Clinical features of cats with aqueous tear deficiency: a retrospective case series of 10 patients (17 eyes)

Objectives The aim of this study was to describe the clinical findings, diagnostic test results and response to therapy of cats with Schirmer tear test 1 (STT-1) values below the reference interval. Methods The medical records of three institutions were searched for cats with ocular surface disease and STT-1 values/min, confirmed at two or more separate visits. Results Ten cats (17 eyes) were included. The mean ± SD (range) age and STT-1 values in affected eye(s) were 6.1 ± 5.7 (0.2–16) years and 2.4 ± 3.1 (0–8) mm/min, respectively. Concurrent ocular surface disease was bilateral in 5/10 cats. Clinical signs included conjunctivitis (14/17 eyes), corneal ulceration (6/17 eyes), non-ulcerative keratitis (4/17 eyes), symblepharon (4/17 eyes), eosinophilic keratitis (3/17 eyes), corneal sequestrum (3/17 eyes), corneal fibrosis (2/17 eyes) and meibomitis (2/17 eyes). Management included topically applied lacrimomimetics, antiviral drugs, corticosteroids or immunomodulatory drugs; orally administered famciclovir; or surgical procedures, in various combinations. Response to therapy (defined as an increase in STT-1 value of ⩾5 mm/min) was transient (seen at a single reassessment) in 65% of eyes and sustained (seen at ⩾2 consecutive reassessments) in 18% of eyes. Conclusions and relevance Clinical features seen in cats with low STT-1 values are described, although the association between aqueous deficiency and the reported ocular changes is unknown at this time. We encourage clinicians to assess the tear film in cats with ocular surface disease, and initiate therapy with lacrimomimetics if STT-1 values are repeatedly below normal. Such information will further define aqueous tear deficiency in cats, providing a better understanding of disease prevalence, pathogenesis and treatment

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.

Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs

Current status of clinical outcome measures in inclusion body myositis: a systematised review

OBJECTIVES: Sporadic inclusion body myositis (IBM) is a debilitating idiopathic inflammatory myopathy (IIM) which affects hand function, ambulation, and swallowing. There is no approved pharmacological therapy for IBM, and there is a lack of suitable outcome measure to assess the effect of an intervention. The IBM scientific interest group under IMACS reviewed the previously used outcome measures in IBM clinical studies to lay the path for developing a core set of outcome measures in IBM. METHODS: In this systematised review, we have extracted all outcome measures reported in IBM clinical studies to determine what measures were being used and to assess the need for optimising outcome measures in IBM. RESULTS: We found 13 observational studies, 17 open-label clinical trials, and 15 randomised control trials (RCTs) in IBM. Six-minute walk distance, IBM-functional rating scale (IBM-FRS), quantitative muscle testing, manual muscle testing, maximal voluntary isometric contraction testing, and thigh muscle volume measured by MRI were used as primary outcome measures. Twelve different outcome measures of motor function were used in IBM clinical trials. IBM-FRS was the most used measure of functionality. Swallowing function was reported as a secondary outcome measure in only 3 RCTs. CONCLUSIONS: There are inconsistencies in using outcome measures in clinical studies in IBM. The core set measures developed by the IMACS group for other IIMs are not directly applicable to IBM. As a result, there is an unmet need for an IBM-specific core set of measures to facilitate the evaluation of new potential therapeutics for IBM

Altered Dopamine and Serotonin Metabolism in Motorically Asymptomatic R6/2 Mice

The pattern of cerebral dopamine (DA) abnormalities in Huntington disease (HD) is complex, as reflected by the variable clinical benefit of both DA antagonists and agonists in treating HD symptoms. In addition, little is known about serotonin metabolism despite the early occurrence of anxiety and depression in HD. Post-mortem enzymatic changes are likely to interfere with the in vivo profile of biogenic amines. Hence, in order to reliably characterize the regional and chronological profile of brain neurotransmitters in a HD mouse model, we used a microwave fixation system that preserves in vivo concentrations of dopaminergic and serotoninergic amines. DA was decreased in the striatum of R6/2 mice at 8 and 12 weeks of age while DA metabolites, 3-methoxytyramine and homovanillic acid, were already significantly reduced in 4-week-old motorically asymptomatic R6/2 mice. In the striatum, hippocampus and frontal cortex of 4, 8 and 12-week-old R6/2 mice, serotonin and its metabolite 5-hydroxyindoleacetic acid were significantly decreased in association with a decreased turnover of serotonin. In addition, automated high-resolution behavioural analyses displayed stress-like behaviours such as jumping and grooming and altered spatial learning in R6/2 mice at age 4 and 6 weeks respectively. Therefore, we describe the earliest alterations of DA and serotonin metabolism in a HD murine model. Our findings likely underpin the neuropsychological symptoms at time of disease onset in HD

Establishment and characterization of turtle liver organoids provides a potential model to decode their unique adaptations

Painted turtles are remarkable for their freeze tolerance and supercooling ability along with their associated resilience to hypoxia/anoxia and oxidative stress, rendering them an ideal biomedical model for hypoxia-induced injuries (including strokes), tissue cooling during surgeries, and organ cryopreservation. Yet, such research is hindered by their seasonal reproduction and slow maturation. Here we developed and characterized adult stem cell-derived turtle liver organoids (3D self-assembled in vitro structures) from painted, snapping, and spiny softshell turtles spanning ~175My of evolution, with a subset cryopreserved. This development is, to the best of our knowledge, a first for this vertebrate Order, and complements the only other non-avian reptile organoids from snake venom glands. Preliminary characterization, including morphological, transcriptomic, and proteomic analyses, revealed organoids enriched in cholangiocytes. Deriving organoids from distant turtles and life stages demonstrates that our techniques are broadly applicable to chelonians, permitting the development of functional genomic tools currently lacking in herpetological research. Such platform could potentially support studies including genome-to-phenome mapping, gene function, genome architecture, and adaptive responses to climate change, with implications for ecological, evolutionary, and biomedical research

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3–4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half‐life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr−1 kg−1, volume of distribution at steady‐state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half‐life, volume of distribution at steady‐state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg−1 hr−1. Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half‐life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.This is the pre-peer reviewed version of the following article: Smith, J. S., J. F. Coetzee, I. W. G. Fisher, D. J. Borts, and J. P. Mochel. "Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation." Journal of Veterinary Pharmacology and Therapeutics 41, no. 4 (2018): 555-561, which has been published in final form at DOI: 10.1111/jvp.12501. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.</p