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Introduction Degenerative scoliosis most commonly presents with lower back pain. Literature suggests that adults who have degenerative scoliosis are at greater risk of both hiatal hernia and gastroesophageal reflux disease (GERD). The objective of this study was to evaluate scoliosis as being the risk factor of GERD in adults. Materials and methods This prospective study was conducted at Dow University of Health Sciences over a period of two years (May 2018 to April 2020). The investigation included 210 participants with spinal disorders. The mean age was 71.6±9.6 years. The X-rays of the participants' whole spine were taken in a standing position, in the sagittal and coronal planes. Symptoms of GERD were measured through the quality of life and utility evaluation survey technology (QUEST) score, taking six points as cutoff values. The evaluation was done using radiographs to determine any relationship between spinal disorders and GERD. Negative values were analyzed in a right-sided convex curve while positive values in the left-sided convex curve were viewed in the coronal plane. Degenerative scoliosis was explained as a lumbar/thoracolumbar Cobb angle of more than 10 degrees. Univariate and multivariate logistic regression analyses were done to assess the risk factors related to GERD. Results Out of 210 patients, 146 were found to have degenerative scoliosis at the level of the lumbar and thoracolumbar spine. Fifty-two patients had a right convex curve, and 94 had a left convex curve. Sixty-nine patients had GERD. According to the analysis of the multivariate logistic regression, the Cobb angle was highly related to GERD (p-value <0.05 and odds ratio of 1.031). The participants were grouped according to the Cobb angle of curve at the lumbar spine (less than 30 degrees with a large right-sided convex curve, 30 and more with a small curve, and more than 30+ degrees with a large left-sided convex curve). The study revealed that a large left-sided convex curve was highly related to GERD, with a p-value <0.05 and odds ratio of 10.935. Conclusions The left-sided large convex curve at the thoracolumbar or lumbar spine, especially when the Cobb angle was more than 30 degrees, was highly associated with GERD. Therefore, the symptoms of GERD should be monitored in the elderly population with degenerative scoliosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Eryilmaz et al.)

Introduction This brief study shows the consumption of two medications that are related to those patients who have gone through the complicated procedure of craniotomy. The basic aim of these drugs is to subside the after-effects of the procedure like postoperative nausea and vomiting in patients. Hereby, the study outlines the functional efficiency of dexamethasone along with the metoclopramide and dexamethasone alone. Materials and methods  Randomly two groups were listed of 120 patients that have undergone elective craniotomy with ASA I-II. These groups were called out as group A and group B. Group A was under the medication of combination of dexamethasone and metoclopramide 8 mg and 10 mg, respectively, induced separately while group B was induced with 8 mg of dexamethasone along with 2 ml of normal saline. These drugs were induced right before anesthesia. The procedure from here on gets the same for both groups. After the surgical approach, a verbal evaluation was taken from the members of each group to collect specific data accordingly within the first 24 hours. As the method is double-blinded thus the patients were unaware of the ongoing research study. In any case of a mishap, rescue antiemetic drugs were also considered for the patients who would have experienced uncontrolled nausea and vomiting in the timeframe. Results  The results show that only 16.7% of the patients from group A showed signs of nausea and only 5% showed vomiting while 31.7% of the patients from group B showed signs of nausea and 11.7% showed vomiting. It clearly showed that the patients tend to have either no sign of nausea and vomiting or showed little controllable nausea and vomiting when induced with dexamethasone and metoclopramide compared to those who were induced with the dexamethasone alone. Conclusions Postoperative nausea and vomiting are studied in terms of those who had undergone craniotomy. This study shows the prophylaxis of adverse effects of postoperative nausea and vomiting between the two groups under the influence of altered drugs. Thus, the results were noticeably in the favor of the combination treatment of dexamethasone and metoclopramide., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Eryilmaz et al.)

Introduction Cervical myelopathy (CM) is caused by degenerative or congenital changes in the discs and soft tissues of the cervical spine, leading to chronic compression of the spinal cord. The current treatment for moderate-to-severe CM is surgical decompression, which is effective in most cases; however, it can cause inflammation of the nervous system and spinal cord reperfusion injury, resulting in perioperative neurological complications and suboptimal neurological recovery. The aim of this study was to investigate the therapeutic effects of the combination of erythropoietin and methylprednisolone in the treatment of ischemia-reperfusion injury to the spinal cord and to analyze its effects on the levels of interleukin-1 beta (IL-1β), interleukin-1 receptor antagonist (IL-1RA), and interleukin-8 (IL-8). Materials and methods This study included 110 patients admitted to the hospital due to cervical spondylotic myelopathy. They were randomized into two groups of 55 patients each: a control and an observation group. In both groups of patients, fusion internal fixation and anterior cervical discectomy were performed. The difference, however, was that the control group received a rapid intravenous injection of 30 mg/kg methylprednisolone 30 minutes prior to spinal cord decompression, while the observation group received an intravenous injection of 30 mg/kg methylprednisolone and 3,000 U/kg erythropoietin 30 minutes before spinal cord decompression. The study was approved by the Hospital Ethical Committee of the Dow University of Health Sciences, Karachi. The neurological function of both groups of patients was assessed before the procedure and three months after the treatment using the Japanese Orthopedic Association (JOA) method of assessing spinal cord function (40-point rating method). Enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of neuron-specific enolase (NSE), S-100β, IL-1RA, IL-1β, and IL-8 in both groups. The quality of life of patients in both groups was assessed three months after the treatment with the World Health Organization Quality of Life assessment instrument (WHOQOL-100). Results Before the treatment, there was no significant variance between the two groups in the JOA score and the 40-point rating method. Similarly, there was no significant difference in the levels of IL-1β, IL-1RA, and IL-8 between the two groups (p-value = 0.262, 0.387, and 0.154 respectively) prior to the treatment. Three months after the treatment, the levels of IL-1β and IL-8 in the observation group were 21.83 ±3.65 ng/l and 357.07 ±32.36 ng/l respectively, both lower than the control group value (p-value = 0.026, 0.028 respectively). The level of IL-1RA in follow-up was 21.59 ±1.15 ng/l, which was higher than that in the control group. Three months after the treatment, all the WHOQOL-100 parameters of the observation group for psychology, physiology, social relations, independence, spirituality, environment, and general quality of life were higher than those of the control group; the variance among the groups was statistically significant (p-value: <0.001). Conclusions The combination therapy with erythropoietin and methylprednisolone is effective for ischemia-reperfusion injuries of the spinal cord. It also reduces S-100β and NSE, inhibits IL-1β, and increases IL-8 and IL-1RA. Therefore, it preserves and improves spinal nerve function and the quality of life of patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Eryilmaz et al.)

Heterotrimeric G protein subunits Gαq and Gα11 are inhibited by two cyclic depsipeptides, FR900359 (FR) and YM-254890 (YM), both of which are being used widely to implicate Gq/11 proteins in the regulation of diverse biological processes. An emerging major research question therefore is whether the cellular effects of both inhibitors are on-target, that is, mediated via specific inhibition of Gq/11 proteins, or off-target, that is, the result of nonspecific interactions with other proteins. Here we introduce a versatile experimental strategy to discriminate between these possibilities. We developed a Gαq variant with preserved catalytic activity, but refractory to FR/YM inhibition. A minimum of two amino acid changes were required and sufficient to achieve complete inhibitor resistance. We characterized the novel mutant in HEK293 cells depleted by CRISPR-Cas9 of endogenous Gαq and Gα11 to ensure precise control over the Gα-dependent cellular signaling route. Using a battery of cellular outcomes with known and concealed Gq contribution, we found that FR/YM specifically inhibited cellular signals after Gαq introduction via transient transfection. Conversely, both inhibitors were inert across all assays in cells expressing the drug-resistant variant. These findings eliminate the possibility that inhibition of non-Gq proteins contributes to the cellular effects of the two depsipeptides. We conclude that combined application of FR or YM along with the drug-resistant Gαq variant is a powerful in vitro strategy to discern on-target Gq against off-target non-Gq action. Consequently, it should be of high value for uncovering Gq input to complex biological processes with high accuracy and the requisite specificity., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Transmembrane signals initiated by a range of extracellular stimuli converge on members of the Gq family of heterotrimeric G proteins, which relay these signals in target cells. Gq family G proteins comprise Gq, G11, G14, and G16, which upon activation mediate their cellular effects via inositol lipid-dependent and -independent signaling to control fundamental processes in mammalian physiology. To date, highly specific inhibition of Gq/11/14 signaling can be achieved only with FR900359 (FR) and YM-254890 (YM), two naturally occurring cyclic depsipeptides. To further development of FR or YM mimics for other Gα subunits, we here set out to rationally design Gα16 proteins with artificial FR/YM sensitivity by introducing an engineered depsipeptide-binding site. Thereby we permit control of G16 function through ligands that are inactive on the WT protein. Using CRISPR/Cas9-generated Gαq/Gα11-null cells and loss- and gain-of-function mutagenesis along with label-free whole-cell biosensing, we determined the molecular coordinates for FR/YM inhibition of Gq and transplanted these to FR/YM-insensitive G16. Intriguingly, despite having close structural similarity, FR and YM yielded biologically distinct activities: it was more difficult to perturb Gq inhibition by FR and easier to install FR inhibition onto G16 than perturb or install inhibition with YM. A unique hydrophobic network utilized by FR accounted for these unexpected discrepancies. Our results suggest that non-Gq/11/14 proteins should be amenable to inhibition by FR scaffold-based inhibitors, provided that these inhibitors mimic the interaction of FR with Gα proteins harboring engineered FR-binding sites., (© 2019 Malfacini et al.)

Somatic gain-of-function mutations of GNAQ and GNA11 , which encode α subunits of heterotrimeric Gα q/11 proteins, occur in about 85% of cases of uveal melanoma (UM), the most common cancer of the adult eye. Molecular therapies to directly target these oncoproteins are lacking, and current treatment options rely on radiation, surgery, or inhibition of effector molecules downstream of these G proteins. A hallmark feature of oncogenic Gα q/11 proteins is their reduced intrinsic rate of hydrolysis of guanosine triphosphate (GTP), which results in their accumulation in the GTP-bound, active state. Here, we report that the cyclic depsipeptide FR900359 (FR) directly interacted with GTPase-deficient Gα q/11 proteins and preferentially inhibited mitogenic ERK signaling rather than canonical phospholipase Cβ (PLCβ) signaling driven by these oncogenes. Thereby, FR suppressed the proliferation of melanoma cells in culture and inhibited the growth of Gα q -driven UM mouse xenografts in vivo. In contrast, FR did not affect tumor growth when xenografts carried mutated B-Raf V600E as the oncogenic driver. Because FR enabled suppression of malignant traits in cancer cells that are driven by activating mutations at codon 209 in Gα q/11 proteins, we envision that similar approaches could be taken to blunt the signaling of non-Gα q/11 G proteins., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)