This study examined the dynamics of the cerebral blood flow response to hypoxia and hypercapnia in humans. Middle cerebral artery blood flow (MCAF) was assessed continuously using transcranial Doppler ultrasound. MCAF was calculated on a beat-by-beat basis as the product of the intensity-weighted mean velocity and the total power of the reflected signal. End-tidal PCO2 (PETCO2) and PO2 (PETO2) were controlled using a dynamic end-tidal forcing system. Six repeats of each of four protocols were administered to six subjects. The first was a control protocol with PETO2 held at 100 Torr and PETCO2 held 1-2 Torr above eucapnia throughout. The second was a hypoxic step protocol with PETO2 lowered from control values to 50 Torr for 20 min. The third was a hypercapnic step protocol with PETCO2 elevated from control by 7.5 Torr for 20 min. The fourth was a hypoxic-and-hypercapnic step protocol lasting 20 min. The total power of the Doppler signal remained relatively constant, suggesting that the cross-sectional area of the vessel changed little. After the initial transient in MCAF at the onset of the stimulus, no adaptation or progressive increase was observed over the remaining 20 min. A simple model consisting of a single pure delay, gain terms, time constants, and offsets for the on and off transients was fitted to the hypoxic and hypercapnic protocols. For hypercapnia, all the parameters for the onset were significantly different from the relief of the stimulus. The asymmetry was characterized by a slower on transient than off transient and also by a degree of undershoot after the relief of hypercapnia. Finally, the results from this study show that the cerebral blood flow response to hypoxia and hypercapnia in humans is much faster than has previously been thought.

Juvenile diabetes (type 1) is an autoimmune disease in which CD4 ؉ T cells play a major role in pathogenesis characterized by insulitis and ␤ cell destruction leading to clinical hyperglycemia. To date, no marker for autoimmune T cells has been described, although it was previously demonstrated that autoimmune mice have a large population of CD4 ؉ cells that express CD40. We show here that established, diabetogenic T cell clones of either the Th1 or Th2 phenotype are CD40-positive, whereas nondiabetogenic clones are CD40-negative. CD40 functionally signals T cell clones, inducing rapid activation of the transcription factor NFB. We show that autoimmune diabetes-prone nonobese diabetic mice have high levels of CD40 ؉ CD4 ؉ T cells in the thymus, spleen, and importantly, in the pancreas. Finally, as demonstrated by adoptive transfers, CD4 ؉ CD40 ؉ cells infiltrate the pancreatic islets causing ␤-cell degranulation and ultimately diabetes.

To our knowledge, this is the first trial of n-3 supplementation in the treatment of PD and depressive symptoms in middle-aged women. In women with PD without MDE at baseline, the 8-wk changes in PD and depressive scales improved significantly more with E-EPA than with placebo. This trial was registered at http://www.controlled-trials.com as ISRCTN69617477.

It has been speculated that autoimmune diseases are caused by failure of central tolerance. However, this remains controversial. We have suggested that CD40 expression identifies autoaggressive T cells in the periphery of autoimmune prone mice. In this study, we report that CD40 was cloned from autoaggressive T cells and that engagement induces expression and nuclear translocation of the recombinases, recombination activating gene (RAG) 1 and RAG2 in the autoaggressive, but not in the nonautoaggressive, peripheral T cell population. Furthermore, we demonstrate that CD40 engagement induces altered TCR Vα, but not Vβ, expression in these cells. Therefore, CD40-regulated expression of RAG1 and RAG2 in peripheral T cells may constitute a novel pathway for the generation of autoaggressive T cells.