Comparison of 2-Ethyl-Cyanoacrylate and 2-Butyl-Cyanoacrylate for Use on the Calvaria of CD1 Mice

Short-chain cyanoacrylates (SCCA), such as ethyl-2-cyanoacrylate (KrazyGlue, Aron Alpha, Columbus, OH) are commonly used as commercial fast-acting glues. Although once used in clinical medicine as skin adhesives, these products caused tissue toxicity and thus their use in live tissue was discontinued. SCCA were replaced by longer-chain versions (LCCA), such as butyl-cyanoacrylate (Vetbond, 3M, St Paul, Minnesota), which were found to be less toxic than the short-chain formulations. Some researchers prefer to use SCCA due to the belief that they create a stronger bond than do the longer-chain counterparts. In survival surgeries, we compared the bone thickness, bone necrosis, fibrosis, inflammation, and bone regeneration in the calvaria of control (naïve), surgery-only, SCCA-treated, and LCCA-treated mice (n = 20 per group). At 1 and 14 d after surgery, all mice except those treated with SCCA showed statistically similar bone measurements to those of the naive control group. The SCCA group had significantly less bone regeneration than did all other groups. These results suggest that the application of SCCA causes bone damage resulting in the loss of bone regeneration. This finding may assist investigators in choosing a tissue glue for their studies and may support the IACUC in advocating the use of pharmaceutical-grade tissue glues.Abbreviations: LCCA, long-chain cyanoacrylates; SCCA, short-chain cyanoacrylatesCyanoacrylates have been used as tissue adhesives since their synthesis in 1949.⁶ Synthetic cyanoacrylate adhesives belong in the family of liquid monomers formed by alkyl esters of 2-cyanoacrylic acid. The basic formula of the cyanoacrylate adhesive (alkyl-2-cyanoacrylate) has been manipulated to form different cyanoacrylate adhesives with different properties.²⁹ Several 2-cyanoacrylate esters have been synthesized by changing the length of the alkyl chain attached.⁴² The first cyanoacrylates were short-chained, poorly manufactured, and toxic to animals at pharmacologic doses.²⁴ Short-chain cyanoacrylates (SCCA), such as methyl-2-cyanoacrylate and ethyl-2-cyanoacrylate (KrazyGlue [Aron Alpha, Columbus, OH]), continue to be used as fast-acting adhesives.⁵ Although appropriated as tissue glues soon after their discovery, these early SCCA caused tissue toxicity and thus were discontinued in the clinical arena.⁴ Research showed that changing the type of alcohol in the compound to one with a longer molecular chain reduced tissue toxicity. Over time, nontoxic, longer-chain cyanoacrylates (LCCA), such as butyl-cyanoacrylate (Vetbond [3M, St Paul, Minnesota]) and octylcyanoacrylate, were manufactured, leading to their use once again in clinical medicine³³ (Figure 1).Open in a separate windowFigure 1.Trade names for different types of cyanoacrylates.Many researchers contend that SCCA is superior to LCCA in regard to the strength and tenacity of the bond when used to create cranial windows and as an application prior to an overlay of acrylic for cranial implants. However, SCCA is not pharmaceutical-grade, as mandated by the USDA in Policy 3² and the Guide for the Care and Use of Laboratory Animals,²² and therefore can only be used after specific review and approval by an institution''s IACUC. The determination for substitution is generally based on scientific necessity or compound availability.In this study, the effects of applying an SCCA product to mice calvaria were compared with those of an LCCA glue. Specifically, we evaluated bone regeneration, osteocyte numbers, inflammation, and bone remodeling at 2 time points after application. We hypothesized that mice calvaria treated with the SCCA product would show signs of toxicity, compared with skulls treated with the LCCA glue.     

Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice

Intraneuronal alpha-synuclein (alphaSYN) inclusions constitute the hallmark lesions of a number of neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. In a transgenic mouse model expressing mutant [A30P]alphaSYN under control of the pan-neuronal Thy1 promoter, motor impairment became significant beyond 17 months of age. Cognitive performance was measured in the Morris water maze and upon fear conditioning. At 4 months of age, transgenic mice performed like controls. However, performance in these tasks was significantly impaired in (Thy1)-h[A30P]alphaSYN mice at 12 months of age. After completion of the cognition tests, mice were sacrificed and the regional distribution of neuropathology was examined. In contrast to 4 months old animals, 12 months old transgenic mice showed alpha-synucleinopathy in several brain regions, including the central nucleus of the amygdala, which is involved in cognitive behavior of mice, and is susceptible to alphaSYN pathology in human patients. Thus, age-dependent fibrillization of alphaSYN in specific cortical regions concomitant with cognitive decline may reflect dementia with Lewy bodies in a transgenic mouse model.     

Effect of chamber capacitance on Doppler flow pattern across restrictive defects in obligatory atrial-level shunts

The right atrium has a significantly higher capacitance than the left atrium, and this may affect the Doppler flow pattern across an atrial septal defect (ASD) in unilateral atrioventricular (AV) valve atresia. This Doppler flow pattern is often used to assess ASD adequacy in this setting. We studied the effect of atrial capacitance and ASD size on the trans-ASD Doppler flow pattern in an in vivo flow model of alternate left or right AV valve atresia (LAVVA and RAVVA). We assessed trans-ASD Doppler flow patterns using the max/min velocity ratio and mean interatrial pressure gradients (PGs). In both models, ASD flow rate correlated with mean trans-ASD PG, but for similar flow rates the slope was higher in the LAVVA model. In LAVVA, a persistent PG was consistently observed, with low max/min ratio (median, 1.46; range, 1.03-3.13), whereas in RAVVA, phasic flow was common (median, 8.0; range, 2.8-20). Because atrial capacitance affects mean PG and Doppler flow pattern across the ASD, we propose that the assessment of ASD adequacy in RAVVA should not rely on Doppler findings.     

Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice

Immunotherapies use components of the immune system, such as T cells, to fight cancer cells, and are changing cancer treatment, causing durable responses in some patients. Bone metastases are a debilitating complication in advanced breast and prostate cancer patients. Approved treatments fail to cure bone metastases or increase patient survival and it remains unclear whether immunotherapy could benefit patients. The bone microenvironment combines various immunosuppressive factors, and combined with T cell products could increase bone resorption fueling the vicious cycle of bone metastases. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell depleted mice. This effect seemed caused by the TILs specifically in bone, because T-cell depletion increased 4T1 orthotopic tumors and did not affect bone metastases from RM-1 prostate cancer cells, which lack TILs. T cells increased osteoclast formation ex vivo and in vivo contributing to bone metastasis vicious cycle. This pro-osteoclastic effect is specific to unactivated T cells, because activated T cells, secreting interferon γ (IFNγ) and interleukin 4 (IL-4), actually suppressed osteoclastogenesis, which could benefit patients. However, non-activated T cells from bone metastases could not be activated in ex vivo cultures. 4T1 bone metastases were associated with an increase of functional polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs), potent T-cell suppressors. Although effective in other models, sildenafil and zoledronic acid did not affect MDSCs in bone metastases. Seeking other therapeutic targets, we found that monocytic MDSCs are more potent suppressors than polymorphonuclear MDSCs, expressing programmed cell death receptor-1 ligand (PD-L1)⁺ in bone, which could trigger T-cell suppression because 70% express its receptor, programmed cell death receptor-1 (PD-1). Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases. Our results also provide a rationale for using immunotherapy because T-cell activation would increase their anti-cancer and their anti-osteoclastic properties. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Interventions to Increase Medication Adherence in African-American and Latino Populations: A Literature Review

The objective of this systematic review was to investigate the effectiveness of interventions to improve medication adherence in ethnic minority populations. A literature search from January 2000 to August 2012 was conducted through PubMed/Medline, Web of Science, The Cochrane Library, and Google Scholar. Search terms used included: medication (MeSH), adherence, medication adherence (MeSH), compliance (MeSH), persistence, race, ethnicity, ethnic groups (MeSH), minority, African-American, Hispanic, Latino, Asian, Pacific Islander, and intervention. Studies which did not have ≥75% of the sample population comprised of individuals of any one ethnic background were excluded, unless the authors performed sub-group analyses by race/ethnicity. Of the 36 studies identified, 20 studies showed significant post-intervention differences. Sample population sizes ranged from 10 to 520, with a median of 126.5. The studies in this review were conducted with patients of mainly African-American and Latino descent. No studies were identified which focused on Asians, Pacific Islanders, or Native Americans. Interventions demonstrating mixed results included motivational interviewing, reminder devices, community health worker (CHW) delivered interventions, and pharmacist-delivered interventions. Directly observed therapy (DOT) was a successful intervention in two studies. Interventions which did not involve human contact with patients were ineffective. In this literature review, studies varied significantly in their methods and design as well as the populations studied. There was a lack of congruence among studies in the way adherence was measured and reported. No single intervention has been seen to be universally successful, particularly for patients from ethnic minority backgrounds.Keyword: Medication adherence, compliance, intervention, ethnic minority