Vergleich zwischen AIDS-Patienten mit zerebraler Toxoplasmose bzw. Pneumocystis-Pneumonie hinsichtlich des virologischen und immunologischen Ansprechens auf hochaktive antiretrovirale Therapie

Objectives: There is scarce data on immune reconstitution in antiretroviral naïve AIDS-patients with toxoplasmosis. The observation of several cases with reduced increase of CD4-cells upon start of antiretroviral treatment (ART) prompted us to investigate the topic in the ClinSurv cohort. Methods: 17 German HIV treatment centers contribute to ClinSurv, a multicentre observational cohort under the auspices of the Robert Koch Institute. We retrospectively selected all antiretroviral-naïve patients with toxoplasmosis (Toxo) and - as comparator group - with pneumocystosis (PCP) between January 1999 and December 2005. Results: A total of 257 patients were included in the analysis, 61 with Toxo and 196 with PCP. Demographic baseline data showed differences with regard to gender, transmission group, and baseline CD4+ counts (60.9 vs. 44.7/µl, p=0.022). After ART initiation the increase in CD4+ lymphocytes was lower in the Toxo versus the PCP-group in the first, second and fourth three-month-period (74.4 vs. 120.3/µl, p=0.006; 96.6 vs. 136.2/µl, p=0.021; 156.5 vs. 211.5/µl, p=0.013). Viral load (VL) was higher in the PCP-group at baseline (4.46 log10cop/ml vs. 5.00 log10cop/ml, p=0.008), while virological success of ART was equal. Conclusions: Our data show for the first time that the average CD4+ T-cell increase of patients with toxoplasmosis is slower as compared to PCP. Most clinicians would not be prepared to discontinue follow-up Toxo-therapy unless CD4+ counts of 200/µl are reached. Explanation for our finding might be the myelosuppressive side effect of pyrimethamine, possible interactions of toxoplasmosis therapy with ART, or an unknown direct biological influence of toxoplasmosis on immune restoration

Genotoxicity of nitroso compounds and sodium dichromate in a model combining organ cultures of human nasal epithelia and the comet assay

Genotoxic effects of xenobiotics are a possible step in tumor initiation in the mucosa of the upper aerodigestive tract. Using the comet assay, detecting genotoxicity in human tissue has been restricted to single incubations in vitro, but in vivo most xenobiotics harm their target in a repetitive or chronic manner. Therefore, we propose a model, which provides repetitive incubations in human upper aerodigestive tract mucosa cultures. Samples of human inferior nasal turbinate mucosa (n = 25) were cultured according to a modified version of a technique originally described by Steinsvag. On day 1 fresh samples and on days 7, 9 and 11 organ cultures were incubated with N-nitrosodiethylamine (NDEA), sodium dichromate (Na2Cr2O7) and N'-methyl-N-nitro-N-nitrosoguanidine(MNNG). Mucosa samples and organ cultures, respectively, underwent a modified comet assay on days 1, 7 and 11. Genotoxicity could be shown for NDEA, Na2Cr2O7 and MNNG on days 1, 7 and 11. Duration of tissue culture and repetitive incubations did not significantly influence the results for NDEA. Nevertheless, Na2Cr2O7 and MNNG caused higher genotoxic effects on cultures subjected to the comet assay on day 11. This model may help to assess genotoxic hazards posed by environ mental pollutants that have a cumulative character in repetitive or chronic exposure in vivo. Copyright (C) 2001 S. Karger AG, Basel

Dramatic reduction of mortality in pneumococcal meningitis

Background Acute bacterial meningitis is still a life threatening disease. Methods We performed a retrospective observational study on the clinical characteristics of consecutively admitted patients with acute pneumococcal meningitis in a single tertiary care center in central Europe (from 2003 until 2015). Data were compared with a previously published historical group of 87 patients treated for pneumococcal meningitis at the same hospital (from 1984 until 2002). Results Fifty-five consecutive patients with microbiologically proven pneumococcal meningitis were included. Most striking, mortality was down to 5.5 %, which was significantly lower than in the historical group where 24.1 % of the patients did not survive. Intracranial complications during the course of the disease were common and affected half of the patients. Unlike in the historic group, most of the intracranial complications (except ischemic stroke) were no longer associated with a low Glasgow Outcome Score at discharge. Conclusion The drastic reduction of mortality proves there have been important advances in the treatment of pneumococcal meningitis. Nevertheless, the fact that only 44.2 % of survivors had a full recovery indicates that the search for new adjunctive treatment options must be ongoing

The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis

<p>Abstract</p> <p>Background</p> <p>The chemokine CXCL13 is known to dictate homing and motility of B cells in lymphoid tissue and has been implicated in the formation of ectopic lymphoid tissue in chronic inflammation. Whether it influences B cell trafficking during acute infection, is largely unclear. In previous studies, we showed that (I) CXCL13 levels are markedly increased in the B cell-rich cerebrospinal fluid (CSF) of patients with acute Lyme neuroborreliosis (LNB), and (II) CXCL13 is released by monocytes upon recognition of borrelial outer surface proteins by Toll-like receptor 2. Here, we assessed the role of CXCL13 - in comparison to other chemokines - in the recruitment of B cells to the CSF of patients with acute LNB.</p> <p>Methods</p> <p>Measurement of chemokines was done by ELISA. B cells were isolated from whole blood using magnetic cell separation (MACS). For migration experiments, a modified Boyden chamber assay was used and the migrated B cells were further analysed by FACS. The migration was inhibited either by preincubation of the CSF samples with neutralizing antibodies, heating to 60°C, removal of proteins >3 kDa, or by pre-treatment of the B cells with pertussis toxin. The principal statistical tests used were one-way analysis of variance and Bonferroni test (chemokine measurements) as well as paired Student's t-test (migration experiments).</p> <p>Results</p> <p>Measurements of chemokine levels revealed an increase in three of the four known major B cell chemoattractants CXCL13, CCL19 and CXCL12 in LNB CSF. The CXCL13 CSF:serum ratio, as a measure of the chemotactic gradient, was substantially higher than that of CCL19 and CXCL12. Moreover, the chemotactic activity of LNB CSF was reduced up to 56% after preincubation with a neutralizing CXCL13 antibody, while combined preincubation with antibodies against CXCL13, CCL19, and CXCL12 did not lead to further reduction. Since treatment with pertussis toxin, heating to 60°C, and removal of proteins >3 kDa abrogated the chemotactic activity, further not yet identified chemokines seem to be involved in B cell recruitment to LNB CSF.</p> <p>Conclusion</p> <p>Combined, our study suggests a key role of CXCL13 in B cell migration to sites of infection as shown here for the CSF of LNB patients.</p

Primary Diffuse Leptomeningeal Gliomatosis: Report of a Case Presenting with Chronic Meningitis

Neoplastic meningitis occurs in approximately 5% of patients with cancer. Primary diffuse leptomeningeal gliomatosis is a rare condition whereby a glioma arises from heterotopic cell nests in the leptomeninges. We report here a case presenting with clinical features similar to those of chronic infectious meningitis without positive cerebrospinal fluid cytology. Neurological signs in our patient deteriorated progressively without responding to antitubercular, antiviral, or antibiotic therapy. Leptomeningeal biopsy sampling revealed the condition to be primary diffuse leptomeningeal gliomatosis

NF-κB1 Inhibits TLR-Induced IFN-β Production in Macrophages Through TPL-2-dependent ERK Activation

available in PMC 2012 February 15.Although NF-κB1 p50/p105 has critical roles in immunity, the mechanism by which NF-κB1 regulates inflammatory responses is unclear. In this study, we analyzed the gene expression profile of LPS-stimulated Nfkb1−/− macrophages that lack both p50 and p105. Deficiency of p50/p105 selectively increased the expression of IFN-responsive genes, which correlated with increased IFN-β expression and STAT1 phosphorylation. IFN Ab-blocking experiments indicated that increased STAT1 phosphorylation and expression of IFN-responsive genes observed in the absence of p50/p105 depended upon autocrine IFN-β production. Markedly higher serum levels of IFN-β were observed in Nfkb1−/− mice than in wild-type mice following LPS injection, demonstrating that Nfkb1 inhibits IFN-β production under physiological conditions. TPL-2, a mitogen-activated protein kinase kinase kinase stabilized by association with the C-terminal ankyrin repeat domain of p105, negatively regulates LPS-induced IFN-β production by macrophages via activation of ERK MAPK. Retroviral expression of TPL-2 in Nfkb1−/− macrophages, which are deficient in endogenous TPL-2, reduced LPS-induced IFN-β secretion. Expression of the C-terminal ankyrin repeat domain of p105 in Nfkb1−/− macrophages, which rescued LPS activation of ERK, also inhibited IFN-β expression. These data indicate that p50/p105 negatively regulates LPS-induced IFN signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK.National Institutes of Health (U.S.) (NIH AI52267)National Institutes of Health (U.S.) (NIH CA108854)National Institutes of Health (U.S.) (NIH CA67529)Medical Research Council (Great Britain

Postoperative irradiation for squamous cell carcinoma of head and neck: Retrospective comparison of accelerated radiochemotherapy and standard radiotherapy

Background: Comparison of accelerated radiochemotherapy (aRCT) and standard radiotherapy (sRT) in postoperative treatment after macroscopically complete resection of squamous cell cancers of head and neck. Material and Methods: 229 patients treated within the same period had either (no randomization) postoperative radiotherapy with conventional fractionation (60-70 Gy, 2.0 Gy per day) or received 2 fractions of 2.1 Gy per day, 8 times\textbackslash{}week, up to a total dose of 56.7 Gy with a treatment split after 2 weeks and simultaneous low dose cisplatin or carboplatin on treatment clays (cumulative dose >66 mg/m(2) or 550 mg/m(2) in 83% of patients). Results: 65 patients completed their course of twice-daily irradiations within a maximum of 35 days and therefore had aRCT; their 3-year locoregional tumor control (Kaplan-Meier estimate) was 86%, whereas that of 42 patients with prolonged twice-daily radiochemotherapy was 65% (p=0.0509). After sRT, i.e. 1 fraction daily and treatment time up to 45 days, locoregional tumor control was 67%, this result being significantly inferior to that after aRCT (p=0.0282). In multivariate analysis, pN stage, tumor site oral cavity/floor of mouth, high/moderate differentiation of squamous cell carcinoma and conventional surgery (versus CO2-laser surgery) were significantly predictive of locoregional failure. Whereas nodal status, the strongest prognostic factor, was evenly distributed among aRCT and sRT patients, there was a misbalance of 3 risk factors favoring the aRCT collective. Superior tumor control after aRCT was confirmed unilaterally for nearly each subgroup (significant for recurrent tumors, close margins, pN1/2a-b). For pN2c/pN3 nodal stage, the results after aRCT were by tendency worse than after sRT, possibly due to a particularly long interval between surgery and start of radio(chemo)therapy for the patients with aRCT (mean 58.0 days vs. 43.8 days, p=0.037). Among the total of patients the 3-year hazard for late toxicity Ill-IV was 31% after twice-daily treatment and 17% after conventionally fractionated radiotherapy (p=0.083). Conclusions:This retrospective analysis provides some evidence that accelerated radiotherapy with simultaneous chemotherapy is more potent than standard radiotherapy. However, as multivariate analysis misses significance and the influence of misbalance of some prognostic factors among aRCT and sRT patients remains unclear, only a randomized trial with stratification according to risk factors as well as a defined interval between surgery and initiation of RT can provide more evidence

Unusual exanthema combined with cerebral vasculitis in pneumococcal meningitis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Bacterial meningitis is a complex, rapidly progressive disease in which neurological injury is caused in part by the causative organism and in part by the host's own inflammatory responses.</p> <p>Case presentation</p> <p>We present the case of a two-year-old Greek girl with pneumococcal meningitis and an atypical curvilinear-like skin eruption, chronologically associated with cerebral vasculitis. A diffusion-weighted MRI scan showed lesions with restricted diffusion, reflecting local areas of immunologically mediated necrotizing vasculitis.</p> <p>Conclusions</p> <p>Atypical presentations of bacterial meningitis may occur, and they can be accompanied by serious unexpected complications.</p