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.

An agonist of CXCR4 induces a rapid recovery from the neurotoxic effects of Vipera ammodytes and Vipera aspis venoms.

People bitten by Alpine vipers are usually treated with antivenom antisera to prevent the noxious consequences caused by the injected venom. However, this treatment suffers from a number of drawbacks and additional therapies are necessary. The venoms of Vipera ammodytes and of Vipera aspis are neurotoxic and cause muscle paralysis by inducing neurodegeneration of motor axon terminals because they contain a presynaptic acting sPLA2 neurotoxin. We have recently found that any type of damage to motor axons is followed by the expression and activation of the intercellular signaling axis consisting of the CXCR4 receptor present on the membrane of the axon stump and of its ligand, the chemokine CXCL12 released by activated terminal Schwann cells. We show here that also V. ammodytes and V. aspis venoms cause the expression of the CXCL12-CXCR4 axis. We also show that a small molecule agonist of CXCR4, dubbed NUCC-390, induces a rapid regeneration of the motor axon terminal with functional recovery of the neuromuscular junction. These findings qualify NUCC-390 as a promising novel therapeutics capable of improving the recovery from the paralysis caused by the snakebite of the two neurotoxic Alpine vipers.

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.

Peri-Intubation Hypoxia After Delayed Versus Rapid Sequence Intubation in Critically Injured Patients on Arrival to Trauma Triage: A Randomized Controlled Trial.

BACKGROUND: Critically injured patients who are agitated and delirious on arrival do not allow optimal preoxygenation in the emergency area. We investigated whether the administration of intravenous (IV) ketamine 3 minutes before administration of a muscle relaxant is associated with better oxygen saturation levels while intubating these patients. METHODS: Two hundred critically injured patients who required definitive airway management on arrival were recruited. The subjects were randomized as delayed sequence intubation (group DSI) or rapid sequence intubation (group RSI). In group DSI, patients received a dissociative dose of ketamine followed by 3 minutes of preoxygenation and paralysis using IV succinylcholine for intubation. In group RSI, a 3-minute preoxygenation was performed before induction and paralysis using the same drugs, as described conventionally. The primary outcome was incidence of peri-intubation hypoxia. Secondary outcomes were first-attempt success rate, use of adjuncts, airway injuries, and hemodynamic parameters. RESULTS: Peri-intubation hypoxia was significantly lower in group DSI (8 [8%]) compared to group RSI (35 [35%]; P = .001). First-attempt success rate was higher in group DSI (83% vs 69%; P = .02). A significant improvement in mean oxygen saturation levels from baseline values was seen in group DSI only. There was no incidence of hemodynamic instability. There was no statistically significant difference in airway-related adverse events. CONCLUSIONS: DSI appears promising in critically injured trauma patients who do not allow adequate preoxygenation due to agitation and delirium and require definitive airway on arrival.

Adverse effects following botulinum toxin A injections in children with cerebral palsy.

The study aimed to analyze the adverse events associated with botulinum toxin A (BoNT-A) injections in children with cerebral palsy (CP). The literature search was completed using the Medline, PubMed, Google Scholar, Scopus, and Cochrane Library databases from the earliest date possible up to December 2021. Search terms included 'botulinum toxin', 'cerebral palsy', 'spasticity', 'adverse effects', 'side effects', 'undesirable effects', 'complications', 'lower limb', 'upper limb', and 'children' including combinations of index and free-text terms. Fifty-five studies were included in the study. Data on 6333 pediatric patients and more than 14 080 BoNT-A injections were collected. Respiratory symptoms and respiratory tract infections were the most frequently registered adverse events (AEs). Other common AEs included procedural/focal AEs, flu-like symptoms, and asthenia. Sentinel events including four cases of death were reported. AEs were more frequent and severe in high-dose patients; however, the capacity of BoNT-A to spread systemically remains unclear. Since severe adverse events are not common, further research is needed to collect more definitive clinical and homogeneous data to support the findings of the present research and clarify the safety profile of BoNT-A, especially regarding the incidence of respiratory issues and complications in GMFCS IV or V patients.

Neuro-ophthalmologic symptoms after coronavirus disease 2019 vaccination: a retrospective study.

BACKGROUND: There have been several studies on inflammatory ophthalmic diseases; however, few studies have reported neuro-ophthalmological symptoms, such as diplopia and ocular motor nerve palsy, after coronavirus disease 2019 (COVID-19) vaccination. Therefore, this study aimed to report neuro-ophthalmological symptoms in patients after COVID-19 vaccination. METHODS: This was a retrospective study based on the medical records of 10 patients who visited our ophthalmology clinic in 2021 with symptoms, such as diplopia (nine patients) and decreased visual acuity (one patient), and showed findings, such as ocular motor nerve palsy, after vaccination against COVID-19. RESULTS: One patient had third nerve palsy, two had sixth nerve palsy, and five had fourth nerve palsy. One patient complained of subjective binocular diplopia but all test results were normal. One patient presented with decreased visual acuity accompanied by a sudden increase in intraocular pressure and orbital cellulitis in the other eye. The symptoms improved gradually in most patients. Compared with previous studies, this study reported three cases of antiplatelet therapy that was initiated due to the older age of the patients and underlying diseases. CONCLUSION: As COVID-19 vaccines can cause neuro-ophthalmological diseases, such as ocular motor nerve palsy, patients' age and underlying diseases should be considered while administering them.

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.

Diethylcarbamazine mediated potentiation of emodepside induced paralysis requires TRP-2 in adult Brugia malayi.

Human and veterinary filarial nematode infections are a major health concern in tropical countries. They are transmitted by biting insects and mosquitoes. Lymphatic filariasis, a group of filarial infections caused by Brugia spp. and Wucheria bancrofti affect more than 120 million people worldwide. Infected individuals develop swollen limbs and disfigurement, leading to an inability to work and ostracization from society. Control and prophylaxis for these infections involve mass drug administration combinations of anthelmintics including diethylcarbamazine (DEC). DEC has actions on microfilariae, but its effects on adult worms are less pronounced. The SLO-1 (BK) channel activator, emodepside, kills adults of many filarial species. However, the in vivo efficacy of emodepside is suboptimal against B. malayi, possibly due to reduced bioavailability in the lymphatic system. Expressing different slo-1 splice variants in B. malayi also affects sensitivity to emodepside. This study explores the potentiation of emodepside mediated paralysis by DEC in adult female B. malayi. Worminator motility measurements show that co-application of DEC and emodepside increases the potency of emodepside 4-fold. The potentiation of the emodepside effect persists even after the worms recover (desensitize) from the initial effects of DEC. RNAi knock-down demonstrates that the DEC-mediated potentiation of emodepside requires the presence of TRP-2 channels. Our study demonstrates that the addition of DEC could enhance the effect of emodepside where bioavailability or activity against a specific species may be low.

Tenofovir-induced distal renal tubular acidosis: A rare cause of recurrent hypokalaemic paralysis.

Tenofovir disoproxil fumarate was the first nucleotide analogue reverse transcriptase inhibitor to be approved for treatment of human immunodeficiency virus infection. It is a relatively safe drug but can present with nephrotoxicity. We report a case of 36-year-old male who presented with acute onset flaccid paraparesis. He was a diagnosed case of acquired immunodeficiency syndrome for 9 years ago and was on tenofovir-based antiretroviral therapy for last 6 months. As the patient had normal anion gap metabolic acidosis, hypokalaemia and urine pH > 5.5, distal renal tubular acidosis (RTA) was suspected. He improved dramatically within 24 h of hospitalisation after potassium correction to regain normal power. Tenofovir-induced distal RTA presenting as hypokalaemic paralysis is a very rare complication of tenofovir; hence, we are reporting this case. In addition, we suggest regular follow-up of patients taking tenofovir with urine analysis and serum potassium to detect this complication earlier as it is reversible.

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.

Diterpenoid Caesalmin C Delays Aß-Induced Paralysis Symptoms via the DAF-16 Pathway in Caenorhabditis elegans.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world. However, there is no effective drug to cure it. Caesalmin C is a cassane-type diterpenoid abundant in Caesalpinia bonduc (Linn.) Roxb. In this study, we investigated the effect of caesalmin C on Aß-induced toxicity and possible mechanisms in the transgenic Caenorhabditis elegans AD model. Our results showed that caesalmin C significantly alleviated the Aß-induced paralysis phenotype in transgenic CL4176 strain C. elegans. Caesalmin C dramatically reduced the content of Aß monomers, oligomers, and deposited spots in AD C. elegans. In addition, mRNA levels of sod-3, gst-4, and rpt-3 were up-regulated, and mRNA levels of ace-1 were down-regulated in nematodes treated with caesalmin C. The results of the RNAi assay showed that the inhibitory effect of caesalmin C on the nematode paralysis phenotype required the DAF-16 signaling pathway, but not SKN-1 and HSF-1. Further evidence suggested that caesalmin C may also have the effect of inhibiting acetylcholinesterase (AchE) and upregulating proteasome activity. These findings suggest that caesalmin C delays the progression of AD in C. elegans via the DAF-16 signaling pathway and that it could be developed into a promising medication to treat AD.