<p><b>Background. </b>Newborn infants, especially preterm infants, have an increased susceptibility to serious and overwhelming bacterial as well as fungal infections. Symptoms of septicaemia in especially the very preterm neonates are vague and unspecific. No really good biochemical parameter exists today that can confirm or exclude the existence of neonatal septicaemia. The access to such a test in neonates would be most valuable, not only to assure early institution of effective antibiotic therapy when needed, but also to avoid unnecessary use of antibiotics, thereby reducing the risk of further development of antimicrobial resistance. </p><p><b>Aim. </b>To investigate the possible use of the expression of the phagocyte receptor CD64 (FcγRI) on neutrophils for early diagnosis of bacterial infections with special reference to neonatal septicaemia. </p><p><b>Results. </b>Neutrophils from preterm and term newborn infants, older infants, children, and adults examined during the early phase of a bacterial infection showed a significantly higher expression of CD64 compared with non-infected controls (p<0.001). Neutrophils from even extremely preterm infants expressed CD64 to the same extent as did neutrophils from children and adult patients. The expression of CD64 was not affected by the respiratory distress syndrome (RDS) or by such factors as premature rupture of the membranes, gestational age, steroid treatment before delivery, method of delivery, birth weight or postnatal age.</p><p>Major surgery in adults (total hip replacement) did not affect the CD64 expression to an extent comparable to that found during bacterial infections. Indirectly CD64 was found to be at least equal to CRP for differentiation between Influenza A infection and bacterial infections in adults.</p><p><b>Conclusion.</b> CD64 was found to be a specific and reliable marker for early detection of bacterial infections in preterm and term newborn infants, as well as after surgery. For differentiation between bacterial and viral infections it is probably at least as effective as CRP.</p>

<b>Background. </b>Newborn infants, especially preterm infants, have an increased susceptibility to serious and overwhelming bacterial as well as fungal infections. Symptoms of septicaemia in especially the very preterm neonates are vague and unspecific. No really good biochemical parameter exists today that can confirm or exclude the existence of neonatal septicaemia. The access to such a test in neonates would be most valuable, not only to assure early institution of effective antibiotic therapy when needed, but also to avoid unnecessary use of antibiotics, thereby reducing the risk of further development of antimicrobial resistance. <b>Aim. </b>To investigate the possible use of the expression of the phagocyte receptor CD64 (FcγRI) on neutrophils for early diagnosis of bacterial infections with special reference to neonatal septicaemia. <b>Results. </b>Neutrophils from preterm and term newborn infants, older infants, children, and adults examined during the early phase of a bacterial infection showed a significantly higher expression of CD64 compared with non-infected controls (p&lt;0.001). Neutrophils from even extremely preterm infants expressed CD64 to the same extent as did neutrophils from children and adult patients. The expression of CD64 was not affected by the respiratory distress syndrome (RDS) or by such factors as premature rupture of the membranes, gestational age, steroid treatment before delivery, method of delivery, birth weight or postnatal age. Major surgery in adults (total hip replacement) did not affect the CD64 expression to an extent comparable to that found during bacterial infections. Indirectly CD64 was found to be at least equal to CRP for differentiation between Influenza A infection and bacterial infections in adults. <b>Conclusion.</b> CD64 was found to be a specific and reliable marker for early detection of bacterial infections in preterm and term newborn infants, as well as after surgery. For differentiation between bacterial and viral infections it is probably at least as effective as CRP.

<p>All aspects of cell life are regulated by signal transduction mechanisms. This thesis describes the regulatory roles of a few key signal transduction molecules involved in three major biological responses. The studied pathways include platelet derived growth factor (PDGF)-BB induced transformation of murine fibroblasts, interferon (IFN)-γ stimulated monocyte activation and all-trans retinoic acid (ATRA) induced myeloid differentiation. </p><p>We found that intact phosphoinositide 3OH-kinase (PI3K) activity is essential in the signaling pathway that leads to the morphological alterations and migration pattern characteristic of PDGF-BB transformed NIH/sis and NIH/COL1A1 fibroblasts. Furthermore, our data indicated that the small Rho-GTPase, Rac1 is the predominant mediator of these signals downstream of PI3K.</p><p>The study of the IFN-γ induced activation of monocytic U-937 cells showed that upregulation of the high affinity receptor for IgG (FcγRI) is dependent on the coordination of several regulatory events: the PKR-mediated serine 727 phosphorylation of Stat1, the expression of the hematopoietic lineage specific transcription factor PU.I, and the activation of the NFκB pathway.</p><p>ATRA-induced differentiation and cell cycle arrest are impaired in U-937 sublines expressing phosphorylation deficient Stat1 (Stat1Y701F and Stat1S727A). The findings in paper III indicated that the expression pattern of the myeloid specific transcription factors Stat2, ICSBP and c/EBPε was altered in the sublines and that intact Stat1 activation is critical for maintaining the balance of the transcriptional network during ATRA induced terminal differentiation.</p><p>Finally, ATRA-induced differentiation and growth arrest were blocked by treatment with the IKKα/β inhibitor BMS345541 or by ectopic expression of the NFκB super repressor IκBα (S32A/S36A). The fact that IκB(AA) sublines differentiated normally in response to vitamin D3, showed that NFκB inhibition specifically affected ATRA induced responses. Notably we suggest that the activity of the NFκB pathway may interfere with the differentiation process via a direct effect on the RAR/RXR mediated transcription.</p>

All aspects of cell life are regulated by signal transduction mechanisms. This thesis describes the regulatory roles of a few key signal transduction molecules involved in three major biological responses. The studied pathways include platelet derived growth factor (PDGF)-BB induced transformation of murine fibroblasts, interferon (IFN)-γ stimulated monocyte activation and all-trans retinoic acid (ATRA) induced myeloid differentiation. We found that intact phosphoinositide 3OH-kinase (PI3K) activity is essential in the signaling pathway that leads to the morphological alterations and migration pattern characteristic of PDGF-BB transformed NIH/sis and NIH/COL1A1 fibroblasts. Furthermore, our data indicated that the small Rho-GTPase, Rac1 is the predominant mediator of these signals downstream of PI3K. The study of the IFN-γ induced activation of monocytic U-937 cells showed that upregulation of the high affinity receptor for IgG (FcγRI) is dependent on the coordination of several regulatory events: the PKR-mediated serine 727 phosphorylation of Stat1, the expression of the hematopoietic lineage specific transcription factor PU.I, and the activation of the NFκB pathway. ATRA-induced differentiation and cell cycle arrest are impaired in U-937 sublines expressing phosphorylation deficient Stat1 (Stat1Y701F and Stat1S727A). The findings in paper III indicated that the expression pattern of the myeloid specific transcription factors Stat2, ICSBP and c/EBPε was altered in the sublines and that intact Stat1 activation is critical for maintaining the balance of the transcriptional network during ATRA induced terminal differentiation. Finally, ATRA-induced differentiation and growth arrest were blocked by treatment with the IKKα/β inhibitor BMS345541 or by ectopic expression of the NFκB super repressor IκBα (S32A/S36A). The fact that IκB(AA) sublines differentiated normally in response to vitamin D3, showed that NFκB inhibition specifically affected ATRA induced responses. Notably we suggest that the activity of the NFκB pathway may interfere with the differentiation process via a direct effect on the RAR/RXR mediated transcription.