Blockade of neurotensin receptors suppresses the dopamine D1/D2 synergism on immediate early gene expression in the rat brain

A remarkable feature of dopamine functioning is that the concomitant activation of D1-like and D2-like receptors acts to intensify the expression of various dopamine-dependent effects, in particular the expression of the immediate-early genes, c-fos and zif268. Using non-peptide neurotensin receptor antagonists, including SR48692, we have determined that blockade of neurotensin receptors reduced the cooperative responses of direct acting D2-like (quinpirole) and partial D1-like (SKF38393) dopamine agonists on the expression of Fos-like antigens and zif268 mRNA. Pretreatment with SR48692 (3 and 10 mg/kg) reduced the number of Fos-like immunoreactive cells produced by the combined administration of SKF38393 (20 mg/kg) and quinpirole (1 mg/kg) in the caudate-putamen, nucleus accumbens, globus pallidus and ventral pallidum. High-affinity neurotensin receptors are likely to be involved in these D1-like/D2-like cooperative responses, as compounds structurally related to SR48692, SR48527 (3 mg/kg) and its (-)antipode, SR49711 (3 mg/kg), exerted a stereospecific antagonism in all selected brain regions. Pretreatment with SR48692 (10 mg/kg) also diminished Fos induction by the indirect dopamine agonist, cocaine (25 mg/kg), particularly at the rostral level of the caudate-putamen. In situ hybridization experiments in the caudate-putamen indicated that SR48692 (10 mg/kg) markedly reduced zif268 mRNA labelling produced by SKF38393 plus quinpirole in cells not expressing enkephalin mRNA, but was unable to affect the concomitant decrease of zif268 mRNA labelling in enkephalin-positive cells. Taken together, the results of the present study indicate that neurotensin is a key element for the occurrence of cooperative responses of D2-like and partial D1-like agonists on immediate-early gene expression.     

Radical prostatectomy. The surgical complications

Study of 165 patients with prostate adenocarcinoma who underwent radical prostatectomy using a retropubic approach. Mean PSA is 19 ng/ml, mean age 63 years and median follow-up 26 months. 22 patients (13.2%) reported complications during the first month post-surgery, primarily urinary fistula of more than 5 days long in 5 patients and rectal injury in 3.49 patients (29%) reported complications after the first month, mainly urinary incontinence in 26 cases and stenosis of the urethrovesical juncture in 15. The group with early complications showed no significant differences compared to those who had none, neither in PSA (p = 0.3) or a worse pathological stage (p = 0.1), and no evidence is shown in terms of biochemical progression or in disease free progression (p = 1). Patients with urethrovesical juncture stenosis have higher mean PSA (p = 0.01), greater biochemical progression (p = 0.006), worse Gleason (p = 0.03 = and worse progression free survival (p = 0.01). Patients with stress incontinence showed no differences compared to the other groups relative to the studied factors.     

Spontaneous retroperitoneal hematoma: our experience

We report 15 cases of spontaneous retroperitoneal haematoma. The etiology and the diagnostic and therapeutic procedures were evaluated. The haematoma source was the adrenal gland in 4 patients and the causes were pheochromocytoma (1), adenoma (1), myelolipoma (1) and idiopathic (1). In 10 patients the source was the kidney and the causes were angiomyolipoma rupture (6), renal cell carcinoma (3) and ureteral calculi (1). In the remaining case, the haematoma was produced by fibrinolytic and anticoagulant therapy in a patient with acute myocardial infarction. The imaging diagnostic techniques employed were abdominal ultrasonography and CT scan, which allowed the diagnosis of haematoma and showed his size and extension in all the cases. With these two techniques, and with the retrograde pyelography in one patient, we obtained the etiologic diagnosis in 12 of the 15 cases. Surgical treatment was performed in 12 patients (adrenalectomy in 2, simple nephrectomy in 3, radical nephrectomy in 5 and partial nephrectomy in 2).     

Congenital absence of portal vein in a girl with biliary atresia treated with liver transplant

The congenital absence of the portal vein is a rare malformation, which has been generally discovered in association with another anomalies like a cardiac, gastrointestinal or genitourinary defects. With portal hypertension and hepatic cirrhosis, this anomaly is similar to spontaneous porto-systemic derivation, and for that not collateral venous drainage is present. In these patients, total interruption of mesentaric venous drainage during procurement of liver transplant produce a very important bowel and mesenteric edema, which can promote an injert fatal evolution. The authors present the first paediatric liver transplant, in a patient with portal venous agenesia, with de piggy-back technique was done and this complication was obviated, and a review of the literature about this issue is done.     

Improved immunogenicity of a core-coated tetanus toxoid delivery system.

A new microparticulate delivery system composed of a stabilizing gelatin/poloxamer microcore surrounded by a PLGA coat was designed to improve the stability of tetanus toxoid (TT) encapsulated in PLGA microspheres. Microcores were prepared by a spray-congealing technique and encapsulated within PLGA using an oil-in-oil (o/o) solvent evaporation technique. SEM analysis of the cross-sections of the microcapsules revealed the adequate encapsulation of the cores, showing an intimate contact between the core and the coating. This structure was responsible for an osmotic phenomenon observed in vitro, which led to the release of the encapsulated TT in a short period of time. Nevertheless, it was observed that the release was affected by the presence of the poloxamer in the core: microspheres without poloxamer in the core exhibit a faster release (2 h) than those that incorporate the surfactant (24 h). The in vivo evaluation of this system showed that the encapsulated toxoid induced a low but continuous levels of neutralizing antibodies (Nt), whereas those obtained for the control (aluminum phosphate-adsorbed toxoid) decreased after reaching the maximum level at 14 weeks. Moreover, the administration of a mixture of encapsulated and adsorbed TT led to significant higher and more prolonged Nt levels than those measured for the adsorbed toxoid.     

4-trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitors of nuclear factor kappaB activation

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the activation of NF-kappaB elicited by tumour necrosis factor-alpha (TNF-alpha) on human umbilical vein endothelial cells (HUVEC) was tested. 2. The expression of the mRNA of vascular cell adhesion molecule-1 (VCAM-1) was studied as an example of a gene the expression of which is regulated by NF-kappaB. To extend these findings to other systems, the induction of nitric oxide synthase in rat adherent peritoneal macrophages was studied. 3. Both HTB and triflusal were more potent than aspirin or salicylate as inhibitors of the nuclear translocation of NF-kappaB. The calculation of the IC50 values showed approximately 2 mM for HTB, 4 mM for aspirin and >4 mM for salicylate. 4. Comparison of the potency of these compounds on VCAM-1 mRNA expression showed complete inhibition by both triflusal and HTB at a concentration of 4 mM whereas aspirin and salicylate produced only 36-43% inhibition at the same concentration. 5. Inhibition of NF-kappaB activation was also observed in rat peritoneal macrophages stimulated via their receptors for the Fc portion of the antibody molecule with IgG/ovalbumin immune complexes. This was accompanied by a dose-dependent inhibition of nitrite production by the L-arginine pathway via iNOS. IC50 values for this effect were 1.13+/-0.12 mM (triflusal), 1.84+/-0.34 (HTB), 6.08+/-1.53 mM (aspirin) and 9.16+/-1.9 mM (salicylate). 6. These data indicate that the incorporation of a 4-trifluoromethyl group to the salicylate molecule strongly enhances its inhibitory effect on NF-kappaB activation, VCAM-1 mRNA expression and iNOS induction, irrespective of the presence of the acetyl moiety involved in the inhibition of cyclo-oxygenase.