Annals of the New York Academy of Sciences
-
Ann. N. Y. Acad. Sci. · Jan 2005
ReviewProgress toward the genetic treatment of the beta-thalassemias.
The beta-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the beta-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated beta-globin gene in autologous HSCs is a highly attractive alternative treatment. ⋯ The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.
-
Ann. N. Y. Acad. Sci. · Jan 2005
Comparative StudyMethods for noninvasive measurement of tissue iron in Cooley's anemia.
To examine the relationship between myocardial storage iron and body iron burden, as assessed by hepatic storage iron measurements, we studied 22 patients with transfusion-dependent thalassemia syndromes, all being treated with subcutaneous deferoxamine, and 6 healthy subjects. Study participants were examined with a Philips 1.5-T Intera scanner using three multiecho spin echo sequences with electrocardiographic triggering and respiratory navigator gating. Myocardial and hepatic storage iron concentrations were determined using a new magnetic resonance method that estimates total tissue iron stores by separately measuring the two principal forms of storage iron, ferritin and hemosiderin. ⋯ By contrast, in the subset of 10 patients with beta-thalassemia major, the correlation between the 5-year average of hepatic iron concentration and the current myocardial storage iron was significant (R = .67, P = .03). In these patients, myocardial storage iron concentrations seem to reflect the control of body iron over a period of years. Magnetic resonance methods promise to provide more effective monitoring of iron deposition in vulnerable tissues, including the liver, heart, and endocrine organs, and could contribute to the development of iron-chelating regimens that more effectively prevent iron toxicity.
-
Ann. N. Y. Acad. Sci. · Dec 2004
Early events in antigen-specific regulatory T cell induction via nasal and oral mucosa.
Mucosal Tr prevent harmful immune responses to innocuous antigens that are encountered at the mucosae. This unique subset of Tr is adaptive, antigen specific, and suppresses irrespective of cytokine polarization. Here we study the earliest events of mucosal Tr induction and factors that control their differentiation from naive T cells.
-
Ann. N. Y. Acad. Sci. · Dec 2004
Role of constitutively activated and insulin-like growth factor-stimulated ERK1/2 signaling in human hepatoma cell proliferation and apoptosis: evidence for heterogeneity of tumor cell lines.
Enhanced insulin-like growth factor II (IGF-II) and type I IGF receptor (IGF-IR) gene expression in liver tumors and the development of liver tumors in transgenic mice overexpressing IGF-II in the liver suggest that the IGFs and underlying signaling cascades may play auto/paracrine roles in the control of hepatocarcinoma (HCC) cell proliferation and in their protection against apoptosis. We have focused on the role of mitogen-activated protein kinase (ERK1/2) signaling on human HepG2 and Huh-7 hepatoma cell proliferation and on the protection of these cells against drug-induced apoptosis. Physiological concentrations of IGF-I stimulated DNA replication in HepG2 cells (1.5-fold) but not in Huh-7 cells, and this effect was abolished by PD98059 (MEK-1 inhibitor). ⋯ We have shown that drug treatment enhanced (17-fold) or did not modify constitutive ERK1/2 activity in cultured HepG2 or Huh-7 cells, respectively. In both cell lines, inhibition of constitutive and drug-induced ERK1/2 activity by PD98059 yielded a complete inhibition of drug-induced apoptosis. Altogether, our data demonstrate the heterogeneous response of human hepatoma cells to an IGF stimulus and suggest (1) that auto/paracrine effects of IGF-I/-II might contribute to the proliferation of HCC cells and to their protection against apoptosis in vivo and (2) that drug-induced activation of ERK1/2 plays a role in drug-induced apoptosis in human hepatoma cells.
-
Ann. N. Y. Acad. Sci. · Dec 2004
Randomized Controlled Trial Comparative Study Clinical TrialSubarachnoid analgesia in advanced labor: a comparison of subarachnoid analgesia and pudendal block in advanced labor: analgesic quality and obstetric outcome.
Pain control during labor is a primary objective of antalgic therapy. The use of the peridural as an elective procedure for labor analgesia is now corroborated by the international scientific community. Sometimes a combined spinal-peridural procedure is used together with the intrathecal administration of opioids to also cover the first stage of labor. ⋯ In Group P, however, 10 minutes after placement of the pudendal nerve block, 40 patients reported no improvement in pain symptomatology during contractions and only 16 reported less painful contractions (P < 0.0001). The duration of spinal analgesia (128 +/- 38 minutes) was enough in most cases for delivery to be completed. These results suggest that low-dose bupivacaine-fentanyl spinal analgesia represents an important option for pain relief in late labor, not the least because the procedure does not upset the dynamics of delivery or alter vital parameters and is welcomed by women in labor who are still able to collaborate actively in the birth of their baby.