogenesis of STs. Patients and methods: This case–control study included 40 ST patients and 20 controls. We searched for (CA) 19 single-nucleotide polymorphism (SNP) using conversional PCR and for rs6214 gene polymorphism using real-time PCR. IGF-1 tissue immunoreactivity was investigated using polyclonal IGF-1 antibody. Results: IGF-1 immunoreactivity showed significantly strong upregulation in epidermis (p=0.002) and dermal components (endothelial cells [p=0.038] and fibroblasts [p=0.004]) of excised STs than control skin. TT and CT rs6214 genotypes and its T allele were significantly associated with STs (p=0.006 and P=0.002, respectively). Also (

Background The axillary brachial plexus block is a popular nerve block for forearm, wrist, and hand surgery. The use of local anesthetic peripheral nerve blocks for surgical anesthesia and postoperative pain management has increased significantly with the advent of ultrasound-guided techniques. The discovery of peripheral opioid receptors led to the clinical application of adding opioids to local anesthetics for peripheral nerve blocks. This study is done to evaluate effect of morphine on onset, duration, and quality of analgesia when added to local anesthetics in axillary brachial plexus block and to detect any complications that occurred with this technique. Patients and methods In this prospective controlled clinical trial, 60 adult patients aged 18–60 years scheduled for orthopedic surgery of the forearm and hand with axillary brachial plexus block were selected and randomly allocated to two groups. Placebo group received 24 ml bupivacaine 0.5%, and morphine group received 24 ml bupivacaine 0.5%+5 mg morphine. The onset and duration of sensory and motor blocks, duration of analgesia, and adverse events (such as nausea and pruritus) during perioperative period were recorded. Results Onset of touch and pain block was faster in morphine group, with P values of 0.016 and 0.025, respectively. Onset of motor block was similar in the two groups. Duration of touch block was longer in morphine group, with P value of 0.022. Duration of motor block showed no change between the two groups. Duration of analgesia was longer in the morphine group, with P value of 0.001, with lower consumption of analgesia. No complications were recorded perioperatively. Conclusion We concluded that morphine provide better postoperative analgesia when injected with local anesthetics in ultrasound-guided axillary brachial plexus block without an increase in the frequency of complications.