Bacterial resistance: a sensitive issue complexity of the challenge and containment strategy in Europe.

The development of antimicrobial agents has been a key achievement of modern medicine. However, their overuse has led to an increasing incidence of infections due to antibiotic-resistant microorganisms. Quantitative figures on the current economic and health impact of antimicrobial resistance are scant, but it is clearly a growing challenge that requires timely action. That action should be at the educational, ethical, economic and political level. An important first step would be to increase public awareness and willingness to take the necessary measures to curb resistance. Hence, studies are needed that would provide solid, quantitative data on the societal impact of antibiotic resistance. This review discusses the complexity of resistance, identifies its main drivers and proposes measures to contain it on a European scale.     

Client-Provider relationship in comprehensive substance abuse treatment: differences in residential and nonresidential settings

As the substance abuse service system shifts from primarily residential to primarily nonresidential settings, it becomes important to understand how substance abuse treatment processes and outcomes may vary across service setting. Research increasingly indicates that, along with specific treatment and service strategies, client–provider relationship is an important ingredient in effective substance abuse treatment. This study uses a moderator–mediator analysis of a comprehensive service model to examine how the relation between client–provider relationship and substance abuse treatment outcomes may differ in residential and nonresidential settings. The study used data collected for the National Treatment Improvement Evaluation Study, a prospective, cohort-based study of U.S. substance abuse treatment programs and their clients, with an analytic sample of 59 publicly funded service delivery units and 3,027 clients. Structural equation modeling is used to assess the structural relations and causal connections between treatment process and treatment outcome variables. Results indicate that for nonresidential settings, a better client–provider relationship is directly related to improved outcomes of treatment duration and reduced posttreatment substance use and is indirectly related to both outcomes through provision of services matched to client needs. In residential settings, the quality of the client–provider relationship is unrelated to process or outcome variables. The findings point to the importance of the client–provider relationship in all settings but particularly in outpatient settings where there are limited physical constraints on the treatment process.     

M cell targeting by lectins: a strategy for mucosal vaccination and drug delivery

Bioadhesins are a recognised method of enhancing the absorption of drugs and vaccines at mucosal surfaces. Additionally, bioadhesins allow for cell specific targeting. Lectin-mediated targeting and delivery exploits unique surface carbohydrates on mucosal epithelial cells. The antigen-sampling M cells offer a portal for absorption of colloidal and particulate delivery vehicles, including bacteria, viruses and inert microparticles. We review work supporting the use of lectins to aid targeting to intestinal M cells. Consideration is also given to lectin-mediated targeting in non-intestinal sites and to the potential application of other bioadhesins to enhance M cell transport. While substantial hurdles must be overcome before mucosal bioadhesins can guarantee consistent, safe, effective mucosal delivery, this strategy offers novel opportunities for drug and vaccine formulation.     

Cost containment measures in hospital pharmacy: a bibliography

The pharmacy literature was searched for cost containment articles. The articles were classified according to content and the Canadian studies were identified. In total, 170 publications were identified, of which 51 (30%) were Canadian. Overall, 28.2% dealt with hospital administrative measures, 20.0% with pharmacy operations management, 14.7% with pharmacy materiels management, and 37.1% with clinical pharmacy services. The area of most frequent focus for Canadian articles was clinical pharmacy (43.1%), followed by hospital administrative measures (35.3%). References were provided for all articles.     

Hospital diversification: corporate restructuring as a survival strategy

Corporate restructuring of hospitals as a strategy for survival and continued success is described. Health-care providers' traditional orientation has been toward service and mission; now, profits and new markets in health care must be considered also. To remain competitive, hospitals must be prepared to act rapidly on opportunities. Corporate reorganization, the creation of new corporate entities that perform diversified medical and nonmedical functions, may provide the flexibility needed for quick action. Legal and accounting costs will be incurred by corporate reorganization. Tax issues, staff morale, community support, and effect on hospital managers and board members should be considered. Hospitals can cut costs through vertical integration of existing services; in this system-building strategy, new services can be added to broaden the patient base. Corporate reorganization is more important for diversification--the extension of a hospital's medical and health businesses--than for system building. Guidelines for diversification are offered. Corporate reorganization is a technique that should be considered in an institution's planning process.     

Towards mitochondrial gene therapy: DQAsomes as a strategy

Mitochondrial dysfunction is a cause, or major contributing factor in the development, of degenerative diseases, aging, cancer, many cases of Alzheimer's and Parkinson's disease and Type II diabetes (D. C. Wallace, Science 283, 1482-1488, 1999). Despite major advances in understanding mtDNA defects at the genetic and biochemical level, there is no satisfactory treatment for the vast majority of patients available. Objective limitations of conventional biochemical treatment for patients with defects of mtDNA warrant the exploration of gene therapeutic approaches. However, mitochondrial gene therapy has been elusive, due to the lack of any mitochondria-specific transfection vector. We review here the current state of the development of mitochondrial DNA delivery systems. In particular, we are summarizing our own efforts in exploring the mitochondriotropic properties of dequalinium, a cationic bolaamphiphile with delocalized charge centers, for the design of a vector suited for the transport of DNA to mitochondria in living cells.     

Preventing drug use problems: the university as a site for local action

While the prevention of drug use problems comes well recommended, there is limited agreement on which preventive strategies are the most effective. Furthermore there is debate as to where activity most effectively occurs—should it be at the national or local level? In this study a university community was investigated with the aim of determining whether members of that community appreciated the need for prevention of drug use problems and which preventive strategies they deemed to be of value. The difficulties inherent in taking action within a tertiary environment are also considered and an agenda for action described. [Lockwood A, Saunders B. Preventing drug use problems: the university as a site for local action. Drug Alcohol Rev 1991; 10: 29-35]     

Maternal vaccination and preterm birth: using data mining as a screening tool

OBJECTIVE: The main purpose of this study was to identify possible associations between medicines used in pregnancy and preterm deliveries using data mining as a screening tool. SETTINGS: Prospective cohort study. METHODS: We used data mining to identify possible correlates between preterm delivery and medicines used by 92,235 pregnant Danish women who took part in the Danish National Birth Cohort (DNBC). We then evaluated the association between one of the identified exposures (vaccination) and the risk for preterm birth by using logistic regression. The women were classified into groups according to their exposure to vaccination. The regression analyses were adjusted for the following covariates: parity, infant's gender, maternal Body-Mass Index (BMI), age, smoking, drinking, job, number of inhabitants in the place of residence, infections, diabetes, high blood pressure and preeclampsia. MAIN OUTCOME MEASURE: Preterm birth, a delivery occurring before the 259th day of gestation (i.e., less than 37 full weeks). RESULTS: Data mining had indicated that maternal vaccination (among other factors) might be related to preterm birth. The following regression analysis showed that, the women who reported being vaccinated shortly before or during gestation had a slightly higher risk of giving preterm birth (O.R. = 1.14; 95% CI 1.04-1.25) as compared to the non-vaccinated group. CONCLUSION: Whether the association between maternal vaccination and the risk for preterm birth found here is causal or not deserves further studies. Data mining, especially with additional refinements, may be a valuable and very efficient tool to screen large databases for relevant information which can be used in clinical and public health research.     

Drug abuse treatment as an HIV prevention strategy: a review

We review drug abuse treatment as a means of preventing infection with HIV. Thirty-three studies, with an aggregate of over seventeen thousand subjects, were published in peer-reviewed journals from 1988-1998. Research on the utility of drug abuse treatment as an HIV prevention strategy has focused primarily on methadone maintenance treatment (MMT) rather than other modalities such as residential or outpatient drug-free treatment. Recent research provides clear evidence that MMT reduces HIV risk behaviors, particularly needle-use, and strong evidence that MMT prevents HIV infection. There is less definitive evidence that MMT reduces needle-sharing and unsafe sexual behavior, or that other treatment modalities prevent HIV infection. Future research should take into account patient self-selection processes and investigate other treatment modalities for heroin and stimulant abuse to determine their effects on HIV risk behaviors and HIV infection.     

Induced disorder in protein-ligand complexes as a drug-design strategy

Protein associations are poorly understood from a chemical perspective. If the contrary were true, drug inhibitors would be routinely designed based on target structure. While enthalpy/entropy balance is critical for affinity optimization, most drug-design strategies focus solely on promoting favorable intermolecular interactions. However, protein-drug associations often entail an entropic penalty, mostly arising from induced fits, which compromises affinity. Rather than restricting the conformational freedom of the protein, this work reports on an alternative design strategy to enhance affinity by inducing conformational disorder. This approach is adopted to target kinases by boosting their conformational entropy, taking advantage of their structural plasticity. As proof of concept we redesigned the anticancer drug imatinib to inhibit the imatinib-resistant D816V mutant of the C-Kit kinase, one of imatinib's primary targets. The prototype is engineered to promote an entropic boost on the activation loop that restores affinity. We also show that induced disorder is actually operational in kinase inhibitory action: a comparison of the binding of imatinib and PD173955 to Bcr-Abl kinase reveals that imatinib forms stronger intermolecular nonbonded interactions than PD173955, yet the latter binds with higher affinity by boosting the complex entropy. Induced disorder thus becomes a promising concept for drug design.     

Co-stimulation blockade as a new strategy in kidney transplantation: benefits and limits

New immunosuppressive drugs have greatly decreased the frequency of graft failure due to acute rejection but have had little impact on long-term graft survival. This is due, at least in part, to the broad non-immune effects of the current immunosuppressive drugs, which are involved in the death of patients and in chronic allograft dysfunction, particularly due to their nephrotoxicity. Recent progress in the development of biologicals, i.e. antibodies and fusion proteins, allows precise targeting of the immune system, preventing the non-immune side effects encountered with current protocols. In particular, targeting of the two most important co-stimulation pathways critical for T-cell activation, i.e. B7/CD28 and CD40/CD40L, has provided excellent results in many experimental models of organ transplantation. This has led to the clinical development of belatacept, a cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA4-Ig) fusion protein, which has proved to be efficient in preventing acute rejection in kidney transplant recipients. Its use is associated with improved renal function and a better metabolic profile than calcineurin inhibitors. However, because belatacept does not selectively target alloreactive T lymphocytes and must be combined with classical immunosuppressive drugs, infectious and neoplastic complications may occur, particularly post-transplantation lymphoproliferative disorders. We also address the current development of molecules targeting other co-stimulatory pathways (CD40/CD40L, leukocyte function-associated antigen [LFA]-1/intercellular adhesion molecule [ICAM], CD2/LFA-3). Many unresolved issues regarding the use of co-stimulation blocking agents are also discussed, e.g. their long half-life, which can be problematic in cases of serious adverse events, their long-term safety and efficacy, and the lack of monitoring tools to allow modulation of their use over time.     

Pathological and nonpathological gamblers: a survey in gambling settings

In this first study on gambling in Brazil, pathological and non-pathological gamblers were surveyed at three bingo clubs, one video poker club, and one horse-racing club in S?o Paulo. The South Oaks Gambling Screen and a questionnaire were administered to 171 subjects. When compared to nonpathological gamblers, a significantly higher proportion of pathological gamblers played cards, horse races, video poker, and dice in their lifetime. The two groups were similar with respect to socially acceptable games such as lotteries, bingo, sports, and the stock market. No significant differences were observed in drug consumption except for a higher lifetime consumption of tobacco among pathological gamblers. Only 4.9% of the gamblers sought help for gambling-related problems, suggesting that gambling is not generally perceived as a mental health problem by these subjects.     

JNK inhibition as a potential strategy in treating Parkinson's disease

Parkinson's disease is characterized by the pathological loss of dopaminergic neurons in the substantia nigra. The current therapy for Parkinson's disease is aimed to replace the lost transmitter. But the ultimate objective in the neurodegenerative therapy is the functional restoration and/or cessation of progression of neuronal loss. Given the critical role that the c-Jun N-terminal kinase (JNK) pathway plays in regulating the cellular processes that are involved in Parkinson's disease, the importance of JNK in this disease's pathogenesis is being increasingly recognized. Much evidence suggests that JNK plays an important role in mediating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridnium ion (MPP(+))-induced neurotoxicity. Therefore, direct blockade of JNK may prevent or effectively slow the progression of Parkinson's disease. Studies including our own showed that the inhibition of JNK with SP-600125, a specific inhibitor of JNK, protects dopaminergic neurons both from MPP(+)-induced neuronal apoptosis in vitro and in MPTP Parkinson's disease model. These results support JNK inhibition as a potential strategy in treating Parkinson's disease.