Importance of compartment formation for a self-encoding system

A self-encoding system designed to have strict "compartition" of the molecules, i.e., to contain only a single molecule of DNA in each compartment, was established, and its evolutionary fate was analyzed. The system comprised the Thermus thermophilus DNA polymerase gene as the informational molecule and its protein product replicating the gene as the functional molecule. Imposing strict compartition allows the self-encoding system to last up to at least the tenth generation, whereas the system ceased to work after the third generation when loose compartition initiated with 100 molecules was imposed. These results provide experimental evidence on the importance of compartition for the maintenance of a self-encoding system. In addition, the extent of diversity in self-replication activity of the compartments was found to be another vital difference in the evolutionary dynamics between the strict and loose compartitions. Although the system with strict compartition provides widely diversified activity of the compartments at each generation, the values of the activity diverge only within a small range in the system with loose compartition. When the variety in the activity of a compartment is small, functional selection becomes weak, and to conform Darwinian evolution may become unfeasible. Therefore, strict compartition is essential for the evolvability of a self-encoding system.     

Leukemic transformation with trisomy 8 in essential thrombocythemia: a report of four cases

Abstract: Karyotype analysis of bone marrow samples was performed in 20 cases of essential thrombocythemia (ET) at the time of diagnosis. Three patients had karyotype abnormalities at the time of diagnosis; trisomy 8, deletion of Y, and del(9)(q?) in each. The patient who had trisomy 8 at the time of diagnosis underwent myeloid blastic transformation in 35 months. Three patients whose karyotypes were normal at the time of diagnosis developed a chromosome abnormality with trisomy 8 when they developed myeloid blastic transformation 38, 79 and 86 months after initial diagnosis of ET. Two patients with blastic transformation had been treated with busulfan, one with hydroxyurea and one with methyl‐6‐[3‐(2‐chloroethyl)‐3‐nitorosoureido]‐6‐deoxy‐α‐d ‐glucopyranoside (MCNU). It is suggested that progression of the disease may have increased the incidence of trisomy 8 and the development of leukemic transformation.     

Economical efficacy of measurement of bone mineral content for osteoporosis

Bone mineral content is measured both to disclose a person with fragile bone in the elders and to recognize the effect of anti-osteoporotics in the treatment of osteoporosis. If the persons with fragile bone are given the anti-osteoporotics, applied the hip protectors and guided the prevention of fall, frequency of femoral neck fracture would be reduced to one eighth, indicating 300 billion yen reduction of annual medico-welfare costs in Japan. Although 10% of cost in medicament treatment of osteoporosis are consumed for the measurement of bone mineral content, efficacy proved 2% increase of bone mineral content during 4 months encourages to continue the treatment for both medical doctors and patients.     

Efficacy in medical cost of concurrent therapy for osteoporosis

Medical cost of concurrent therapy (alphacalcidol and etidronate) for osteoporosis was compared with those of no treatment and single therapies (alphacalcidol or etidronate) . Although concurrent therapy reduced by one fifth in medical costs for low back pain and fractures, 3 to 6 times reduced medical costs were consumed in those for pharmaceutical therapies, radiological examinations and so on by concurrent therapy compared with no treatment and single therapies.     

Economical efficacy of physical exercises for osteoporosis

From mean 12.5% increase of lumbar bone mineral density by one year's physical training, it is calculated to reduce the frequency of femoral neck fracture by 80% and the rate of falls by 50%. And 60% reduction of femoral neck fracture by physical exercise gains about 200 billion yen of medical and care costs annually, because a patient with femoral neck fracture consumes mean 1,320,000 yen for medical treatments and about 19% of the patients become bed-ridden state after the treatments for mean 5 years.     

An increase in serum phenytoin concentration by changes of dosage form: case reports and its mechanism

Phenytoin (PHT) exhibits nonlinear pharmacokinetics in the therapeutic range. Therefore a slight increase in dose may lead to considerable elevation of the serum PHT level. Although its bioavailability is dependent on the formulation, bioequivalence is considered to be preserved between the three major formulations, of tablet, 97% fine granules, and 10% powder. However, we experienced many cases of increases serum PHT concentration after changes in formulation from 97% fine granules to 97/4% hospital-made fine granules, and from the latter to 10% powder. Retrospective analysis revealed that these alterations were accompanied by 55% and 16% increases in the serum concentration-to-dose ratio of PHT, respectively. We investigated the factors of this increase by analyzing the weight of remaining powder in a package and the PHT content of each formulation. Each package of PHT formulation prepared with 97% fine granules and 10% powder was unsealed, and the contents were weighed to calculate the rate of recovery. The rate of ingestion was estimated by correcting the rate of recovery by PHT strength (i.e., 1.0 for 10% powder and 0.97 for fine granules). The rates of recovery and ingestion for 10% powder were 13% and 16% higher than those for 97% fine granules, respectively (p < 0.01). In conclusion, Changing the PHT formulation from 97% fine granules to 10% powder may lead to a considerable increase in the serum PHT concentration and possibly induce PHT toxicity.     

Contribution of P-glycoprotein to efflux of ramosetron,a 5-HT3 receptor antagonist,across the blood-brain barrier

In-situ rat and mouse brain perfusion data indicated that the brain distribution of ramosetron (R-ramosetron), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was extremely low compared with that expected from its lipophilicity. We hypothesized the involvement of an efflux system(s) and investigated the contribution of P-glycoprotein to efflux transport of ramosetron across the blood-brain barrier by means of an in-vitro uptake study in cell lines that over-express P-glycoprotein. We examined the contributions of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LLC-GA5-COL300 cells, which over-express mdr1a P-glycoprotein, mdr1b P-glycoprotein and MDR1 P-glycoprotein, respectively. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly lower than that by the respective parental cells. Next, we studied the effects of P-glycoprotein inhibitors, verapamil and ciclosporin, on uptake of [14C]ramosetron by these cell lines. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly increased in the presence of verapamil or ciclosporin, while verapamil did not affect the uptake of [14C]ramosetron by MBEC4 cells. These results indicate that the efflux of [14C]ramosetron is partly mediated by mdr1a P-glycoprotein, but not by mdr1b P-glycoprotein, and that there is a difference in substrate specificity between mdr1a P-glycoprotein and mdr1b P-glycoprotein. Further, [14C]ramosetron was confirmed to be effluxed by human MDR1 P-glycoprotein. We conclude that the limited distribution of ramosetron to the brain is due, at least in part, to efflux mediated by the P-glycoprotein at the blood-brain barrier.     

Molecular therapy via transcriptional regulation with double-stranded oligodeoxynucleotides as decoys

The number of reports on in vivo gene therapies with decoy ODNs complexed with HVJ liposomes has recently increased. Diligent efforts to improve HVJ vectors as gene carriers and to expand the therapeutic applications of NFkB and E2F decoy ODNs will be important for the improved treatment of many genetic diseases.     

Effects of Grapefruit Juice and Orange Juice on the Intestinal Efflux of P-Glycoprotein Substrates

Purpose. The aim of this study is to investigate the effects of 50% ethyl acetate extracts of grapefruit juice (GFJ) and orange juice (OJ) on the transport activity of P-glycoprotein (P-gp) in the rat small intestine. Methods.The efflux of P-gp substrates from rat everted sac in the absence or presence of verapamil, GFJ, OJ or erythromycin was measured. Rhodamine123, fexofenadine and saquinavir were used as P-gp substrates. P-gp expression levels in the rat jejunum and ileum were determined by Western blot analysis. Results. The efflux of rhodamine123 from the everted sac increased from the apex of the jejunum to the low ileum and the expression of P-gp in the ileum was 2.31-fold higher than that in the jejunum. Verapamil and the 50% GFJ and OJ extracts inhibited the efflux from the intestine of all three drugs tested. Erythromycin decreased the efflux of rhodamine123 and fexofenadine, but did not affect the efflux of saquinavir in the intestine. Conclusions. GFJ and OJ extracts inhibited the efflux of P-gp substrates from the small intestine. Therefore, they may enhance the oral bioavailability of P-gp substrates by increasing absorption in the small intestine.