What is clinical effectiveness?

Clinical trials and other forms of evaluation of medical treatment are held to give an objective assessment of the ‘clinical effectiveness’ of the medical treatments under evaluation. This kind of evaluation is central to the evidence-based medicine movement, as it provides a basis for the rational selection of treatment. The ethical status of randomised clinical trials is widely agreed to depend crucially upon the state of equipoise regarding which of two (or more) treatments is more (or most) effective in a defined population. However, the meaning and nature of ‘clinical effectiveness’ are unclear. in this paper, I discuss the proposals to define clinical effectiveness as a relational property and as an intrinsic property, and the way effectiveness may supervene upon more fundamental physical properties of treatments. I discuss whether effectiveness is a single property or a family of properties; the types of outcome which can be explained by effectiveness properties; and the relationship between ‘objective’ and ‘preference’ outcomes. This paper suggests that while it may be possible to put clinical effectiveness on a proper metaphysical footing, in practice the language of clinical effectiveness is more properly a topic of the human sciences than of the natural sciences.     

Parkinson’s disease: clinical aspects

Parkinsonism is a clinical syndrome characterized by akinesia, muscular rigidity, and resting tremor. The most frequent cause of parkinsonism is Parkinsons disease (PD). Progressive loss of substantia nigra neurons together with the occurrence of Lewy bodies are considered essential neuropathological features of PD. Recent neuropathological studies suggest that nigral degeneration is only part of a more extended brain degeneration that starts in the medulla oblongata and then spreads to the mesencephalon and cerebral cortex. Correspondingly, the clinical symptoms occurring in PD go far beyond parkinsonism. Depending on the disease stage, autonomic dysfunction, olfactory disturbances, depression, and dementia are frequently encountered in PD. These neuropathological and clinical observations have major implications for future research in PD. In particular, the analysis of the properties that the neuronal cell types involved in PD have in common and that might make them susceptible to degeneration is essential.     

Postgraduate clinical education — the Canadian experience

To obtain a quantitative measure of the extent to which graduate education and qualification for specialty practice have become an integral part of the total educational experience, samples of the graduating classes of 1960, 1964, 1968 and 1970 of Canadian medical schools were tracked through postgraduate educational training and into specialty certification. From the 1960 cohort 65% chose a career recognized by special certifying exams in Canada and/or the United States, entered a residency, completed it and achieved certification of special competence. From the 1970 cohort, by the end of 1972 approximately 50% had entered a recognized specialty training program leading to certification. The diminishing trend toward specialty practice is demonstrated by reviewing the comparative figures in the 1964 and 1968 cohorts. Evidence garnered in this study indicates a continuing strong motivation for specialty practice although family medicine and/or general practice appear increasingly attractive as career choices. Strong provincial educational forces as well as social and other forces will probably continue to modify career selection and may lead an increasing number of Canadian medical graduates into family practice.     

Apathy syndrome: a clinical entity?

Apathy is defined as a disorder of motivation that expresses itself at an emotional, cognitive and behavioural level. Apathy can occur as a symptom and a syndrome. In the recent years diagnostic criteria and a number of scales for measuring apathy in elderly with psychiatric or neurological disorders have been introduced. Two scales are specifically developed to measure apathy, the Apathy Evaluation Scale (AES) from Marin and the Apathy Scale (AS) from Starkstein. Both scales have been translated into Dutch. The AS is more convenient. The AS in addition can be used when applying the criteria for the apathy syndrome which has been introduced in 2001 by Starkstein. In addition, the Neuropsychiatric Inventory (NPI) and the 'Gedragsobservatieschaal voor de Intramurale Psychogeniatrie' (GIP) (a scale in Dutch) have an apathy domain. Conceptual problems surrounding apathy have only partly been resolved. The criteria for the apathy syndrome can only be used for assessing the extent of the problem. Apathy and depression are strongly correlated. Studies show that apathy as a syndrome can occur without concomitant depression in the elderly, but regularly occurs besides a depressive disorder, in percentages varying between 9% and 53% of the population under study. Especially the varying validity of an apathy syndrome in relation to late life depression needs further clarification.     

Autophagy—from molecular mechanisms to clinical relevance

Autophagy is a lysosomal degradation pathway of eukaryotic cells that is highly conserved from yeast to mammals. During this process, cooperating protein complexes are recruited in a hierarchic order to the phagophore assembly site (PAS) to mediate the elongation and closure of double-membrane vesicles called autophagosomes, which sequester cytosolic components and deliver their content to the endolysosomal system for degradation. As a major cytoprotective mechanism, autophagy plays a key role in the stress response against nutrient starvation, hypoxia, and infections. Although numerous studies reported that impaired function of core autophagy proteins also contributes to the development and progression of various human diseases such as neurodegenerative disorders, cardiovascular and muscle diseases, infections, and different types of cancer, the function of this process in human diseases remains unclear. Evidence often suggests a controversial role for autophagy in the pathomechanisms of these severe disorders. Here, we provide an overview of the molecular mechanisms of autophagy and summarize the recent advances on its function in human health and disease.     

Is the clinical lipidomics a potential goldmine?

Clinical lipidomics is a new extension of lipidomics to study lipid profiles, pathways, and networks by characterizing and quantifying the complete lipid molecules in cells, biopsy, or body fluids of patients. It undoubtfully has more values if lipidomics can be integrated with the data of clinical proteomic, genomic, and phenomic profiles. A number of challenges, e.g., instability, specificity, and sensitivity, in lipidomics have to be faced and overcome before clinical application. The association of lipidomics data with gene expression and sequencing of lipid-specific proteins/enzymes should be furthermore clarified. Therefore, clinical lipidomics is expected to be more stable during handling, sensitive in response to changes, specific for diseases, efficient in data analyses, and standardized in measurements, in order to meet clinical needs. Clinical lipidomics will become a more important approach in clinical applications and will be the part of “natural” measures for early diagnosis and progress of disease. Thus, clinical lipidomics will be one of the most powerful approaches for disease-specific diagnosis and therapy, once the mystery of lipidomic profiles and metabolic enzymes is deciphered.     

Albumin–drug interaction and its clinical implication

Background

Human serum albumin acts as a reservoir and transport protein for endogenous (e.g. fatty acids or bilirubin) and exogenous compounds (e.g. drugs or nutrients) in the blood. The binding of a drug to albumin is a major determinant of its pharmacokinetic and pharmacodynamic profile.

Scope of review

The present review discusses recent findings regarding the nature of drug binding sites, drug-albumin binding in certain diseased states or in the presence of coadministered drugs, and the potential of utilizing albumin–drug interactions in clinical applications.

Major conclusions

Drug–albumin interactions appear to predominantly occur at one or two specific binding sites. The nature of these drug binding sites has been fundamentally investigated as to location, size, charge, hydrophobicity or changes that can occur under conditions such as the content of the endogenous substances in question. Such findings can be useful tools for the analysis of drug–drug interactions or protein binding in diseased states. A change in protein binding is not always a problem in terms of drug therapy, but it can be used to enhance the efficacy of therapeutic agents or to enhance the accumulation of radiopharmaceuticals to targets for diagnostic purposes. Furthermore, several extracorporeal dialysis procedures using albumin-containing dialysates have proven to be an effective tool for removing endogenous toxins or overdosed drugs from patients.

General significance

Recent findings related to albumin–drug interactions as described in this review are useful for providing safer and efficient therapies and diagnoses in clinical settings. This article is part of a Special Issue entitled Serum Albumin.     

Smoker's face: an underrated clinical sign?

In a prospective survey of patients attending a general medical outpatient clinic roughly half the current cigarette smokers who had smoked for 10 years or more were identified, using defined criteria, by their facial features alone. These facial features, designated "smoker''s face," were present in three (8%) of those who had smoked cigarettes for 10 years or more in the past and in none of the non-smokers. The association of smoker''s face with current smoking that had continued for 10 years or more was significant (p less than 0.001) and remained after the patient''s age, social class, exposure to sunlight, recent change of weight, and estimated lifetime consumption of cigarettes were controlled for. Smoker''s face may be a helpful indicator in antismoking campaigns.     

Proteomic analysis of Aspergillus fumigatus – clinical implications

Introduction: Aspergillus fumigatus is a ubiquitous saprophytic fungus capable of producing small airborne spores, which are frequently inhaled by humans. In healthy individuals, the fungus is rapidly cleared by innate mechanisms, including immune cells. However, in individuals with impaired lung function or immunosuppression the spores can germinate and prompt severe allergic responses, and disease with limited or extensive invasiveness.

Areas covered: The traits that make A. fumigatus a successful colonizer and pathogen of humans are multi-factorial. Thus, a global investigative approach is required to elucidate the mechanisms utilized by the fungus to cause disease.

Expert commentary: In doing so, a better understanding of disease pathology can be achieved with improved therapeutic/diagnostic solutions, thereby improving patient outcome. Proteomic analysis permits such investigations and recent work has yielded insight into these mechanisms.     

Can students learn clinical method in general practice? A randomised crossover trial based on objective structured clinical examinations.

OBJECTIVE: To determine whether students acquired clinical skills as well in general practice as in hospital and whether there was any difference in the acquisition of specific skills in the two environments. DESIGN: Randomised crossover trial. SUBJECTS AND SETTING: Annual intake of first year clinical students at one medical school. INTERVENTION: A 10 week block of general internal medicine, one half taught in general practice, the other in hospital. Students started at random in one location and crossed over after five weeks. OUTCOME MEASURES: Students'' performance in two equivalent nine station objective structured clinical examinations administered at the mid and end points of the block: a direct comparison of the two groups'' performance at five weeks; analysis of covariance, using their first examination scores as a covariate, to determine students'' relative improvement over the second five weeks of their attachment. RESULTS: 225 students rotated through the block; all took at least one examination and 208 (92%) took both. For the first half of the year there was no significant difference in the students'' acquisition of clinical skills in the two environments; later, however, students taught in general practice improved slightly more than those taught in hospital (P = 0.007). CONCLUSIONS: Students can learn clinical skills as well in general practice as in hospital; more work is needed to clarify where specific skills, knowledge, and attitudes are best learnt to allow rational planning of the undergraduate curriculum.     

Zinc and diabetes — clinical links and molecular mechanisms

Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options.     

Hypertrophic cardiomyopathy：from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions.Hypertrophic cardiomyopathy(HCM)was the first cardiac disorder in which a genetic basis was identified and as such,has acted as a paradigm for the study of an inherited cardiac disorder.HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death.HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes.At least ten genes have now been identified,defects in which cause HCM.All of these genes encode proteins which comprise the basic contractile unit of the heart,i.e.the sarcomere.While much is now known about which genes cause disease and the various clinical presentations,very little is known about how these gene defects cause disease,and what factors modify the expression of the mutant genes.Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM,and the role of both environmental and genetic modifying factors.Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function,and will therefore provide new avenues for treating cardiovascular disease in man.