Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

The effect of a ketamine constant rate infusion on cardiovascular variables in sheep anesthetized at the minimum alveolar concentration of sevoflurane that blunts adrenergic responses

OBJECTIVE To evaluate the effect of a constant rate infusion of ketamine on cardiac index (CI) in sheep, as estimated using noninvasive cardiac output (NICO) monitoring by partial carbon dioxide rebreathing, when anesthetized with sevoflurane at the previously determined minimum alveolar concentration that blunts adrenergic responses (MACBAR). ANIMALS 12 healthy Dorset-crossbred adult sheep. PROCEDURES Sheep were anesthetized 2 times in a balanced placebo-controlled crossover design. Anesthesia was induced with sevoflurane delivered via a tight-fitting face mask and maintained at MACBAR. Following induction, sheep received either ketamine (1.5 mg/kg IV, followed by a constant rate infusion of 1.5 mg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (placebo). After an 8-day washout period, each sheep received the alternate treatment. NICO measurements were performed in triplicate 20 minutes after treatment administration and were converted to CI. Blood samples were collected prior to the start of NICO measurements for analysis of ketamine plasma concentrations. The paired t test was used to compare CI values between groups and the ketamine plasma concentrations with those achieved during the previous study. RESULTS Mean ± SD CI of the ketamine and placebo treatments were 2.69 ± 0.65 and 2.57 ± 0.53 L/min/m2, respectively. No significant difference was found between the 2 treatments. Mean ketamine plasma concentration achieved prior to the NICO measurement was 1.37 ± 0.58 µg/mL, with no significant difference observed between the current and prior study. CLINICAL RELEVANCE Ketamine, at the dose administered, did not significantly increase the CI in sheep when determined by partial carbon dioxide rebreathing.

The Role of Multimodality Imaging in Left-Sided Prosthetic Valve Dysfunction

Prosthetic valve (PV) dysfunction (PVD) is a complication of mechanical or biological PV. Etiologic mechanisms associated with PVD include fibrotic pannus ingrowth, thrombosis, structural valve degeneration, and endocarditis resulting in different grades of obstruction and/or regurgitation. PVD can be life threatening and often challenging to diagnose due to the similarities between the clinical presentations of different causes. Nevertheless, identifying the cause of PVD is critical to treatment administration (thrombolysis, surgery, or percutaneous procedure). In this report, we review the role of multimodality imaging in the diagnosis of PVD. Specifically, this review discusses the characteristics of advanced imaging modalities underlying the importance of an integrated approach including 2D/3D transthoracic and transesophageal echocardiography, fluoroscopy, and computed tomography. In this scenario, it is critical to understand the strengths and weaknesses of each modality according to the suspected cause of PVD. In conclusion, for patients with suspected or known PVD, this stepwise imaging approach may lead to a simplified, more rapid, accurate and specific workflow and management.

Therapeutic Benefits of Balneotherapy on Quality of Life of Patients with Rheumatoid Arthritis: A Systematic Review

Background: Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease. RA symptoms make the disease disabling and strongly impact the quality of life of patients. Among the available forms of treatment, balneotherapy seems to be one of the most common forms of nonpharmacological treatment for rheumatic disease. The aim was to explore the effectiveness of balneotherapy for improving the quality of life of patients with RA. Methods: Pubmed, Scopus, Web of Science and The Cochrane library were searched for randomized or clinical controlled trials published in English or Spanish until May 2021. Risk of bias of included articles were assessed using the Cochrane tool. A total 535 records were retrieved, and seven met the inclusion criteria. All the included studies showed statistically significant improvements in the quality of life of patients who received balneotherapy treatment despite differences in treatment administration. Sessions should be approximately 20 min long and use natural mineral waters enriched with elements, or mud, at a water temperature between 35–38 °C. Conclusions: Balneotherapy benefits the quality of life of people with RA. The obtained results show positive effects for both mineral bathing and immersion in sand or mud on the quality of life of people who suffer from RA.

Electrochemical Strategies for the Screening of Synthetic Cannabinoid BB-22 (QUCHIC) within a Toxicological Specimen

Synthetic Cannabinoids (SC) are amongst the most prevalent class of novel psychoactive substances (NPS) which have emerged. The increase in hospitalisation and fatalities as a result of the prevalence of these SC and their abuse, highlights the necessity for the rapid and reliable screening for the substance within toxicological samples. Being able to rapidly screen for these substances would aim to improve overdose triage and ultimately improve treatment administration. Not only this but it would have further advantages for in-field applications such as the identification of drivers under the influence. To this avail we investigate the ability of a simple electrochemical screening strategy for the detection of SC, BB-22 and its primary metabolite BB-22-3-Carboxyindole. Assessment of the feasibility of the strategy for implementation into toxicological sample analysis was performed through detection not only under ideal electrolyte conditions (down to 5 µM for BB-22 and 2 µM for its metabolite) but also within the complex biological matrix of human pooled serum (between 200 and 700 µM), a relevant matrix it would likely encounter if employed within this field.

Incidence of Second Malignancies in the History of Chronic Lymphocytic Leukemia

Introduction The occurrence of other neoplasms in patients diagnosed with chronic lymphocytic leukemia (CLL) is a known but insufficiently studied complication, highlighting the need for further research. Our study aims to analyze the incidence of other malignancies in CLL. Methods We performed a retrospective observational study of patients diagnosed with CLL between 2000-2016 at our center. Variables collected included: demographics, stage at diagnosis, treatment, response to treatment, death, other neoplasm (type, date of diagnosis, outcome), biomarker profiles studied by karyotyping, FISH, immunoglobulin heavy chain gene variable region mutational status, and TP53 mutational status. A descriptive study was performed. Quantitative variables are described as medians with their range, and qualitative variables as percentages. The relationship between qualitative variables and the development of second malignancies was performed using Chi-square and Fisher's exact test. Survival analyses were performed using the Kaplan-Meier method and the difference between groups was analyzed using the log-rank test. Results A total of 182 patients were evaluated, 104 men (57%) and 78 women (43%); median age: 74 years (39 - 97). Most patients were diagnosed at early stages (74% at Rai stage 0 and 84% at Binet stage A) and the median CIRS scale score at diagnosis was 4 (0 - 15). With a median follow-up of 76 months (20-212), 77/182 (42%) patients had received ≥1 line(s) of treatment: 1: 53%, 2: 26%, 3: 8%, ≥4: 13%. Forty-nine cases (27%) were reported with other malignancies in addition to CLL; cases with Richter transformation (n=5, 2.7%) were excluded. The diagnosis of CLL preceded the other neoplasm in 33/182 cases (18%): 8 hematologic and 27 non-hematologic neoplasms. Half of the hematologic malignancies involved MGUS (n=4), 1 mutated JAK2 (V617F) cMPN, 1 AML and 1 MALT lymphoma. As for non-hematologic tumors, non-melanoma skin cancer accounted for 30% of cases (n=8), followed by breast cancer (n=5, 18.5%). Neoplasms of the stomach, colon, liver, bladder and prostate together accounted for 37%, in the same proportion each (n=2, 7.4%). The remaining neoplasms corresponded to lung and bronchus, kidney, melanoma and pancreas. Five of the 27 patients had a third solid organ neoplasm, with non-melanoma skin cancer again being the most frequent (n=2). The other neoplasms were lung, small bowel and thyroid. The incidence of second neoplasms was higher in treated patients (26% vs. 12.4%, p=0.019). The incidence of a second hematologic malignancy was related to treatment administration (9%) compared to 1% in untreated patients (p=0.011), especially in those with ≥ 3 lines (37.5% vs. 3%), p=0.024. We could not find any association between the variables analyzed and the development of second non-hematologic malignancies. The development of second neoplasms after the diagnosis of CLL did not have a negative impact on the overall survival of these patients. Conclusions The incidence of second malignancies is high in patients with CLL, being higher in those patients who have received treatment, and especially in those with a greater number of lines received. In contrast, the development of solid tumors did not seem to be affected by treatment administration, which should motivate further investigation in specific subgroups of patients. In our series, the development of second neoplasms after the diagnosis of CLL did not have a negative impact on the overall survival of these patients. Disclosures Gonzalez-Lopez: Novartis: Other: Advisoryboard and speakers honoraria, Research Funding; Amgen: Other: Advisory board and speakers honoraria, Research Funding; Sobi: Other: Advisory board honoraria; Grifols: Other: Advisory board honoraria.

Strategic administration of an appeasing substance to improve performance and physiological responses of Bos indicus feedlot cattle

This study was designed to evaluate the timing of administration of the bovine appeasing substance (BAS) on performance and physiological responses of Bos indicus feedlot cattle. Nellore bulls (n = 100) were ranked by initial body weight (BW; 341 ± 18.5 kg) and assigned to receive BAS (n = 50) or placebo (CON; n = 50) on d -2 of the experiment. Treatments (5 mL) were applied topically to the nuchal skin area of each bull. Bulls were loaded into commercial livestock trailers immediately after treatment administration, transported for 880 km, and unloaded on d -1 at a commercial feedyard. On d 0, bulls within each treatment were again assigned to receive, in a 2 x 2 factorial arrangement, BAS or CON as previously described (25 bulls/treatment combination). Upon treatment administration on d 0, bulls were housed in 12 feedlot pens (3 pens/treatment) for a 108-d feeding period, which was divided into an adaptation (d 0 – 19), growing (d 20 – 60), and finishing (d 61 – 108) phases. Dry matter intake (DMI) was measured daily from d 0 to 108, whereas blood samples and hair from the tail switch were collected on d -2, 0, 19, 60, and 108. Administration of BAS prior to loading (d -2) improved ADG, FE, and DMI during adaptation and across the 108-d feeding period (P ≤ 0.08), resulting in greater (P = 0.03) hot carcass weight and dressing percentage upon slaughter on d 109. A treatment × day interaction was detected for serum glucose concentrations (P = 0.05), which was greater (P = 0.03) on d 60 of the feeding period in bulls receiving CON prior to loading. Administration of BAS at feedlot entry (d 0) improved DMI, ADG, and FE during adaptation (P ≤ 0.05), but it did not impact (P ≥ 0.18) performance and carcass traits during the 108-d feeding period. Bulls administered BAS prior to loading and at feedlot entry had less (P ≤ 0.05) mean serum cortisol concentrations across the 108-d feeding period (loading × feedlot entry interaction; P = 0.10), and greater (P ≤ 0.05) serum insulin concentration on d 60 (loading × feedlot entry × day interaction; P = 0.05). In summary, BAS administration prior to loading increased overall feedlot performance of Nellore bulls. These outcomes were noted in bulls that received or not a second BAS administration at feedlot entry, suggesting that the benefits of BAS are exploited when this substance is administered before transport to the feedlot.

Superovulatory responses using pregnant mare serum gonadotropin hormone in Murrah buffalo cows

Superovulation plays an important role in embryo transfer program. A preliminary study carried out in the Research Institute for Animal Production evaluated superovulatory responses in Murrah buffalo cows using pregnant mare serum gonadotropin (PMSG) hormone. The three buffalo cows were estrus synchronized using 5 ml prostaglandin (PGF) twice, with an interval of 11 days. PMSG was injected intra-muscularly 3000 IU on day-10 after estrus. Prostaglandins were administered 48 hours after PMSG injection. Fixed-Time artificial insemination (FTAI) was carried out at 72 hours after the last PGF treatment. Administration of hCG 2 ml/head was given at the time of FTAI. A non-surgery flushing was performed on day 6 after FTAI. Parameters observed using ultrasonography (USG) were diameter of follicle (DFL), total follicle (TFL), and number embryos (NE). Data were analyzed descriptively. The mean of DFL before PMSG treatment was 8.2 mm and after PMSG treatment was 12.5 mm. The mean of TFL before PMSG treatment was 7.7 and after PMSG treatment was 16.1. The NE obtained was one degenerative embryo. Superovulation using PMSG increased TCL and DFL. It can be concluded that the Murrah buffalo cows superovulated by PMSG showed a good response but no transferable embryo was found.

PSX-A-2 Late-Breaking: Acute Endotoxinemia May Increase Intercostal Temporary Mechanical Nociception in Wethers

Systemic inflammation induced by lipopolysaccharide (LPS; endotoxin) is associated with generalized hyperalgesia in humans and some animal models. However, the effects of endotoxin-induced inflammation on pain threshold in livestock, such as sheep, is unknown. Eight wethers [~1 year of age; 61.3 ± 0.5 kg BW] were administered saline (2 mL; n = 4) or endotoxin (2 mL; 400 ng of LPS / kg BW; n = 4) intravenously. A handheld algometric unit was used to administer temporary mechanical nociception (TMN) before (Day -2) and after (Day 1) treatment administration by the same person three times at two locations on the right thorax (intercostal spaces 6 and 9). Two-way ANOVA was completed in SAS v9.4 (Cary, NC). There were effects of day (P < 0.001) and location (P < 0.0001) on TMN, such that the force needed to induce TMN on Day -2 (2.04 +/- 0.15 kgF) was less than on Day 1 (2.93 +/- 0.15 kgF) and the force needed to induce TMN at intercostal space 6 (1.81 +/- 0.15 kgF) was less than at intercostal space 9 (3.15 +/- 0.15 kgF). While there was no effect of treatment (P = 0.96), or interaction of treatment and location (P = 0.19), day and location (P = 0.25), or treatment and day and location (P = 0.49), there was a tendency for an interaction of treatment and day (P = 0.06), such that TMN was not different on Day 1 (2.73 +/- 0.30 kgF) and Day -2 (2.24 +/- 0.30 kgF) for animals receiving saline but was greater on Day 1 (3.12 +/- 0.30 kgF) than Day -2 (1.83 +/- 0.30 kgF) for animals receiving LPS. While systemic inflammation is associated with reduced pain threshold in some models, acute LPS-induced inflammation may increase intercostal TMN in castrated sheep.

PSX-A-25 Late-Breaking: The Effects of Chronic Endotoxinemia on Rectal and Subcutaneous Temperature in Wethers

Lipopolysaccharide (LPS) is responsible for inflammation and fever resulting from infections associated with gram-negative bacteria. Twenty-two wethers underwent a chronic LPS challenge in which they were assigned to one of five groups – control (CON; saline IV daily; n=4), single acute dose (SAD; 400 ng/kg bw on D1 and saline D2-7 IV; n=4), daily acute dose (DAD; 400 ng/kg bw IV; n=5), daily increasing dose (DID; 400 ng/kg bw with 20% increase each day IV; n=5), and subcutaneous steady dose (SSD; 20 ug /kg bw per day SQ; n=4). Wethers were equipped with subcutaneous temperature (SCT) sensors (data analyzed hourly; -1 to 148 h) and rectal temperatures (RT) were determined multiple times a day for six days (-1 to 147 h). Two-way ANOVA was completed using SAS v9.4 (Cary, NC) on both the SCT and RT data. There was an effect of treatment, time and an interaction of time and treatment (all P < 0.0001) on RT. Rectal temperature was greater than CON (38.9°C) in SAD (40.5°C), DAD (40.5°C), and DID (40.9°C) groups 3 h after treatment on D1, and the SSD (40.5°C) by 5 h after treatment on D1. While the greatest RT was at 5 h after treatment on D1 for SAD (41.1°C), DAD (41.3°C) and DID (41.8°C) groups. Compared to CON (~38.6°C), RT was increased 3 h after treatment administration on D2 (40.1°C), D3 (39.9°C), D5 (40.1°C), and D6 (39.9°C) for DAD and on D2 (40.1°C) and D5 (39.9°C) for DID. For SCT, there were effects of treatment and time (P < 0.0001), but no interaction (P = 1.00). The SSD group had the greatest SCT (38.3°C) followed by DID (37.7°C), DAD (37.5°C), SAD (37.3°C) and CON (36.9°C). Overall, chronic endotoxin did induce an increase in RT and SCT, but differently with RT changing over time.