A retrospective systematic data review on the use of a polihexanide-containing product on burns in children.

BACKGROUND: It is current practice for physicians to use the Prontosan® range of products in children based on their personal clinical experience, despite the lack of safety data in this population. This retrospective data review was designed to obtain information on the safety profile of the Prontosan® range of products in children in routine clinical practice. METHODS: Data from newborns, infants and children with burns treated with the Prontosan® range were collected retrospectively from patient medical records. RESULTS: The majority of children treated for burns (80.1%) were under the age of four. More boys than girls were subject to burn injury (58.1% vs. 41.9%). The majority of burns (74.7%) were partial thickness burn (IIa and IIb). Safety was analysed based on the adverse events/reactions, infections and interactions/symptoms related to Prontosan® reported in the CRFs. AEs were reported in five children after the use of Prontosan® products: itching (3 cases), rash (1 case) and hypergranulating tissue (1 case). No event was severe and all events resolved favourably with good healing results. In addition, 11 patients developed clinical signs of infection during treatment (mainly Staphylococcus aureus). CONCLUSIONS: The Prontosan® range of products is demonstrated as safe and tolerable for use in children as part of burn treatment. Inclusion of this range of products in the protocol of paediatric burn care allows a good healing process starting with appropriate wound cleansing and maintaining moist wound environment.

Anticoagulant-related gastrointestinal bleeding--could this facilitate early detection of benign or malignant gastrointestinal lesions?

INTRODUCTION: The higher incidence of gastrointestinal (GI) bleeding with the non-vitamin K oral anticoagulants (NOACs) may be related to pre-existing malignancies; diagnostic measures triggered by these bleedings could lead to early detection of these malignancies. METHODS: We retrieved the preferred terms on GI bleeding and GI cancer reported as adverse events (AEs) from phase III studies in patients with atrial fibrillation for each NOAC on ClinicalTrials.gov . We also analyzed the RE-LY trial database. RESULTS: From ClinicalTrials.gov , AE-GI bleeding incidence was: dabigatran 110 mg b.i.d. (D110: 1.42% versus 1.37%), dabigatran 150 mg b.i.d. (D150: 1.93% versus 1.37%), rivaroxaban (3.52% versus 2.68%), and apixaban (1.93% versus 1.59%), compared with warfarin, respectively. The incidence of AE-GI cancer was similar between the NOACs (D110 [0.79%], D150 [0.61%], rivaroxaban [0.83%], and apixaban [0.69%]), but numerically higher compared with warfarin (0.37%; 0.73%; 0.57%, respectively). In the RE-LY database, the same pattern was seen for dabigatran, with an association between GI bleeding and GI cancer diagnosis. CONCLUSION: Anticoagulant-related GI bleeding may represent the unmasking of pre-existing malignancies leading to increased detection of GI cancer. This may be especially in the first month of treatment and could explain the numerically higher numbers of GI malignancies observed with NOACs.

Expression pattern and cellular sources of chemokines in primary central nervous system lymphoma.

The expression pattern of a subset of chemokines and their corresponding receptors was investigated in primary central nervous system lymphomas (PCNSL). The tumor cells consistently expressed CXCR4, CXCL12, CXCR5, and CXCL13, both at mRNA and protein levels. Cerebral endothelial cells were positive for CXCL12 and CXCL13, while reactive astrocytes and microglial cells expressed CXCL12, CCR5, and CCR6. Inflammatory T cells in PCNSL were characterized by CCR5 and CCR6 positivity. Taken together, our data indicate a cell type-specific repertoire of chemokine and chemokine receptor expression in PCNSL suggesting that chemokine-mediated interactions facilitate crossing of the blood-brain barrier as well as intracerebral dissemination of PCNSL cells. In addition, chemokines expressed by tumor cells may contribute to induction of reactive glial changes and influence the composition of inflammatory infiltrates in PCNSL. Therefore, cell type specific expression of distinct chemokine profiles likely plays a role in the pathogenesis of PCNSL and may contribute to their characteristic histological appearance.

Chemokines are differentially expressed by astrocytes, microglia and inflammatory leukocytes in Toxoplasma encephalitis and critically regulated by interferon-gamma.

The intracerebral formation of inflammatory infiltrates is a complex process, which may be regulated by chemokines. This study defines the kinetics and cellular sources of T cell- and macrophage-attracting chemokines in murine Toxoplasma encephalitis (TE) by ribonuclease protection assay, reverse transcription-PCR, in situ hybridization, and immunohistochemistry. Whereas astrocytes were the major source of interferon (IFN)-gamma-inducible protein-10 (CRG-2/IP-10) and monocyte chemoattractant protein (MCP)-1, microglia expressed RANTES, monokine induced by IFN-gamma (MuMIG) and occasionally CRG-2/IP-10 RNA. Despite being ubiquitously activated, only astrocytes and microglia confined to inflammatory infiltrates expressed chemokine genes. Intracerebral leukocytes transcribed RANTES, MuMIG, and occasionally CRG-2/IP-10 and MCP-1. IFN-gamma-deficient mice failed to produce CRG-2/IP-10, MuMIG, RANTES and expressed macrophage inflammatory protein (MIP-1)alpha, MIP-1 beta, and MCP-1 mRNA at reduced levels, functionally resulting in a strongly reduced recruitment of leukocytes across the blood-brain barrier and prevented their further invasion of the brain parenchyma. Since T cells are the single source of IFN-gamma in TE, these findings indicate that T cells pave the way of leukocytes to parenchymatous parasites via IFN-gamma.

Regulation of the kinetics of intracerebral chemokine gene expression in murine Toxoplasma encephalitis: impact of host genetic factors.

The expression and kinetics of a panel of chemokines during Toxoplasma encephalitis (TE) were analyzed in a comparative study of genetically resistant BALB/c and susceptible C57BL/6 mice. In parallel with disease activity and the number of postinfection (p.i.) leukocytes, C57BL/6 mice induced CRG-2/IP-10, MuMIG, RANTES, MCP-1, MIP-1alpha, and MIP-1beta earlier and reached increased levels, as compared with BALB/c mice. These differences in the kinetics of intracerebral (i.c.) chemokines may serve as a compensatory mechanism to prevent death from necrotizing TE in C57BL/6 mice; in contrast, BALB/c mice downregulated i.c. chemokines with efficient parasite control in the chronic latent phase. Furthermore, this study showed that the pattern of i.c. chemokines and the cellular sources were identical in both strains of mice, with astrocytes and microglia expressing CRG-2/IP-10 and MCP-1 or RANTES and MuMIG, respectively, and leukocytes transcribing CRG-2/IP-10, MCP-1, and RANTES. Thus, the present study demonstrates that host genetic factors exert a strong impact on i.c. chemokines in experimental murine TE.

Mice with neonatally induced inactivation of the vascular cell adhesion molecule-1 fail to control the parasite in Toxoplasma encephalitis.

Under various inflammatory conditions, cell adhesion molecules are up-regulated in the central nervous system (CNS) and may contribute to the recruitment of leukocytes to the brain. In the present study, the functional role of vascular cell adhesion molecule (VCAM)-1 in Toxoplasma encephalitis (TE) was addressed using VCAM(flox/flox MxCre) mice. Neonatal inactivation of the VCAM-1 gene resulted in a lack of induction of VCAM-1 on cerebral blood vessel endothelial cells, whereas the constitutive expression of VCAM-1 on choroid plexus epithelial cells and the ependyma was unaffected; in these animals, resistance to T. gondii was abolished, and VCAM(flox/flox MxCre) mice died of chronic TE caused by a failure to control parasites in the CNS. Although leukocyte recruitment to the CNS was unimpaired, the B cell response was significantly reduced as evidenced by reduced serum levels of anti-T. gondii-specific IgM and IgG antibodies. Furthermore, the frequency and activation state of intracerebral T. gondii-specific T cells were decreased, and microglial activation was markedly reduced. Taken together, these data demonstrate the crucial requirement of VCAM-1-mediated immune reactions for the control of an intracerebral infectious pathogen, whereas other cell adhesion molecules can efficiently compensate for VCAM-1-mediated homing across cerebral blood vessels.

Phenotype and regulation of persistent intracerebral T cells in murine Toxoplasma encephalitis.

Toxoplasma gondii is a parasite causing asymptomatic, persistent encephalitis. Protective CD4 and CD8 T cells are recruited to and accumulate in the brain in acute Toxoplasma encephalitis (TE), with slowly decreasing numbers in chronic TE. It is unclear how the size of the intracerebral T cell pool is regulated. Conceivably, permanent recruitment, proliferation, and apoptosis may be involved. We observed that in murine TE recruitment of T cells to the brain was terminated in chronic TE. In vivo 5-bromo-2'-deoxyuridine incorporation and in vitro T cell proliferation experiments revealed that intracerebral T cells did not proliferate, which was explained by the expression of the cell cycle inhibitors p21(Waf/cip1) and p27(Kip1) and the inhibitory activity of intracerebral F4/80(+) cells. TUNEL staining detected apoptotic T cells at low frequency corresponding to an increased expression of the anti-apoptotic molecules Bcl-2 and Bcl-x(L) and a reduced expression of the pro-apoptotic molecules Bad, Bax, and Fas ligand in CD4 and CD8 T cells. During progression from acute to chronic TE, both CD4 and CD8 T cells down-regulated CD45RB expression and expressed a differential pattern of cytokines. From these experiments it is concluded that the number of intracerebral T cells increases by recruitment of T cells during acute infection, whereas proliferation of intracerebral T cells does not play a role. In chronic TE, T cell recruitment is terminated, the phenotype of intracerebral T cells changes, and their number is gradually downsized by low level apoptosis, which, however, does not completely resolve the T cell infiltrates.