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PubMed2005

Heterogeneous model of schistosomiasis transmission and long-term control: the combined influence of spatial variation and age-dependent factors on optimal allocation of drug therapy.

Prior field studies and modelling analyses have individually highlighted the importance of age-specific and spatial heterogeneities on the risk for schistosomiasis in human populations. As long-term, large-scale drug treatment programs for schistosomiasis are initiated in subSaharan Africa and elsewhere, optimal strategies for timing and distribution of therapy have yet to be fully defined on the working, district-level scale, where strong heterogeneities are often observed among sublocations. Based on transmission estimates from recent field studies, we develop an extended model of heterogeneous schistosome transmission for distributed human and snail population clusters and age-dependent behaviour, based on a 'mean worm burden + snail infection prevalence' formulation. We analyse its equilibria and basic reproduction patterns and their dependence on the underlying transmission parameters. Our model allows the exploration of chemotherapy-based control strategies targeted at high-risk behavioural groups and localities, and the approach to an optimal design in terms of cost. Efficacy of the approach is demonstrated for a model environment having linked, but spatially-distributed, populations and transmission sites.

Adolescent↗

PubMed2002

Vaccination against hepatitis B in low endemic countries.

A mathematical model that takes transmission by sexual contact and vertical transmission into account was employed to describe the transmission dynamics of hepatitis B virus (HBV) and vaccination against it. The model is an extension of a model by Williams et al. (Epidemiol Infect 1996: 116; 71-89) in that it takes immigration of hepatitis B carriers from countries with higher prevalence into account. Model parameters were estimated from data from The Netherlands where available. The main results were that, given the estimates for the parameters describing sexual behaviour in The Netherlands, the basic reproduction number R0 is smaller than 1 in the heterosexual population. As a consequence, the immigration of carriers into the population largely determines the prevalence of HBV carriage and therefore limits the possible success of universal vaccination. Taking into account the prevalence of hepatitis B carriage among immigrants and an age-dependent probability of becoming a carrier after infection, we estimate that a fraction of between 5 and 10% of carrier states could be prevented by universal vaccination.

Adolescent↗

PubMed2000

Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo-controlled feasibility study for male contraception.

OBJECTIVE: Approaches to hormonal male contraception are based on injectable testosterone esters alone or in combination with gestagens or GnRH analogs but the short half-life of clinically used testosterone esters have long hindered further development. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with oral levonorgestrel (LNG) in a phase II clinical trial. DESIGN AND SUBJECTS: Twenty-eight healthy men were randomized to receive injections of 1000 mg TU every 6 weeks in combination with daily oral LNG (250 microg) or daily oral placebo treatment over a period of 24 weeks, followed by a control period of 28 weeks. MEASUREMENTS: During the course of the study semen analysis, reproductive hormone analysis, analysis of clinical chemistry and lipid parameters, well-being and sexual function, sonography of scrotal contents and prostate were performed. RESULTS: Marked suppression of gonadotrophins in both treatment groups resulted in azoospermia in 8/14 and 7/14 volunteers and severe oligozoospermia (< 3 x 1012/l) in 4/14 and 7/14 in the placebo and gestagen treated groups, respectively. Time to induction of azoospermia (mean +/- SEM) was not significantly different between the placebo (week 19.5 +/- 2.2) and LNG groups (week 15.4 +/- 2.2). During the whole treatment period mean testosterone serum concentrations remained within normal limits. Although not significant, it was evident that volunteers who became azoospermic had a better suppression of gonadotrophins and lower SHBG levels during treatment compared to non-azoospermic volunteers. Despite better gonadotrophin suppression in the LNG group no significant differences compared to placebo could be observed in the extent and kinetics of suppression of spermatogenesis, thus not demonstrating a major beneficial effect of LNG in the combination with injectable TU. Treatment led in both groups to a decrease of HDL and Lp(a) which was more pronounced in the LNG group (P > 0.05). CONCLUSION: Treatment with 1000 mg testosterone undecanoate injected at 6 weekly intervals or in combination with levonorgestrel showed suppression of spermatogenesis comparable to weekly injections of 200 mg testosterone enanthate. Because of its long half-life and in the absence of severe side-effects, testosterone undecanoate can be considered as first choice testosterone ester in further studies of hormonal male contraception.

Adolescent↗

PubMed1981

Radioprotection by thiazolidines at the cellular level.

Radioprotection by a number of thiazolidine derivatives was studied in vitro. Reproductive integrity of single cells was used as a parameter for survival after irradiation. Thiazolidine itself did not protect when dissolved in culture medium, but a good protective activity was found when it was dissolved in rat blood. Rat blood improved also the radioprotective activity of most other thiazolidine derivatives. The best protection was obtained with thiazolidines in which the carbon at the 2 position was substituted by germanium. No correlation was evident between the degree of protection and release of a free SH group by hydrolysis of the thiazolidine ring. The results support a previous suggestion by Terol, Fernandez, Robbe, Châpat, Granger and Sentenac-Rovmanov (1978) that the thiazolidines proper and not their hydrolysis products are responsible for radioprotection.

Cell Line↗

PubMed2004

The toxicity profile of hydrolyzed aqueous olive pulp extract.

The toxicity profile of HIDROX (Hydrolyzed Aqueous Olive Pulp Extract; OPE) was characterized in a series of toxicology studies. A limit dosage of 2000 mg/kg produced no toxicity in mice (acute oral NOAEL: 2000 mg/kg). In rats, an acute oral NOAEL of 2000 mg/kg was established, based on reductions in weight gains in both sexes at 5000 mg/kg. Reduced gains in female rats at 1500 and 2000 mg/kg were not significantly different from control values. Daily oral dosages of 1000, 1500 and 2000 mg/kg/day for 90 days produced small decreases in body weight gains at 2000 mg/kg/day in the male rats and in all groups of female rats. Feed consumption was comparable to controls. There were no adverse clinical, hematologic, biochemical, organ weight or gross necropsy effects. Focal, minimal or mild hyperplasia of the mucosal squamous epithelium of the limiting ridge of the forestomach occurred in some rats at 2000 mg/kg/day; this change was attributed to local irritation by repeated intubation of large volumes of viscous, granular dosing suspension. A NOAEL of 2000 mg/kg/day was established for the 90-day study, based on the lack of significant adverse effects. Toxicokinetic data indicated that hydroxytyrosol (HT, the major component of OPE) was rapidly absorbed. Mean concentrations were measurable through 1 to 4 hours (t(last)) at 1000 and 1500 mg/kg/day and through 8 hours at 2000 mg/kg/day. Dosages of OPE ranging from 500 to 2000 mg/kg/day did not adversely affect any of the mating, fertility, delivery or litter parameters investigated in an oral rat dosage-range reproduction study. Adverse effects were also absent in a rat developmental toxicity study in which pregnant dams were treated with 1000, 1500 or 2000 mg/kg/day on days 6 through 20 of gestation. Plasma levels for pregnant and lactating rats were comparable to non-pregnant rats; minimal levels crossed the placenta. Quantifiable levels were not identified in maternal milk or plasma from nursing pups. A bacterial reverse mutation and a CHO chromosome aberration assay revealed evidence of mutagenic activity at high dosages with S9 metabolic activation. However, three rat micronucleus evaluations performed after single and repeated (28-day) dosages of up to 2000 mg/kg/day and dosages of 5000 mg/kg/day for 29 days resulted in negative findings; therefore, OPE was not considered to be mutagenic in this in vivo assay.

Abnormalities, Drug-Induced↗

PubMed2006

Parameter estimate of signal transduction pathways.

BACKGROUND: The "inverse" problem is related to the determination of unknown causes on the bases of the observation of their effects. This is the opposite of the corresponding "direct" problem, which relates to the prediction of the effects generated by a complete description of some agencies. The solution of an inverse problem entails the construction of a mathematical model and takes the moves from a number of experimental data. In this respect, inverse problems are often ill-conditioned as the amount of experimental conditions available are often insufficient to unambiguously solve the mathematical model. Several approaches to solving inverse problems are possible, both computational and experimental, some of which are mentioned in this article. In this work, we will describe in details the attempt to solve an inverse problem which arose in the study of an intracellular signaling pathway. RESULTS: Using the Genetic Algorithm to find the sub-optimal solution to the optimization problem, we have estimated a set of unknown parameters describing a kinetic model of a signaling pathway in the neuronal cell. The model is composed of mass action ordinary differential equations, where the kinetic parameters describe protein-protein interactions, protein synthesis and degradation. The algorithm has been implemented on a parallel platform. Several potential solutions of the problem have been computed, each solution being a set of model parameters. A sub-set of parameters has been selected on the basis on their small coefficient of variation across the ensemble of solutions. CONCLUSION: Despite the lack of sufficiently reliable and homogeneous experimental data, the genetic algorithm approach has allowed to estimate the approximate value of a number of model parameters in a kinetic model of a signaling pathway: these parameters have been assessed to be relevant for the reproduction of the available experimental data.

Algorithms↗

PubMed2003

Can shaking alone cause fatal brain injury? A biomechanical assessment of the Duhaime shaken baby syndrome model.

A biomechanical model of a one-month old baby was designed and tested by Duhaime and co-workers in 1987 in an attempt to assess the biomechanics of the shaken baby syndrome (SBS). The study implied that pure shaking alone cannot cause fatal head injuries, a factor which has been applied in criminal courts. In an attempt to test the validity of the model a preliminary study was undertaken in which a replica was constructed and tested. The broad description of the design and construction of the Duhaime model allowed for variations and therefore uncertainties in its reproduction. It was postulated therefore that differences in certain parameters may increase angular head accelerations. To further investigate this observation, an adjustable replica model was developed and tested. The results indicated that certain parameter changes in the model did in fact lead to an increase in angular head acceleration. When these parameter changes were combined and an injurious shake pattern was employed, using maximum physical effort, the angular head acceleration results exceeded the original Duhaime et al. (1987) results and spanned two scaled tolerance limits for concussion. Additionally, literature suggests that the tolerance limits used to assess the shaking simulation results in the original study may not be reliable. Results from our study were closer to the internal head injury, subdural haematoma, tolerance limits. A series of end point impacts were identified in the shake cycles, therefore, an impact-based head injury measure (Head Injury Criterion - HIC) was utilized to assess their severity. Seven out of ten tests conducted resulted in HIC values exceeding the tolerance limits (critical load value, Stürtz, 1980) suggested for children. At this present stage the authors conclude that it cannot be categorically stated, from a biomechanical perspective, that pure shaking cannot cause fatal head injuries in an infant. Parameters identified in this study require further investigation to assess the accuracy of simulation and increase the biofidelity of the models before further conclusions can be drawn. There must now be sufficient doubt in the reliability of the Duhaime et al. (1987) biomechanical study to warrant the exclusion of such testimony in cases of suspected shaken baby syndrome.

Biomechanical Phenomena↗

PubMed2005

Electroporation: introduction and expression of transgenes in plant protoplasts.

An optimized protocol for the electroporation-based transfection of tobacco protoplasts is described that routinely results in transgene expression frequencies approaching 90%. The overall efficiency of the procedure depends collectively on numerous key parameters, including protoplast viability; DNA concentration, purity, and topology; carrier DNA; and electrical conditions such as ionic strength of the electroporation buffer, electric field strength, pulse duration, and capacitance. Individual methodologies that address each one of these parameters are presented in sufficient detail to enable successful reproduction of this method along with notes that describe helpful tips.

Electroporation↗

PubMed1985

Long-term effect of incubation temperatures on production parameters and changes in luteinizing hormone and gonadal steroids during the onset of lay in the hen.

Earlier studies demonstrated that different incubation temperatures (33.8 or 37.8 C) from Day 17 of incubation until hatching resulted in differences in postnatal growth rate and hormonal parameters. These studies were repeated and extended to the reproduction period. The onset of egg laying was significantly delayed by 5 days in the 33.8 C group compared to the 37.8 C group. No differences in percent egg production were found between the groups after 3 or 5 months of production: however, mean egg weight was significantly reduced in the 33.8 C group by 1.9 and 1.8 g over 3 and 5 months of production, respectively. Serum concentrations of luteinizing hormone (LH), estradiol (E2), estrone (E1), progesterone (P4), and testosterone (T) were measured weekly at the same time of day approximately 4 weeks before to 4 weeks after the onset of lay. The changes in levels of all hormones over the period studied were identical for both experimental groups. Luteinizing hormone, T, and E2, but not E1 and P4, were different before and after onset of lay in both groups. There were no significant correlations between hormonal levels before onset of lay and production traits for individual hens. In the 33.8 C group, after onset of lay, significant positive correlations were observed between serum E2 and egg production and serum LH and egg production; however, these correlation coefficients were not significant in the 37.8 C group. Significant negative correlation coefficients were observed in both groups between serum E2 after onset of lay and age at first egg.

Animals↗

PubMedDate not supplied

[Correlations between mental maturity and higher mental function in preschool children].

This communication presents the results of comparative study of 23 quantitative characteristics of the mental development of a child (the data of neuropsychological diagnosis of higher cortical functions by the procedure developed by I. F. Markovskaya, 1993) and 112 parameters of higher mental functions (perception, memory, assimilation and reproduction of rhythmic stimuli, behavioral strategy in the determined environment) recorded by a complex of microprocessor psychophysiological apparatuses, such as "Rhythmotest", "Mnemotest", and "Binatest".

Age Factors↗

PubMedDate not supplied

[Correlation between the retention of defensive conditioned reflexes and rat brain acetylcholinesterase activity].

The comparison of the characteristics of temporary connection retention (repeated elaboration) with the activity of acetylcholinesterase (AChE) of the motor, visual cerebral cortical areas and hippocampus was done at different time (1, 2 and 4 weeks) following elaboration of defensive conditioned reflexes (CR) in rats in a chamber of two-way avoidance with electrified floor. The maximal retention of CR was observed 2 weeks after the initial elaboration. The dynamics of AChE activity on the whole doesn't correspond to the changes in CR retention. Pronounced AChE activity decrease in the motor and visual cortex was observed during CR reproduction 4 weeks after elaboration. Significant differences by this parameter were observed between trained animals and the rats, presented with non-paired photic and electrical stimuli (active control).

Acetylcholinesterase↗

PubMed1995

Oocyst output, periodicity, and immunity of two deer mouse (Peromyscus maniculatus) eimerians (Eimeria arizonensis and Eimeria delicata).

We compared the life histories of 2 eimerians (Eimeria arizonensis and Eimeria delicata), which co-occur in the deer mouse (Peromyscus maniculatus). Laboratory-reared deer mice were given 10(3), 10(4) (E. delicata), or 10(3), 10(4), or 10(5) (E. arizonensis) oocysts by stomach intubation. Eimeria arizonensis infections lasted longer (11-13 days) than E. delicata infections (9-10 days). Eimeria arizonensis infections also produced more oocysts for each oocyst ingested at both levels compared. Both parasites exhibited periodicity in oocyst output at all levels compared. However, peaks in E. arizonensis output occurred at approximately 20-24-hr intervals, whereas peaks in E. delicata output occurred at 12-16-hr intervals. Finally, deer mice developed immunity to both eimerians after only 1 inoculation at all levels tested. Based on these parameters, we expect E. arizonensis to have a greater reproductive potential than E. delicata in free-living deer mice.

Analysis of Variance↗

PubMedDate not supplied

[Methods of production and perspectives for use of transgenic domestic animals].

The technique of microinjection is so far the only successful method of gene transfer in farm animals. Fertilized oocytes are collected from superovulated donors by flushing the oviducts and the exogenous gene construct is injected into the male pronucleus of zygotes before transfer into the oviducts or uteri of synchronized recipients. The resulting pups have to be tested for integration and expression of the foreign gene. Potential applications of gene transfer in farm animals are the improvement of growth parameters, the increase of disease resistance, the enhancement of reproduction rates, the increase of wool production of sheep, the alteration of metabolic pathways, the production of human hemoglobin in the blood of transgenic animals, the generation of transgenic animals as organ donors and the proteins in the milk of transgenic animals. Many studies showed, that farm animals are able to direct the expression of partially large amounts of foreign proteins for biomedical purposes into their milk. Therefore transgenic livestock could be an attractive alternative for conventional production methods.

Animals↗

PubMedDate not supplied

[The use of the fluorescent probe method for the diagnosis of acute coronavirus intestinal infections in people].

The scientific investigations conducted first allow using a method of fluorescent probes for the diagnosis of human coronaviral intestinal infection. The method is characterised by sensitivity, specificity, reproductivity and proximity. It is comparable, according to these parameters, with the methods of the third generation and may be recommended for putting into practical work of virological laboratories.

Acute Disease↗

PubMed2000

Effects of sildenafil (Viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males.

Sildenafil is a specific inhibitor of phosphodiesterase (PDE) type 5 and represents a powerful therapy for male erectile dysfunction (ED) of different aetiology. Recently, sildenafil has been shown to restore erections in temporary ED related to the need of semen collection for assisted reproductive techniques. In this study, we investigated whether sildenafil administration modifies seminal parameters and/or erectile function in normal healthy volunteers. In a double-blind, randomized, placebo-controlled, cross-over two period investigation we enrolled 20 healthy male volunteers (mean +/- SE age 32 +/- 0.5 years). Subjects were not using any medication for the 3 month period prior to the study and were engaged in a stable relationship with proven fertility. The effects of sildenafil (100 mg) on seminal parameters and erectile function after audiovisual sexual stimulation were evaluated by semen analysis and by colour-Duplex ultrasound (the Resistive Index) respectively. In all subjects, sildenafil caused no changes in seminal and erection parameters when compared to placebo. Interestingly, sildenafil administration led to a marked reduction of the post-ejaculatory refractory time (10.8 +/- 0.9 min versus 2.6 +/- 0.7 min for placebo and sildenafil respectively; P < 0.0001). These results indicate that in normal subjects acute sildenafil treatment does not modify semen characteristics and has a positive influence over the resumption of erections following ejaculation in the presence of a continuous erotic stimulus.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

Are the universes of antibodies and antigens symmetrical?

This paper discusses the assumed infinite numbers of antigens and antibodies, and the nature of their interactions, in relation to reproductive immunology. Classical models offered by Pauling, Burnet and Crick are discussed. The author's own model is described, based on selectionist principles, proposing that the numbers are defined, discrete and not infinite. The binding specificity of monoclonal antibodies of four to six amino acids limits the number on the total number of antibody-binding peptides. This limitation on size enables the total number of these peptides to define 'one-hit' or 'two-hit' protein sequences in databases of known proteins. Estimate of the combinations of variable heavy and light chains of different numerical magnitude is 2.5 x 10(6). The author proposes the equivalence principle, where equivalent numbers of antigens and antibodies exist and theorizing a limited number of antigen-antibody pairs in the magnitude of 3.2 x 10(6) or slightly less. The nature of various protein-ligand interactions, indicated by their limited numbers of interactions, clarifies why a particular amino acid is encoded by a particular codon and the nature of encoding by tRNA. In relation to reproductive phenomena, specific proteins for contact with sperm ligands were designed using these parameters.

Allergy and Immunology↗

PubMed2005

Fish full life-cycle testing for 17beta-estradiol on medaka (Oryzias latipes).

We studied the chronic effects of 17beta-estradiol (E2) on the reproductive status of medaka (Oryzias latipes) over two generations under continuous exposure to assess its hazard on this species. The exposure of parental (F0) medaka to E2 was begun on embryos within 12 h postfertilization and continued for up to 101 d; the assessment endpoints included embryological development, hatching, posthatch survival, growth, sexual differentiation, reproduction, and hepatic vitellogenin (VTG) levels under flow-through exposure to E2 at each mean measured concentration of 0.939, 2.86, 8.66, 27.9, and 92.4 ng/L. Eggs (F1) spawned from the F0 fish at 98, 99, and 100 d posthatch were also examined for hatchability, survival after hatching, growth, sexual differentiation, and hepatic VTG level until 59 d posthatch. In the F0 medaka, no concentration-related effect of E2 was observed on hatching, posthatch mortality, and growth. However, we observed abnormal sex differentiation, induction of VTG, and reproductive impairment in a dose-dependent manner. The lowest-observed-effect concentration and no-observed-effect concentration of E2 for these effects were 8.66 and 2.86 ng/L, respectively. In the F1 medaka treated with E2 at < or = 8.66 ng/L, however, dose-dependent effects were not observed in any parameter. The results indicate that E2 can have significant effects on reproductive potential of medaka at concentrations as low as 8.66 ng/L, suggesting that the ecological risk of E2 is higher than that of weak estrogens, such as nonylphenol and octylphenol.

Animals↗

PubMed1989

[Glucose metabolism in sheep in different reproductive stages and with ketosis using the intravenous glucose tolerance test (IVGTT)].

Kinetic parameters of glucose metabolism were determined in 17 healthy ewes during different metabolic stages and in 8 spontaneously ketotic sheep by the IVGTT with low doses of glucose (0.8 mmol/kg) as well. The endogenous turnover rate (R) was calculated by using the total clearance (Cl), derived from the IVGTT. The values of R, determined in healthy ewes by this technique are in agreement with values presented in the literature, which were derived from kinetic studies with 3H- or 14C-labeled glucose. There were no differences in the mean values of R and Cl in non-pregnant, highly pregnant and ketotic ewes in our study. The plasma concentration of glucose (C) was significantly correlated with R in highly pregnant healthy and ketotic ewes; there was no such correlation in the group of non-pregnant and early pregnant sheep. In highly pregnant ketotic ewes the mean value of C was lower than in healthy ewes but there was no significant correlation between the plasma concentration of glucose and that of 3-hydroxybutyrate. It is concluded from the study, that the control of glucostasis fails frequently during late pregnancy in ewes and that ketosis of sheep is related closer to the excessive lipid mobilisation than to disturbance of glucostasis.

Acidosis↗