Effects of terazosin on serum lipid levels in hypertensive blacks

The effects of terazosin, a new, selective, alpha 1-adrenoceptor antagonist, on the serum lipid levels were examined in 103 black patients with uncomplicated, mild to moderate essential hypertension in six randomized, double-blind, placebo-controlled trials conducted in the United States. Terazosin produced statistically significant (P less than 0.05) reductions in total serum cholesterol and triglyceride levels and a marginally significant (P = 0.080) reduction in the combined low-density lipoprotein (LDL-C) and very-low-density lipoprotein (VLDL-C) cholesterol fraction when compared with placebo. We conclude that terazosin, unlike thiazide diuretics, has a favourable effect on the serum lipid profiles of hypertensive blacks.     

Antisense oligonucleotide inhibition of Bcl-xL and Bid expression in liver regulates responses in a mouse model of Fas-induced fulminant hepatitis

Activation of the cell-surface receptor Fas can lead to apoptosis in parenchymal cells in the liver, and if severe enough, result in fulminant hepatic failure and animal death. In the present study, we have examined the roles played by the Bcl-2 family members Bcl-xL and Bid in regulating this response. To do this, we have developed chemically modified 2'-O-(2-methoxy) ethyl antisense inhibitors of both Bid and Bcl-xL expression. In Balb/c mice, dosing with these antisense oligonucleotides reduced expression of the targeted mRNA by greater than 80% in the liver. This reduction was highly dependent upon oligonucleotide sequence and oligonucleotide dose. Reduction of Bcl-xL expression resulted in a potentiation of Fas-mediated apoptosis in liver and significant increase of the lethality of Fas-mediated fulminant hepatitis (p < 0.0001). In contrast, reduction of Bid expression protected the animals against Fas-mediated fulminant hepatitis and death (p < 0.0001). Simultaneous dosing of mice with Bcl-xL and Bid-targeting antisense oligonucleotides resulted in an inhibition of expression of both targeted proteins and protection of the animals from Fas-mediated apoptosis. These results demonstrate, for the first time, the role of Bcl-xL in regulating responses to proapoptotic Fas signaling in mouse liver. In addition, this is the first reported example demonstrating the ability of antisense inhibitors to reduce expression of multiple proteins in animals by simultaneous dosing.     

Age-specific activities that support successful transition to adulthood for children with disabilities

Twenty-two activities that support transition to adulthood previously published by Blomquist et al. 1998) were explored in a focus group with parents of successful young adults with disabilities. Parents rated these activities on a 5-point Likert scale, and comments were gathered about the activities parents felt were essential for transition to adulthood. Parents rated the activities high with highest agreement being: "Do not do for them what they can do for themselves," "Assign appropriate household chores," and "Help children interact with others in varied settings." The lowest agreement ratings involved issues about school to work transitions, vocational programs within schools, and strategies assuring continuity of care with adult health care providers. Parents offered insights into the daily activities in school, home, and community that support transition to adulthood. Through review and understanding of these transition activities, health care professionals gain insight into the activities fostering a child's independence throughout their development.     

Treatment of murine disseminated candidiasis with L-743,872.

L-743,872 (M991), which is a pneumocandin derivative, was evaluated in a mouse model of disseminated candidiasis caused by a fluconazole-resistant isolate of Candida albicans. In immunocompetent mice M991 prolonged survival at doses as low as 0.0125 mg/kg of body weight per day. In neutropenic mice 0.05 mg/kg was the lowest effective dose. M991 is a very potent drug for treatment of disseminated candidiasis.     

Guiding blind T cells and dendritic cells: A closer look at fibroblastic reticular cells found within lymph node T zones

It is within the T cell rich zone of secondary lymphoid organs (SLO) that dendritic cells (DC) present the captured pathogens to recirculating T cells in order to activate the rare antigen-specific T cells. While we have made considerable progress in understanding the biology of mobile hematopoietic cells found within SLO, notably DC and lymphocytes, we still have a lot to learn about the sessile stromal cells. This review is focused on the recent progress made in our understanding of the fibroblastic reticular stromal cells that form the 'niches' within the T zone.     

Subcellular localization of p27 and prostate cancer recurrence: automated digital microscopy analysis of tissue microarrays

Previous investigations have linked decreased nuclear expression of the cell cycle inhibitor p27 with poor outcome in prostate cancer. However, these reports are inconsistent regarding the magnitude of that association and its independence from other predictors. Moreover, cytoplasmic translocation of p27 has been proposed as a negative prognostic sign. Given the cost and accuracy limitations of manual scoring, particularly of tissue microarrays, we determined if laser-based fluorescence microscopy could provide automated analysis of p27 in both nuclear and cytoplasmic locations and, thus, clarify its significance as a prognostic biomarker. We constructed tissue microarrays covering 202 recurrent cases (rising prostate-specific antigen) and 202 matched controls without recurrence. Quadruplicate tumor samples encompassed 5 slides and 1616 cancer histospots. Cases and controls matched on age, Gleason grade, stage, and hospital. We immunolabeled epithelial cytoplasm with Alexafluor 647, p27 with Alexafluor 488, and nuclei with 4c6-diamidino-2-phenylindole·2HCl. Slides were scanned on an iCys laser scanning cytometer (CompuCyte Corp, Cambridge, MA). Nuclear crowding required a stereological approach--random arrays of circles (phantoms) were layered on images and the content of each phantom was analyzed in scatter plots. Both nuclear and cytoplasmic p27 were significantly lower in cases versus controls (P = .014 and P = .004, respectively). Regression models controlling for matching variables plus prostate-specific antigen showed strong linear trends for increased risk of recurrence with lower p27 in both nucleus and cytoplasm (highest versus lowest quartile; odds ratio, 0.35; P = .006). Manual scoring identified an inverse association between p27 expression and tumor grade but no independent association with recurrence. In conclusion, we developed an automated method for subcellular scoring of p27 without the need to segment individual cells. Our method identified a strong relationship, independent of tumor grade, stage, and prostate-specific antigen, between p27 expression--regardless of subcellular location--and prostate cancer recurrence. This relationship was not observed with manual scoring.     

Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties

The electrical and synaptic properties of neurons are essential for determining the function of the nervous system. Thus, understanding the mechanisms that control the appropriate developmental acquisition and maintenance of these properties is a critical problem in neuroscience. A great deal of our understanding of these developmental mechanisms comes from studies of soluble growth factor signaling between cells in the peripheral nervous system. The sympathetic nervous system has provided a model for studying the role of these factors both in early development and in the establishment of mature properties. In particular, neurotrophins produced by the targets of sympathetic innervation regulate the synaptic and electrophysiological properties of postnatal sympathetic neurons. In this review we examine the role of neurotrophin signaling in the regulation of synaptic strength, neurotransmitter phenotype, voltage-gated currents and repetitive firing properties of sympathetic neurons. Together, these properties determine the level of sympathetic drive to target organs such as the heart. Changes in this sympathetic drive, which may be linked to dysfunctions in neurotrophin signaling, are associated with devastating diseases such as high blood pressure, arrhythmias and heart attack. Neurotrophins appear to play similar roles in modulating the synaptic and electrical properties of other peripheral and central neuronal systems, suggesting that information provided from studies in the sympathetic nervous system will be widely applicable for understanding the neurotrophic regulation of neuronal function in other systems.