Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Extended thromboprophylaxis following colorectal surgery in patients with inflammatory bowel disease: a comprehensive systematic clinical review.

AIM: Patients with inflammatory bowel disease (IBD) are at increased risk of postoperative venous thromboembolism (VTE) following major abdominal surgery. The pathogenesis is multifactorial and not fully understood. A combination of pathophysiology, patient and surgical risk factors increase the risk of postoperative VTE in these patients. Despite being at increased risk, IBD patients are not regularly prescribed extended pharmacological thromboprophylaxis following colorectal surgery. Currently, there is a paucity of evidence-based guidelines. Thus, the aim of this review is to evaluate the role of extended pharmacological thromboprophylaxis in IBD patients undergoing colorectal surgery. METHOD: A search of Ovid Medline, EMBASE and PubMed databases was performed. A qualitative analysis was performed using 10 clinical questions developed by colorectal surgeons and a thrombosis haematologist. The Newcastle-Ottawa Scale was utilized to assess the quality of evidence. RESULTS: A total of 1229 studies were identified, 38 of which met the final inclusion criteria (37 retrospective, one case-control). Rates of postoperative VTE ranged between 0.6% and 8.9%. Patient-specific risk factors for postoperative VTE included ulcerative colitis, increased age and obesity. Surgery-specific risk factors for postoperative VTE included open surgery, emergent surgery and ileostomy creation. Patients with IBD were more frequently at increased risk in the included studies for postoperative VTE than patients with colorectal cancer. The risk of bias assessment demonstrated low risk of bias in patient selection and comparability, with variable risk of bias in reported outcomes. CONCLUSION: There is a lack of evidence regarding the use of extended pharmacological thromboprophylaxis in patients with IBD following colorectal surgery. As these patients are at heightened risk of postoperative VTE, future study and consideration of the use of extended pharmacological thromboprophylaxis is warranted.

Prospective multicentre PCR-based Aspergillus DNA screening in high-risk patients with and without primary antifungal mould prophylaxis.

Invasive aspergillosis (IA) is associated with significant morbidity and mortality, and, among other factors, this is due to a delay in diagnosis performed with conventional techniques. A prospective, multicentre study was conducted to evaluate the efficacy of Aspergillus DNA screening in the early diagnosis of IA. Patients undergoing haematopoietic stem cell transplantation or chemotherapy for acute leukaemia were enrolled for biomarker screening. Three centres applied the same protocol for in-house PCR, which was compliant with the European Aspergillus PCR Initiative recommendations, to guarantee the highest diagnostic standards. Two thousand one hundred and twenty-eight sera from 213 patients were investigated and stratified according to the revised European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria for invasive fungal disease. The incidence rates of probable and possible IA were 18% and 38%, respectively. The sensitivity, specificity and positive predictive value (PPV) of PCR were superior in antifungal drug-naive patients, being 71.4%, 92.3%, and 62.5%, respectively. The last of these key performance indicators (PPV) was moderate in patients receiving primary prophylaxis, at 5.4%. Negative predictive values for both strategies applied were 100% with and 98.3% without antifungal mould prophylaxis. PCR has the potential to play a decisive role in the diagnosis and management of Aspergillus infections in centres not applying primary antifungal mould prophylaxis.

Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium.

Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10(-4) and P50.000 permutation test = 9.34 · 10(-5)). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

Low-dose aspirin desensitization in individuals with aspirin-exacerbated respiratory disease.

BACKGROUND: Nasal polyposis frequently occurs within the clinical picture of aspirin-exacerbated respiratory disease (AERD). A derailed arachidonic acid metabolism is regarded to be part of the pathophysiology of AERD, and aspirin desensitization is the only causal therapeutic option, so far. The optimal maintenance dose of aspirin desensitization to prevent nasal polyp recurrence on the one hand and to minimize aspirin-related side-effects, on the other hand, is still a matter of debate. The aim of this trial was to investigate the efficacy and safety of a low-dose aspirin desensitization protocol. METHODS: After sinus surgery, 70 individuals with AERD were randomly allocated to a prospective double-blind placebo-controlled aspirin desensitization protocol with a maintenance dose of 100 mg daily. The primary outcome was polyp relapse after 36 months. Nasal endoscopy status, quality of life, and patients' symptom score as well as aspirin-related side-effects were monitored. RESULTS: Due to the high dropout rate, only 31 individuals were evaluated. After 36 months, nasal polyp relapse was less frequent (P = 0.0785) and the polyposis score was lower (P = 0.0702) in the therapy group. Quality of life obviously improved (P = 0.0324), clinical complaints (P = 0.0083) were significantly reduced, and no severe aspirin-related side-effects were observed. CONCLUSION: Aspirin desensitization with a maintenance dose of 100 mg daily has a positive impact on nasal polyp relapse and seems to be a safe and suitable therapy to improve clinical complaints and the quality of life of individuals with AERD.

Endophthalmitis as primary clinical manifestation of fatal fusariosis in an allogeneic stem cell recipient.

The occurrence of infections due to previously rare opportunistic pathogens is increasing despite the use of novel treatment strategies for immunocompromised patients. Here, we report the case of a patient presenting with fever, muscle pain, and bilateral endophthalmitis after allogeneic hematopoietic stem cell transplantation. Fusarium solani was isolated from peripheral blood samples and identified as the cause of gradual bilateral vision loss, despite appropriate antifungal prophylaxis, and therapy including vitrectomy and intraocular instillation of antifungal agents. The patient became comatose; basal meningitis involving both optic nerves was suspected based on magnetic resonance tomography. The patient died 8 days later due to septic multi-organ failure. Autopsy revealed that both kidneys, but no other organs, were infiltrated by Fusarium. No fungus was found in cerebral tissues or cerebrospinal fluid. Our case demonstrates some of the typical clinical features of systemic fusariosis and its potentially fatal outcome. The clinical observations reported here may help clinicians caring for immunocompromised patients to accelerate diagnosis and initiate treatment early at the onset of this fatal complication, and highlight the urgent need for interdisciplinary management of invasive fusariosis.

Neurokinin-1 receptor activation induces reactive oxygen species and epithelial damage in allergic airway inflammation.

BACKGROUND: An induction of reactive oxygen species (ROS) is characteristic for inflammation but the exact pathways have not been identified for allergic airway diseases so far. OBJECTIVE: The aim of this study was to characterize the role of the tachykinin NK-1 receptor on ROS production during allergen challenge and subsequent inflammation and remodelling. METHODS: Precision-cut lung slices of ovalbumin (OVA)-sensitized mice were cultivated and ROS-generation in response to OVA challenge (10 microg/mL) was examined by the 2',7'-dichloroflourescein-diacetate method. Long-term ROS effects on epithelial proliferation were investigated by 5-bromo-2'-deoxyuridine incorporation (72 h). In vivo, the results were validated in OVA-sensitized animals which were treated intra-nasally with either placebo, the tachykinin neurokinin 1 (NK-1) receptor antagonist SR 140333 or the anti-oxidant N-acetylcystein (NAC) before allergen challenge. Inflammatory infiltration and remodelling were assessed 48 h after allergen challenge. RESULTS: ROS generation was increased by 3.7-fold, which was inhibited by SR 140333. [Sar(9),Met(11)(O(2))]-Substance P (5 nM) caused a tachykinin NK-1 receptor-dependent fourfold increase in ROS generation. Epithelial proliferation was decreased by 68% by incubation with [Sar(9),Met(11)(O(2))]-SP over 72 h. In-vivo, treatment with SR 140333 and NAC reduced epithelial damage (91.4% and 76.8% vs. placebo, respectively, P<0.01) and goblet cell hyperplasia (67.4% and 50.1% vs. placebo, respectively, P<0.05), and decreased inflammatory cell influx (65.3% and 45.3% vs. placebo, respectively, P<0.01). CONCLUSION: Allergen challenge induces ROS in a tachykinin NK-1 receptor-dependent manner. Inhibition of the tachykinin NK-1 receptor reduces epithelial damage and subsequent remodelling in vivo. Therefore, patients may possibly benefit from treatment regime that includes radical scavengers or tachykinin NK-1 receptor antagonists.

Transcriptional up-regulation of histamine receptor-1 in epithelial, mucus and inflammatory cells in perennial allergic rhinitis.

BACKGROUND: Histamine receptors play an important role in the pathogenesis of nasal allergy. Activation of histamine receptor 1 (H1R) and 2 (H2R) can cause allergic symptoms which can be blocked effectively by antihistamines. H1R and H2R transcript levels have been found to be up-regulated in perennial - but not in seasonal - allergic rhinitis (AR). The present study aimed to explore H1R and H2R expression in complex tissues of the nasal mucosa of perennial allergic rhinitis (PAR). METHODS: Ten patients with PAR and 13 non-AR subjects were recruited for the study by medical history, physical examination and laboratory screening tests. In this study, we have analysed single cells dissected from the nasal mucosa biopsies by laser-assisted microdissection. H1R mRNA expression was analysed in different cell types such as epithelial, endothelial, mucus and inflammatory cells isolated from the nasal mucosa of PAR in comparison with non-AR subjects. RESULTS: H1R mRNA gene expression level was significantly increased in the nasal mucosa of PAR in comparison with non-AR (P<0.0001). H1R mRNA was significantly elevated in epithelial (P<0.001) and mucus cells (P<0.05) of PAR in comparison with non-AR whereas H1R gene expression levels in endothelial cells between both groups were not changed (P=0.23). Interestingly, inflammatory cells in the nasal mucosa of PAR patients were also strongly expressed H1R mRNA (P<0.001). CONCLUSION: The present study indicates that PAR alters the expression of H1R mRNA in epithelial, mucus and inflammatory cells of the nasal mucosa and but not in endothelial cells. Therefore, epithelial, mucus and inflammatory cells may play an important role in histamine-mediated allergic airway inflammation in PAR.

Understanding prevention effectiveness in real-world settings: the National Cross-Site Evaluation of high risk youth programs.

The National Cross-Site Evaluation is a large multisite evaluation (MSE) of 48 substance abuse prevention programs, 5,934 youth participating in programs, and 4,539 comparison youth programs. Data included a self-report questionnaire administered at 4 points in time, detailed dosage data on over 217,000 program contacts, and detailed site visit information. In a pooled analysis, the programs did not demonstrate significant positive effects on a composite outcome measure of tobacco, alcohol, and marijuana use in the previous 30 days. However, disaggregated analyses indicated that 1) sites in which comparison groups had strong opportunity to participate in prevention programs suppressed observed effects; 2) youth who had already started using before they entered programs reduced use significantly more than comparison youth who had started using; and 3) both males and females who participated in programs significantly reduced use relative to comparisons, but in very different patterns. Combining these patterns produced an apparent null effect. Finally, programs that incorporated at least 4 out of 5 effective intervention characteristics identified in the study significantly reduced use for both males and females relative to comparison youth. The lessons produced by this study attest to the value of MSE designs as a source of applicable knowledge about prevention interventions.

Nerve growth factor-induced substance P in capsaicin-insensitive vagal neurons innervating the lower mouse airway.

BACKGROUND: Nerve growth factor (NGF) is elevated in allergic diseases such as bronchial asthma and can lead to an induction of substance P (SP) and related neuropeptides in guinea-pigs large-diameter, neurofilament-positive airway neurons. OBJECTIVE: In the present study, the effect of NGF on tyrosine kinase receptor trkA and the capsaicin receptor TRPV1 expression in airway-specific vagal sensory neurons located in the jugular-nodose ganglia complex (JNC) of mice was investigated. METHODS: Using retrograde neuronal tracing in combination with double-labelling immunohistochemistry, SP, trkA- and TRPV1-receptor expression was examined in airway-specific sensory neurons of BALB/c mice before and after NGF treatment. RESULTS: NGF injected into the lower airway was able to induce SP (13.0+/-2.03% vs. 5.9+/-0.33%) and trkA expression (78+/-2.66% vs. 60+/-2.11%) in larger diameter (>25 microm), capsaicin-insensitive and trkA-positive vagal sensory neurons that were retrograde-labelled with Fast Blue dye from the main stem bronchi. CONCLUSION: Based on the extent of SP and trkA co-expression in airway-specific neurons by NGF treatment, the present study suggests that, following a peripheral activation of trkA receptor on SP afferent by NGF which is elevated in allergic inflammation, there may be trkA-mediated SP induction to mediate neurogenic airway inflammation.

Immunohistochemical localization of cardio-active neuropeptides in the heart of a living fossil, Nautilus pompilius L. (Cephalopoda, Tetrabranchiata).

Neuropeptides play an important role in modulating the effects of neurotransmitters such as acetylcholine and noradrenaline in the heart and the vascular system of vertebrates and invertebrates. Various neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP) and FMRFamide, have been localized in the brain in cephalopods and the neurosecretory system of the vena cava. Previous studies involving cephalopods have mainly focussed on the modern, coleoid cephalopods, whereas little attention was paid to the living fossil Nautilus. In this study, the distributions of the peptides related to tachykinins (TKs) and the high affinity receptor for the best characterized TK substance P (tachykinin NK-1), VIP, as well as FMRFamide were investigated in the heart of Nautilus pompilius L. by immunohistochemistry. TK-like immunoreactivity (TK-LI) was seen associated to a sub-population of hemocytes, VIP-LI glial cells in larger nerves entering the heart, whereas FMRFamide immunoreactivity was distributed throughout the entire heart, including the semilunar atrioventricular valves. The pattern of FMRFamide immunoreactivity matched that of Bodian silver staining for nervous tissue. The NK-1-LI receptor was located on endothelial cells, which were also positive for endothelial nitric oxide synthase-LI (eNOS). The results indicate that neuropeptides may be involved in the regulation of the Nautilus heart via different mechanisms, (1) by direct interaction with myocardial receptors (FMRFamide), (2) by interacting with the nervus cardiacus (VIP-related peptides) and (3) indirectly by stimulating eNOS in the endothelium throughout the heart (TK-related peptides).

[Internal rotational strength of the thigh after ACL reconstruction. Prospective comparison of harvesting of the semitendinosus and gracilis tendons and the patella tendon]. / Innenrotationskraft des Unterschenkels nach Kreuzbandrekonstruktion. Prospektiver Vergleich zwischen Entnahme der Semitendinosus- und Grazilissehnen und der Patellasehne.

AIM: The aim of the present study was the prospective, randomized evaluation of the internal rotation strength in patients, undergoing ACL reconstruction using either semitendinosus and gracilis tendon autografts (ST/G) or the central third of the patella tendon (BPT). METHOD: 40 patients (20 male, 20 female, average age 32 years [16 - 49]) underwent reconstruction of the ACL. In 20 patients ST/G was used, in 20 matched patients the central third of the patella tendon (BPT) was used. Rehabilitation was identical for both groups. The isometric strength of internal tibial rotation in neutral position was measured preoperatively, 3, 6 and 12 months postoperatively. RESULTS: After 3 months no difference to the preoperative data was found. After six months the internal tibial torque was significantly higher (p < 0.05) than preoperatively. No additional increase was found after 12 months. There was no statistically significant difference between both groups at any time. CONCLUSION: The internal tibial torque, which is predominantly a function of the pes anserinus, recovers shortly after operation and is, due to postoperative rehabilitation, significantly elevated after 6 months. The randomized comparison with the harvesting of the central third of the patellar tendon showed no significant difference.

Risk, protection, and substance use in adolescents: a multi-site model.

This article reports findings from a national longitudinal cross-site evaluation of high-risk youth to clarify the relationships between risk and protective factors and substance use. Using structural equation modeling, baseline data on 10,473 youth between the ages of 9 and 18 in 48 high-risk communities around the nation are analyzed. Youth were assessed on substance use (cigarette, alcohol, and marijuana use), external risk factors including family, school, peer and neighborhood influences, and individual risk and protective factors including self-control, family connectedness, and school connectedness. Findings indicate strong direct relationships between peer and parental substance use norms and substance use. Individual protective factors, particularly family and school connectedness were strong mediators of individual substance use. These findings suggest that multi-dimensional prevention programming stressing the fostering of conventional anti-substance use attitudes among parents and peers, the importance of parental supervision, and development of strong connections between youth and their family, peers, and school may be most effective in preventing and reducing substance use patterns among high-risk youth.

Abundant expression of c-Jun in guinea pig sympathetic ganglia under basal conditions and allergen challenge.

Airway hyperresponsiveness, a keystone of allergic asthma, is mediated by the extrinsic airway innervation. As pathophysiological stimuli can induce the expression JUN proteins, which belong to the immediate early gene (IEG) family of transcription factors, the expression of c-Jun was examined under basal conditions and allergen challenge in guinea pig paravertebral and prevertebral sympathetic ganglia by quantitative double-labeling immunohistochemistry. C-Jun immunoreactivity was seen in 78.4 +/- 3.5% under normal and 82.6 +/- 4.6% under allergen-challenged conditions of protein-gene product (PGP) 9.5-positive sympathetic neurons of guinea pig superior cervical ganglia and 73.1 +/- 2.8% (normal) and 76.1 +/- 3.5% (allergen) of stellate ganglion neurons. In the coeliac-superior mesenteric ganglion, 59.5 +/- 5.0% (normal) and 57.5 +/- 4.4% (allergen) of the PGP 9.5-positive sympathetic neurons were labeled for c-Jun. The high basal levels of c-Jun expression indicate that the presence of c-Jun is not exclusively related to noxious stimulation such as allergic airway inflammation in the guinea pig.

Expression of immediate early genes in sensory ganglia.

C-Jun and c-Fos belong to the family of immediate early genes. Apart from their role as transcription factors, a basal expression was shown for them in central nervous system tissues. The expression of c-Jun and c-Fos in sensory ganglia of guinea pig, rat and murine sensory ganglia was examined under normal, unstimulated conditions by quantitative double-immunohistochemistry. 4.6 +/- 2.8% of neuron-specific protein gene-product 9.5 -positive cells in nodose ganglia, 51.6 +/- 2.1% in jugular ganglia, 46.4 +/- 3.0% in trigeminal ganglia and 42.5 +/- 1.3% of cervical dorsal root ganglia neurons were positive for c-Jun in the guinea pig (less than 1% for c-Fos). In rat and mouse, less than 1% of the sensory neurons exhibited c-Jun and c-Fos-immunoreactivity. The high basal expression of c-Jun in guinea pig sensory neurons suggests that in this species the presence of c-Jun does not only depend on specific stimulation and is not exclusively associated with neuronal plasticity of gene expression and functional changes.

Vasoactive intestinal polypeptide as mediator of asthma.

Vasoactive intestinal polypeptide (VIP) is one of the most abundant, biologically active peptides found in the human lung. VIP is a likely neurotransmitter or neuromodulator of the inhibitory non-adrenergic non-cholinergic airway nervous system and influences many aspects of pulmonary biology. In human airways VIP-immunoreactive nerve fibres are present in the tracheobronchial airway smooth muscle layer, the walls of pulmonary and bronchial vessels and around submucosal glands. Next to its prominent bronchodilatory effects, VIP potently relaxes pulmonary vessels. The precise role of VIP in the pathogenesis of asthma is still uncertain. Although a therapy using the strong bronchodilatory effects of VIP would offer potential benefits, the rapid inactivation of the peptide by airway peptidases has prevented effective VIP-based drugs so far and non-peptide VIP-agonists did not reach clinical use.