JAK3 is principally activated by members of the interleukin-2 receptor family and plays an essential role in lymphoid development, with inactivating JAK3 mutations causing autosomal-recessive severe combined immunodeficiency (SCID). This study aimed to generate an equivalent zebrafish model of SCID and to characterize the model across the life-course. Genome editing of zebrafish jak3 created mutants similar to those observed in human SCID. Homozygous jak3 mutants showed reduced embryonic T lymphopoiesis that continued through the larval stage and into adulthood, with B cell maturation and adult NK cells also reduced and neutrophils impacted. Mutant fish were susceptible to lymphoid leukemia. This model has many of the hallmarks of human SCID resulting from inactivating JAK3 mutations and will be useful for a variety of pre-clinical applications.
We describe the clinicopathologic features of an ovine case of Krabbe disease (globoid cell leukodystrophy). Brain lesions, sometimes bilaterally distributed, were present in the cerebellar peduncles, cerebellar folia white matter, medulla, pons, and spinal cord and characterized by marked myelin loss and numerous large macrophages (globoid cells), which tended to aggregate perivascularly. Gemistocytic astrocytes were abundant, and their nuclei were frequently abnormal. The activity of the deficient enzyme, galactosylceramide β-galactosidase, was undetectable in this neurologic disorder compared to age-and breed-matched control brains, and levels of the neurotoxic substrate, psychosine, were markedly elevated.
Sheep blowfly strike imposes significant economic costs of $260 million annually from disruptions to farm management operations 1, 2 associated with high labour cost of controlling flystrike, 3 sheep morbidity and mortality, and loss of wool productivity. 4 Mulesing, the surgical removal of skin from the breech which minimises soiling and reduces susceptibility to flystrike, is performed without anaesthetic and is therefore perceived as cruel and painful as reflected by physiological and behavioural alterations in affected lambs. 5,6 Intra-dermal sodium lauryl sulfate (SLS) was trialled in this study as a potential chemical alternative to mulesing. A sound mulesing alternative would ideally provide efficient wound healing and hairless scar formation which increases the bare area of the breech while causing minimal discomfort to the animal.In a sighting study, 3 Merino wethers were given intra-dermal injections of SLS at specific sites on the flank which were biopsied at different time points over 28 days. Assessments were made on gross and histological changes of wound healing as well as early behavioural indicators of pain.Based on the results of the sighting study, the following protocol refinements were made for the main study which used 6 Merino wethers, to:1) reduce biopsy frequency with concentration around specimens of histopathologic interest;2) expand lesion parameters and sharpen the grading process;3) improve SLS delivery using a pressurized needleless applicator; 4) incorporate analysis of SLS's mode of action at the ultrastructural level; 5) improve the approach for pain assessment.Treated sheep showed minimal behavioural or postural indicators of pain or discomfort, their appetite was normal and there was a net gain in body weight, when compared with their untreated cohorts. Gross appearance of the treatment site consisted of initial swelling which subsided by day 14 leaving a firm, slightly raised, crust. At day 21, the treated area was depressed and covered by a scab (eschar) which partially sloughed off by day 28.Histological examination revealed necrosis of soft tissue structures (including hair bulbs, collagen, vessels and nerves) in the subcutis and deep dermis at 2 minutes after treatment, followed by subsequent additional ischaemic necrosis of the superficial dermis and epidermis with progressive inflammation, proliferation and remodelling of the wound. Fibroplasia and angiogenesis were accompanied with reepithelialisation starting at day 7, subjacent to areas of full dermal-epidermal
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