The effect of cannabis edibles on driving and blood THC.

BACKGROUND: Cannabis has been shown to impact driving due to changes produced by delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis. Current legal thresholds for blood THC while driving are based predominantly on evidence utilizing smoked cannabis. It is known that levels of THC in blood are lower after eating cannabis as compared to smoking yet the impact of edibles on driving and associated blood THC has never been studied. METHODS: Participants drove a driving simulator before and after ingesting their preferred legally purchased cannabis edible. In a counterbalanced control session, participants did not consume any THC or cannabidiol (CBD). Blood was collected for measurement of THC and metabolites as well as CBD. Subjective experience was also assessed. RESULTS: Participants consumed edibles with, on average, 7.3 mg of THC, which is less than the maximum amount available in a single retail package in Ontario, providing an ecologically valid test of cannabis edibles. Compared to control, cannabis edibles produced a decrease in mean speed 2 h after consumption but not at 4 and 6 h. Under dual task conditions in which participants completed a secondary task while driving, changes in speed were not significant after the correction for multiple comparison. No changes in standard deviation of lateral position (SDLP; 'weaving'), maximum speed, standard deviation of speed or reaction time were found at any time point or under either standard or dual task conditions. Mean THC levels were significantly increased, relative to control, after consuming the edible but remained relatively low at approximately 2.8 ng/mL 2 h after consumption. Driving impairment was not correlated with blood THC. Subjective experience was altered for 7 h and participants were less willing/able to drive for up to 6 h, suggesting that the edible was intoxicating. INTERPRETATION: This is the first study of the impact of cannabis edibles on simulated driving. Edibles were intoxicating as revealed by the results of subjective assessments (VAS), and there was some impact on driving. Detection of driving impairment after the use of cannabis edibles may be difficult.

OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.

Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the α-ketoglutarate dehydrogenase (OGDH) gene, which encodes an enzyme that is part of the tricarboxylic acid (TCA) cycle, as essential for GBM growth. Moreover, by combining transcriptome and metabolite screening analyses, we discovered that loss of function of OGDH by the clinically validated drug compound CPI-613 was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3 mimetic, ABT263) in patient-derived xenografts as well neurosphere GBM cultures. CPI-613-mediated energy deprivation drove an integrated stress response with an upregulation of the BH3-only domain protein, Noxa, in an ATF4-dependent manner, as demonstrated by genetic loss-of-function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with disruption of the TCA cycle might be a treatment strategy for GBM.

Radiotherapy Results in Locally Advanced Sinonasal Cancer: Turkish Society for Radiation Oncology, Head and Neck Study Group 01-005.

OBJECTIVES: This study aims to examine the treatment outcomes and related factors in locally advanced sinonasal cancer across Turkiye. METHODS: Twelve centers participants of the Turkish Society for Radiation Oncology Head and Neck Study Group attended the study. One hundred and ninety-four patients treated with intensity-modulated radiation therapy between 2001 and 2021 were analyzed retrospectively. The survival analysis was performed using the Kaplan-Meier method. Acute and late toxicity were recorded per Common Toxicity Criteria for Adverse Events V4.0. RESULTS: The median age was 58 years and 70% were male. The majority of tumors were located in maxillary sinus (59%). Most of the patients (%83) had T3 and T4A disease. Fifty-three percent of patients were in stage 4A. Radiotherapy was administered to 80% of the patients in the adjuvant settings. Median 66 Gy dose was administered in median 31 fractions. Chemotherapy was administered concomitantly with radiotherapy in 45% of the patients mostly with weekly cisplatin. No grade ≥4 acute and late toxicity was observed. The median follow-up was 43 months. The 5-year and 10-year overall survival (OS); locoregional recurrence-free survival (LRFS); distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 61% and 47%; 69% and 61%; 72%, and 69%, and 56% and 49%, respectively. In the multivariate analysis, several factors demonstrated significant influence on OS, such as performance status, surgery, and lymph node involvement. Moreover, surgery was the key prognostic factor for LRFS. For DMFS, lymph node involvement and surgical margin were found to be influential factors. In addition, performance status and lymph node involvement were identified as significantly affecting PFS. CONCLUSIONS: In our study, the authors obtained promising results with IMRT. Performance status, lymph node involvement, and surgery emerged as the primary factors significantly influencing OS.

Blended learning in undergraduate dental education: a global pilot study.

AIMS: To explore the global trends in blended learning in undergraduate dental education during the COVID pandemic and during the recovery phase by engaging with the students and faculty and evaluate the implications for dental education in the post-COVID era. METHODS: It was a pilot cross-sectional study which employed a convenience sampling technique to recruit representatives of dental faculty and undergraduate students in 80 dental institutions globally. A previously validated questionnaire consisting of a combination of closed and open-ended items was used for data collection. Responses to these online questionnaires were processed and analysed using the R statistical computing environment. RESULTS: A total of 320 dental students and 169 faculty members from 47 different dental institutions participated in the study. Video and Live Online Tutorials were considered to be the most effective method of online learning followed by online question banks by both groups. Significant differences were noted between faculty and students regarding time spent and effectiveness of online teaching and learning, respectively, both before and after the start of COVID. The results highlight the faculty need to engage more closely with the students to address their learning needs. Finally, the participants provided several recommendations regarding the future development of teaching and learning strategies as well as assessments in the post-pandemic era. CONCLUSIONS: This is the first study which explores blended learning in dental education with participants from multiple institutions in different regions of the globe. Compared to the faculty, students considered online learning to be less interactive and preferred learning activities and all assessments to be delivered face-to-face. The results underscore the need to adapt teaching practices to suit the learning needs of the students.

Evaluation of maxillary sinus dimensions and volume using cone beam computed tomography in patients with unilaterally displaced palatal and buccal maxillary canines.

OBJECTIVES: To evaluate and compare the maxillary sinus (MS) dimensions and volume in unilaterally displaced palatal and buccal maxillary canines. METHODS: CBCT images for 133 patients were included in the study. Maxillary canines were unilaterally displaced palatally in 83 patients (PDCs) and buccally in 50 patients(BDCs). The following variables were measured: canine position in relation to MS walls, MS pneumatization and MS dimensions and volume. RESULTS: MS was extended to the incisor region in 10% and 13% and to the canine region in 48% and 23% in BDCs and PDCs subjects, respectively. In BDC subjects, maxillary canine crown tip was more laterally (24.23 mm compared to 22.93 mm (p < 0.05)) and closer vertically (5.82 mm compared to 9.58 mm (p < 0.001)) to the MS, maxillary canine root tip was closer to the MS anterior (0 mm compared to 1.64 mm (p < 0.05)) and lateral (19.70 mm compared to 22.02 mm (p < 0.001)) walls and the MS volume (11.57mm3 compared to 9.09 mm3 (p < 0.001)) was increased in the displaced side compared to the non-displaced side. In PDC subjects, a significant difference between the displaced and non-displaced sides was detected in the vertical (3.28 mm compared to 5.89 mm (p < 0.001)) and lateral (21.63 mm compared to 24.25 mm (p < 0.001)) position of maxillary canine to the MS wall, the anterior (- 0.84 mm compared to 1.13 mm (p < 0.05)) and lateral (20.48 mm compared to 22.44 mm (p < 0.001)) position of canine root tip to the MS and the MS volume (7.71mm3 compared to 9.14mm3 (p < 0.001)). PDC sides differed from BDC sides in the lateral and vertical position of canine crown tip to MS and in MS volume. PDC showed negative association with MS volume and anteroposterior skeletal relationship and a positive association with MS height. CONCLUSIONS: PDCs subjects have a reduced MS volume and BDCs subjects have an increased MS volume. PDCs are associated with reduced MS volume, increased MS height and Class III skeletal relationship.

Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients.

Bullous pemphigoid (BP), the by far most frequent autoimmune subepidermal blistering disorder (AIBD), is characterized by the deposition of autoantibodies against BP180 (type XVII collagen; Col17) and BP230 as well as complement components at the dermal-epidermal junction (DEJ). The mechanisms of complement activation in BP patients, including the generation of C5a and regulation of its two cognate C5aRs, i.e., C5aR1 and C5aR2, are incompletely understood. In this study, transcriptome analysis of perilesional and non-lesional skin biopsies of BP patients compared to site-, age-, and sex-matched controls showed an upregulated expression of C5AR1, C5AR2, CR1, and C3AR1 and other complement-associated genes in perilesional BP skin. Of note, increased expressions of C5AR2 and C3AR1 were also observed in non-lesional BP skin. Subsequently, double immunofluorescence (IF) staining revealed T cells and macrophages as the dominant cellular sources of C5aR1 in early lesions of BP patients, while C5aR2 mainly expressed on mast cells and eosinophils. In addition, systemic levels of various complement factors and associated molecules were measured in BP patients and controls. Significantly higher plasma levels of C3a, CD55, and mannose-binding lectin-pathway activity were found in BP patients compared to controls. Finally, the functional relevance of C5aR1 and C5aR2 in BP was explored by two in vitro assays. Specific inhibition of C5aR1, resulted in significantly reduced migration of human neutrophils toward the chemoattractant C5a, whereas stimulation of C5aR2 showed no effect. In contrast, the selective targeting of C5aR1 and/or C5aR2 had no effect on the release of reactive oxygen species (ROS) from Col17-anti-Col17 IgG immune complex-stimulated human leukocytes. Collectively, this study delineates a complex landscape of activated complement receptors, complement factors, and related molecules in early BP skin lesions. Our results corroborate findings in mouse models of pemphigoid diseases that the C5a/C5aR1 axis is pivotal for attracting inflammatory cells to the skin and substantiate our understanding of the C5a/C5aR1 axis in human BP. The broad expression of C5aRs on multiple cell types critical for BP pathogenesis call for clinical studies targeting this axis in BP and other complement-mediated AIBDs.

Effect of coronal fracture angle on the stability of screw fixation in medial malleolar fractures: A finite element analysis.

Malleolar screw fixation is the most widely used treatment method for medial malleolar (MM) fractures. Here, although buttress plate fixation is advocated for vertical MM fractures, the angular discrimination between oblique and vertical MM fractures is still not fully understood. The purpose of this study is to test the adequacy of screw fixation in MM fractures with different angles and determination of a 'critical fracture angle' to guide surgeons in the decision-making for screw fixation for MM fractures by utilizing an advanced engineering simulation approach. In addition to loading of the healthy tibia structure, various cases of the MM fracture double screw fixation (14 simulation scenarios in total with fracture angles between 30° and 90°, in 5° increments) were considered in this research and their static loading conditions just after fixation operation were simulated through nonlinear (geometric and contact nonlinearity) finite element analysis (FEA). Patient-specific computed tomography scan data, parametric three-dimensional solid modelling and finite element method (FEM) based engineering codes were employed in order to simulate the fixation scenarios. Visual and numerical outputs for the deformation and stress distributions, separation and sliding behaviours of the MM fracture fragments of various screw fixations were clearly exhibited through FEA results. Minimum and maximum separation distances (gap) of 3.75 and 150.34 µm between fracture fragments at fracture angles of 30° and 90° were calculated respectively against minimum and maximum sliding distances of 25.87 and 41.37 µm between fracture fragments at fracture angles of 90° and 35°, respectively. The FEA results revealed that while the separation distance was increasing, the sliding distance was decreasing and there were no distinct differences in sliding distances in the scenarios from fracture angles of 30°-90°. The limitations and errors in a FEA study are inevitable, however, it was interpreted that the FEA scenarios were setup in this study by utilizing acceptable assumptions providing logical outputs under pre-defined boundary conditions. Finally, the fracture healing threshold for separation and/or sliding distance between fracture fragments was assigned as 100 µm by referring to previous literature and it was concluded that the screws fixed perpendicular to the fracture in a MM fracture with more than 70° angle with the tibial plafond results in a significant articular separation (>100 µm) during single-leg stand. Below this critical angle of 70°, two screws provide sufficient fixation.

A comparative assessment of the amount and rate of orthodontic space closure toward a healed vs recent lower premolar extraction site.

OBJECTIVES: To investigate and compare the amount and rate of space closure and tooth tipping during orthodontic space closure toward a recent vs healed first premolar extraction site. MATERIALS AND METHODS: The mandibular arches of 23 patients were included. Treatment plans included lower first premolar extractions. After reaching 0.019 × 0.025-inch stainless-steel archwires (SSAW), patients were subdivided into two groups (Group 1: space closure was carried out toward a healed first premolar extraction space and Group 2: space closure was carried out immediately after first premolar extraction). Elastomeric power chain from second molar to second molar was used to close lower extraction spaces. The following time points were defined: T1: just before space closure; T2-T4: 1-3 months after initial space closure. Records consisted of dental study models. The amount and rate of extraction space closure were evaluated at each time point. RESULTS: In Group 1 (healed socket), a total amount of 1.98 mm (coronally) and 1.75 mm (gingivally) of space closure was achieved. The rate of space closure was 0.66 mm/month coronally and 0.58 mm/month gingivally. In Group 2 (recent socket), the total amount of space closure was 3.02 mm coronally and 2.68 mm gingivally. The rate of space closure was 1.01 mm/month coronally and 0.89 mm/month gingivally. Differences between the two groups were significant (P < .01). Tipping of adjacent teeth during space closure was similar in both groups (P > .05). CONCLUSIONS: In the lower arch, the amount and rate of space closure toward a recent extraction site were higher than that toward a healed extraction socket with similar tipping of teeth in both groups.

Pulpal blood flow changes and pain scores related to using Superelastic 0.018-inch Nickel Titanium as the first orthodontic alignment archwire: a prospective clinical trial.

BACKGROUND: Optimal orthodontic force results in maximum rate of tooth movement without tissue damage. Even though starting orthodontic treatment with a thicker archwire may shorten treatment duration, the evidence on the effect of using 0.018-inch NiTi as the first alignment archwire on pulpal blood flow (PBF) status is still scarce. OBJECTIVES: to record PBF changes and pain scores associated with using 0.018-inch NiTi as the first alignment archwire during fixed orthodontic treatment. METHODOLOGY: Patients were selected from subjects attending postgraduate orthodontic teaching clinics at Jordan University of Science and Technology. In total, forty healthy patients who exhibited mild lower arch crowding were included. A split-mouth trial design was used. Each patient received two archwire sizes at one time joined in the midline by crimpable hook and applied in the lower arch. Patients were assigned into one of two groups based on archwire sizes used. Group 1: 0.014-inch and 0.018-inch NiTi (Six males, 14 females aged 19.4±1.33 years) and Group 2: 0.016-inch and 0.018-inch NiTi (Seven males, 13 females aged 19.6±1.45 years). The archwire size group was randomly allocated with a 1:1 allocation ratio. A Laser Doppler Flowmeter was used to measure PBF at different time intervals (T0-T5). Pain scores were recorded using a visual analogue scale (VAS). A repeated measures ANOVA and a post-hoc Bonferroni comparison tests were conducted to examine differences at the different time points before and during orthodontic alignment. RESULTS: For all studied archwire sizes, PBF decreased 20 minutes after their placement. Most PBF changes occurred within 24hours and continued to decrease until 72 hours after archwire placement where the maximum reduction was reached. Eventually, normal values were reverted within 1 month. PBF changes were similar between all alignment - groups. CONCLUSIONS: Initial orthodontic alignment with 0.018-inch NiTi does not cause irreversible changes to pulpal vasculature or produces higher pain scores.

Pulpal blood flow changes and pain scores related to using Superelastic 0. 018-inch Nickel Titanium as the first orthodontic alignment archwire: a prospective clinical trial

Abstract Background Optimal orthodontic force results in maximum rate of tooth movement without tissue damage. Even though starting orthodontic treatment with a thicker archwire may shorten treatment duration, the evidence on the effect of using 0.018-inch NiTi as the first alignment archwire on pulpal blood flow (PBF) status is still scarce. Objectives to record PBF changes and pain scores associated with using 0.018-inch NiTi as the first alignment archwire during fixed orthodontic treatment. Methodology Patients were selected from subjects attending postgraduate orthodontic teaching clinics at Jordan University of Science and Technology. In total, forty healthy patients who exhibited mild lower arch crowding were included. A split-mouth trial design was used. Each patient received two archwire sizes at one time joined in the midline by crimpable hook and applied in the lower arch. Patients were assigned into one of two groups based on archwire sizes used. Group 1: 0.014-inch and 0.018-inch NiTi (Six males, 14 females aged 19.4±1.33 years) and Group 2: 0.016-inch and 0.018-inch NiTi (Seven males, 13 females aged 19.6±1.45 years). The archwire size group was randomly allocated with a 1:1 allocation ratio. A Laser Doppler Flowmeter was used to measure PBF at different time intervals (T0-T5). Pain scores were recorded using a visual analogue scale (VAS). A repeated measures ANOVA and a post-hoc Bonferroni comparison tests were conducted to examine differences at the different time points before and during orthodontic alignment. Results For all studied archwire sizes, PBF decreased 20 minutes after their placement. Most PBF changes occurred within 24hours and continued to decrease until 72 hours after archwire placement where the maximum reduction was reached. Eventually, normal values were reverted within 1 month. PBF changes were similar between all alignment - groups. Conclusions Initial orthodontic alignment with 0.018-inch NiTi does not cause irreversible changes to pulpal vasculature or produces higher pain scores.

Combination of Salinomycin and AZD3463 Reveals Synergistic Effect on Reducing the Viability of T98G Glioblastoma Cells.

BACKGROUND: Salinomycin, an ionophore antibiotic, is known to be an effective agent in reducing the viability of Glioblastoma (GBM) cells. The combination of salinomycin with other chemotherapeutic drugs would help to overcome the drug resistance of GBM cells. OBJECTIVE: This study aims to test the combinatorial effect of salinomycin and AZD3463 in T98G GBM cells. METHODS: The cytotoxic effects of drugs on T98G GBM cells were determined by using WST-8 assay. Flow cytometry was used to identify apoptosis and cell cycle profiles after treatments. Real-time PCR was used to portray mRNA expression profiles of genes in the Wnt-signaling pathway after treatments. RESULTS: IC50 concentrations of AZD3463 and salinomycin were 529nM and 7.3µM for 48h, respectively. The combination concentrations of AZD3463 and salinomycin were 3.3µM and 333nM, respectively. The combination treatment showed a synergistic effect on reducing the viability of GBM cells. AZD3463, salinomycin, and their combination induced apoptosis in 1.2, 1.4, and 3.2 folds, respectively. AZD3463 and the combination treatment induced the cell cycle arrest at the G1 phase. Salinomycin and AZD3463 treatments, either alone or in combination, resulted in the downregulation or upregulation of mRNA expression levels of genes in the Wntsignaling pathway. CONCLUSION: Salinomycin, AZD3463, and their combination may inhibit proliferation and induce apoptosis in GBM cells due to a decrease in expression levels of genes acting in both the canonical and non-canonical Wnt signaling pathways. The Wnt signaling pathway may be involved in salinomycin-AZD3463 drug interaction.

Pulmonary effects of ozone therapy at different doses combined with antibioticotherapy in experimental sepsis model

Abstract Purpose This experimental sepsis model created with Escherichia coli aimed to investigate the histopathological effects of two different doses of ozone combined with antibiotherapy on lung tissue. Methods Rats were divided into 5 groups. Then sepsis was induced intraperitoneally in the first 4 groups. The 1st group was treated with cefepime, the 2nd and 3rd groups were treated with cefepime combined with ozone at a dose of 0.6 mg/kg and 1.1 mg/kg. Lung tissue sections were stained with hematoxylin-eosin and assessed under light microscope and scored between 0-4 in terms of histopathological findings. Results In the comparisons between Group 1 and Group 4 in terms of cellular damage (p=0.030), inflammation (p=0.000) and overall score (p=0.007), statistically significant positive effects were observed in favor of Group 1. In the comparisons of Groups 2 and 3 with Group 4, only positive effects were observed in terms of inflammation (p=0.020, p=0.012, respectively). Conclusion Although negative histopathological effects of ozone on tissue injury were detected, it was noteworthy that the increase in the ozone dose reduced the number of damaged parameters.

Bioavailability and cytosolic kinases modulate response to deoxynucleoside therapy in TK2 deficiency.

BACKGROUND: TK2 is a nuclear gene encoding the mitochondrial matrix protein thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial nucleotide salvage pathway. Deficiency of TK2 activity causes mitochondrial DNA (mtDNA) depletion, which in humans manifests predominantly as a mitochondrial myopathy with onset typically in infancy and childhood. We previously showed that oral treatment of the Tk2 H126N knock-in mouse model (Tk2-/-) with the TK2 substrates, deoxycytidine (dCtd) and thymidine (dThd), delayed disease onset and prolonged median survival by 3-fold. Nevertheless, dCtd + dThd treated Tk2-/- mice showed mtDNA depletion in brain as early as postnatal day 13 and in virtually all other tissues at age 29 days. METHODS: To enhance mechanistic understanding and efficacy of dCtd + dThd therapy, we studied the bioavailability of dCtd and dThd in various tissues as well as levels of the cytosolic enzymes, TK1 and dCK that convert the deoxynucleosides into dCMP and dTMP. FINDINGS: Parenteral treatment relative to oral treatment produced higher levels of dCtd and dThd and improved mtDNA levels in liver and heart, but did not ameliorate molecular defects in brain or prolong survival. Down-regulation of TK1 correlated with temporal- and tissue-specificity of response to dCtd + dThd. Finally, we observed in human infant and adult muscle expression of TK1 and dCK, which account for the long-term efficacy to dCtd + dThd therapy in TK2 deficient patients. INTERPRETATIONS: These data indicate that the cytosolic pyrimidine salvage pathway enzymes TK1 and dCK are critical for therapeutic efficacy of deoxynucleoside therapy for Tk2 deficiency. FUND: National Institutes of Health P01HD32062.

Ankle Arthrodesis using Ilizarov Ring Fixator: A Primary or Salvage Procedure? An Analysis of Twenty Cases.

Introduction: Ankle arthrodesis using the Ilizarov technique provides high union rate with the added benefits of early weight-bearing, and the unique advantage of its ability to promote regeneration of soft tissue around the bone, including skin, muscle and neuro-vascular structures, and its versatility to allow correction of the position of the foot by adjusting the frame post-operatively as needed. We describe our experience with this technique and the functional outcomes in our patients. Materials and Methods: This retrospective study was conducted in 20 ankle fusion cases using the Ilizarov method between the years 2007 and 2017. We defined success in treatment by loss of preoperative symptoms and radiological union on plain radiographs of the ankle. Results: Fusion was achieved in all patients (100%). Immediate post-operative ambulation was with full weight bearing (FWB) in 16 (83%) of the participants and non-weight bearing (NWB) in 3 patients (17%). Post-procedure 11 patients (67%) of the participants who were full weight bearing required some form of support for walking for 2-3 weeks. Post-operatively three patients had pin tract infection requiring intravenous antibiotics. Radiological union took range of 6-12 weeks, mean union time was 8 weeks. Only one patient required bone grafting due to bone loss. Average follow-up period was 10-45 months. Conclusion: The Ilizarov technique has a high union rate and leads to general favourable clinical outcome and may be considered for any ankle arthrodesis but is especially useful in complex cases such as for revisions, soft-tissue compromise, infection and in patients with risk for non-union. Early weight bearing is an extra benefit.

USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis.

Leigh syndrome is a frequent, heterogeneous pediatric presentation of mitochondrial oxidative phosphorylation (OXPHOS) disease, manifesting with psychomotor retardation and necrotizing lesions in brain deep gray matter. OXPHOS occurs at the inner mitochondrial membrane through the integrated activity of five protein complexes, of which complex V (CV) functions in a dimeric form to directly generate adenosine triphosphate (ATP). Mutations in several different structural CV subunits cause Leigh syndrome; however, dimerization defects have not been associated with human disease. We report four Leigh syndrome subjects from three unrelated Ashkenazi Jewish families harboring a homozygous splice-site mutation (c.87 + 1G>C) in a novel CV subunit disease gene, USMG5. The Ashkenazi population allele frequency is 0.57%. This mutation produces two USMG5 transcripts, wild-type and lacking exon 3. Fibroblasts from two Leigh syndrome probands had reduced wild-type USMG5 mRNA expression and undetectable protein. The mutation did not alter monomeric CV expression, but reduced both CV dimer expression and ATP synthesis rate. Rescue with wild-type USMG5 cDNA in proband fibroblasts restored USMG5 protein, increased CV dimerization and enhanced ATP production rate. These data demonstrate that a recurrent USMG5 splice-site founder mutation in the Ashkenazi Jewish population causes autosomal recessive Leigh syndrome by reduction of CV dimerization and ATP synthesis.

Ankle Arthrodesis using Ilizarov Ring Fixator: A Primary or Salvage Procedure? An Analysis of Twenty Cases

@#Introduction: Ankle arthrodesis using the Ilizarov technique provides high union rate with the added benefits of early weight-bearing, and the unique advantage of its ability to promote regeneration of soft tissue around the bone, including skin, muscle and neuro-vascular structures, and its versatility to allow correction of the position of the foot by adjusting the frame post-operatively as needed. We describe our experience with this technique and the functional outcomes in our patients. Materials and Methods: This retrospective study was conducted in 20 ankle fusion cases using the Ilizarov method between the years 2007 and 2017. We defined success in treatment by loss of preoperative symptoms and radiological union on plain radiographs of the ankle. Results: Fusion was achieved in all patients (100%). Immediate post-operative ambulation was with full weight bearing (FWB) in 16 (83%) of the participants and non-weight bearing (NWB) in 3 patients (17%). Postprocedure 11 patients (67%) of the participants who were full weight bearing required some form of support for walking for 2-3 weeks. Post-operatively three patients had pin tract infection requiring intravenous antibiotics. Radiological union took range of 6-12 weeks, mean union time was 8 weeks. Only one patient required bone grafting due to bone loss. Average follow-up period was 10-45 months. Conclusion: The Ilizarov technique has a high union rate and leads to general favourable clinical outcome and may be considered for any ankle arthrodesis but is especially useful in complex cases such as for revisions, soft-tissue compromise, infection and in patients with risk for non-union. Early weight bearing is an extra benefit.

Using Functional Near-Infrared Spectroscopy to Measure Effects of Delta 9-Tetrahydrocannabinol on Prefrontal Activity and Working Memory in Cannabis Users.

Intoxication from cannabis impairs cognitive performance, in part due to the effects of Δ9-tetrahydrocannabinol (THC, the primary psychoactive compound in cannabis) on prefrontal cortex (PFC) function. However, a relationship between impairment in cognitive functioning with THC administration and THC-induced change in hemodynamic response has not been demonstrated. We explored the feasibility of using functional near-infrared spectroscopy (fNIRS) to examine the functional changes of the human PFC associated with cannabis intoxication and cognitive impairment. Eighteen adult regular cannabis users (final sample, n = 13) performed a working memory task (n-back) during fNIRS recordings, before and after receiving a single dose of oral synthetic THC (dronabinol; 20-50 mg). Functional data were collected using a continuous-wave NIRS device, in which 8 Sources and 7 detectors were placed on the forehead, resulting in 20 channels covering PFC regions. Physiological changes and subjective intoxication measures were collected. We found a significant increase in the oxygenated hemoglobin (HbO) concentration after THC administration in several channels on the PFC during both the high working memory load (2-back) and the low working memory load (0-back) condition. The increased HbO response was accompanied by a trend toward an increased number of omission errors after THC administration. The current study suggests that cannabis intoxication is associated with increases in hemodynamic blood flow to the PFC, and that this increase can be detected with fNIRS.

Impact of Chronic Rheumatic Valve Diseases on Large Vessels.

BACKGROUND AND AIM OF STUDY: Rheumatic valvular heart disease, which remains a common health problem in developing countries, has numerous consequences on the heart chambers and circulation. The study aim was to investigate the effects of chronic rheumatic valve disease on the diameters of the descending aorta (DA) and inferior vena cava (IVC). METHODS: A total of 88 patients with echocardiographically documented rheumatic valvular heart disease and 112 healthy controls were enrolled into the study. All patients underwent detailed echocardiographic examinations, while their height and body weight were recorded and adjusted to their body surface area. RESULTS: The most common involvement was mitral valve disease, followed by aortic valve disease and tricuspid valve disease. The mean diameter of the DA (indexed to BSA) was 1.79 ± 0.49 cm for patients and 1.53 ± 0.41 for controls (p <0.001). The mean diameter of the IVC (indexed to BSA) was 1.69 ± 0.73 for patients and 1.38 ± 0.35 cm for controls (p <0.001). There was a significant positive correlation between mitral valve mean gradient and IVC diameter (p = 0.01, r = 0.18). There were also strong associations between the mitral valve area and the diameters of the DA (p = 0.001, r = -0.239) and IVC (p <0.001, r = -0.246). CONCLUSION: Rheumatic valve disease, especially mitral stenosis, was closely related to remodeling of the great vessels.