Antipsychotics with inverse agonist activity at the dopamine D3 receptor

Summary In NG 108-15 cells expressing the recombinant human D₃ receptor, dopamine agonists enhance [³H]thymidine incorporation and decrease cAMP accumulation. In these cells, but not in wild type cells, haloperidol, fluphenazine, and various other antipsychotics inhibited basal [³H]thymidine incorporation in a concentration-dependent manner. In contrast, other dopamine antagonists such as nafadotride or (+)AJ 76, two D₃-preferring antagonists, were without effect. The concentration-response curve of haloperidol was shifted to the right in presence of nafadotride, with a potency compatible with its nanomolar apparent affinity as neutral antagonist. Pertussis toxin treatment abolished or markedly reduced the responses to haloperidol or fluphenazine. In contrast, no significant enhancement of cAMP accumulation could be observed, under the influence of haloperidol or eticlopride. These data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D₃ receptor on [³H]thymidine incorporation pathway, but not on the cAMP pathway.     

Risk factors of early and late complications in patients undergoing endovascular aneurysm repair.

OBJECTIVES: to identify pre-operative factors that could predict complications following from transluminal repair of abdominal aortic aneurysms (AAA). METHODS: during a 5-year period, 96 consecutive patients underwent elective endovascular treatment of a AAA. In all patients, helical CT and/or Magnetic Resonance Imaging (MRI), and plain abdominal roentgenogram were performed at 1, 3, 6, 12, 18, and 24 months and yearly thereafter. Angiography was performed systematically 1 year after the stent-graft implantation, or earlier if helical CT or MRI diagnosed an increase in the maximal transverse diameter or a high flow endoleak. RESULTS: early (<30 days) morbidity (12%) was significantly increased by pre-operative renal insufficiency (p < 0.01). Early mortality (2%) correlated with ASA score (p = 0.01). Median follow-up was 27 months (range 3-66). Mortality (12%) during follow-up was correlated to the pre-operative coronary status (p = 0.01). A type I endoleak was diagnosed in 18 patients (19%). Common iliac artery diameter was correlated with the presence of type I endoleak (p < 0.001). A type II endoleak was diagnosed in 47 (49%) patients. The diagnostic of type II endoleak was significantly increased (p = 0.001) in patients with pre-operative patent IMA associated with more than four patent lumbar arteries. The anatomic characteristics of the aneurysm were correlated to the additional endovascular procedures during stentgraft implantation (p = 0.01), and to the implantation of a complementary iliac limb extension during follow-up (p = 0.01). CONCLUSIONS: the risk factors determined by this statistical analysis could help surgeons to select more accurately patients suitable for endovascular treatment.     

Direct measurement of the lambda of the lumped constant of the deoxyglucose method in rat brain: determination of lambda and lumped constant from tissue glucose concentration or equilibrium brain/plasma distribution ratio for methylglucose

Steady-state distribution spaces of 2-[14C]deoxyglucose ([14C]DG), glucose, and 3-O-[14C]methylglucose at various concentrations of glucose in brain and plasma ranging from hypoglycemic to hyperglycemic levels have been determined by direct chemical analyses in the brains of conscious rats. The hexose concentrations were measured chemically in freeze-blown brain extracted with ethanol to avoid the degradation of acid-labile products of [14C]DG back to free [14C]DG that has been found to occur with the more commonly used perchloric acid extraction of brain. Corrections were also made for nonphosphorylatable, labeled products of [14C]DG found in the nonacidic fractions of the brain extracts, which were previously included with the assayed [14C]DG, and for the contribution of the hexose contents in the blood in the brain, which was found to be particularly critical for the determination of the glucose distribution space, especially in hypoglycemic states. From the measured contents of the hexoses in brain and plasma, the relationships of the tissue concentrations and distribution spaces of each of the hexoses and of the lambda (i.e., ratio of tissue distribution space of DG to that of glucose) of the DG method to the tissue glucose concentration were derived. The lambda was then quantitatively related to the measured equilibrium ratio for [14C]methylglucose over the full range of brain and plasma glucose levels. By combining these new data with the values for the lumped constant, the factor that converts the rate of DG phosphorylation to glucose phosphorylation, previously determined in rats over the same range of plasma glucose levels, the phosphorylation coefficient was calculated and the lumped constant graphed as a function of the measured distribution space in brain for [14C]methylglucose.     

Modeling the dependence of hexose distribution volumes in brain on plasma glucose concentration: implications for estimation of the local 2-deoxyglucose lumped constant

The steady-state distribution volumes of glucose, 3-O-methylglucose, and 2-deoxyglucose (2DG) are known to change as the concentration of glucose in plasma ranges from hypo- to hyperglycemic values. Model estimates of the three distribution volumes were compared with distribution volume values experimentally measured in the brains of conscious rats as the concentration of glucose in plasma was varied from 2 to 28 mM. The dependence on plasma glucose concentration of the 2DG lumped constant, the factor that relates the phosphorylation rate of 2DG to the net rate of glucose utilization at unit specific radioactivity in the plasma, had been determined previously in separate series of experiments. The model was extended to incorporate this dependence of the lumped constant. In the model both the transport and the phosphorylation barriers were assumed to be single and saturable. The values of their respective half-saturation concentrations and the ratio of the two maximum velocities for glucose were assumed to be invariant over the entire range of plasma glucose concentration. Good agreement between measured and estimated values for the distribution volumes and the lumped constant was attained over the full range of plasma glucose concentration. The model estimates reflected the progressive transport limitation of the brain glucose content as plasma glucose levels were reduced to hypoglycemic values. The results also indicated that these changes should be evident in the time course of 2DG in brain following administration by bolus or continuous infusion, and thus that indexes of local lumped constant change could be derived from the time course data.     

Shoulder instability: impact of glenohumeral arthrotomography on treatment

We used arthrotomography to study the glenoid labrum in 114 patients. Sixty-nine of the patients had anatomic instability of the shoulder (including recurrent dislocation and subluxation of the shoulder), and 45 patients had functional instability of the shoulder (denoted by chronic pain, clicking of the joint, and the sensation that an unstable condition exists without the objective signs of it). Labral tears were revealed arthrotomographically in 86% of the patients with anatomic instability, while only 40% of the patients with functional instability had labral abnormalities, and these were primarily of minor severity. Fifty-six patients (44 of whom had anatomic instability; 12, functional instability) required surgery. The surgical findings were correlated with the arthrotomographic findings, and no false-positive results were revealed. However, arthrotomography demonstrated only part of the pathologic condition of two patients. These results confirm that there is a strong correlation between labral pathologic conditions and anatomic instability of the shoulder. Arthrotomographic studies have a great impact on the selection of therapy in cases of both anatomic and functional instability of the shoulder.