Effects of vatinoxan in dogs premedicated with medetomidine and butorphanol followed by sevoflurane anaesthesia : a randomized clinical study

Publisher Copyright: © 2022 The Author(s)Objective: To investigate effects of vatinoxan in dogs, when administered as intravenous (IV) premedication with medetomidine and butorphanol before anaesthesia for surgical castration. Study design: A randomized, controlled, blinded, clinical trial. Animals: A total of 28 client-owned dogs. Methods: Dogs were premedicated with medetomidine (0.125 mg m−2) and butorphanol (0.2 mg kg−1) (group MB; n = 14), or medetomidine (0.25 mg m−2), butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2) (group MB-VATI; n = 14). Anaesthesia was induced 15 minutes later with propofol and maintained with sevoflurane in oxygen (targeting 1.3%). Before surgical incision, lidocaine (2 mg kg−1) was injected intratesticularly. At the end of the procedure, meloxicam (0.2 mg kg−1) was administered IV. The level of sedation, the qualities of induction, intubation and recovery, and Glasgow Composite Pain Scale short form (GCPS-SF) were assessed. Heart rate (HR), respiratory rate (fR), mean arterial pressure (MAP), end-tidal concentration of sevoflurane (FE′Sevo) and carbon dioxide (PE′CO2) were recorded. Blood samples were collected at 10 and 30 minutes after premedication for plasma medetomidine and butorphanol concentrations. Results: At the beginning of surgery, HR was 61 ± 16 and 93 ± 23 beats minute−1 (p = 0.001), and MAP was 78 ± 7 and 56 ± 7 mmHg (p = 0.001) in MB and MB-VATI groups, respectively. No differences were detected in fR, PE′CO2, FE′Sevo, the level of sedation, the qualities of induction, intubation and recovery, or in GCPS-SF. Plasma medetomidine concentrations were higher in group MB-VATI than in MB at 10 minutes (p = 0.002) and 30 minutes (p = 0.0001). Plasma butorphanol concentrations were not different between groups. Conclusions and clinical relevance: In group MB, HR was significantly lower than in group MB-VATI. Hypotension detected in group MB-VATI during sevoflurane anaesthesia was clinically the most significant difference between groups.Peer reviewe

Sublingual administration of detomidine to calves prior to disbudding: a comparison with the intravenous route.

Objective: To study the effects of oromucosal detomidine gel administered sublingually to calves prior to disbudding, and to compare its efficacy with intravenously administered detomidine. Study design: Randomised, prospective clinical study. Animals: Twenty dairy calves aged 12.4 ± 4.4 days (mean ± SD), weight 50.5 ± 9.0 kg. Methods: Detomidine at 80 μg kg-1 was administered to ten calves sublingually (GEL) and at 30 μg kg-1 to ten control calves intravenously (IV). Meloxicam (0.5 mg kg-1) and  local anaesthetic (lidocaine 3 mg kg-1) were administered before heat cauterization of horn buds. Heart rate (HR), body temperature and clinical sedation were monitored over  240 minutes. Blood was collected during the same period for drug concentration  analysis. Pharmacokinetic variables were calculated from the plasma detomidine  concentration-time data using non-compartmental methods.  Results: The maximum plasma detomidine concentration after GEL was 2.1 ± 1.2 ng  mL-1 (mean ± SD) and the time of maximum concentration was 66.0 ± 36.9 minutes. The bioavailability of detomidine was approximately 34% with GEL. Similar sedation  scores were reached in both groups after administration of detomidine, but maximal sedation was reached earlier in the IV group (10 minutes) than in the GEL group (40 minutes). HR was lower after IV than GEL from 5 to 10 minutes after administration. All animals were adequately sedated, and we were able to administer local anaesthetic without resistance to all of the calves before disbudding. Conclusions and clinical relevance: Oromucosally administered detomidine is an  effective sedative agent for calves prior to disbudding.Peer reviewe

Dominant Distal Myopathy 3 (MPD3) Caused by a Deletion in the HNRNPA1 Gene

Background and Objectives To determine the genetic cause of the disease in the previously reported family with adult-onset autosomal dominant distal myopathy (myopathy, distal, 3; MPD3). Methods Continued clinical evaluation including muscle MRI and muscle pathology. A linkage analysis with single nucleotide polymorphism arrays and genome sequencing were used to identify the genetic defect, which was verified by Sanger sequencing. RNA sequencing was used to investigate the transcriptional effects of the identified genetic defect. Results Small hand muscles (intrinsic, thenar, and hypothenar) were first involved with spread to the lower legs and later proximal muscles. Dystrophic changes with rimmed vacuoles and cytoplasmic inclusions were observed in muscle biopsies at advanced stage. A single nucleotide polymorphism array confirmed the previous microsatellite-based linkage to 8p22-q11 and 12q13-q22. Genome sequencing of three affected family members combined with structural variant calling revealed a small heterozygous deletion of 160 base pairs spanning the second last exon 10 of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) gene, which is in the linked region on chromosome 12. Segregation of the mutation with the disease was confirmed by Sanger sequencing. RNA sequencing showed that the mutant allele produces a shorter mutant mRNA transcript compared with the wild-type allele Immunofluorescence studies on muscle biopsies revealed small p62 and larger TDP-43 inclusions. Discussion A small exon 10 deletion in the gene HNRNPA1 was identified as the cause of MPD3 in this family. The new HNRNPA1-related phenotype, upper limb presenting distal myopathy, was thus confirmed, and the family displays the complexities of gene identification.Peer reviewe

Uterine Leiomyoma-Linked MED12 Mutations Disrupt Mediator-Associated CDK Activity

Peer reviewe

Effects of vatinoxan in dogs premedicated with medetomidine and butorphanol followed by sevoflurane anaesthesia : a randomized clinical study

Publisher Copyright: © 2022 The Author(s)Objective: To investigate effects of vatinoxan in dogs, when administered as intravenous (IV) premedication with medetomidine and butorphanol before anaesthesia for surgical castration. Study design: A randomized, controlled, blinded, clinical trial. Animals: A total of 28 client-owned dogs. Methods: Dogs were premedicated with medetomidine (0.125 mg m−2) and butorphanol (0.2 mg kg−1) (group MB; n = 14), or medetomidine (0.25 mg m−2), butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2) (group MB-VATI; n = 14). Anaesthesia was induced 15 minutes later with propofol and maintained with sevoflurane in oxygen (targeting 1.3%). Before surgical incision, lidocaine (2 mg kg−1) was injected intratesticularly. At the end of the procedure, meloxicam (0.2 mg kg−1) was administered IV. The level of sedation, the qualities of induction, intubation and recovery, and Glasgow Composite Pain Scale short form (GCPS-SF) were assessed. Heart rate (HR), respiratory rate (fR), mean arterial pressure (MAP), end-tidal concentration of sevoflurane (FE′Sevo) and carbon dioxide (PE′CO2) were recorded. Blood samples were collected at 10 and 30 minutes after premedication for plasma medetomidine and butorphanol concentrations. Results: At the beginning of surgery, HR was 61 ± 16 and 93 ± 23 beats minute−1 (p = 0.001), and MAP was 78 ± 7 and 56 ± 7 mmHg (p = 0.001) in MB and MB-VATI groups, respectively. No differences were detected in fR, PE′CO2, FE′Sevo, the level of sedation, the qualities of induction, intubation and recovery, or in GCPS-SF. Plasma medetomidine concentrations were higher in group MB-VATI than in MB at 10 minutes (p = 0.002) and 30 minutes (p = 0.0001). Plasma butorphanol concentrations were not different between groups. Conclusions and clinical relevance: In group MB, HR was significantly lower than in group MB-VATI. Hypotension detected in group MB-VATI during sevoflurane anaesthesia was clinically the most significant difference between groups.Peer reviewe

Donor genetic burden for cerebrovascular risk and kidney transplant outcome

Kidney grafts from donors who died of stroke and related traits have worse outcomes relative to grafts from both living donors and those who died of other causes. We hypothesise that deceased donors, particularly those who died of stroke, have elevated polygenic burden for cerebrovascular traits. We further hypothesise that this donor polygenic burden is associated with inferior graft outcomes in the recipient. Using a dataset of 6666 deceased and living kidney donors from seven different European ancestry transplant cohorts, we investigated the role of polygenic burden for cerebrovascular traits (hypertension, stroke, and intracranial aneurysm (IA)) on donor age of death and recipient graft outcomes. We found that kidney donors who died of stroke had elevated intracranial aneurysm and hypertension polygenic risk scores, compared to healthy controls and living donors. This burden was associated with age of death among donors who died of stroke. Increased donor polygenic risk for hypertension was associated with reduced long term graft survival (HR: 1.44, 95% CI [1.07, 1.93]) and increased burden for hypertension, and intracranial aneurysm was associated with reduced recipient estimated glomerular filtration rate (eGFR) at 1 year. Collectively, the results presented here demonstrate the impact of inherited factors associated with donors' death on long-term graft function

Donor genetic burden for cerebrovascular risk and kidney transplant

Background and hypothesis: Kidney grafts from donors who died of stroke and related traits have worse outcomes relative to grafts from both living donors and those who died of other causes. We hypothesise that deceased donors, particularly those who died of stroke, have elevated polygenic burden for cerebrovascular traits. We further hypothesise that this donor polygenic burden is associated with inferior graft outcomes in the recipient. Methods: Using a dataset of 6666 deceased and living kidney donors from seven different European ancestry transplant cohorts, we investigated the role of polygenic burden for cerebrovascular traits (hypertension, stroke, and intracranial aneurysm (IA)) on donor age of death and recipient graft outcomes. Results: We found that kidney donors who died of stroke had elevated intracranial aneurysm and hypertension polygenic risk scores, compared to healthy controls and living donors. This burden was associated with age of death among donors who died of stroke. Increased donor polygenic risk for hypertension was associated with reduced long term graft survival (HR: 1.44, 95% CI [1.07, 1.93]) and increased burden for hypertension, and intracranial aneurysm was associated with reduced recipient estimated glomerular filtration rate (eGFR) at 1 year. Conclusions: Collectively, the results presented here demonstrate the impact of inherited factors associated with donors' death on long-term graft function</p