Adeno-associated virus transduction of islets with interleukin-4 results in impaired metabolic function in syngeneic marginal islet mass transplantation

Previous studies suggest that therapeutic expression of interleukin (IL)-4 by islet cells improves their efficacy in transplantation models directed at reversing type 1 diabetes. We investigated the effects of introducing IL-4 into islets with recombinant adeno-associated virus (rAAV) on the reversal of hyperglycemia in a syngeneic marginal islet mass transplantation model. C57BL/6 islets were mock-transduced or transduced with rAAV expressing murine IL-4 (rAAV-IL-4) or rAAV expressing green fluorescent protein (rAAV-GFP) before transplantation of a marginal mass into diabetic mice. Normoglycemia was achieved in only 1/7 mice receiving rAAV-IL-4 transduced islets in comparison to 6/6 mock-transduced and 4/6 rAAV-GFP transduced animals. The failure of IL-4 expressing islets was not associated with cellular toxicity of rAAV or impairment of glucose-stimulated insulin release in vitro. Islet expression of IL-4 led to impaired metabolic function in mice receiving a marginal mass of syngeneic islets.     

Antithrombotic effects of DX-9065a,a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin

BACKGROUND: Recent evidence suggests that TF may play a causal role in acute coronary syndromes, and may be an important therapeutic target. Several inhibitors of TF, coagulation factors VIIa and Xa are under investigation as novel antithrombotic approaches. We compared the antithrombotic effects of DX-9065a, a new FXa inhibitor, vs. enoxaparin. METHODS AND RESULTS: The protocol was an open-label crossover study. Subjects (n = 6) participated in 3 consecutive study-arms: a) enoxaparin + ASA (1 mg/Kg s. c + 162 mg/day x 3 days), b) three escalating doses of DX-9065a (1 mg bolus + 0.25 mg/h x 2 h, followed by an additional 1 mg bolus + 0.625 mg/h x 2 h and, a final 1 mg bolus + 1.25 mg/h x 2 h), and c) the same doses of DX-9065a in Arm 2 plus ASA pre-treatment. The antithrombotic effects were assessed using the Badimon perfusion chamber at each dose level. The administration of DX-9065a whether alone or combined with ASA significantly inhibited thrombus formation at high and low shear rate conditions while enoxaparin did not have a significant effect. Furthermore, these antithrombotic effects were obtained without significant prolongations of the standard coagulation parameters as those induced by enoxaparin. CONCLUSIONS: The direct inhibition of FXa by DX-9065a appears to be a safe and effective new approach for preventing the thrombotic complications of atherosclerotic disease. The clinical effectiveness of the direct FXa inhibitors should be further investigated.     

Prefrontal neurons in networks of executive memory

The neuronal networks of the frontal lobe that represent motor or executive memories are probably the same networks that cooperate with other cerebral structures in the temporal organization of behavior. The prefrontal cortex, at the top of the perception-action cycle, plays a critical role in the mediation of contingencies of action across time, an essential aspect of temporal organization. That role of cross-temporal mediation is based on the interplay of two short-term cognitive functions: one retrospective, of short-term active perceptual memory, and the other prospective, of attentive set (or active motor memory). Both appear represented in the neuronal populations of dorsolateral prefrontal cortex. At least one of the mechanisms for the retention of active memory of either kind seems to be the reentry of excitability through recurrent cortical circuits. With those two complementary and temporally symmetrical cognitive functions of active memory for the sensory past and for the motor future, the prefrontal cortex seems to secure the temporal closure at the top of the perception-action cycle.     

Treatment of metastatic bone pain with repeated doses of strontium-89 in patients with prostate neoplasm

This study has aimed to evaluate the usefulness of repeated treatment with 89Sr in patients with prostate neoplasm and metastatic bone pain. Seventeen patients with partial or complete response after the first dose were retreated with two or more doses (total of 39 doses). The Karnofsky functional status, pain and degree of analgesia were assessed. After the first dose the response was good in 68% of the patients and partial in 32%. After the second dose, the response was good in 62% of the patients, partial in 15% and there was no response in 23% of the cases. The pre-treatment Karnofsky functional status and duration of the effect of 89Sr was lower after the second dose (p = 0.03, p = 0.02), but there were no statistically significant differences in the type of response. In conclusion, re-treatment with 89Sr can be administered safely and with a similar response to that achieved after the first dose.