Carprofen Attenuates Postoperative Mechanical and Thermal Hypersensitivity after Plantar Incision in Immunodeficient NSG Mice.

Immunodeficient NSG mice are reported to be less responsive to buprenorphine analgesia. Here, we used NSG mice to compare the efficacy of the commonly used dose of carprofen (5 mg/kg) with 5 and 10 times that dose (25 and 50 mg/kg) for attenuating postoperative mechanical and thermal hypersensitivity following an incisional pain model. Male and female NSG mice (n = 45) were randomly assigned to one of 4 groups and received daily subcutaneous injections for 3 d: saline (5 mL/kg), 5 mg/kg carprofen (Carp5), 25 mg/kg carprofen (Carp25), and 50 mg/kg carprofen (Carp50). Mechanical and thermal hypersensitivity were assessed 24 h before and at 4, 24, and 48 h after surgery. Plasma carprofen concentrations were measured in a separate group of mice (n = 56) on days 0 (at 2, 4, 12, and 23 h), 1, and 2 after the first, second, and third doses, respectively. Toxicity was assessed through daily fecal occult blood testing (n = 27) as well as gross and histopathologic evaluation (n = 15). Our results indicated that the saline group showed both mechanical and thermal hypersensitivity throughout the study. Carp5 did not attenuate mechanical or thermal hypersensitivity at any time point. Carp25 attenuated mechanical and thermal (except for the 4-h time point) hypersensitivity. Carp50 attenuated only thermal hypersensitivity at 24 h. Fecal occult blood was detected in 1 of 8 Carp25-treated mice at 48 and 72 h. Histopathologic abnormalities (gastric ulceration, ulcerative enteritis, and renal lesions) were observed in some Carp50-treated mice. Plasma carprofen concentrations were dose and time dependent. Our results indicate that Carp25 attenuated postoperative mechanical and thermal hypersensitivity more effectively than Carp5 or Carp50 in NSG mice with incisional pain. Therefore, we recommend providing carprofen at 25 mg/kg SID for incisional pain procedures using immunodeficient NSG mouse.

Assessment of a Combination of Tiletamine/Zolazepam, Ketamine, and Dexmedetomidine for Anesthesia of Swine (Sus domesticus).

This study investigated the induction of anesthesia in swine by injection of tiletamine/zolazepam and ketamine in combination with either dexmedetomidine (TKD) or xylazine (TKX). We hypothesized that TKD would accelerate anesthesia onset and prolong recovery as compared TKX in swine undergoing a noninvasive radiographic procedure. A randomized crossover experiment was performed on 6 healthy, intact, male miniature swine undergoing radiographic examination. Swine were randomly assigned to one of 2 groups: 1) 5mg/kg tiletamine/zolazepam, 2.5mg/kg ketamine, and 0.0125mg/kg dexmedetomidine (TKD) or 2) 5mg/kg tiletamine/zolazepam, 2.5mg/kg ketamine, and 2.5mg/kg xylazine (TKX). Either TKD or TKX was administered intramuscularly at 0.05mL/kg to provide anesthesia for a 45-min radiographic procedure. At 45min after drug administration, atipamezole was administered. During anesthesia, swine were monitored for duration parameters (time to sternal recumbency [onset of anesthesia], lateral recumbency, loss of palpebral reflex, return of the palpebral reflex, and return to sternal recumbency [onset of recovery]) and physiologic parameters (heart rate, %SpO2, noninvasive blood pressure, and body temperature). Duration and physiologic parameters did not differ between groups at any time point. The results indicate TKD and TKX provide comparable general anesthesia in swine undergoing a radiographic examination.

Dexmedetomidine Effectively Sedates Asian Elephants (Elephas maximus).

This study investigated the sedative effects of dexmedetomidine in Asian elephants. We hypothesized that 2 µg/kg dexmedetomidine would provide sufficient standing sedation. A crossover design study was performed in three Asian elephants. Each elephant was assigned to 1 of 3 treatment groups-1 (D1), 1.5 (D1.5) or 2 (D2) µg/kg dexmedetomidine (intramuscular injection, IM) with a two-week 'washout period' between doses. Elephants were monitored for 120 min. At 120 min (Ta), atipamezole was administered IM. Sedation and responsiveness scores were evaluated. Physiological parameters (pulse rate, respiratory rate, and %SpO2) and clinical observations were monitored during the study and for 3 days post drug administration. D2 provided the longest sedation (approximately 70 min), compared to D1 and D1.5. After Ta, each elephant's sedative stage lessened within 10-15 min without complications. No significant abnormal clinical observations were noted throughout and during the 3-days post study period. These data suggest that a single 2 µg/kg IM dexmedetomidine injection provides sufficient standing sedation for approximately 70 min in Asian elephants.

Efficacy of 3 Buprenorphine Formulations for the Attenuation of Hypersensitivity after Plantar Incision in Immunodeficient NSG Mice.

Buprenorphine is perhaps the most prescribed analgesic for management of postoperative pain in mice. Although various buprenorphine formulations are effective in commonly used immunocompetent mouse strains, a knowledge gap exists regarding its efficacy in immunodeficient mice. Here we used a plantar incision to evaluate the efficacy of 3 buprenorphine formulations for attenuating postoperative mechanical and thermal hypersensitivity in the immunodeficient NSG mouse strain. We also characterized the pharmacokinetics of these formulations over a 72-h period. We hypothesized that all 3 buprenorphine formulations evaluated-the standard preparation and 2 extended-release products (Bup-HCl, Bup-ER, and Bup-XR, respectively)-would attenuate postoperative mechanical and thermal hypersensitivity resulting from a plantar incision in NSG mice. Male and female NSG mice (n = 48) were allocated to 4 treatment groups: saline (0.9% NaCl, 5 mL/kg SC once); Bup-HCl (0.1 mg/kg SC, BID for 2 d); Bup-ER (1.0 mg/kg SC once); and Bup-XR (3.25 mg/kg SC once). Mechani- cal and thermal hypersensitivity assessments were conducted 24 h before surgery and at 4, 8, 24, 48, and 72 h afterward. All groups of mice showed mechanical and thermal hypersensitivity within the first 24 h after surgery. Behavioral pain indicators (guarding, toe-touching [intermittent partial weight bearing], licking the incision, vocalizations) were observed in some mice from each group at every postoperative time point. Plasma buprenorphine was measured in a separate group of mice and concentrations surpassed the suggested therapeutic level (1.0 ng/mL) for less than 4 h for Bup-HCl, for at least 24 h for Bup-ER, and for 72 h for Bup-XR. Our results indicate that at the dosages studied, these buprenorphine formulations do not adequately attenuate postoperative mechanical and thermal hypersensitivity in the plantar incisional model in NSG mice. These findings support the need for strain-specific analgesic protocols for mice used in research.

The use of person-first language in scientific literature focused on drug-seeking behavior: a cross-sectional analysis.

CONTEXT: Person first language (PFL) - a way of referring to individuals with medical conditions or disability that emphasizes the person over their condition or disability - is important in reducing the stigma surrounding individuals who exhibit drug-seeking behavior. Drug-seeking behavior is generally associated with a negative connotation by healthcare professionals, which may create poor provider perceptions of these individuals and potentially impact patient care. Therefore, to reduce stigmatization surrounding drug-seeking behavior and to improve patient care in these individuals, the use of PFL should be promoted. OBJECTIVES: The primary objective of this study is to investigate how frequently research articles focused on drug-seeking behavior adhere to PFL. METHODS: We performed a cross-sectional analysis systematically searching PubMed for articles published between May 1, 2011, and April 30, 2020, focused on drug-seeking behavior. To be included, the article must have met the following criteria: (1) published in a peer-reviewed journal; (2) relevant to drug-seeking behavior; and (3) must include human subjects and be retrievable in English. All articles were screened and data were extracted independently in a masked, duplicate fashion. Each article was reviewed for 19 predefined non-PFL terms with certain terms adopted from the American Medical Association Manual of Style. RESULTS: Our search returned 699 articles related to drug-seeking behavior, of which 390 articles met inclusion criteria and were analyzed for non-PFL. Our analysis found only 13.6% (53/390) of articles adhered to PFL while 86.4% (337/390) of articles contained at least some form of non-PFL. There was no association between PFL adherence and extracted study characteristics. CONCLUSIONS: PFL adherence is uncommon among research literature focused on drug-seeking behavior. The power of language can be profound, and should be understood by researchers, health care providers, and educators alike, specifically when dealing with known and exhibited characteristics of substance use disorders. This is relevant because of the high prevalence of substance use disorders, limited amount of prior research, and the impact stigma has on patients and healthcare providers.

Mouse Anesthesia: The Art and Science.

There is an art and science to performing mouse anesthesia, which is a significant component to animal research. Frequently, anesthesia is one vital step of many over the course of a research project spanning weeks, months, or beyond. It is critical to perform anesthesia according to the approved research protocol using appropriately handled and administered pharmaceutical-grade compounds whenever possible. Sufficient documentation of the anesthetic event and procedure should also be performed to meet the legal, ethical, and research reproducibility obligations. However, this regulatory and documentation process may lead to the use of a few possibly oversimplified anesthetic protocols used for mouse procedures and anesthesia. Although a frequently used anesthetic protocol may work perfectly for each mouse anesthetized, sometimes unexpected complications will arise, and quick adjustments to the anesthetic depth and support provided will be required. As an old saying goes, anesthesia is 99% boredom and 1% sheer terror. The purpose of this review article is to discuss the science of mouse anesthesia together with the art of applying these anesthetic techniques to provide readers with the knowledge needed for successful anesthetic procedures. The authors include experiences in mouse inhalant and injectable anesthesia, peri-anesthetic monitoring, specific procedures, and treating common complications. This article utilizes key points for easy access of important messages and authors' recommendation based on the authors' clinical experiences.

Tiletamine/zolazepam and dexmedetomidine with tramadol provide effective general anesthesia in rats.

Background: Tiletamine/zolazepam is a dissociative anesthetic combination commonly used in small animals but information is limited in rats. The alpha-2 agonist, dexmedetomidine, has gained popularity in laboratory animal anesthesia. Tramadol is a weak opioid mu agonist. The aim of this study was to assess whether the tiletamine/zolazepam/dexmedetomidine (ZD) combination effectively provides a surgical anesthesia plane comparable to tiletamine/zolazepam/dexmedetomidine with tramadol (ZDT) in a minor procedure in rats. Methods: Rats were induced with ZD or ZDT. After the loss of paw withdrawal, a small incision was made on the rats' left thighs as a surgical stimulus. Rats were maintained under a surgical anesthesia plane by assessing the loss of the paw withdrawal reflex for 45 minutes, then atipamezole was administered. Monitored anesthesia parameters included: (a) physiological parameters - pulse rate (PR), respiratory rate (RR), tissue oxygen saturation (%SpO2), and body temperature; (b) duration parameters - induction time, onset and duration of surgical anesthesia plane, onset of recovery, and recovery time. Results: PR was significantly lower at 10 minutes in ZD and 5 minutes in ZDT groups. No difference was observed for RR, %SpO2, and body temperature. Likewise, there were no differences for duration parameters: induction time was less than 3 minutes; onset and duration of surgical anesthesia plane were approximately 5 and 45 minutes, respectively; onset of recovery (time to move) was 51 minutes; and recovery time was 52 minutes, respectively. Conclusion: These data suggest the ZD combination provides a surgical anesthesia plane comparable to ZDT in a rat incisional pain model.

Tighter accuracy standards within point-of-care blood glucose monitoring: how six commonly used systems compare.

INTRODUCTION: Blood glucose monitoring systems (BGMS) are used in the hospital environment to manage blood glucose levels in patients at the bedside. The International Organization for Standardization (ISO) 15197:2003 standard is currently used by regulatory bodies as a minimum requirement for the performance of BGMS, specific to self-testing. There are calls for the tightening of accuracy requirements and implementation of a standard specifically for point-of-care (POC) BGMS. METHODS: The accuracy of six commonly used BGMS was assessed in a clinical setting, with 108 patients' finger stick capillary samples. Using the accuracy criteria from the existing standard and a range of tightened accuracy criteria, system performance was compared. Other contributors to system performance have been measured, including hematocrit sensitivity and meter error rates encountered in the clinical setting. RESULTS AND DISCUSSION: Five of the six BGMS evaluated met current accuracy criteria within the ISO 15197 standard. Only the Optium Xceed system had >95% of all readings within a tightened criteria of ±12.5% from the reference at glucose levels ≥72 mg/dl (4 mmol/liter) and ±9 mg/dl (0.5 mmol/liter) at glucose levels <72 mg/dl (4 mmol/liter). The Nova StatStrip Xpress had the greatest number of error messages observed; Optium Xceed the least. OneTouch Ultra2, Nova StatStrip Xpress, Accu-Chek Performa, and Contour TS products were all significantly influenced by blood hematocrit levels. CONCLUSIONS: From evidence obtained during this clinical evaluation, the Optium Xceed system is most likely to meet future anticipated accuracy standards for POC BGMS. In this clinical study, the results demonstrated the Optium Xceed product to have the highest level of accuracy, to have the lowest occurrence of error messages, and to be least influenced by blood hematocrit levels.

Diversity in laboratory animal science: issues and initiatives.

Since diversity in the workplace began receiving scholarly attention in the late 1980s, many corporations and institutions have invested in programs to address and manage diversity. We encourage laboratory animal science to address the challenges and to build on the strengths that personal diversity brings to our field and workplaces. Diversity is already becoming increasingly relevant in the workplace and the laboratory animal science field. By addressing issues related to diversity, laboratory animal science could benefit and potentially fulfill its goals more successfully. To date, diversity has received minimal attention from the field as a whole. However, many individuals, workplaces, and institutions in industry, academia, and the uniformed services that are intimately involved with the field of laboratory animal science are actively addressing issues concerning diversity. This article describes some of these programs and activities in industry and academia. Our intention is that this article will provide useful examples of inclusion-promoting activities and prompt further initiatives to address diversity awareness and inclusion in laboratory animal science.

Morphometrics and pelage characterization of longtailed macaques (Macaca fascicularis) from Pulau Bintan, Indonesia; Singapore; and Southern Vietnam.

Cynomolgus (or longtailed) macaques (Macaca fascicularis) are used extensively as laboratory animals in biomedical research. Their use in Singapore, an emerging biomedical hub in Southeast Asia, is now increasing widely, with research subjects currently originating from Singapore, Vietnam, and Pulau Bintan, Indonesia. Limited data exist on the genetic and phenotypic polymorphisms and phylogenetic relationships of these groups, and the animals are used as research subjects without regard to potential differences or homogeneity. Here we characterize their phenotypes by using established primatology tools to detail morphometrics and pelage erythrism and saturation. Pelage analyses supported the Gloger rule, in which heavily pigmented forms predominate near the equator, with Singaporean and Bintan macaques having darker pelage than Vietnamese macaques. Morphometric variation patterns suggest a tendency toward insular dwarfism and correlate generally with the Bergmann rule, in which body mass increases with latitude and colder climate. Although the 3 populations all belong to the nominotypical subspecies M. f. fascicularis, phenotypic differences are evident and are valuable tools to analyze their phylogeographic history and phylogenetic relationships.

Improving murine health surveillance programs with the help of on-site enzyme-linked immunosorbent assay.

Timely and accurate detection of murine pathogens is essential in contemporary biomedical research. Cost, accuracy, and reproducibility of test results are frequent concerns when initiating an on-site serology program. This study was conducted to evaluate the advantages of on-site serology performed by enzyme-linked immunosorbent assay (ELISA) versus pathogen surveillance conducted off-site by a commercial vendor. We divided 92 sentinel mouse serum samples and tested them in parallel for a panel of 10 murine pathogens at our institution and by an off-site vendor. On-site testing was performed with commercially available test kits and according to the kit manufacturer's directions, whereas serum samples for off-site testing were prepared according to the vendor's specifications. Results from the 2 testing strategies were compared, and a good beyond- chance level of agreement was demonstrated by means of the kappa test (kappa = 0.86). The turn-around time between sample preparation and results availability for on-site ELISA was 16 h versus 72 h for off-site testing. On-site ELISA demonstrated considerable cost reduction, ranging from 15.10% to 43.33% depending on the number of agents being tested. This study demonstrates the accuracy and time- and cost-effectiveness of on-site ELISA as well as its potentially valuable role in achieving more timely and efficient disease surveillance and control programs in contemporary biomedical research facilities.

Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy.

AIMS: To determine the prevalence and clinical predictors of subclinical atherosclerosis and myocardial ischaemia in uncomplicated type 2 diabetes and assess their relationship to short-term outcome. METHODS AND RESULTS: Established risk factors and coronary artery calcium (CAC) scores were prospectively measured in 510 asymptomatic type 2 diabetic subjects (mean age 53+/-8 years, 61% males) without prior cardiovascular disease. Myocardial perfusion scintigraphy (MPS) was performed in all subjects with CAC > 100 Agatston units (AU) (n=127), and a random sample of the remaining patients with CAC < or = 100 AU (n=53). Significant CAC (> 10 AU) was found in 46.3%. Twenty events occurred (two coronary deaths, nine non-fatal myocardial infarctions, three acute coronary syndromes, three non-haemorrhagic strokes, and three late revascularisations) during a median follow-up of 2.2 years (25th-75th percentile = 1.9-2.5 years). The age, systolic blood pressure, the duration of diabetes, United Kingdom Prospective Diabetes Study risk score, CAC score, and extent of myocardial perfusion abnormality were significant predictors of time to cardiovascular events in a univariable Cox proportional hazard model. No cardiac events or perfusion abnormalities occurred in subjects with CAC < or = 10 AU up until 2 years of follow-up. CAC and MPS findings were synergistic for the prediction of short-term cardiovascular events. CONCLUSION: Subclinical atherosclerosis, measured by CAC imaging, is superior to the established cardiovascular risk factors for predicting silent myocardial ischaemia and short-term outcome. Further studies evaluating the impact of CAC imaging on clinical outcomes and its cost effectiveness are warranted.

Intensive insulin therapy in type 1 and type 2 diabetes.

Intensive insulin regimens can produce substantial clinical benefits for patients with type 1 and type 2 diabetes, but they are associated with an increased incidence of hypoglycaemia. This article discusses such regimens and whether the risk of hypoglycaemia can be reduced by using the new basal insulin analogue, insulin glargine.

Advanced glycation end products modulate the maturation and function of peripheral blood dendritic cells.

Advanced glycation end products (AGEs), a complex and heterogeneous group of posttranslational modifications of proteins in vivo, have been widely studied for their involvement in diabetic complications; these complications are largely vascular and accompanied by inflammation. Because dendritic cells (DCs) initiate and modulate inflammatory responses, we hypothesized that AGEs might exert immunomodulatory effects via antigen-presenting DCs. To test this hypothesis, we investigated effects of the AGE peptide, compared with the naked peptide, on maturation, costimulatory molecule expression, and function of DCs in peripheral blood. From flow cytometry, we found a dose-dependent inhibition in CD83 expression on DCs exposed for 2.5 h to each of two synthetic AGE peptides. A similar culture for 24 h additionally produced an inhibition of CD80 expression, whereas exposure to AGEs for 3 days induced a large increase in DC numbers and a concomitant loss of monocyte/macrophages. Exposure of DCs to AGEs resulted in a dose-dependent loss in their capacity to stimulate primary proliferation of allogeneic T-cells. We conclude that AGEs promote development of DCs but that these DCs fail to express maturation markers and lose the capacity to stimulate primary T-cell responses. Effects of AGEs on DCs could be instrumental in the immunological changes associated with diabetes.

Continuous glucose monitoring and haemoglobin A(1c).

BACKGROUND: Measurement of HbA(1c) is the standard test for assessment of glycaemic control in diabetic subjects. Using new glucose sensing technology we re-evaluated the significance of HbA(1c) in terms of the aspects of the blood profile it measures in patients with diabetes. METHODS: In a group of 27 patients with type 1 diabetes, interstitial fluid glucose concentrations were monitored for a mean of 2.6 days using the Continuous Glucose Monitoring System trade mark (MiniMed Inc, CA, USA). Results were correlated with an HBA(1c) measurement taken at the time of sensor insertion. RESULTS: Results were available in 25 subjects, two datasets being lost due to patient error. There was a correlation between mean sensor glucose value, and the HbA(1c) value (r = 0.59, P = 0.002). The correlation with standard deviation of the readings was weaker (r = 0.3, P = 0.15). No other descriptor of the sensor glucose concentration correlated with HbA(1c). CONCLUSION: The mean interstitial glucose concentration recorded with the Continuous Glucose Monitoring System correlates with HbA(1c) level recorded at the time, but with no other marker of glucose control in diabetic subjects. These results have implications for the interpretation of HbA(1c) concentrations in type 1 diabetes.