Synthesis and biological activities of novel 5-(2-acylethynyl)uracils

5-(2-Acylethynyl)-2,4-dimethoxypyrimidines (3-6) were synthesized in excellent yields from 2,4-dimethoxy-5-[2-(trimethylsilyl)ethynyl]pyrimidine (2) by treatment with acid chlorides in the presence of anhydrous aluminum chloride. Compounds 3-6 were deblocked with chlorotrimethylsilane and sodium iodide in acetonitrile to the corresponding 5-[(2-acyl-1-iodo)vinyl]uracils (7-10), which on treatment with potassium hydroxide in dioxane yielded the corresponding 5-(2-acylethynyl)uracils (11-14). The 5-(2-acylethynyl)uracils were found to be active against Ehrlich ascites carcinoma (EAC) cells in vivo, the most active compounds being 5-(2-benzoylethynyl)uracil (11) and 5-(2-p-toluoylethynyl)uracil (12). The T/C values of 281 and 300 were obtained for compounds 11 and 12, respectively, in the case of mice bearing EAC cells. The 5-(2-acylethynyl)uracils have also shown in vitro activity against CCRF-CEM and L1210/0 tumor cell lines. The lead compound 5-(2-p-toluoylethynyl)uracil effectively inhibited thymidylate synthetase.     

Affinity labeling of endothelin receptors in bovine and rat lung membranes by N epsilon 9-azidobenzoyl-125I-endothelin-1.

Endothelin-1 (ET-1) is a potent, vasoconstrictive peptide isolated from culture media of vascular endothelial cells. The binding of ET-1 to membrane preparations from rat and bovine lung was studied using radioiodinated ET-1 (125I-ET-1). With both membrane preparations, 125I-ET-1 showed saturable binding to a single class of high affinity sites. Scatchard analysis of the binding data gave dissociation constants (Kd) for ET-1 of 0.22 nM and 0.15 nM, and receptor densities (Bmax) of 6.1 pmol/mg and 2.7 pmol/mg for rat and bovine lung membranes, respectively. Photo-reactive radioiodinated ET-1, N epsilon 9-azidobenzoyl-125I-ET-1, was synthesized and purified as a mono-reactive affinity labeling reagent. This reagent was used for affinity labeling of ET-1 receptor in bovine and rat lung membranes. Photoaffinity labeling followed by sodium dodecyl sulfate gel electrophoresis and autoradiography gave a radiolabeled protein band with an apparent Mr of 34,000 in both membrane preparations. The labeling of this protein band was inhibited by cold ET-1 in a concentration-dependent manner. Labeling was not abolished by unrelated peptides such as angiotensin II and [Arg8]-vasopressin, or by structurally related bee venom apamin. These results indicate that the ET-1 receptor or its ligand binding subunit consists of a 34,000 Da polypeptide.     

Measurement of material elastic constants of trabecular bone: a micromechanical analytic study using a 1 GHz acoustic microscope.

The propagation speed (C) of surface acoustic waves (SAW), e.g. Rayleigh (R-waves) and longitudinal lateral waves (L-waves), the latter being the surface manifestation of the longitudinal waves, strongly reflect mechanical properties of materials. In view of an increasing interest in ultrasonic methodology in the field of bone biomechanics, we tested the hypothesis that both R- and L-waves can be excited in trabecular bone using an acoustic microscope at 1 GHz and that their speeds (C(R) and C(L)) can be extracted from V(z)-curves, i.e. plots of lens output voltage as a function of the lens focal point position with respect to the specimen surface. In accordance with V(z)-curves theoretically synthesized on the basis of incident field theory, experimental curves for canine femoral trabecular bone showed evidence of both R- and L-waves in almost all regions of recording. The measured CR ranged between 1.93 and 2.07 km/s (mean +/- SD.: 2.00=0.06 km/s) and the C(L) ranged between 2.33 and 4.33 km/s (3.37+/-0.61 km/s). Knowledge of both speeds allowed computation of a number of material constants by means of simple theory of elasticity and assumptions of the material density. We found values of Poisson ratio (v) ranging from 0.14 to 0.32 (0.23+/-0.07). Young's modulus (E) from 15 to 22.8 GPa (19.9+/-2.5 GPa) and the shear modulus (G) from 7.6 to 8.9 GPa (8.4+/-0.5 GPa). Anisotropy in the trabecular bone material was clearly detected at the micrometer level. In conclusion, the V(z)-curve method was successfully used to determine the distribution of material elastic constants of trabecular bone with micrometer resolution.     

Extraskeletal chondroma of the hand--a case report

Extraskeletal chondroma is a rare entity. A fairly benign condition, it is usually seen in adults. It presents as an enlarging mass, most commonly in the hand. Local excision is the treatment of choice. We present a case of extraskeletal chondroma of hand in a 12 year male child. Its variable histological appearance not infrequently leads to a mistaken diagnosis of chondrosarcoma.     

Detection of beet yellows virus by RT-PCR and immunocapture RT-PCR in Tetragonia expansa and Beta vulgaris

Two sensitive methods, RT-PCR with phenol-extracted RNA or Triton X-100-released RNA and immunocapture RT-PCR (IR-RT-PCR) were used for the detection of Beet yellows virus (BYV) in young and old leaves of Tetragonia expansa and sugar beet (Beta vulgaris) and in sugar beet roots. Four oligonucleotide primer pairs proved suitable for the detection of BYV. The release of BYV RNA with Triton X-100 was shown to be a very effective and easy as compared to isolation of total RNA by phenol extraction with the same or higher sensitivity of subsequent PCR. Using the Triton X-100 release of RNA and IC-RT-PCR the sensitivity of detection was so high that pg amounts of BYV RNA occurring in dilutions up to 10(-6) of saps from young Tetragonia and sugar beet leaves could be detected.     

Prospective adverse event risk evaluation in clinical trials

Health Care Management Science - Proactive and objective regulatory risk management of ongoing clinical trials is limited, especially when it involves the safety of the trial. We seek to...     

Double-stranded RNA and bacterial lipopolysaccharide enhance sensitivit to TNF-{alpha}-mediated cell death

The effect of double-stranded RNA (dsRNA) and bacterial lipopolysaccharideon the sensitivity to tumor necrosis factor (TNF)--medlatedcell death was studied In an In vitro system. Since secretionof TNF- Is a part of the early host response to viral and bacterialinfection, we examined whether mimicking the Infection withviral and bacterial products could affect the response of cellsto TNF-. Incubation of WEHI 164 fibrosarcoma cells with dsRNAor lipopolysaccharide (LPS) significantly increased their sensitivityto TNF--mediated lysis and to TNF-secreting inflammatory T cell-mediatedlysis. Thus, these products could induce Increased sensitivityto TNF- In cells In an inflammatory focus, possibly contributingto selective elimination of Infected but not healthy cells bythis non-specific cytokine. Additionally, our data show thatboth dsRNA and LPS, as well as TNF- Itself, rapidly Induce nuclearfactor-xB (NF-*B), a DNA-bindlng protein Implicated In regulationof gene expression. We suggest that NF-xB could regulate genescrucial for the induction of cell death by TNF-.     

Bioprosthetic heart valves--replacing order with chaos: electron microscopic study

Rheumatic heart disease is a significant clinical entity in young children, especially in the developing world. One of the major long-term effects of ill managed rheumatic fever is irreversible damage to the cardiac valve leaflets, primarily on the left side. With the limited success of currently available mechanical and bioprosthetic valves, there is an urgent need for new directions in bioprosthetic valves, both in material, including source, degree of fixation, surface, bulk modifications, etc., and design. In the present paper, new proposals in the material selection and fabrication of bioprosthetic valves are proposed based on electron microscopic studies of natural valve leaflets and the pericardial surface. Current approaches for bioprosthetic valve fabrications include the wide use of the pericardium as a leaflet material. The present study indicates a need for nondestructive surface examination of pericardial sheets for the elimination of areas of surface voids resulting from gross fiber disorientation. Also, there seems to be a need for incorporation of an in situ fiber renewal mechanism in bioprosthetic leaflets to emulate the natural valve more closely. Apparently natural leaflets have built-in fiber renewal mechanism(s).     

Elevated Plasma S100B,Psychotic Symptoms,and Cognition in Schizophrenia

S100B is a calcium binding protein mainly produced by glial cells. Previous studies have shown elevated levels of S100B in patients with schizophrenia. We measured S100B levels in fasting plasma of 39 patients with schizophrenia and 19 adult healthy controls. We used linear regression to compare S100B between patients and controls. In patients only, we also investigated the relationship between S100B levels and psychotic symptoms (assessed by the Positive and Negative Syndrome Scale), and cognitive function (assessed by the NIH Toolbox Cognition Battery), respectively by calculating Pearson’s correlation coefficients. Mean plasma S100B was significantly higher in the patient group than in the control group. There were no significant correlations between plasma S100B and psychotic symptoms or cognition.