Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.

SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases.

Microcomputed tomography used in the analysis of the morphology of root canals in extracted wisdom teeth.

Microcomputed tomography is a new technique for the non-destructive study of porous biological materials. We examined 11 wisdom teeth that had been removed prophylactically by microcomputed tomography operating in the cone beam mode. The two-dimensional sections of the teeth were reconstructed with surface rendering software to provide three-dimensional models that were observed and handled in virtual reality. The tooth itself, or the pulp chamber and canals, can be reconstructed and observed separately or simultaneously. Many teeth looked dystrophic with abnormal distributions of roots and canals. Microcomputed tomography seems to be a promising way of studying dental anatomy.

Characterization and localization of leptin receptors in the rat kidney.

Characterization and localization of leptin binding sites were investigated in rat kidneys using [125I]leptin as a ligand. [125I]Leptin specific binding was found in high amounts in rat renomedullary membranes. This binding was specific, saturable, time-dependent (K(obs) = 0.055 +/- 0.008 min(-1)) and the dissociation of receptor-bound ligand was slowly reversible (K(-1) = 0.048 +/- 0.013 min(-1)). From saturation experiments, a single class of high-affinity binding sites for leptin was identified with an apparent K(d) of 0.57 +/- 0.14 nM and a B(max) of 45 +/- 10 fmol/mg protein. [125I]Leptin binding was inhibited in a dose-dependent manner by cold leptin and was highly selective since not displaceable by a number of other hormones or peptides. Autoradiographic experiments performed on adult rat kidney sections showed the intense presence of [125I]leptin receptors only in specific areas of the renal inner medulla and also consistent labeling associated with vascular structures in the corticomedullary region. The study of the postnatal developmental expression of leptin receptors in the kidney showed very low expression during the early postnatal period (8-21 days). Full expression of leptin sites was achieved at about 30 days and remained stable throughout adulthood (60 days and upwards). Moreover, in vivo administration of leptin (0.5 mg/kg i.p.) induced a significant and rapid diuretic effect in normally hydrated conscious rats. Thus, these data constitute the first characterization and mapping of [125I]leptin specific binding sites in the rat kidney and raise the possibility of a renal control by leptin.

SR 120819A, an orally-active and selective neuropeptide Y Y1 receptor antagonist.

An orally-active antagonist of neuropeptide Y (NPY) Y1 receptors, SR 120819A, has been characterized. This compound displays highly selective and competitive affinity for rat, guinea-pig and human (Ki = 15 nM) NPY Y1 receptors. In vitro, SR 120819A blocks the inhibitory effect of NPY on adenylyl cyclase activity in human SK-N-MC cells and that of the selective Y1 agonist, [Leu31,Pro34]NPY, on rabbit vas deferens contraction (pA2 = 7.20 +/- 0.07). In vivo, by intravenous route, this compound acts as an antagonist in anesthetized guinea-pigs and, notably, after oral administration, SR 120819A counteracts the pressor response of [Leu31,Pro34]NPY (5 micrograms/kg i.v.) with a long duration of action (> 4 h at 5 mg/kg p.o.). Thus, SR 120819A is the first orally-effective NPY Y1 receptor antagonist yet described. It could be a useful tool for exploring the role of NPY and the therapeutic relevance of an antagonist at NPY Y1 receptors.

Human immunodeficiency virus type 1 replication within cystic lymphoepithelial lesion of the salivary gland.

Cystic lymphoepithelial lesions of salivary glands (CLLSG) are nodular or diffuse salivary gland enlargements that are observed in patients who tested positive for human immunodeficiency virus type 1 (HIV-1). Two cases of CLLSG are reported. Particular emphasis is placed on the presence of HIV-1 major-core protein (P24), HIV-1 RNA sequences, Epstein-Barr virus (EBV) DNA sequences, and lymphocyte receptor gene rearrangement. Lymphoid alterations consisted of explosive hyperplasia with a prominent follicular reticular dendritic cell (DRC) network and numerous intrafollicular CD8+ lymphocytes. Intrafollicular DRC strongly expressed HIV-1 major-core protein and HIV-1 RNA, indicating that most DRCs actively replicated the HIV-1 virus. The presence of active HIV-1 replication within DRC and the absence of clonal EBV infected lymphoid population strongly suggest that CLLSG pathogenesis is primarily induced by HIV-1. The presence of oligoclonal immunoglobulin gene rearrangements in our cases, however, suggest the need of long-term follow-up of such patients to determine whether CLLSG could be a benign prelymphomatous disease.

Fatty acids and plasma antioxidants in HIV-positive patients: correlation with nutritional and immunological status.

OBJECTIVE: To investigate red blood cell (RBC) and plasma fatty acids (FA) in HIV-positive patients in relation to oxidative stress and nutritional or immunological status. DESIGN AND METHODS: FA, plasma selenium, vitamins A and E were measured in 95 patients divided into four groups according to CD4 cells. RESULTS: Poly- and di-unsaturated FA (PUFA, DUFA) decreased and saturated FA (SFA) increased in RBC in the patients below 400/mm3 and in plasma in the patients below 50/mm3. RBC SFA correlated to CD4 cells, PUFA to MDA. Unlike vitamin E, plasma vitamin A and selenium decreased in most groups. Plasma SFA and MUFA correlated negatively to selenium and PUFA and DUFA to vitamin E. No correlation was found between PUFA and nutritional markers. CONCLUSION: FA seem to be modified during HIV infection by oxidative stress and disease evolution, but not by denutrition.

[Value and limitations of the endomyocardial biopsy in HIV infection]. / Intérêt et limites de la biopsie endomyocardique au cours de l'infection par le VIH.

The authors evaluated the interest of endomyocardial biopsy in 19 consecutively hospitalized patients with AIDS. Histopathological study dit not exhibit opportunistic infection but showed aspecific myocarditis in nine patients.

[Syndrome of macrophagic activation with hemophagocytosis in human immunodeficiency virus infection]. / Syndrome d'activation macrophagique avec hémophagocytose au cours de l'infection par le virus de l'immunodéficience humaine.

The authors report two cases of hematophagic histiocytosis in HIV positive patients. In the first case, a patient with Kaposi sarcoma and Mycobacterium avium infection had a rapidly deteriorating course with progressive pancytopenia and death, as generally described in the literature. In the second case, hematophagic histiocytosis appeared during HIV primo infection and reversed spontaneously. Although few cases of hemophagocytic syndrome have been reported in HIV positive patient, it could represent an underestimated cause of pancytopenia. Both opportunistic microorganisms and HIV are able to cause hematophagic histiocytosis.

[Interferon and blood tumor necrosis factor in 95 patients with HIV infection]. / Interféron et facteur de nécrose tumorale sériques chez 95 patients infectés par le VIH.

We have measured TNF-alpha and interferon alpha in 95 HIV positive patients and 20 healthy subjects. TNF-alpha was higher in the HIV+ patients (P = 0.0001) and was correlated to the CD4 cell count (P = 0.02) and cholesterol (negatively) (P = 0.04). Interferon-alpha was correlated to the wasting syndrome (P = 0.002), hypertriglyceridemia (P = 0.004) and haematocrit (P = 0.04).

[Membrane fatty acids and blood antioxidants in 77 patients with HIV infection]. / Acides gras membranaires et anti-oxydants sériques chez 77 patients infectés par le VIH.

We have measured the fatty acid (FA) composition of erythrocyte membranes and plasma anti-oxidants in HIV+ patients. Saturated FA are higher and poly-unsaturated FA lower than in controls (P = 0.02). Selenium (Se) is lower in patients less than 400 CD4 cells/mm3 (P = 0.002). Vitamin A is lower in the HIV+ regardless of the CD4 cell count. Se and vitamin A are correlated to nutritional markers (body mass index and albumin).

[Shouldice steel wire repair and under local anesthesia: prospective evaluation of postoperative comfort]. / Shouldice au fil d'acier et sous anesthésie locale: évaluation prospective du confort post-opératoire.

This study evaluates postoperative comfort of patients who have undergone inguinal hernia operations by Shouldice technique. The low analgesic consumption, the out patient management of 77% of patients, the resumption of normal activity after one week and a satisfaction index of nearly 100%, are the main results of this study. For the authors, this comfort is another argument in favour of the use of this technique.

[Duodenal duplication in adults. Laparoscopic treatment]. / Duplication duodénale chez l'adulte. Traitement coelioscopique.

The authors report a case of duodenal duplication in a adult. This lesion is rare. The clinical course is dominated by a risk of cancer. These lesions should be recognized to avoid a mutilating excision procedure in favour of a conservative procedure. The originality of this case is the laparoscopic approach which confirmed the diagnosis by the elective implantation on the first part of the duodenum. This approach, by mobilisation of the duodenum, allows excision by a very short laparotomy.

[Inflammatory pseudotumor of the liver. Apropos of a case]. / Pseudotumeur inflammatoire du foie. A propos d'un cas.

The authors report a case of inflammatory pseudotumor of the liver, a rare lesion of unknown pathogenesis. Conservative management could be justified due to the good prognosis of this disease, when it is diagnosed preoperatively. However, when in doubt, surgical resection is usually recommended to obtain histological diagnosis.

[Primary prophylaxis against cerebral toxoplasmosis. Efficacy of folinic acid in the prevention of hematologic toxicity of pyrimethamine]. / Prophylaxie primaire de la toxoplasmose cérébrale. Efficacité de l'acide folinique dans la prévention de la toxicité hématologique de la pyriméthamine.

OBJECTIVES: Cerebral toxoplasmosis is the most frequent opportunistic infection in patients with acquired immune deficiency syndrome in France. We evaluated the effect of adding folic acid to the standard treatment (including pyrimethamine) on preventing induced cytopenia in order to determine the optimal dose. METHODS: From January to September 1990, pyrimethamine (50 mg 3 times per week) was given as primary prophylaxis against toxoplasmosis to 30 patients who were positive for human immunodeficiency virus (CDC classes II or II, CD4 counts < 200/mm3). The patients were randomly divided into three groups given 5, 25 and 0 mg folic acid 3 times per week. Associated treatments were the same in all patients (zidovudine 600 mg/d, pentamidine isethionate aerosol, 300 mg, once a month). Blood cell counts and lymphocyte subset counts were made on days 0, 30, 90 and 180. RESULTS: Two patients were lost to follow-up and between day 90 and 180, 3 were excluded due to other opportunist infection and 1 due to zidovudine induced anaemia. Between the groups, there was no difference in haemoglobin level or cell counts on day 0. No haematologic toxicity was observed at day 90. Haemoglobin was significantly reduced in the control group (0 mg folic acid) on day 180 (mean haemoglobin on day 180, 13.8, 13.1 and 12.1 g/dl in groups 1, 2 and 3 respectively). No variation in polynuclear neutrophil counts was observed. CONCLUSION: These findings suggest that folic acid has a moderate beneficial effect on preventing haematologic disease in patients treated with pyrimethamine. There was no observed dose effect.

[CD8 hyperlymphocytosis in HIV infection. 63 cases. GECSA (Groupe d'Epidémiologie Clinique du SIDA en Aquitaine)]. / Hyperlymphocytose CD8 au cours de l'infection par le VIH. 63 observations.

A group of 63 patients infected by HIV and presenting with CD8 hyperlymphocytosis (CD8+) has been studied. CD8 hyperlymphocytosis was defined by the presence, during at least three months, of at least 1,500 CD8 circulating lymphocytes. The CD8+ patients (n = 63) were identified and followed within the cohort (1,444 patients) of the "Groupe d'Epidémiologie Clinique du SIDA en Aquitaine " (GECSA). CD8+ patients were compared with a control group of 126 HIV infected patients without CD8 hyperlymphocytosis recruited within the GECSA cohort and followed in the same manner during two years. The occurrence of opportunistic infections was less frequent in CD8+ patients. The proportion of patients with a CD4 lymphocyte count below 200/mm3 was lower in the CD8+ group than in the CD8- group at inclusion and at the last check-up (P less than 0.01). A tendency for longer survival and delayed onset of AIDS was noted in CD8+ patients. Such a difference in prognosis might be due to a peculiar cytotoxic response against HIV among CD8+ patients. Further follow-up of a larger group of patients is needed to confirm this hypothesis.