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PubMed1984

Pharmacokinetics and toxicity testing.

The pharmacokinetic basis for the design of toxicity tests is discussed with reference to the absorption and clearance of drugs. The absorption and clearance of a wide range of drugs by laboratory animals and man has been examined and reviewed to provide a firm basis against which new drugs can be compared. Some pitfalls in either the empirical approach to toxicology or the incorrect interpretation of kinetic data are highlighted. An approach is outlined for the rational application of animal pharmacokinetic data in the assessment of the safety in man of a new therapeutic agent.

Administration, Oral↗
PubMed1998

Evaluation of models for balancing the protein requirements of dairy cows.

Most diets for dairy cattle in the US are formulated using the mathematical model developed by the National Research Council (NRC). This model is simpler than more mechanistic models and is largely empirical. Based on the research reviewed in this paper, the simpler empirical approach is recommended for routine diet formulation at the present time. Under typical conditions using feed tables for most feed descriptions, the NRC model was more accurate than the Cornell Net Carbohydrate and Protein System, and, in its present form, the model developed by Baldwin et al. (4) is too difficult to run routinely in the field. However, the more mechanistic approaches are recommended to investigate diet and animal interactions under nonstandard environmental conditions, animals, or feeds. Because the NRC model does not address many of the potential limitations of some diets or management conditions, more complex models are needed to identify why some herds appear to underperform. Mechanistic models can be used to study or explain nutritional or physiological concepts and to develop and test research hypotheses. Ultimately, it is the fundamental research in nutrition modeling that enables advances in routine diet formulation procedures. Nonetheless, models used routinely to balance diets need to be as simple and as accurate as possible.

Animal Nutritional Physiological Phenomena↗
PubMed1980

Neutron flux self-shielding in activation analysis.

Some effects of self-shielding of neutron flux in neutron activation analysis have been investigated. Induced specific activities in dilute samples were compared with those in solid elements irradiated under the same conditions. Two factors affecting the neutron flux were investigated: thermal neutron self-shielding and epithermal neutron self-shielding. The former effect can be computed reasonably accurately, using a well-known approximation. Self-shielding of epithermal neutrons cannot be calculated rigorously, so an empirical approach was used. The self-shielding effects of neutron flux were evaluated for uranium and a maximum permissible weight has been calculated by assuming that the product of the maximum permissible weight and the atom density is a function of the ratio of the resonance integral of the absorbing element to that of uranium.

Activation Analysis↗
PubMed2004

Transcript signatures in experimental asthma: identification of STAT6-dependent and -independent pathways.

The analysis of polygenic diseases such as asthma poses a challenging problem. In an effort to provide unbiased insight into disease pathogenesis, we took an empirical approach involving transcript expression profiling of lung tissue from mice with experimental asthma. Asthmatic responses were found to involve sequential induction of 4.7% of the tested genome; notably, there was ectopic expression of a series of genes not previously implicated in allergic or pulmonary responses. Genes were widely distributed throughout all chromosomes, but preferentially included genes involved in immunity, development, and homeostasis. When asthma was induced by two independent experimental regimens, unique gene transcript profiles were found depending upon the mode of disease induction. However, the majority of genes were common to both models representing an asthma signature genome. Analysis of STAT6-deficient mice revealed that an unexpectedly large segment of the asthma genes were STAT6 independent; this correlated with sustained inflammatory events in these mice. Notably, induction of asthma in STAT6-deficient mice resulted in gene induction not seen in wild-type mice. These results raise concern that therapeutic blockade of STAT6 in the asthmatic setting may reprogram the genetic signature, resulting in alternative lung pathology, which we indeed observed in STAT6-deficient mice. These results provide unprecedented insight into the complex steps involved in the pathogenesis of allergic airway responses; as such, these results have significant therapeutic and clinical implications.

Administration, Intranasal↗
PubMed1994

Immunity to erythrocytic stages of malarial parasites.

In those individuals who live in endemic areas, immunity to malaria is slow to develop and stage-specific. The nature and antigenic specificity of this response, which may involve components of both cell-mediated and humoral immunity, is not well understood. Rodent models provide useful systems to explore the spectrum of host responses that may contribute to resolution of erythrocytic-stage infection or possibly to pathogenesis. Moreover, these models allow identification of plasmodial molecules that can induce different types of host responses. Two different mouse model systems, Plasmodium yoelii yoelii and P. chabaudi adami are presented. These have been selected because resolution of infection by P. yoelii yoelii has been shown to require B cell-dependent mechanisms, while control of acute P. chabaudi adami infection can be achieved by T cell-dependent mechanisms. A monoclonal antibody that provides passive protection to P. yoelii challenge infection has been shown to recognize the cysteine-rich, carboxyl-terminal region of the merozoite surface protein-1. This region, obtained in an appropriate configuration from recombinant Escherichia coli, can induce significant protective immune responses in naive mice. In contrast, cell-mediated immune mechanisms make a major contribution to resolution of asexual-stage P. chabaudi adami infection. An empirical approach using continuous flow electrophoresis has identified several low molecular weight plasmodial proteins that can induce partial protective responses in susceptible hosts. These observations are briefly discussed with respect to human malaria.

Animals↗
PubMed1999

[Congestive heart failure in the aged. Therapeutic management].

TOWARDS OPTIMAL CARE: It is essential to distinguish between systolic and diastolic dysfunction to achieve optimal management of patients with congestive heart failure. Data is lacking in the literature for validation of the guidelines usually applied in the elderly population. A specific analysis of therapeutic management of diastolic heart failure has never been performed. Altered response to drugs and associated disease states argue for an assessment of therapeutic options. The therapeutic objectives to test are different in the elderly population where quality of life and morbidity are more important than mortality criteria. In clinical practice, the empirical approach still predominates over evidence based medicine. THERAPEUTIC GOALS: At the acute phase, volume overload requires rapid action diuretics and a treatment of the triggering cause. For chronic situations, diet and lifestyle play a major role (reduced salt intake, regular exercise). Drug therapy, particularly converting enzyme inhibitors have been found to be quite effective. Rehabilitation and secondary preventive measures are the only validated methods proven to improve quality of life.

Aged↗
PubMed1999

[Anti-infective aerosols].

Anti-infectious agents such as pentamidine, antibiotics (mainly colistine and aminoglycosides) and amphotericin B can be administered by aerosol. This route of administration is not officially approved and it constitutes an empirical approach which has benefited from recent research which is summarized hereafter. The most fundamental question is related to the potentially deleterious effects of nebulization processes, especially ultrasound, on the anti infectious properties of the drugs. Colimycin, which was chosen as a reference because its polypeptide structure makes it unstable a priori, proved to be resistant to high frequency ultrasound, which is encouraging for other molecules such as aminoglycosides or betalactamins. The nebulizer characteristics have also to be taken into account. An aerosol can be produced from an amphotericin B suspension and from colistine using both an ultrasonic nebulizer and a jet nebulizer. Distinction between good and bad nebulizers does not depend upon the physical process involved to nebulize the drug, but on the intrinsic characteristics of the device and its performance with a known drug. The inhaled mass of an aerosol in the respirable range must be high and dosimetric nebulizers represent a significant progress. Finally, adminnistration of anti infectious aerosols requires a new pharmacological approach to monitor treatment and urinary assays are promising.

Aerosols↗
PubMed1999

Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population.

The contribution of malaria to morbidity and mortality among people in Africa has been a subject of academic interest, political advocacy, and speculation. National statistics for much of sub-Saharan Africa have proved to be an unreliable source of disease-specific morbidity and mortality data. Credible estimates of disease-specific burdens are required for setting global and national priorities for health in order to rationalize the use of limited resources and lobby for financial support. We have taken an empirical approach to defining the limits of Plasmodium falciparum transmission across the continent and interpolated the distributions of projected populations in 1995. By combining a review of the literature on malaria in Africa and models of acquired functional immunity, we have estimated the age-structured rates of the fatal, morbid and disabling sequelae following exposure to malaria infection under different epidemiological conditions.

Adolescent↗
PubMed2000

[Uncertainty of practitioners between rational and evidence-based dermatology].

In opposition to intuitive and empirical approaches, rigorous medicine relies on two axes of development. Evidence-Based Medicine is currently put forward. However, it can not replace rational medicine rooted in physiopathological explanations. Dermatology does not escape such conceptual duality. Dermatopathology is one major pillar of rational dermatology. Such situation is jeopardized by health planners who deny the perennial skill of dermatologists and concede hegemony of dermatopathology to general pathologists.

Decision Making↗
PubMed1999

[The work of nursing in the production of health care in a clinical model].

The subject of this research study is the technological and social organization of health work in hospital, considering the position of nursing practice within production of care. The aim is to analyze the work process at a University Hospital to apprehend the configuration of practices, knowledges, social relations and technologies that are operated by agents in intervention on the body of an ill person. Using a dialectical approach, empirical data were collected by direct observation of the work process in a medical in-patient unit and by semi-structured interviews with professionals. It was found that the production of care is developed based on collective work, that is structured by the division in parts and fragmentation of the actions of the different agents, in order to produce a diagnosis and therapy. The agents articulate their actions around the medical act which takes up a central position in the production of care. The importance of broadening the clinical model to contemplate the social and subjective dimension of the health/disease process is pointed out in a therapeutical project shared by different health care team professionals. It is proposed to change the work process associated with the construction of new management models in health care institutions.

Attitude of Health Personnel↗
PubMed2001

Differences in rehabilitation services and outcomes among stroke patients cared for in veterans hospitals.

OBJECTIVE: To examine the relationship of services for post-acute care (PAC) to stroke patient outcomes. DATA SOURCES/STUDY SETTING: Veterans Health Administration (VHA) hospitals from two facility-level surveys and extant data files. STUDY DESIGN: Cross-sectional study of veterans hospitalized with acute stroke during the period June 1995 through May 1996 in one of 182 geographically distinct locations within the VHA. Study variables included (1) a typological classification of hospitals according to the level of PAC; (2) a taxonomy of rehabilitation characteristics, including personnel, physical facilities, coordination of care, and hospital characteristics; and (3) patient outcomes (discharge destination, length of stay). DATA COLLECTION/EXTRACTION METHODS: Data were collected from two mailed surveys and extant data files. Rehabilitation variables were identified for the study in conjunction with a panel of expert rehabilitation researchers and clinicians, using an a priori model for measuring rehabilitation characteristics. Two sets of variables were derived to categorize these rehabilitation characteristics: (1) a rehabilitation typology, classifying the VA hospitals according to the continuum of PAC settings in the facility, and (2) a rehabilitation taxonomy that used an empirical approach to derive a list of key rehabilitation characteristics. PRINCIPAL FINDINGS: Twenty-seven percent of veterans with acute stroke were cared for in VA hospitals with neither a geriatric nor a rehabilitation unit, and 50 percent were cared for in hospitals without a rehabilitation unit. Hospitals with rehabilitation units had the greatest sophistication, and those with geriatric units had intermediate sophistication in rehabilitation organization and resources. Statistically significant differences were found in outcomes for stroke patients cared for in hospitals classified according to the continuum of post-acute care on site. Exploratory multivariable analyses revealed independent associations between stroke patient outcomes and (1) staffing ratios for nurses and physicians, (2) the diversity of physician and rehabilitation staff, (3) presence of a simulated home environment, and (4) the total number of care settings on site. CONCLUSIONS: The PAC continuum defines an important hierarchy of stroke rehabilitation services.

Aged↗
PubMed2000

Hybridization of antisense reagents to RNA.

Despite the simplicity of the concept, almost every step in an antisense experiment poses difficulties. Finding a site that is accessible to intermolecular hybridization with complementary nucleic acids is a major problem and determines the success or failure of an antisense experiment. A major determinant of accessibility appears to be the intramolecular folding in mRNAs that renders much of the molecule inaccessible. However, owing to our poor understanding of RNA folding and the mechanisms of heteroduplex formation, theoretical methods have limited use in finding accessible sites. Such methods are unable to address two major considerations when designing an antisense reagent, i.e., which is the most accessible sequence in the target and what length of the reagent works best in terms of activity and specificity. Empirical approaches appear more successful. Of notable interest, and reviewed here, are 'global' methods based on DNA arrays and on mapping of transcripts with RNase H.

Animals↗
PubMedDate not supplied

Effect of sodium pool changes on blood pressure in patients undergoing PFD: design of a prospective randomized multicenter trial.

Blood pressure control is important during dialysis and the interdialytic period because of the frequency and potential seriousness of hypotension and hypertension. Water and sodium removal play an important role in the genesis of intradialytic cardiovascular instability or hypertension. Changing dialysate sodium concentrations without the aid of a kinetic model can sometimes give good results but is only an empirical approach. Therefore, this clinical trial was designed to prospectively investigate the advantages of changes in the sodium pool on the blood pressure profile of patients undergoing paired filtration dialysis (PFD). The hypothesis to be tested is whether using a dialysate conductivity which, according to the conductivity kinetic model, ensures that the conductivity of the ultrafiltrate at the end of each dialysis session is 0.3 mS/cm more (B) or less (C) than the mean during the run-in period, improves blood pressure control either in patients prone to intradialytic hypotension or patients who are hypertensive or normotensive with antihypertensive treatment. Patients will be randomly allocated to one of two treatment sequences (where treatment A is standard PFD): AABB or ABAA for patients with intradialytic hypotension; AACC or ACAA for hypertensive patients. During the experimental phase arterial blood pressure will be measured and symptoms reported by the patients will be recorded.

Blood Pressure↗
PubMed2001

Expression and meaning of medical language: building an epistemological framework for the study of semantic distance.

The use of language for communication purposes introduces a semantic gap in data processing. We have developed a new tool called semantic distance to overcome this gap. A previous presentation of our tool was based on an empirical approach. Here, we examine the properties and theoretical foundation of semantic distance from a rationalistic perspective. We present an epistemological framework to explain the meaning of semantic distance. As a tool, the purpose of semantic distance is the exchange of data or knowledge based on linguistic expressions between software components. We propose a review of the relationship between language and its representation for data processing based on the underlying philosophical assumptions. Description logic is a new paradigm in the medical informatics community to express relations between terms in "is-a" hierarchies. The utility of semantic distance is compared to description logic for communication purposes in different use cases.

Knowledge↗
PubMed1994

[Not Available].

The philosophical interpretation of nature around 1800 exercised a deep influence on the natural sciences and medical disciplines, especially in regard to organisms, diseases and the relationship between nature and culture. Natural scientists and speculative philosophers in the Romantic era, a special phase between the 18th and 19th century, criticized the science of their time, but they in no way challenged the value and justification of an empirical approach to nature, though they rejected the absolutizing aspect of its positivistic perspective and pleaded for the unity of natural phenomena, the responsibility of man for nature, the concept of medicine as science and art.

Environment↗