Rational approaches to combating resistance

Traditional treatment paradigms based on national guidelines and administrative policies, such as restricted formularies, that are intended to guide antibiotic selection for empirical therapy of community- and hospital-acquired infections have been largely unsuccessful in curbing the spread of antimicrobial resistance. Evidence suggests that restricting antibiotic availability may lead to potential misuse of unrestricted agents as well as to increased adverse drug reactions, costs and, potentially, increased antibiotic resistance. New treatment paradigms, such as that embodied in the LDS Hospital computer-based "automated antibiotic assistant", that address antibiotic use from a process-of-care approach, using local clinician-derived solutions implemented at the patient's bedside, may offer strategic advantages over traditional approaches based on restricting antibiotic use. By using patient- and institution-specific data to tailor therapy to individual patient circumstances, such systems can help reduce the dosage, duration, frequency of adverse events and cost of antibiotic therapy as well as improving clinical outcomes and potentially avoiding drug resistance.     

Transport proteins in drug resistance: biology and approaches to circumvention

At least two transport proteins, P-glycoprotein (Pgp) and the multidrug resistance associated protein (MRP), are believed to play a significant role in clinical resistance to cytotoxic therapy. These proteins are expressed at relatively high levels in a number of malignant diseases including various types of leukaemias. They are variably expressed on both the plasma membrane and intracellular vesicular membranes resulting in cellular drug efflux or vesicular drug sequestration, respectively. The action of MRP as a drug transporter depends on intracellular levels of glutathione. A number of strategies for circumvention of these drug resistance mechanisms have been developed and some of these are now in clinical trial.     

New anti-HIV agents

Since the introduction of zidovudine into HIV clinical practice in 1985, the history of antiretroviral treatment has been started. Even in well controlled patients with HIV loads under the detection limit for many years, viral load rebound could occur followed by CD4 cell count decline, if the antiretroviral treatment is interrupted. Because life-long treatment seems inevitable, long-term safety has been an important issue. During these 25 years, not only antiretroviral potency but also long-term tolerability is one of the main foci of the development of new antiretroviral agents. A particular drive to the once-daily single-tablet regimen has been seen over the last few years.     

Therapeutic anti-HIV vaccine

Highly active antiretroviral therapy (HAART) of HIV-infected people results in viral control. When HAART is interrupted, however, HIV-infected individuals lose viral control and show reappearance of plasma viremia. Thus, they need to continue HAART almost forever for prevention of AIDS progression. Cytotoxic T lymphocyte (CTL) responses play an important role in viral suppression but are mostly reduced during HAART. There have been many attempts to develop therapeutic vaccines inducing CTL responses during HAART toward better control, although none of them has yet shown sufficient efficacy.     

Appropriate antimicrobial prescribing: approaches that limit antibiotic resistance

Since the introduction of antimicrobial agents, there has been an association between antibiotic use and the development of antimicrobial resistance. Antibiotic therapy eradicates not only pathogenic organisms but also the protective normal flora. This so-called "selective pressure" results in colonization with bacteria that are resistant to the original therapy. The result has been an increase over the past two decades in antibiotic resistance among common bacterial causes of outpatient infections. Several studies have demonstrated that a substantial portion of the antibiotics prescribed in the outpatient setting are given for viral illnesses or bacterial diseases where the benefit of antibacterial therapy is marginal. The reasons for prescribing antibiotics in these situations are related to medical and social factors. Physicians should be familiar with the clinical situations in which they should provide antibiotics and those in which they may safely be withheld. Physicians should understand the motivations of patients who are seeking antibiotics and provide education, empathy and alternative treatments.     

Multidrug resistance in oncology: diagnostic and therapeutic approaches

Resistance to anticancer drugs is often mediated by the overexpression of a membrane pump able to extrude many xenobiotics out of the tumour cells. The most frequently expressed of these pumps is called P-glycoprotein and is encoded by a gene called MDR1 (for multidrug resistance). There could be great clinical interest for investigating the expression of this gene or of its product in patients' tumours, as well as in developing ways of circumventing this mechanism of resistance. Multidrug resistance can be diagnosed in tumours by molecular biology techniques (gene expression at the mRNA level), by immunological techniques (quantification of P-glycoprotein itself) or by functional approaches (measuring dye exclusion). Numerous studies have tried to use the MDR status of tumours as a predictor of response to treatment, but they have not yet reached definitive conclusions to allow the use of this approach in routine determinations. This is because no consensus has emerged concerning the optimal technique and the best conditions for MDR determination. Continuous efforts are still required for defining appropriate standardization of the techniques. The development of MDR modulators for the treatment of resistant tumours is a promising approach requiring rigorous clinical trials with successive phase I, phase II and phase III studies. Phase I can be omitted when the reverter is already being used in therapeutics; phase II should be performed using a sequential design, in order to prove the inefficacy of the anticancer therapy before combining it to a modulator; and phase III must only be undertaken after the demonstration that responders can be recruited by the combination. However, the effect of some reverters on anticancer drug pharmacokinetics may hamper rapid evaluation. Several drugs are good candidates for MDR modulation, but definitive results are still lacking for the introduction of such combinations in standard therapeutic protocols.     

Basic understanding and therapeutic approaches to target toll‐like receptors in cancerous microenvironment and metastasis

Toll‐like receptors (TLRs) are transmembrane components that sense danger signals, like damage‐ and pathogen‐associated molecular pattern molecules, as receptors, and maintain homeostasis in tissues. They are mainly involved in immune system activation through a variety of mediators, which either carry out (1) elimination of pathogenic threats and redressing homeostatic imbalances or (2) contribution to the initiation and worsening of pathological conditions, including cancers. Under physiological conditions, TLRs coordinate the innate and adaptive immunity, and inhibit autoimmune disorders. In pathological conditions, such as cancer, they can present both tumor and receptor‐specific roles. Although the roles of individual TLRs in various cancers have been described, the effects of targeting TLRs to treat cancer and prevent metastasis are still controversial. A growing body of literature has suggested contribution of both activators and inhibitors of TLR signaling pathway for cancer treatment, dependent on several context‐specific factors. In short, TLRs can play dual roles with contradictory outcomes in neoplastic conditions. This hampers the development of TLR‐based therapeutic interventions. A better understanding of the interwoven TLR pathways in cancerous microenvironment is necessary to design TLR‐based therapies. In this review, we consider the molecular mechanisms of TLRs signaling and their involvement in tumor progression. Therapeutic modalities targeting TLRs for cancer treatment are discussed as well.     

Psychotherapeutic approaches to masochism

Self-defeating personality disorder (SDPD) is quite well defined in the appendix of DSM-III-R, and preliminary research indicates that it is a robust entity with a high prevalence. The hallmark of the SDPD or masochistic character is the mechanism of "injustice collecting," a behavioral syndrome that can be readily identified. However, a number of special difficulties arise in the treatment of SDPD. These are identified, and techniques for handling them are described. A knowledge of the psychodynamics of this disorder is at least helpful and probably necessary to conduct successful psychotherapy.     

Practical approaches to marketing

Marketing in health care is the process of developing, promoting, and administrating health care services to a client for the benefit of both. The success of a nurse executive in the area of marketing is dependent on the appropriate application of marketing principles, including assessment and/or awareness of needs, development of new services, promotion of current and new services, and target market development. The author discusses how the nurse executive can aggressively promote services based on consumer demand states and effectively use advertising, publicity, and personal promotion strategies.     

Methodological approaches to pharmaco-economics

Summary— Due to the increased need for cost-containment policies, most decision makers are facing the issue of the efficiency of health care strategies. In this context, economic evaluation becomes a major instrument. However, the credibility of economic data depends on a number of methodological steps: selection of strategy of economic evaluation (cost/effectiveness, cost/benefit, generation of economic hypotheses, study design (cross-sectional, prospective, naturalistic), data collection (data-base, physicians), data analysis (costing, statistics). In this respect, the conduct of proper economic evaluation relies on a combination of expertise in clinical epidemiology as well as in health economics.     

Positive approaches to dying

All relationships end in separation, the greatest separation of all being death. Recognizing and admitting the mortality of all people is the first stage in learning to cope positively with death and dying. This paper focuses on other stages, including the re-evaluation of loss and mourning, and making grief a healthy, not a destructive, emotion.     

Novel approaches to tendinopathy

Purpose. The last decade has seen an evolution in the thinking of tendinopathy from inflammatory to degenerative and hence a change in approaches to treatment.

Method. We review the literature in this field to highlight the possibility of neural and neural-induced inflammation in this field.

Results. Neuropathy is a possible source of pain in tendinopathy.

Conclusion. Further work is required to develop the neuropathic model of tendinopathy, and to determine whether these neuropathic factors are responsible. The concept of neoneurovascularization being the issue in tendinopathy is established. The underlying mechanisms for the process require further evaluation.     

Positive approaches to dying

Abstract

All relationships end in separation, the greatest separation of all being death. Recognizing and admitting the mortality of all people is the first stage in learning to cope positively with death and dying. This paper focuses on other stages, including the re-evaluation of loss and mourning, and making grief a healthy, not a destructive, emotion.