Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells

Indoleamine 2,3-dioxygenase (IDO) suppresses adaptive immunity. T-cell proliferation and differentiation to effector cells require increased glucose consumption, aerobic glycolysis and glutaminolysis. The effect of IDO on the above metabolic pathways was evaluated in alloreactive T-cells. Mixed lymphocyte reaction (MLR) in the presence or not of the IDO inhibitor, 1-DL-methyl-tryptophane (1-MT), was used. In MLRs, 1-MT decreased tryptophan consumption, increased cell proliferation, glucose influx and lactate production, whereas it decreased tricarboxylic acid cycle activity. In T-cells, from the two pathways that could sense tryptophan depletion, i.e. general control nonrepressed 2 (GCN2) kinase and mammalian target of rapamycin complex 1, 1-MT reduced only the activity of the GCN2 kinase. Additionally 1-MT treatment of MLRs altered the expression and/or the phosphorylation state of glucose transporter-1 and of key enzymes involved in glucose metabolism and glutaminolysis in alloreactive T-cells in a way that favors glucose influx, aerobic glycolysis and glutaminolysis. Thus in alloreactive T-cells, IDO through activation of the GCN2 kinase, decreases glucose influx and alters key enzymes involved in metabolism, decreasing aerobic glycolysis and glutaminolysis. Acting in such a way, IDO could be considered as a constraining factor for alloreactive T-cell proliferation and differentiation to effector T-cell subtypes.

A mixed epithelial and stromal tumor of the kidney in a ringtail lemur (Lemur catta)

Primary renal tumors are rare neoplasms in nonhuman primates. This report describes a mixed epithelial and stromal tumor of the kidney (MESTK) in a 14.5-year-old female ringtail lemur. The well-demarcated, solid, and cystic mass was located in the pelvis of the left kidney and consisted histologically of both epithelial and mesenchymal components. The mesenchymal cells were arranged in fascicles around cysts lined by a well-differentiated epithelium. Neither the mesenchymal nor the epithelial parts showed significant nuclear atypia or mitotic figures. To our knowledge, only 1 similar case, classified as adenoleiomyofibromatous hamartoma, has been reported in a ringtail lemur. In humans this tumor affects predominantly perimenopausal women and can express estrogen and progesterone receptors. However, neither estrogen nor progesterone receptors could be identified by immunohistochemistry in the tumor of the present ringtail lemur. Therefore, a hormonal mechanism could not be demonstrated in this case.

rCBF in hemorrhagic, non-hemorrhagic and mixed contusions after severe head injury and its effect on perilesional cerebral blood flow

Intracerebral contusions can lead to regional ischemia caused by extensive release of excitotoxic aminoacids leading to increased cytotoxic brain edema and raised intracranial pressure. rCBF measurements might provide further information about the risk of ischemia within and around contusions. Therefore, the aim of the presented study was to compare the intra- and perilesional rCBF of hemorrhagic, non-hemorrhagic and mixed intracerebral contusions. In 44 patients, 60 stable Xenon-enhanced CT CBF-studies were performed (EtCO2 30 +/- 4 mmHg SD), initially 29 hours (39 studies) and subsequent 95 hours after injury (21 studies). All lesions were classified according to localization and lesion type using CT/MRI scans. The rCBF was calculated within and 1-cm adjacent to each lesion in CT-isodens brain. The rCBF within all contusions (n = 100) of 29 +/- 11 ml/100 g/min was significantly lower (p < 0.0001, Mann-Whitney U) compared to perilesional rCBF of 44 +/- 12 ml/100 g/min and intra/perilesional correlation was 0.4 (p < 0.0005). Hemorrhagic contusions showed an intra/perilesional rCBF of 31 +/- 11/44 +/- 13 ml/100 g/min (p < 0.005), non-hemorrhagic contusions 35 +/- 13/46 +/- 10 ml/100 g/min (p < 0.01). rCBF in mixed contusions (25 +/- 9/44 +/- 12 ml/100 g/min, p < 0.0001) was significantly lower compared to hemorrhagic and non-hemorrhagic contusions (p < 0.02). Intracontusional rCBF is significantly reduced to 29 +/- 11 ml/100 g/min but reduced below ischemic levels of 18 ml/100 g/min in only 16% of all contusions. Perilesional CBF in CT normal appearing brain closed to contusions is not critically reduced. Further differentiation of contusions demonstrates significantly lower rCBF in mixed contusions (defined by both hyper- and hypodense areas in the CT-scan) compared to hemorrhagic and non-hemorrhagic contusions. Mixed contusions may evolve from hemorrhagic contusions with secondary increased perilesional cytotoxic brain edema leading to reduced cerebral blood flow and altered brain metabolism. Therefore, the treatment of ICP might be individually modified by the measurement of intra- and pericontusional cerebral blood.

Mixed inheritance of equine recurrent airway obstruction

BACKGROUND: Mode of inheritance of equine recurrent airway obstruction (RAO) is unknown. HYPOTHESIS: Major genes are responsible for RAO. ANIMALS: Direct offspring of 2 RAO-affected Warmblood stallions (n = 197; n = 163) and a representative sample of Swiss Warmbloods (n = 401). METHODS: One environmental and 4 genetic models (general, mixed inheritance, major gene, and polygene) were tested for Horse Owner Assessed Respiratory Signs Index (1-4, unaffected to severely affected) by segregation analyses of the 2 half-sib sire families, both combined and separately, using prevalences estimated in a representative sample. RESULTS: In all data sets the mixed inheritance model was most likely to explain the pattern of inheritance. In all 3 datasets the mixed inheritance model did not differ significantly from the general model (P= .62, P= 1.00, and P= .27) but was always better than the major gene model (P < .01) and the polygene model (P < .01). The frequency of the deleterious allele differed considerably between the 2 sire families (P= .23 and P= .06). In both sire families the displacement was large (t= 17.52 and t= 12.24) and the heritability extremely large (h(2)= 1). CONCLUSIONS AND CLINICAL RELEVANCE: Segregation analyses clearly reveal the presence of a major gene playing a role in RAO. In 1 family, the mode of inheritance was autosomal dominant, whereas in the other family it was autosomal recessive. Although the expression of RAO is influenced by exposure to hay, these findings suggest a strong, complex genetic background for RAO.