Pilot, randomized, placebo-controlled clinical field study to evaluate the effectiveness of bupivacaine liposome injectable suspension for the provision of post-surgical analgesia in dogs undergoing stifle surgery

Abstract Background Local anesthetics are an important component of perioperative pain management, but the duration of action of available products is limited. We hypothesized that a single local infiltration of a novel bupivacaine liposome injectable suspension (AT-003) would provide clinically effective analgesia over a 72-h period. In a masked, randomized, placebo-controlled, multi-center pilot field study, dogs undergoing lateral retinacular suture placement for cranial cruciate insufficiency were randomly assigned to surgical site infiltration with AT-003 (5.3 mg/kg) or an equivalent volume of saline. Infiltration of the surgical site was done prior to closure. Primary outcome measure was the Glasgow Composite Measure Pain Scale (CMPS-SF) assessed prior to surgery and at 2, 4, 8, 12, 24, 30, 36, 48, 54, 60 and 72 h following surgery by trained individuals. Provision for rescue analgesia was employed. Repeated measures analysis of variance were utilized to test for possible differences between treatment groups and a success/failure analysis was also employed, based on the need for rescue analgesia. Results Forty-six dogs were enrolled and evaluated. For CMPS-SF scores there was a significant overall treatment effect (p = 0.0027) in favor of AT-003. There were significantly more successes in the AT-003 group compared to placebo over each time period (p = 0.0001 for 0–24 h, p = 0.0349 for 0–48 h, and p = 0.0240 for 0-72 h). No significant adverse events were seen. Conclusions AT-003 (bupivacaine liposome injectable suspension) provided measurable local analgesia over a 72-h period following post-stifle surgery surgical site tissue infiltration. Further work is indicated to develop this product for clinical use

Impact of Normothermic Preservation with Extracellular Type Solution Containing Trehalose on Rat Kidney Grafting from a Cardiac Death Donor

BACKGROUND: The aim of this study was to investigate factors that may improve the condition of a marginal kidney preserved with a normothermic solution following cardiac death (CD) in a model of rat kidney transplantation (RTx). METHODS: Post-euthanasia, Lewis (LEW) donor rats were left for 1 h in a 23°C room. These critical kidney grafts were preserved in University of Wisconsin (UW), lactate Ringer's (LR), or extracellular-trehalose-Kyoto (ETK) solution, followed by intracellular-trehalose-Kyoto (ITK) solution at 4, 23, or 37°C for another 1 h, and finally transplanted into bilaterally nephrectomized LEW recipient rats (n = 4-6). Grafts of rats surviving to day 14 after RTx were evaluated by histopathological examination. The energy activity of these marginal rat kidneys was measured by high-performance liquid chromatography (HPLC; n = 4 per group) and fluorescence intensity assay (n = 6 per group) after preservation with UW or ETK solutions at each temperature. Finally, the transplanted kidney was assessed by an in vivo luciferase imaging system (n = 2). RESULTS: Using the 1-h normothermic preservation of post-CD kidneys, five out of six recipients in the ETK group survived until 14 days, in contrast to zero out of six in the UW group (p<0.01). Preservation with ITK rather than ETK at 23°C tended to have an inferior effect on recipient survival (p = 0.12). Energy activities of the fresh donor kidneys decreased in a temperature-dependent manner, while those of post-CD kidneys remained at the lower level. ETK was superior to UW in protecting against edema of the post-CD kidneys at the higher temperature. Luminescence intensity of successful grafts recovered within 1 h, while the intensity of grafts of deceased recipients did not change at 1 h post-reperfusion. CONCLUSIONS: Normothermic storage with extracellular-type solution containing trehalose might prevent reperfusion injury due to temperature-dependent tissue edema

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G&gt;A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.</p

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.Genetics of disease, diagnosis and treatmen

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders (vol 108, pg 1692, 2021)

Neurolog

You Shake My Nerves and You Rattle My Brain

Bradykinesia; Dysphagia; Social withdrawal; Retropulsive gaitA 39-year old male with a progressive inability to perform daily activities, worsening falls and dysphagia presumed to be harbingers of early-onset Parkinson. Previous history significant for traumatic brain injury.Abnormal, intrusive eye movementMRIPositive anti-Ma2 antibodyHormonal antineoplastic agents; IV immunoglobulin1. Castle J, Sakonju A, Dalmau J, Newman-Toker DE, Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease, Nature Clinical Practice Neurology, 2 (10), 566-572, 2006. 2. Dalmau J, Graus F, Villargo A, Posner JB, Blumenthal D, Thiessen B, Sarz A, Meneses P, Rosenfeld M, Clinical analysis of anti-Ma 2 associated encephalitis, Brain, 127, 1831-1844, 2004. 3. Gerard A, Sarrot-Reynauld F, Liozon E, Cathebras P, Besson G, Robin C, Vignetto A, Monsnier J, Durieu I, Durand D, Rousset H, Neurologic presentation of Whipple disease: Report of 12 cases and review of the literature, Medicine, 81(6), 443-457, 2002. 4. Louis ED, Lynch T, Kaufman P, Fahn S, Odel J, Diagnostic guidelines in central nervous system Whipple's disease, Annals of Neurology, 40(4), 561-568, 1996. 5. Rosenfeld M, Eichen J, Wade D, Posner J, Dalmau J, Molecular and clinical diversity in paraneoplastic immunity to Ma proteins, Annals of Neurology, 50, 339-348, 2001