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PubMed1995

A basic mathematical model of the immune response.

Interaction of the immune system with a target population of, e.g., bacteria, viruses, antigens, or tumor cells must be considered as a dynamic process. We describe this process by a system of two ordinary differential equations. Although the model is strongly idealized it demonstrates how the combination of a few proposed nonlinear interaction rules between the immune system and its targets are able to generate a considerable variety of different kinds of immune responses, many of which are observed both experimentally and clinically. In particular, solutions of the model equations correspond to states described by immunologists as "virgin state," "immune state" and "state of tolerance." The model successfully replicates the so-called primary and secondary response. Moreover, it predicts the existence of a threshold level for the amount of pathogen germs or of transplanted tumor cells below which the host is able to eliminate the infectious organism or to reject the tumor graft. We also find a long time coexistence of targets and immune competent cells including damped and undamped oscillations of both. Plausibly the model explains that if the number of transformed cells or pathogens exeeds definable values (poor antigenicity, high reproduction rate) the immune system fails to keep the disease under control. On the other hand, the model predicts apparently paradoxical situations including an increased chance of target survival despite enhanced immune activity or therapeutically achieved target reduction. A further obviously paradoxical behavior consists of a positive effect for the patient up to a complete cure by adding an additional target challenge where the benefit of the additional targets depends strongly on the time point and on their amount. Under periodically pulsed stimulation the model may show a chaotic time behavior of both target growth and immune response. (c) 1995 American Institute of Physics.

Journal Article↗

PubMed2003

Research in nondomestic species: experiences in reproductive physiology research for conservation of endangered felids.

Tremendous strides have been made in recent years to broaden our understanding of reproductive processes in nondomestic felid species and further our capacity to use this basic knowledge to control and manipulate reproduction of endangered cats. Much of that progress has culminated from detailed scientific studies conducted in nontraditional laboratory settings, frequently at collaborating zoological parks but also under more primitive conditions, including in the field. A mobile laboratory approach is described, which incorporates a diverse array of disciplines and research techniques. This approach has been extremely useful, especially for conducting gamete characterization and function studies as well as reproductive surveys, and for facilitating the development of assisted reproductive technology. With continuing advances in assisted reproduction in rare felids, more procedures are being conducted primarily as service-related activities, targeted to increase effectiveness of species propagation and population management. It can be a challenge for both investigators and institutional animal care and use committees (IACUCs) to differentiate these service-based procedures from traditional research studies (that require IACUC oversight). For research with rare cat species, multi-institutional collaboration frequently is necessary to gain access to scientifically meaningful numbers of study subjects. Similarly, for service-based efforts, the ability to perform reproductive procedures across institutions under nonstandard laboratory conditions is critical to applying reproductive sciences for managing and preserving threatened cat populations. Reproductive sciences can most effectively assist population management programs (e.g., Species Survival Plans) in addressing conservation priorities if these research and service-related procedures can be conducted "on the road" at distant national and international locales. This mobile laboratory approach has applications beyond endangered species research, notably for other scientific fields (e.g., studies of hereditary disease in domestic cat models) in which bringing the laboratory to the subject is of value.

Animals↗

PubMedDate not supplied

Cystic fibrosis--an Indian perspective on recent advances in diagnosis and management.

Cystic fibrosis (CF) is a common inherited disorder in caucasians. The estimated incidence of CF in Asians varies from 1:10,000 to 1:12,000. Indian data is restricted to few case reports. The gene for CF is located on the long arm of chromosome 7 at position 7q13. There are more than 300 identified mutations in CF. The basic defect in CF is a mutational change in the gene for chloride conductance channel. Failure of chloride conductance by epithelial cells leads to dehydration of secretions that are too viscid and difficult to clear. The disease is characterized by abnormal secretions in the respiratory, gastrointestinal and reproductive tract and sweat glands. The common clinical manifestations include meconium ileus in neonatal period, recurrent lower respiratory tract infections (pseudomonas pneumonia, bronchiectasis), steatorrhoea, azoospermia, and in late stages hepatobiliary and endocrine pancreatic dysfunctions. The diagnosis of disease is established by clinical criteria and sweat chloride concentration more than 60 mEq/L. Facilities for DNA diagnosis of common CF mutations are now available in India. The treatment of CF includes early diagnosis, daily clearance of respiratory passages, appropriate antibiotic therapy, aerosolised recombinant human DNase and antibiotics, and nutritional supplementation. The latter include changes in diet composition, pancreatic enzyme supplementation and vitamins and trace mineral supplementation. Gene therapy for the pulmonary manifestations is being tried in a number of centres abroad. Other considerations include heart lung transplantation and ameloride inhalation therapy.

Adolescent↗

PubMed1980

Preclinical pharmacologic investigations on a new group of acridine derivatives with oncostatic activity. I. Acute and subchronic action.

The influence of l-nitro-9-/2-dihydroxyethylamino-ethylamino-/-acridine (C-835) and l-nitro-9/3-izopropylaminopropylamino/-acridine (C-846) on the basic functions of animal organism in acute and subchronic experiments was studied. Both compounds displayed distinct all-biologic activity. Their toxicity (LD50) in mice was contained in milligramme interval (i.v.), while LD50 administered into the stomach was several dozen times higher. Even administration in protective phosphate buffer, which provides the most neutral pH, produced quite strong local irritant action. The range between LD50 and LD10 was relatively small, which proved relatively small tolerance factor. Both preparations injected intravenously in the doses starting from several mg/kg had hypotensic influence due to their affinity with the myocardium, the parasymphatetic system and the vascular system. The preparations acted spasmolytically on intestine muscles both in vivo and in vitro in a number of animal species. Central action showed clear stimulating component in a behavioric test. The effect of the compounds in interaction to hypnotic and convulsant drugs was equivocal and dependent on the dose and the reference-preparation. The examined compounds did not influence reproduction processes and did not display the teratogenic action. They impaired only the speed of growth of the newborns. The effect of both examined compounds was qualitatively and quantitatively similar.

Aminacrine↗

PubMed2004

Effect of chemically defined culture medium supplemented with beta-mercaptoethanol and amino acids on implantation and development of different stage in vivo- or in vitro-derived mouse embryos.

In vitro culture (IVC) systems are required for many biotechnological and assisted reproductive technologies and the researchers have been modifying in vitro embryo culture conditions to reach the comparable efficiencies provided in vivo. In the present study, the effects of beta-mercaptoethanol (Beta-ME) and amino acids (AA) on the development of mouse embryos obtained in vivo or in vitro at different stages were investigated. Chemically defined potassium simplex optimized medium (KSOM) was used as basic culture medium and six experimental groups were established and by supplementation of Beta-ME and AA into KSOM media. The quality of blastocysts was evaluated by counting the cells and determining the ratio of inner cell mass (ICM) to trophoectoderm (TE) cells. In addition, embryo transfer (ET) was performed to investigate the rate of implantation and live fetuses. The results obtained in the present study demonstrated that the combined treatment of Beta-ME and AA to 1-cell stage embryos not only enhanced in vitro development to the blastocyst stage but also improved both the number of blastocysts cells and live fetuses.

Amino Acids↗

PubMed2005

Reproducible research: a bioinformatics case study.

While scientific research and the methodologies involved have gone through substantial technological evolution the technology involved in the publication of the results of these endeavors has remained relatively stagnant. Publication is largely done in the same manner today as it was fifty years ago. Many journals have adopted electronic formats, however, their orientation and style is little different from a printed document. The documents tend to be static and take little advantage of computational resources that might be available. Recent work, Gentleman and Temple Lang (2003), suggests a methodology and basic infrastructure that can be used to publish documents in a substantially different way. Their approach is suitable for the publication of papers whose message relies on computation. Stated quite simply, Gentleman and Temple Lang (2003) propose a paradigm where documents are mixtures of code and text. Such documents may be self-contained or they may be a component of a compendium which provides the infrastructure needed to provide access to data and supporting software. These documents, or compendiums, can be processed in a number of different ways. One transformation will be to replace the code with its output -- thereby providing the familiar, but limited, static document. In this paper we apply these concepts to a seminal paper in bioinformatics, namely The Molecular Classification of Cancer, Golub et al (1999). The authors of that paper have generously provided data and other information that have allowed us to largely reproduce their results. Rather than reproduce this paper exactly we demonstrate that such a reproduction is possible and instead concentrate on demonstrating the usefulness of the compendium concept itself.

Journal Article↗

PubMed2000

Anthropological cybernetic model of demography of the island of Hvar.

Intentions of the present investigation were to apply a cybernetic model in description of demography on the island of Hvar for a time period from year 1800 till now. The basic idea of the model applied in this anthropological study (LOPI) is that the rate of reproduction is given by the non-linear controller: Y2/Te(1-(Y3/G)). Constant G represents an environmental carrying capacity of a community with respect to the cohort of older people (no longer a part of the pool of reproductive inhabitants; Y3) sharing limited survival resources. The proportional constant 1/Te connected with the pool of reproductive inhabitants (Y2) correspond to the reproduction maximum. The consistency of the model is evaluated through comparison between model data and census. The LOPI model describes incredibly well the demography of the island of Hvar from the year 1800 till 1940. After year 1950 there were more inhabitants on the island then the model would predict. This fact is connected with changes in the migration or also in the increased carrying capacity (G). On the basis LOPI model, population dynamic oscillates in its development. The example of the island of Hvar has proved that population reaches a maximal number of inhabitants every 200 years. The oscillation of population dynamics is influenced by the migration processes. The mere fact that oscillating population size is connected to population genetics and probably also to sociocultural factors suggests that a cybernetics demographic model can be a guide in the holistic anthropological approach.

Adult↗

PubMed1996

Genetic and geometric optimization of three-dimensional radiation therapy treatment planning.

The thesis of this report is that potentially useful treatment beams can be chosen based on geometric heuristics and that a genetic algorithm (GA) can be constructed to find an optimal combination of beams based on a formal objective function. The paper describes the basic principles of a GA and the particular implementation developed. The code represents each plan in the population as two paired lists comprised of beam identifiers and relative weights. Reproduction operators, which mimic sexual reproduction with crossover, mutation, cloning, spontaneous generation, and death, manipulate the lists to grow optimal plans. The necessary gene pool is created by software modules which generate beams, distribute calculation points, obtain clinical constraints, add wedges, and calculate doses. The code has been tested on a set of artificial patients and on four clinical cases: prostate, pancreas, esophagus, and glomus. All demonstrated consistent results, indicating that the code is a reliable optimizer. Additional experiments compared the results for a full set of open beams to the geometrically selected set and the GA code with simulated annealing. Geometric selection of beam directions did not significantly compromise optimization quality. Compared to simulated annealing, the genetic algorithm was equally able to optimize the objective function, and calculations suggest it may be the faster method when the number of beams to be considered exceeds approximately 70.

Algorithms↗

PubMed2001

Biological ageing research in the Netherlands.

After an introduction on the development of biological ageing research in the Netherlands during the past decades, 606 papers on aging published by Dutch institutes in the period 1991-2000, collected from PubMed, were analysed for their relevance to research into biological ageing. For the period 1996-2000, the total number of research papers on biological ageing amounted to 142, which accounts for 23% of all publications on ageing in that period. The number of publications per year did not change. On the basis of these papers and additional information provided by research groups a comprehensive overview of biological ageing research in the Netherlands is presented, together with an extensive literature list. Ageing of the central nervous system (CNS), of the endocrinological system and of the cardiovascular system are the topics most studied. It is concluded that general biological ageing research has not increased in the Netherlands over the last ten years, and that the infrastructure for basic biological ageing research in the Netherlands is weak.

Academies and Institutes↗

PubMed1999

Joint effects on cancer risk of age at childbirth, time since birth and attained age: circumventing the problem of collinearity.

In previous studies of female cancer risk, we introduced a new method for circumventing the problem of collinearity in age-adjusted analysis of the joint effects of age at birth and time since birth. The basic idea was to estimate the pure age effect considering nulliparous women, assuming that the age effect is common to all women. However, risk estimates for attained age obtained in this manner may suffer from bias, in particular in small data sets, which may in turn influence risk estimates for reproductive factors among parous women. Certain factors possibly affecting cancer risk among nulliparous women only, for instance biological infertility, might also introduce bias. The purpose of this paper is to investigate the accuracy of risk estimates obtained by the joint approach, and to reveal the extent of bias in traditional separate age-adjusted analyses of age at birth or time since birth among parous women. Results are based on analyses of simulated data sets reflecting reproductive and demographic characteristics of a cohort of 1.1 million Norwegian women. Incidence rate ratios are calculated in Poisson regression analyses of person-years at risk. Our simulations show that the joint analysis in general yields unbiased risk estimates, but the number of cases must be rather high to achieve reliable results. Risk estimates from separate analyses can be seriously biased, although the amount of bias depends on the strength and direction of associations with cancer risk. With a total of 5500 cancer cases, the estimators for age at last birth and time since last birth were 13-78 per cent and 5-66 per cent more efficient in the joint than in the separate analysis, respectively. Significance levels were close to the nominal 5 per cent in the joint analysis, but about twice as high in the separate analysis. Adding an effect of biological infertility on cancer risk among nulliparous women, without taking it into account in the analyses, did not seriously affect risk estimates in the joint model.

Adult↗

PubMed2005

International industry initiatives to improve the glycol ether health effects knowledge base.

Following the recognition in the early 1980s of the potential reproductive hazards of certain glycol ethers, industry organizations were formed in the US and Europe having a number of stated goals to: (1) provide hazard information by expanding the toxicity database for glycol ethers; (2) promote cooperation among scientists, governmental authorities, and industry; and (3) promote scientifically sound regulatory actions and to assist in the setting of scientifically defensible safety standards. This effort led to early recommendations that EGME, EGEE, and their acetates be removed from consumer products. Also, studies conducted by industry under US EPA test rules have led to a better understanding of the hazards associated with glycol ether constituents of brake fluids, paints, and other products. Industry-provided information has greatly assisted the setting of occupational and public safety standards in a number of countries. Hazard assessments for a number of large-volume glycol ethers have been performed under the OECD SIDS program. This work continues with the industry-funded ICCA/HPV testing initiative. To provide sound risk assessment data, industry continues to sponsor basic research aimed at better understanding human versus mouse versus rat sensitivities to certain glycol ethers. Industry has also prepared and supported the publication of toxicological data compendia for glycol ethers.

Animals↗

PubMed2002

The fitness of filamentous fungi.

Fitness is a common currency in comparative biology. Without data on fitness, hypotheses about the adaptive significance of phenotypes or basic mechanisms of evolution, for example natural selection, remain speculative. Experiments with fungi can address questions specific to fungi or questions with a broader significance. Fungi can challenge the generality of fundamental evolutionary principles, yet there are no standard measures of fungal fitness. We argue that focusing on a single aspect of a complex life cycle, or a single measure of fitness (e.g. the number of asexual spores) is appropriate. Choosing which aspect of fitness to measure can be facilitated by an understanding of how fitness measures are correlated. Choices can also be based on the ecology of a species, for example whether a fungus is semelparous and reproduces once, or iteroparous and reproduces multiple times.

Biological Evolution↗

PubMed2005

What do individuals in different science groups within a life sciences organization think about genetic modification?

An assessment was undertaken of the attitudes of individuals within the science community towards a program to produce genetically modified cattle for altered milk composition, expectantly allowing for research into the treatment of multiple sclerosis in humans. The majority of respondents to an electronic survey expressed favorable attitudes to the program, thought it beneficial, respected individual freedom and was fair and just and disagreed that it was harmful. A passion for science and having a suitable lifestyle were the most important motivating factors for individuals. Finally, there were a wide range of responses to a number of cultural beliefs or myths. Science grouping significantly affected the responses. Compared with Systems and Land groups, Plant and Reproduction groups more strongly agreed with the project, thought it less harmful to interest groups, felt that genetic modification of animals was more morally acceptable, and more strongly agreed with the myth statements. These results indicate a diversity of beliefs and attitudes towards genetic modification amongst those within the science community, and highlight the importance of understanding ethics and myths in dealing with them. It is suggested that the diversity of beliefs could be better used to help shape public policy and understanding of biotechnology.

Agriculture↗

PubMed1988

The ovarian prorenin-angiotensin system. Lessons from IVF.

Recent evidence suggests that prorenin and other active components of the renin-angiotensin system may be linked to ovarian physiology. Prorenin, the inactive form of the enzymatically active renin, is present in the fluid of mature human ovarian follicles in concentrations more than 10 times higher than that found in the plasma of women undergoing ovarian stimulation. Only 1% of the renin in follicular fluid is in active form. Concentrations of prorenin in fluid of immature follicles are lower than levels detected in concomitantly aspirated mature follicles. Study of prorenin levels disclosed a positive correlation to testosterone and E2 in fluids of mature follicles. Plasma prorenin increases about twofold at midcycle at the time of the LH surge; the peak of prorenin is sustained for about 40 hours. In patients undergoing ovarian stimulation for IVF, hCG administration results in much higher plasma prorenin levels and the height of prorenin response is directly related to the number of mature follicles. It peaked 4 to 6 days after hCG injection and then fell, close to baseline, by about 12 days after hCG administration. Examination of the time course of hormonal changes in response to hCG revealed a temporal relationship between prorenin and both plasma E2 and progesterone. In women who conceived, prorenin began to rise again on days 8 to 12 after embryo transfer when endogenous hCG was detected in the blood. No such changes in prorenin occurred in women with ovarian failure who conceived after transfer of a donor egg. These findings indicate that prorenin is produced by the mature follicle and the corpus luteum in response to LH/hCG. Since angiotensin II affects intracellular calcium and phospholipase activity, there are many potential roles for prorenin via angiotensin II action. Putative actions of the ovarian renin system may include control of oocyte maturation, ovulation, ovarian blood flow, and ovarian steroid biosynthesis. Future work to elucidate the function of this new renin system may have relevance to many basic and clinical aspects of human reproduction.

Enzyme Precursors↗

PubMed2001

[The development of new drugs for osteoporosis in Japan].

In a rapidly aging society, the number of patients becoming bed-ridden due to osteoporosis-related fracture has become a socially important health issue that includes the problem of adequate nursing. Recently, the introduction of a rapidly acting bone absorption suppressant with a clear mechanism accelerated the development of osteoporosis treatment. A selective estrogen receptor modulator in a estrogen preparation is expected, because it has antagonism for the acceptor of the reproductive organ. It is noted that a new steroid with a weak androgen action and estrogen- and progestogen-like actions both prevents bone quantity decrease in women and increases bone quantity in osteoporotic patients after menopause. The second and third generation of bisphosphanate is more powerful than etidronate, the first generation of bisphosphanate, allows continual medication, and is now in clinical trial. The introduction of new drugs, which have clear efficacy and fewer side effects may be expected, along with the combined use of the drugs in which action mechanisms differ. The introduction of pharmaceutical new approaches is also expected as the expression mechanism of osteoporosis is further clarified by basic studies.

Anabolic Agents↗

PubMed1999

Rho Chi lecture. Pharmaceutical sciences in the next millennium.

Even a cursory survey of this article suggests that the pharmaceutical sciences are being rapidly transformed under the influence of both the new technologies and sciences and the economic imperatives. Of particular importance are scientific and technological advances that may greatly accelerate the critical process of discovery. The possibility of a drug discovery process built around the principles of directed diversity, self-reproduction, evolution, and self-targeting suggests a new paradigm of lead discovery, one based quite directly on the paradigms of molecular biology. Coupled with the principles of nanotechnology, we may contemplate miniature molecular machines containing directed drug factories, circulating the body and capable of self-targeting against defective cells and pathways -- the ultimate "drug delivery machine." However, science and technology are not the only factors that will transform the pharmaceutical sciences in the next century. The necessary reductions in the costs of drug discovery brought about by the rapidly increasing costs of the current drug discovery paradigms means that efforts to decrease the discovery phase and to make drug development part of drug discovery will become increasingly important. This is likely to involve increasing numbers of "alliances," as well as the creation of pharmaceutical research cells -- highly mobile and entrepreneurial groups within or outside of a pharmaceutical company that are formed to carry out specific discovery processes. Some of these will be in the biotechnology industry, but an increasing number will be in universities. The linear process from basic science to applied technology that has been the Western model since Vannevar Bush's Science: The Endless Frontier has probably never been particularly linear and, in any event, is likely to be rapidly supplanted by models where science, scientific development, and technology are more intimately linked. The pharmaceutical sciences have always been an example of use-directed basic research, but the relationships between the pharmaceutical industry, small and large, and the universities seems likely to become increasingly developed in the next century. This may serve as a significant catalyst for the continued transformation of universities into the "knowledge factories" of the 21st century. Regardless, we may expect to see major changes in the research organizational structure in the pharmaceutical sciences even as pharmaceutical companies enjoy record prosperity. And this is in anticipation of tough times to come.

Chemistry, Pharmaceutical↗

PubMed2003

Public health context of women's mental health research.

As more attention is directed to the mental health care of women, sex and gender differences in research design and in regulatory policies have interfaced with clinical care and public policy. An emphasis on women's mental health issues in the provision of treatment and care as well as the design of large-scale screening strategies to identify and treat women with mental disorders promises to be effective public health approaches to reducing the burden of mental illness in women. The past decade has seen increased emphasis on women's mental health and sex/gender differences in the federal sector and in the research community. Federal regulations (summarized in the NIH Outreach Notebook) call for the inclusion of women and minorities in NIH-funded clinical research. The regulations also place emphasis on gender analysis of the results of clinical trials, in particular phase III trials, the findings of which are likely to influence practice. There has been substantial progress toward the goal of including women in research, but more remains to be done. A 2000 GAO report titled "Women's Health: NIH Has Increased Its Efforts to Include Women in Research" commended NIH for tracking the number of women in clinical research but the report also noted that relatively few NIH-funded studies, including major clinical trials, had reported findings by gender of study participants. This was seen as an impediment to progress in developing gender-based effective treatments. In the past decade, the women's health field has moved beyond an exclusive emphasis on women's reproductive function to one that defines health as a scientific enterprise to identify clinically important sex and gender differences in prevalence, etiology, course, and treatment of illnesses affecting men and women in the population as well as conditions specific to women. Nonetheless, for mental disorders, women's reproductive function and its impact on mental health conditions is still understudied. Based on the epidemiology of mental disorders, the course of mental disorders in women in relation to reproductive transitions remains an important issue for the mental health field because the burden of mental disorders, such as depression and anxiety, fall disproportionately on women of childbearing and childrearing age. The public health emphasis on women's mental health does not lessen the basic scientific opportunities to be had by a focus on gender and sex differences. A 2001 report of the Institute of Medicine titled "Exploring the Biological Contributions to Health: Does Sex Matter?" underscores the benefit to health care of looking for sex differences at the biological level. Basic and clinical neuroscience research is rapidly accruing a knowledge base that will provide information at the level of genes and cells of the influences of biological sex on mental health outcomes in both women and men. A focus on women's mental health and gender/sex differences research promises to yield improvement in treatments and services and thereby to improve the public health as well as to increase fundamental knowledge about the etiology and neurophysiology of mental disorders.

Ethnicity↗

PubMedDate not supplied

Population crises and population cycles.

To prevent a population irretrievably depleting its resources, mammals have evolved a behavioural and physiological response to population crisis. When a mammalian population becomes dangerously dense, there is a reversal of behaviour. Co-operation and parental behaviour are replaced by competition, dominance and aggressive violence, leading to high mortality, especially of females and young, and a reduced population. The stress of overpopulation and the resulting violence impairs both the immune and the reproductive systems. Hence epidemics complete the crash of the population, and reproduction is slowed for three or four generations, giving the resources ample time to recover. In some mammal species, crisis and crisis response recur regularly, leading to cycles of population growth and relapse, oscillating about a fixed mean. Population crisis response and population cycles have been equally prominent in the history of human societies. But in man successive advances in food production have made possible growing populations, though with every such advance population soon outgrew resources again. Hence human cycles have been superimposed on a rising curve, producing a saw-tooth graph. Because advances in food production amounted to sudden disturbances in the relations between human populations and their environments, the crisis response in man has failed to avert famine and resource damage. In the large human societies evolved since the coming of settled agriculture and cities, the basic effects of violence, epidemics, famine and resource damage have been mediated by such specifically human disasters as inflation, unemployment, and political tyranny. An account of past crises, periods of relative relief from population pressure, and resulting cycles, is given for a number of regions: China, North Africa and Western Asia, the northern Mediterranean, and north-western Europe. The paper ends with an account of the present world-wide population crisis, and the solution made possible by Malthus's discovery that, unlike animals, we can choose to check population growth by reducing the birth-rate, instead of raising the death-rate, as in other mammals, by the population crisis response.

Animals↗