Claus Henrik Nielsen

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis.

Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex‐matched and age‐matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose‐dependent release of interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α) and interleukin‐10 (IL‐10) by patient‐derived MNCs. The patients’ cells produced higher amounts of IFN‐γ and TNF‐α, and lower amounts of IL‐10, than cells from healthy controls (P < 0·03 to P < 0·04). Five patients with MS and no controls, displayed MBP‐induced CD4+ T‐cell proliferation. These high‐responders exhibited enhanced production of IL‐17, IFN‐γ, IL‐5 and IL‐4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P < 0·002 to P < 0·01). A strong correlation was found between the MBP‐induced CD4+ T‐cell proliferation and production of IL‐17, IFN‐γ, IL‐5 and IL‐4 (P < 0·0001 to P < 0·01) within the patient group, and the production of IL‐17 and IL‐5 correlated with the number of active plaques on magnetic resonance images (P = 0·04 and P = 0·007). These data suggest that autoantigen‐driven CD4+ T‐cell proliferation and release of IL‐17 and IL‐5 may be associated with disease activity. Larger studies are needed to confirm this.

Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves’ disease

The possible adverse consequences of biological therapies in inflammatory bowel diseases (IBDs) were recently highlighted in this journal by D’Haens ( Gut 2007; 56 :725–32). We here describe a hitherto unappreciated adverse effect to treatment with the B lymphocyte (B cell) depleting agent rituximab (RTX),1 namely the occurrence of ulcerative colitis and arthritis shortly after treatment with RTX. Our patient, a 45-year-old Caucasian female, had had mild irritable bowel symptoms since 1992 at which time rigid sigmoidoscopy and bowel x ray were normal. She had never received any therapy, had never previously had joint pain, and was not predisposed to IBD. In April 2005 she was diagnosed with Graves’ disease, and after uncomplicated standard methimazole therapy she received four weekly doses of 375 mg/m2 RTX from day 1 to 22 as part of a clinical trial.2 The trial was approved by the local ethics committee …

Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia

In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007) in the rituximab + dexamethasone group. There was an increased incidence of grade 3 to 4 adverse events in the rituximab + dexamethasone group (P = .04). In conclusion, rituximab + dexamethasone induced higher response rates and longer time to relapse than dexamethasone alone. This study is registered at http://clinicaltrials.gov as NCT00909077.

Activated Platelets Enhance IL-10 Secretion and Reduce TNF-α Secretion by Monocytes

Activated platelets are known to modulate immune responses by secreting or shedding a range of immunomodulatory substances. We examined the influence of activated platelets on cytokine production by normal human mononuclear cells, induced by tetanus toxoid (TT), human thyroglobulin (TG), Escherichia coli LPS, or intact Porphyromonas gingivalis. Addition of platelets activated by thrombin-receptor–activating peptide enhanced IL-10 production induced by LPS (p < 0.001), TG (p < 0.05), and P. gingivalis (p < 0.01), and reduced the production of TNF-α induced by LPS (p < 0.001), TG (p < 0.05), and P. gingivalis (p < 0.001), and of IL-6 in LPS- and P. gingivalis–stimulated cultures (p < 0.001). Similar effects on IL-10 and TNF-α production were observed on addition of platelet supernatant to mononuclear cells, whereas addition of recombinant soluble CD40L mimicked the effects on IL-10 production. Moreover, Ab-mediated blockade of CD40L counteracted the effect of platelets and platelet supernatants on TNF-α production. Monocytes separated into two populations with respect to IL-10 production induced by TG; the high-secreting fraction increased from 0.8 to 2.1% (p < 0.001) on addition of activated platelets. Adherence of platelets increased TG- and TT-induced IL-10 secretion by monocytes (p < 0.05). In addition, activated platelets inhibited CD4+ T cell proliferation elicited by TT (p < 0.001) and P. gingivalis (p < 0.001). Our findings suggest that activated platelets have anti-inflammatory properties related to the interaction between CD40L and CD40, and exert a hitherto undescribed immunoregulatory action by enhancing IL-10 production and inhibiting TNF-α production by monocytes.

Bacterial profiles of saliva in relation to diet, lifestyle factors, and socioeconomic status.

Background and objective The bacterial profile of saliva is composed of bacteria from different oral surfaces. The objective of this study was to determine whether different diet intake, lifestyle, or socioeconomic status is associated with characteristic bacterial saliva profiles. Design Stimulated saliva samples from 292 participants with low levels of dental caries and periodontitis, enrolled in the Danish Health Examination Survey (DANHES), were analyzed for the presence of approximately 300 bacterial species by means of the Human Oral Microbe Identification Microarray (HOMIM). Using presence and levels (mean HOMIM-value) of bacterial probes as endpoints, the influence of diet intake, lifestyle, and socioeconomic status on the bacterial saliva profile was analyzed by Mann–Whitney tests with Benjamini–Hochbergs correction for multiple comparisons and principal component analysis. Results Targets for 131 different probes were identified in 292 samples, with Streptococcus and Veillonella being the most predominant genera identified. Two bacterial taxa (Streptococcus sobrinus and Eubacterium [11][G-3] brachy) were more associated with smokers than non-smokers (adjusted p-value<0.01). Stratification of the group based on extreme ends of the parameters age, gender, alcohol consumption, body mass index (BMI), and diet intake had no statistical influence on the composition of the bacterial profile of saliva. Conversely, differences in socioeconomic status were reflected by the bacterial profiles of saliva. Conclusions The bacterial profile of saliva seems independent of diet intake, but influenced by smoking and maybe socioeconomic status.

Does a causal relation between cardiovascular disease and periodontitis exist

Inflammation is believed to play a central part in the pathogenesis of atherosclerosis, and much attention has been paid to the possible association between atherosclerosis and other inflammatory diseases. Periodontal disease is a common inflammatory disease affecting up to 50% of the adult population, and during the past two decades much research has focused on a possible association between periodontitis and cardiovascular disease. Here, we review the existing literature on the association between the two diseases.

Benzoxazinoids: Cereal phytochemicals with putative therapeutic and health-protecting properties.

Benzoxazinoids (BXs) are a group of natural chemical compounds with putative pharmacological and health-protecting properties. BXs were formerly identified in and isolated from selected dicot medicinal plants and young cereal plants. Recently, BXs were found to be present in mature cereal grains and bakery products, such that knowledge about the pharmacological properties of BXs, which until now have unknowingly been consumed through the daily bread and breakfast cereals, has come into new focus. This review discusses published results from in vitro studies and a few human and animal model studies on the health effects and pharmacological responses of various BX compounds. Many of these studies have reported antimicrobial, anticancer, reproductive system stimulatory, central nervous system stimulatory, immunoregulatory, and appetite- and weight-reducing effects of BXs and/or BX derivatives. The health benefits of wholegrain intake may be associated with the solitary and/or overlapping biological effects of fibers, lignans, phenolic acids, alkylresorcinols, BXs, and other bioactive compounds. In the context of BXs as dietary ingredients, further comprehensive investigations are required to understand their biological functions, to elucidate the underlying mechanisms, to explore their potential contribution on the health effects associated with wholegrain consumption, and to examine their potential as functional food ingredients.

Altered bacterial profiles in saliva from adults with caries lesions: a case-cohort study.

The aim of this study was to learn whether presence of caries in an adult population was associated with a salivary bacterial profile different from that of individuals without untreated caries. Stimulated saliva samples from 621 participants of the Danish Health Examination Survey were analyzed using the Human Oral Microbe Identification Microarray technology. Samples from 174 individuals with dental caries and 447 from a control cohort were compared using frequency and levels of identified bacterial taxa/clusters as endpoints. Differences at taxon/cluster level were analyzed using Mann-Whitneys test with Benjamini-Hochberg correction for multiple comparisons. Principal component analysis was used to visualize bacterial community profiles. A reduced bacterial diversity was observed in samples from subjects with dental caries. Five bacterial taxa (Veillonella parvula, Veillonella atypica, Megasphaera micronuciformis, Fusobacterium periodontium and Achromobacter xylosoxidans) and one bacterial cluster (Leptotrichia sp. clones C3MKM102 and GT018_ot417/462) were less frequently found in the caries group (adjusted p value <0.01) while two bacterial taxa (Solobacterium moorei and Streptococcus salivarius) and three bacterial clusters (Streptococcus parasanguinis I and II and sp. clone BE024_ot057/411/721, Streptococcus parasanguinis I and II and sinensis_ot411/721/767, Streptococcus salivarius and sp. clone FO042_ot067/755) were present at significantly higher levels (adjusted p value <0.01). The principal component analysis displayed a marked difference in the bacterial community profiles between groups. Presence of manifest caries was associated with a reduced diversity and an altered salivary bacterial community profile. Our data support recent theories that ecological stress-induced changes of commensal microbial communities are involved in the shift from oral health to tooth decay.

Cell saver for on-pump coronary operations reduces systemic inflammatory markers: a randomized trial.

BACKGROUND This study investigated whether intraoperative use of a cell saver reduces the systemic inflammatory response after coronary operations using cardiopulmonary bypass (CPB). METHODS The study randomized 29 patients, 15 to cell saving of pericardial suction blood and residual blood in the CPB circuit after perfusion (cell saver group) vs 14 who received direct retransfusion of the suction blood and the CPB circuit blood (control group). Outcome measures were plasma concentrations of the inflammatory markers interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-alpha, soluble tumor necrosis factor receptors I and II, and procalcitonin at 6, 24, and 72 hours postoperatively. RESULTS At 6 hours postoperatively, the cell saver group displayed significantly reduced plasma levels of IL-6 and IL-8 (p < 0.05). A reduction in IL-10 was also found (p = 0.05), along with nonsignificant reductions in the remaining markers. At 24 and 72 hours, significant differences between groups no longer existed. In the cell saver group, the suction blood and CPB circuit blood were cleared for tumor necrosis factor receptors (p < 0.005), and IL-6, IL-8, IL-10, and procalcitonin were significantly reduced (p < 0.05). Median intraoperative blood loss was 250 mL in the cell saver group vs 475 mL (p < 0.02). Immediately postoperatively the hemoglobin level was higher in the cell saver group (p < 0.03). Transfusion requirements were similar. CONCLUSIONS The cell saver reduced the systemic levels of the proinflammatory markers IL-6 and IL-8 at 6 hours after CPB. The role of the anti-inflammatory molecules IL-10 and soluble tumor necrosis factor receptors is undefined in this setting.

Systemic adverse events following rituximab therapy in patients with Graves’ disease

Background and aim: Rituximab (RTX) therapy has shown promising results in Graves’ disease (GD), with or without ophthalmopathy. We examined the occurrence of adverse events in GD patients treated with RTX. Subjects and methods: Ten patients received RTX and methimazole, while 10 patients received methimazole only. Adverse events were recorded, and the presence of circulating immune complexes (CIC) was measured as IgG, IgM and complement component 3 (C3) depositing on normal monocytes following incubation with patient plasma. Results: Five patients had benign infusion-related adverse events at first infusion. Two patients developed a serum sickness-like reaction 11 days after the first RTX-infusion. One of these patients developed diarrhea, raised orosomucoid levels, low-grade inflammation in colonoscopic biopsies, and iridocyclitis 1 yr later. At day 14, the most pronounced immunoglobulin/C3-adherent to the test monocytes, indicative of CIC, was observed in the presence of plasma from these 2 patients (p=0.003 to p=0.01 vs asymptomatic patients). A 3rd patient had recurrent fever and symmetric polyarthritis from day 38, and colonoscopy-verified ulcerative colitis at day 68. This patient had the 3rd highest increase in Ig deposition on monocytes by day 14. The arthralgias persisted in 2 of the patients, despite glucocorticoid rescue therapy. Conclusions: We report articular adverse events in 3 and gastrointestinal symptoms in 2 out of 10 GD patients who received RTX without concurrent immunosupression. The joint symptoms were related to CIC formation.