The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Treatment of macular holes by vitrectomy and gas

Five cases of retinal detachment with macular hole show the effectiveness of the treatment: Vitrectomy + exchange Fluid-gas. Red krypton laser applied around macular hole is not necessary. Treatment vitrectomy-exchange Fluid gas must be performed rather than Aspiration-gas in a first attempt.     

High hyperopia with papillomacular fold.

We report a case of evolutive high hyperopia in a child aged 10 years. It is associated with organic amblyopia due to a large papillomacular retinal fold. Ultrasonography and CT scan helped to establish the diagnosis. This is probably a hereditary disease affecting the development of the posterior sclera.     

Obesity Surgery Poly-parametric Patient Auto-evaluation

A simple auto-evaluation sheet is presented for the proper assessment of the patient's condition after surgery. Stress is put not only on weight loss, but on other important factors as well.     

Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia

Seventy-five patients, 13 to 49 years of age, with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, fractionated total body irradiation, and marrow transplantation from an HLA-identical sibling and randomized to receive either cyclosporine (CSP) (n = 36) or methotrexate (MTX) (n = 39) as prophylaxis for graft-v-host disease (GVHD). All patients engrafted, and 22 who were given CSP and 21 who were given MTX, are alive at 20 to 47 (median, 35) months (P = .5). Engraftment as assessed by granulocyte recovery (P less than .0005) and platelet transfusion requirement (P = .01) was faster in patients on CSP. Twelve patients (33%) on CSP and 22 (56%) on MTX developed acute GVHD of grades II through IV (P = .07) and 15 of 30 on CSP and 14 of 32 on MTX that were at risk developed chronic GVHD. The most frequent causes of death were interstitial pneumonitis and marrow relapse of leukemia, which occurred with similar frequency in both groups. Beneficial effects observed in patients on CSP included less severe mucositis and shorter duration of hospitalization; adverse effects included renal function impairment and hypertension. These data confirm that CSP is a useful immunosuppressant in patients undergoing marrow transplantation but fail to show a significant improvement in survival as compared with the standard regimen of MTX.     

Peripheral T cell lymphoma: immunologic and cell-kinetic observations associated with morphological progression

Peripheral T cell lymphomas (PTCLs) form a morphologically heterogeneous group of non-Hodgkin's lymphomas that are generally considered to have immunophenotypes associated with mature T cells, usually those of helper T cells. We now describe and correlate the clinical, morphological, immunologic, and cell-kinetic findings based on the evaluation of eight tissue samples obtained at various times from a 13-year-old girl with PTCL. The early morphological expressions of this patient's PTCL were those of diffuse mixed-cell lymphoma and focal large-cell lymphoma (LCL) evolving from the histologic picture of an atypical immune response (AIR). These morphological findings were associated with an immature T cell immunophenotype associated with cortical thymocytes--namely, sheep erythrocyte rosette (sER)+, T11+, Leu-2a+, Leu-3a+, HLA-DR+, OKT6-, OKT9+, OKT10+--and with cell-kinetic findings that showed no evidence of aneuploidy and few cells in S phase. Diffuse pleomorphic LCL developed, which was associated with further dedifferentiation of the neoplastic T cells to the immunophenotype sER-, T11+, Leu-2a-, Leu-3a-, HLA-DR+, OKT6-, OKT9+, OKT10- and with cell-kinetic findings that demonstrated a distinct aneuploid population and a dramatic increase in the percentage of cells in the S phase. The immunophenotype of the PTCL at the time of the patient's death was T11-, Leu-2a-, Leu-3a-, HLA-DR+, OKT6-, OKT9+, OKT10-, an immunophenotype indistinguishable from that of a non-B non-T cell lymphoma. The immunologic findings in this case also suggest that an AIR in some cases may represent a prelymphomatous state or may be a morphological expression of PTCL. These observations indicate that PTCLs may be characterized by rapidly changing clinical, morphological, immunologic, and cell kinetic findings which are best evaluated by multidisciplinary studies.     

Human skeletal muscle: sodium MR imaging and quantification-potential applications in exercise and disease

PURPOSE: To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human muscle and to apply the technique in exercise and musculoskeletal disease. MATERIALS AND METHODS: Total [Na] sodium was determined from the ratio of the relaxation-corrected (23)Na signal intensities measured from short echo-time (0.4 msec) (23)Na images to those from an external saline solution reference. The method was validated with the blinded use of saline solutions of varying sodium concentrations. [Na] was measured in the calf muscles in 10 healthy volunteers. (23)Na MR imaging also was performed in two healthy subjects after exercise, two patients with myotonic dystrophy, and two patients with osteoarthritis. RESULTS: (23)Na MR imaging yielded a total [Na] value of 28.4 mmol/kg of wet weight +/- 3.6 (SD) in normal muscle, consistent with prior biopsy data. Spatial resolution was 0.22 mL, with signal-to-noise ratio of 10-15. Mean signal intensity elevations were 16% and 22% after exercise and 47% and 70% in dystrophic muscles compared with those at normal resting levels. In osteoarthritis, mean signal intensity reductions were 36% and 15% compared with those in unaffected knee joints. CONCLUSION: (23)Na MR imaging can be used to quantify total [Na] in human muscle. The technique may facilitate understanding of the role of the sodium-potassium pump and perfusion in normal and diseased muscle.     

Multi-detector computed tomography in coronary artery bypass graft assessment: a meta-analysis

Multi-detector computed tomography (MDCT) has become an alternative to coronary angiography in diagnosis of graft occlusion and stenosis after coronary artery bypass. A literature search was performed for studies comparing angiography to 8-slice, 16-slice, and 64-slice MDCT in the assessment of coronary grafts. In assessing occlusion, 14 studies produced pooled sensitivity of 97.6%, specificity of 98.5%, diagnostic odds ratio of 934.2, area under the curve of 0.996, and Q* of 0.977. Ninety-six percent of all grafts were visualized for occlusion assessment. Beta blockers, symptomatic status, and postoperative period did not significantly affect diagnostic performance. Stenosis assessment produced sensitivity of 88.7% and specificity of 97.4%. Eighty-eight percent of patent grafts could be assessed for stenosis. The diagnostic accuracy of MDCT approaches angiography for diagnosing graft occlusion and stenosis in patients with venous and arterial coronary bypass grafts. Our findings show that cardiac surgeons will need to interpret MDCT images of both native and grafted vessels soon in preparation for primary or re-do coronary bypass grafting procedures.     

Application of self-expandable metal stents for ureteroileal anastomotic strictures: long-term results

PURPOSE: We report our long-term experience with the management of benign ureteroileal anastomotic strictures using self-expandable metal stents. MATERIALS AND METHODS: A total of 16 male and 2 female patients with a mean+/-SD age of 72+/-7 years (range 66 to 78) with benign fibrotic strictures at the site of ureteroileal anastomosis underwent implantation of self-expandable metal stents with a nominal diameter of 6 to 8 mm. A total of 24 ureteroileal conduits were treated. The external nephrostomy tubes were removed after fluoroscopic validation of ureteral patency. Patients were followed with blood biochemistry, ultrasonography, urography and/or virtual endoscopy. Retrograde external-internal catheter insertion through the cutaneous stoma was performed in cases of recalcitrant stricture. RESULTS: The technical success rate of ureteroileal stricture crossing and stenting was 100% (24 of 24 cases). Mean followup was 21 months (range 7 to 50). The clinical success rate during the immediate post-stenting period was 70.8% (17 of 24 cases). The 1 and 4-year primary patency rates were 37.8% and 22.7%, respectively. Secondary interventions included repeat balloon dilation in 15 ureters, of which 8 also underwent subsequent coaxial stent placement. The 1 and 4-year secondary patency rates were 64.8% and 56.7%, respectively. Except in 2 patients who died external-internal Double-J catheters continued to be inserted retrograde in 6 ureteroileal conduits. They are periodically exchanged to prevent mucous inspissation and stent encrustation. CONCLUSIONS: Metal stents served as the definitive treatment for stricture in more than half of the cases, whereas in the remainder the stents allowed the uncomplicated and regular exchange of Double-J catheters in retrograde fashion. This combined, less invasive treatment for ureteroileal anastomotic strictures may help patients avoid surgical revision and preserve quality of life.