Assessment of luteal rescue and desensitization of macaque corpus luteum brought about by human chorionic gonadotrophin and deglycosylated human chorionic gonadotrophin treatment

The objective of the current study was to investigate the mechanism by which the corpus luteum (CL) of the monkey undergoes desensitization to luteinizing hormone following exposure to increasing concentration of human chorionic gonadotrophin (hCG) as it occurs in pregnancy. Female bonnet monkeys were injected (im) increasing doses of hCG or dghCG beginning from day 6 or 12 of the luteal phase for either 10 or 4 or 2 days. The day of oestrogen surge was considered as day '0' of luteal phase. Luteal cells obtained from CL of these animals were incubated with hCG (2 and 200 pg/ml) or dbcAMP (2.5, 25 and 100 mu M) for 3 h at 37 degrees C and progesterone secreted was estimated. Corpora lutea of normal cycling monkeys on day 10/16/22 of the luteal phase were used as controls, In addition the in vivo response to CG and deglycosylated hCG (dghCG) was assessed by determining serum steroid profiles following their administration. hCG (from 15-90 IU) but not dghCG (15-90 IU) treatment in vivo significantly (P < 0.05) elevated serum progesterone and oestradiol levels. Serum progesterone, however, could not be maintained at a elevated level by continuous treatment with hCG (from day 6-15), the progesterone level declining beyond day 13 of luteal phase. Administering low doses of hCG (15-90 IU/day) from day 6-9 or high doses (600 IU/day) on days 8 and 9 of the luteal phase resulted in significant increase (about 10-fold over corresponding control P < 0.005) in the ability of luteal cells to synthesize progesterone (incubated controls) in vitro. The luteal cells of the treated animals responded to dbcAMP (P < 0.05) but not to hCG added in vitro, The in vitro response of luteal cells to added hCG was inhibited by 0, 50 and 100% if the animals were injected with low (15-90 IU) or medium (100 IU) between day 6-9 of luteal phase and high (600 IU on day 8 and 9 of luteal phase) doses of dghCG respectively; such treatment had no effect on responsivity of the cells to dbcAMP, The luteal cell responsiveness to dbcAMP in vitro was also blocked if hCG was administered for 10 days beginning day 6 of the luteal phase. Though short term hCG treatment during late luteal phase (from days 12-15) had no effect on luteal function, 10 day treatment beginning day 12 of luteal phase resulted in regain of in vitro responsiveness to both hCG (P < 0.05) and dbcAMP (P < 0.05) suggesting that luteal rescue can occur even at this late stage. In conclusion, desensitization of the CL to hCG appears to be governed by the dose/period for which it is exposed to hCG/dghCG. That desensitization is due to receptor occupancy is brought out by the fact that (i) this can be achieved by giving a larger dose of hCG over a 2 day period instead of a lower dose of the hormone for a longer (4 to 10 days) period and (ii) the effect can largely be reproduced by using dghCG instead of hCG to block the receptor sites. It appears that to achieve desensitization to dbcAMP also it is necessary to expose the luteal cell to relatively high dose of hCG for more than 4 days.

Effect of curve crossing on absorption and resonance Raman spectra: analytical treatment for delta-function coupling in parabolic potentials

We propose an exactly solvable model for the two-state curve-crossing problem. Our model assumes the coupling to be a delta function. It is used to calculate the effect of curve crossing on the electronic absorption spectrum and the resonance Raman excitation profile.

Influence of heat treatment on the strength and fracture behaviour of Fe-12Cr-6Al ferritic stainless steel

The changes in the tensile properties and fracture mode brought about by heat treatment of Fe-12Cr-6Al ferritic stainless steel have been studied. A favourable combination of high strength and good ductility is obtained by heating the material at 1370 K for 2 h followed by a water quench. The high-temperature treatment results in carbide dissolution as well as an increase in the grain size. The mechanism of strengthening has been evaluated from the apparent activation energy (28 kJ mol–1) and is identified to be the unpinning of dislocations from the atmosphere of carbon atoms. As the heat-treatment temperature is increased, the fracture behaviour changes from ductile to brittle mode and this is related to the changes in grain size and friction stress.

Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes.

Expression Profiling of Nucleotide Metabolism-Related Genes in Human Breast Cancer Cells After Treatment with 5-Fluorouracil

5-Fluorouracil (5-FU) is one of the most widely used drugs for treatment of cancers, including breast cancer that exhibits its anticancer activity by inhibiting DNA synthesis and also incorporated into DNA and RNA. The objective of this investigation was to find out the total nucleotide metabolism genes regulated by 5-FU in breast cancer cell line. The breast cancer cell line MCF-7 was treated with the drug 5-FU. To analyze the expression of genes, we have conducted the experiment using 1.7k and 19k human microarray slide and confirmed the expression of genes by semiquantitative reverse transcription-polymerase chain reaction. The expression of 44 genes involved in the nucleotide metabolism pathway was quantified. Of these 44 genes analyzed, transcription of 6 genes were upregulated and 9 genes were downregulated. Earlier studies revealed that the transcription of genes for key enzymes like thymidylate synthase, thymidinekinase, and dihydropyrimidine dehydrogenase are regulated by 5-FU. This study identified some novel genes like thioredoxin reductase, ectonucleotide triphosphate dephosphorylase, and CTP synthase are regulated by 5-FU. The data also reveal large-scale perturbation in transcription of genes not involved directly in the known mechanism of action of 5-FU.

Adriamycin treatment increases 3-hydroxy-3-methylglutaryl CoA reductase and isoprene biosynthesis in the rat liver

Treatment of rats with Adriamycin caused an increase in the incorporation into hepatic cholesterol of [1-14C] acetate, but not of [2-14C] mevalonate. The step affected was found to be 3-hydroxy-3-methylglutaryl CoA reductase whose activity in the liver microsomes increased in Adriamycin-treated animals, but was inhibited when the drug was added in the assay medium. Also, the concentration of ubiquinone in the liver and of cholesterol in the plasma increased.

Pulsed laser surface treatment of magnesium alloy: Correlation between thermal model and experimental observations

The effect of deposition of Al +Al2O3 on MRI 153 M Mg alloy processed using a pulsed Nd:YAG laser is presented in this study. A composite coating with metallurgical joint to the substrate was formed. The microstructure and phase constituents were characterized and correlated with the thermal predictions. The laser scan speed had an effect on the average melt depth and the amount of retained and/or reconstituted alumina in the final coating. The coating consisted of alumina particles and highly refined dendrites formed due to the extremely high cooling rates (of the order of 10(8) K/s). The microhardness of the coating was higher and several fold improvement of wear resistance compared to the substrate was observed for the coatings. These microstructural features and physical properties were correlated with the effects predicted by a thermal model.

Origin of the activation barrier in the process of hydrogen abstraction: the perturbation treatment

The perturbation treatment previously given is extended to explain the process of hydrogen abstraction from the various hydrogen donor molecules by the triplet nπ* state of ketones or the ground state of the alkyl or alkoxy radical. The results suggest that, as the ionization energy of the donor bonds is decreased, the reaction is accelerated and it is not influenced by the bond strength of the donor bonds. The activation barrier in such reactions arises from a weakening of the charge resonance term as the ionization energy of the donor bond increases.

Influence of heat-treatment on the strength and fracture-behavior of fe-12cr-6al ferritic stainless-steel

The changes in the tensile properties and fracture mode brought about by heat treatment of Fe-12Cr-6Al ferritic stainless steel have been studied. A favourable combination of high strength and good ductility is obtained by heating the material at 1370 K for 2 h followed by a water quench. The high-temperature treatment results in carbide dissolution as well as an increase in the grain size. The mechanism of strengthening has been evaluated from the apparent activation energy (28 kJ mol–1) and is identified to be the unpinning of dislocations from the atmosphere of carbon atoms. As the heat-treatment temperature is increased, the fracture behaviour changes from ductile to brittle mode and this is related to the changes in grain size and friction stress.

Origin of the activation barrier in the process of hydrogen abstraction: the perturbation treatment

The perturbation treatment previously given is extended to explain the process of hydrogen abstraction from the various hydrogen donor molecules by the triplet nπ* state of ketones or the ground state of the alkyl or alkoxy radical. The results suggest that, as the ionization energy of the donor bonds is decreased, the reaction is accelerated and it is not influenced by the bond strength of the donor bonds. The activation barrier in such reactions arises from a weakening of the charge resonance term as the ionization energy of the donor bond increases.

Antitumor immunity in rats against Yoshida ascites sarcoma after treatment with antibiotics

Chromomycin A3, mithramycin, olivomycin and actinomycin D, four antitumor antibiotics inhibit growth of Yoshida ascites sarcoma (YAS). The antibiotic treated tumor-free rats exhibit antitumor immunity as judged by rejection of subsequent tumor transplant. The lymphocytes from immune rats are able to inhibit tumor growth in syngenic animals.

Catalyzed air oxidation for treatment of thiosalt effulents

Continuous slurry reactor runs of two to four weeks duration were carried out for catalyzed air oxidation of thiosalts under a variety of conditions using poly (4-vinylpyridine) - Cu (II) and quaternized poly (4-vinylpyridine) - Cu (II) catalysts. Results obtained indicate that these catalysts have high activity and relatively long-term catalyst stability for thiosalt waste streams of < 1000 ppm thiosalt level. Using 2% (w/w) slurries of the poly (4-vinylpyridine) Cu (II) catalyst, effective oxidation of 700 ppm S2O32− influent to an effluent of < 100 ppm total thio-salts can be carried out continuously for at least one month when operating at 20 to 30°C with solution flow rates of$˜1l/h and aeration of 1300 XXX/h using a two-stage reactor system comprised of 12 l reactors. At higher thiosalt influent levels (i.e. > 1600 ppm) increased reaction temperatures enable depletion to < 100 ppm thiosalt effluent levels for up to one week of continuous operation. The catalysts deactivate much more readily at these higher influent levels as a result of greater copper losses and appreciable adsorption of S2O32− and S4O62−. The behaviour of continuous slurry reactors employed in the experimental studies, by use of batch reaction data for the poly (4-vinylpyridine) Cu (II) catalyzed oxidation of thiosalts, can be modelled successfully. Quaternized poly (4-vinylpyridine) Cu (II) catalyst has good long-term stability and copper losses are very low. The poly (4-vinylpyridine) Cu (II) catalyst, however, is susceptible to appreciable oxidation of the polymer matrix on long-term usage. This oxidation of the polymer matrix results in a substantial loss in the activity of the regenerated catalyst.

Miconazole in the treatment of superficial mycoses

Miconazole nitrate (2%) cream was evaluated in the treatment of superficial mycoses. Out of 116 patients having multiple clinical diagnoses, 66 cases were found to be positive by culture. Species of Trichophyton were the predominant etiological agents (in over 60%) followed by Candida species (20%) and Epidermophyton floccosum (15%). All the cases selected for study were followed up to a period of 4–18 months. A cure rate of 94.6 per cent was observed in all the cases where causal organisms were isolated. Significantly high cure rate (66%) was also seen in cases where causal organisms could not be isolated, including cases of tinea versicolor. Results of mycological examination were in confirmity with the clinical results

The perturbational treatment of the process of hydrogen abstraction by ketones

The change in energy during hydrogen abstraction by ketones is estimated for different electronic states as a function of the intermolecular orbital overlap employing perturbation theory. The results suggest that ketones preferentially undergo the in-plane reaction and abstract a hydrogen atom in their triplet nπ* state. For ketones where the triplet ππ* state lies below the triplet nπ* state, hydrogen abstraction can take place in the ππ* state owing to the crossing of the zero order reaction surfaces of the nπ* and ππ* states.