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PubMed2003

Effects of tacrolimus on ischemia-reperfusion injury.

In addition to efficacious immunosuppression for the benefit of organ transplantation, tacrolimus has diverse actions that result in amelioration of ischemia-reperfusion injury. Knowledge is accumulating rapidly on the mechanisms through which tacrolimus exerts these cytoprotective effects, including alterations in microcirculation, free radical metabolism, calcium-activated pathways, inflammatory cascades, mitochondrial stability, apoptosis, stress-response proteins, and tissue recovery. Within the nucleus, actions mediating the effects of tacrolimus appear to be dominantly influenced by interactions with the transcription factor, nuclear factor-kappaB. Because tacrolimus is a cornerstone agent in immunosuppression regimens throughout the world and knowledge of its cellular mechanisms is evolving, it is important to update the clinical literature with this information. We reviewed the published literature with intent to portray the interactions of tacrolimus in the intricate cellular mechanisms initiated by ischemia and reperfusion.

Adenosine Triphosphate↗

PubMed2003

Aging in place: knowing where you are.

Research on aging in place appropriately emphasizes the value of familiar surroundings. The current study contributes an exploration of elders' personal knowledge of where and with whom they are aging in place, knowledge actively accumulated from a lifetime spent in the same area. Structured conversations over a four-month period with 10 elders living on a peninsula in northern Maine provide richly detailed narratives of physical and social particulars of where they live. I use Rowles's (1978) image of concentric circles radiating out from home to organize the information gathered regarding each elder's dwelling, neighborhood and community. Most notable is the depth and detail of their personal knowledge of where they are and with whom they are growing old. I conclude that both the knowledge itself, and the sharing of that knowledge with others, contribute to the implicit and explicit support deemed so valuable for elders who age in place.

Aged↗

PubMed1994

[Alcohol and the liver. Present knowledge of pathogenic mechanisms].

Intensive longtime experimental and clinically-experimental investigations have not yet succeeded unriddling the intimate mechanism of liver alcoholic damage. Earlier knowledge on accumulation of fats in liver under the influence of alcohol (ethanol) is still actual, but it probably represents only epiphenomenon and does not explain the intimate mechanism of events. It still can be stated that, although the aim has not been achieved, gradually, as a consequence of very studious investigations we have signification information which bring more light in regard to identify the mechanism of this frequent disease of modern mankind. We have tried to summarize the latest knowledge on alcoholic liver damages. However, some of the most simple questions still do not have an answer: why do, for example, some longtime alcoholics, whose everyday intake of alcohol is big, develop liver cirrhosis at the end of their lives, while the others, under the same circumstances, develop it very early?

Humans↗

PubMedDate not supplied

Changes in students' knowledge and attitudes following a course in human sexuality: report of a pilot study.

Eleven female undergraduate nursing students and 12 male undergraduates from a private southern university responded to a 163-item questionnaire, the Human Sexuality Knowledge and Attitude inventory, prior to and immediately following a formal course in human sexuality. The results of a pilot test indicated that improvement in respondents' total knowledge score (TOTSC) was correlated with completion of the course. No correlation existed between liberalization of attitudes toward sexuality and completion of the course. Demographic variables of age, sex, perception of self as "somewhat" or "slightly religious" and "somewhat liberal politically", and residence in small cities in the New England/Middle Atlantic area were significantly correlated with improvement of TOTSC. Demographic variables did not appear to affect liberalization of attitudes. The investigators concluded that the course is an effective model for assisting students to accumulate a knowledge base about sexuality. Although attitudinal change was not an immediate outcome of the course, perhaps this variable will change on a long-term basis.

Attitude of Health Personnel↗

PubMed1996

[Sick of food? Knowledge and hypothesis on food intolerance].

Food intolerance is frequently reported by patients and represent a diagnostic and therapeutic challenge. We review the nomenclature and report on symptoms, diagnostic tests and treatment. The nomenclature presented is based on the primary events such as toxic reactions, allergy or an undefined mechanism, including psychosomatic, although these subgroups may involve common pathogenetic mechanism. Double blind placebo controlled food challenge is the golden standard in the diagnostic workup and the importance of elimination diets--individually tailored to each patients requirements in cooperation with a nutritionist--is stressed. Through strict adherence to diagnostic and therapeutical guidelines, therapy may resolve food induced symptoms. Based on preliminary findings of signal transduction, we propose that symptoms in some patients may depend on an allergy type IV reaction. This working hypothesis forms the basis for further accumulation of knowledge of food intolerance reactions.

Algorithms↗

PubMed2004

Pheromones and other semiochemicals of ticks and their use in tick control.

This review addresses the role of compounds secreted into the external environment that mediate important aspects of tick behaviour. Known as semiochemicals, these information-containing compounds include pheromones (used for conspecific communication), allomones (defence secretions) and kairomones (used for host identification and location). An impressive body of knowledge has accumulated concerning the identification of the compounds that comprise these semiochemicals. Pheromones are the best known and intensively studied, including arrestment (=assembly) pheromones, attraction-aggregation-attachment (AAA) pheromones and sex pheromones. Arrestment behaviour is mediated by contact with excreta from other ticks. In contrast, aggregating and sexual behaviours comprise a hierarchy of responses to different types of chemical compounds that must be recognized in a sequential order to achieve the end result. Ixodid ticks also produce an allomone that protects against certain insect predators. Finally, ticks use kairomones for host identification, e.g. volatiles such as CO2 and NH3 and various oils such as glandular secretions from deer. Knowledge of tick pheromones has been used to develop innovative new technologies for tick control. These products incorporate tick pheromones and small amounts of pesticide to attract and kill ticks on their hosts or in vegetation. The kairomones and the tick allomone also may be of interest for use in controlling ticks.

Animals↗

PubMed1992

Undergraduate surgical education for the twenty-first century.

This article addresses the problems associated with current undergraduate surgical education and discusses the requirements necessary for its improvement during the third and fourth years of medical school. It asserts that, coincident with the emphasis on faculty research and publication and expanded resident patient care duties, teaching, particularly medical student teaching, has assumed a very low priority. Third-year medical students are attached to surgical teams, where their education is haphazard and disorganized. Furthermore, because any teaching that occurs is teacher oriented rather than student centered, knowledge is accumulated passively and is not well retained. Traditional evaluation using shelf multiple choice examinations and ward ratings by residents and faculty may provide inaccurate assessments of the students' performance. The undergraduate surgical education program should be directed by a faculty member who has been grounded in educational techniques and research and supported by a department chairman committed to bettering the program. In the clerkship, medical students should be assigned to faculty rather than to services and should be presented problems that require solution. Students also should be provided with the resources to solve the problems and should be given sufficient time to solve them. Some operating room experience and bedside teaching should occur during the clerkship. A variety of evaluation and testing methods based on the learning objectives of the clerkship should be used. Third-year students should not be promoted until they have demonstrated their acquisition of appropriate knowledge and skills.(ABSTRACT TRUNCATED AT 250 WORDS)

Education, Medical, Undergraduate↗

PubMed1984

The muscle satellite cell: a review.

Since the first reports of satellite cells in 1961, considerable knowledge has accumulated concerning their phylogenetic distribution and their location, morphology, and function. There is no doubt that satellite cells are capable of undergoing mitosis and that they have considerable motility. These cells function as the progenitors of the myofiber nuclei that must be added during normal (postnatal) growth of muscle. In muscle undergoing or attempting to undergo regeneration, the satellite cell functions as a myogenic stem cell to produce myoblasts that line up and fuse within the scaffolding of the remnant basal lamina or migrate into the interstitium to produce neofibers . A number of problems remain to be solved concerning the regulation of satellite cell function. At this time it is equivocable whether or not the presumptive myoblast and the satellite cell are functionally identical and at the same stage of myogenic differentiation. Apparently there is species variation in terms of the ability of myotubes from embryonic myogenic cells and satellite cells to synthesize protein. The mechanism(s) by which a wide variety of stimuli activate satellite cells is not known, nor is the mechanism(s) by which satellite cells become inactive during the latter stages of growth and adulthood known. Mitogenic factors are present in damaged muscle; but the specific characteristics of these factors and their mechanism of activation are also unknown. Hormones are certainly involved in the regulation of proliferation and differentiation of myogenic cells, but whether presumptive myoblasts and satellite cells or their myotubes respond similarly to hormones in culture has not been adequately examined. Greater understanding of these mechanisms will increase the possibility of total muscle recovery from severe injury or disease. Such knowledge would also have particular application to the production of meat animals and to a greater understanding of the growth process in general.

Animals↗

PubMed1995

Collection of domestic waste. Review of occupational health problems and their possible causes.

During the last decade, a growing interest in recycling of domestic waste has emerged, and action plans to increase the recycling of domestic waste have been agreed by many governments. A common feature of these plans is the implementation of new systems and equipment for the collection of domestic waste which has been separated at source. However, only limited information exists on possible occupational health problems related to such new systems. Occupational accidents are very frequent among waste collectors. Based on current knowledge, it appears that the risk factors should be considered as an integrated entity, i.e. technical factors (poor accessibility to the waste, design of equipment) may act in concert with high working rate, visual fatigue due to poor illumination and perhaps muscle fatigue due to high work load. Musculoskeletal problems are also common among waste collectors. A good deal of knowledge has accumulated on mechanical load on the spine and energetic load on the cardio-pulmonary system in relation to the handling of waste bags, bins, domestic containers and large containers. However, epidemiologic studies with exposure classification based on field measurement are needed, both to further identify high risk work conditions and to provide a detailed basis for the establishment of occupational exposure limits for mechanical and energetic load particularly in relation to pulling, pushing and tilting of containers. In 1975, an excess risk for chronic bronchitis was reported for waste collectors in Geneva (Rufèner-Press et al., 1975) and data from the Danish Registry of Occupational Accidents and Diseases also indicate an excess risk for pulmonary problems among waste collectors compared with the total work force. Surprisingly few measurements of potentially hazardous airborne exposures have been performed, and the causality of work-related pulmonary problems among waste collectors is unknown. Recent studies have indicated that implementation of some new waste collection systems may result in an increased risk of occupational health problems. High incidence rates of gastrointestinal problems, irritation of the eye and skin, and perhaps symptoms of organic dust toxic syndrome (influenza-like symptoms, cough, muscle pains, fever, fatigue, headache) have been reported among workers collecting the biodegradable fraction of domestic waste. The few data available on exposure to bio-aerosols and volatile compounds have indicated that these waste collectors may be simultaneously exposed to multiple agents such as dust containing bacteria, endotoxin, mould spores, glucans, volatile organic compounds, and diesel exhaust. Several studies have reported similar health problems as well as high incidence rates of pulmonary disease among workers at plants recycling domestic waste.(ABSTRACT TRUNCATED AT 400 WORDS)

Accidents, Occupational↗

PubMed1999

Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician.

At one time, the diagnosis of a deficiency of vitamin B12 or folate was considered to be relatively straightforward. As knowledge has accumulated, the limitations of such tests as serum vitamin level measurements and the Schilling test have become apparent. With the development of newer tests, atypical and subclinical deficiency states have been recognized. In this review, available tests used in the diagnosis of vitamin B12 and folate deficiency are discussed, and a rational approach to the diagnosis of these deficiency states is presented.

Antibodies↗

PubMed2005

The search and prime hypothesis for growth cone turning.

In the fields of axonal and dendritic guidance, there is now a significant accumulation of knowledge of how extracellular signaling molecules activate their cognate growth cone receptors. Relatively little is known about the subsequent activation of intracellular signaling pathways and actin reorganization, and very little is known about how microtubules (MTs) reorganize during growth cone turning. I hypothesize that dynamic MTs are required in order to catalyze the polarized actin assembly necessary for growth cone turning, that MTs and actin filaments promote each other's assembly through positive feedback, that MT stability is enhanced further through the formation of membrane-associated MT attachment sites, and that these MT stabilization events subsequently accelerate axonal/dendritic shaft formation.

Actin Cytoskeleton↗

PubMed2006

Confirmatory clinical trials with an adaptive design.

Adaptive designs are one of the most promising developments in statistics with applications to clinical trials. Obviously, knowledge at the beginning of a clinical trial will always be limited. Thus it may seem logical that the knowledge from accumulating information should be used to optimize the design of the trial. This paper discusses conditions under which this may be possible in phase III clinical trials where the principal aim is confirmation of hypotheses that have been developed in earlier stages of drug development.

Biometry↗

PubMedDate not supplied

Tumor suppressor genes.

Tumor suppressor genes are negative regulators of cell growth. When their normal function is compromised, absence of their inhibitory effects can lead to unrestrained cell cycling and growth. Strong evidence now confirms that loss of proper function of these genes is a common occurrence leading to cancer. Their failure can be caused by alterations in the gene DNA or malfunction of their protein products. The recent extraordinary accumulation of knowledge about these genes reveals that normal carcinogenesis represents breakdown of normal regulatory processes.

Cell Transformation, Neoplastic↗

PubMed1993

New approaches to atherosclerosis: an overview.

The mechanisms of action and selected agents for a variety of approaches to the treatment of atherosclerosis have been reviewed. In Table I, each approach is listed according to its primary physiological effect. This is a simplification, of course, and some agents, such as ACAT inhibitors, may have primary effects in all of these categories. As one goes from left to right, the benefit of each physiological effect becomes more speculative. There is no question of the benefit of LDL reduction, but less evidence exists for the clinical benefits of HDL elevation. With regard to direct anti-atherosclerotic effects, most approaches have yet to gather clinical data of any type. Perhaps as a result, the degree of medicinal chemistry effort in each area to date declines as one goes from left to right. This situation is changing rapidly, however. As evidence supporting the HDL hypothesis accumulates and knowledge of how to elevate HDL levels grows, very exciting opportunities for medical advances present themselves. Likewise, the knowledge base for nonlipid intervention is growing and very rapid advances are being achieved with the plaque-imaging techniques needed for evaluating such agents in man. Such results can only lead to greater opportunities for pharmacological intervention. Thus, in the future, much greater research effort will likely be dedicated to HDL elevation and nonlipid approaches. Through these efforts, physicians of the future should be armed with several complementary agents that can reduce the risk of cardiovascular disease in all patient populations.

Anticholesteremic Agents↗

PubMed1995

Regionalization and segmentation of the leech.

Regionalization and segmentation of the leech body plan have been examined by numerous approaches over the years. A wealth of knowledge has accumulated regarding the normally invariant cell lineages of the leech and the degree of developmental plasticity that is possible in each cell line in early development and in neurogenesis. Homologues of genes that control regionalization and segmentation in Drosophila have been cloned from the leech and the expression patterns reveal conserved features with those in Drosophila and other organisms. Possible developmental functions of the en-class proteins in spatial and temporal modes of segment formation are discussed in light of leech and Drosophila development. Annelida and Arthropoda cell lineages of engrailed-class gene expression are compared in leech blast cell clones and crustacean parasegments. In addition, future directions for molecular analysis of segmentation of the leech are summarized.

Animals↗

PubMed1996

A moving image of flagella: news and views on the mechanisms involved in axonemal beating.

Beating of cilia and flagellae allows movement of the fluid surrounding isolated cells (for example: protists) or epithelia (bronchial tissue) but is also responsible for the movement of unicellular organisms in this medium (such as spermatozoa or protists). This paper aims to describe: (1) the biochemical and structural elements of the '9 + 2' structure called the axoneme; (2) the mechanisms of wave generation and propagation along the axoneme of cilia and flagellae are then described, stating that in most models of wave propagation, a clear distinction is made between the dynein-dependent microtubule sliding which represents the oscillatory motor and the bending mechanism which regulates wave propagation. In current models, the bending propagation is supported by a bind/relax cyclic mechanism which propagates in register, but frame-shifted, with the powering action of the dynein motor along the axoneme. While a large amount of knowledge was accumulated about the motor, little is known about the resisting elements regulating the bending. (3) The present study also puts forward ideas as to how these organelles have been highly conserved throughout eucaryotic evolution, and concludes with suggestions for further fields of investigation into this unique mechanical device used for cell movement.

Animals↗

PubMed1999

The molecular biology of acute promyelocytic leukemia.

The preceding two years have witnessed an explosion in the accumulation of knowledge relating to the molecular pathogenesis of APL. Critical advances include: The molecular delineation of atypical APL cases with alternative RAR alpha fusion partners, and the demonstration that cells from 2 of the 3 types of 'atypical' APL retain sensitivity to ATRA. Perhaps the key question is why such cases are so rare. However, at a minimum, the presence of such cases argues persuasively that disruption of the retinoid signaling pathway is a (perhaps the) key pathogenetic feature of APL. Although certainly not 'passive' partners, it is likely that PML, PLZF, NPM, and NuMA serve similar functions in the pathogenesis of APL. The demonstration, in transgenic mice, that PML-RAR alpha (and PLZF-RAR alpha) can disrupt normal hematopoiesis and, given sufficient time, cause an APL-like syndrome. the variation in phenotype of the mice, which appears to be a consequence of the specific expression vector used, emphasizes the cell-type-specific nature of PML-RAR alpha function. Continuing functional analysis of PML, PLZF, and RAR alpha. In particular, the demonstration that PML and PLZF can form heterodimers provides a critical functional link between these proteins and offers a tantalizing glimpse at how both, when linked with RAR alpha, can cause APL. The demonstration that PML-RAR alpha is degraded, perhaps via a ubiquitin-dependent pathway, in response to ATRA. This result offers a unifying, if not yet proven, hypothesis to explain the sensitivity of leukemic promyelocytes to ATRA. Unfortunately, it is not known if ATRA can also cause degradation of NPM-RAR alpha or NuMA-RAR alpha (atypical cytogenetic APL variants that retain ATRA responsiveness). Whether PML-RAR alpha degradation is a cause, or consequence, of promyelocytic maturation remains unclear. Continuing insight into retinoid resistance, including the first demonstration of mutations in the PML-RAR alpha molecule from ATRA-resistant patients. The definitive demonstration that the two major PML-RAR alpha isoforms, while having subtle differences in biological activity and producing slightly different APL phenotypes, nevertheless do not, in and of themselves, have prognostic significance in patients treated with ATRA/chemotherapy combinations. Further functional analysis of PML-RAR alpha in vitro. The fascinating finding that PML-RAR alpha is cytotoxic to most cell types suggests that it must function as an oncogene in a very specialized milieu. In addition, the demonstration that both the DBD (from RAR alpha) and dimerization interface (from PML) are required for full in vitro functional activity, coupled with the finding that PML itself is a strong transcriptional suppressor, suggests that PML-RAR alpha may directly repress transcription of RA target genes. The challenge in APL research now is to integrate the above findings into a cohesive, unifying model that explains the biology of APL at a molecular level. The creation and validation of such a model will clarity whether APL is a fortunate medical curiosity or whether it will serve as a paradigm for the development of effective differentiation therapies in other types of human cancers.

Animals↗

PubMed1991

The 5-HT1A receptor: an overview of recent advances.

Progress in the field of neuronal receptor research has accelerated during the last few years due to developments in pharmacology and molecular biology. This is particularly true in the case of the serotonin 5-HT1A receptor. In 1983 the very selective, high affinity 5-HT1A agonist 8-OH-DPAT was developed which allowed the pharmacology and distribution of the 5-HT1A receptor in the central nervous system of the rat and man to be extensively characterized. By 1987, the gene encoding this receptor protein was cloned and sequenced, allowing not only elucidation of its structure, but also better insight into the nature of its coupling to transmembrane signal transduction systems. Thus in a short period of time considerable knowledge has accumulated on how serotonin exerts its functions in the central nervous system via the 5-HT1A receptor. In the present review we will briefly discuss some of the latest developments regarding the 5-HT1A receptor.

Amino Acid Sequence↗