High rhinovirus burden in lower airways of children with cystic fibrosis

Rhinovirus (RV)-induced pulmonary exacerbations are common in cystic fibrosis (CF) and have been associated with impaired virus clearance by the CF airway epithelium in vitro. Here, we assess in vivo the association of RV prevalence and load with antiviral defense mechanisms, airway inflammation, and lung function parameters in children with CF compared with a control group and children with other chronic respiratory diseases.

Noncovalent interactions of drugs with immune receptors may mediate drug-induced hypersensitivity reactions

Drug-induced hypersensitivity reactions are instructive examples of immune reactions against low molecular weight compounds. Classically, such reactions have been explained by the hapten concept, according to which the small antigen covalently modifies an endogenous protein; recent studies show strong associations of several HLA molecules with hypersensitivity. In recent years, however, evidence has become stronger that not all drugs need to bind covalently to the major histocompatibility complex (MHC)-peptide complex in order to trigger an immune response. Rather, some drugs may bind reversibly to the MHC or possibly to the T-cell receptor (TCR), eliciting immune reactions akin to the pharmacological activation of other receptors. While the exact mechanism is still a matter of debate, noncovalent drug presentation clearly leads to the activation of drug-specific T cells. In some patients with hypersensitivity, such a response may occur within hours of even the first exposure to the drug. Thus, the reaction to the drug may not be the result of a classical, primary response but rather be mediated by existing, preactivated T cells that display cross-reactivity for the drug and have additional (peptide) specificity as well. In this way, certain drugs may circumvent the checkpoints for immune activation imposed by the classical antigen processing and presentation mechanisms, which may help to explain the idiosyncratic nature of many drug hypersensitivity reactions.

Sleep disturbance, norepinephrine, and D-dimer are all related in elderly caregivers of people with Alzheimer disease

STUDY OBJECTIVE: Caregiving for a relative with Alzheimer disease has been associated with sympathoadrenal medullary arousal and morbidity and mortality. In this study, we examined if sleep disturbance of elderly caregivers was associated with physiologic markers of cardiovascular risk, including plasma norepinephrine, epinephrine, and the hemostasis marker D-dimer. DESIGN: Cross-sectional. SETTING: Community-based sample of elderly caregivers of spouses with Alzheimer disease assessed within their homes. PARTICIPANTS: A sample of 40 elderly spousal caregivers of patients with Alzheimer disease. MEASUREMENTS AND RESULTS: Participants underwent in-home full-night polysomnography and had plasma assayed for norepinephrine and epinephrine. Using multiple regression analyses and controlling for a number of cardiovascular risk factors (e.g., age, sex, blood pressure, body mass index), increased wake after sleep onset was positively associated with norepinephrine levels (beta = .35; t = 2.45, df = 32, p = .020) and plasma D-dimer (beta = .31; t = 2.18, df = 29, p = .038). Further, plasma norepinephrine was significantly associated with D-dimer (beta = .34; t = 2.11, df = 29, p = .044). Additional analyses indicated that norepinephrine accounted for 28% of the relationship between wake after sleep onset and D-dimer. No association was observed between sleep variables and epinephrine. CONCLUSIONS: These findings provide preliminary evidence that sleep disturbance may contribute to morbidity in caregivers through sympathoadrenal medullary arousal and downstream physiologic effects such as altering the hemostasis environment.

Demographic characteristics of patients with extrapulmonary tuberculosis in Germany

The aim of the present study was to determine the demographics of patients with extrapulmonary tuberculosis in Germany. Data on 26,302 tuberculosis cases from a national survey carried out during the period 1996-2000 were analysed. The crude proportion of tuberculosis patients with extrapulmonary manifestations was 21.6%. Extrapulmonary tuberculosis was most likely among females, children aged <15 yrs and persons originating from Africa and Asia. Females tended to be more likely to have any form of extrapulmonary tuberculosis than males, except pleural tuberculosis. The strength of this association was strongest in the age range 25-64 yrs and less pronounced amongst the oldest patients. Children were particularly prone to the development of lymphatic and meningeal tuberculosis, whereas the likelihood of genitourinary tuberculosis increased with increasing age. Asian and African patients were generally more likely than persons from other areas to have lymphatic, osteoarticular, meningeal and miliary tuberculosis. The analysis shows important differences, by age, sex and origin, in the likelihood of a tuberculosis patient presenting with extrapulmonary tuberculosis. Since the relative contribution of the foreign-born to tuberculosis in low-prevalence countries is rising, extrapulmonary tuberculosis must be taken into account more often in the differential diagnostic work-up of these patients, particularly among those originating from Asia and Africa.

Association of lipopolysaccharide-binding protein and coronary artery disease in men

OBJECTIVES: In this study we tested the hypothesis that lipopolysaccharide-binding protein (LBP) might be able to be used as a biomarker for coronary artery disease (CAD). BACKGROUND: The mechanisms by which the innate immune recognition of pathogens could lead to atherosclerosis remain unclear. Lipopolysaccharide-binding protein is the first protein to encounter lipopolysaccharide and to deliver it to its cellular targets, toll-like receptors; therefore, its presence might be a reliable biomarker that indicates activation of innate immune responses. METHODS: A total of 247 men undergoing elective coronary angiography were studied, and the extent of coronary atherosclerosis was assessed by 2 established scores: "extent score" and "severity score." Levels of LBP, markers of inflammation, and traditional risk factors for CAD were assessed. RESULTS: Serum LBP concentration was significantly increased in 172 patients with angiographically confirmed CAD compared with 75 individuals without coronary atherosclerosis (20.6 +/- 8.7 pg/ml vs. 17.1 +/- 6.0 pg/ml, respectively; p = 0.002). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of prevalent CAD (p < 0.05 in all models). CONCLUSIONS: Lipopolysaccharide-binding protein might serve as a novel marker for CAD in men. The present results underlie the potential importance of innate immune mechanisms for CAD. Further studies are warranted to bolster the data and to identify pathogenetic links between innate immune system activation and atherosclerosis.

Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology

Therapy has improved the survival of heart failure (HF) patients. However, many patients progress to advanced chronic HF (ACHF). We propose a practical clinical definition and describe the characteristics of this condition. Patients that are generally recognised as ACHF often exhibit the following characteristics: 1) severe symptoms (NYHA class III to IV); 2) episodes with clinical signs of fluid retention and/or peripheral hypoperfusion; 3) objective evidence of severe cardiac dysfunction, shown by at least one of the following: left ventricular ejection fraction<30%, pseudonormal or restrictive mitral inflow pattern at Doppler-echocardiography; high left and/or right ventricular filling pressures; elevated B-type natriuretic peptides; 4) severe impairment of functional capacity demonstrated by either inability to exercise, a 6-minute walk test distance<300 m or a peak oxygen uptake<12-14 ml/kg/min; 5) history of >1 HF hospitalisation in the past 6 months; 6) presence of all the previous features despite optimal therapy. This definition identifies a group of patients with compromised quality of life, poor prognosis, and a high risk of clinical events. These patients deserve effective therapeutic options and should be potential targets for future clinical research initiatives.

Association of 1,5-anhydroglucitol and 2-h postprandial blood glucose in type 2 diabetic patients

To assess the association of 1,5-anhydroglucitol (1,5-AG) with 2-h postprandial glucose values in type 2 diabetic patients followed over 12 months in an outpatient setting.

A MIF haplotype is associated with the outcome of patients with severe sepsis: a case control study

BACKGROUND: Macrophage migration inhibitory factor (MIF) plays an important regulatory role in sepsis. In the promoter region a C/G single nucleotide polymorphism (SNP) at position -173 (rs755622) and a CATT5-8 microsatellite at position -794 are related to modified promoter activity. The purpose of the study was to analyze their association with the incidence and outcome of severe sepsis. METHODS: Genotype distributions and allele frequencies in 169 patients with severe sepsis, 94 healthy blood donors and 183 postoperative patients without signs of infection or inflammation were analyzed by real time PCR and Sequence analysis. All included individuals were Caucasians. RESULTS: Genotype distribution and allele frequencies of severe sepsis patients were comparable to both control groups. However, the genotype and allele frequencies of both polymorphisms were associated significantly with the outcome of severe sepsis. The highest risk of dying from severe sepsis was detectable in patients carrying a haplotype with the alleles -173 C and CATT7 (p = 0.0005, fisher exact test, RR = 1,806, CI: 1.337 to 2.439). CONCLUSION: The haplotype with the combination of the -173 C allele and the -794 CATT7 allele may not serve as a marker for susceptibility to sepsis, but may help identify septic patients at risk of dying.

[Preoperative preparation of patients with cardiovascular disease for noncardiac surgery]

Preoperative preparation of patients with cardiovascular disease is best initiated by the general practitioner. Updated Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery have been published by the American Heart Association und American College of Cardiology (2007). Individual cardiac evaluation must take into account active cardiac conditions, functional capacity, additional clinical risk factors and surgical risk. Stable, asymptomatic patients with normal functional capacity can proceed to elective anesthesia and surgery without further cardiac evaluation. Active cardiac conditions require evaluation and treatment by a cardiology service prior to elective surgery. In stable patients with poor (<4 metabolic equivalents, MET) or unknown functional capacity and clinical risk factors, who are scheduled for intermediate- or high-risk surgery, further cardiac evaluation and preparation is to be considered. Established indicated beta blocker and statin medication is to be continued; timely institution of beta blocker medication (target heart rate, <65 bpm) may be required depending on the risk of surgery, the presence of coronary heart disease, and the number of clinical risk factors present. Following percutaneous coronary intervention, specific waiting periods are required prior to elective surgery. In patients on antiplatelet therapy, the risk of stopping it should be weighed against the benefit of reduction in bleeding complications from the planned surgery.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Association of gastroschisis and choledochal cyst

Two infants are described who presented in the neonatal period with a direct hyperbilirubinemia. This was initially presumed to be because of the diagnosis of gastroschisis and the prolonged use of parenteral nutrition. However, both infants were eventually found to have an associated choledochal cyst. The cases are a novel association not previously reported and should heighten the awareness that anatomical causes of a direct hyperbilirubinemia need to be ruled out in all neonates.

Comparison of three bone ultrasounds for the discrimination of subjects with and without osteoporotic fractures among 7562 elderly women

Bone ultrasound measures (QUSs) can assess fracture risk in the elderly. We compared three QUSs and their association with nonvertebral fracture history in 7562 Swiss women 70-80 years of age. The association between nonvertebral fracture was higher for heel than phalangeal QUS.

Differential association of MUC5AC and CLCA1 expression in small cartilaginous airways of RAO-affected and control horses

REASONS FOR PERFORMING STUDY: Airway mucus accumulation is associated with indoor irritant and allergen exposure in horses with recurrent airway obstruction (RAO). Epidermal growth factor receptor (EGFR) and a chloride channel (calcium activated, family member 1; CLCA1) are key signalling molecules involved in mucin gene expression. OBJECTIVES: We hypothesised that exposure to irritants and aeroallergens would lead to increased expression of the mucin gene eqMUC5AC and increased stored mucosubstance in the airways of RAO-affected horses, associated with increased neutrophils and CLCA1 and EGFR mRNA levels. METHODS: We performed quantitative RT-PCR of eqMUC5AC, CLCA1 and EGFR; volume density measurements of intraepithelial mucosubstances; and cytological differentiation of intraluminal inflammatory cells in small cartilaginous airways from cranial left and right and caudal left and right lung lobes of 5 clinically healthy and 5 RAO-affected horses that had been exposed to indoor stable environment for 5 days before euthanasia. RESULTS: Neutrophils were increased in RAO-affected horses compared to clinically healthy controls. EqMUC5AC mRNA levels were positively correlated with both CLCA1 and EGFR mRNA levels in RAO-affected horses but only with CLCA1 in controls. The relationship between eqMUC5AC and CLCA1 differed in the 2 groups of horses with RAO-affected animals overexpressing CLCA1 in relation to eqMUC5AC. CONCLUSIONS: These data implicate CLCA1 as a signalling molecule in the expression of eqMUC5AC in horses but also suggest differential regulation by CLCA1 and EGFR between horses with RAO and those with milder degrees of airway inflammation.

Bovine Staphylococcus aureus: association of virulence genes, genotypes and clinical outcome

Based on our clinical experience on bovine mastitis, we hypothesized that subtypes of Staphylococcus aureus (S. aureus) exist which differ in their contagious and pathogenic properties. In order to investigate this hypothesis, we analyzed strains of S. aureus isolated from spontaneous intramammary infection (IMI) with their virulence gene patterns and genotypes obtained by PCR amplification of the 16S-23S rRNA intergenic spacer (RS-PCR). The genotypes were then associated with epidemiological and clinical data including 26 herds. The results demonstrated a high association between genotypes and virulence gene patterns as well as between epidemiological and pathogenic properties of S. aureus. In particular, genotype B was related to high contagiosity and increased pathogenicity whereas the other types (C, OG) were found with infection of single cows. Because of the high clinical relevance, our results indicate the need to subtype the IMI-associated strains of S. aureus in the future.

Clinical outcomes of patients with low-flow, low-gradient, severe aortic stenosis and either preserved or reduced ejection fraction undergoing transcatheter aortic valve implantation

AIMS Our aim was to evaluate the invasive haemodynamic indices of high-risk symptomatic patients presenting with 'paradoxical' low-flow, low-gradient, severe aortic stenosis (AS) (PLF-LG) and low-flow, low-gradient severe AS (LEF-LG) and to compare clinical outcomes following transcatheter aortic valve implantation (TAVI) among these challenging AS subgroups. METHODS AND RESULTS Of 534 symptomatic patients undergoing TAVI, 385 had a full pre-procedural right and left heart catheterization. A total of 208 patients had high-gradient severe AS [HGAS; mean gradient (MG) ≥40 mmHg], 85 had PLF-LG [MG ≤ 40 mmHg, indexed aortic valve area [iAVA] ≤0.6 cm(2) m(-2), stroke volume index ≤35 mL/m(2), ejection fraction (EF) ≥50%], and 61 had LEF-LG (MG ≤ 40 mmHg, iAVA ≤0.6 cm(2) m(-2), EF ≤40%). Compared with HGAS, PLF-LG and LEF-LG had higher systemic vascular resistances (HGAS: 1912 ± 654 vs. PLF-LG 2006 ± 586 vs. LEF-LG 2216 ± 765 dyne s m(-5), P = 0.007) but lower valvulo-arterial impedances (HGAS: 7.8 ± 2.7 vs. PLF-LG 6.9 ± 1.9 vs. LEF-LG 7.7 ± 2.5 mmHg mL(-1) m(-2), P = 0.027). At 30 days, no differences in cardiac death (6.5 vs. 4.9 vs. 6.6%, P = 0.90) or death (8.4 vs. 6.1 vs. 6.6%, P = 0.88) were observed among HGAS, PLF-LG, and LEF-LG groups, respectively. At 1 year, New York Heart Association functional improvement occurred in most surviving patients (HGAS: 69.2% vs. PLF-LG 71.7% vs. LEF-LG 89.3%, P = 0.09) and no significant differences in overall mortality were observed (17.6 vs. 20.5 vs. 24.5%, P = 0.67). Compared with HGAS, LEF-LG had a higher 1 year cardiac mortality (adjusted hazard ratio 2.45, 95% confidence interval 1.04-5.75, P = 0.04). CONCLUSION TAVI in PLF-LG or LEF-LG patients is associated with overall mortality rates comparable with HGAS patients and all groups profit symptomatically to a similar extent.