Disruptive Lesions Research Articles

In Vivo Tumorigenicity of the 20q11.21 Amplicon in an Engraftment Model of hPSCs and Differentiated Liver Cells.

Human pluripotent stem cells (hPSCs) are a promising source of somatic cells for clinical applications and disease modelling. However, during culture they accumulate genetic aberrations such as amplification of 20q11.21 which occurs in approximately 20% of extensively cultured hPSC lines and confers a BCL2L1-mediated survival advantage. During the production of the large number of cells required for transplantation and therapy these aberrations may become unavoidable which has important safety implications for therapies and may also impact upon disease modelling. Presently, these risks are poorly understood; whilst it is apparent that large-scale genetic aberrations can pose an oncogenic risk, the risks associated with smaller, more insidious changes have not been fully explored. In this report, the effects of engraftment of human embryonic stem cells (hESCs) and hESC-derived hepatocyte-like cells (HLCs) with and without amplification of the 20q11.21 minimal amplicon and isochromosome 20q (i20q) in SCID-beige mice are presented. The cells were tracked in vivo using a luminescent reporter over a period of approximately four months. Intrasplenic injection of hESCs showed greater engraftment potential and the formation of more severely disruptive lesions in the liver and spleen of animals injected with cells containing 20q11.21 compared with i20q and wild type. HLCs with 20q11.21 engrafted more successfully and formed more severely disruptive lesions than wild type cells or cells with i20q. These results reinforce the notion that karyotyping of therapeutic hPSC is required for transplant, and suggest that screening for known common aberrations is necessary. Further work to identify commonly arising genetic aberrations should be performed and routine screening for hPSCs intended for therapeutic use should be used.

Treatment protocols for claw horn lesions and their impact on lameness recovery, pain sensitivity, and lesion severity in moderately lame primiparous dairy cows.

This study aims to investigate the effects of routine treatment protocols for claw horn disruptive lesions (CHDL) on lameness recovery rates, pain sensitivity, and lesion severity in moderately lame primiparous cows. A cohort of first parity cows was recruited from a single commercial dairy herd and randomly allocated to five treatments, comprising four lame groups (LTNB, LTN, LTB, and LT) and a single group non-lame group. Eligibility criteria for the lame cows included a first lameness score (score 3/5), presence of CHDL on a single foot, good body condition score of 3.0 to 3.5, and no history of previous lameness. LTNB received a combination of therapeutic trim, administration of a non-steroidal anti-inflammatory drug (NSAID; Ketoprofen) for 3 days, and hoof block on the healthy claw. Both LTN and LTB received the same treatment as LTNB without hoof block and NSAID, respectively. LT received only a therapeutic trim, whereas non-LT (negative control) received either a therapeutic or preventive trim. Pain sensitivity was assessed using the limb withdrawal reflex while lesion severity was recorded using the International Committee Animal Records (ICAR) Atlas guide. The enrolled cows were observed at weekly intervals, and the primary outcomes were assessed 28 days after treatment. The number (%) of recovered cows was 15 of 20 (75%), 13 of 21 (61.9%), 6 of 14 (42.9%), and 6 of 15 (40%) for LTNB, LTN, LTB, and LT, respectively. LTNB had significantly higher odds of successful treatment (OR = 4.5; 95% 1.1-19.1) compared to LT. Pain sensitivity based on limb withdrawal reflex was absent in a significantly higher number of cows (15/20; 75.0%) in LTNB compared to LTB and LT. LTB had a significantly lower lesion severity score in comparison to LTN. Overall, cows with limb withdrawal at day 28 after treatment were less likely (OR = 0.06; 95% CI 0.01-0.24) to develop a non-lame score. In conclusion, the treatment with therapeutic trim, hoof block, and NSAID led to better recovery and reduced pain sensitivity in moderately lame primiparous cows with good BCS compared to those that received only therapeutic trim. Further research on the changes within the hoof capsule following various treatment protocols is needed to elucidate the clinical benefits observed in this study.

Comparison of claw horn disruption lesions in four dairy herds using two different trimming techniques: A case study

Claw disorders are a major problem for health, welfare, and economy in dairy production. This retrospective observational study investigated the association between cow-level prevalence of claw horn disruptive lesions and two different trimming methods - the traditional Danish Method (DAM) and the White Line Atlas Method (WLAM). Trimming records from four herds in Denmark over a 4-year period were analysed. Within each herd, claw trimming was performed with the DAM for the first 2 years, and the WLAM for the next 2 years. The data comprised 3316 claw trimmings of 1027 cows with the WLAM and 3898 claw trimmings of 1080 cows with the DAM. The association between claw trimming method and claw lesions was determined using binominal logistic analysis. There were significant differences between trimming methods for sole haemorrhage (odds ratio = 0.44), sole ulcer (odds ratio = 0.42), and white line separation (odds ratio = 0.64), with a lower prevalence during the period of trimming with the WLAM. No significant difference between trimming methods could be found in the occurrence of white line abscess or double sole. The lower prevalence of claw horn disruption lesions found in this study when cows were trimmed with WLAM justifies and necessitates further experimental studies of claw trimming methods to validate these findings.

Tissue Morphology and Expression of Myelin Basic Protein and Inducible Nitric Oxide Synthase in Wistar Rats Treated with Sodium Arsenite: The Beneficial Effects of Ethanol Leaf Extract of Tridax Procumbens

Arsenical compounds cause significant issues in both humans and animals including an increased risk of developing cancer. In the present study, the role of Tridax procumbens leaf extract (TPLE) on the toxicities caused by sodium arsenite in rats was assessed. Thirty‐two male Wistar rats (80–100 g) were equally assigned into four groups (A–D) and treatment was as follows: Group A (control) were administered 1 ml/kg body weight (bwt.) olive oil; B: 2.5 mg/kg bwt sodium arsenite (SA); C: 100 mg/kg bwt TPLE; D: 100 mg/kg bwt TPLE and 2.5 mg/kg bwt SA. TPLE was administered daily for 14 days while SA was given on day 7 and 14. The route of administration was oral. Histological analysis and expression of inducible nitric oxide synthase (iNOS) (in liver, lung, cerebrum and cerebellum) and myelin basic protein (MBP) (in cerebellum) was performed. Histological examinations showed that sodium arsenite caused disruptive lesions in the liver, lungs and cerebral cortex of rats in group B. However, Tridax procumbens extract ameliorated these effects when co‐administered with arsenite in group D. There was significant elevation (p<0.05) in the expression of iNOS protein in the tissues of rats in group B when compared to other groups as revealed by immunostaining. In addition, the white mater cells of the cerebellum showed significant elevation (p<0.05) in the expression of myelin basic protein in group C as compared to groups A, B and D when quantified. In conclusion, the ethanol leaf extract of Tridax procumbens shows beneficial effects against sodium arsenite induced toxicities in Wistar rats.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Development of a Device-Assisted Nerve-Regeneration Procedure in Disruptive Lesions of the Brachial Plexus.

We describe the development of a new surgical procedure to be used in the treatment of disruptive brachial plexus (BP) lesions. It is centered on an artificial device designed to assist nerve regeneration by providing a confined and protected environment. Nerve fibers can repair inside the device, while the adverse massive scar-tissue formation is limited to the outside of the device. Steps in the development of the procedure were (1) definition of the rationale, (2) design of the device, (3) choice of an in vivo translational model, (4)refinement of the surgical procedure, and (5) performance of an in vivo pilot study as a proof of concept. An interdisciplinary team from several laboratories was involved in this work over a period of 6 years. Results showed the absence of significant scar tissue in the regenerate and the presence of myelinated fibers aligned proximodistally between the stumps. This surgical approach can be seen not only as a definitive treatment but also as an early examination and stabilization before some different surgery will be later performed. It may also be used as additional protection for traditional surgery like end-to-end coaptation. We conclude that the availability of a suitable device-assisted early treatment, even if not to be considered definitive, could help in addressing the BP lesions at an earlier stage and this may improve the final outcome. Our evidence justifies further experimentation on this approach.

When mismatch repair met translesion synthesis

When mismatch repair met translesion synthesis

Hypertrophic olivary degeneration in a child following midbrain tumor resection: longitudinal diffusion tensor imaging studies

Hypertrophic olivary degeneration (HOD) is a dynamic process caused by disruptive lesions affecting components of the Guillain-Mollaret triangle (GMT). The authors applied diffusion tensor imaging (DTI) to investigate longitudinal changes of the GMT components in a child with HOD after neurosurgery for a midbrain tumor. Diffusion tensor imaging data were acquired on a 1.5-T MRI scanner using a balanced pair of diffusion gradients along 20 noncollinear directions 1 day and 3, 6, and 9 months after surgery. Measurements from regions of interest (ROIs) were sampled in the affected inferior olivary nucleus, ipsilateral red nucleus, and contralateral superior and inferior cerebellar peduncles and dentate nucleus. For each ROI, fractional anisotropy and the mean, axial, and radial diffusivities were calculated. In the affected inferior olivary nucleus, the authors found a decrease in fractional anisotropy and an increase in mean, axial, and radial diffusivities 3 months after surgery, while 3 months later fractional anisotropy increased and diffusivities decreased. For all other GMT components, changes in DTI scalars were less pronounced, and fractional anisotropy mildly decreased over time. A detailed analysis of longitudinal DTI scalars in the various GMT components may shed light on a better understanding of the dynamic complex histopathological processes occurring in pediatric HOD over time.

Diffusion Tensor Imaging in a Child with Hypertrophic Olivary Degeneration

Hypertrophic olivary degeneration (HOD) is caused by disruptive lesions affecting components of the Guillain-Mollaret triangle (GMT). We present conventional magnetic resonance and diffusion tensor imaging (DTI) findings in a 6-year-old girl with HOD after surgery for a midbrain pilocytic astrocytoma. To our knowledge, this is the first dedicated DTI analysis of GMT in a child with HOD in the literature. In our patient, we found higher fractional anisotropy (FA) and axial diffusivity values of the inferior olivary nucleus (ION) and lower FA, but higher radial diffusivity (RD) values of all other GMT components compared to age-matched controls. Increased FA values of the ION may be explained by increased packing of white matter fibers. However, associated hyperintense T2 signal is contradictory and the association between increased FA values and hyperintense T2 signal remains unclear. Low FA and high RD values of the other GMT components likely reflect demyelination with axonal degeneration and correlate well with histopathological findings.

Clinical Technique: Myelography in Rabbits

Spinal disease in rabbits is most often the result of trauma; however, other causes have been reported including congenital defects and degenerative spinal diseases. Diagnosis of spinal disease is based on history, physical and neurologic examination findings, and imaging. Fractures and luxations of the spine are often apparent on plain radiographs; however, myelography is used to determine if the lesion is causing spinal cord compression that may be amenable to surgical decompression. Unless intervertebral discs are mineralized, they are not visible when viewing plain radiographic images; therefore, myelography may be useful to diagnose spinal cord compression from a herniated disc. Myelography can also define lesions that do not result in a disruption of the osseous vertebral architecture such as tumors and granulomas. In rabbits, myelography is performed when the animal is under general anesthesia and in lateral recumbency. A nonionic iodinated contrast agent is injected into the subarachnoid space, usually at the level of the lumbar spine, to outline the spinal cord and identify cord compressive or disruptive lesions.

Incidence, mechanisms, and patterns of fetal cerebral lesions in twin-to-twin transfusion syndrome

Objective. To determine the incidence of fetal cerebral lesions and their characteristics in twin-to-twin transfusion syndrome (TTTS).Design and setting. This was a retrospective analysis at a single center for the period 1999 to 2004 in which 299 cases of severe TTTS at 15–28 weeks of gestation were reviewed.Methods. Only cerebral injuries diagnosed during pregnancy or ischemic lesions diagnosed within the first week of life were considered in order to exclude those related to prematurity. We only included cases resulting in at least one survivor at one week after delivery, as well as fetuses that were terminated because of severe cerebral abnormalities. We excluded all fetuses delivered at <24 weeks of gestation that died prior to undergoing postnatal cranial ultrasonography. The main outcome measures were fetal cerebral lesions, intrauterine death, survival, and neonatal death.Results. Two hundred and ninety-nine pregnancies were evaluated. Three hundred and fifteen fetuses were reviewed. Cerebral abnormalities developed antenatally in 26/315 fetuses (8.25%). All lesions but one were diagnosed prenatally. Prenatal diagnosis of these lesions was achieved primarily by ultrasound (US) and magnetic resonance imaging (MRI), in 20/25 (80%) and in 5/25 (20%) fetuses, respectively. Cerebral abnormalities developed following primary laser coagulation in 12/222 (5.40%), following serial amnioreduction in 9/66 (13.63%), and following expectant management in 3/14 (21.4%) fetuses. Abnormalities developed after single intrauterine fetal death (IUFD) in 14 cases.Conclusions. Cerebral morbidity in TTTS mainly occurs following vascular disruptive lesions. Both donors and recipients are at risk of developing either ischemic or hemorrhagic lesions. The risk of developing cerebral lesions in single survivors is significantly lower following laser treatment. Combined use of a targeted US and fetal MRI could detect most cerebral abnormalities antenatally. Timing of the triggering event is critical for planning serial US and MRI follow-up examinations.

OC84: How early do imaging changes occur in MC/DA surviving twins following co‐twin demise?

Results: Cerebral abnormalities developed prenatally in 27 fetuses (9.37%, 27/288). Prenatal diagnosis of these lesions was achieved primarily by US and MRI in 21/27 (78%) and in 6/27 (22%) fetuses respectively. Cerebral abnormalities developed following primary laser coagulation, serial amnioreduction or expectant management in 12/222 (5.40%), in 9/124 (13.63%) and in 3/14 (21.4%) fetuses respectively. Abnormalities developed after single intrauterine fetal death (IUD) in 14 cases including 6 severely anemic survivors as a result of exsanguination in their dead co-twin. These lesions developed following primary laser coagulation, amniodrainage and expectant management in 3/55 (5.45%), 7/20 (35%) and 1/14 (7%) cases respectively. Conclusions: Cerebral morbidity in TTTS mainly occurs following vascular disruptive lesions. Both donors and recipients are at risk of developing either ischemic or hemorrhagic lesions. The risk of developing cerebral lesions in single survivors is significantly less following laser treatment. Timing of the triggering event is critical for serial US and MRI follow-up examination.

Retinal hemorrhages associated with in utero exposure to cocaine. Experimental and clinical findings.

The use of drugs of abuse--e.g., cocaine--during pregnancy has been associated with abnormalities of the visual system. The authors studied the effects of prenatal exposure to drugs of abuse, especially cocaine, on the vascular system of the retina in newborn infants and in an experimental model in the rat. The animal study was conducted in pregnant Wistar rats injected subcutaneously with cocaine hydrochloride (60 mg/kg body weight/day) from gestation days 8 to 22. Male offspring were killed at postnatal days 7, 14, and 30 and perfused with fixative, and the retinas were dissected and processed for microscopic observation. The ophthalmologic observations were conducted in a population of newborn infants born to women who abused many drugs during pregnancy and in a control group of women with no history of illicit drug use. Vascular disruptive lesions were seen after prenatal exposure to cocaine in the rat: round intraretinal hemorrhages, ischemic and hypoperfused areas located at the temporal part and often extending from the posterior pole to the periphery of the retina. The ophthalmologic observation of the newborns showed a higher incidence of vascular disruptive lesions in infants in whom exposure to drugs of abuse was affirmative during pregnancy. In the cases in which cocaine consumption was reported, they consisted in blot full-thickness hemorrhages with rounded domed contours suggestive of venous occlusion and retinal ischemia, very similar to the lesions seen in the animal model. These hemorrhagic lesions, morphologically similar to neonatal retinal hemorrhages, had a higher incidence than in controls; they also took longer to resolve when compared with the reabsorption time of the neonatal hemorrhages due to birth trauma and the hemorrhagic lesions in newborns of mothers in whom consumption of other drugs--but not cocaine--were reported. A topographic and morphologic parallelism can be established between the retinal vascular alterations found in humans consuming cocaine and in the animal model of prenatal exposure to this drug of abuse; although findings from animal studies may be difficult to apply directly to humans, these data strongly support that cocaine can be a causal factor for the occurrence of retinal vascular disruption in newborns.

Association of Ebola-related Reston virus particles and antigen with tissue lesions of monkeys imported to the United States

During 1989–1990, an epizootic involving a filovirus closely related to Ebola virus occurred in a Reston, Virginia, primate-holding facility. Tissues were collected from cynomolgus monkeys and examined by electron microscopy and immunohistochemistry for Ebola-related viral antigen. Viral replication was extensive in fixed tissue macrophages, interstitial fibroblasts of many organs, circulating macrophages and monocytes, and was observed less frequently in vascular endothelial cells, hepatocytes, adrenal cortical cells and renal tubular epithelium. Viral replication was observed infrequently in epithelial cells lining ducts or mucous membranes, intestinal epithelial cells, eosinophils and plasma cells. Replication of Reston virus in lymphocytes was never observed, in contrast to reports of lymphocytes of monkeys experimentally infected with the Ebola-Zaire virus. Free filoviral particles were seen in pulmonary alveoli and renal tubular lumina, which correlates with epidemiological evidence of droplet and fomite transmission. Viral infection of interstitial fibroblasts and macrophages caused multisystemic disruptive lesions involving connective tissue. Focal necrosis in organs where viral replication was minimal may have been secondary to ischaemia caused by fibrin deposition and occasional platelet-fibrin thrombi. Immunoelectron microscopy on sections of liver, differentiated viral tubular inclusion masses and precursor material from non-viral tubuloreticular inclusions. Immunohistochemistry showed that the distribution of viral antigen in affected tissue correlated well with ultrastructural localization of virions.

Effects of the competitive NMDA antagonist CPP on performance of a place and cue radial maze task

Using a within-subjects design, rats were trained to run on a radial maze with a procedure that involved two types of learning (pi ace and eue) and two memory functions (working and reference memory). After performance had stabilized, injections of saline, 4, 8, and 16 mg/kg of the competitive NMDA antagonist CPP (±)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid were administered in a Latin-square design. Choiee accuraey on both the place task and the cue task was significantly impaired by 8 and 16 mg/kg ofCPP, whereas running times were signifieantly slowed only with 16 mg/kg. This pattern of results is different from the selective impairment on the place task found following disruptive lesions of and kindling within the hippocampus. These findings suggest that care should be taken in attributing ehanges in behavior following injeetions of NMDA antagonists to selective effects on the hippocampus.

Mode of action of mouse epidermal growth factor on the wool follicles of Merino sheep: an ultrastructural study

The follicular mechanisms involved in and associated with the depilatory action of infused mouse epidermal growth factor (mEGF) on wool follicles were investigated ultrastructurally in the course of research into biological wool harvesting as an alternative to conventional shearing. Ultrastructural alterations observed during mEGF-induced follicle involution indicated three separate follicular responses to mEGF. (i) Catagenic regression lasting 4 days occurred in all follicles. This process initially (at 1 day) involved decline in cellular proliferation in the follicle bulbs, decline in the formation of precursor structural proteins in inner root sheath (IRS) and fibre cells and a delay in their hardening, and deletion of cells by apoptosis. Synthesis of precursor proteins subsequently ceased in a proportion of the follicles at 2 days, culminating in the formation of tapered fibre ends at 4 days. Regeneration of these follicles commenced at 4-6 days. Fibre production continued in the remaining follicles, though on a much reduced scale, resulting in the formation of transiently thinned fibres. (ii) Disruptive lesions formed in IRS and fibre cells in the keratogenous zone of all follicles during infusion. Their formation involved initial dilatation and vesiculation of endoplasrnic reticulum and mitochondria1 swelling, evident as early as 1 h, and subsequent intercellular accumulation of flocculent material within 12 h, indicative of abnormal fluid transport. (iii) The sebaceous glands underwent transient hypcrplasia involving extensive deposition of glycogen at 2 days, before returning to normal by 4-6 days through apoptosis. These follicular responses demonstrate two diverse modes of action of mEGF infusion on the wool follicles: a quasi-physiological, catagenic, inhibitory action on fibre growth, resembling in part catagen of cyclic hair growth, thereby culminating in a fleece 'break' and/or fleece shedding, and an apparently unrelated pathological action on differentiating IRS and fibre cells and undifferentiated sebaceous cells.

Microdissection studies of the structural alterations induced in rat kidneys by experimental postischemic acute renal failure.

A unique opportunity presented itself for a morphologic study of experimental unilateral acute renal failure (ARF) in male rats. The ARF had been induced in the rats by temporary occlusion (1h) of the left renal artery. Twenty-nine rats were divided into subsets as follows: 2-3 h, 24 h, 1 week, 2, 4, 8, and 12 weeks following release of occlusion. Microdissection showed a heterogeneous population of abnormally structured proximal tubules in which the regressive lesions of tubular necrosis were combined with the progressive reaction of repair. The lesions demonstrated are reminiscent of those which have been described in ARF in the human and in experimental animals. Many proximal tubules in the 2- to 3-hour subset presented 1-3 disruptive lesions (DLs) while greater numbers of proximal tubules from the 24-hour group presented 1-5 DLs. Many proximal tubules presented no DLs, but nearly all from the 24-hour subset (97-100%) displayed a squamate appearance which paralleled and was caused by acute tubular necrosis. At 1 week, a dilated pars recta was common, but by this time, the squamate pattern had disappeared. Many casts were present. At 2 weeks, many fewer casts were present in proximal tubules and none were seen at 4, 8 or 12 weeks. The nephrons, particularly the proximal tubules, presented a variety of structural alterations at 2, 4, 8 and 12 weeks. Changes of special interest include (1) the presence of swan-necks; (2) a distinctive squamate appearance of the proximal tubules in the animals killed at 24 h; (3) a spiral, curled appearance caused by differential hyperplasia in animals at 4, 8 and 12 weeks, and (4) a tendency for ischemic lesions to involve all layers of the renal cortex.