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.     

A new technique for assessing the efferent innervation of the human striated urethral sphincter

A technique is described for recording the electromyographic response of the striated urethral sphincter to transcutaneous magnetic stimulation of the brain and spinal cord. A series of 11 control patients have been studied and 3 examples of patients with neurological disease also are reported. The most reliable response was recorded after facilitated transcranial stimulation of the cerebral cortex, with the mean latency of the electromyographic response in the striated sphincter being 26.4 msec. (standard deviation 2.21). It is concluded that assessment of the latency of the striated urethral sphincter electromyographic response to transcranial magnetic stimulation may be a useful technique in the investigation of patients with disorders of micturition.     

Metabolic syndrome: contributing factors and treatment strategies.

Metabolic syndrome is associated with increased risk for cardiovascular and cerebrovascular disease. The World Health Organization and National Cholesterol Education Program Adult Treatment Panel III have identified physiologic abnormalities associated with metabolic syndrome, including impaired glucose metabolism, high blood pressure, elevated cholesterol levels, and abdominal obesity. It is estimated that 47 million Americans have metabolic syndrome. A variety of therapies may help reduce the incidence and risk, including diet, weight loss, physical exercise, glycemic control, and pharmacological treatments. Nursing care is focused on developing an individualized plan of care that includes family members and providing education, psychosocial support, close monitoring, and continued follow-up to ensure adherence and success in achieving patient outcomes.     

The clinical laboratory practitioner.

OBJECTIVE: This study was designed to investigate potential areas of practice for the clinical laboratory scientist (CLS) and to propose a graduate curriculum to prepare the practitioner for an advanced level of practice. DESIGN: Meta-analysis of PharmD, physician assistant, physical therapy, and nurse practitioner curricula focusing on academic and clinical advanced practice was used to develop an educational model and curriculum for a professional doctorate in clinical laboratory science (CLS). MAIN OUTCOME MEASURE: (1) New educational model for CLS advanced practice; (2) A proposed curriculum for a Doctorate of Clinical Laboratory Science degree. RESULTS: A new curriculum model was adapted from established healthcare educational models. CONCLUSION: Although there is a need for a baccalaureate degree in CLS there is also a role for expanded education and responsibilities for CLS practitioners. The CLS Advanced Practitioner design focuses on moving students from the baccalaureate level to the doctoral level and prepares the individual to become an integral part of the healthcare team.     

Co-operative mineralization and protein self-assembly in amelogenesis: silica mineralization and assembly of recombinant amelogenins in vitro

An amorphous silica mineralization technique was used to produce inorganic/protein composites to elucidate the structure and mechanism of formation of amelogenin assemblies, which may play an important role in regulating enamel structure during the initial stages of amelogenesis. Full-length recombinant amelogenins from mouse (rM179) and pig (rP172) were investigated along with key degradation products (rM166 and native P148) lacking the hydrophilic C terminus found in parent molecules. The resulting products were examined using transmission electron microscopy and/or small-angle X-ray scattering. Using protein concentrations of 0.1–3 mg ml⁻¹, large monodisperse spheres of remarkably similar mean diameters were observed using rM179 (124 ± 4 nm) and rP172 (126 ± 7 nm). These spheres also exhibited 'internal structure', comprising nearly spherical monodisperse particles of ≈ 20 nm in diameter. In the presence of rM166, P148, and bovine serum albumin (control), large unstructured and randomly shaped particles (250–1000 nm) were observed. Without added protein, large dense spherical particles of silica (mean ≈ 500 nm) lacking internal structure were produced. These findings demonstrate that full-length amelogenins have the ability to form higher-order structures, whereas amelogenins that lack the hydrophilic C terminus do not. The results also suggest that full-length amelogenin can guide the formation of organized mineralized structures through co-operative interactions between assembling protein and forming mineral.