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PubMed1996

Genetic screening for colorectal cancer and intervention.

There is a complex interaction between environmental/dietary factors and genetics underlying the pathogenesis of colon carcinogenesis. Little data exist concerning the impact of diet on the phenotypic expression of genetically linked colon cancer. As a result, it has been difficult to develop rationally designed dietary intervention studies in first-degree relatives of patients with established familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and other familial colon cancer syndromes. Only 2 double-blinded, placebo-controlled trials have been published concerning the use of preventive strategies in patients with genetically inherited colorectal cancer syndromes, both in patients with FAP. One study evaluated the effects of vitamin C plus vitamin E with or without a high-dose wheat bran fiber supplement on the recurrence of rectal adenomas. Over a 48-month intervention period, only the wheat bran fiber intervention significantly reduced polyp growth. A second study reported that intervention with the NSAID sulindac for 9 months in young patients with FAP resulted in a significant reduction in both polyp number and size in the rectosigmoid colon. All of the large-scale (i.e., >500 randomized participants) phase III nutrient or chemopreventive agent intervention studies thus far have targeted participants with a history of non-familial, sporadic colorectal adenomas. Current clinical adenoma trials do not measure whether the regimen being tested can prevent genotoxic events occurring in early stages of abnormal cell development that contribute to the eventual formation of adenomas nor whether the agent(s) can inhibit events occurring during the progression of adenomas to carcinomas. Therefore, future clinical trial designs may have to consider (i) lengthening the clinical trial period before adenomas develop, (ii) testing at early patient ages and/or (iii) measuring the growth of adenomas as they progress to carcinomas.

Clinical Trials as Topic↗

PubMed1991

Vector population responses to control interventions.

In 1981, Kenyan authorities attempted eradication of tsetse (Glossina pallidipes) from the Lambwe valley, by sequential aerial spraying of endosulfan. Fly populations were reduced by over 99.9% in the main habitats, but recovered to their original levels within one year. In 1986, an Argentine research team attempted local elimination of domestic Triatominae (Triatoma infestans) in an area of Santiago del Estero. House infestation rates were reduced to an apparent zero, but recovered to pre-control levels in two years. In Sri Lanka, a combination of mosquito control with active case detection and treatment reduced malaria incidence to just 17 cases in 1964. Interruption of the programme then saw case incidence return to over 500,000 by 1969. These three examples-from African trypanosomiasis, South American Chagas disease and malaria-all illustrate the same process. Vector populations, infestation rates, and rates of disease transmission, can be reduced. The real problem is not in achieving the initial reduction, but in subsequently either driving the disease to extinction or maintaining it below acceptable levels. And this problem takes us beyond the simple analysis of interventions, into the complex realms of population behaviour set in its political, social and economic context. It seems that we have been too rarely concerned to plan and implement the long term surveillance and selective interventions that are required to translate initial gains into real success. In biological terms, we tend to ignore the complexity and robustness of vector populations and disease transmission cycles, especially their varied capacity to recover from interference. Moreover, in socio-political terms, a reduced problem-even one representing potential for future catastrophe-tends to claim less priority than present problems, even though premature redeployment of resources may abnegate gains already achieved. The problem is strongly compounded by methods of economic analysis where the benefits of avoiding future problems are strongly discounted in favour of short-term temporary gains. This paper seeks to open discussion on these long-term planning issues.

Animals↗

PubMed1990

Poverty and early childhood parenting: toward a framework for intervention.

The relationship between poverty and child rearing has been a persistent source of social concern in the United States. Drawing on available literature, this paper seeks to establish a conceptual approach to the interaction of these two complex variables. Appropriate interventions and strategies for their implementation are considered.

Child↗

PubMed1995

Effect of cholesterol lowering on intravascular pools of TFPI and its anticoagulant potential in type II hyperlipoproteinemia.

Tissue factor pathway inhibitor (TFPI) inhibits the extrinsic coagulation system. A major pool of TFPI is associated with the vascular endothelium and can be mobilized into the circulation by heparin. In circulating blood, TFPI is mainly associated with LDL (80%), whereas 10% to 20% is carrier free. In this study, heparin administration caused a 2.2-fold and a 7.5-fold increase in TFPI activity and TFPI antigen, respectively, in 25 patients with phenotypes IIa and IIb hyperbetalipoproteinemia. Because the antigen determination of TFPI almost exclusively measures carrier-free TFPI, more than 90% of the heparin-induced increase in TFPI activity was caused by mobilization of carrier-free TFPI from the vascular endothelium. Therapeutic lowering of total cholesterol (a decrease of 31.1 +/- 11.6%, P < .001) by 40 mg/d lovastatin in 17 patients with hyperbetalipoproteinemia was accompanied by a parallel decrease in TFPI activity (of 27.7 +/- 24.2%, P < .001) because of a reduction in LDL-TFPI complexes. However, drug intervention did not affect carrier-free TFPI or the magnitude of the vascular pool of TFPI that could be mobilized into the circulation by heparin. Moreover, this reduction of LDL-TFPI complexes did not reduce the anticoagulant potency of TFPI in plasma or of the vascular endothelial pool. The results of this study may imply that the anticoagulant potency of TFPI is associated with its carrier-free form in plasma or on the endothelium and that downregulation of LDL affects neither the size nor the anticoagulant potency of the endothelial pool of TFPI.

Adult↗

PubMed1982

A data-based approach to assessing clinical interventions in the setting of chronic disease.

Accurately assessing the effect of a clinical intervention is a complex task based on observing patients and their outcomes. Two strategies, the randomized trial and the observational data bank, represent different approaches toward detecting an outcome gradient across treatments. The observational data base is rooted on prospective data collected on an unselected group of patients with continuous surveillance of outcome events. As such, this approach captures a broad spectrum of patients within which prognostically important factors can be identified. In addition, the ongoing nature of the observational approach provides a means for capturing the dynamics of the disease process as well as the dynamics of the surrounding technology. These factors are particularly useful in the study of chronic illness where time frames of years to decades are encountered. In assessing treatment effects, both the randomized trial and the observational data base are subject to inferential errors due to multiple comparisons. In this paper, we describe some of the complexity associated with the study of chronic illness and demonstrate the multiple comparison problem. We have found multivariate models helpful in attenuating multiple comparison problems, but it still seems that independent confirmatory studies are required to establish confidence in a questionable intervention.

Analysis of Variance↗

PubMed1993

Diarrhoeal disease: current concepts and future challenges. Water, sanitation and diarrhoea: the limits of understanding.

This paper reviews the application of epidemiological understanding of diarrhoeal disease to interventions in water and sanitation. Over the past 20 years, great efforts have been made to elucidate the relationships between water supply, sanitation and diarrhoeal disease. At the outset, it was hoped that improved understanding of these relations could provide a rational framework for the planning of public health engineering interventions. This paper also reviews historical and recent perceptions of water, sanitation, and diarrhoeal disease, and summarizes progress to date. On the one hand, some fundamental ideas about the relative importance of water quality and quantity in the transmission of diarrhoeal disease have changed, and there is increased recognition of the complex interrelationships between interventions, hygiene behaviour and health. On the other hand, our understanding of the impact of interventions is painfully incomplete, and is unlikely to improve dramatically in the near future. While further research can usefully illustrate a variety of interactions in specific contexts, globally applicable planning guidelines and design criteria appear a dangerous will-o'-the-wisp. While we know more than ever before about water, sanitation and diarrhoea, much remains unknown, and is perhaps unknowable.

Child↗

PubMed1988

Management of ventricular arrhythmias.

Left ventricular dysfunction and complex VPCs are independent risk factors for subsequent cardiac death in patients with ischemic or nonischemic heart disease. The use of antiarrhythmic drugs during acute myocardial infarction is discussed. Patients with complex VPCs associated with heart disease should be treated with antiarrhythmic drugs. Drug efficacy should be evaluated by a 24-hour ambulatory ECG recording and by a treadmill exercise stress test. Blood drug levels should be measured at appropriate times. Maintenance doses of the various antiarrhythmic drugs are listed. Electrophysiologic testing with induction of ventricular tachycardia by extrastimulation may predict the clinical efficacy of the antiarrhythmic drug or combination of drugs needed for the long-term treatment of ventricular tachyarrhythmias. Electrophysiologic testing must be used for selecting antiarrhythmic drugs in patients who have experienced sustained ventricular tachycardia or ventricular fibrillation but who are free of VPCs during ambulatory ECG monitoring and exercise stress testing. If patients have life-threatening ventricular tachycardia or fibrillation resistant to antiarrhythmic drugs, surgical intervention is indicated. Complex VPCs in asymptomatic patients without heart disease should not be treated with antiarrhythmic drugs.

Anti-Arrhythmia Agents↗

PubMedDate not supplied

[Australia antigen in rheumatoid arthritis].

Australian antigen (Au Ag) was first described by Blumberg in the serum of an Australian aborigen. Its main clinical significance is based on the fact of its association with the presence of hepatitis B (Okochi, Nurakami, 1968; Prince, 1968) (9). Almeida (1969) outlines the intervention of immune complexes on the production of the referred illness. Later works show the importance of the type of immunologic response created by Au Ag (2). Alpert et al. (1) (1970) state the possibility that immune complexes developed by Au Ag and anti Au Ag antibodies may produce in patients with hepatitis B other allied manifestations including arthritis. On the basis of similar immunopathological findings (illnesses including immunocomplexes on their production), Au Ag investigation in rheumatoid arthritis (RA) has been the object of several works, whose results reveal certain discrepancies. We have investigated the presence of Au Ag on 70 patients whose diagnostic was RA "classical (according to the judgement of the American Rheumatism Association). We used immunoelectrophoresis (counter immunoelectrophoresis-CIEP-) and radioimmunoassay (RIA) techniques. We prepared individual records including clinical, epidemic, biochemical and personal data. Au Ag investigation both through different techniques gave negative results in 70 cases, of which only four referred a possible previous hepatitis B clinic history, not showing during the investigation suggestive clinical data of hepatitis or biochemical alterations. Panus et al. (1970) (5), Desche-Labarte et al. (1972), Trempo (1972), Burrel (1973) (6), Serré et al. (1973) (8), obtained negative results in the matter, with similar or lower casuistics than ours. Notwithstanding Roqués et al. (1975) (7), in 300 cases of RA showed the presence of Au Ag in a significant number of cases (5%) as compared to Au Ag incidence in the French population (estimated in about 0.22%) (6). However, Roqués did not find in their Au Ag positive cases any evidence which enables to think that this antigen has played an important role on the origin and development of the rheumatic illness. These important discrepancies may be due to different reasons: a) Use of different techniques for Au Ag detection. b) The transitory character of the presence of Au Ag in the serum. c) Important differences in the antigen geographic distribution. d) Previous hepatitis B. There are som other factors which have attained importance recently, as a consequence of the broad epidemiological studies carried out. So, Au Ag increased incidence has been found--statistically significant--on groups of persons who have been submitted to several surgical interventions and/or have needed repeated hospitalizations or reiterated blood transfusions (6). These three conditions--especially the first two--are accomplished in an illness with chronic and invalidating characteristics as RA...

Arthritis, Rheumatoid↗

PubMed1993

Dietary strategies for cancer prevention.

BACKGROUND: Two-thirds of cancer cases are associated with two lifestyle practices: 35% with the typical American diet, and 30% with tobacco use. In contrast to the field of tobacco control, research and resources dedicated to the field of nutrition have been limited, in part because dietary change has been considered controversial and requires a more complex set of interventions. METHODS: This series of papers reviews the science base underlying diet as a cancer control strategy, including research about diet-cancer relationships, current nutrition policy recommendations, American dietary trends, models of dietary behavior change, and diet in health care delivery. The history of technology transfer of new knowledge into widespread application will be compared and contrasted with other cancer control measures. RESULTS: There is scientific and policy agreement about three priority dietary goals for the year 2000: increase fruit and vegetable consumption to 5 or more servings every day, increase breads, cereals, and legumes to 6 or more servings daily, and decrease fat to no more than 30% of total calories. Current data do not indicate that these goals will be reached. As yet there is no organized effort, with clearly identified steps, to translate research into practice. The parallel with delays in implementing other cancer control measures, including Papanicolaou testing, mammography, and tobacco intervention, is striking. CONCLUSION: Without resources dedicated to dietary modification in the general population, it is not likely that the potential savings of more than 300,000 new cases, 160,000 deaths, and the $25 billion in associated costs will be realized in the foreseeable future.

American Cancer Society↗

PubMedDate not supplied

Diagnostic laparoscopy in the intensive care patient. Avoiding the nontherapeutic laparotomy.

Evaluation of a potential acute abdomen in patients who require intensive care for concurrent medical/surgical problems is often difficult due to ambiguities in the physical exam and ancillary diagnostic tests. Between August 1990, and February 1992, 25 ICU patients underwent diagnostic laparoscopy to evaluate a suspected acute intraabdominal process. Thirteen laparoscopies were negative, and 12 were positive. The overall accuracy for laparoscopy was 96% as confirmed by subsequent laparotomy, autopsy, or clinical course. Laparoscopic findings led to a change in management in nine patients (36%), leading to earlier exploration in four patients, and avoidance of laparotomy in five. No significant hemodynamic effects were noted during laparoscopy, and the procedure-related morbidity was low (8.0%). Diagnostic laparoscopy is a safe and accurate guide for managing the ICU patient with a suspected acute surgical abdomen. The use of laparoscopy can help avoid nontherapeutic laparotomy or confirm the need for operative intervention in these complex cases.

Abdomen, Acute↗

PubMed1990

Current techniques for infrainguinal arterial reconstruction.

Infrainguinal reconstruction for peripheral vascular occlusive disease comprises an increasingly complex array of interventions which provide unparalleled options for the salvage of threatened limbs. Conventional autogenous saphenous vein bypass remains the most durable revascularization with anticipated graft patency rates approaching 80 percent after five years and excellent long term limb salvage. These excellent results are equally applicable to vein grafts carried to infrapopliteal and even inframalleolar levels, possibly reflecting increased utilization of the in situ method. Although 20 per cent of grafts fail within five years, secondary intervention results in sustained limb salvage in the majority of patients. In the absence of autogenous vein, however, prosthetic material performs poorly such that new interventions consisting of percutaneous transluminal angioplasty, rotary atherectomy devices and laser systems are under aggressive development. Although initial results with these devices are encouraging, long term patency rates remain poor largely due to restenosis. Further progress seems to depend primarily on an increased understanding of the natural healing response of the injured artery.

Angioplasty, Laser↗

PubMedDate not supplied

Mismatch of coronary risk and treatment intensity under the National Cholesterol Education Program guidelines.

OBJECTIVE: To assess the match between multifactorial risk of coronary heart disease (CHD) and treatment intensity under the National Cholesterol Education Program (NCEP) guidelines for primary prevention of CHD. METHODS: The multiple logistic regression equation from the Framingham Study was used to derive predicted risks for development of CHD over eight years of follow-up for different age-gender groupings, with serum total cholesterol (TC) values chosen in light of the NCEP cutoff points for both TC and low-density-lipoprotein cholesterol levels. Additional risk factors--hypertension, glucose intolerance, and smoking--were considered in combination for each of these values. RESULTS: Controlling for the effects of age and gender, there is little difference in the ranges of absolute CHD risks for persons who would receive interventions of differing intensities (i.e., general dietary advice, dietary treatment, or drug therapy). Those who are candidates for drug treatment because of serum lipids alone are often at low levels of risk for the development of CHD when compared with those of the same age with lower TC values who have other risk factors. Discrepancies in CHD risk are wider still when age is also allowed to vary. Furthermore, in every age grouping, women with high TC levels (e.g., 6.9 mmol/L) and two other risk factors are eligible for drug treatment but have a CHD risk that is no higher, and often much lower, than that of males with one other risk factor and TC levels of 4.8 mmol/L or 5.7 mmol/L who are candidates for dietary advice or dietary therapy, respectively. CONCLUSIONS: Inconsistencies exist in the NCEP guidelines such that persons at low risk for the development of CHD are offered more intensive interventions than are other who actually are at much higher risks, and vice versa. Women in particular tend to be overtreated, relative to men. These findings point out the difficulties of promulgating guidelines that will appropriately match risk to preventive interventions in a complex multifactorial disease.

Adult↗

PubMed1991

Automated real-time data acquisition and analysis of cardiorespiratory function.

Microcomputer generation of an automated record without complexity or operator intervention is desirable in many circumstances. We developed a microcomputer system specifically designed for simplified automated collection of cardiorespiratory data in research and clinical environments. We tested the system during possible extreme clinical conditions by comparison with a patient simulator. Ranges used were heart rate of 35-182 beats per minute, systemic blood pressures of 65-147 mmHg and venous blood pressures of 14-37 mmHg, all with superimposed respiratory variation of 0-24 mmHg. We also tested multiple electrocardiographic dysrhythmias. The results showed that there were no clinically relevant differences in vascular pressures, heart rate, and other variables between computer processed and simulator values. Manually and computer recorded physiological variables were compared to simulator values and the results show that computer values were more accurate. The system was used routinely in 21 animal research experiments over a 4 month period employing a total of 270 collection periods. The file system integrity was tested and found to be satisfactory, even during power failures. Unlike other data collection systems this one (1) requires little or no operator intervention and training, (2) has been rigorously tested for accuracy using a wide variety of extreme patient conditions, (3) has had computer derived values measured against a standardized reference, (4) is reliable against external sources of computer failure, and (5) has screen and printout presentations with quick and easily understandable formats.

Computer Systems↗

PubMedDate not supplied

The intracellular equilibrium thermodynamic and steady-state concentrations of metabolites.

A new model for the organization and flow of metabolites through a metabolic pathway is presented. The model is based on four major findings. (1) The intracellular concentrations of enzyme sites exceed the concentrations of intermediary metabolites that bind specifically to these sites. (2) The concentration of the excessive enzyme sites in the cell is sufficiently high so that nearly all the cellular intermediary metabolites are enzyme-bound. (3) Enzyme conformations are perturbed by the interactions with substrates and products; the conformations of enzyme-substrate and enzyme-product complexes are different. (4) Two enzymes, catalyzing reactions that are sequential in a metabolic pathway, transfer the common metabolite back and forth via an enzyme-enzyme complex without the intervention of the solvent environment. The model proposes that the enzyme-enzyme recognition is ligand-induced. Conversion of E2S and E2P results in the loss of recognition of E2 by E1 and the concomitant recognition of E2 by E3. This model substantially alters existent views of the bioenergetics and the kinetics of intracellular metabolism. The rates of direct transfer of metabolite from enzyme to enzyme are comparable to the rates of interconversion between substrate and product within an individual enzyme. Consequently, intermediary metabolites are nearly equipartitioned among their high-affinity enzyme sites within a metabolic pathway. Metabolic flux involves the direct transfer of metabolite from enzyme to enzyme via a set of low and nearly equal energy barriers.

Biological Evolution↗

PubMedDate not supplied

Management of anticipated and actual shoulder dystocia. Interpreting the literature.

Shoulder dystocia is a rare but serious obstetric complication that can result in significant neonatal and maternal morbidity and in costly litigation. Conflict exists in the literature regarding definition, incidence, predictability and preventability, relationship to neonatal injury, and appropriate management models. Anticipatory clinical interventions for potential shoulder dystocia have included ultrasound assessment of macrosomia; elective induction of labor; elective caesarean section; altered place of birth; and generous episiotomy/episioproctotomy. The authors note that these interventions often conflict with client desires and nurse-midwifery philosophy of birth, generate significant risks and costs in themselves, and do not address the poor predictability of shoulder dystocia. In recent literature, the safety and efficacy of maternal position change maneuvers (such as McRoberts maneuver, hands-knees position, and squatting) have been presented as methods to resolve most cases of shoulder dystocia. Despite the success of these more benign, external maneuvers, the episiotomy mandate remains in nearly all obstetric and midwifery texts and handbooks (1-8) and journal references (9-19). A literature review of related professional disciplines was undertaken to study these conflicts and to identify support for applying a philosophy of minimal, appropriate intervention to the complex issue of shoulder dystocia.

Delivery, Obstetric↗

PubMed2026

High-Fat Diet and a High Amyloid Load Interact to Induce PKC-α Dependent Synaptic Insulin Resistance.

A plethora of studies suggest that a high-fat diet in combination with a high amyloid load causes synaptic insulin resistance and is a risk factor for Alzheimer's disease. Our understanding of the underlying mechanisms is still fragmented. To gain new insights, we conducted integrated proteomic and phosphoproteomic profiling of hippocampal synaptosomes from WT and a transgenic mouse line with a high amyloid load (heterozygous TBA2.1 mice) that show no overt signs of neurodegeneration and dementia. Mice were fed with a regular or high-fat diet. Data-independent acquisition quantified over 5400 proteins, revealing a stable synaptic proteome across conditions. However, the combination of high amyloid load and high-fat diet triggered coordinated remodeling of lipid metabolism pathways, particularly mitochondrial and peroxisomal fatty acid catabolism. Phosphoproteomic analysis showed pronounced activation of lipid- and stress-responsive kinases, including protein kinase C-α, along with increased inhibitory phosphorylation of insulin receptor substrates (IRS1/2). In vitro experiments indicate that blocking protein kinase C-α indeed prevents synaptic insulin resistance in primary neurons. The findings suggest that this proteomic workflow, combined with kinase pathway analysis, can reveal nodal points for interventions in a complex disease state with a trajectory to Alzheimer's disease.

Animals↗

PubMedDate not supplied

[Pharmacological and molecular aspects of the regulation of eating behavior. With special reference to the role of catecholamines and effects of amphetamine].

Among the numerous endogenous substances involved in the regulation of feeding behaviours, the catecholamines are in the front rank. The numerous studies devoted to this aspect of catecholamines emphasize the importance and complexity of their intervention. Depending on the cerebral structures on which they act and on whether noradrenaline or dopamine are concerned, orexigenic or anorexigenic effects have been described. Alpha-2 and beta adrenergic receptors as well as D1 and D2 dopaminergic receptors participate in these effects. Amphetamine, which is an indirect catecholaminergic agonist, mobilizes neuronal catecholamines and fosters their various effects. Moreover, it exercises direct effects by its association with sites borne by glycaemia-sensitive neurons. This target seems to be common to a wide variety of anorectic agents. They are thought to reproduce on this hypothalamic "glucostat" the effect of a high blood glucose level, thus triggering off signals of satiety. In this unifying hypothesis, the diverse pharmacological profiles these agents are known to possess would result from associated properties.

Amphetamine↗

PubMed1992

Trust, control strategies and allocation of function in human-machine systems.

As automated controllers supplant human intervention in controlling complex systems, the operators' role often changes from that of an active controller to that of a supervisory controller. Acting as supervisors, operators can choose between automatic and manual control. Improperly allocating function between automatic and manual control can have negative consequences for the performance of a system. Previous research suggests that the decision to perform the job manually or automatically depends, in part, upon the trust the operators invest in the automatic controllers. This paper reports an experiment to characterize the changes in operators' trust during an interaction with a semi-automatic pasteurization plant, and investigates the relationship between changes in operators' control strategies and trust. A regression model identifies the causes of changes in trust, and a 'trust transfer function' is developed using time series analysis to describe the dynamics of trust. Based on a detailed analysis of operators' strategies in response to system faults we suggest a model for the choice between manual and automatic control, based on trust in automatic controllers and self-confidence in the ability to control the system manually.

Adult↗