Costimulation and Autoimmune Diabetes in BB Rats

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55–120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.     

Beta-adrenergic blockade increases the hepatic extraction of glucose in sepsis

To determine the relationship between hepatic glucose clearance and elevated epinephrine levels in sepsis, dogs with gangrenous cholecystitis were anesthetized and received either propranolol hydrochloride (mean dose, 0.29 mg/kg) or saline solution before intraduodenal glucose injection (2.5 g/kg). The amounts of glucose, insulin, and glucagon in the portal vein, the hepatic artery, and the hepatic vein were determined from the concentrations and the blood flows in these vessels over a two-hour period. Normal dogs served as controls. The amounts of glucose, insulin, and glucagon reaching the livers of both septic groups were the same. However, propranolol treatment increased the percent of glucose extracted by the liver without affecting the extractions of insulin or glucagon. Propranolol reverses the limitation of hepatic glucose extraction in sepsis by a direct effect. Whether the extracted glucose is utilizable as an energy substrate needs to be established.     

Hallucinations and associated factors in Alzheimer's disease.

In a consecutive sample of 230 community-dwelling patients with probable Alzheimer's disease, a structured interview yielded evidence of current hallucinations in 29.1% and misperceptions in another 11.3%. Visual and auditory modalities were similarly represented in apparent hallucinations. Hallucinations prior to the current monitoring period were rare among patients with misperceptions or with no perceptual abnormality. The probability of hallucinations was associated with the severity of cognitive dysfunction, the degree of other behavioral disturbances, and the presence of extrapyramidal signs. A logistic regression model predicting hallucinations based on these diverse clinical features accurately classified 87.0% of the sample.     

Effects of 1-week head-down tilt bed rest on bone formation and the calcium endocrine system.

To understand the potential early responses of human bone and the calcium endocrine system to spaceflight, we studied 8 healthy men, aged 35-44 years before, during, and after bed rest in a -6 degrees head-down tilt model for microgravity. Based on a novel single-dose labeling schedule, average rates of bone formation in the iliac crest were reduced in 6, unchanged in 1, and increased in 1 following the bed rest period. The decrease was greatest for subjects whose daily walking miles were highest (r = -0.762, p less than 0.05, n = 7). Before a measurable increase in ionized serum calcium the sixth bed rest day, there was increased excretion of urinary calcium and sodium, evident the first 2 bed-rest days and parallel for the entire week (r = 0.92, p less than 0.001). Reduced excretion of phosphorus and 3', 5' cyclic adenosine monophosphate on the first and second bed rest days was followed by an increase in serum phosphorus by the sixth bed rest day. Depressed serum concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D were manifest by the sixth and seventh bed rest days. The similarity of the response of bone and the calcium endocrine system of healthy men after only 7 days to results of longer term bed rest studies emphasizes the responsiveness of the adult human skeleton to biomechanical stimuli induced by changes in activity and/or position.     

Quantitative MRI studies for assessment of multiple sclerosis.

Although magnetic resonance imaging (MRI) is a valuable aid in the initial diagnosis of multiple sclerosis (MS), quantitatively MRI has been disappointing in staging and evaluating therapy protocols by means of serial examinations. In this study, image processing algorithms were developed for the global analysis of MR images of the cerebrum. Limited three-dimensional segmentation was achieved through histogram analysis by these algorithms, which are essentially operator independent. The effects of coil response and tip angles, patient positioning, and interslice gap thicknesses were examined for 10 MS patients with repeated examinations for a total of 72 images. Effects of technique and instrumentation errors were approximately 6%, and agreement between two independent operators for measuring the total MR pixel sum from periventricular effusions and intense MS plaques was better than 97% with a standard deviation of 2.9%.     

TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice.

Tumor necrosis factor-alpha (TNFalpha) and Fas are induced after traumatic brain injury (TBI); however, their functional roles are incompletely understood. Using controlled cortical impact (CCI) and mice deficient in TNFalpha, Fas, or both (TNFalpha/Fas-/-), we hypothesized that TNFalpha and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNFalpha/Fas-/- mice had improved motor performance from 1 to 4 days (P<0.05), improved spatial memory acquisition at 8 to 14 days (P<0.05), and decreased brain lesion size at 2 and 6 weeks after CCI (P<0.05). Protection in TNFalpha/Fas-/- mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNFalpha before CCI, and TNFalpha-/- mice administered anti-Fas ligand antibodies had improved spatial memory acquisition versus similarly treated WT mice (P<0.05). Tumor necrosis factor-alpha/Fas-/- mice had decreased the numbers of cortical cells with plasmalemma damage at 6 h (P<0.05 versus WT), and reduced matrix metalloproteinase-9 activity in injured brain at 48 and 72 h after CCI. In immature mice subjected to CCI, genetic inhibition of TNFalpha and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P<0.05 versus WT), suggesting that the beneficial effects of TNFalpha/Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNFalpha and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNFalpha/Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.