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.     

Primary extraosseous osteogenic sarcoma of the mediastinum: clinical, pathologic, and radiologic correlation

We have presented a rare case of primary involvement of the anterior mediastinum by osteogenic sarcoma in which CT was useful in demonstrating calcium within the mass, and in distinguishing the mass from surrounding bony structures. Although rare, extraosseous osteogenic sarcoma should be included in the differential diagnosis of a calcified anterior mediastinal mass.     

Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients.

PURPOSE: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. EXPERIMENTAL DESIGN: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. RESULTS: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. CONCLUSIONS: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.     

The mechanics and biology of intramedullary fracture fixation

Intramedullary (IM) fracture fixation serves to stabilize fracture fragments and maintains alignment, while permitting motion at the fracture site during functional activities. Acting as an internal splint, the implant serves as a load-sharing device and fracture healing progresses with the formation of peripheral callus. By allowing motion of adjacent joints, rehabilitation is concurrent with treatment, and stress-shielding is thought to be minimal using these techniques. Recently, IM nails have been introduced to widen indications for their use based on variations in the cross-sectional geometry, length and shape of nails, interlocking designs, and surgical techniques. Although the most important mechanical factors in the design of IM nails are strength, stiffness, and rigidity, anatomic constraints and surgical technique limit nail variations. Closed nailing is preferred to open procedures to preserve periosteal blood supply and minimize surgical trauma adjacent to the fracture. Blood flow to the fractured bone is elevated in nailing experiments, although callus maturation is somewhat delayed. However, the end result in terms of healing was similar to that of plate fixation.     

LIPOPROTEIN(α) IN HEALTH AND DISEASE

SUMMARY Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).     

Alprazolam in the treatment of cardiology patients with atypical chest pain and panic disorder

Ten cardiology chest pain patients without clinical evidence of coronary artery disease and with panic disorder were enrolled in an open label trial of alprazolam. Two dropped out at week 3 because of excessive side effects. The eight study completers showed significant decreases in both Hamilton Anxiety and Hamilton Depression scales by week 2 that remained significant by week 8. On the physician's global impression of change since baseline, all completers were rated at least "much improved." Seven experienced a 50% or greater reduction in panic frequency at week 8 compared to baseline. These results suggest that alprazolam is likely to be of benefit to this patient population.     

A PCR Specific for Escherichia coli O157 Based on the rfb Locus Encoding O157 Lipopolysaccharide

A PCR was developed for the detection of Escherichia coli O157 based on the rfbE O-antigen synthesis genes. A 479-bp PCR product was amplified specifically from E. coli O157 in cell lysates containing 200 or 2 CFU following crude DNA extraction. The PCR detected <1 CFU of E. coli O157 per ml in raw milk following enrichment.