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New approaches for antigen discovery, production and delivery: vaccines for veterinary and human use.

Vaccination of individuals has been practiced for many years and has been one of the most effective methods of controlling infectious diseases. Unfortunately, even with this success, society continues to suffer multi-billion dollar economic losses annually due to infectious diseases. These losses occur in all animal species as well as in humans. In order to further reduce these losses, academicians and companies are employing the multidisciplinary approach to develop better and safer vaccines. These include capitalizing on advances in molecular biology, chemistry, pharmacy, immunology, genomics, proteomics, and fermentation. Thus, we are moving from a more empirical approach to vaccine production to a more focused, and, hopefully, more logical approach to identification and production of protective antigens. Furthermore, formulation and delivery of these antigens in playing a major role in revolutionizing how we deliver vaccines to induce the most appropriate immune response and ensure protection. The current review summarizes some of these advances and speculates as to how future vaccines will be produced and delivered for the benefit of society.

Animals↗

Studies of clonogenic human tumor stem cells.

In vitro tissue culture methods for cloning human tumor cells from fresh biopsy samples appear to provide a simple yet quantitative approach to study the biology and chemosensitivity of neoplastic cells which are likely to be responsible for micrometastasis and tumor progression in vivo. Use of this assay technique may provide a useful empirical approach to improve adjuvant therapy of cancer.

Biopsy↗

Community heritability measures the evolutionary consequences of indirect genetic effects on community structure.

The evolutionary analysis of community organization is considered a major frontier in biology. Nevertheless, current explanations for community structure exclude the effects of genes and selection at levels above the individual. Here, we demonstrate a genetic basis for community structure, arising from the fitness consequences of genetic interactions among species (i.e., interspecific indirect genetic effects or IIGEs). Using simulated and natural communities of arthropods inhabiting North American cottonwoods (Populus), we show that when species comprising ecological communities are summarized using a multivariate statistical method, nonmetric multidimensional scaling (NMDS), the resulting univariate scores can be analyzed using standard techniques for estimating the heritability of quantitative traits. Our estimates of the broad-sense heritability of arthropod communities on known genotypes of cottonwood trees in common gardens explained 56-63% of the total variation in community phenotype. To justify and help interpret our empirical approach, we modeled synthetic communities in which the number, intensity, and fitness consequences of the genetic interactions among species comprising the community were explicitly known. Results from the model suggest that our empirical estimates of broad-sense community heritability arise from heritable variation in a host tree trait and the fitness consequences of IGEs that extend from tree trait to arthropods. When arthropod traits are heritable, interspecific IGEs cause species interactions to change, and community evolution occurs. Our results have implications for establishing the genetic foundations of communities and ecosystems.

Animals↗

A preliminary continental risk map for malaria mortality among African children.

Approaches to global public health are increasingly driven by an understanding of regional patterns of disease-specific mortality and disability. Current estimates of disease risks associated with Plasmodium falciparum in sub-Saharan Africa remain poorly defined. Through the integration of high-resolution population and climate probability models of P. falciparum transmission, geographical information systems have been used to define the spatial limits of populations exposed to the risk of infection in Africa. These estimates were combined with a range of annual malaria-specific mortality rates, derived from a variety of epidemiological approaches, among children aged 0-4 years. The best estimates of malaria-attributable mortality using this approach ranged between 0. 43 million and 0.68 million deaths per annum among an exposed population of approximately 66 million children in 1990. Despite the limitations of modelled transmission and population distributions, these empirical approaches to probabilities of infection risk and epidemiological data on mortality provide a novel approach to present and projected burdens of malaria mortality, as discussed here by Bob Snow, Marlies Craig, Uwe Deichmann and Dave le Sueur.

Africa South of the Sahara↗

Dose and outcome: the hurdle of neutropenia (Review).

The development of chemotherapy in the early 1970s resulted in the availability of curative therapeutic strategies for hematological malignancies and several types of solid tumors. It is evident that drugs should be used at their optimal dose and schedule, and drug combinations should be given at consistent intervals. According to the mathematical models that suggested the direct dose-response relationship in the improvement of outcomes in cancer chemotherapy, the dose intensity and, more recently, the dose-dense approach was considered one of the most important tools in conventional chemotherapy. Anticancer drugs are often associated with myelotoxicity, and reducing the dose or increasing the time interval between each cycle of treatment is a frequent empiric approach. Unfortunately, a dose reduction of >or=20% causes a loss of 50% in the cure rate, particularly in chemosensitive tumors. To accelerate bone marrow recovery and prevent the onset of severe myelosuppression and its complications, the standard use of granulocyte colony-stimulating factors (G-CSF), such as filgrastim and the long-acting pegfilgrastim, is recommended. The aim of this review is to analyze how dose intensification concepts and dose-dense regimens are able to increase the cure rate of chemosensitive solid tumors and lymphomas.

Antineoplastic Agents↗

A practical guideline for management of hypertension in patients with diabetes.

Hypertension is common in patients with non-insulin-dependent diabetes mellitus and is also an early sign of diabetic nephropathy in those with insulin-dependent diabetes. Hypertension contributes to the progression of both macrovascular disease and nephropathy in patients with diabetes. Certain antihypertensive agents can adversely affect carbohydrate and lipid metabolism. Angiotensin-converting enzyme inhibitors and calcium channel blockers may slow the progression of renal complications in patients with diabetes. The pharmacologic approaches to treatment of hypertension in patients with diabetes potentially differ from those in nondiabetic persons. On the basis of a review of the recent literature related to antihypertensive therapy for patients with diabetes, we describe an empiric approach to treatment of hypertension in such patients. The proposed approach must be modified as new data from randomized clinical trials become available.

Antihypertensive Agents↗

Treatment of bipolar depression: current status, continued challenges, and the STEP-BD approach.

Even though at least 10% (if not 20%) of those who experience a first lifetime episode of depression will subsequently develop bipolar disorder, the alliance of academic and industry research agendas that leads to developing and testing new antidepressants has failed to produce a sufficient knowledge base. It is therefore impossible to apply a truly empirical approach to guide the treatment of people with bipolar depression. Consequently, there are holes in contemporary evidenced-based practice guidelines large enough to drive a truck through; furthermore, there are some recommendations that have no factual basis other than expert opinion. However, with new research emerging on lamotrigine and olanzapine, in addition to the pending results of larger studies supported by the National Institute of Mental Health and the Stanley Foundation, there is evidence that some progress is being made.

Antidepressive Agents↗

[Quality of the physician-patient pedagogic relationship in external consultation: the case of Oaxaca, Mexico ].

This research seeks to explore the quality of the pedagogical relationship physician-patient in primary care, in several health centers (A, B, C) depending from the Health Ministry (SSA) in the state of Oaxaca, Mexico. It is assumed that the out-patient clinic constitutes a setting for the educative transmission, and that the physician-patient encounter must result in an increase of the knowledge that the patient has on his body and his health, with the help of the former. It is assumed also that the physician not only seeks to elaborate a diagnosis and to solve the health problems, but also to contribute to the education of the patient on this matter. This research seeks to contribute to the reflection in this direction, from a perspective that explores the quality and the nature of the educative processes that there take place. In order to reach this goal, two levels of analysis have been established: the first one, a theoretic approach, which refers to the main aspects of the historic evolution of the medicine -key element that permits to understand the type of physician-patient relationship that it is established in out-patient clinic. The second one, an empirical approach, which seeks to characterize -by using indicators previously determined and through the implementation of the technic "shadow study" (direct observation)- the six tasks (identification, clinic history, exploration, diagnosis, medical treatment, and following) that give structure to the physician-patient relationship in out-patient clinic. This elements, indeed, are useful for defining the nature of the pedagogical relationship that is established between these two actors. This investigation was conducted with a sample of 168 patients and 17 physicians, distributed all of them in 9 localities. The results allow us to conclude that, in the majority of the cases, it does not exist a physician-patient relationship, but that it is possible to talk just of a physician-problem relationship. Due to this fact, it is not possible to find the health education of the individuals, as a basic input for the training of the population as co- responsible of his/her health-illness process.

Adolescent↗

Prediction of drug clearance in children from adults: a comparison of several allometric methods.

AIMS: In recent years with the advent of paediatric exclusivity and requirements to conduct clinical studies in children, the current emphasis is to find a safe and efficacious dose of a drug in children. It has been suggested that one can predict the clearance of a drug in children according to the equation: CL in the child=adult CLx(weight of the child/70)0.75. Considering the controversy surrounding the exponent of 0.75 for the prediction of clearance and lack of any systematic evaluation of the aforementioned proposal, the objectives of the study were as follows: (i) to determine if indeed the exponent 0.75 is the most suitable exponent for the prediction of clearance in children from adult data; (ii) to explore and search for other exponents that are more accurate or as good as 0.75; and (iii) to propose a new approach (if any) based on the findings of the current evaluation. METHODS: Six methods were used to predict clearance of drugs in children from adult data. Besides evaluating the exponent of 0.75, exponents of 0.80, 0.85 and 1.0 were also evaluated. An empirical approach based on kidney and liver weights was also examined. Based on the results of five methods, a sixth method was introduced. RESULTS: The results of the study indicate that no single method is suitable for all drugs or for all age groups. The exponents 0.75, 0.80, and 0.85 provided the same degree of accuracy or error in the prediction of clearance in children. CONCLUSIONS: Since no single method is suitable for all drugs or for all age groups. A combination of approaches is suggested which may help in improving the prediction of clearance in children from adult data.

Adult↗

Present studies of therapy for anaerobic infections.

Therapeutic approaches to anaerobic infections are changing. Debridement, drainage, and other surgical approaches remain extremely important. Resistance to antimicrobial agents currently used for treatment of anaerobic infections is increasing. However, promising new agents are being introduced. We review the current status of therapy for anaerobic infections and discuss the potential role of these new agents. We stress an empirical approach to therapy that is based on the usual infecting flora in various types of infections.

Anti-Bacterial Agents↗

Can we measure the social importance of health care?

This paper examines the extent to which it is possible to measure the social importance, or macro benefits, of health care. In contrast to the many micro studies of the benefits of specific health care interventions, methodology relating to such macro benefits is at a very rudimentary stage. A theoretical model is presented that seeks to capture the social consequences of a health care system. In light of this model, three existing empirical approaches to answering the question are examined: the inventory approach, the avoidable mortality approach, and the production function approach. All three have severe limitations in terms of the underlying theoretical model, data availability, and analytic tools employed. A more fruitful approach may be to investigate the value of undertaking a direct survey of citizens' attitudes toward their health care system.

Delivery of Health Care↗

Confounder selection in environmental epidemiology: assessment of health effects of prenatal mercury exposure.

PURPOSE: The purpose of the study is to compare different approaches to the identification of confounders needed for analyzing observational data. Whereas standard analysis usually is conducted as if the confounders were known a priori, selection uncertainty also must be taken into account. METHODS: Confounders were selected by using backward elimination (BE), change in estimate (CIE) method, Akaike information criterion, Bayesian information criterion (BIC), and an empirical approach using a priori information. A modified ridge regression estimator, which shrinks effects of confounders toward zero, also was considered. For each criterion, uncertainty in the estimated exposure effect was assessed by using bootstrap simulations for which confounders were selected in each sample. These methods were illustrated by using data for mercury neurotoxicity in Faroe Islands children. Point estimates and standard errors of mercury effects on confounder-sensitive neurobehavioral outcomes were calculated for each selection procedure. RESULTS: The full model and the empirical a priori model showed approximately the same precision, and these methods were (slightly) inferior to only modified ridge regression. Lower precisions were obtained by using BE with a low cutoff level, BIC, and CIE. CONCLUSIONS: Standard analysis ignores model selection uncertainty and is likely to yield overoptimistic inferences. Thus, the traditional BE procedure with p = 5% should be avoided. If data-dependent procedures are required for confounder identification, we recommend that inferences be based on bootstrap statistics to describe the selection process.

Animals↗

Transvenous and subcutaneous electrode system for an implantable defibrillator, improved on large pigs.

The currently required surgical procedure for implantable defibrillator implantation is a limiting factor and several groups are therefore investigating transvenous approaches. Our electrode system consists of a nondistal right ventricular catheter electrode and two or three subcutaneously (SC) placed electrodes. An optimal location for these SC electrodes is important to obtain the lowest possible defibrillation threshold (DFT) by allowing a more homogeneous current distribution within the thorax. An empirical approach consists of placing randomly the SC electrodes to find out the lowest possible DFT. A mathematical approach is to calculate the SC electrode locations for an optimal electric field distribution by using magnetic resonance images of thorax cross-sections and a specially designed computer program. Our recent experimental results are based on a series of 15 pigs weighing between 60 and 102 Kg. DFT ranged between 10 and 26 joules. We conclude that an electrode system with a right ventricular electrode and two or three subcutaneous electrodes can be optimized to reach a DFT for pigs with human-near body weights which is compatible with the energy capabilities of our implantable device.

Animals↗

Pharmacological treatment of vertigo.

This review discusses the physiology and pharmacological treatment of vertigo and related disorders. Classes of medications useful in the treatment of vertigo include anticholinergics, antihistamines, benzodiazepines, calcium channel antagonists and dopamine receptor antagonists. These medications often have multiple actions. They may modify the intensity of symptoms (e.g. vestibular suppressants) or they may affect the underlying disease process (e.g. calcium channel antagonists in the case of vestibular migraine). Most of these agents, particularly those that are sedating, also have a potential to modulate the rate of compensation for vestibular damage. This consideration has become more relevant in recent years, as vestibular rehabilitation physical therapy is now often recommended in an attempt to promote compensation. Accordingly, therapy of vertigo is optimised when the prescriber has detailed knowledge of the pharmacology of medications being administered as well as the precise actions being sought. There are four broad causes of vertigo, for which specific regimens of drug therapy can be tailored. Otological vertigo includes disorders of the inner ear such as Ménière's disease, vestibular neuritis, benign paroxysmal positional vertigo (BPPV) and bilateral vestibular paresis. In both Ménière's disease and vestibular neuritis, vestibular suppressants such as anticholinergics and benzodiazepines are used. In Ménière's disease, salt restriction and diuretics are used in an attempt to prevent flare-ups. In vestibular neuritis, only brief use of vestibular suppressants is now recommended. Drug treatments are not presently recommended for BPPV and bilateral vestibular paresis, but physical therapy treatment can be very useful in both. Central vertigo includes entities such as vertigo associated with migraine and certain strokes. Prophylactic agents (L-channel calcium channel antagonists, tricyclic antidepressants, beta-blockers) are the mainstay of treatment for migraine-associated vertigo. In individuals with stroke or other structural lesions of the brainstem or cerebellum, an eclectic approach incorporating trials of vestibular suppressants and physical therapy is recommended. Psychogenic vertigo occurs in association with disorders such as panic disorder, anxiety disorder and agoraphobia. Benzodiazepines are the most useful agents here. Undetermined and ill-defined causes of vertigo make up a large remainder of diagnoses. An empirical approach to these patients incorporating trials of medications of general utility, such as benzodiazepines, as well as trials of medication withdrawal when appropriate, physical therapy and psychiatric consultation is suggested.

Antiemetics↗

Occupational hygiene considerations in the development of a structured approach to select chemical control strategies.

This paper explains the occupational hygiene basis of a new scheme to help small firms control the health risks from supplied chemicals. The scheme groups hazard information and the potential for a material to become airborne into bands and, from this information, predicts the control strategy necessary to ensure that the hazardous substance is used safely. To do this a simple model based upon an empirical approach to risk assessment and risk management has been developed. This work was undertaken in a working group established by the Health and Safety Commission's Advisory Committee on Toxic Substances.

Air Pollutants, Occupational↗

[Behavior analytic approaches of research in psychiatry].

Biologically oriented psychiatric research usually relies more on abstract nosological concepts than on purely descriptive psychopathological syndromes. However, biological validation of psychiatric diagnoses has not been possible so far. More recent findings emphasize the nosological unspecificity, but syndromal specificity of biological data. It seems promising therefore to differentiate psychopathological descriptions more clearly by using objective methods of behavioural assessment and analysis. Concept, methods and examples of this empirical approach will be outlined.

Humans↗

Antiepileptic drug therapy: general treatment principles and application for special patient populations.

Over the past 10 years, the goal of treating epilepsy has evolved from attaining complete control of seizures, regardless of medication-related side effects or psychosocial problems, to enabling the patient to lead a lifestyle consistent with his or her capabilities. The recent introduction of new medications has brought hope to patients who have previously been unable to function optimally because of refractory seizures or side effects. A rational approach to selecting antiepileptic drug (AED) therapy for a particular patient would require a detailed understanding of the underlying cause(s) of seizures in that patient. Unfortunately, this is often not possible. Furthermore, currently available AEDs have been tested on the basis of seizure type rather than etiology. Nevertheless, an individualized empirical approach based on an open dialog with the patient and perseverance is often successful. There have also been significant advances in the understanding of seizures at the cellular level, notably in the role of gamma-aminobutyric acid. Medical, social, and psychosocial issues relevant to particular patient populations (such as women of childbearing age and elderly patients) also must be considered when treatment plans are formulated. The recent addition of new AEDs, with unique mechanisms of action and favorable pharmacokinetic and tolerability profiles, has greatly widened the range of therapeutic options for patients.

Adult↗

Implanted cardioverter-defibrillators are preferable to drugs as primary therapy in sustained ventricular tachyarrhythmias.

The choice of initial therapy for patients with malignant ventricular tachyarrhythmias is examined based on clinical efficacy, patient safety, and cost. Antiarrhythmic drug therapy can be administered using a guided or empiric approach. Guided type-1 antiarrhythmic drug therapy has been associated with high arrhythmia recurrence rates (> 40% at 1 year) and moderate sudden death rates (10% at 1 year). Sotalol is associated with lower arrhythmia recurrence rates (20% at 1 year) that increase to 50% at 4 years. Beta-blocking agents have a limited role as stand-alone therapy in this condition. Empiric amiodarone therapy has sudden death-free survival rates of 82% at 2 years but has significantly poorer results in patients with ejection fractions < or = 40%. In contrast, implantable cardioverter-defibrillator (ICD) therapy has reported sudden death recurrence rates of 1% to 2% per year, with a cumulative index of 10% at 5 years. Total survival rate of ICD recipients ranges from 85% to 92% at 2 years. In patients with good left ventricular function, it approaches 90% at 5 years, whereas it is between 50% to 60% in patients with severe left ventricular dysfunction. Data from device memory indicate an absolute reduction in mortality rates with ICD intervention. Comparison of drug and device therapy has been performed in retrospective and prospective studies. Improved survival with device therapy is noted, particularly in patients with ejection fractions < or = 35% to 40% in retrospective studies. The results of two small prospective randomized trials also show significant survival advantage as compared with those for type-1C drugs and a mixed group of antiarrhythmic drugs. An initial strategy of ICD therapy was shown to be superior in the Netherlands Cooperative Study. The 30-day perioperative mortality rate of ICD therapy of 0.8% contrasts favorably with a 13% mortality rate in the ESVEM trial with antiarrhythmic drugs and a 3.5% mortality rate in the CASCADE study. Economic analyses show that drug therapy and device therapy are both within the range of other current cardiovascular therapies. An improving economic profile for device therapy has been observed with nonthoracotomy and pectoral implantation and direct use of ICD therapy because primary therapy shortens hospital stay and reduces costs. Based on available data, ICD therapy is preferable as initial therapy in patients with malignant ventricular tachyarrhythmias.

Adrenergic beta-Antagonists↗