Treatment of impulsivity and aggression in a patient with vascular dementia

This case illustrates how treatment with divalproex sodium, an agent approved for use as an anticonvulsant and mood stabilizer, led to a reduction in overt aggression, diminished impulsivity, and improved functional status in a patient with vascular dementia. Improved receptivity to care and reduced hostility also led to an increased quality of life for the family caregivers. The daughter also benefited greatly from participation in a family support group.     

Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis

Differentiation-inducing agents, such as retinoids and short-chain fatty acids, have an inhibitory effect on tumor cell proliferation and tumor growth in preclinical studies. Clinical trials involving these compounds as single agents have been suboptimal in terms of clinical benefit. Our study evaluated the combination of phenylbutyrate (PB) and 13-cis retinoic acid (CRA) as a differentiation and antiangiogenesis strategy for prostate cancer. On the basis of previous evidence, common signal transduction pathways and possible modulation of retinoid receptors and retinoid response elements by PB could be responsible for such activities. We assessed the effect of the combination of PB and CRA on human and rodent prostate carcinoma cell lines. The combination of PB and CRA inhibited cell proliferation and increased apoptosis in vitro in an additive fashion as compared with single agents (P < 0.014). Prostate tumor cells treated with both PB and CRA revealed an increased expression of a subtype of retinoic acid receptor (retinoic acid receptor-beta), suggesting a molecular mechanism for the biological additive effect. The combination of PB and CRA also inhibited prostate tumor growth in vivo (up to 82-92%) as compared with single agents (P < 0.025). Histological examination of tumor xenografts revealed decreased in vivo tumor cell proliferation, an increased apoptosis rate, and a reduced microvessel density in the animals treated with combined drugs, suggesting an antiangiogenesis effect of this combination. Thus, endothelial cell treatment with both PB and CRA resulted in reduced in vitro cell proliferation. In vivo testing using the Matrigel angiogenesis assay showed an additive inhibitory effect in the animals treated with a combination of PB + CRA (P < 0.004 versus single agents). In summary, this study showed an additive inhibitory effect of combination of differentiation agents PB and CRA on prostate tumor growth through a direct effect on both tumor and endothelial cells.     

Toluene diisocyanate colocalizes with tubulin on cilia of differentiated human airway epithelial cells.

Toluene diisocyanate (TDI), a highly reactive industrial chemical with widespread use in the manufacture of polyurethane and plastics, is the leading cause of occupational asthma associated with chemical exposure. We report the effects of TDI vapor (20, 100, 500, 1000 ppb) in vitro on differentiated human bronchial epithelial cells. Increased mucus was observed by electron microscopy at all TDI concentrations. Cytotoxicity, as evidenced by cell pyknosis and DNA fragmentation, was detected following a 30-min exposure to TDI concentrations of 100 ppb or higher. At 1000 ppb, transepithelial resistance was lost. Using confocal microscopy and double staining, TDI was found colocalized with ciliary tubulin in cultures that had been exposed to 20 and 100 ppb. These findings are the first to identify TDI binding to human pulmonary epithelial cells and indicate extensive binding to the cilia of differentiated epithelial cells. The in vivo implications of these findings include decreased ciliary movement and longer retention of TDI and hence increased exposure. Altered cytoskeletal-derived signal transduction may be a consequence of tubulin involvement. The effects of such changes on respiratory sensitization remain to be explored.     

Production of genetically stable high-titer retroviral vectors that carry a human gamma-globin gene under the control of the alpha-globin locus control region

The ability to generate stable high-titer vectors that give rise to high levels of expression of transduced globin genes in erythroid cells is a prerequisite for effective retroviral-mediated globin gene therapy. The human beta-globin gene with its immediate flanking sequences does not contain all the regulatory elements necessary for regulated high-level and position-independent expression in erythroid cells. The regulatory element known as the beta-globin locus control region (BetaLCR) can provide a linked Beta-globin gene with these properties. However, addition of BetaLCR sequences to a retrovirus carrying a beta-globin gene increases its genetic instability. We have developed a new generation of retroviral vectors in which a human gamma- globin gene is placed under the control of the alphaLCR, the major regulatory element of the alpha-globin gene cluster. We demonstrate that these retroviruses are genetically stable in producer cell lines and can be produced at high titers that exceed 5 x 10(6) colony-forming units (CFU)/mL. In addition, we show that the transduced gamma-globin gene can be expressed in the adult erythroid environment of mouse erythroleukemia (MEL) cells at a level comparable to that of a single endogenous Betamaj-globin gene. These retroviruses can also transduce primary murine bone marrow progenitor cells as efficiently as retroviruses that carry the neomycin resistance (neor) gene. This new generation of globin retroviral vectors may prove useful for gene therapy of human beta-globin gene disorders such as sickle cell disease and beta-thalassemia.     

Biomarkers of periodontal inflammation in the Australian adult population

Background:  Several inflammatory biomarkers are implicated in the pathogenesis of periodontitis including interleukin-1β (IL-1β) and C-reactive protein (CRP). This study investigated the presence of these factors in gingival crevicular fluid (GCF) and their relationship to clinical and social determinants of periodontitis in the Australian population.
Methods:  Equal numbers of periodontitis cases and non-cases were sampled during oral epidemiologic examination in the National Survey of Adult Oral Health. GCF was sampled from four sites where probing pocket depth (PPD) and recession were recorded. From these, IL-1β and CRP were quantified by ELISA and the log amount of GCF IL-1β (pg) per person and the proportion of adults with detectable CRP was computed.
Results:  Periodontitis cases (n = 511) had significantly higher levels of IL-1β and CRP than non-cases (n = 562). PPD, clinical attachment loss, plaque and gingivitis indices were positively associated with elevated levels of both biomarkers. Levels of both were positively associated with age, low socio-economic position and non-Australian birth.
Conclusions:  The presence of IL-1β and CRP in GCF are associated with periodontal disease parameters within the Australian population. The levels of both biomarkers are influenced by age, education and eligibility for public dental care.     

Clonal evolution in B-lineage acute lymphoblastic leukemia by contemporaneous VH-VH gene replacements and VH-DJH gene rearrangements

B-cell acute lymphoblastic leukemia (B-ALL), more frequently than any other B-lineage neoplasm, exhibits oligoclonal Ig heavy chain (IgH) gene rearrangement in 15% to 43% of all cases studied. To study the molecular processes that promote multiple IgH rearrangements, a comprehensive sequence analysis of a B-ALL case was performed in which seven clonal IgH gene rearrangements were identified. The genetic profiles suggested that a single leukemic progenitor clone evolved into several subclones through dual processes of variable (VH) to preexisting diversity-joining (DJH) gene segment rearrangement and VH to VH gene replacement. Predominant IgH-V usage and the uniquely rearranged clonotype-specific VHDJH region gene sequences were identified using a novel DNA-based gene amplification strategy. Polymerase chain reaction (PCR) was directed by an IgH-J generic primer and a complement of family-specific IgH-V primers that defined the major B-cell IgH-V gene usage. Clonality of rearranged VHDJH bands was substantiated by high resolution denaturant gel electrophoretic analysis. Sequence patterns of the amplified VHDJH fragments segregated into two groups defined by common DJH sequences. Partial N region homology at the VHD junction as well as shared DJH sequences firmly established VH to VHDJH gene replacement as a mechanism generating clonal evolution in one group. In the second subset, oligoclonality was propagated by independent VH gene rearrangements to a common DJH precursor. The contributions of all clonal Ig-VHDJH repertoires for each group was approximately 50% and reflected a symmetric distribution of leukemic subclones generated by either process. Thus, oligoclonal rearrangements evolved by two independent, yet seemingly contemporaneous molecular genetic mechanisms. All seven clones displayed nonfunctional Ig-VHDJH recombinations. These observations may have relevance to the recombinatorial opportunities available during normal B-cell maturation.