Cannabis and orofacial pain: a systematic review.

The naturally occurring cannabis plant has played an established role in pain management throughout recorded history. However, in recent years, both natural and synthetic cannabis-based products for medicinal use (CBPM) have gained increasing worldwide attention due to growing evidence supporting their use in alleviating chronic inflammatory and neuropathic pain associated with an array of conditions. In view of these products' growing popularity in both the medical and commercial fields, we carried out a systematic review to ascertain the effects of cannabis and its synthetically derived products on orofacial pain and inflammation. The application of topical dermal cannabidiol formulation has shown positive findings such as reducing pain and improving muscle function in patients suffering from myofascial pain. Conversely, two orally-administered synthetic cannabinoid receptor agonists (AZD1940 and GW842166) failed to demonstrate significant analgesic effects following surgical third molar removal. There is a paucity of literature pertaining to the effects of cannabis-based products in the orofacial region; however, there is a wealth of high-quality evidence supporting their use for treating chronic nociceptive and neuropathic pain conditions in other areas. Further research is warranted to explore and substantiate the therapeutic role of CBPMs in the context of orofacial pain and inflammation. As evidence supporting their use expands, healthcare professionals should pay close attention to outcomes and changes to legislation that may impact and potentially benefit their patients.

Dental Service and Resource Needs during COVID-19 among Underserved Populations.

INTRODUCTION: In response to the coronavirus disease 2019 (COVID-19) outbreak, dental services in British Columbia, Canada, were restricted to urgent and emergency cases between March 16 and May 18, 2020. It is unclear how the curtailment of oral health services has affected underserved populations who already often have limited access to dental care due to cost, fear, stigma, and discrimination. OBJECTIVES: To explore the experiences of underserved populations and their community organizations when accessing oral health services and information in British Columbia and identify their coping mechanisms employed during the curtailment of oral health care services. METHODS: Semistructured, remote interviews were conducted with 13 staff and 18 members from 6 community-based organizations. These organizations serve men and women with a history of incarceration and/or experiencing poverty and homelessness, persons living with human immunodeficiency virus/AIDS, adults living with mental illness, and older adults in long-term care facilities. The interviews were audio-recorded, transcribed verbatim, and coded for emerging themes using NVivo 12 software. Thematic analysis was performed. RESULTS: The pandemic raised concerns and hesitancy among underserved populations and further reduced access to care. In turn, those with unmet dental needs resorted to coping mechanisms, including turning to community support or medical services, self-management of dental issues, and not dealing with dental issues altogether. Community organizers and members outlined needed resources such as assistance navigating the dental care system, having a contact for dental-related questions, and member preparation for dental service changes, while emphasizing the importance of positive relationships with dental providers. CONCLUSION: Underserved populations who already face barriers to oral health care services experienced increased difficulty in addressing their oral health needs and concerns during the beginning of the COVID-19 pandemic. Strategies aimed at reaching out to this population and those who support them are needed to help mitigate negative coping strategies and increased oral health disparities. KNOWLEDGE TRANSFER STATEMENT: This study depicts ways of addressing unmet oral health-related issues during the COVID-19 pandemic for underserved populations and their community organizations with policy implications as well as practical strategies.

Engineering P450 TamI as an Iterative Biocatalyst for Selective Late-Stage C-H Functionalization and Epoxidation of Tirandamycin Antibiotics.

Iterative P450 enzymes are powerful biocatalysts for selective late-stage C-H oxidation of complex natural product scaffolds. These enzymes represent useful tools for selectivity and cascade reactions, facilitating direct access to core structure diversification. Recently, we reported the structure of the multifunctional bacterial P450 TamI and elucidated the molecular basis of its substrate binding and strict reaction sequence at distinct carbon atoms of the substrate. Here, we report the design and characterization of a toolbox of TamI biocatalysts, generated by mutations at Leu101, Leu244, and/or Leu295, that alter the native selectivity, step sequence, and number of reactions catalyzed, including the engineering of a variant capable of catalyzing a four-step oxidative cascade without the assistance of the flavoprotein and oxidative partner TamL. The tuned enzymes override inherent substrate reactivity, enabling catalyst-controlled C-H functionalization and alkene epoxidation of the tetramic acid-containing natural product tirandamycin. Five bioactive tirandamycin derivatives (6-10) were generated through TamI-mediated enzymatic synthesis. Quantum mechanics calculations and MD simulations provide important insights into the basis of altered selectivity and underlying biocatalytic mechanisms for enhanced continuous oxidation of the iterative P450 TamI.

Umbilical cord bilirubin as a predictor of neonatal jaundice: a retrospective cohort study.

BACKGROUND: Hyperbilirubinaemia is a major cause of neonatal morbidity. Early identification of those infants most at risk might allow the development of targeted primary preventative therapy and follow-up. The objective of this study was to assess whether arterial umbilical cord bilirubin (aUCB) level at delivery predicts the development of neonatal jaundice in term deliveries. METHODS: Retrospective analysis of hospital biochemistry records identified term deliveries with recorded aUCB. Infant medical records were reviewed to identify those who developed neonatal hyperbilirubinaemia (requiring treatment according to UK NICE guidelines) with/without a positive direct antiglobulin test (DAT). RESULTS: Of 1411 term deliveries with a clearly recorded aUCB, 30 infants developed clinically-significant jaundice (2.7%), of whom 8 were DAT + ve (0.6%) mostly due to ABO incompatibility. aUCB strongly predicted the development of DAT + ve jaundice (area under the ROC curve = 0.996), as well as all-cause jaundice (area under the ROC curve = 0.74). However, this effect was critically dependent on maternal blood group. Amongst infants at risk of ABO incompatibility (maternal blood groups O + ve/O-ve, 39.7%) the predictive value of aUCB for all cause jaundice was strengthened (area under the ROC curve = 0.88). Amongst those not at risk (defined maternal blood group not O + ve/O-ve, 51.0%) it disappeared completely (area under the ROC curve = 0.46). A cutoff of 35 µmol/l for mothers with blood group O + ve/O-ve increased the pre-test probability for all-cause jaundice of 4% to a post-test probability of 30%. CONCLUSIONS: For infants of mothers with blood group O, aUCB predicts development of neonatal jaundice. There was no evident utility for infants of mothers with other blood groups. Estimation of aUCB should be considered as a strategy for early identification of those at risk of neonatal haemolytic jaundice.

Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia.

Overexpression of the transcriptional coregulators C-terminal binding proteins 1 and 2 (CtBP1 and 2) occurs in many human solid tumors and is associated with poor prognosis. CtBP modulates oncogenic gene expression programs and is an emerging drug target, but its oncogenic role is unclear. Consistent with this oncogenic potential, exogenous CtBP2 transformed primary mouse and human cells to anchorage independence similarly to mutant H-Ras. To investigate CtBP's contribution to in vivo tumorigenesis, Apcmin/+ mice, which succumb to massive intestinal polyposis, were bred to Ctbp2+/- mice. CtBP interacts with adenomatous polyposis coli (APC) protein, and is stabilized in both APC-mutated human colon cancers and Apcmin/+ intestinal polyps. Ctbp2 heterozygosity increased the median survival of Apcmin/+ mice from 21 to 48 weeks, and reduced polyp formation by 90%, with Ctbp2+/- polyps exhibiting reduced levels of ß-catenin and its oncogenic transcriptional target, cyclin D1. CtBP's potential as a therapeutic target was studied by treating Apcmin/+ mice with the CtBP small-molecule inhibitors 4-methylthio-2-oxobutyric acid and 2-hydroxy-imino phenylpyruvic acid, both of which reduced polyposis by more than half compared with vehicle treatment. Phenocopying Ctbp2 deletion, both Ctbp inhibitors caused substantial decreases in the protein level of Ctbp2, as well its oncogenic partner ß-catenin, and the effects of the inhibitors on CtBP and ß-catenin levels could be modeled in an APC-mutated human colon cancer cell line. CtBP2 is thus a druggable transforming oncoprotein critical for the evolution of neoplasia driven by Apc mutation.

Site locked headaches in paediatric patients do not require routine brain imaging and rarely have a serious aetiology.

AIM: The main aim of this study was to examine the aetiology and the yield of brain imaging of children with site locked headaches (SLH). METHODS: This study was carried out at Queen's University Hospital, Essex, UK, from August 2011 to August 2015 and focused on patients who were at least five years of age, had experienced at least five SLH attacks and had a normal neurological examination. Bilateral or alternating unilateral headaches were excluded. Data were collected prospectively, and the headache diagnosis was based on the International Classification of Headache Disorders. RESULTS: We identified 292 eligible patients (60% female) aged 5.1-17 years: 177 with unilateral SLH, 104 with occipital SLH and 11 with vertex SLH. Anterior headaches were the most frequent (n = 133), and the diagnoses included migraine (n = 192), tension type headaches (n = 30) and medication-overuse headaches (n = 22). The headache was unspecified in 43 cases. Magnetic resonance imaging was normal in 96% of the 283/292 scanned or showed a nonspecific, nonsignificant abnormality in 4%. CONCLUSION: Site locked headaches were most likely to be caused by primary headaches, particularly migraine. An SLH without abnormal neurological findings is unlikely to have an underlying sinister aetiology, and routine brain imaging is not required in such cases.

Contagious itch: what we know and what we would like to know.

All humans experience itch in the course of their life. Even a discussion on the topic of itch or seeing people scratch can evoke the desire to scratch. These events are coined "contagious itch" and are very common. We and others have shown that videos showing people scratching and pictures of affected skin or insects can induce itch in healthy persons and chronic itch patients. In our studies, patients with atopic dermatitis (AD) were more susceptible to visual itch cues than healthy. Also, personality traits like agreeableness and public self-consciousness were associated with induced scratching in skin patients, while neuroticism correlated with induced itch in healthy subjects. The underlying course of contagious itch is not yet fully understood. It is hypothesized that there are human mirror neurons that are active when we imitate actions and/or negative affect. Until now, there has been only limited data on the mechanisms of brain activation in contagious itch though. We have barely begun to understand the underlying physiological reactions and the triggering factors of this phenomenon. We summarize what we currently know about contagious itch and provide some suggestions what future research should focus on.

Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

OBJECTIVES: The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. METHODS: The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. RESULTS: Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. CONCLUSION: These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

Nucleoside 5'-phosphorothioate derivatives are highly effective neuroprotectants.

The brain is especially sensitive to oxidative stress due to its high rate of oxidative metabolism, relatively low levels of antioxidant enzymes, and high concentrations of Fe/Cu ions. During the neurodegeneration process, the aggregation of proteins Aß, accompanies oxidative stress. We explored the potential of thiophosphate derivatives to rescue neurons from oxidative stress and Aß toxicity. We evaluated the neuroprotective effect of ATP-γ-S, ADP-ß-S, and GDP-ß-S on primary cortical neuronal cells exposed to several insults, including treatment with FeSO4, co-application of H2O2 and FeSO4, and addition of Aß42. Upon treatment with FeSO4, phosphorothioate analogues exhibited up to 3000-fold better neuroprotectant activity than the corresponding parent nucleotides. Likewise, phosphorothioate analogues proved to be up to 30-fold better neuroprotectants than the corresponding parent nucleotides upon treatment with both H2O2 and FeSO4. When we exposed primary neuron and astrocyte cultures to 50 µM Aß42-induced cell death, we found that ATP-γ-S significantly improved cell morphology and maintained culture viability with an IC50 value of 0.8 µM. Finally, we evaluated the viability of neuroblastoma cells under hypoxic conditions in the presence of ATP-γ-S and found that the latter was involved in the regulation of HIF-1a and stabilized mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), which promote cell survival and proliferation. Based on its high potency as a neuroprotectant, we propose ATP-γ-S as a highly promising, biocompatible, and water-soluble drug candidate for the treatment of neurodegenerative disorders.

The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme.

Neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammatory response and its elevation has recently been shown to be a poor prognostic factor in many malignancies including colon, prostate and bladder cancer. The primary aim of this study was to assess the prognostic impact of NLR in a clinically annotated cohort of patients with glioblastoma multiforme (GBM). We hypothesised that elevated NLR would be associated with worse prognosis. Between 2004 and 2009, 137 patients had surgery for GBM and were assessed for consideration of adjuvant therapy at our institution. Of these, 84 patients with an evaluable pre-corticosteroid full blood count result were identified and included in the final analysis. Median overall survival was 9.3 months (range 0.7-82.1). On univariate analysis, age >65 years, gender, ECOG performance status ≥2, frontal tumour, extent of surgical resection, completion of adjuvant chemoradiation protocol and NLR > 4 were significantly correlated with overall survival. Patients with NLR > 4, had a worse median overall survival at 7.5 months versus 11.2 months in patients with NLR ≤ 4 (hazard ratio 1.6, 95 % CI 1.00-2.52, p = 0.048). On multivariate analysis NLR > 4 remained an independent prognostic indicator for poor outcome. These data are an important reminder of the potential relevance of host immunity in GBM. In our cohort, NLR > 4 conferred a worse prognosis independent of other well established prognostic factors. If validated in other cohorts NLR may prove to be a useful addition in predicting prognosis in GBM patients. The demonstration that host immunity plays a role in GBM biology suggests that investigation of emerging therapies which modulate host immune response are warranted in this disease.

[Treatment tactics of hemorroidal disease stage III-IV].

The Miligan-Morgan's operation has long been considered to be the "golden standard" of hemorrhoids' stage I-III treatment. The invention of distal branches of the upper rectal artery' suture ligation with mucopexia and lifting of the anal canal mucosa discovered new possibilities for hemorrhoids surgery, though there are still some questions considering long-term results. 151 cases of recurrence within 1-6 months were analyzed. The use of CT-angiography with 3D reconstruction of the upper rectal artery allowed to chose the operative technique more relevant and thus improve the treatment results.

Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma.

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis.

The alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent functions. The corepressor C-terminal binding protein (CtBP) interacts with ARF, resulting in proteasome-mediated degradation of CtBP. ARF can induce apoptosis in p53-null colon cancer cells, in a manner dependent on ARF interaction with CtBP. Bik was uniquely identified in an apoptotic gene array as coordinately upregulated in colon cancer cells after either CtBP2 knockdown or ARF overexpression. Validating the array findings, ARF induced Bik mRNA and protein expression, and this activity required an intact CtBP binding domain. Apoptosis induced by CtBP deficiency was substantially impaired when Bik expression was simultaneously silenced. An analysis of the Bik promoter revealed binding sites for the CtBP-interacting basic Kruppel-like factor (BKLF). A Bik promoter luciferase reporter was repressed by BKLF and CtBP2, and ARF reversed CtBP-associated repression. Chromatin immunoprecipitation analyses showed that CtBP was recruited to the Bik promoter largely by BKLF. Expression profiling of BH3-only gene expression in ARF-expressing or CtBP-deficient cells revealed that Bik was uniquely regulated by ARF/CtBP in colon cancer cells, whereas additional BH3-only proteins (Bim, Bmf) showed CtBP-dependent repression in osteosarcoma cells. ARF antagonism of CtBP repression of Bik and other BH3-only genes may have a critical role in ARF-induced p53-independent apoptosis and tumor suppression.