Regulation of synaptic plasticity in a schizophrenia model

The pathology of schizophrenia is characterized by increased hippocampal activity at baseline and during auditory hallucinations. Animal-model studies in which the flow of activity to the hippocampus is increased through decreased amygdalar GABAergic inhibition have shown alterations of hippocampal circuitry similar to schizophrenia, but the functional importance of this phenomenon remains unclear. We provide evidence of decreased hippocampal feed-forward and tonic GABA-mediated inhibition in this animal model, complementing increased hippocampal activity seen in neuroimaging and postmortem studies. We demonstrate that GABA dysfunction increases long-term potentiation through activation of the cholinergic system, offering a new mechanism for pharmacological strategies of this disorder.     

Sequence-specific DNA strand cleavage by <Superscript>111</Superscript>In-labeled peptide nucleic acids

Peptide nucleic acids (PNAs) bind tightly and sequence-specifically to single- and double-stranded nucleic acids, and are hence of interest in the design of gene-targeted radiotherapeutics that could deliver the radiodamage to designated DNA and/or RNA sites. As a first step towards this goal, we developed a procedure for incorporation of Auger electron-emitting radionuclide (indium-111) into PNA oligomers and studied the efficiency of PNA-directed cleavage of single-stranded DNA targets. Accordingly, diethylene triamine penta-acetic acid (DTPA) was conjugated to the lysine-appended mixed-base PNAs and sequence-homologous DNA oligomer with a proper linker for comparative studies. By chelation of PNA-DTPA and DNA-DTPA conjugates with ¹¹¹In³⁺ in acidic aqueous solutions, ¹¹¹In-labeled PNA and DNA oligomers were obtained. Targeting of single-stranded DNA with PNA-DTPA-[¹¹¹In] conjugates yielded highly localized DNA strand cleavage; the distribution of breaks along the target DNA strand has two maxima corresponding to both termini of PNA oligomer. After 10–14 days, the overall yield of breaks thus generated within the PNA-targeted DNA by ¹¹¹In decay was 5–7% versus 2% in the case of control oligonucleotide DNA-DTPA-[¹¹¹In]. The estimated yield of DNA strand breaks per nuclear decay is ~0.1 for the PNA-directed delivery of ¹¹¹In, which is three times more than for the DNA-directed delivery of this radionuclide. This in vitro study shows that ¹¹¹In-labeled PNAs are much more effective than radiolabeled DNA oligonucleotides for site-specific damaging of DNA targets. Accordingly, we believe that PNA oligomers are promising radionuclide delivery tools for future antisense/antigene radiotherapy trials.     

Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir

The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.     

Damage of vascular endothelium in the treatment of acute leukemia: in vitro study

AIM: Cytostatic drugs used in the treatment of hemopoietic malignancies affect cells of other organs and systems, vascular endothelium, in particular. This leads to cardiovascular complications. We studied effects of some drugs and their combinations on cultured human endothelial cells (EC). MATERIAL AND METHODS: Primary culture of umbilical human vein EC was used in the study. Cytosinearabinoside (cytozar, alexan, cytarabin) and daunorubicin were added in concentration from 1 ng/ml to 1 mg/ml; the action of the drugs was assessed by morphology of the cells, their viability, inclusion of bromodesoxyuridine by means of cloning, immunohistochemistry and flow cytofluorimetry. RESULTS: It is shown that in a wide range of concentrations cytosinearabinoside and daunorubicine cause specific structural-functional changes in the cells related to cytostatic and cytotoxic effects. CONCLUSION: The data of the study confirm that cardiovascular complications in the course of acute leukemia treatment are resultant from systemic damage to vascular endothelium.     

Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo

OBJECTIVE: The objective of this study was to assess the potential of 3 spectroscopic techniques (intrinsic fluorescence, diffuse reflectance, and light scattering) individually and in combination (trimodal spectroscopy) for the detection of cervical squamous intraepithelial lesions. STUDY DESIGN: The study was conducted with 44 patients who underwent colposcopy for the evaluation of an abnormal Papanicolaou smear. Fluorescence and reflectance spectra were collected from colposcopically normal and abnormal sites and analyzed to extract quantitative information about tissue biochemistry and morphologic condition. This information was compared with histopathologic classification, and diagnostic algorithms were developed and validated with the use of logistic regression and cross-validation. RESULTS: Diagnostically significant differences exist in the composition of fluorescing biochemicals, the scattering properties, and the epithelial cell nuclear morphology of cervical squamous intraepithelial lesions and non-squamous intraepithelial lesions. Trimodal spectroscopy is a superior tool for the detection of cervical squamous intraepithelial lesions than any 1 of the techniques alone. CONCLUSION: Trimodal spectroscopy has the potential to improve the in vivo detection of precancerous cervical changes.