Association of the OPRM1 variant rs1799971 (A118G) and clinical manifestations in tramadol poisoned patients: a cross-sectional study.

INTRODUCTION: The opioid receptor mu1 is a protein coding gene that can have different codes for a protein and may have variations (polymorphisms) affecting how opioids work. The aim of this study was to investigate the prevalence of the most common opioid receptor mu1 polymorphism (A118G) and any relationship between this polymorphism and features following tramadol overdose. MATERIALS AND METHODS: This was a cross-sectional study of patients admitted with tramadol poisoning to an Iranian hospital. These patients were not taking any other drugs or medications and had no history of seizures. RESULTS: The results showed that among the 83 patients included in the study, 57 (69 per cent) had the AA genotype, 25 (30 per cent) had the AG genotype, and one (1 per cent) had the GG genotype for the opioid receptor mu1 A118G polymorphism. Nausea and/or vomiting occurred in nine (11 per cent) patients and dizziness in 38 (46 per cent) patients. Serious adverse events included seizures in 51 (60 per cent) patients and respiratory failure requiring mechanical ventilation in 21 (25 per cent) patients. However, there was no significant association between the opioid receptor mu1 A118G polymorphism and these adverse events. DISCUSSION: In our study, the frequency of the A allele was greater than the G allele, and the AA genotype was more prevalent than AG. The GG genotype was the least common among the polymorphisms of opioid receptor mu1 rs1799971. There was no significant association between the opioid receptor mu1 A118G polymorphism and symptoms in tramadol-poisoned patients. Although these allele proportions are similar to the results reported in other Caucasian populations, they are dissimilar to the findings in Chinese and Singaporean populations. In these Asian studies, the predominant allele was the G allele. It has been suggested that a mutated G allele will decrease the production of opioid receptor mu1-related messenger ribonucleic acid and related proteins, leading to fewer mu-opioid receptors in the brain. CONCLUSIONS: This study found no significant association between the opioid receptor mu1 A118G polymorphism and adverse outcomes in tramadol-poisoned patients. However, more research is needed to draw more definitive conclusions due to the limited evidence and variability of opioid receptor mu1 polymorphisms in different populations.

Toll-Like Receptor 7 a Novel Non-Invasive Inflammatory Genetic Sensor for Ulcerative Colitis Remission Monitoring.

Background: Ulcerative colitis (UC) and Crohn's disease (CD) are two major types of inflammatory bowel diseases (IBDs). Toll-like receptors (TLRs) are expressed in the innate immune system compartments, in charge of identifying a wide range of microorganisms. The aim of the present study was to evaluate the expression of TLR-2, -7, and -8 in peripheral blood mononuclear cells (PBMC) of UC patients as a novel non-invasive primary inflammation sensor for monitoring the clinical course of UC candidates. Materials and Methods: In this cross-sectional study, total RNA was extracted from the PBMC of 42 UC patients along with 20 healthy donors. The mRNA levels of TLR-2, -7, and -8 were assessed using the quantitative real-time polymerase chain (qRT-PCR) reaction. Results: The present research study demonstrated no significant changes in TLR-2 mRNA expression in UC patients in comparison with the control group (P = 0.1264), whereas significant elevation (P = 0.0008) was distinguished in the TLR-7 expression of UC participants specifically during the remission course compared with healthy donors and flareup patients (P = 0.0004 and P = 0.0063, respectively). The last selected TLR, TLR-8 was not shown remarkable changes either between UC patients and the control group or between clinical courses of the disease. Conclusion: Here, among three nominated TLRs for predicting UC patients, TLR-7 was potentially selected according to the significant difference in mRNA expression in flareup UC patients and control donors. TLR-7 could be used as a novel non-invasive biomarker for monitoring UC patients in the active course of the disease.

Chronic exposure to methadone induces activated microglia and astrocyte and cell death in the cerebellum of adult male rats.

Methadone is a centrally-acting synthetic opioid analgesic widely used in the methadone maintenance therapy (MMT) programs throughout the world. Considering its neurotoxic effects particularly on the cerebellum, this study aims to address the behavioral and histological alterations in the cerebellar cortex associated with methadone administration. Twenty-four adult male albino rats were randomized into two groups of control and methadone treatment. Methadone was subcutaneously administered (2.5-10 mg/kg) once a day for two consecutive weeks. The functional and structural changes in the cerebellum were compared to the control group. Our data revealed that treating rats with methadone not only induced cerebellar atrophy, but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. We further demonstrated that treating rats with methadone increased complexity of astrocyte processes and decreased complexity of microglia processes. Our result showed that methadone impaired motor coordination and locomotor performance and neuromuscular activity. Additionally, relative gene expression of TNF-α, caspase-3 and RIPK3 increased significantly due to methadone. Our findings suggest that methadone administration has a neurodegenerative effect on the cerebellar cortex via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

Chronic exposure to methadone impairs memory, induces microgliosis, astrogliosis and neuroinflammation in the hippocampus of adult male rats.

Methadone is a centrally-acting synthetic opioid analgesic widely used in methadone maintenance therapy (MMT) programs throughout the world. Given its neurotoxic effects, particularly on the hippocampus, this study aims to address the behavioral and histological alterations in the hippocampus associated with methadone administration. To do so, twenty-four adult male albino rats were randomized into two groups, methadone treatment and control. Methadone was administered subcutaneously (2.5-10 mg/kg) once a day for two consecutive weeks. A comparison was drawn with behavioral and structural changes recorded in the control group. The results showed that methadone administration interrupted spatial learning and memory function. Accordingly, treating rats with methadone not only induced cell death but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. Furthermore, the results demonstrated that treating rats with methadone decreased the complexity of astrocyte processes and the complexity of microglia processes. These findings suggest that methadone altered the special distribution of neurons. Also, a substantial increase was observed in the expression of TNF-α due to methadone. According to the findings, methadone administration exerts a neurodegenerative effect on the hippocampus via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

Strategies for the treatment of acute benzodiazepine toxicity in a clinical setting: the role of antidotes.

INTRODUCTION: Although not a potentially life-threatening poisoning, benzodiazepine (BZD) intoxication may be life-threatening in special situations/populations or those with background diseases. AREAS COVERED: The aim of this review is to evaluate all possible treatment options available in the literature for the management of benzodiazepine poisoning with special attention to antidote administration. We conducted a literature search using PubMed, Google Scholar, EMBASE, and Cochrane central register from 1 January 1980 to 10 November 2021 using keywords 'benzodiazepine,' 'poisoning,' 'toxicity,' 'intoxication,' and 'treatment.' EXPERT OPINION: Careful patient selection, ideally by a clinical toxicologist, may decrease the complications of flumazenil and add to its efficacy. The cost-to-benefit ratio should be considered in every single patient who is a candidate for flumazenil administration. In case a decision has been made to administer flumazenil, careful consideration of the possible contraindications is essential. We recommend slow administration of low doses of flumazenil (0.1 mg/minute) to avoid complications or withhold the administration with development of first signs of adverse effects. The main treatment of benzodiazepine toxicity is conservative with administration of activated charcoal, monitoring of the vital signs, prevention of aspiration and development of deep vein thrombosis due to prolonged immobilization, and respiratory support.

Effects of Physical Hardness on the Perception of Rendered Stiffness in an Encountered-Type Haptic Display.

Rendering stable hard surfaces is an important problem in haptics; current haptic devices cannot render hard objects and free space together. In our previous work, we addressed these limitations using an encountered-type haptic display system, which showed significant improvements compared to traditional rendering methods. In our approach, we attach a plate with the desired hardness to the kinesthetic device's end-effector, which the user interacts with using an untethered stylus. This method allows us to directly change the hardness of the end-effector based on the rendered object. In this paper, we evaluate how changing the hardness of the end-effector can mask the device's stiffness and affect the user's perception of the interaction. Our human subject experiment results indicate that when the end-effector is made of a hard material, it is difficult for users to perceive the stiffness change rendered by the device. On the other hand, this stiffness change is easily distinguished when the end-effector is made of a soft material. These results show promise for our combined hardness-stiffness display in avoiding the limitations of haptic devices when rendering hard surfaces.

Ecofriendly Biomolecule-Capped Bifidobacterium bifidum-Manufactured Silver Nanoparticles and Efflux Pump Genes Expression Alteration in Klebsiella pneumoniae.

Background: Klebsiella pneumoniae is currently considered as an immediate threat to human health due to its various multidrug efflux pumps. Microbially synthesized silver nanoparticles (AgNPs) are an attractive and eco-friendly approach to prevent antibiotic resistance in bacteria. In the present study, we compared the inhibitory effect of both commercial and green AgNPs by Bifidobacterium bifidum on OxqAB efflux pump genes in ciprofloxacin-resistant strains of K. pneumoniae. Materials and Methods: AgNPs were characterized by ultraviolet-visible spectrophotometer, Fourier transform infrared spectroscopy, X-ray diffraction, zeta potential, transmission electron microscopy, and scanning electron microscopy. Antibiogram was used to identify resistant isolates and the effect of the biosynthesized AgNPs against OxqAB efflux pump strains was assessed by the minimum inhibitory concentration (MIC) method. The expression levels of oxqAB genes were evaluated using real-time polymerase chain reaction (PCR) followed by exposure to subMICs of the AgNPs. Results: PCR results showed that 25 strains had OxqAB efflux pump and the MIC method indicated that AgNPs had an inhibitory effect on all resistant strains with OxqAB efflux pump. The efficacy of the synthetic nanoparticles was assessed by comparing the antiefflux pump activity with commercial AgNPs. In ciprofloxacin-resistant isolates, the oxqAB genes expression levels reduced in the subMIC of both AgNPs, whereas biosynthesized AgNPs had greater bactericidal effects compared with the commercial AgNPs. Conclusions: Efflux pumps could be an attractive target for our biosynthesized AgNPs. The oxqAB genes expression levels reduced in subMIC of both AgNPs, whereas biosynthesized AgNPs had greater bactericidal effects than the commercial AgNPs.

A Novel Approach for Assessing and Training the Drilling Skills of Orthopaedic Surgeons.

BACKGROUND: Although experiences in the operating room can help surgeons to learn simple bone-drilling techniques, outside training may be better suited for complex procedures. We adapted a rotary handpiece to evaluate the bone-drilling skills of orthopaedic resident physicians during the 2017 Southwest Orthopaedic Trauma Association (SWOTA) motor skills course. METHODS: Twenty-five postgraduate year (PGY)-1 orthopaedic residents from 7 institutions were asked to perform a bicortical drilling task 3 times both before and after attending a motor skills course. Kinetic and kinematic data were collected using force, acceleration, and visual sensors. RESULTS: Sixteen parameters were measured. The interdependence of these parameters (taken separately for precourse and postcourse performance) is presented. Evidence for motor skill acquisition across a short time scale is elucidated. Noteworthy correlations include overpenetration with force (0.65 mm), palmar-dorsal (P-D) toggle (0.65°), vibration in the P-D direction (0.53 m/s), time (-0.41 sec), and RPM (revolutions per minute; -0.36); time with both RPM (0.38) and P-D toggle (-0.40°); and force with both RPM (-0.41) and P-D toggle (0.32°). Differences in performance before and after the motor skills course include reduction in overpenetration (28.8 to 18.2 mm), reduction in skiving (22% to 6%), and reduction in preparation time (27.3 to 9.65 sec). Additionally, there were several differences in performance by institution that were significant (overpenetration, toggle in the P-D and radial-ulnar [R-U] directions, and both drilling force and drilling time). CONCLUSIONS: Understanding how performance and outcome parameters are correlated provides powerful insight into how surgical procedures can be best performed. In particular, we hope that these findings will inform new training paradigms. Variations in resident training from 1 institution to another are evidenced in surgical performance. Similarly, the methods used here to quantify changes in performance across the 3-day SWOTA training course allow a unique vehicle for optimization of these types of training opportunities outside of the operating room.

Treatment of adult lead poisoning with D-penicillamine.

Background The aim of the current study was to evaluate the efficacy of D-penicillamine in the treatment of lead poisoning mainly in the outpatient setting. Methods In a case series study performed during the recent epidemic of lead poisoning in Iran, lead-poisoned patients referring to our outpatient clinic were treated with 250-mg D-penicillamine capsules administered every 6 h for 5 or 10 days based on availability of the medication. They were recommended to re-check blood lead level (BLL) 4 weeks after cessation of the treatment and refer to our clinic again. Results In 63 patients with lead poisoning but without signs and symptoms of lead encephalopathy, median BLL was 106 [84, 131] µg/dL on presentation, which declined to a mean of 52.6 ± 28.8 µg/dL after a median treatment period of 7 [5, 10] days (p < 0.001). There was no statistically significant difference between the 5- and 10-day treatment protocols regarding complications and recovery. Treatment had resulted in a median decrease of 54 µg/dL [33, 90] (range: -20 to 231 µg/dL) in the patients' BLLs (33.9% declined in BLL measurements; range: -29.69% to 99.06%). Conclusions D-penicillamine may be an acceptable substitute treatment in adult lead poisoning. Although our sample size was limited, we could not detect any serious adverse effects in our cases showing that D-penicillamine resulted in acceptable recovery rates. This may be helpful especially in epidemics with limitations in antidote access.

Mechanical model of orthopaedic drilling for augmented-haptics-based training.

In this study, augmented-haptic feedback is used to combine a physical object with virtual elements in order to simulate anatomic variability in bone. This requires generating levels of force/torque consistent with clinical bone drilling, which exceed the capabilities of commercially available haptic devices. Accurate total force generation is facilitated by a predictive model of axial force during simulated orthopaedic drilling. This model is informed by kinematic data collected while drilling into synthetic bone samples using an instrumented linkage attached to the orthopaedic drill. Axial force is measured using a force sensor incorporated into the bone fixture. A nonlinear function, relating force to axial position and velocity, was used to fit the data. The normalized root-mean-square error (RMSE) of forces predicted by the model compared to those measured experimentally was 0.11 N across various bones with significant differences in geometry and density. This suggests that a predictive model can be used to capture relevant variations in the thickness and hardness of cortical and cancellous bone. The practical performance of this approach is measured using the Phantom Premium haptic device, with some required customizations.