Development of a robust cytopathic effect-based high-throughput screening assay to identify novel inhibitors of dengue virus

We have developed a robust cytopathic effect-based high-throughput screening assay to identify inhibitors of dengue virus (DENV) infection. Screening of a small natural product library yielded 11 hits. Four of these were found to be potent inhibitors of DENV, although serotype differences were noted. Taken together, these data suggest that screening of larger and more complex molecule libraries may result in the identification of more potent and specific DENV inhibitors.     

Evaluation and treatment of vasculitis in the critically ill patient

The systemic vasculitides, if left untreated, often lead to major organ damage and death. When a patient presents with features that may be consistent with vasculitis, especially with pulmonary and renal findings, it is important to make a specific diagnosis as quickly as possible so that specific therapy can be started. Diagnosis is dependent on familiarity with the myriad of typical and unusual clinical features of the various vasculitides together with performance of supportive tests including serologies, angiograms, and biopsies. When evaluating a potential case of vasculitis, clinicians must comprehensively search for other more common, non-vasculitic diseases. The diagnosis may be even more difficult in patients with established diagnoses of vasculitis on immunosuppressive treatment who develop new clinical findings. Rapid initiation of immunosuppressive therapy for critically ill patients with vasculitis is crucial and may be life-saving.     

Statistics review 10: further nonparametric methods

This review introduces nonparametric methods for testing differences between more than two groups or treatments. Three of the more common tests are described in detail, together with multiple comparison procedures for identifying specific differences between pairs of groups.     

Statistics review 10: Further nonparametric methods

This review introduces nonparametric methods for testing differences between more than two groups or treatments. Three of the more common tests are described in detail, together with multiple comparison procedures for identifying specific differences between pairs of groups.     

A liberalized approach to diets for diabetes in long term care

These guidelines allow for liberalization of the dietary treatment of diabetes in type 2 diabetics in long term care facilities. The care team should work together to promote specific policies and protocols in the facility to address how individual type 2 diabetics will be assessed, and which diets will be offered as an adjunct to treatment. Careful monitoring of blood glucose levels, medications and response to treatment may allow for more liberalization of the diet. Diet liberalization can help to promote better health and improved quality of life for our elderly residents.     

Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. II. 2-Phenylpropionic acid protein binding

The binding of 2-phenylpropionic acid (2PPA) enantiomers to rabbit albumin has been studied using fatty-acid-free albumin, with and without oleic acid, and using plasma from control rabbits and from rabbits rendered uremic with uranyl nitrate. The models of binding examined included specific binding at one and at two species of binding site, nonspecific binding and with inhibition between enantiomers with competitive or noncompetitive kinetics. Although any one aspect of the data is adequately modeled by nonspecific binding together with a single species of specific site, the simplest physical model consistent with the whole data requires two species of specific site together with nonspecific binding. Oleic acid in vitro, or other modifiers in vivo, inhibit the binding at both specific sites and reduce nonspecific binding. The inhibition at one site is sufficient that the situation in whole plasma simplifies to one site plus nonspecific binding. Competition between enantiomers occurs at this remaining site, at which R-2PPA binds more avidly than S-2PPA. Both specific and non-specific binding are reduced further in uranyl nitrate-induced renal failure. In the light of these findings, we discuss the implications of enantioselective binding and of competition between enantiomers for binding sites on the interpretation of drug disposition studies.     

Engaging Client's Family and Friends in Online Counseling

This paper describes how online counseling can be used to engage family members in the recovery of clients. The counselor guides both the client and the family member separately through the stages of change, helping them commit to joint action. Each participant thinks through his or her concerns and the advantages of getting involved, each makes a specific commitment to working together under the guidance of the counselor. Finally each celebrates, with specific rituals, their decision to work together. Once the client and the family members commit to working together, the counselor guides them through the stages of change as a group. In the pre-contemplation stage, the family members are taught the goals of working together and the procedures to avoid dysfunctional conflict. In the contemplation phase, the client and the family members examine the shared environment and its links to target behavior. In the commitment to action stage, the client and the family members decide on specific changes in their shared environment. In the maintenance phase, the client and the family members analyze if the change has led to improvements. They analyze relapses and make additional cycles of improvement.     

Cancer coalitions and cancer politics

OBJECTIVES: To review the evolution of formal and informal coalitions and their involvement in cancer politics and policy. DATA SOURCES: Organizational and political experience. CONCLUSIONS: Cancer has gone through several stages of growth, from single institutions seeking specific favorable treatment, to competitive coalitions. With more than 850 cancer organizations and associations representing the various cancer constituencies, the practicalities of politics demand some consensus and cooperation remains a significant challenge. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses must be aware of the various cancer coalitions and have an understanding of how many organizations work together for the improvement of cancer care.     

Clinical laboratory testing for the antiphospholipid syndrome

The first aCL test was developed in 1983 and subsequently standardized. Although in the last 6 to 7 years, new and more specific tests have become available, the aCL ELISA and the LA tests are still the first choice to be used in diagnosis of APS. While there is now doubt that the anticardiolipin test is useful in the diagnosis of APS, limitations of the assay have caused uncertainty and misinterpretation of the value of the test. Utilization of validated ELISA kits with well-tested calibrators and an "in-house standard" may enable more reproducible measurements. Reporting results semiquantitatively preserves the clinical utilize of the test without the misinterpretation of a quantitative result that may lack precision. The development of newer tests such as the beta2GPI ELISA and the APhL ELISA Kit, utilizing the phospholipid mixture, give promise to a more specific and reliable diagnosis of APS, while retaining good sensitivity. Other tests such as ELISA for prothrombin antibodies and annexin V antibodies are still under development and will require standardization and extensive evaluation. The aCL test should continue to be done and included in the Sapporo criteria. The aCL test is not as specific as the anti-beta2GPI test, but it is very sensitive and together with the LA test should capture the majority of the APS patients. IgA aCL and anti-beta2GPI positivity alone is rare but occasionally found and shown to be associated with major clinical manifestations of APS. Therefore, it is now recommended to include both tests, IgA aCL and IgG, IgM and IgA anti-beta2GPI to confirm diagnosis of APS.     

Probiotics: overview of microbiological and immunological characteristics

Over the last few years, probiotics (commercialized as food, dietary supplements of living bacteria or pharmaceuticals) have attracted the interest of scientists as well as consumers. Recent public interest in healthier lifestyles, together with the acceptance by physicians of nonmainstream therapies, has refocused attention on the role of human microbiota in the prevention and therapy of diseases. Modulation of the intestinal microbiota may be achieved by consuming living bacteria or by consuming a combination of probiotics and prebiotics. In addition, we are learning more about the biology of probiotic microorganisms, through sequencing their genomes, and the interactions of probiotics with human cells and with pathogenic bacteria. Results from well-conducted clinical studies help to increase the acceptance of probiotics for the treatment and prevention of selected diseases, both inside and outside the GI tract. Moreover, the use of selected probiotics for particular subject groups may provide more specific health effects. The medical profession is in an ideal position to guide the consumer towards appropriate prophylactic or therapeutic uses of probiotics in health or in specific disease states.     

Place de la rééducation dans la prise en charge des patients porteurs de séquelles de poliomyélite

Specialist rehabilitation physicians have a coordinator/mediator role to play in the care of patients with post-polio sequelae. Their neuro-orthopedic knowledge and forward-looking, multiform, and progressive vision of the handicap, makes them natural managers who monitor patients from young children who must grow up, to the elderly who become highly dependent. Their medical-technical knowledge must match the progression of an existence where the patient is a co-player in his own care, especially with the occurrence of the unforeseeable complications of the natural ageing process, the more specific complications of the disease, and intercurrent comorbidity. With each stage, diagnostic discussion and therapeutic plans must be debated in order to be readjusted, together with the medical and possibly social personnel who are involved in this approach.     

Monoclonal Antibodies for Therapeutic Use: Specific Characteristics of Clinical Development,Evaluation by the Agencies,and Long-term Monitoring of Safety

Monoclonal antibodies (MoAb) are very different from other drugs. The Round Table aimed to determine whether the specific characteristics of MoAb have repercussions on their clinical development, evaluation by the health authorities, and long-term monitoring. As regards the structure-activity relationship of MoAb, classification according to mechanism of action (neutralising or agonist MoAb, cytolytic MoAb) is more relevant than to their degree of humanisation. Recommendations on their clinical development would be useful since the early phases give rise to a number of problems and are insufficiently codified. The pharmacokinetic profile is very different from that of other drugs. The concentration-effect relationship is difficult to study since the biomarkers may be apparently disconnected from the therapeutic effect. The methodology for evaluation of MoAb by the agencies, and postmarketing surveillance do not differ from the procedures used for other drugs; however, MoAb bring together a number of specific characteristics as compared with other drugs.     

Cases of Elder Abuse,Intervention and Hopes for the Future,as Reported by Home Service Personnel

This study aimed at describing cases of elder abuse reported by witnesses, intervention offered and opinions of further intervention strategies. Home service personnel from various parts of Sweden reported 97 cases. The abused person was a women in 75% of the cases. Many of the abused persons were physically and psychologically handicapped. In most of the cases the perpetrator was a spouse or a child and in one third of the cases they had a caregiving responsibility. Psychological abuse together with financial exploitation was most frequently reported. The perpetrators' possibilities to profit financially from the abused and the family conflicts were commonly reported to be contributory causes. In 75% of the cases intervention was offered. The Swedish welfare system has no specific intervention strategies in case of abuse of the elderly and therefore more possibilities to intervene and more research concerning intervention are needed.     

Natural antibody status in patients with Hashimoto's thyroiditis.

Raised levels of circulating natural antibodies (NABS) have been found in association with systemic lupus erythematosus (SLE) and chronic active hepatitis (CAH), indicative of polyclonal B-cell activation associated with these relatively non-organ specific autoimmune diseases. This study examined the natural antibody response in the organ-specific autoimmune disease Hashimoto's thyroiditis. Serum samples obtained from 69 women with newly diagnosed Hashimoto's thyroiditis together with 64 controls were analysed for IgG and IgM NABS directed at DNA, actin, myoglobin, myosin, trinitrophenyl hapten (TNP) and tubulin as the NAB antigen panel using an established ELISA. The same technique was also used to estimate thyroglobulin and thyroid microsomal autoantibody activities. Compared to a reference panel of normal serum samples, 31 of the Hashimoto's samples showed a greater than 2SD elevation of IgG and/or IgM NABS against one or more of the panel antigens together with elevated IgG thyroglobulin and thyroid microsomal antibody levels. The cases positive for one or more of the NAB panel also showed a greater incidence of active Hashimoto's thyroiditis as indicated by the presence of antibodies directed against the thyroid specific antigens. The above findings suggest that raised levels of NABS are also a feature of this organ-specific autoimmune disease. The wide ranging NAB specificities involved are consistent with an underlying or epiphenomenal state of polyclonal B-cell activation.     

Clinical significance of cross-linked fibrin degradation products in essential mixed cryoglobulinemia

Cross-linked fibrin degradation products (XDP) were measured with a highly sensitive and specific ELISA in 21 patients with essential mixed cryoglobulinemia (EMC) and in 16 controls. Patients had significantly increased levels of XDP, together with abnormalities in routine coagulation tests. Moreover, XDP were higher in patients with more severe disease. These results support the hypothesis that EMC patients have a chronic disseminated intravascular coagulation (DIC), and underline the significance of XDP measurement in the evaluation of these patients.     

Combinations of cyclophilin inhibitor NIM811 with hepatitis C Virus NS3-4A Protease or NS5B polymerase inhibitors enhance antiviral activity and suppress the emergence of resistance

Chronic hepatitis C virus (HCV) infection remains a major global health burden while current interferon-based therapy is suboptimal. Efforts to develop more effective antiviral agents mainly focus on two viral targets: NS3-4A protease and NS5B polymerase. However, resistant mutants against these viral specific inhibitors emerge quickly both in vitro and in patients, particularly in the case of monotherapy. An alternative and complementary strategy is to target host factors such as cyclophilins that are also essential for viral replication. Future HCV therapies will most likely be combinations of multiple drugs of different mechanisms to maximize antiviral activity and to suppress the emergence of resistance. Here, the effects of combining a host cyclophilin inhibitor NIM811 with other viral specific inhibitors were investigated in vitro using HCV replicon. All of the combinations led to more pronounced antiviral effects than any single agent, with no significant increase of cytotoxicity. Moreover, the combination of NIM811 with a nucleoside (NM107) or a non-nucleoside (thiophene-2-carboxylic acid) polymerase inhibitor was synergistic, while the combination with a protease inhibitor (BILN2061) was additive. Resistant clones were selected in vitro with these inhibitors. Interestingly, it was much more difficult to develop resistance against NIM811 than viral specific inhibitors. No cross-resistance was observed among these inhibitors. Most notably, NIM811 was highly effective in blocking the emergence of resistance when used in combination with viral protease or polymerase inhibitors. Taken together, these results illustrate the significant advantages of combining inhibitors targeting both viral and host factors as key components of future HCV therapies.     

Specific course of neurocirculatory dystonia in pregnancy

AIM: To study specific features of a course of neurocirculatory dystonia (NCD) in pregnancy, effects of NCD on a gestational process. MATERIAL AND METHODS: The examination of 50 pregnant women with NCD and 30 healthy pregnant women in trimesters I, II and III included clinical, laboratory, ultrasonic, dopplerometric and cardiotocographic investigations. RESULTS: Pregnancy deteriorates NCD by enhancing such clinical syndromes as respiratory, asthenic, hemorrhagic, aggravating peripheral vascular disorders. NCD women develop gestosis, placental insufficiency, had spontaneous abortions more frequently. Neonates have abnormal neonatal adaptation. CONCLUSION: In spite of enhanced clinical symptoms, pregnancy for NCD patients is not contraindicated. Management of pregnancy in NCD women should be conducted by an obstetrician together with a therapist (cardiologist).     

Clindamycin

Clindamycin is an excellent, well tolerated, effective antimicrobial agent that can be used clinically in the treatment of specific anaerobic infections as well as clinical situations when both S. aureus and anaerobes occur together.     

The role of electrotherapy in contemporary physiotherapy practice

Although electrotherapy has a well established role within physiotherapy practice, the current concepts that influence its application vary considerably from those proposed historically. It is argued that there is a place for electrophysical modalities in contemporary practice, and several basic principles are considered together with more specific information regarding two modalities namely, ultrasound and interferential therapy.Electrophysical agents are utilised to bring about physiological effects, and it is these changes which bring about the therapeutic benefit rather than the modality itself. Clinical decision protocols employing the available evidence should enable the most appropriate modality to be employed for a particular patient. Indiscriminate use of electrotherapy is unlikely to yield significant benefit, however used at the right time, it has the potential to achieve beneficial effect. The patient management programme which combines manual therapy, exercise therapy and electrotherapy, based on current evidence, should enable the most efficacious management of a patients' dysfunction. This paper aims to consider some of the current concepts in electrotherapy and to relate this to both general and specific treatments.