Cytotoxic effects,alkylating properties and molecular modelling of coumarin derivatives and their phosphonic analogues

The cytotoxic effects and alkylating activity of a series of 3-[1-(alkylamino)-ethylidene]-chroman-2,4-dione (4a-4c), 2-methoxy-3-[1-(alkylamino)-ethylidene]-2,3-dihydro-2,4-dioxo-2lambda(5)-benzo[e][1,2] oxaphosphinane (5a-5c) and [2-oxo-4-phenyl(alkyl)-2H-chromen-3-yl]-phosphonic acids dimethyl ester (6a-6c) on the two leukemia cell lines HL-60 and NALM-6 have been determined. The test compounds are much more toxic to NALM-6 cells than to HL-60 cells. IC(50) data are up to nine times lower for the NALM-6 than for the HL-60 cell lines. As determined in an in vitro Preussmann test phosphonic derivatives 6a-6c possess very high (+++) alkylating activity, phosphoric derivatives 5a-5c are less active (++) while the derivatives 4a-4c can be included in the group of low activity (+) alkylating agents. Using regression analysis QSAR we found a relationship between biological activity and the physicochemical properties of the test compounds. Their cytotoxic effect increases with an increase of the hydrophobic parameters in the region of the substituents at the 2-, 3- and 4-positions of the benzopyrone skeleton of 4-6.     

Dietary calcium and obesity in men

Increased calcium intake has been associated with lower body weight, BMI and adiposity, mostly in children, youth and women. In men results are inconclusive. In this study the relation between calcium intake and body weight and body fat in obese men was investigated. 200 men, the mean age 45.1 +/- 9.4 y, the mean BMI 33.2 +/- 4.8 kg/m2, were divided into 4 groups on the basis of their calcium/protein index. No significant differences in body weight, BMI, fat mass, percentage of body fat were found across subgroups and no significant correlations between calcium intake and body variables were stated. This study did not confirm the association between calcium intake and body weight and adiposity in men.     

Radiopaque alginate microcapsules for X-ray visualization and immunoprotection of cellular therapeutics

Alginate-poly-L-lysine-alginate (APA) microcapsules have been explored as vehicles for therapeutic drug and cell delivery. The permselectivity of these capsules provides a unique means of controlled drug release and immunoisolation of encapsulated cells. Immunoisolation is especially attractive as it abrogates the need for chronic immunosuppressive therapy and opens up the possibility for the delivery of numerous cell sources including xenogeneic grafts. APA microcapsules containing cellular therapeutics have proven effective in the short-term treatment of a wide range of diseases requiring enzyme or endocrine replacement therapy, including type I diabetes. If these microcapsules could be noninvasively monitored with X-ray imaging modalities (i.e., fluoroscopy, CT, and digital subtraction angiography), questions such as the ideal transplantation site, the best means of delivery, and the long-term survival of grafts could be better addressed. We have developed two novel alginate-based radiopaque microcapsule formulations containing either barium sulfate (Ba X-Caps) or bismuth sulfate (Bi X-Caps). As compared to conventional, nonradiopaque APA capsules, Ba X-Caps and Bi X-Caps containing human cadaveric islets resulted in a decrease in cellular viability of less than 5% up to 14 days after encapsulation. Both radiopaque capsules were found to be permeable to lectins < or =75 kDa, but were impermeable to lectins > or =120 kDa, thus ensuring the blockage of the penetration of antibodies while allowing free diffusion of insulin and nutrients. The glucose-responsive insulin secretion of the radiopaque encapsulated human islets was found to be unaltered compared to that of unlabeled controls, with human C-peptide levels ranging from 3.21 to 2.87 (Ba X-Caps) and 3.23 to 2.87 (Bi X-Caps) ng/islet at 7 and 14 days postencapsulation, respectively. Using fluoroscopy, both Ba X-Caps and Bi X-Caps could be readily visualized as single radiopaque entities in vitro. Furthermore, following transplantation in vivo in mice and rabbits, single capsules could be identified with no significant change in contrast for at least 2 weeks. This study represents the first attempt at making radiopaque microcapsules for X-ray guided delivery and imaging of cellular therapeutics. While human cadaveric islets were used as a proof-of-principle, these radiopaque capsules may have wide ranging therapeutic applications for a variety of cell types.     

Synthesis and antimicrobial activity of thiosemicarbazides, s-triazoles and their Mannich bases bearing 3-chlorophenyl moiety

A fast and efficient synthesis of some 1,4-disubstituted thiosemicarbazide derivatives is described. The reaction of 3-chlorobenzoic acid hydrazide with various aryl isothiocyanates gave thiosemicarbazide derivatives (1-11) in good yield. The cyclization of compounds (1-11) in the presence of 2% NaOH resulted in the formation of compounds (12-22) containing the 1,2,4-triazole ring. A series of new Mannich bases (23-33) related to the structure of 1,2,4-triazole has been also synthesized. All of these compounds were tested for their in vitro antibacterial activity against the reference strains of aerobic bacteria - 6 Gram-positive and 3 Gram-negative ones; 12 Staphylococcus aureus clinical isolates were also examined. An attempt was made to clarify the influence of the nature/position of substituents on antibacterial activity of compounds described.     

Identifying Smokers with a Medical Extraction System

The Clinical Language Understanding group at Nuance Communications has developed a medical information extraction system that combines a rule-based extraction engine with machine learning algorithms to identify and categorize references to patient smoking in clinical reports. The extraction engine identifies smoking references; documents that contain no smoking references are classified as UNKNOWN. For the remaining documents, the extraction engine uses linguistic analysis to associate features such as status and time to smoking mentions. Machine learning is used to classify the documents based on these features. This approach shows overall accuracy in the 90s on all data sets used. Classification using engine-generated and word-based features outperforms classification using only word-based features for all data sets, although the difference gets smaller as the data set size increases. These techniques could be applied to identify other risk factors, such as drug and alcohol use, or a family history of a disease.     

Effects of voluntary wheel running on goserelin acetate-induced bone degeneration

A common treatment option for many breast and prostate cancer patients is the use of a luteinizing hormone-releasing hormone agonist such as goserelin acetate (GA) which reduces sex hormone levels. This treatment, however, is associated with bone degeneration, and exercise has been suggested as a means of preventing this side effect. Little is known about the effects of low intensity, low volume exercise on GA-induced bone loss. The purpose of this study, therefore, was to investigate the effects of voluntary wheel running on bone architecture in growing male (M) and female (F) rats receiving GA treatment. Rats received an 8-week GA treatment or placebo (CON) and were either housed in cages equipped with voluntary running wheels (WR) or remained sedentary (SED) in standard cages throughout the experimental period. Following treatments, tibiae were excised and analyzed for cortical bone (cross-sectional volume, cortical volume, marrow volume, cortical thickness) and cancellous bone (bone volume/total volume, trabecular number, trabecular thickness, trabecular spacing) using micro-computed tomography. Treatment with GA resulted in a significant reduction in running wheel distances in both sexes throughout the study period (P < 0.05). GA treatment had no effect on cortical bone architecture in neither sex (P > 0.05). Cancellous bone degeneration, however, was observed in M and F SED + GA (P < 0.05). No significant differences were observed in M WR + GA animals in bone volume/total volume, trabecular number and trabecular spacing when compared to M SED + CON (P > 0.05). In F WR + GA, trabecular thickness did not differ from that of F SED + CON (P > 0.05), and trabecular spacing was found to be significantly lower than F SED + GA (P < 0.05). The current report indicates that 8 weeks of GA treatment promotes cancellous bone degeneration, and voluntary wheel running provides no clear osteoprotection in growing male and female rats.     

Biochemical diagnostics of bone metastases

The skeleton is a frequent localization of cancer metastases. The method of choice in their diagnostics is scintigraphy, but at high sensitivity, it is characterized by limited diagnostic specificity. Discussed are the possibilities of using the examination of some tumor markers as well as biochemical factors of the resorption and bone formation process in bone metastases diagnostics. At the present stage, it can be found that the studies of such factors introduce a number of additional significant information, but they cannot fully replace bone scan.     

Metabolic Coupling Between Bone Marrow Adipose Tissue and Hematopoiesis

Purpose of Review

Mesenchymal stem cells (MSCs) located in the bone marrow have the capacity to differentiate into multiple cell lineages, including osteoblast and adipocyte. Adipocyte density within marrow is inversely associated with bone mass during aging and in some pathological conditions, contributing to the prevailing view that marrow adipocytes play a largely negative role in bone metabolism. However, a negative association between marrow adipocytes and bone balance is not universal. Although MAT levels appear tightly regulated, establishing the precise physiological significance of MAT has proven elusive. Here, we review recent literature aimed at delineating the function of MAT.

Recent Findings

An important physiological function of MAT may be to provide an expandable/contractible fat depot, which is critical for minimization of energy requirements for sustaining optimal hematopoiesis. Because the energy requirements for storing fat are negligible compared to those required to maintain hematopoiesis, even small reductions in hematopoietic tissue volume to match a reduced requirement for hematopoiesis could represent an important reduction in energy cost. Such a physiological function would require tight coupling between hematopoietic stem cells and MSCs to regulate the balance between MAT and hematopoiesis. Kit-ligand, an important regulator of proliferation, differentiation, and survival of hematopoietic cells, may function as a prototypic factor coupling MAT and hematopoiesis.

Summary

Crosstalk between hematopoietic and mesenchymal cells in the bone marrow may contribute to establishing the balance between MAT levels and hematopoiesis.

     

Near-infrared spectroscopy in evaluation of cerebral oxygenation during vasovagal syncope

Near-infrared spectroscopy (NIRS) offers a non-invasive, real-time monitoring of cerebral oxygenation. This method is based on the oxygenation and the light wavelength dependent absorption of near-infrared light by tissue chromophores, e.g. oxyhaemoglobin and deoxyhaemoglobin. The objective of the present study was the application of NIRS for evaluation of the brain function during vasovagal syncope (VVS). The VVS is a clinical syndrome affecting ca 3.5% of the population and for which the widely used diagnostic examination in this disease entity is the head-up tilt table test (HUT). In this study 69 patients with a history of VVS were examined using HUT. In 42 patients VVS was provoked. Results of the examination have shown that the changes in cerebral oxygenation measured by the NIRS technique are distinctly visible before the syncope. A gradual decrease of oxyhaemoglobin followed by its sudden drop was observed in all the VVS patients. Changes in the oxyhaemoglobin concentration measured by NIRS were observed on average 3.3 min before the syncope. They preceded the presyncope symptoms about 1.3 min (p < 0.005), the blood pressure and heart rate drop 2.2 min (p < 0.0001) and the arterial blood saturation 2.6 min (p < 0.00001).