Occurrence of comorbidity following osteoarthritis diagnosis: a cohort study in the Netherlands.

OBJECTIVE: To determine the risk of comorbidity following diagnosis of knee or hip osteoarthritis (OA). DESIGN: A cohort study was conducted using the Integrated Primary Care Information database, containing electronic health records of 2.5 million patients from the Netherlands. Adults at risk for OA were included. Diagnosis of knee or hip OA (=exposure) and 58 long-term comorbidities (=outcome) were defined by diagnostic codes following the International Classification of Primary Care coding system. Time between the start of follow-up and incident diagnosis of OA was defined as unexposed, and between diagnosis of OA and the end of follow-up as exposed. Age and sex adjusted hazard ratios (HRs) comparing comorbidity rates in exposed and unexposed patient time were estimated with 99.9% confidence intervals (CI). RESULTS: The study population consisted of 1,890,712 patients. For 30 of the 58 studied comorbidities, exposure to knee OA showed a HR larger than 1. Largest positive associations (HR with (99.9% CIs)) were found for obesity 2.55 (2.29-2.84) and fibromyalgia 2.06 (1.53-2.77). For two conditions a HR < 1 was found, other comorbidities showed no association with exposure to knee OA. For 26 comorbidities, exposure to hip OA showed a HR larger than 1. The largest were found for polymyalgia rheumatica 1.81 (1.41-2.32) and fibromyalgia 1.70 (1.10-2.63). All other comorbidities showed no associations with hip OA. CONCLUSION: This study showed that many comorbidities were diagnosed more often in patients with knee or hip OA. This suggests that the management of OA should consider the risk of other long-term-conditions.

The nitrate reductase and nitrite reductase operons and the narT gene of Staphylococcus carnosus are positively controlled by the novel two-component system NreBC.

In Staphylococcus carnosus, the nreABC (for nitrogen regulation) genes were identified and shown to link the nitrate reductase operon (narGHJI) and the putative nitrate transporter gene narT. An nreABC deletion mutant, m1, was dramatically affected in nitrate and nitrite reduction and growth. Transcription of narT, narGHJI, and the nitrite reductase (nir) operon was severely reduced even when cells were cultivated anaerobically without nitrate or nitrite. nreABC transcripts were detected when cells were grown aerobically or anaerobically with or without nitrate or nitrite. NreA is a GAF domain-containing protein of unknown function. In vivo and in vitro studies showed that NreC is phosphorylated by NreB and that phospho-NreC specifically binds to a GC-rich palindromic sequence to enhance transcription initiation. This binding motif was found at the narGHJI, nir, and narT promoters but not at the moeB promoter. NreB is a cytosolic protein with four N-terminal cysteine residues. The second cysteine residue was shown to be important for NreB function. In vitro autophosphorylation of NreB was not affected by nitrate, nitrite, or molybdate. The nir promoter activity was iron dependent. The data provide evidence for a global regulatory system important for aerobic and anaerobic metabolism, with NreB and NreC forming a classical two-component system and NreB acting as a sensor protein with oxygen as the effector molecule.

Role of macrophage colony-stimulating factor in the differentiation and expansion of monocytes and dendritic cells from CD34+ progenitor cells.

The present study focused on whether it is possible to expand monocytic cells from CD34+ progenitor cells by using macrophage colony-stimulating factor (M-CSF) in the absence and presence of mast cell growth factor (MGF) and IL-6. It was demonstrated that CD34+ cells differentiate without expansion to functional mature monocytic cells in the presence of M-CSF or combinations of M-CSF plus IL-6 and MGF. A different response pattern was observed for the number of clonogenic cells. The addition of IL-6 or both IL-6 and MGF to M-CSF containing cultures resulted in significant higher numbers of colony-forming unit-macrophage (CFU-M) as tested in clonogenic and 3H-thymidine assays. Furthermore, M-CSF plus both IL-6 and MGF appeared to be the most potent combination to preserve the monocytic precursor in cell suspension culture assays. These results indicate that IL-6 and MGF in conjunction with M-CSF affect CD34+ cells especially at precursor level without distinct effect on the more mature stages. Secondly we studied whether M-CSF is only critical for the monocytic lineage or also affects dendritic cell (DC) development. Indeed, we were able to culture CD83+ DC from CD34+ progenitor cells in the presence of M-CSF in conjunction with TNF-alpha, IL-4, and MGF although their absolute number is almost threefold lower than the number of CD83+ cells yielded from GM-CSF plus TNF-alpha, IL-4, and MGF stimulated CD34+ cells.

The Ch14.18-GM-CSF fusion protein is effective at mediating antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro.

Granulocyte/macrophage-colony stimulating factor (GM-CSF) is very effective at enhancing antibody-dependent cellular cytotoxicity (ADCC) mediated by granulocytes and monocytes. Recently, a fusion protein consisting of GM-CSF and chimeric human/mouse anti-ganglioside G(D2) antibody Ch14.18 (Ch14.18-GM-CSF) has been generated to improve the effectiveness of immunotherapy by directing GM-CSF to the tumor microenvironment and prolonging its relatively short half-life. In this study, we examined the ability of this fusion protein to enhance the in vitro killing of G(D2)-expressing human neuroblastoma cells by granulocytes and mononuclear cells, as well as by complement. The Ch14.18-GM-CSF fusion protein was equally effective as the combination of equivalent amounts of free Ch14.18 and GM-CSF in mediating the killing of NMB7 neuroblastoma cells by granulocytes from seven of eight neuroblastoma patients. The fusion protein was also equally effective as the combination of Ch14.18 and GM-CSF in mediating ADCC by neuroblastoma patients' mononuclear cells. In addition, the fusion protein was as effective as Ch14.18 alone in directing complement-dependent cytotoxicity against NMB7 cells. Our results demonstrate that the biological activities expressed by ADCC and complement-dependent cytotoxicity of both monoclonal antibody Ch14.18 and GM-CSF are retained by the Ch14.18-GM-CSF fusion protein and lend further support for future clinical trials of this fusion protein in patients with neuroblastoma.