Assessment of an Orofacial Operant Pain Assay as a Preclinical Tool for Evaluating Analgesic Efficacy in Rodents

A model system capable of providing clinically relevant analgesic doses with minimal trauma has been elusive in laboratory animal medicine. Our laboratory has developed an orofacial operant pain system that effectively discriminates between nonnoxious and noxious thermal stimuli in rats and mice. Male and female rats (Crl:SD) and mice (Crl:SKR-HR^hr) were trained to perform a task (placing their face through an opening and having their cheeks stay in contact with thermodes) to receive a reward (a solution of sweetened condensed milk). Currently accepted doses of buprenorphine were tested by using a crossover design. Pain was induced in both species by sensitizing the depilated skin over both cheeks with capsaicin cream or by creating a surgical incision (rats only) and then allowing the animals to contact a temperature-regulated thermode while obtaining a reward. Optimal antinociceptive doses included 0.05 and 0.1 mg/kg in male mice but only 0.05 mg/kg in female mice. In rats, optimal antinociceptive doses included 0.03 and 0.05 mg/kg for male rats but only 0.03 mg/kg for female rats. The 2 pain-induction models in rats (capsaicin cream and surgical incision) did not differ. Our orofacial operant pain assay can determine clinically relevant analgesic doses for rodents in a preclinical assay. The automated, investigator-independent nature of the assay, in conjunction with its high sensitivity, makes this method an improvement over traditional noninvasive methods, providing better data for developing optimal analgesic recommendations for rats and mice.Abbreviation: TRVP1, transient receptor vanilloid receptor potential 1The relief of postsurgical pain in rats and mice has been a major topic of discussion during the past decades. However, the availability of a model system capable of assessing clinically relevant analgesic doses in the context of minimal trauma has been elusive in laboratory animal medicine. Traditionally, the methods for assessing analgesic efficacy in rodents have included thermal (for example, hot-plate test, tail-flick test) and mechanical (for example, von Frey filament) assays. Albeit simple to perform and nontraumatic when performed correctly, these assays may not represent the best way to assess analgesic clinical efficacy, given that they rely on either reflex-derived outcomes (for example, tail-flick assay) or unlearned, brainstem-mediated responses (for example, grooming).^14,15Postoperative behavior-based pain assessment techniques, including the recently described facial grimace scale, have been used as a more comprehensive method for assessing clinical analgesic efficacy in rats and mice.^20-22 The basic premise in these assays consists of quantifying the relative magnitude of behavioral alterations after producing an injury, typically a laparotomy. Although these models have improved the assessment accuracy for recommended analgesic dosages, they can be time-consuming to perform.⁹ In addition, these methods typically include a vehicle- or untreated control group, which introduces the ethical dilemma of uncontrolled pain in regard to some animals.The lack of clinical relevancy of the noninvasive methods on the one hand and the complexity of the behavior-based pain models on the other has limited the number of clinically effective analgesics or analgesic combinations that can be used effectively in rodents to minimize postoperative pain. As a consequence, several commonly available, centrally acting analgesics, such as tramadol, and multimodal analgesic combinations frequently used in human and other species remain underused in rodents. For this reason, there is still a need for a preclinical, minimally invasive pain model system that evaluates pain throughout the entire neuraxis, thus increasing the probability of providing clinically relevant analgesic doses.Our laboratory has developed an orofacial operant pain system that effectively discriminates between nonnoxious and noxious thermal stimuli in rats and mice.^1,15,16 The system uses a reward-conflict paradigm in which animals choose between obtaining a reward in the presence of a thermal nociceptive stimulus and avoiding both the stimulus and the reward. The objective of the current study was to evaluate the analgesic effects of currently recommended doses of buprenorphine in our novel orofacial operant pain system. Our hypothesis was that this operant assay would reliably predict an analgesic effect of buprenorphine within the currently published dose range and would clarify optimal doses for male and female rats and mice.     

Determination of urinary hexosamines for diagnosis of bladder pain syndrome

Introduction and hypothesis

Bladder pain syndrome (BPS) is a chronic disease characterized by urgency, bladder pain, and frequency, and urinary glycosaminoglycans are thought to reflect bladder epithelial deficiency in BPS. Sensitive and specific evaluation of total urinary glycosaminoglycans may be useful for the clinical diagnosis of BPS and its treatment.

Methods

A procedure for the simultaneous determination of glucosamine and galactosamine produced from urinary glycosaminoglycans has been performed in BPS patients and healthy subjects.

Results

The total content of urinary hexosamines in BPS patients significantly increased by ~130% with the increase in glucosamine greater than galactosamine.

Conclusions

A significant increase in total hexosamines content and in particular in glucosamine belonging to urinary heparan sulfate was determined in BPS patients compared with controls. We propose HS and in particular its low-molecular mass fragments and glucosamine assay as useful markers for a biochemical diagnosis of BPS and for monitoring this syndrome.     

A collaborative approach to expand clinical experiences and cultural awareness among undergraduate nursing students.

Nurse educators are constantly seeking opportunities to expose undergraduate students to different cultures. This requirement is essential to prepare tomorrow's nursing professionals to practice culturally component care in diverse health care environments. This article describes a unique collaborative experience between the University of Pittsburgh School of Nursing and the Miami Children's Hospital that offers senior baccalaureate students the opportunity to complete one term of clinical experience in a culturally diverse health care facility.     

Pathological and clinical features of multiple cancers and lung adenocarcinoma: a multicentre study

Open in a separate window OBJECTIVESLung cancer is increasingly diagnosed as a second cancer. Our goal was to analyse the characteristics and outcomes of early-stage resected lung adenocarcinomas in patients with previous cancers (PC) and correlations with adenocarcinoma subtypes.METHODSWe retrospectively reviewed data of patients radically operated on for stage I–II lung adenocarcinoma in 9 thoracic surgery departments between 2014 and 2017. Overall survival (OS) and time to disease relapse were evaluated between subgroups.RESULTSWe included 700 consecutive patients. PC were present in 260 (37.1%). Breast adenocarcinoma, lung cancer and prostate cancer were the most frequent (21.5%, 11.5% and 11.2%, respectively). No significant differences in OS were observed between the PC and non-PC groups (P = 0.378), with 31 and 75 deaths, respectively. Patients with PC had smaller tumours and were more likely to receive sublobar resection and to be operated on with a minimally invasive approach. Previous gastric cancer (P = 0.042) and synchronous PC (when diagnosed up to 6 months before lung adenocarcinoma; P = 0.044) were related, with a worse OS. Colon and breast adenocarcinomas and melanomas were significantly related to a lower incidence of high grade (solid or micropapillary, P = 0.0039, P = 0.005 and P = 0.028 respectively), whereas patients affected by a previous lymphoma had a higher incidence of a micropapillary pattern (P = 0.008).CONCLUSIONSIn patients with PC, we found smaller tumours more frequently treated with minimally invasive techniques and sublobar resection, probably due to a more careful follow-up. The impact on survival is not uniform and predictable; however, breast and colon cancers and melanoma showed a lower incidence of solid or micropapillary patterns whereas patients with lymphomas had a higher incidence of a micropapillary pattern.     

Safety of Intraoperative Cell Salvage in Cancer Surgery: An Updated Meta-Analysis of the Current Literature

BackgroundAllogeneic blood transfusions in oncologic surgery are associated with increased recurrence and mortality. Adverse effects on outcome could be reduced or avoided by using intraoperative autologous blood cell salvage (IOCS). However, there are concerns regarding the safety of the autologous IOCS blood. Previous meta-analyses from 2012 and 2020 did not identify increased risk of cancer recurrence after using autologous IOCS blood. The objective of this review was to reassess a greater number of IOCS-treated patients to present an updated and more robust analysis of the current literature.MethodsThis systematic review includes full-text articles listed in PubMed, Cochrane, Cochrane Reviews, and Web of Science. We analyzed publications that discussed cell salvage or autotransfusion combined with the following outcomes: cancer recurrence, mortality, survival, allogeneic transfusion rate and requirements, length of hospital stay (LOS). To rate the strength of evidence, a Grading of Recommendations Assessment, Development and Evaluation (GRADE) of the underlying evidence was applied.ResultsIn the updated meta-analysis, 7 further observational studies were added to the original 27 observational studies included in the former 2020 analysis. Studies compared either unfiltered (n = 2,311) or filtered (n = 850) IOCS (total n = 3,161) versus non-IOCS use (n = 5,342). Control patients were either treated with autologous predonated blood (n = 484), with allogeneic transfusion (n = 4,113), or did not receive a blood transfusion (n = 745). However, the current literature still contains only observational studies on these topics, and the strength of evidence remains low. The risk of cancer recurrence was reduced in recipients of autologous salvaged blood with or without LDF (odds ratio [OR] 0.76, 95% confidence interval [CI]: 0.64–0.90) compared to nontransfused patients or patients with allogeneic transfusion. There was no difference in mortality (OR 0.95, 95% CI: 0.71–1.27) and LOS (mean difference −0.07 days, 95% CI: −0.63 to 0.48) between patients treated with IOCS blood or those in whom IOCS was not used. Due to high heterogeneity, transfusion rates or volumes could not be analyzed.ConclusionRandomized controlled trials comparing mortality and cancer recurrence rate of IOCS with or without LDF filtration versus allogeneic blood transfusion were not found. Outcome was similar or better in patients receiving IOCS during cancer surgery compared to patients with allogeneic blood transfusion or nontransfused patients.     

Senescent CD4+CD28null cells are increased in chronic hyperuricemia,show aberrant effector phenotypes,and are reversed after allopurinol therapy: a proof-of-concept pilot study

Clinical Rheumatology - To characterize CD4+CD28null cells in chronic hyperuricemia and investigate whether allopurinol could restore CD28 expression and the balance of T helper phenotypes....