Combination insulin and sulfonylurea therapy in insulin-requiring type 2 diabetes mellitus

OBJECTIVES: To identify ethical dilemmas experienced by occupational and physical therapists working in the UK National Health Service (NHS). To compare ethical contexts, themes and principles across the two groups. DESIGN: A structured questionnaire was circulated to the managers of occupational and physical therapy services in England and Wales. SUBJECTS: The questionnaires were given to 238 occupational and 249 physical therapists who conformed to set criteria. RESULTS: Ethical dilemmas experienced during the previous six months were reported by 118 occupational and 107 physical therapists. The two groups were similar in age, grade, and years of experience. Fifty of the occupational therapy dilemmas occurred in mental health settings but no equivalent setting emerged for physical therapy. Different ethical themes emerged between the two groups, with the most common in occupational therapy being difficult/dangerous behaviour in patients and unprofessional staff behaviour, and for physical therapists resource limitations and treatment effectiveness. No differences were found in the ethical principles used. CONCLUSION: The ethical dilemmas reported by the therapists were primarily concerned with health care ethics, rather than the more dramatic ethics reported in much of the biomedical ethics literature. Differences were found between the two professional groups when ethical contexts and themes were compared but not when ethical principles were compared. This suggests that educators and researchers need to be aware of work settings and the interdisciplinary nature of employment as well as ethical principles held by individual therapists.     

Novel applications of liposomes

Opinions of the usefulness of liposomes in various biotechnological applications range from unsubstantiated optimism to undeserved pessimism. This article reviews the background and development of liposomes, describes products that are commercially available and speculates optimistically about some future applications. The current deepening and widening of interest in liposomes in many scientific disciplines, and their application in medicine, immunology, diagnostics, cosmetics, ecology, cleansing and the food industry are promising novel breakthroughs and products.     

Molecular recognition of cyclic urea HIV-1 protease inhibitors

As long as the threat of human immunodeficiency virus (HIV) protease drug resistance still exists, there will be a need for more potent antiretroviral agents. We have therefore determined the crystal structures of HIV-1 protease in complex with six cyclic urea inhibitors: XK216, XK263, DMP323, DMP450, XV638, and SD146, in an attempt to identify 1) the key interactions responsible for their high potency and 2) new interactions that might improve their therapeutic benefit. The structures reveal that the preorganized, C2 symmetric scaffolds of the inhibitors are anchored in the active site of the protease by six hydrogen bonds and that their P1 and P2 substituents participate in extensive van der Waals interactions and hydrogen bonds. Because all of our inhibitors possess benzyl groups at P1 and P1', their relative binding affinities are modulated by the extent of their P2 interactions, e.g. XK216, the least potent inhibitor (Ki (inhibition constant) = 4.70 nM), possesses the smallest P2 and the lowest number of P2-S2 interactions; whereas SD146, the most potent inhibitor (Ki = 0.02 nM), contains a benzimidazolylbenzamide at P2 and participates in fourteen hydrogen bonds and approximately 200 van der Waals interactions. This analysis identifies the strongest interactions between the protease and the inhibitors, suggests ways to improve potency by building into the S2 subsite, and reveals how conformational changes and unique features of the viral protease increase the binding affinity of HIV protease inhibitors.     

Diversification of subtype E human immunodeficiency virus type 1 env in heterosexual seroconverters from Northern Thailand

The C2-V3 region of the human immunodeficiency virus (HIV)-1 env was determined from 15 northern Thailand seroconverters between 1993 and 1995. Similar sequences were also determined from 18 seroconverting injection drug users in Baltimore. All seroconverters from northern Thailand were infected with subtype E HIV-1 on the basis of env sequences. Intersubject viral DNA distances increased from 2.3% in asymptomatic HIV-1-infected subjects characterized between 1990 and 1992 to 7.8% in these more recent seroconverters from Thailand. On the other hand, sequences from 18 seroconverters from Baltimore had a mean intersubject distance of 13.2%. The genetic diversity within HIV-1 subtype E in seroconverters in Thailand has increased significantly but is still less than that observed in HIV-1 from seroconverters in the United States, where the epidemic of HIV-1 infection is more mature. These results suggest that continued monitoring of the molecular epidemiology of HIV-1 infection in Thailand will be important for HIV vaccine development and evaluation.     

Ulcus cruris--vascular etiology and surgical treatment options

Leg ulcers comprise a problem with various contributing factors requiring selective therapy adapted to the underlying cause. The majority can be classified as arterial (approx. 20%) or venous (approx. 80%) ulcers. Arterial ulcers as well as most mixed (arterial-venous) ulcers can be treated by arterial reconstruction and subsequent skin grafting, with additional ligation of perforator veins or (segmental) stripping of the saphenous vein. Leg ulcers due to chronic insufficiency of the deep venous system are most often the result of previous deep venous thrombosis followed by recanalization and development of a postthrombotic syndrome. Compression regimens remain standard therapy with emphasis on preventing ulcer formation. Ulcer healing can be achieved by compression therapy although recurrence rates are high. Surgery is not the treatment of first choice for leg ulcers, however, in selected cases surgical therapy is indicated. To prevent recurrence, continued consistent compression, keeping the patient well-informed and offering supportive guidance are imperative.     

Quantitative assay for epinephrine in dental anesthetic solutions by capillary electrophoresis

A simple and robust method for the separation and quantification of epinephrine in dental anesthetic solutions was developed. The method allows the direct injection of high salt solutions without sample pre-treatment. Large sample plugs (5.7% of the total capillary length) are used for epinephrine determination by selective analyte focusing in capillary electrophoresis. The concentration detection limit for epinephrine is about 5.0 x 10(-7) M (90 ng ml-1) with a commercial UV detector. The separation protocol was validated in terms of its precision, linearity, accuracy and specificity.     

Halogen-substituted trimetoquinol analogs as thromboxane A2 receptor antagonists in platelets and aorta

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.