Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART.

The 'Berlin Patient', who maintains suppressed levels of HIV viremia in the absence of antiretroviral therapy, continues to be a standard bearer in HIV eradication research. However, the unique circumstances surrounding his functional cure are not applicable to most HIV(+) patients. To achieve a functional or sterilizing cure in a greater number of infected individuals worldwide, combinatorial treatments, targeting multiple stages of the viral life cycle, will be essential. Several anti-HIV gene therapy approaches have been explored recently, including disruption of the C-C chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptor loci in CD4(+) T cells and CD34(+) hematopoietic stem cells. However, less is known about the efficacy of these strategies in patients and more relevant HIV model systems such as non-human primates (NHPs). Combinatorial approaches, including genetic disruption of integrated provirus, functional enhancement of endogenous restriction factors and/or the use of pharmacological adjuvants, could amplify the anti-HIV effects of CCR5/CXCR4 gene disruption. Importantly, delivering gene disruption molecules to genetic sites of interest will likely require optimization on a cell type-by-cell type basis. In this review, we highlight the most promising gene therapy approaches to combat HIV infection, methods to deliver these therapies to hematopoietic cells and emphasize the need to target viral replication pre- and post-entry to mount a suitably robust defense against spreading infection.

3D solution structure of copper and silver-substituted yeast metallothioneins.

3D solution structural calculations for yeast silver(I)-substituted metallothionein (MT) and native copper(I) MT were completed using experimentally determined NOE and dihedral angle constraints, in conjunction with experimentally derived metal-to-Cys connectivities for AgMT which were assumed identical for CuMT. For the first 40 residues in both structures, the polypeptide backbone wraps around the metal cluster in two large parallel loops separated by a deep cleft containing the metal cluster. Minor differences between the two structures include differences in hydrogen bonds and the orientation of the N-terminus with the overall protein volume conserved to within 6.5%.

Venous thrombosis: an overview.

Venous thromboembolic disease contributes to morbidity and mortality in certain groups of hospitalized patients, particularly those who have undergone surgery. Although principles of treatment have changed relatively little during the past 20 years, significant advances have been made in the diagnosis of deep vein thrombosis (DVT). Venography, once the only reliable diagnostic technique, has been largely replaced by noninvasive tests: impedance plethysmography, venous Doppler, 125I-radiofibrinogen-uptake test, and phleborheography. Virchow's triad of stasis, vessel injury, and hypercoagulability remains a valid explanation of the pathogenesis of thrombus formation, but laboratory and clinical data have refined our knowledge of how these factors interact to result in clinically significant disease. Knowledge of the natural history of venous thrombosis, plus heightened awareness of the long-term morbidity and expense associated with the postphlebitic syndrome, have led to increased interest in preventing DVT. Clinically and economically, venous thrombosis is best managed by prevention.

Exploring psychiatric prescribing practices: the relationship between the role of the provider and the appropriateness of prescribing.

The prescribing habits of psychiatrists and neurologists in a large, urban Veterans Administration medical center were surveyed. It was determined that these physicians prescribed a large amount of nonpsychotropic medication, and the rationale for this practice was explored and is presented. Patient expectations in this population derived from certain established sociocultural biases toward the medical profession appeared to significantly influence prescribing practices. Such prescribing behavior suggests that the psychiatrist in this setting is often required to assume the role of primary care provider as part of a larger patient therapist relationship.

Treating hemophilia.

Hemophilias A and B are inherited disorders of clotting-factor production that are characterized by low levels of factor VIII- or IX-coagulant activity. The clinical course of patients with hemophilia is marked by episodes of hemorrhage, some spontaneous and some related to trauma or medical procedures. The physical well-being of patients with hemophilia is maintained by the prevention of bleeding when possible and by prompt, effective treatment of bleeding when it occurs. Factor-replacement therapy continues to be the mainstay of hemophilia treatment, but like pharmacotherapy for other disease states, it is most effective when provided within the framework of a well-designed, individualized therapeutic plan. Currently available factor concentrates have a much greater safety profile than older products, but they are not free of adverse effects. Patients with inhibitors continue to present a challenge in restoring hemostasis. Pharmacists can play an important role in the pharmaceutical care of patients with hemophilia.