Increased cardiovascular and renal risk is associated with low nephron endowment in aged females: an ovine model of fetal unilateral nephrectomy

Previously we have shown that ovariectomised (OVX) female sheep have reduced renal function and elevated blood pressure from 6 months of age following fetal uninephrectomy (uni-x) at 100 days of gestation (term  = 150 days). In the current study we examined if in intact female sheep the onset of decline in renal function and elevation in blood pressure was prevented. Studies were performed at 1 year, 2 and 5 years of age. Following fetal uni-x at 100 days, intact female sheep had ∼30% reduction in glomerular filtration rate (GFR) at 1 year, which did not exacerbate with age (P_treatment = 0.0001, P_age = 0.7). In contrast renal blood flow was similar between the treatment groups at 1 year of age but had declined in the uni-x animals at 5 years of age (P_{treatment × age} = 0.046). Interestingly, intact uni-x sheep did not develop elevations in arterial pressure until 2 years of age. Furthermore, uni-x animals had a similar capacity to respond to a cardiac challenge at 1 year and 2 years of age, however, cardiac functional reserve was significantly reduced compared to sham group at 5 years of age. Uni-x animals exhibited an increase in left ventricular dimensions at 5 years of age compared to the sham animals and compared to 2 years of age (P_treatment<0.001, P_{treatment × age}<0.001). In conclusion, the onset of renal dysfunction preceded the onset of hypertension in intact female uni-x sheep. Furthermore, this study showed that the intact females are protected from the impact of a reduced nephron endowment on cardiovascular health early in life as opposed to our findings in young male sheep and OVX uni-x female sheep. However, with ageing this protection is lost as evidenced by presence of left ventricular hypertrophy and impaired cardiac function in 5 year old uni-x female sheep.     

Anti-apoptotic peptides protect against radiation-induced cell death

The risk of terrorist attacks utilizing either nuclear or radiological weapons has raised concerns about the current lack of effective radioprotectants. Here it is demonstrated that the BH4 peptide domain of the anti-apoptotic protein Bcl-xL can be delivered to cells by covalent attachment to the TAT peptide transduction domain (TAT-BH4) and provide protection in vitro and in vivo from radiation-induced apoptotic cell death. Isolated human lymphocytes treated with TAT-BH4 were protected against apoptosis following exposure to 15Gy radiation. In mice exposed to 5Gy radiation, TAT-BH4 treatment protected splenocytes and thymocytes from radiation-induced apoptotic cell death. Most importantly, in vivo radiation protection was observed in mice whether TAT-BH4 treatment was given prior to or after irradiation. Thus, by targeting steps within the apoptosis signaling pathway it is possible to develop post-exposure treatments to protect radio-sensitive tissues.     

TAM receptor ligands in lupus: Protein S but not Gas6 levels reflect disease activity in systemic lupus erythematosus

Introduction  

The TAM (tyro 3, axl, mer) kinases are key regulators of innate immunity and are important in the phagocytosis of apoptotic cells. Gas6 and protein S are ligands for these TAM kinases and bind to phosphatidyl serine residues exposed during apoptosis. In animal models, absence of TAM kinases is associated with lupus-like disease. To test whether human systemic lupus erythematosus (SLE) patients might have deficient levels of TAM ligands, we measured Gas 6 and protein S levels in SLE.     

Suppression of murine experimental autoimmune encephalomyelitis by interleukin-2 receptor targeted fusion toxin, DAB389IL-2

Previously we have shown that DAB₃₈₉IL-2, a recombinant fusion toxin targeting IL-2R bearing cells, suppressed disease in the rat experimental autoimmune encephalomyelitis (EAE) model of acute multiple sclerosis (MS). Our present study demonstrates that DAB₃₈₉IL-2 can also effectively suppress acute (A)-EAE, relapsing (R)-EAE and chronic (C)-EAE in mouse demyelinating models. DAB₃₈₉IL-2 significantly suppressed mitogenic proliferation of spleen cells while mutant fusion proteins DA_glu53B₃₈₉IL-2 and DAB₃₈₉IL-2_8-10 did not. EAE was successfully suppressed when DAB₃₈₉IL-2 was administered in various regimens between days 1 and 15 post immunization in all three models. CD4⁺IL-2R⁺ cells were reduced in the spleen but not in the lymph nodes of DAB₃₈₉IL-2-treated mice during A-EAE while the number of CD8⁺ cells was unchanged. DAB₃₈₉IL-2 also significantly reduced the number of CD4⁺, CD8⁺, CD25⁺, TCRγδ⁺ phenotype and CD11b⁺ macrophages/microglia within spinal cord lesions. These data strongly suggest that DAB₃₈₉IL-2 specifically targeted myelin protein-activated CD4⁺ T cells and strengthens the argument for the use of DAB₃₈₉IL-2 in treatment strategies for MS.     

Ultrastructure of human labial salivary glands. 3. Myoepithelium and ducts

Myoepithelial cells were present between the basal lamina and the acinar secretory cells of human labial salivary glands. In form and disposition, they resembled myoepithelial cells in the major salivary glands. Many of these cells possessed single cilia on their upper surfaces. Such cilia occasionally extended into invaginations of the overlying secretory cell. The intercalated ducts were variable in occurrence. Their epithelium ranged from columnar to squamous, and showed few signs of secretory activity. Few intralobular ducts possessed basal striations. While mitochondria were abundant in non-striated cells, they were randomly disposed in both basal and apical cytoplasm, and the basal plasmalemma showed only occasional infoldings. The paucity of true striated ducts in labial salivary glands may be responsible for the high concentration of sodium and chloride in unstimulated labial gland salivary secretions.