Induction maintenance concept for HAART as initial treatment in HIV infected infants

<p>Abstract</p> <p>Background</p> <p>Early initiated antiretroviral therapy (ART) in HIV infected infants leads to improved long-term viral suppression and survival. Guidelines recommend initiating therapy with a triple ART consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either one additional non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Compared to older children and adults, viral relapse is seen more frequently in infants receiving triple ART. We now address the possibility of a more potent ART with a quadruple induction and triple maintenance therapy.</p> <p>Methods</p> <p>We examine the longitudinal course in four HIV infected infants, who were referred from other centers and could not be recruited to multicentre trials. We introduced ART initially consisting of two NRTIs, one NNRTI and one PI and later discontinued the PI at the age of 12 months maintaining a triple regime consisting of two NRTIs and one NNRTI.</p> <p>Results</p> <p>Provided that therapy adherence was maintained we observed an effective sustained decline of viral load and significant CD4 cell reconstitution even after switching to a triple regime. No drug associated toxicity was seen.</p> <p>Conclusion</p> <p>We suggest that a four drug therapy might be a possible initial therapy option in HIV infected infants, at least in those with a high viral load, followed by a maintenance triple regime after 12 months of therapy.</p

Protein-based identification of quantitative trait loci associated with malignant transformation in two HER2+ cellular models of breast cancer

Background A contemporary view of the cancer genome reveals extensive rearrangement compared to normal cells. Yet how these genetic alterations translate into specific proteomic changes that underpin acquiring the hallmarks of cancer remains unresolved. The objectives of this study were to quantify alterations in protein expression in two HER2+ cellular models of breast cancer and to infer differentially regulated signaling pathways in these models associated with the hallmarks of cancer. Results A proteomic workflow was used to identify proteins in two HER2 positive tumorigenic cell lines (BT474 and SKBR3) that were differentially expressed relative to a normal human mammary epithelial cell line (184A1). A total of 64 (BT474-184A1) and 69 (SKBR3-184A1) proteins were uniquely identified that were differentially expressed by at least 1.5-fold. Pathway inference tools were used to interpret these proteins in terms of functionally enriched pathways in the tumor cell lines. We observed protein ubiquitination and apoptosis signaling pathways were both enriched in the two breast cancer models while IGF signaling and cell motility pathways were enriched in BT474 and amino acid metabolism were enriched in the SKBR3 cell line. Conclusion While protein ubiquitination and apoptosis signaling pathways were common to both the cell lines, the observed patterns of protein expression suggest that the evasion of apoptosis in each tumorigenic cell line occurs via different mechanisms. Evidently, apoptosis is regulated in BT474 via down regulation of Bid and in SKBR3 via up regulation of Calpain-11 as compared to 184A1

Quantitative modeling of the physiology of ascites in portal hypertension

Although the factors involved in cirrhotic ascites have been studied for a century, a number of observations are not understood, including the action of diuretics in the treatment of ascites and the ability of the plasma-ascitic albumin gradient to diagnose portal hypertension. This communication presents an explanation of ascites based solely on pathophysiological alterations within the peritoneal cavity. A quantitative model is described based on experimental vascular and intraperitoneal pressures, lymph flow, and peritoneal space compliance. The model's predictions accurately mimic clinical observations in ascites, including the magnitude and time course of changes observed following paracentesis or diuretic therapy

A hormone-dependent post-translationally regulated mutant for investigating type I cadherin function

5Type I cadherins are Ca2+-dependent cell adhesion molecules. Their function in early Xenopus laevis development has been extensively studied in recent years, by injecting synthetic mRNAs encoding dominant negative mutants with deletions of the extracellular domain into embryos. However, studies at post-gastrula stages have been hampered by the inability to progress through post-gastrula development in embryos expressing these mutant proteins. This problem has been partly overcome by injecting into a few targeted blastomeres in stage 6 N.F. embryos, but only restricted studies are possible with this technique. Several studies have made use of the hormone-binding domain (HBD), which is activated by hormones. In this study, we used this method to analyze the activity of dominant negative cadherins. We generated a mutant E-cadherin (DeltaE-Cad, consisting of the cytoplasmic domain and transmembrane domain) fused to the hormone-binding domain of estradiol receptor (HBDER) and we validated this technique with functional analyses. The function of the mutant DeltaE-HBDER was strictly dependent on hormone induction. This conditional mutant had the same effects and exerted the same dominant negative function as the corresponding constitutive mutant.nonemixedGiacomello, E.*; Morali, O.; Vallin, J.; Thiery, J.-P.; Broders, F.Giacomello, E.; Morali, O.; Vallin, J.; Thiery, J. -P.; Broders, F

The electrophysiological findings of subclinical neuropathy in patients with recently diagnosed type 1 diabetes mellitus

To assess the prevalence of subclinical neuropathy within the first year of type I diabetes mellitus, 30 patients and 14 healthy subjects have been studied prospectively. The patients whose diabetes duration was longer than 1 year have been excluded from the study. Control group consisted of healthy volunteers

The electrophysiological findings of subclinical neuropathy in patients with recently diagnosed type 1 diabetes mellitus

To assess the prevalence of subclinical neuropathy within the first year of type I diabetes mellitus, 30 patients and 14 healthy subjects have been studied prospectively. The patients whose diabetes duration was longer than 1 year have been excluded from the study. Control group consisted of healthy volunteers

Type I cadherins are required for differentiation and coordinated rotation in Xenopus laevis somitogenesis

7siIn Xenopus laevis somitogenesis, somitic blocks undergo coordinated movements resulting in their detachment from the rest of the mesodermal ridge, followed by a 90° rotation of the entire metamere. Here we investigated the function of type I cadherins in somitogenesis. Type I cadherins are Ca2+-dependent cell-cell adhesion molecules concentrated in the adherens junctions and highly expressed in the somitic tissue. We analyzed their role in somitogenesis by overexpressing either the intracellular (∆E) and the extracellular (C-trunc) dominant-negative forms of cadherin. The resulting phenotype was a downward bend of the anterior-posterior axis in tadpole stage embryos. 12/101 antigen and X-Myo-D expression were altered. Microscopy revealed disorganization of the myotomes. Conversely, segmentation was conserved at the microscopic and molecular levels.nonemixedGiacomello, Emiliana; Vallin, Jerome; Morali, Olivier; Coulter, Ivan S.; Boulekbache, Habib; Thiery, Jean P.; Broders, FlorenceGiacomello, Emiliana; Vallin, Jerome; Morali, Olivier; Coulter, Ivan S.; Boulekbache, Habib; Thiery, Jean P.; Broders, Florenc