3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity.

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer's and Huntington's disease. Alzheimer's disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer's, Huntington's, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here, we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling the proteotoxicity in Alzheimer's and Huntington's disease, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO), delays the age-associated paralysis in both models. This effect on paralysis was independent of the protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event linking HAAO knockdown to delayed paralysis. This work demonstrates the potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.

The effect of common paralytic agents used for fluorescence imaging on redox tone and ATP levels in Caenorhabditis elegans.

One aspect of Caenorhabditis elegans that makes it a highly valuable model organism is the ease of use of in vivo genetic reporters, facilitated by its transparent cuticle and highly tractable genetics. Despite the rapid advancement of these technologies, worms must be paralyzed for most imaging applications, and few investigations have characterized the impacts of common chemical anesthetic methods on the parameters measured, in particular biochemical measurements such as cellular energetics and redox tone. Using two dynamic reporters, QUEEN-2m for relative ATP levels and reduction-oxidation sensitive GFP (roGFP) for redox tone, we assess the impact of commonly used chemical paralytics. We report that no chemical anesthetic is entirely effective at doses required for full paralysis without altering redox tone or ATP levels, and that anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. We also assess the use of cold shock, commonly used in combination with physical restraint methods, and find that cold shock does not alter either ATP levels or redox tone. In addition to informing which paralytics are most appropriate for research in these topics, we highlight the need for tailoring the use of anesthetics to different endpoints and experimental questions. Further, we reinforce the need for developing less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters.

Hemidiaphragmatic paralysis after costoclavicular approach versus other brachial plexus blocks in upper limb surgery: a meta-analysis.

BACKGROUND: The costoclavicular brachial plexus block (CCB) is a recently established technique that uses the infraclavicular approach and is performed just below the clavicle. This meta-analysis aimed to determine whether CCB can reduce the incidence of hemidiaphragmatic paralysis (HDP), which is a major adverse event related to brachial plexus block (BPB), while yielding comparable block performance as other BPB techniques. METHODS: We searched electronic databases to identify relevant studies that compared the incidence of HDP between CCB and other BPB techniques. The primary outcome was the incidence of HDP following CCB and other BPB techniques. The secondary outcomes were pulmonary function test results, other adverse events, and block performance parameters such as onset and performance time. RESULTS: We included six randomized controlled trials that included 414 patients. Compared with the other BPB group, the CCB group had a significantly lower incidence of HDP (relative ratio: 0.21, 95% CI [0.12, 0.36], P < 0.001) and higher peak expiratory flow rate (mean difference: 0.68 L/s, 95% CI [0.13, 1.23], P = 0.015). There were no significant between-group differences with respect to other adverse events and block performance parameters. CONCLUSIONS: Compared with other BPB techniques, CCB involves a lower incidence of HDP with comparable onset and performance time.

A Dose-finding Study of Sugammadex for Reversal of Rocuronium in Cardiac Surgery Patients and Postoperative Monitoring for Recurrent Paralysis.

BACKGROUND: The dose of sugammadex recommended by the manufacturer for reversal of rocuronium is 2 mg/kg when the train-of-four count is 2 or more and 4 mg/kg when it is less than 2 but there is a posttetanic count of at least 1. The purpose of this dose-finding study was to titrate sugammadex to produce a train-of-four ratio 0.9 or greater at the conclusion of cardiac surgery, and to continue monitoring neuromuscular blockade in the intensive care unit to identify recurrent paralysis. The hypothesis was that many patients would require less than the recommended dose of sugammadex, but that some would require more, and that recurrent paralysis would not occur. METHODS: Neuromuscular blockade was monitored using electromyography during cardiac surgery. Administration of rocuronium was at the discretion of the anesthesia care team. During sternal closure, sugammadex was titrated in 50-mg increments every 5 min until a train-of-four ratio 0.9 or greater was obtained. Neuromuscular blockade was monitored with electromyography in the intensive care unit until sedation was discontinued before extubation or for a maximum of 7 h. RESULTS: Ninety-seven patients were evaluated. The dose of sugammadex required to achieve a train-of-four ratio of 0.9 or greater varied from 0.43 to 5.6 mg/kg. There was a statistically significant relationship between the depth of neuromuscular blockade and the sugammadex dose required for reversal, but there was a large variation in dose required at any depth of neuromuscular blockade. Eighty-four of 97 patients (87%) required less than the recommended dose, and 13 (13%) required more. Two patients required additional sugammadex administration for recurrent paralysis. CONCLUSIONS: When sugammadex was titrated to effect, the dose was usually less than the recommended dose, but it was more in some patients. Therefore, quantitative twitch monitoring is essential for ascertaining that adequate reversal has taken place after sugammadex administration. Recurrent paralysis was observed in two patients.

Routine administration of neostigmine after recovery of spontaneous breathing versus neuromuscular monitor-guided administration of neostigmine in pediatric patients: a parallel, randomized, controlled study.

BACKGROUND: Neostigmine used to reverse the muscle relaxants should be guided by neuromuscular monitoring, as the degree of spontaneous pre-reversal recovery is the key to success to reverse the neuromuscular block. But neuromuscular monitoring is not always available for some patients during anesthesia and, in consequence, we need to use other clinical judgment to guide the use of neostigmine to reverse the neuromuscular block. In this trial, we aimed to evaluate the incidence of residual neuromuscular blockade (rNMB) in pediatric patients with routine use of neostigmine after recovery of spontaneous breathing compared with the patients with the use of neostigmine guided by neuromuscular monitoring. METHODS: A parallel, randomized, controlled noninferiority study was conducted. We enrolled aged 3 months to 12 years old patients who underwent inguinal hernia repair under general anesthesia. The enrolled patients were randomly divided into experimental and control groups. After surgery, children in the experimental group were given 0.02 mg/kg neostigmine after recovery of spontaneous breathing. Children in the control group were given 0.02 mg/kg neostigmine when the train-of-four (TOF) ratio was between 0.4 and 0.9. However, no neostigmine was administered if the TOF ratio was higher than 0.9. The primary outcome was the incidence of rNMB after extubation (TOF ratio < 0.9). Secondary outcomes included the incidence of neostigmine-induced muscle paralysis, end of surgery - extubation interval, end of surgery - exit OR interval, the length of stay in the PACU, the incidence of hypoxia in the PACU, the number of children who required assisted ventilation during the PACU stay, and neostigmine-related adverse events. RESULTS: A total of 120 children were included in this study, with 60 in the experimental group and 60 in the control group. There was no significant difference in the incidence of rNMB after extubation between the groups (45/60 vs 44/60, RR 1.02 [95% CI, 0.83 to 1.26], p = 0.84). There was no neostigmine-induced muscle paralysis in either group. Adverse events were similar occurred in both groups. However, time from end of the surgery to leaving the operating room was earlier in the experimental group than in the control group (13.6 ± 5.2 vs 15.7 ± 5.6 min, MD -2.10 min [95% CI, -3.70 to -0.50], p = 0.04). The risk ratio of the incidence of TOF ratio < 0.3 for the experimental group was 31.12 (95%CI, 1.89 to 512.61) compared with the control group (12/60 vs 0/60, p = 0.00) in exploratory analysis. CONCLUSIONS: Recovery of spontaneous breathing could be used as a substitute of neuromuscular monitoring to guide neostigmine use in pediatric patients following minor surgeries. However, care should be taken for the residual neuromuscular block. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-IOR-17012890. Registered on 5 October 2017.

Comparison of ultrasound-guided supraclavicular and costoclavicular brachial plexus blocks in pediatric patients: a randomized clinical trial.

PURPOSE: Costoclavicular brachial plexus block has been described recently as a new technique in adults and pediatric patients. In this study, we aimed to compare the supraclavicular and costoclavicular approaches, which are claimed to be effective and practical in pediatric patients. METHODS: Sixty children were randomized to receive supraclavicular (SC group) or costoclavicular (CC group) brachial plexus blocks prior to surgical incision. Block performance times were recorded as the primary outcome. Procedural features (ideal brachial plexus cord visualization/needle pathway planning time, needle tip/shaft visualization difficulty, number of needle maneuvers, requirement of extra needle maneuvers due to insufficient local anesthetic distribution) and postoperative pain-related data (sensorimotor block intensities, Wong-Baker and FLACC pain scores and analgesic requirements) were also evaluated. To observe the tendency toward respiratory complications, ultrasonographic diaphragm movement amplitude (with M-mode) and diaphragm thickness (with B-mode) were measured postoperatively. RESULTS: A total of 56 patients were included. Block performance times [70(7-97) vs. 115(75-180) s] were significantly lower in the CC group (p < 0.01). The block success rates did not differ (p > 0.05). The incidence of hemidiaphragm paralysis was 44% in the SC group (p < 0.001), and inspiratory diaphragm thickness was significantly lower (p < 0.01). None of CC group patients experienced hemidiaphragm paralysis. All other parameters were comparable (p > 0.05). CONCLUSIONS: Although costoclavicular block did not show superiority in pain management, the block performance was perceived as more practical than supraclavicular block. We believe that costoclavicular brachial plexus block stands as a good option in upper extremity surgeries with the advantages of shorter block performance time and reduced ipsilateral hemidiaphragm paralysis risk in pediatric patients.

Catatonia and Neuroleptic Malignant Syndrome in Patients With Cerebral Palsy: Two Case Reports and a Systematic Review of the Literature.

BACKGROUND: Patients with cerebral palsy, a group of movement disorders with motor, and possibly communication and behavioral features that mimic catatonic signs, may benefit from efforts to improve the detection and treatment of comorbid catatonia. Given that cerebral palsy frequently co-occurs with conditions associated with catatonia, such as autism spectrum disorder, epilepsy, intellectual disability, and mood and psychotic disorders, lifetime prevalence of catatonia in this population may be high. OBJECTIVE: This study aimed to systematically review the literature on catatonia and the related condition of neuroleptic malignant syndrome (NMS) in patients with cerebral palsy while presenting 2 additional cases of catatonia. METHODS: We used the terms "cerebral palsy" in combination with "catatoni∗," related terms for catatonia, and "neuroleptic malignant syndrome" to query Ovid MEDLINE (1948 to November 28, 2022), PsycINFO, Cumulative Index to Nursing, and Allied Health Literature, and Embase for applicable case reports. The Neuroleptic Malignant Syndrome Information Service database was also manually searched. RESULTS: In addition to our 2 catatonia reports, we identified 10 reports of catatonia in patients with cerebral palsy, as well as 8 reports of NMS. Patients with both conditions responded well, and sometimes rapidly, to treatment. Notably, of the 5 patients with catatonia and cerebral palsy who received electroconvulsive therapy, 2 developed recurrent self-limited hyperthermia posttreatment. We also identified several cases of baclofen withdrawal, which can be life threatening because of seizure risk, presenting with NMS-like features in patients with cerebral palsy who had malfunctioning intrathecal baclofen pumps for spasticity management. CONCLUSIONS: Given frequent comorbidity of conditions associated with catatonia in patients with cerebral palsy, as well as routine treatment with medications that can induce NMS, such as metoclopramide and anticholinergics, catatonia and NMS may be underreported in the cerebral palsy patient population, despite being highly treatable. Possible underdiagnosis of catatonia in patients with cerebral palsy may be because of misattribution of overlapping features between the 2 conditions to cerebral palsy. Clinicians should be aware of possible recurrent self-limited fever when using electroconvulsive therapy to treat patients with catatonia and cerebral palsy while also being vigilant for intrathecal baclofen withdrawal when encountering NMS-like features in patients with cerebral palsy.

Peri-operative management of neuromuscular blockade: A guideline from the European Society of Anaesthesiology and Intensive Care.

Recent data indicated a high incidence of inappropriate management of neuromuscular block, with a high rate of residual paralysis and relaxant-associated postoperative complications. These data are alarming in that the available neuromuscular monitoring, as well as myorelaxants and their antagonists basically allow well tolerated management of neuromuscular blockade. In this first European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on peri-operative management of neuromuscular block, we aim to present aggregated and evidence-based recommendations to assist clinicians provide best medical care and ensure patient safety. We identified three main clinical questions: Are myorelaxants necessary to facilitate tracheal intubation in adults? Does the intensity of neuromuscular blockade influence a patient's outcome in abdominal surgery? What are the strategies for the diagnosis and treatment of residual paralysis? On the basis of this, PICO (patient, intervention, comparator, outcome) questions were derived that guided a structured literature search. A stepwise approach was used to reduce the number of trials of the initial research ( n  = 24 000) to the finally relevant clinical studies ( n  = 88). GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was used for formulating the recommendations based on the findings of the included studies in conjunction with their methodological quality. A two-step Delphi process was used to determine the agreement of the panel members with the recommendations: R1 We recommend using a muscle relaxant to facilitate tracheal intubation (1A). R2 We recommend the use of muscle relaxants to reduce pharyngeal and/or laryngeal injury following endotracheal intubation (1C). R3 We recommend the use of a fast-acting muscle relaxant for rapid sequence induction intubation (RSII) such as succinylcholine 1 mg kg -1 or rocuronium 0.9 to 1.2 mg kg -1 (1B). R4 We recommend deepening neuromuscular blockade if surgical conditions need to be improved (1B). R5 There is insufficient evidence to recommend deep neuromuscular blockade in general to reduce postoperative pain or decrease the incidence of peri-operative complications. (2C). R6 We recommend the use of ulnar nerve stimulation and quantitative neuromuscular monitoring at the adductor pollicis muscle to exclude residual paralysis (1B). R7 We recommend using sugammadex to antagonise deep, moderate and shallow neuromuscular blockade induced by aminosteroidal agents (rocuronium, vecuronium) (1A). R8 We recommend advanced spontaneous recovery (i.e. TOF ratio >0.2) before starting neostigmine-based reversal and to continue quantitative monitoring of neuromuscular blockade until a TOF ratio of more than 0.9 has been attained. (1C).

Asymptomatic unilateral phrenic nerve palsy after bortezomib treatment in a newly diagnosed multiple myeloma patient.

INTRODUCTION: Bortezomib is the first chemotherapeutic agent of proteosome inhibitor class that can be used in newly diagnosed and relapsed/refractory multiple myeloma. It is well known that bortezomib has side effects such as peripheral sensory, motor, or autonomic neuropathy. In this paper, we will present our patient who developed unilateral phrenic nerve palsy as an autonomic neuropathy after six cycles of subcutaneous bortezomib treatment. This case differs from other cases in that our patient was asymptomatic. CASE REPORT: A 57-year-old male patient was admitted with back pain and gait disturbances. In the thorax computed tomography, a soft tissue mass causing compression on the spinal canal was observed in the T12 vertebra. Bone biopsy pathology report resulted in diffuse plasma cell infiltration. The patient was diagnosed with stage ISS-3, IgG kappa type multiple myeloma. MANAGEMENT AND OUTCOME: Subcutaneous bortezomib 1 × 2.2 mg (Days 1-4-8-11) + intravenous cyclophosphamide 1000 mg (Day 1) + intravenous dexamethasone 40 mg (Days 1-2-3-4) (VCD chemotherapy protocol) was started. Totally six cycles of VCD were administered. While the patient did not have any respiratory symptoms, an elevation consistent with phrenic nerve palsy was observed in the left hemidiaphragm in the thorax computed tomography that was taken during the preparation for autologous hematopoietic stem cell transplantation. DISCUSSION: Bortezomib is a frequently used chemotherapeutic agent in patients with multiple myeloma and care should be taken in terms of the risk of developing phrenic nerve palsy in patients. There are cases of autonomic neuropathy developing after bortezomib treatment.

Success rates of botulinum toxin in different types of strabismus and dose effect.

OBJECTIVE: To determine the effect of botulinum toxin in different types of strabismus and analyze its dose effect. DESIGN: This was an interventional clinical study performed in a tertiary care university hospital. METHODS: Eighty six patients treated with botulinum toxin for strabismus were included. Main outcome measures involved success of botulinum toxin, alignment change per unit of toxin, and dose effect on complications and outcomes. RESULTS: Success rates were 31% for infantile esotropia, 25% for partially accommodative esotropia, 61.5% for residual esotropia, 25% for third cranial nerve paralysis, 13.3% for sixth cranial nerve paralysis, 75% for Duane retraction syndrome, and 38.5% for nonaccomodative esotropia. Improvement in deviation size after botulinum toxin treatment was significant in patients with infantile esotropia (p = 0.001), residual esotropia (p = 0.001), and nonaccomodative esotropia (p = 0.03). Mean deviation change per 1 unit of toxin was 2.7 ± 2.4 prism diopters (PD) with a single injection and 2.1 ± 1.9 PD with multiple injections. A 3.32 PD of early deviation change with botulinum toxin corrected 1 PD of final deviation. Success rate was not correlated with age (r = 0.040, p = 0.8), sex (r = -0.083, p = 0.6), mean dose (r = -0.149, p = 0.35), or total dose (r = 0.165, p = 0.29) but was significantly correlated with deviation size (ß = -0.077, p = 0.0001). Complications were not associated with the dose of botulinum toxin (p > 0.05). CONCLUSIONS: Botulinum toxin has variable outcomes in different types of strabismus. Still, it reduces the deviation size in most patients, thus allowing for a smaller amount of subsequent muscle surgery. Early overcorrection is a more powerful indicator of better outcome than postinjection duction deficit.

Ascending Flaccid Paralysis Secondary to Hypokalemia in A Cancer Patient using Abiraterone - A Case Report.

BACKGROUND: Prostate cancer (PC) is the most common type of neoplasm in men and the fourth leading cause of mortality in Brazil. The prostate cancer refractory metastatic castration can be treated with abiraterone acetate (AA). CASE PRESENTATION: Its use has been associated with increased survival. However, there are also side effects associated with the use of this drug, such as severe electrolyte disturbances. CONCLUSION: The objective is to report the clinical case of a patient with castration-resistant metastatic prostate cancer who developed ascending flaccid paralysis secondary to severe hypokalemia, probably due to hyperaldosteronism secondary to the use of Abiraterone Acetate, despite the use of Prednisone.

Hypokalemic Paresis in a 26-Year-Old Man After Recreational Cannabis Use.

BACKGROUND Hypokalemia (serum potassium level below 3.5 mmol/L) is present in approximately 11% of patients admitted to emergency departments. Hypokalemia can be a manifestation of many underlying causes and if untreated can be fatal. A careful approach to work-up and management is required in hypokalemic patients. CASE REPORT Here we report a 26-year-old previously healthy male patient who was admitted to the Emergency Department with rapidly progressing paresis of the lower and upper extremities. Initial laboratory results revealed severe hypokalemia of 2.1 mmol/l, which aggravated to 1.6 mmol/l before receiving treatment with intravenous potassium chloride supplementation. In addition, the patient developed rhabdomyolysis secondary to prolonged paralysis and immobilization induced by hypokalemia. Following this treatment, the patient's symptoms eased rapidly, and his potassium concentration was normalized. The patient admitted to smoking cannabis the day before admission. In this case report, we systematically elaborate and exclude the causes of hypokalemia in this otherwise healthy young adult, including medication, gastrointestinal symptoms, licorice consumption, and genetical testing. Cannabis has been associated with hypokalemia, proposedly through activation of the cannabinoid receptor 1 (CB1)-mediated activation of G protein-coupled inwardly rectifying potassium (GIRK) channels. CONCLUSIONS This case report emphasizes that hypokalemia can cause paralysis and cannabis should be included in the diagnostic mindset.

Carnosic acid ameliorated Aß-mediated (amyloid-ß peptide) toxicity, cholinergic dysfunction and mitochondrial defect in Caenorhabditis elegans of Alzheimer's Model.

Amyloid-ß peptide (Aß)-induced cholinergic system and mitochondrial dysfunction are major risk factors for Alzheimer's disease (AD). Our previous studies found that carnosic acid (CA), an important polyphenol antioxidant, could significantly delay Aß1-42-mediated acute paralysis. However, many details and underlying mechanisms of CA's neuroprotection against Aß-induced cholinergic system defects and mitochondrial dysfunction remain unclear. Herein, we deeply investigated the effects and the possible mechanisms of CA-mediated protection against Aß toxicity in vivo through several AD Caenorhabditis elegans strains. The results showed CA delayed age-related paralysis and Aß deposition, and significantly protected neurons from Aß-induced toxicity. CA might downgrade the expression of ace-1 and ace-2 genes, and upregulate cha-1 and unc-17 genes to inhibit acetylcholinesterase activity and relieve Aß-caused cholinergic system defects. Furthermore, CA might also ameliorate Aß-induced mitochondrial imbalance and oxidative stress through up-regulating the expression of phb-1, phb-2, eat-3, and drp-1 genes. The enhancements of the cholinergic system and mitochondrial function might be the reasons for the amelioration of Aß-mediated toxicity and Aß aggregation mediated by CA. These findings have helped us to understand the CA anti-Aß activity in C. elegans and the potential mechanism of action.

Red-Beet Betalain Pigments Inhibit Amyloid-ß Aggregation and Toxicity in Amyloid-ß Expressing Caenorhabditis elegans.

Betalain pigments are mainly produced by plants belonging to the order of Caryophyllales. Betalains exhibit strong antioxidant activity and responds to environmental stimuli and stress in plants. Recent reports of antioxidant, anti-inflammatory and anti-cancer properties of betalain pigments have piqued interest in understanding their biological functions. We investigated the effects of betalain pigments (betanin and isobetanin) derived from red-beet on amyloid-ß (Aß) aggregation, which causes Alzheimer's disease. Non-specific inhibition of Aß aggregation against Aß40 and Aß42 by red-beet betalain pigments, in vitro was demonstrated using the thioflavin t fluorescence assay, circular dichroism spectroscopy analysis, transmission electron microscopy and nuclear magnetic resonance (NMR) analysis. Furthermore, we examined the ability of red-beet betalain pigments to interfere with Aß toxicity by using the transgenic Caenorhabditis elegans model, which expresses the human Aß42 protein intracellularly within the body wall muscle. It responds to Aß-toxicity with paralysis and treatment with 50 µM red-beet betalain pigments significantly delayed the paralysis of C. elegans. These results suggest that betalain pigments reduce Aß-induced toxicity.

Residual paralysis caused by 50 mg rocuronium after reversal with 4 mg/kg sugammadex: a case report.

BACKGROUND: Rocuronium-induced neuromuscular blockade can be quickly and completely reversed by administration of an optimal dose of sugammadex. Sugammadex antagonizes rocuronium-induced neuromuscular blockade by encapsulating rocuronium. Herein, we report a case of residual neuromuscular paralysis in which the recommended dose of sugammadex (4 mg·kg- 1) failed to antagonize a rocuronium-induced blockade. CASE PRESENTATION: A 71-year-old man (body mass index: 26.7 kg·m- 2) underwent endoscopic submucosal dissection of early-stage gastric cancer. He had no known factors that may have affected the effects of rocuronium and sugammadex. He received rocuronium (50 mg; 0.7 mg·kg- 1) for anesthesia induction. No additional rocuronium was administered during the 71-min procedure. Ninety-four minutes after rocuronium administration, neuromuscular monitoring showed 20 twitches in response to post-tetanic count stimulation. The train-of-four (TOF) ratio was not measurable despite sugammadex (280 mg; 4 mg/kg) administration, although four weak twitches in response to TOF stimulation appeared in 3 min. The TOF ratio became detectable following administration of an additional dose of sugammadex (120 mg; 1.7 mg·kg- 1), and it recovered to 107% 8 min after the second dose. The patient opened his eyes; moved his neck, arms, and limbs; and regained consciousness. The trachea was extubated and the patient was transferred to the ward. CONCLUSIONS: Neuromuscular monitoring should be used if a neuromuscular blockage agent is administered, even if the recommended dose of sugammadex is administered.

Effect of policosanol from insect wax on amyloid ß-peptide-induced toxicity in a transgenic Caenorhabditis elegans model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD), an age-related neurodegenerative disorder and a serious public health concern, is mainly caused by ß-amyloid (Aß)-induced toxicity. Currently, a limited number of drugs are effective against AD, and only a few are used for its treatment. According to traditional Chinese medicine, white wax is mainly composed of policosanol, hexacosanol, and octacosanol. Policosanol has been shown to reduce lipid levels in blood and alleviate the symptoms associated with diabetic complications and neurodegenerative disorders, such as Parkinson's disease and AD. However, the efficacy of policosanol depends on the purity and composition of the preparation, and the therapeutic efficacy of policosanol derived from insect wax (PIW) in AD is unknown. METHODS: Here, we identified the main components of PIW and investigated the effects of PIW on Aß-induced toxicity and life-span in a transgenic Caenorhabditis elegans model of AD, CL4176. Furthermore, we estimated the expression of amyloid precursor-like protein (apl-1) and the genes involved in various pathways associated with longevity and alleviation of AD-related symptoms in PIW-fed CL4176. RESULTS: PIW mainly consists of tetracosanol, hexacosanol, octacosanol, and triacontanol; it could decrease the Aß-induced paralysis rate from 86.87 to 66.97% (P < 0.01) and extend the life-span from 6.2 d to 7.8 d (P < 0.001) in CL4176 worms. Furthermore, PIW downregulated apl-1, a gene known to be associated with the levels of Aß deposits in C. elegans. Additionally, our results showed that PIW modulated the expression of genes associated with longevity-related pathways such as heat shock response, anti-oxidative stress, and glutamine cysteine synthetase. CONCLUSION: Our findings suggest that PIW may be a potential therapeutic agent for the prevention and treatment of AD. However, its effects on murine models and patients with AD need to be explored further.

OnabotulinumtoxinA Displays Greater Biological Activity Compared to IncobotulinumtoxinA, Demonstrating Non-Interchangeability in Both In Vitro and In Vivo Assays.

Differences in botulinum neurotoxin manufacturing, formulation, and potency evaluation can impact dose and biological activity, which ultimately affect duration of action. The potency of different labeled vials of incobotulinumtoxinA (Xeomin®; 50 U, 100 U, or 200 U vials; incobotA) versus onabotulinumtoxinA (BOTOX®; 100 U vial; onabotA) were compared on a unit-to-unit basis to assess biological activity using in vitro (light-chain activity high-performance liquid chromatography (LCA-HPLC) and cell-based potency assay (CBPA)) and in vivo (rat compound muscle action potential (cMAP) and mouse digit abduction score (DAS)) assays. Using LCA-HPLC, incobotA units displayed approximately 54% of the protease activity of label-stated equivalent onabotA units. Lower potency, reflected by higher EC50, ID50, and ED50 values (pooled mean ± SEM), was displayed by incobotA compared to onabotA in the CBPA (EC50: incobotA 7.6 ± 0.7 U/mL; onabotA 5.9 ± 0.5 U/mL), cMAP (ID50: incobotA 0.078 ± 0.005 U/rat; onabotA 0.053 ± 0.004 U/rat), and DAS (ED50: incobotA 14.2 ± 0.5 U/kg; onabotA 8.7 ± 0.3 U/kg) assays. Lastly, in the DAS assay, onabotA had a longer duration of action compared to incobotA when dosed at label-stated equivalent units. In summary, onabotA consistently displayed greater biological activity than incobotA in two in vitro and two in vivo assays. Differences in the assay results do not support dose interchangeability between the two products.

A Paralyzing Case of Myalgias.

BACKGROUND Myalgia, which describes muscle pain or soreness, is a common presenting complaint encountered in the Emergency Department, in inpatient settings and in outpatient settings. Its differential diagnosis is broad and includes benign as well as more serious clinical entities. Some of the common causes of myalgias include viral infections, strenuous exercise, and medications. Succinylcholine is a well-known neuromuscular blockade agent that is frequently used for rapid sequence intubation and short surgeries. CASE REPORT We present the case of a 70-year-old male who presented to the Emergency Department with a chief complaint of acute, severe onset diffuse myalgia leading to the inability to mobilize. He was being investigated for recent onset generalized lymphadenopathy and had undergone a diagnostic lymph node biopsy under general anesthesia 2 days prior to his presentation. He was diagnosed with presumed succinylcholine-induced myalgias after other etiologies were deemed less likely with thorough history, physical examination, and laboratory investigations. Succinylcholine binds nicotinic acetylcholine receptors of the neuromuscular junction and produces prolonged depolarization during which activation of the muscle is blocked. Initial depolarization of the neuromuscular junction induces hectic fasciculation of the muscle fibers, which in turn may be responsible for the occurrence of post-operative myalgias (POM). This entity can be severe and debilitating and is self-limited. CONCLUSIONS Succinylcholine remains a commonly used agent in anesthesia and succinylcholine-induced myalgia should remain in the differential diagnosis of acute, non-inflammatory myalgia. Its recognition can help avoid unwarranted, possibly invasive investigations and their associated additional healthcare costs.

Selective muscle botulinum toxin A component paralysis in complex ventral hernia repair.

INTRODUCTION: Repair of complex ventral hernia presents a significant challenge plagued by high morbidity and recurrence. Recent studies have demonstrated significant benefits achievable with preoperative Botulinum Toxin A (BTA) chemical component paralysis to the abdominal wall muscles, facilitating primary closure of complex ventral hernia defects. However, transversus abdominis is known to play an integral role in truncal stability, and its paralysis can result in unwanted physiological changes. This is the first study to report on selective administration of preoperative BTA to internal and external oblique muscles only, thus sparing transversus abdominis from paralysis. METHODS: This is a prospective observational study of 46 patients who underwent either selective two-layer or standard three-layer abdominal wall muscle BTA injection prior to elective laparoscopic ventral hernia repair. Serial abdominal CT imaging was performed to compare defect size and length of the lateral abdominal musculature. RESULTS: 46 patients received preoperative BTA injections (23 in each group). A comparison of gains achieved from chemical component paralysis demonstrated no statistically significant difference between the two groups. Fascial closure was achieved in all cases, with no post-operative sequelae of abdominal hypertension. There are no hernia recurrences to date. CONCLUSION: Preoperative selective muscle chemical component paralysis is an effective technique to counteract the chronic muscle retraction observed in large ventral hernias. Transversus abdominis plays a significant role in truncal and spinal stability, and sparing it from paralysis preserves an important component of abdominal wall physiology and does not detract from the ability to primarily close complex defects.

Venom characterization of the bark scorpion Centruroides edwardsii (Gervais 1843): Composition, biochemical activities and in vivo toxicity for potential prey.

In this study, we characterize the venom of Centruroides edwardsii, one of the most abundant scorpions in urban and rural areas of Costa Rica, in terms of its biochemical constituents and their biological activities. C. edwardsii venom is rich in peptides but also contains some higher molecular weight protein components. No phospholipase A2, hemolytic or fibrinogenolytic activities were found, but the presence of proteolytic and hyaluronidase enzymes was evidenced by zymography. Venom proteomic analysis indicates the presence of a hyaluronidase, several cysteine-rich secretory proteins, metalloproteinases and a peptidylglycine α-hydroxylating monooxygenase like-enzyme. It also includes peptides similar to the K+-channel blocker margatoxin, a dominant toxin in the venom of the related scorpion C. margaritatus. MS and N-terminal sequencing analysis also reveals the presence of Na+-channel-modulating peptides with sequence similarity to orthologs present in other scorpion species of the genera Centruroides and Tityus. We purified the hyaluronidase (which co-eluted with an allergen 5-like CRiSP) and sequenced ~60% of this enzyme. We also sequenced some venom gland transcripts that include other cysteine-containing peptides and a Non-Disulfide Bridged Peptide (NDBP). Our in vivo experiments characterizing the effects on potential predators and prey show that C. edwardsii venom induces paralysis in several species of arthropods and geckos; crickets being the most sensitive and cockroaches and scorpions the most resistant organisms tested. Envenomation signs were also observed in mice, but no lethality was reached by intraperitoneal administration of this venom up to 120 µg/g body weight.