DNA damage effects of a polyamide-CBI conjugate in SV40 virions

Polyamides are a class of synthetic molecules that exhibit high-affinity, sequence-specific reversible binding in the DNA minor groove but are incapable of inducing DNA damage. In cell-free systems, polyamides have been shown to regulate gene expression by activation, repression, and antirepression. However, effectiveness in cell culture has met with limited success and seems to be cell-dependent. By combining a polyamide with a moiety of a DNA-alkylating agent of the cyclopropylpyrroloindole (CPI) family, a conjugate molecule [polyamide 1-CBI (1-(chloromethyl)-5-hydroxyl-1,2-dihydro-3H-benz[e]indole) conjugate] capable of sequence-specific DNA alkylation was shown to exhibit cellular activity (i.e., cell-growth inhibition and cell-cycle arrest) in mammalian cells. These effects, however, occur at concentrations several orders of magnitude higher than those of its parent CPI agent adozelesin. In addition, 1-CBI is able to interact sequence-specifically with viral DNA and inhibit SV40 DNA replication in infected BSC-1 (African green monkey kidney epithelial) cells, albeit at a greatly reduced ability compared with its CPI parent. On the basis of results from previous studies, we tested whether pretreatment of virus with 1-CBI, compared with direct treatment of infected cells, would enhance its cellular activity. Therefore, using SV40 virions as a model system, we examined the ability of this conjugate molecule to penetrate SV40 virions and damage viral DNA. Our results demonstrate that 1-CBI is able to damage encapsidated SV40 DNA. Both DNA replication and virus production are effectively inhibited in a concentration-dependent manner after infection of BSC-1 cells with 1-CBI-pretreated virions. It is surprising that, unlike in mammalian cells, the relative activity of 1-CBI in SV40 virions is comparable with that of the highly cytotoxic CPI agent adozelesin. Because 1-CBI is able to efficiently penetrate virions and damage DNA, these findings may provide the framework for the development of polyamide-based antiviral agents with enhanced sequence-preference capabilities.     

Periprosthetic bone remodeling around a prosthesis for distal femoral tumors: longitudinal follow-up

Serial measurements using dual-energy x-ray absorptiometry (DEXA) were undertaken to evaluate progressive periprosthetic bone loss in patients treated for primary bone tumors of the distal femur using an uncemented tumor prosthesis. Twelve patients underwent sequential DEXA analysis on average 26.5 and 90.9 months postsurgery. Changes in bone mineral density were measured in regions of interest (ROIs) around the prosthesis stem. The test-retest reliability coefficient (r) ranged from 0.92 to 0.99 for all ROI. In the most distal ROI (ROI1), 10 of 11 patients with 2 measurements showed no change or a small increase in absolute bone mineral density. The results in other ROIs were similar. This longitudinal DEXA data suggest that progressive bone resorption is not problematic with an uncemented distal femur endoprosthesis at intermediate follow-up. Key words: DEXA, stress shielding, uncemented endoprothesis, tumor, bone loss.     

BDNF-induced facilitation of afferent-evoked responses in lamina II neurons is reduced after neonatal spinal cord contusion injury

We previously reported that brain-derived neurotrophic factor (BDNF), a pronociceptive neurotransmitter, induces synaptic facilitation of excitatory postsynaptic current (EPSC) in lamina II neurons of neonatal rats up to P14 in a N-methyl-d-aspartate (NMDA) receptor-dependent manner. Here we used the patch-clamp technique to study synaptic and NMDA-evoked responses in transverse spinal slices in the lumbar enlargement as well as the ability of BDNF to modify these responses from 1 day to 6 wk after neonatal contusion. In older uninjured animals (>P14), BDNF continued to evoke synaptic facilitation although superfusion of NMDA (in TTX) induced inward current of significantly smaller amplitude than that observed in younger rats. After contusion injury, BDNF was unable to facilitate dorsal root-evoked EPSCs in lamina II neurons despite the finding that NMDA-evoked currents were only slightly smaller than those observed in age-matched uninjured animals. These findings suggest that although BDNF-induced facilitation of the AMPA/kainate receptor-mediated response to dorsal root stimulation is maintained in the mature dorsal horn from intact rats, BDNF may no longer elicit these pronociceptive actions after neonatal contusion injury. The lack of change in NMDA-evoked currents in contused cords suggests that diminished NMDA receptor function is not the major cause of the decline in BDNF action after contusion. It seems more likely that diminished trkB expression and enhanced expression of truncated trkB receptors in the contused cord play a significant role in determining the reduced effect of BDNF under these conditions.     

Self-neglect: the role of judgements and applied ethics

Self-neglect is more common than currently recognised. This article highlights the issue of self-neglect and the accompanying ethical values and judgements associated with it. A multidisciplinary framework for managing self-neglect is also described.     

Unrecognised Ovarian Pseudomucinous and Serous Cystadenomata in Late Pregnancy Associated with Procidentia

Ovarian tumours in pregnancy are rare, the incidence in several series being 1:1,000 to 1:8,000 (Gustafson et al., 1954). The commonest tumours are pseudomucinous cystadenomata, and benign cystic terato-mata the second commonest. These two tumours may coexist in the same patient (Novak and Novak, 1965). Coexistent bilateral serous cystadenocarcinoma and bilateral benign cystic teratoma in pregnancy was recorded by Gleichert (1964).     

A nutritional supplement for improving fertility in women: a pilot study

OBJECTIVE: To determine the impact of nutritional supplementation on optimization of reproductive health in women. STUDY DESIGN: A double-blind, placebo-controlled pilot study was initiated to determine the effects of FertilityBlend (Daily Wellness Co., Sunnyvale, California), a proprietary nutritional supplement containing chasteberry and green tea extracts, L-arginine, vitamins (including folate) and minerals. Changes in progesterone level, basal body temperature, menstrual cycle, pregnancy rate and side effects were monitored. RESULTS: Thirty women aged 24-46 years who had tried unsuccessfully to conceive for 6-36 months completed the study. After 3 months, the supplement group (n = 15) demonstrated a trend toward an increase in mean midluteal phase progesterone level (from 8.2 to 12.8 ng/mL, P = .08) and a significant increase in the average number of days in the cycle with basal temperatures >37 degrees C during the luteal phase (6.8-9.7 days, P = .04). The placebo group (n = 15) did not show any notable changes after treatment in any of the parameters studied. After 5 months, 5 of the 15 women in the supplement group were pregnant (33%), and none of the 15 women in the placebo group were (P <.01). No significant side effects were noted. CONCLUSION: Nutritional supplementation may provide an attractive alternative or complement to conventional fertility therapy.