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The vascular endothelial cell as a vehicle for gene therapy.

Increasing knowledge that has accumulated during the past decade reveals that the endothelial cell plays a far larger role than that traditionally assigned to it, namely maintenance of the fluid state of the blood. Unraveling the complex interreactions of the endothelial cell with the other cellular and molecular components of the arterial wall, as well as with the blood and its cellular and particulate components, is leading to better understanding of anastomotic hyperplasia and recurrent stenosis after endarterectomy and balloon angioplasty. More recently with the newly acquired techniques of inserting genetic material into the vascular endothelial cell many new therapeutic possibilities may be developed. Important to the technique of seeding vascular grafts, and the possible use of the genetically modified endothelial cell for gene therapy systems, are the needs to identify the origin of the cell originally seeded and ways to increase their number. Retroviral vectors and genetically conferred antibiotic resistance provide these means.

Animals↗

[Recent advances in pathology and biology of small cell lung cancer].

Small cell lung cancer (SCLC) is histologically simple and looks undifferentiated, but possesses cytoplasmic dense-cored granules resembling neuroendocrine granules, and frequently produces amine and peptide hormones, occasionally presenting related symptoms. Among these bioactive substances, gastrin releasing peptide (GRP) is most important, which is known as autocrine growth factor and one of the useful monitoring markers for SCLC together with neuron-specific enolase. Aromatic L-amino acid decarboxylase is another important enzyme in SCLC. Abnormality of myc family oncogenes is occasionally noted in SCLC, which appears related to proliferative activity of the tumor rather than development. Deletion of chromosomes 3p, 13q and 17p is noted in almost every SCLC, where antioncogene is suspected to be present, and inactivation of antioncogene may play an important role in development of SCLC. Nucleolar size is the important parameter for proliferative potential of SCLC. The larger the nucleoli, the faster is the growth of SCLC. Phenotypes of SCLC in vitro may be altered by change of microenvironment, although it may be due to the selective growth of a certain clone. SCLC and nervous tissue specific membrane antigen is named cluster 1 SCLC antigen, the monoclonal antibody to which will be utilized for immunohistological diagnosis, imaging and treatment of SCLC. Accumulation of basic knowledge is now leading to reconsideration of histological subtyping of SCLC.

Antibodies, Monoclonal↗

[Morgagni hernia. A rare form of diaphragmatic hernia].

The Morgagni hernia is the rarest form of diaphragmatic hernias. Knowledge has been accumulated over time of combinations with other congenital malformations, familial occurrence, and traumatic genesis. Morgagni hernia has been more often recordable from women, along with rising age and usually located on the right hand side. Embryonic disorder of diaphragmatic differentiation is believed to be the major aetiological factor. Vitamin deficit as well as some chemical substances, primarily active in the foetal period, have become known as additional factors of predisposition. Intensive diagnosis to rule out malignancy is absolutely essential because of the variability of symptoms of this type of hernia. Colon fragments and large omentum were found to be most often contained in the hernial sac. Contrast medium X-ray checks of the gastrointestinal tract and pneumoperitoneum are preferential methods of examination. Exploratory laparotomy is generally considered the optional therapeutic approach because of possible saving of liver veins, safe removal of the hernial sac, and the possibility of abdominal exploration. Preoperative wide-range sterile covering of the patient's body around the site of surgery is recommended to allow for possible thoractomy, as may be required.

Female↗

[Interactions between the brain and gastrointestinal tract].

Peptides have been implicated to subserve neurotransmitter function within the brain and the gastrointestinal tract. While the anatomical distribution of neuropeptides suggest that most neuropeptides identified in brain tissue are also present in the gastrointestinal tract and vice versa, the functional interrelationship of the central nervous system and the gastrointestinal tract are less well documented. Most studies examined the peripheral actions of peptide hormones on visceral functions. This paper summarizes the central nervous system actions of neuropeptides on various gastrointestinal entities (secretion, motility, blood flow, absorption and eating behavior). This paper also deliniates the efferent and afferent pathways that allow to occur communication of the brain and the gastrointestinal tract. From this summary it will become evident that over the past ten years progress has mainly been made in the understanding of how the brain regulates gastrointestinal functions and only little knowledge has been accumulated to improve the understanding of afferent information flow from the gut to the brain.

Animals↗

Dietary antioxidants and cancer.

Scientifically valid data on the relationship of antioxidants to cancer come from three major sources: human epidemiological studies, experimental studies with animals and in vitro tests for genetic toxicity. Controversies are inevitable when data are either not clear-cut or incomplete. This is clearly the case for the effects of vitamins A, C, E, synthetic antioxidants and selenium on the risk of cancer. Interpretations therefore depend on the criteria selected for evaluation and are influenced by individual or collective judgment. Considerable research indicates the cancer inhibitory effects of vitamin A, vitamin C, synthetic antioxidants and selenium may be due in part to their ability to alter the enzymes involved in the metabolism of carcinogens or to inhibit cancer promotion, rather than their antioxidant properties per se. Vitamin C and E are generally less active inhibitors of overall carcinogenesis, yet their action may relate to the sequestering of genotoxic free radicals. The overwhelming evidence suggests that what we eat can influence the probability of certain types of cancer. It is not at present possible to specify a diet that protects all people. Characterizing and optimizing defense systems may represent an important strategy for minimizing cancer risk. It must be emphasized that any nutrient taken in excess can be toxic. Therefore, the indiscriminate use of supplements may lead to as many complications as what they are aimed at preventing. Therefore, even with the vast accumulation of new knowledge regarding these dietary constituents, nutrition experts continue to emphasize that it is best to eat a varied and balanced diet and maintain weight within a reasonable range.

Antineoplastic Agents↗

Delivery of anesthesia services throughout the world.

The application of the principles of basic sciences in anesthesiology not only has succeeded in allaying man's pain on Earth, but also within this decade has provided him with a controlled safe environment for successive journeys into outer space and to the moon and soon to planets beyond. These same principles have made possible his exploration of the ocean floors in artifical atmospheres and pressures and his escape, without breathing devices, from depths of 300 feet. The science of anesthesia has contributed immeasurably to the active treatment of paralytic poliomyelitis and to resuscitation. Furthermore, it has introduced needless jet injection for drug and vaccine therapy in epidemics and with increasing rapidity to diabetcs. This accumulating body of knowledge within the past 13 decades has contributed to the development of modern surgery, obstetrics, and dentistry, and provided techniques for the control of pain from metastatic cancer, from trauma, from arthritis, and during postoperative convalescence. The anesthesiologist shares with the surgeon and clinical pathologist the responsibility for the safe use of fluid and blood replacement therapy; and with the internist, psychiatrist, and general practitioner the proper sequential medication of analgesics, anesthetics, ataractics, cortisone, antihypertensive and antihistaminic agents, and prompt reversal of many undesirable depressions during emergence. A new concept is the reversal of many narcotic states with cyclic AMP. Major advances in anesthesia have been developed on every continent. The fact that there are at least 30 anesthetic techniques and 62 agents in worldwide use reemphasizes our present lack of an ideal single anesthetic agent and technique. Iti is encouraging to note that the science of anesthesiology has made more progress during the past three decades than in all of the previous century. The great preponderance of that progress has been largely confined to Canada, the United States, the British Commonwealth, Western Europe, and a few of the metropolitan areas in South America. Happily, the significant progress in the last decade has added monitors and other safeguards, understanding, tecyniques, agents, and pioneer investigators, in increasing proportions for a world that will double its population in the present half-century. Surely, there is no more important field toward the direction of world scientific effort for human betterment than in this broad area of universal agreement.

Altitude↗

The making of the air surgeon: the early life and career of David N. W. Grant.

Few individuals have left a more indelible mark on the history of aviation medicine than the wartime Air Surgeon of the U.S. Army Air Forces, David N. W. Grant. In spite of having built an incomparable air evacuation service, created the Flight Nurse Corps, instituted psychological evaluations for aircrews, and a host of other achievements, little is known about Grant the man, or about how he came to be the Air Surgeon. This paper will describe Grant's early life and military career, and will focus on his gradual accumulation of the knowledge and personal qualities that made him an outstanding, if virtually unsung, leader of World War II.

Aerospace Medicine↗

[Methods for teaching problem-solving in medical schools].

The need to include in the medical curriculum instructional activities to promote the development of problem-solving abilities has been asserted at the national and international levels. In research on the mental process involved in the solution of problems in medicine, problem-solving has been defined as a hypothetical-deductive activity engaged in by experienced physicians, in which the early generation of hypotheses influences the subsequent gathering of information. This article comments briefly on research on the mental process by which medical problems are solved. It describes the methods that research has shown to be most applicable in instruction to develop problem-solving abilities, and presents some educational principles that justify their application. The "trail-following" approach is the method that has been most commonly used to study the physician's problem-solving behavior. The salient conclusions from this research are that in the problem-solving process the diagnostic hypothesis is generated very early on and with limited data; the number of hypotheses is small; the problem-solving approach is specific to the type of medical problem and case in hand; and the accumulation of medical knowledge and experience forms the basis of clinical competence. Four methods for teaching the solution of problems are described: case presentation, the rain of ideas, the nominal groups technique and decision-making consensus, the census and analysis of forces in the field, and the analysis of clinical decisions. These methods are carried out in small groups. The advantages of the small groups are that the students are active participants in the learning process, they receive formative evaluation of their performance in a setting conductive to learning, and are able to interact with their instructor if he makes proper use of the right questioning techniques. While no single problem-solving method can be useful to all students or in all the problems they encounter, teachers of medicine can improve their students' performance by adjusting these available methods to their particular needs and to those of their schools. The problem-solving methods described can help teachers shape the learning environment so as to develop in their students the most coherent, logical, concrete and complete set of skills possible. These methods can so be of value in improving the training of future doctors and the quality of their decisions to the benefit of their patients.

Curriculum↗

The contribution of pediatric nurse practitioners to child health care.

The analysis of present and projected factors in child health care suggests that the future role of pediatric nurse practitioners is likely to be in settings other than the clinical office practice. The school is one setting in which pediatric nurse practitioners might provide preventive and well-child care to all children and additional services to children with special needs or with no access to traditional medical care. In this role, pediatric nurse practitioners are strengthened by their public health tradition. The knowledge they have accumulated in the course of serving communities provides the basis on which new approaches can be developed. The old title "Pediatric Public Health Nurse Practitioner" signifies most keenly the mission of the profession in child health care.

Child↗

Erythropoietin treatment in peritoneal dialysis patients.

The availability of recombinant EPO has greatly improved the lives of patients with end-stage renal disease. Knowledge is still accumulating regarding the use and effects of EPO in patients on PD, and several critical questions remain to be answered: 1. At what hematocrit level and when in the predialysis or dialysis course should EPO be started in PD patients? Recent studies by Golper suggest that the concomitant initiation of EPO and PD results in an increased hematocrit response compared to starting EPO after PD has been initiated for some time (63). 2. What is the best route of administration of EPO in PD patients? It is apparent that i.v., SC, and IP EPO can be effective in this population if utilized properly. The goal should be to tailor the route to the needs of the patient. Perhaps the daily SC route, for example, might be best for minimizing hypertension because of the slow, steady rise of hematocrit, while the IP route would be best tolerated by children (33,64). 3. What should the target hematocrit level be? This may vary depending on which organ function is being assessed. For the whole patient data are not currently available on appropriate hematocrit targets to maximize oxygen utilization, but near normal levels have recently been reported to be safe and beneficial (65-67). 4. What are the end-organ effects of anemia and its correction in PD patients? There is a dearth of information in this area for PD as well as HD patients. Additional research of this kind will increase our understanding of the pathophysiology of anemia as well as uremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗

[Health promotion. Planning process of health promotion programs for individuals with arthritis].

Based on the health conception viewed from the literature on nursing and by the clients, health is defined as a living experience, or as a perception of wellness in this study. That is, it is the perceived wellness that the individual obtains by wholistically integrating all dimensions of health where ever the individual stands in the health continuum. Thus health exists independently, regardless of illness or disability, because the individual is able to perceive the wellness within limitations imposed to him/her. Also, based on the health conception defined in this study and the literature review on health promotion, health promotion is defined as the process of enhancing the perception of wellness (i.e., living experience), where ever the individual stands in the health continuum. Therefore, health promotive care represents the process of making client help himself to improve health experience/perception of wellness by selecting and/or integrating the individual or social health parameters (determinants) based on his reality. After analyzing the data which is provided from the related literature and the results from the descriptive/exploratory research on this group of clients, and then applying those analysis results to the PRECEDE model, planning process for health promotion program is established. However, as planning process is only based on data from literature in the first stage, it will be modified appropriately according to the assessment feedback from the direct participation of client in the following study. Based on the planning model refined through this assessment process, health promotion program is to be developed, implemented and evaluated. Planning process of health promotion for clients with arthritis is begun from the assessment of health outcome as the first phase. It is analyzed from this study that clients with arthritis indicates lower quality of life/satisfaction than the other groups from the several research findings indicate. In the second phase, according to the analysis results in the first phase, clients' health problems (perceived seriousness about illness, uncertainty in illness, helplessness, difficulty of movement), which affect the low quality of life, are identified and then program objective for each problem is demonstrated. As an objective for the perceived seriousness about illness, relief of the mistrust on the general effects of treatment for illness is determined through appropriate data analysis. And clients' accumulation of accurate knowledge on the nature of illness is determined as an objective, for reducing uncertainty in the illness. Also enhancement of distraction ability and self-efficacy perception is defined as objectives for reducing physical, psychological and social helplessness.(ABSTRACT TRUNCATED AT 400 WORDS)

Arthritis↗

Genetic abnormalities and reproductive failure.

Adequate male development and spermatogenesis involve a complex array of events, all prescribed by numerous gene products in an orderly temporal and spatial sequence. A single defect in any portion of these myriad steps may lead to total failure of testicular development or simply subtle spermatogenic deficiency. As emphasis continues to be placed upon elucidation of the molecular and genetic basis underlying clinical and phenotypic human failings, knowledge will slowly accumulate to explain these failings and, it is hoped, to suggest treatment strategies for some.

Abnormalities, Multiple↗

Molecular aspects and mechanism of action of dihydrofolate reductase inhibitors.

Derivatives of tetrahydrofolate (FH4) are involved in a variety of biosynthetic reactions. Inhibition of the enzyme dihydrofolate reductase (DHFR) depletes the available tetrahydrofolate and blocks the formation of thymidylate, purines, the amino acids methionine and glycine, and several other cell constituents. Lack of thymidylate disrupts DNA synthesis and cell growth ceases. Many folate analogues are competitive inhibitors of DHFR, and while some classes show no selectivity, suitably substituted diaminopyrimidines are several thousands times more active against bacterial than mammalian DHFR and are thus effective and safe antibiotics. The ease of isolation, stability and low molecular weight of DHFR has facilitated its study at a molecular level. Considerable knowledge has been accumulated about the interactions of inhibitors with the protein chain in and around the active site, but despite the availability of many sequences and several crystal structures the exact details of how subtle variations of inhibitor structure result in such large differences in affinity for the enzyme are not yet clear.

Amino Acid Sequence↗

Adjuvant therapy for colon adenocarcinoma: current status of clinical investigation.

Colorectal cancer is one of the leading causes of death in western countries. The prognosis is strongly correlated to the TNM-staging system and patients with stage T3-4 and/or N positive disease have a high risk for local or distant relapse. It is now widely accepted that patients with stage III disease should be offered postoperative adjuvant chemotherapy with 5-fluorouracil (5-FU) and levamisole by which cancer related death is reduced by 32%. The use of 5-FU plus folinic acid is based on the experience gathered in metastatic disease where its superiority over 5-FU alone has been proven in randomized trials. In the adjuvant setting, however, this regimen has only been studied in comparison to untreated controls of combined stage II and stage III patients. Due to different patient selection criteria, data are currently not directly comparable to standard 5-FU/levamisole and the results of the intergroup trial 0089 have to mature. Regional short term adjuvant treatment (7 days) seems to be as effective as long term systemic therapy (12 months). Knowledge has been accumulated within at least 8 randomized trials and the NSABP-CO2 trial, with more than 1000 patients, is now demonstrating improved survival with regional therapy applied shortly after curative resection. The EORTC has just started to randomize patients to receive systemic vs. regional therapy or both modalities and will hopefully clarify the role of either strategy. Immunotherapy with autologous tumor cell-BCG or monoclonal antibody treatment also improves patients survival and is currently investigated in randomized comparison to standard 5-FU/levamisole.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

Cerebral circulation in the elderly.

A great deal of knowledge has been accumulated in recent years, concerning the aging human brain in health and disease, with the advent of newer methods of measuring cerebral blood flow (CBF) and metabolism. It is well documented that even in normal aging, the functional metabolism of the brain and its blood supply inevitably decline. This accounts for the widespread clinical observations that the young tolerate disorders of the brain better than do the elderly. It also accounts for difficulties in correctly diagnosing and treating cognitive disorders among the elderly. Neuronal and vascular reserves become progressively depleted during normal aging, so that one or more different disease processes may contribute to cognitive declines. Computed tomography (CT) densitometry, coupled with xenon-enhanced CT CBF measurements, provide a noninvasive method for separating the changes within cerebral cortex, subcortex, and white matter that occur in normal aging from those due to pathological abnormalities.

Aged↗

Dental disease, caries related microflora and salivary IgA of children with severe congenital cardiac disease: an epidemiological and oral microbial survey.

The objectives were to determine levels of dental caries, plaque accumulation, gingival inflammation, knowledge of dental health practices, and oral bacterial loading of S. mutans, Lactobacillus sp., Candida sp., and salivary IgA in the mouths of children afflicted with severe congenital heart disease. A total of 60 children from the cardiac units of the Hospital for Sick Children and Guys Hospital Paediatric Department were compared with 60 case-matched control children from the Department of Orthodontics and Paediatric Dentistry, UMDS (Guys Dental School), London. Using the methodology of the World Health Organization, the decayed, missing and filled surfaces and teeth of primary (dmft) and permanent (DMFT) were compared. There were similar levels of caries in the cardiac (dmft 3.9 and DMFT 2.7) and the control (dmft 3.7 and DMFT 2.0). A significant difference was the proportion of untreated carious lesions in the cardiac group (52%) compared to the control group (32%; P < 0.001). Standard oral microbiological techniques were used to isolate S. mutans, Lactobacillus sp., Candida sp., and conventional methods for estimating salivary IgA. There was no difference between the cardiac and the control group. Children with severe congenital cardiac disease have moderately high levels of dental caries with a significantly greater amount of untreated disease. The high bacterial loading associated with high levels of bacterial dental plaque and gingivitis may put cardiac patients at unnecessary risk of developing bacterial endocarditis.

Adolescent↗

Cerebrovascular reactivity: role of endothelium/platelet/leukocyte interactions.

In the last two decades, a tremendous amount of knowledge has been accumulated in various fields of biomedical research that discloses mechanisms of platelet/leukocyte/endothelium interactions. Occupying a strategically important location between circulating blood and underlying tissues, the endothelium effectively modulates both the functional state of the blood cells and the tone of vascular smooth muscle by generating or metabolizing a host of humoral substances. Under normal conditions, the endothelium releases agents with predominantly vasodilator and antiaggregant/anticoagulant activity that prevent thrombotic and angiospastic disorders. However, a variety of pathophysiological stimuli may trigger endothelial reorganization with the expression of different prothrombotic factors and activation of platelets and leukocytes that, combined, leads to blood cell adhesion to the endothelial monolayer, aggregation as thrombi, and the formation of numerous spasmogenic substances. Activation of the blood cells in the vicinity of the endothelium may induce endothelial dysfunction/injury, resulting in impairment of normal endothelial antispasmodic control. Within the microcirculatory bed, intravascular activation of the blood cells leads to scattered microvessel plugging, increased vascular permeability, edema formation, and cytotoxic actions of blood cell-released agents on the underlying tissue. A growing body of evidence suggests that these processes may be involved in pathophysiological cerebrovascular reactions including symptomatic angiospasm following subarachnoid hemorrhage, segmental occlusive constriction in atherosclerotic cerebral arteries, and constrictive vasomotion in microvessels. A perturbation in the delicate equilibrium between blood cells and endothelium in the microcirculation seems to be a factor aggravating ischemic brain damage or even primarily causing focal cerebral ischemia and scattered microinfarctions. Increased predisposition to these pathophysiologic events might influence unfavorably the effects of risk factors such as hypercholesterolemia, hypertension, and diabetes on cerebrovascular morbidity and mortality. Although the importance of blood cell/endothelium imbalance appears to be clear, its pharmacologic regulation is not sufficiently established. Some drugs have been demonstrated to limit platelet and/or leukocyte activity and protect the endothelial defense mechanisms, but the optimal therapeutic strategy has yet to be elaborated.

Animals↗

MR imaging of normal variants and interpretation pitfalls of the elbow.

Discrimination of normal anatomic landmarks from true disease is one of the fundamental tenets of adept MR imaging. The radiologist is thus compelled to accumulate a comprehensive knowledge of normal structures, variants, and potential MR imaging interpretation pitfalls. In this article the authors focus on a number of normal, bony, ligamentous, and tendinous structures that can simulate disease at the elbow. A discussion of the particular anatomy responsible for the appearance of each of these interpretation pitfalls is provided. In addition, ways to distinguish these pitfalls from true elbow disease are discussed.

Diagnosis, Differential↗