Association of NOD1 polymorphisms with atopic eczema and related phenotypes

BACKGROUND: Interactions with microbial pathogens are crucial for the maturation of the immune system. The nucleotide-binding oligomerization domain protein 1 (NOD1) is a cytosolic receptor sensing a muropeptide found mostly in gram-negative bacterial peptidoglycans. NOD1 is located on chromosome 7p14-p15, a region that has been linked with atopy. Recently, polymorphisms of the closely related NOD2 have been associated with atopy-related traits. OBJECTIVES: Within a large population-based cohort of German adults (n = 1417), a case-control population for atopic eczema (n = 454), and a large cohort of parent-offspring trios for atopic eczema (189 trios), we evaluated 11 NOD1 polymorphisms for associations with atopic phenotypes. Methods Subjects were phenotyped by standardized questionnaires and interviews, skin examination, and serum IgE measurements. Genotyping was performed by using matrix-assisted laser desorption ionization-time of flight mass spectrometry. RESULTS: Analyses revealed significant association of one NOD1 haplotype with atopic eczema in the population-based cohort ( P = .004) and the case-control population ( P = .003). Another NOD1 haplotype was associated with decreased total IgE ( P = .008). In addition, significant associations with total serum IgE levels were observed for polymorphisms rs2907748 ( P = .006), rs2907749 ( P = .012), and rs2075822 ( P = .018). These polymorphisms were significantly associated with atopic eczema and asthma in the family-based association analyses ( P = .001-.043). Seven polymorphisms showed significant transmission distortion for total IgE levels ( P values < .0001-.029). CONCLUSION: These data indicate that genetic variants within NOD1 are important determinants of atopy susceptibility.     

Human immunodeficiency virus 1-associated minor motor disorders: perfusion-weighted MR imaging and H MR spectroscopy

PURPOSE: To investigate whether advanced magnetic resonance (MR) imaging techniques such as diffusion-weighted (DW) and perfusion-weighted (PW) MR imaging and hydrogen 1 (1H) MR spectroscopy can depict functional and pathophysiologic mechanisms in patients who have minor motor deficits (MMDs) associated with human immunodeficiency virus 1 (HIV-1). MATERIALS AND METHODS: Thirty-two patients with results seropositive for HIV-1 and different degrees of HIV-1-related MMD underwent conventional brain MR imaging, as well as DW and PW MR imaging and 1H MR spectroscopy of the basal ganglia. PW MR imaging data were computed pixel by pixel for creation of time-to-peak, relative regional cerebral blood volume, and bolus amplitude parameter maps. In addition, quantitative regional cerebral blood flow (rCBF) maps were calculated with respect to the arterial input function by using the singular value decomposition algorithm. For 1H MR spectroscopy, a stimulated echo acquisition mode 20, or STEAM 20, sequence was used. Spectra were fit for determination of the signal intensities of the different metabolites. According to psychomotor testing results, patients were divided into three groups: group 1, 10 patients with normal motor function; group 2, eight patients with psychomotor slowing for the first time; and group 3, 14 patients who had had sustained pathologic psychomotor slowing for at least 6 months before the MR imaging examination. RESULTS: No patients had an abnormality at either conventional or DW MR imaging. PW MR imaging depicted significantly elevated rCBF in group 2 patients (P =.039, analysis of variance [ANOVA]) and significantly elevated myo-inositol-to-creatine ratio levels in group 3 patients (P =.020, ANOVA). CONCLUSION: Quantitative PW MR imaging and 1H MR spectroscopy can depict pathologic changes in patients who have HIV-1-related MMD but normal clinical examination and conventional MR imaging findings.     

Is V1 necessary for conscious vision in areas of relative cortical blindness?

Visual field defects result from postgeniculate lesions. It is generally assumed that absolute defects are caused by total destruction or denervation of primary visual cortex (V1) and that the degraded but conscious vision that remains or returns in relative or partial defects is mediated by compromised V1 cortex that retains a sufficiently large population of functional neurons. We here report the results of three patients with long-standing postgeniculate lesions who underwent functional magnetic resonance imaging while their partial defect was stimulated with high-contrast reversing checkerboard stimuli. Although the stimulation evoked conscious visual impressions in all three, in only one patient did it activate perilesional V1. In the other two we found no evidence for perilesional activation, indicating that some conscious vision may return in the absence of functional ipsilesional V1.     

Accuracy and precision of transcardiopulmonary thermodilution in patients with cardiogenic shock

Hemodynamic monitoring plays a crucial role in the supportive treatment of critically ill patients. In this setting, the use of the pulmonary artery catheter (PAC) is a standard procedure. In this study we prospectively compare the accuracy and precision of pulmonary thermodilution (PTD) by PAC and transcardiopulmonary thermodilution (TC-PTD) in patients with cardiogenic shock following an acute cardiac event. In this prospective study 77 hemodynamic measurements were taken in 11 patients presenting cardiogenic shock (CS) treated at the medical intensive care unit of our university hospital. Hemodynamic parameters were measured simultaneously by PTD and by TC-PTD. Both techniques assessed showed a strong correlation in the obtained hemodynamic parameters. The mean bias of cardiac index between measured by PTD (CIpa) and by TC-PTD (CIpi) was 0.04 ± 0.35 L/min/m². During intra-aortic balloon pump (IABP) counterpulsation and therapeutic hypothermia (TH) in post-resuscitation care, mean bias between CIpa and CIpi was 0.04 ± 0.36 and 0.04 ± 0.34 L/min/m², respectively. Similarly, patients presenting mitral or tricuspid regurgitation showed interchangeable parameters. Preload parameters obtained by TC-PTD showed significant differences in patients with left ventricular ejection fraction (LVEF) <35 %, compared to patients with LVEF ≥35 %. In contrast, pulmonary arterial occlusion pressure showed no significant difference. Hemodynamic measurements by PTD and TC-PTD are interchangeable during therapy of CS, including patients IABP, TH, mitral or tricuspid regurgitation. Preload parameters measured by TC-PTD seem to be more accurate in these patients than pressure parameters of PTD to gather the acute hemodynamic situation.     

Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum

BACKGROUND: Giardia lamblia causes infection of the small intestine, which leads to malabsorption and chronic diarrhoea. AIM: To characterise the inherent pathomechanisms of G lamblia infection. METHODS: Duodenal biopsy specimens from 13 patients with chronic giardiasis and from controls were obtained endoscopically. Short-circuit current (I(SC)) and mannitol fluxes were measured in miniaturised Ussing chambers. Epithelial and subepithelial resistances were determined by impedance spectroscopy. Mucosal morphometry was performed and tight junction proteins were characterised by immunoblotting. Apoptotic ratio was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining. RESULTS: In giardiasis, mucosal surface area per unit serosa area was decreased to 75% (3%) of control, as a result of which epithelial resistance should increase. Instead, epithelial resistance of giardiasis biopsy specimens was decreased (19 (2) vs 25 (2) Omega cm(2); p<0.05) whereas mannitol flux was not significantly altered (140 (27) vs 105 (16) nmol/h/cm(2)). As structural correlate, reduced claudin 1 expression and increased epithelial apoptosis were detected. Furthermore, basal I(SC) increased from 191 (20) in control to 261 (12) microA/h/cm(2) in giardiasis. The bumetanide-sensitive portion of I(SC) in giardiasis was also increased (51 (5) vs 20 (9) microA/h/cm(2) in control; p<0.05). Finally, phlorizin-sensitive Na(+)-glucose symport was reduced in patients with giardiasis (121 (9) vs 83 (14) microA/h/cm(2)). CONCLUSIONS: G lamblia infection causes epithelial barrier dysfunction owing to down regulation of the tight junction protein claudin 1 and increased epithelial apoptoses. Na(+)-dependent d-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhoea in human chronic giardiasis comprise leak flux, malabsorptive and secretory components.     

Regulation of cardiac cAMP synthesis and contractility by nucleoside diphosphate kinase B/G protein beta gamma dimer complexes

Heterotrimeric G proteins are pivotal regulators of myocardial contractility. In addition to the receptor-induced GDP/GTP exchange, G protein alpha subunits can be activated by a phosphate transfer via a plasma membrane-associated complex of nucleoside diphosphate kinase B (NDPK B) and G protein betagamma-dimers (Gbetagamma). To investigate the physiological role of this phosphate transfer in cardiomyocytes, we generated a Gbeta1gamma2-dimer carrying a single amino acid exchange at the intermediately phosphorylated His-266 in the beta1 subunit (Gbeta1H266Lgamma2). Recombinantly expressed Gbeta1H266Lgamma2 were integrated into heterotrimeric G proteins in rat cardiomyocytes but were deficient in intermediate Gbeta phosphorylation. Compared with wild-type Gbeta1gamma2 (Gbeta1WTgamma2), overexpression of Gbeta1H266Lgamma2 suppressed basal cAMP formation up to 55%. A similar decrease in basal cAMP production occurred when the formation of NDPK B/Gbetagamma complexes was attenuated by siRNA-mediated NDPK B knockdown. In adult rat cardiomyocytes expressing Gbeta1H266Lgamma2, the basal contractility was suppressed by approximately 50% which correlated to similarly reduced basal cAMP levels and reduced Ser16-phosphorylation of phospholamban. In the presence of the beta-adrenoceptor agonist isoproterenol, the total cAMP formation and contractility were significantly lower in Gbeta1H266Lgamma2 than in Gbeta1WTgamma2 expressing cardiomyocytes. However, the relative isoproterenol-induced increased was not affected by Gbeta1H266Lgamma2. We conclude that the receptor-independent activation of G proteins via NDPK B/Gbetagamma complexes requires the intermediate phosphorylation of G protein beta subunits at His-266. Our results highlight the histidine kinase activity of NDPK B for Gbeta and demonstrate its contribution to the receptor-independent regulation of cAMP synthesis and contractility in intact cardiomyocytes.