Spinal Nerve Block and Recovery after Spinal Anesthesia in Frail Patients - a Prospective Cohort Study

BackgroundFrailty in surgical patients is associated with significantly higher incidences of perioperative mortality and complications. Although neuraxial anesthesia is preferable alternative to general anesthesia in frail patients, it remains undetermined whether the pharmacodynamic profiles of local anesthetics used in intrathecal spinal nerve blocks are altered in this population.MethodsThis prospective observational cohort study recruited 62 patients scheduled for operations that were able to be performed under spinal anesthesia between April 22 to June 30, 2020 in our hospitals. Levels of dermatome blockage after spinal anesthesia and the recovery of spinal nerve sensory and motor function were recorded.ResultsThe prevalence of frailty in patients receiving spinal anesthesia in this study was 25.8%. Compared with non-frail patients, frail patients were significantly older, had a higher proportion of females, and tolerated less intense metabolic equivalent activities. The pre-surgical incision sensory blockage levels were not different between frail and non-frail patients following intrathecal administration of similar dose of bupivacaine. Time intervals to pain sensation at surgical sites (sensory recovery) and voluntary knee flexion (motor recovery) were also similar between the frail and non-frail groups. But, frail patients were associated with more episodes of hypotension and required more vasopressors during operations.ConclusionOur study illustrates that bupivacaine sensitivity in spinal nerve blocks is not significantly affected by frailty. However, special attention should be paid to correct intraoperative hypotension after spinal anesthesia in frail patients.

A Fast Ubiquitination of UHRF1 Oncogene Is a Unique Feature and a Common Mechanism of Thymoquinone in Cancer Cells

Downregulation of the ubiquitin-like containing PHD and ring finger 1 (UHRF1) oncogene in cancer cells in response to natural anticancer drugs, including thymoquinone (TQ), is a key event that induces apoptosis. TQ can induce UHRF1 autoubiquitination via the E3 ligase activity of its RING domain, most likely through the downregulation of herpes virus-associated ubiquitin-specific protease (HAUSP). In this study, we evaluated whether HAUSP downregulation and fast ubiquitination of UHRF1 are prerequisites for UHRF1 degradation in response to TQ in cancer cells and whether doxorubicin can mimic the effects of TQ on UHRF1 ubiquitination. RNA sequencing was performed to investigate differentially expressed genes in TQ-treated Jurkat cells. The protein expression of UHRF1, HAUSP and Bcl-2 was detected by means of Western blot analysis. The proliferation of human colon cancer (HCT-116) and Jurkat cells was analyzed via the WST-1 assay. RNA sequencing data revealed that TQ significantly decreased HAUSP expression. TQ triggered UHRF1 to undergo rapid ubiquitination as the first step in its degradation and the inhibition of its cell proliferation. TQ-induced UHRF1 ubiquitination is associated with HAUSP downregulation. Like TQ, doxorubicin induced a similar dose- and time-dependent downregulation of UHRF1 in cancer cells, but UHRF1 did not undergo ubiquitination as detected in response to TQ. Furthermore, TQ decreased Bcl-2 expression without triggering its ubiquitination. A fast UHRF1 ubiquitination is an indispensable event for its degradation in response to TQ but not for its responses to doxorubicin. TQ appears to trigger ubiquitination of UHRF1 but not of the Bcl-2 oncogene, thereby identifying UHRF1 as a specific target of TQ for cancer therapy.

The Influence of SSO on the Optimization Result of Nasopharynx Carcinoma Plan

PurposeTo study the influence of Monaco 5.4 treatment planning system (TPS) on the dosimetry of radiotherapy for nasopharynx carcinoma (NPC) under the condition of different segment shape optimization (SSO) times.MethodsFifteen patients with T3-4N0-2M0 stage NPC were enrolled, and each case was designed with SSO of 3, 5, 7 and 10 times respectively. The dose results of the target area and the major organs at risk (OARs) were statistically analyzed by DVH statistics; moreover, the isodose lines of 70Gy, 60Gy and 54Gy were intercepted at the same plane in the transverse, coronal and sagittal views and the segment shapes were compared at the angle of 30°, 120°, 240° and 330° in beam eye view (BEV); In addition, optimization time (OT), delivery time (DT), segments# and monitor unit (MU#) were obtained and analyzed by optimization console; the plans were verified and analyzed by using ArcCheck phantom.ResultsFor target area D2, the results of the SSO7 group and the SSO10 group were similar and both better than those of SSO3 and SSO5 groups, and the D2 results of the SSO3 group were notable higher than those of the other three groups; for the major OARs, the results of the maximum dose of spinal cord, brain stem, and lens and the mean dose and V30 of parotid glands showed the same trend. It showed that SSO7 and SSO10 share similar dose results, too which are notable better than the similar dose results shared by SSO3 and SSO5; in the dose deprogram distribution of 70Gy, 60Gy and 54Gy, partial 70Gy dose spillover occurred in both groups SSO3 and SSO5 and it was more obvious in group SSO3. While there was a no significant dose spillover in group SSO7 and group SSO10; in the sub-field alignment comparison under the same angle, the alignment became more complicated and the sub-fields were smaller as the number of SSO increased; the results of segment#, MU# and plan delivery time between different SSO groups were slightly different, while the plan optimization time changed significantly. The difference between group SSO3 and group SSO10 was more than 500s; the results were compared in ArcCheck, there was no significant difference between the groups.ConclusionsThe user-defined SSO function of Monaco 5.4 TPS effectively balances the relationship between plan design efficiency and plan quality. When SSO is 7, it is better value for efficiency and quality in clinical radiotherapy for NPC.

Linear Energy Transfer Incorporated Spot-Scanning Proton Arc Therapy Optimization: A Feasibility Study

PurposeTo integrate dose-averaged linear energy transfer (LETd) into spot-scanning proton arc therapy (SPArc) optimization and to explore its feasibility and potential clinical benefits.MethodsAn open-source proton planning platform (OpenREGGUI) has been modified to incorporate LETd into optimization for both SPArc and multi-beam intensity-modulated proton therapy (IMPT) treatment planning. SPArc and multi-beam IMPT plans with different beam configurations for a prostate patient were generated to investigate the feasibility of LETd-based optimization using SPArc in terms of spatial LETd distribution and plan delivery efficiency. One liver and one brain case were studied to further evaluate the advantages of SPArc over multi-beam IMPT.ResultsWith similar dose distributions, the efficacy of spatially optimizing LETd distributions improves with increasing number of beams. Compared with multi-beam IMPT plans, SPArc plans show substantial improvement in LETd distributions while maintaining similar delivery efficiency. Specifically, for the liver case, the average LETd in the GTV was increased by 124% for the SPArc plan, and only 9.6% for the 2-beam IMPT plan compared with the 2-beam non-LETd optimized IMPT plan. In case of LET optimization for the brain case, the SPArc plan could effectively increase the average LETd in the CTV and decrease the values in the critical structures while smaller improvement was observed in 3-beam IMPT plans.ConclusionThis work demonstrates the feasibility and significant advantages of using SPArc for LETd-based optimization, which could maximize the LETd distribution wherever is desired inside the target and averts the high LETd away from the adjacent critical organs-at-risk.

The Influence of SSO on the Optimization Result of Nasopharynx Carcinoma Plan

PurposeTo study the influence of Monaco 5.4 treatment planning system (TPS) on the dosimetry of radiotherapy for nasopharynx carcinoma (NPC) under the condition of different segment shape optimization (SSO) times.MethodsFifteen patients with T3-4N0-2M0 stage nasopharyngeal carcinoma were enrolled, and each case was designed with SSO of 3, 5, 7 and 10 times respectively. The dose results of the target area and the major organs at risk (OAR) were statistically analyzed by DVH statistics; moreover, the isodose lines of 70Gy, 60Gy and 54Gy were intercepted at the same plane in the transverse, coronal and sagittal views and the segment shapes were compared at the angle of 30°, 120°, 240° and 330° in beam eye view (BEV); In addition, optimization time (OT), delivery time (DT), segments# and MU# were obtained and analyzed by optimization console; the plans were verified and analyzed by using ArcCheck phantom.ResultsFor target area D2, the results of the SSO7 group and the SSO10 group were similar and both better than those of SSO3 and SSO5 groups, and the D2 results of the SSO3 group were notable higher than those of the other three groups; for the major OARs, the results of the maximum dose of spinal cord, brain stem, and lens and the mean dose and V30 of parotid glands showed the same trend. It showed that SSO7 and SSO10 share similar dose results, too which are notable better than the similar dose results shared by SSO3 and SSO5; in the dose deprogram distribution of 70Gy, 60Gy and 54Gy, partial 70Gy dose spillover occurred in both groups SSO3 and SSO5 and it was more obvious in group SSO3. While there was a no significant dose spillover in group SSO7 and group SSO10; in the sub-field alignment comparison under the same angle, the alignment became more complicated and the sub-fields were smaller as the number of SSO increased; the results of segment#, MU# and plan delivery time between different SSO groups were slightly different, while the plan optimization time changed significantly. The difference between group SSO3 and group SSO10 was more than 500s; the results were compared in ArcCheck, there was no significant difference between the groups.ConclusionsThe user-defined SSO function of Monaco 5.4 TPS effectively balances the relationship between plan design efficiency and plan quality. When SSO is 7, it is better value for efficiency and quality in clinical radiotherapy for nasopharyngeal carcinoma.

Polymeric Micelles for the Enhanced Deposition of Hydrophobic Drugs into Ocular Tissues, without Plasma Exposure

Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular penetration enhancer is showcased, which may be used for the formulation of hydrophobic actives. The activity of this penetration enhancer is demonstrated in a healthy rabbit model. The Molecular Envelope Technology (MET) polymer (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan), a self-assembling, micelle-forming polymer, was used to formulate CsA into sterile filtered nanoparticulate eye drop formulations and the stability of the formulation tested. Healthy rabbits were dosed with a single dose of a MET–CsA (NM133) 0.05% formulation and ocular tissues analyzed. Optically clear NM133 formulations were prepared containing between 0.01–0.1% w/v CsA and 0.375–0.75% w/v MET polymer. NM133 0.01%, NM133 0.02% and NM133 0.05% were stable for 28 days when stored at refrigeration temperature (5–6 °C) and room temperature (16–23 °C), but there was evidence of evaporation of the formulation at 40 °C. There was no change in drug content when NM133 0.05% was stored for 387 days at 4 °C. On topical dosing to rabbits, corneal, conjunctival and scleral AUC0–24 levels were 25,780 ng.h g−1, 12,046 ng.h g−1 and 5879 ng.h g−1, respectively, with NM133 0.05%. Meanwhile, a similar dose of Restasis 0.05% yielded lower values of 4726 ng.h/g, 4813 ng.h/g and 1729 ng.h/g for the drug corneal, conjunctival and scleral levels, respectively. NM133 thus delivered up to five times more CsA to the ocular surface tissues when compared to Restasis. The MET polymer was non-irritant up to a concentration of 4% w/v. The MET polymer is a non-irritant ocular penetration enhancer that may be used to deliver hydrophobic drugs in optically clear topical ocular formulations.

Anti-inflammatory potential of dichloromethane leaf extracts of Eucalyptus globulus (Labill) and Senna didymobotrya (Fresenius) in mice

Background: Inflammation is an immune response characterized by swelling, redness, pain and heat. Inflammation is main- ly managed using conventional medicines that are associated with many side effects. Plant-based remedies are considerably better alternative therapies for they have fewer side effects. Objective: This study aimed at determining the anti-inflammatory potential of dichloromethane (DCM) leaf extracts of Eucalyptus globulus and Senna didymobotrya in mice. Methods: Fresh leaves of these plants were harvested from Embu County, Kenya. Quantitative phytochemical analysis was done using Gas Chromatography-Mass Spectrometry (GC-MS). Anti-inflammatory test comprised nine groups of five animals each: normal, negative, positive controls and 6 experimental groups. Inflammation was induced with Carrageenan. One hour post-treatment, the different groups were intraperitoneally administered with the reference drug, diclofenac, 3% DMSO and six DCM leaf extracts at doses of 25, 50, 100, 150, 200 and 250mg/kgbw. Results: GC-MS results revealed α-phellandrene, camphene, terpinolene, and limonene among others. Anti-inflammatory effects showed that extract doses of 100,150,200 and 250mg/kg bw significantly reduced the inflamed paw. Doses of 200 and 250mg/kgbw in both plants were more potent and compared with diclofenac. E. globulus extract dose of 250mg kg bw reduced inflamed paw in the 1st , 2nd, 3rd and 4th hours, by 2.27,6.52,9.09 and 10.90% respectively while S.didymobotrya at similar dose ranges, inflamed paw reduced by 2.41, 5.43, 8.31 and 9.05% respectively. Conclusion: E. globulus and S. didymobotrya have potent anti-inflammatory activities, attributed to their constituent phyto- chemicals. This study confirms the traditional use of these plants in treating inflammation. Keywords: Eucalyptus globulus; Senna didymobtrya; inflammation; phytochemicals.

Determination of Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Parameters of Doxycycline against Edwardsiella ictaluri in Yellow Catfish (Pelteobagrus fulvidraco)

This study aimed to examine the pharmacokinetics of doxycycline (DC) in yellow catfish (Pelteobagrus fulvidraco) and to calculate related pharmacokinetic–pharmacodynamic (PK/PD) parameters of DC against Edwardsiella ictaluri. The minimum inhibitory concentration of DC against E. ictaluri was determined to be 500 µg/L. As the increase of oral dose from 10 to 40 mg/kg, the area under the concentration vs. time curve from 0 to 96 h (AUC0–96) values were considerably increased in gill, kidney, muscle and skin, and plasma, except in liver. Cmax values exhibited a similar dose-dependent increase trend in plasma and tissues except in liver, but other PK parameters had no apparent dose-dependence. The PK/PD parameter of the ratio of AUC0–96 to minimum inhibitory concentration (AUC0–96h/MIC) was markedly increased in plasma and tissues dose-dependently except in liver, but %T > MIC values were increased only moderately at some dose groups. After receiving the same dose with disparate time intervals from 96 to 12 h, the AUC0–96h/MIC was distinctly increased in plasma and tissues, but the %T > MIC had a decreasing trend. When administering 20 mg/kg with a time interval of 96 h, the AUC0–96h/MIC values were consistently >173.03 h and the %T > MIC values were above 99.47% in plasma and all tissues. These results suggest that administration of DC at 20 mg/kg every 96 h is a preferable regimen in yellow catfish.

Authentic and Ectopically Expressed MRGPRX2 Elicit Similar Mechanisms to Stimulate Degranulation of Mast Cells

The identification of the Mas-related G-protein-coupled receptors (Mrgpr) as targets of diverse stimuli of mast cells (MCs), including neuropeptides and pseudo-allergy causing drugs, has placed these receptors at a prime position in MC research. However, the species-dependent diversity of these receptors raises the need for an adequate model for investigating the human MRGPRX2 receptor. RBL-2H3 cells, stably transfected with MRGPRX2 (RBL-MRGPRX2), are increasingly used for this purpose. Therefore, we investigated whether ectopically expressed MRGPRX2, in rat MCs, recapitulates its authentic signaling. To this purpose, we performed a broad comparative study of the responses of human LAD-2 MCs that express MRGPRX2 endogenously, and RBL-MRGPRX2 cells to compound 48/80, substance P and vancomycin, three proto-type ligands of MRGPRX2. We demonstrate that both models share similar dose–response relationships, kinetics and sensitivities to a wide range of signaling targeting drugs. Therefore, our results indicate that ectopically expressed MRGPRX2 preserves the signaling pathways employed to evoke human MC degranulation, which we show to rely on ERK1/2 MAP kinases, phospholipase C (PLC) and autophagy-related signaling. Importantly, we also show that the underlying mechanisms of MRGPRX2-triggered MC degranulation in either LAD-2 or RBL-MRGPRX2 cells are different from those elicited by its rodent orthologs.