The aim of this study was to characterize the age-related morphological changes in the equine pituitary and to identify features that allow distinction between pituitary pars intermedia dysfunction ...(PPID)-associated and non-functional/age-associated pars intermedia (PI) adenoma. Pituitary glands of all horses submitted for necropsy examination at the Institute of Veterinary Pathology, Ludwig Maximilians University Munich, between 2008 and 2012 were examined. The pituitary glands of 124 horses were weighed, cut into ∼2 mm slices and examined histologically. A slightly modified grading scheme (grades 1–5) was applied to evaluate histological alterations of the PI semiquantitatively. The volume fractions and total volumes of the three pituitary lobes, PI, pars distalis (PD) and pars nervosa (PN), as well as the total number and mean size of PI cells (PICs), were determined using state-of-the-art quantitative stereological methods.
There were significant associations between histological grade, the appearance of PI adenomas, follicles and cysts in the PI, lipofuscin in the PN (P <0.001) and focal hyperplasia of chromophobes in the PD and age. In contrast, the appearance of follicles and cysts in the PD, invasion of basophil cells into the PN, haemorrhage and necrosis were not age dependent. PI adenomas were observed in 18% (22/124) of the animals, but only four horses were evidently suffering from PPID, therefore clinically overt/PPID-associated PI adenomas were found in 3% (4/124) of all horses. Most PI adenomas were incidental and considered non-functional. Pituitary weight, PI volume, total number and mean volume of PICs increased with age in all horses. The total PI volume and the number of PICs of horses exhibiting PPID-associated PI adenomas were significantly higher, while the mean size of PICs was smaller compared with that of horses showing non-PPID-associated adenoma, which suggests that different growth processes are responsible for adenoma formation. The present study demonstrated various age-associated lesions of the PD and PN and revealed a high frequency of incidental, non-PPID-associated PI adenomas in aged horses. Therefore, post-mortem diagnosis of PPID in horses is possible, by determination of pituitary weight and by demonstration of PIC hyperplasia, using quantitative stereological methods.
Vascular cell adhesion molecule-1 (VCAM-1) is strongly upregulated in hearts of mice with coxsackie virus-induced as well as in patients with viral infection-triggered dilated cardiomyopathy. ...Nevertheless, the role of its soluble form as a biomarker in inflammatory heart diseases remains unclear. Therefore, we investigated whether plasma levels of soluble VCAM-1 (sVCAM-1) directly correlated with disease activity and progression of cardiac dysfunction in the mouse model of experimental autoimmune myocarditis (EAM). EAM was induced by immunization of BALB/c mice with heart-specific myosin-alpha heavy chain peptide together with complete Freund`s adjuvant. ELISA revealed strong expression of cardiac VCAM-1 (cVCAM-1) throughout the course of EAM in immunized mice compared to control animals. Furthermore, sVCAM-1 was elevated in the plasma of immunized compared to control mice at acute and chronic stages of the disease. sVCAM-1 did not correlate with the degree of acute cardiac inflammation analyzed by histology or cardiac cytokine expression investigated by ELISA. Nevertheless, heart to body weight ratio correlated significantly with sVCAM-1 at chronic stages of EAM. Cardiac systolic dysfunction studied with positron emission tomography indicated a weak relationship with sVCAM-1 at the chronic stage of the disease. Our data provide evidence that plasma levels of sVCAM-1 are elevated throughout all stages of the disease but showed no strong correlation with the severity of EAM.
Pancreatic neuroendocrine tumors of glucagon-producing cells are extremely rare in domestic animals. In this report, we describe for the first time, to our knowledge, the incidental finding of ...multiple glucagon-producing neuroendocrine tumors of the pancreas of a horse. The animal was euthanized due to severe local infection after tooth extraction. On postmortem examination, multiple white nodules of up to 4 cm in diameter were observed in the pancreas. Histologically, pancreatic nodules had the appearance of neuroendocrine neoplasms with positive immunoreactivity for glucagon, synaptophysin, chromogranin A, and neuron-specific enolase. Electron microscopy revealed numerous electron-dense granules, similar to those observed in normal pancreatic alpha cells, in the neoplastic cells. In addition, the left adrenal gland showed multiple hyperplastic foci and adenomas in the medulla that were identified as pheochromocytomas. Based on the morphologic appearance and immunohistochemical staining pattern of pancreatic nodules, a diagnosis of multiple glucagon-producing neuroendocrine tumors was made.
•Effects of GH and IGF1 can be dissected in GH transgenic Igf1 knockout mice in vivo.•Permanent GH overabundance cannot reverse Igf1 deletion related dwarfism in mice.•Kidney and liver alterations of ...GH transgenic mice can develop independently of IGF1.
To study insulin-like growth factor 1 (IGF1)-independent effects of permanent growth hormone (GH) excess on body and organ growth and pathology in vivo, hemizygous bovine GH transgenic mice with homozygous disruption of the Igf1 gene (Igf1−/−/GH) were generated, and examined in comparison to Igf1−/−, Igf1+/−, wild-type (WT), Igf1+/−/GH, and GH mice. GH mice and Igf1+/−/GH mice showed increased serum IGF1 levels and the well-known giant-phenotype of GH transgenic mice. In contrast, the typical dwarf-phenotype of Igf1−/− mice was only slightly ameliorated in Igf1−/−/GH mice. Similar to GH mice, Igf1−/−/GH mice displayed hepatocellular hypertrophy, glomerulosclerosis, and reduced volumes of acidophilic cells in the pituitary gland. However, GH excess associated skin lesions of male GH mice were not observed in Igf1−/−/GH mice. Therefore, development of GH excess induced liver-, kidney-, and pituitary gland-alterations in GH transgenic mice is independent of IGF1 whereas GH stimulated body growth depends on IGF1.
•We report effects of P. ovis infestation on skin, lymph node and adrenal morphology.•Bovine psoroptic mange causes dermatitis, lymph node and adrenal gland enlargement.•Psoroptic mange causes ...hyperplasia of the zona fasciculatain the adrenal cortex.•This chronic stress reaction can be prevented by acaricidal treatment.
In cattle, infestation with Psoroptes ovis mites may cause severe dermatitis (psoroptic mange) which compromises the health and welfare of the animals and may lead to significant economic losses. To investigate yet undocumented effects of psoroptic mange mite infestations and how successful therapy promotes animal health, the present study examined alterations of the skin, lymph nodes and adrenal glands of P. ovis infested Fleckvieh (Simmental) bulls treated with either ivermectin long-acting injection (IVM LAI; IVOMEC® GOLD, Merial; 3.15% ivermectin w/v) or saline (n=16 each). Approximately 8 weeks subsequent to experimental infestation with P. ovis, the bulls had developed mange and were administered either IVM LAI or saline once at 1mL/50kg body weight by subcutaneous injection. Mite counts were conducted in weekly intervals for determination of efficacy of treatment, and following humane euthanasia of the animals 8 weeks after treatment, skin samples from affected (mangy or previously mangy) and unaffected areas, prescapular lymph nodes and adrenal glands were collected for gross and pathohistological examination. In addition, four age-matching, uninfested Simmental bulls were sampled as controls for comparison.
No P. ovis mites were detected on any IVM LAI-treated bull after 28 days following treatment whereas saline-treated bulls maintained infestation throughout the study. At sampling (approximately 16 weeks after experimental infestation and 8 weeks following saline or IVM LAI treatment), saline-treated bulls displayed a severe, exsudative dermatitis with significantly increased skin thickness and inflammatory cell infiltration, significantly enlarged, hyperplastic prescapular lymph nodes, as well as significantly increased adrenal gland weights and volumes as compared to P. ovis-infested, IVM LAI-treated bulls and uninfested controls. Quantitative stereological analysis revealed that the adrenal gland enlargement in P. ovis-infested, saline-treated bulls was due to a selective increase of the volume of the zona fasciculata in the adrenal cortex. Compared to uninfested controls and P. ovis-infested, IVM LAI-treated bulls, the number of epithelial cells in the zona fasciculata was significantly increased in P. ovis-infested, saline-treated bulls, while the zona fasciculata cell volumes did not differ between the three groups of cattle. While the single point determination of serum cortisol concentrations did not reveal significant differences between the three groups of cattle at tissue sampling, the hyperplastic growth of the adrenal cortex in the P. ovis-infested, saline-treated bulls provides morphologic evidence that a chronic stress reaction is one consequence of mange mite infestations that can be prevented by efficacious acaricidal treatment.
Aims
Heterozygous male Munich
Ins2
C95S
mutant mice, a model for permanent neonatal diabetes mellitus, demonstrate a progressive diabetic phenotype with severe loss of functional beta cell mass. The ...aim of this study was to investigate the influence of early insulin treatment on glucose homeostasis and beta cell destruction in male Munich
Ins2
C95S
mutants.
Methods
One group of male
Ins2
C95S
mutants was treated with subcutaneous insulin pellets, as soon as blood glucose levels began to rise; placebo-treated mutants and wild-type mice served as controls. An additional group of mutant mice received a sodium-dependent glucose transporter 2 (SGLT2) inhibitor (AVE2268) via rodent chow.
Results
Insulin treatment normalised blood glucose concentrations, improved oral glucose tolerance, preserved insulin sensitivity and inhibited oxidative stress of Munich
Ins2
C95S
mutant mice. Pancreatic C-peptide content, as well as total beta cell and isolated beta cell volumes, of insulin-treated mutant mice were higher than those of placebo-treated mutants. In addition, alpha cell dysfunction and hyperplasia of non-beta cells were completely normalised in insulin-treated mutant mice. Treatment with the SGLT2 inhibitor lowered blood glucose, improved glucose tolerance and normalised insulin sensitivity as well as oxidative stress of
Ins2
C95S
mutants. The abundance of the endoplasmic reticulum (ER) stress markers binding Ig protein (BiP) and phosphorylated eukaryotic translation initiation factor 2 alpha (P-eIF2α) was significantly increased in the islets of mutants, before onset of hyperglycaemia, vs wild-type mice.
Conclusions
We conclude that early insulin treatment protects Munich
Ins2
C95S
mutant mice from insulin resistance, alpha cell hyperfunction, beta cell loss and hyperplasia of non-beta cells, some well-known features of human diabetes mellitus. Therefore, insulin treatment may be considered early for human patients harbouring
INS
mutations.
Canine angiostrongylosis is a nematode infection in domestic dogs and wild carnivores. Few single case reports describing the occurrence of this disease in Germany exist and until recently ...angiostrongylosis has not been considered endemic in this country. The present report focuses on clinical, pathological and parasitological findings in two cases of fatal disseminated canine angiostrongylosis associated with multifocal haemorrhages in the central nervous system. Both animals, which lived in Germany, presented with rapidly progressive neurological signs including depression, ataxia, unilateral central blindness and epileptic seizures. Blood work revealed grossly elevated D-dimers and mild thrombocytopenia. Both animals were subsequently euthanised due to progressive clinical aggravation. Necropsy showed cerebral and lung haemorrhages in both animals. Multiple sections of nematode larvae consistent with
Angiostrongylus vasorum were identified on histopathological sections of the brain, heart, kidney and lung in both animals and a predominantly granulomatous inflammation with the occurrence of multinucleated giant cells was observed. Adult nematodes were found in the larger lung arteries of one dog and Angiostrongylus infection was subsequently confirmed by PCR-analysis and sequencing in both dogs.
A. vasorum larvae were not detected by faecal Baermann examination performed in one of the dogs. It was concluded that canine angiostrongylosis should be considered as differential diagnosis in dogs in Germany, even if faecal examination is negative. There is currently still a lack of studies investigating the occurrence of angiostrongylosis in dogs and intermediate hosts in Germany which would be necessary to survey the endemic realities of this disease.
Oxazolone-induced colitis in mice has become a recognized model to study the efficacy of therapeutics targeting the immunological response underlying the development of inflammatory bowel disease. ...However, this model cannot be used when therapeutics designed to address human targets do not interact with the respective murine counterpart. In this study, we examined the induction of oxazolone mediated colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) (NOD-SCID IL2Rγ(null)) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from ulcerative colitis (UC), atopic dermatitis (AD) and healthy volunteers. NOD-SCID IL2Rγ (null) mice were engrafted with hPBMC followed by challenge with oxazolone or ethanol vehicle. Mice developed the same symptoms as observed previously in immunocompetent mice. The clinical activity score increased and the colon architecture was characterized by the development of oedema, fibrosis, crypt loss and dense infiltration of predominantly T cells into the lamina propria. Fluorescence activated cell sorter (FACS) analysis of lymphocytes in the colon identified natural killer (NK) T cells as a major constituent. In contrast to studies with immunocompetent mice, we observed the same phenotype in the group challenged with ethanol vehicle. The phenotype was most pronounced in mice engrafted with PBMC derived from a patient suffering from UC, suggesting that the immunological history of the donors predisposes the engrafted mice to react to ethanol. The model described here has the potential to study the efficacy of therapeutics targeting human lymphocytes in a model which is more reflective of the human disease. In addition, it might be developed to elucidate molecular mechanisms underlying the disease.
A 16-year-old Friesian gelding with relapsing colic was humanely destroyed during diagnostic laparotomy due to suspected abdominal neoplasia. On post-mortem examination, the pancreas appeared as a ...firm mass (20 × 8 × 8 cm). The cut surface had a lobular structure with multiple cavities. Histological examination revealed severe chronic fibrosing pancreatitis with acinar–ductal metaplasia and duct dysplasia, which was considered to be the cause of the recurrent colic. Formation of tubular complexes within a background of acinar–ductal metaplasia is similar to the regressive lesions detected in the human pancreas in the context of inflammation, duct obstruction, cystic fibrosis and neoplasia. Pancreatic acinar–ductal metaplasia and ductal dysplasia are considered to be preneoplastic conditions in man and in the mouse.
Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed ...cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
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