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Selectively infective phage (SIP) technology: scope and limitations.

We review here the selectively infective phage (SIP) technology, a powerful tool for the rapid selection of protein-ligand and peptide-ligand pairs with very high affinities. SIP is highly suitable for discriminating between molecules with subtle stability and folding differences. We discuss the preferred types of applications for this technology and some pitfalls inherent in the in vivo SIP method that have become apparent in its application with highly randomized libraries, as well as some precautions that should be taken in successfully applying this technology.

Bacteriophage M13↗

Conservative surgery for borderline ovarian tumors: a review.

OBJECTIVE: Borderline tumor of the ovary is an epithelial tumor with a low rate of growth and a low potential to invade or metastasize. This review will outline the most recent information regarding the molecular pathogenesis, pathology, fertility and tumor recurrence rate after conservative management of young women with early-stage borderline ovarian tumors. METHODS: We performed a MEDLINE literature search of relevant clinical trials for the scope of this review that evaluated conservative treatment of borderline ovarian tumors for young women with low-stage disease who wish to preserve their fertility. RESULTS: Recently, investigators have begun to identify subsets of patients with a worse prognosis, such as patients with aneuploid tumors. A number of oncogenes are under investigation to determine their role in the pathogenesis of borderline ovarian tumors. Previous studies have suggested the safety of conservative surgery with unilateral salpingo-oophorectomy or cystectomy for patients with stage I borderline ovarian tumors. Laparoscopic treatment of adnexal masses has proved to be a safe and effective diagnostic and therapeutic tool in the hands of experienced laparoscopists. For women who are treated conservatively, follow-up is important. Surgery remains the most effective therapy for later stage lesions. Adjuvant therapy for advanced stage of borderline ovarian tumors remains controversial. CONCLUSION: Conservative management of borderline ovarian tumors is an appropriate therapeutic option for young women with early-stage lesions who wish to preserve their childbearing potential. Available data indicate that in these patients fertility, pregnancy outcome and survival remain excellent.

Female↗

Transdermal drug delivery: a review of pharmaceutics, pharmacokinetics, and pharmacodynamics.

This article provides a critical literature review on the recent advances in the research and development of rate-controlled transdermal therapeutical systems for systemic medication. The article focuses its discussion on the recent development in the fundamentals, developmental concepts, and biomedical assessment of the transdermal controlled drug administration. The scope of the review consists of the following areas: mechanism of percutaneous absorption; enhancement of skin permeability; in vitro and in vivo evaluations of transdermal permeation kinetics and assessment of in vitro-in vivo relationship; pharmacokinetics and pharmacodynamics of transdermal controlled drug administration and establishment of pharmacokinetic/pharmacodynamic relationship; clinical performance of rate-controlled transdermal therapeutic systems; and potential development in rate-controlled transdermal drug delivery.

Administration, Cutaneous↗

Paradise regained: insights into coronary heart disease prevention from recent clinical trials and basic research.

Many of the uncertainties regarding the place of lipid lowering in the prevention of coronary heart disease have recently been resolved. Some of the newer findings are reviewed, and the scope for a revised clinical approach examined. The results of trials of lipid lowering, based on clinical end-points and particularly on angiographic end-points, and their meta-analyses are discussed. The close relation between coronary-angiographic and clinical outcomes is reviewed in relation to recent advances in understanding of the underlying arterial pathology, and possible underlying mechanisms are proposed. The variables predictive of progression of coronary artery disease, including nutrient intake, are examined. The management of hyperlipidaemia requires that treatment and therapeutic goals are consonant with the patient's cardiovascular risk; for this purpose, clinical and biochemical assessment of risk may be enhanced by angiographic and non-invasive methods to detect potentially-infarctogenic atherosclerotic lesions.

Anticholesteremic Agents↗

Oxygen in the cultivation of stem cells.

Cultivation of stem cells, like all cells in culture, is performed under conditions that cannot and do not replicate normal physiologic conditions. For example, direct exposure of cultured monolayer cells to serum contents is normally prevented in vivo by the vasculature. The heterogeneity of cells and signals between different cell types in an organ is certainly not captured when a single cell type is grown and studied in vitro. Gases, in particular, are not accounted for in routine tissue culture. Oxygen is fundamental for life and its concentration is an important signal for virtually all cellular processes. Nonetheless, oxygen is rarely taken into account in culturing stem and other cells. This review will summarize work that highlights the importance of considering oxygen conditions for culturing and manipulating stem cells. Emphasis is placed on major phenotypic changes in response to oxygen, recognizing that oxygen-mediated transcriptional and post-translational effects are enormously complex, and beyond the scope of this review. The review emphasizes that oxygen is an important signal in all major aspects of stem cell biology including proliferation and tumorigenesis, cell death and differentiation, self-renewal, and migration.

Apoptosis↗

Increased oxidation and decreased conjugation of drugs in the liver caused by starvation. Altered metabolism of certain aromatic compounds and acetone.

Starvation causes several changes in the various processes of biotransformation. The focus of this review is on biotransformation of various aromatic and other compounds whose metabolism is catalyzed in phase I by isozymes belonging to the CYP2E1 gene subfamily, while in phase II phenol-UDPGT or conjugation with GSH play a dominant role. The other ways of conjugation are beyond the scope of this review. The reason why this aspect has been chosen is that the capacity of these reactions is profoundly altered by nutritional conditions. There is a balance between the two phases of biotransformation. Therefore, under standard circumstances in a well-fed state the intermediate formed in the course of phase I is converted to a conjugated compound rapidly, as a result of phase II. However, in starvation the pattern of drug metabolism is altered and the balance between the two phases is changed. This alteration of drug metabolism upon starvation is partly connected to the changes of cofactor supplies due to the metabolic state.

Acetone↗

Energy metabolism in heart failure.

Heart failure (HF) is a syndrome resulting from the inability of the cardiac pump to meet the energy requirements of the body. Despite intensive work, the pathogenesis of the cardiac intracellular abnormalities that result from HF remains incompletely understood. Factors that lead to abnormal contraction and relaxation in the failing heart include metabolic pathway abnormalities that result in decreased energy production, energy transfer and energy utilization. Heart failure also affects the periphery. Patients suffering from heart failure always complain of early muscular fatigue and exercise intolerance. This is linked in part to intrinsic alterations of skeletal muscle, among which decreases in the mitochondrial ATP production and in the transfer of energy through the phosphotransfer kinases play an important role. Alterations in energy metabolism that affect both cardiac and skeletal muscles argue for a generalized metabolic myopathy in heart failure. Recent evidence shows that decreased expression of mitochondrial transcription factors and mitochondrial proteins are involved in mechanisms causing the energy starvation in heart failure. This review will focus on energy metabolism alterations in long-term chronic heart failure with only a few references to compensated hypertrophy when necessary. It will briefly describe the energy metabolism of normal heart and skeletal muscles and their alterations in chronic heart failure. It is beyond the scope of this review to address the metabolic switches occurring in compensated hypertrophy; readers could refer to well-documented reviews on this subject.

Animals↗

Design of freeze-drying processes for pharmaceuticals: practical advice.

Design of freeze-drying processes is often approached with a "trial and error" experimental plan or, worse yet, the protocol used in the first laboratory run is adopted without further attempts at optimization. Consequently, commercial freeze-drying processes are often neither robust nor efficient. It is our thesis that design of an "optimized" freeze-drying process is not particularly difficult for most products, as long as some simple rules based on well-accepted scientific principles are followed. It is the purpose of this review to discuss the scientific foundations of the freeze-drying process design and then to consolidate these principles into a set of guidelines for rational process design and optimization. General advice is given concerning common stability issues with proteins, but unusual and difficult stability issues are beyond the scope of this review. Control of ice nucleation and crystallization during the freezing step is discussed, and the impact of freezing on the rest of the process and final product quality is reviewed. Representative freezing protocols are presented. The significance of the collapse temperature and the thermal transition, denoted Tg', are discussed, and procedures for the selection of the "target product temperature" for primary drying are presented. Furthermore, guidelines are given for selection of the optimal shelf temperature and chamber pressure settings required to achieve the target product temperature without thermal and/or mass transfer overload of the freeze dryer. Finally, guidelines and "rules" for optimization of secondary drying and representative secondary drying protocols are presented.

Chemical Phenomena↗

Reference methods as a basis for accurate measuring systems.

Reference methods, as part of a reference system, are essential for improving the accuracy of routine methods. They can help to establish worldwide compatibility of clinical chemical measurements and they provide an objective basis for quality control measures. The subject of analytical errors is treated in detail, then the concept of reference methods is developed. This review emphasizes the fundamental metrological aspects of reference methods and reference measurement technology. An overview is given of the most important analytical principles used for reference methods in clinical chemistry. The particular problems of reference methods for the determination of the catalytic activity concentration of enzymes are outside the scope of this review.

Chemistry, Clinical↗

A review of 3 current radiosurgery systems.

BACKGROUND: Stereotactic radiosurgery and fractionated stereotactic radiotherapy have become widespread techniques applied to the treatment of a variety of intracranial lesions. Rapid evolution of new technologies has now enabled clinicians to treat tumors outside the cranium and down the spinal axis. This review compares 3 commercially available systems in widespread use throughout the world. METHODS: Literature review and interviews with practitioners in the United States were performed to establish data for a comparative analysis of the Gamma Knife (Elekta, Sweden), Novalis (BrainLabs, Germany), and CyberKnife systems (Accuray, Sunnyvale, CA). Cost analyses were deliberately excluded because of the need for detailed cost-benefit analysis beyond the scope of the review. RESULTS: An unbiased comparative analysis was not possible because of the lack of objective data from a standard metric for these systems. Despite this shortcoming, disparate features of each system were compared and contrasted. CONCLUSION: A careful assessment of each system, including its operational features, capabilities, and yearly capacity must be weighed against the composition of the radiosurgery team, the case mix of the practice, and the objectives of the clinical unit to yield the best fit.

Brain Diseases↗

The emerging roles of BNP and accelerated cardiac protocols in emergency laboratory medicine.

BACKGROUND: The role of the clinical laboratory in emergency cardiac medicine is rapidly evolving; with recent redefinitions of acute myocardial infarction (AMI) and unstable angina (UA) based on troponin levels, recommended acceleration of cardiac testing protocols, and increased clinical measurement of B-type natriuretic peptide (BNP). We briefly review the background pathophysiology of acute coronary syndromes (ACS) and congestive heart failure (CHF), along with an overview of the biochemistry and physiology of the natriuretic peptides. METHODS: The assay principles and performance characteristics of the rapid BNP assays are discussed. The performance characteristics of troponin assays are at the center of controversy regarding the redefinition of AMI and UA, and will be discussed. RESULTS: We review the rapidly expanding evidence regarding the clinical utility of BNP for CHF patients. While BNP has gained wide acceptance as a rapid diagnostic tool, considerable controversy remains concerning its potential for prognosis, screening, and therapeutic monitoring. Although a thorough discussion of the use of cardiac markers is well beyond the scope of this review, overviews of the redefinitions of AMI and UA, and the trend toward accelerated testing protocols to obtain a quicker diagnosis or ruling-out of AMI are included. In addition to accelerating the retesting of existing markers, a recent test for ischemia modified albumin (IMA) promises another quantum leap in cardiac diagnoses. CONCLUSIONS: The positive impact of these developments on the healthcare costs and overall improvement in the quality of healthcare delivery will be discussed. A brief analysis of the downstream costs of BNP testing is also offered.

Atrial Natriuretic Factor↗

Vav proteins, masters of the world of cytoskeleton organization.

Vav proteins are evolutionarily conserved from nematodes to mammals and play a pivotal role in many aspects of cellular signaling, coupling cell surface receptors to various effectors functions. In mammals, there are three family members; Vav1 is specifically expressed in the hematopoietic system, whereas Vav2 and Vav3 are more ubiquitously expressed. Vav proteins contain multiple domains that enable their function in various fashions. The participation of the Vav proteins in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation will be discussed in this review. We will also cover how the Vav proteins succeed in controlling these processes by their function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. The contribution of the Vav proteins in a GEF-independent manner to the organization of the cytoskeleton will also be deliberated. The scope of this review is to highlight the numerous roles of the Vav signal transducer proteins in actin organization.

Actin Cytoskeleton↗

Depression: cost-of-illness studies in the international literature, a review.

BACKGROUND: Depression is one of the most ancient and common diseases of the human race and its burden on society is really impressive. This stems both from the epidemiological spread (lifetime prevalence rate, up to 30 years of age, was estimated as greater than 14.4% by Angst et al.) and from the economic burden on healthcare systems and society, but also as it pertains to patient well-being. AIMS OF THE STUDY: The scope of this review was to examine studies published in the international literature to describe and compare the social costs of depression in various countries. METHODS: A bibliographic search was performed on international medical literature databases (Medline, Embase), where all studies published after 1970 were selected. Studies were carefully evaluated and only those that provided cost data were included in the comparative analysis; this latter phase was conducted using a newly developed evaluation chart. RESULTS: 10 abstracts were firstly selected; 46 of them underwent a subsequent full paper reading, thus providing seven papers, which were the subject of the in-depth comparative analysis: three studies investigated the cost of depression in the USA, three studies in the UK and one study was related to Italy. All the studies examined highlight the relevant economic burden of depression; in 1990, including both direct and indirect costs, it accounted for US$ 43.7 billion in the US (US$ 65 billion, at 1998 prices) according to Greenberg and colleagues, whilst direct costs accounted for £417 million in the UK (or US$ 962.5 million, at 1998 prices), according to Kind and Sorensen. Within direct costs, the major cost driver was indeed hospitalization, which represented something in between 43 and 75% of the average per patient cost; conversely, drug cost accounted for only 2% to 11% in five out of seven studies. DISCUSSION: Indeed, our review suggests that at the direct cost level, in both the United States and the United Kingdom, the burden of depression is remarkable, and this is confirmed by a recent report issued by the Pharmaceutical Research and Manufacturers Association (PhRMA) where prevalence and cost of disease were compared for several major chronic diseases, including Alzheimer, asthma, cancer, depression, osteoporosis, hypertension, schizophrenia and others: in this comparison, depression is one of the most significant diseases, ranked third by prevalence and sixth in terms of economic burden. Moreover, in terms of the average cost per patient, depression imposes a societal burden that is larger than other chronic conditions such as hypertension, rheumatoid arthritis, asthma and osteoporosis. The application of economic methods to the epidemiological and clinical field is a relatively recent development, as evidenced by the finding that, out of the seven studies examined, three refer to the US environment, three to the UK and one to Italy, while nothing was available about the cost of depression for large countries such as France, Germany, Spain, Japan and others. IMPLICATION FOR HEALTH CARE PROVISION AND USE: The high incidence of hospitalization, and the finding that drug cost represents only a minor component of the total direct cost of the disease, suggests that room is still available for disease management strategies that, while effectively managing the patient's clinical profile, could also improve health economic efficiency. IMPLICATION FOR HEALTH POLICIES: Disease management strategies, with particular emphasis on education, should be targeted not only at patients and medical professionals but also at health decision makers in order "to encourage effective prevention and treatment of depressive illness". IMPLICATIONS FOR FURTHER RESEARCH: Cost of illness studies are a very useful tool allowing cost data comparisons across countries and diseases: for this reason, we suggest that further research is needed especially in some western European countries to assess the true economic burden of depression on societies.

Journal Article↗

The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment.

Therapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport. It is with anti-cancer drugs that major progress has been made in the study of partition between the largest cellular blood compartment, i.e., erythrocytes, and the plasma compartment. The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring. Furthermore, techniques generally used in anti-cancer drug monitoring are highlighted. Data for complex Bayesian statistical approaches and population kinetics studies are beyond the scope of this review, since this is generally limited to the plasma compartment only.

Antineoplastic Agents↗

Current status of the institutional review boards in Korea: constitution, operation, and policy for protection of human research participants.

The institutional review board is crucial to ensure the scientific and ethical quality of human participant research. This paper analyzes a survey on the current constitution and operation of institutional review boards (IRBs) in Korea, conducted by the Korean Association of Institutional Review Boards in April 2002. Out of 74 IRBs, 63 responded to the survey (85.1% response rate). IRB membership has a male-to-female ratio of approximately 80:20, a predominance of male clinicians (60%) and an underrepresentation of community people unaffiliated to the institutions (less than 10%). Most IRBs (around 80%) confine the scope of their reviews to the clinical evaluation of drugs or devices, leaving the remaining areas of research involving human participants untouched. As their role is limited, the majority of IRBs do not operate actively: 72% of responding IRBs reviewed less than one protocol per month in 2001. Sixty two percent of institutions have never discussed the need for insuring research participants' risks or making indemnity arrangements. This survey reveals many shortcomings and points for improvement by the institutional support bodies, including the need to establish regular education programs for IRB members and investigators.

Appointments and Schedules↗

Investigation and management of suppurative cough in pre-school children.

Suppurative cough can be defined as a cough where purulent sputum is produced. Chronic suppurative cough may be associated with the destruction of the bronchial wall (bronchiectasis). As mild forms of the disease are not associated with respiratory limitation or failure to thrive, such children may not present for investigation and therefore the true incidence of suppurative cough is difficult to gauge. Chronic suppurative cough remains an important health problem in developing countries and some indigenous populations of developed countries. The purpose of this review is to present the appropriate investigations and evaluate the evidence for current management strategies in children with suppurative cough. To accomplish this, a brief discussion on the aetiology of suppurative cough in childhood is presented. The most commonly identifiable cause of suppurative cough is cystic fibrosis. A detailed discussion on cystic fibrosis is beyond the scope of this review. Other causes of chronic suppurative cough in pre-school children may be classified according to congenital malformations of the airway, immunodeficiency, ciliary dysfunction and, unusually, acquired causes. Microbiology of sputum culture or bronchoalveolar lavage, assessment of immune function, the role of exhaled nitric oxide and ciliary studies, and medical imaging are discussed in detail. One can conclude that the evidence for management strategies for children with suppurative cough is, at best, level 3 evidence, i.e. non-randomised, controlled or cohort studies.

Child, Preschool↗

Update in medical toxicology.

This article examines some current issues in toxicologic care. First there is a review of the scope of pediatric poisonings and some aspects of initial management. Then there is a discussion of the decision-making process required to properly use gastric decontamination in the management of poisonings. Each of the common methods available--emesis, gastric lavage, activated charcoal, catharsis, and whole bowel irrigation--is discussed. Finally, several new and old antidotes are reviewed, namely naloxone, glucagon, bicarbonate, dimercaptosuccinic acid, digoxin-specific fab fragments, and flumazenil.

Antidotes↗