Altered fatty acid metabolism and reduced stearoyl-coenzyme a desaturase activity in asthma.

BACKGROUND: Fatty acids and lipid mediator signaling play an important role in the pathogenesis of asthma, yet this area remains largely underexplored. The aims of this study were (i) to examine fatty acid levels and their metabolism in obese and nonobese asthma patients and (ii) to determine the functional effects of altered fatty acid metabolism in experimental models. METHODS: Medium- and long-chain fatty acid levels were quantified in serum from 161 human volunteers by LC/MS. Changes in stearoyl-coenzyme A desaturase (SCD) expression and activity were evaluated in the ovalbumin (OVA) and house dust mite (HDM) murine models. Primary human bronchial epithelial cells from asthma patients and controls were evaluated for SCD expression and activity. RESULTS: The serum desaturation index (an indirect measure of SCD) was significantly reduced in nonobese asthma patients and in the OVA murine model. SCD1 gene expression was significantly reduced within the lungs following OVA or HDM challenge. Inhibition of SCD in mice promoted airway hyper-responsiveness. SCD1 expression was suppressed in bronchial epithelial cells from asthma patients. IL-4 and IL-13 reduced epithelial cell SCD1 expression. Inhibition of SCD reduced surfactant protein C expression and suppressed rhinovirus-induced IP-10 secretion, which was associated with increased viral titers. CONCLUSIONS: This is the first study to demonstrate decreased fatty acid desaturase activity in humans with asthma. Experimental models in mice and human epithelial cells suggest that inhibition of desaturase activity leads to airway hyper-responsiveness and reduced antiviral defense. SCD may represent a new target for therapeutic intervention in asthma patients.

Histamine receptor 2 modifies iNKT cell activity within the inflamed lung.

BACKGROUND: Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H2 R). The aim of this study was to determine the role of H2 R in modulating lung inflammatory responses. METHODS: H2 R was blocked using famotidine or activated using dimaprit in both the ovalbumin (OVA) and house dust mite extract (HDM) murine models of respiratory inflammation. H2 R-deficient animals and CD1d/H2 R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (αGalCer or OCH) to invariant natural killer T (iNKT) cells. RESULTS: Famotidine treatment resulted in more severe airway disease in the OVA model, while dimaprit treatment significantly reduced disease severity. Both OVA and HDM-induced airway diseases were more severe in H2 R-deficient animals. Flow cytometric analysis of lung tissue from H2 R-deficient animals revealed increased numbers of CD1d+ dendritic cells and increased numbers of iNKT cells. In vitro, αGalCer-stimulated iNKT cells from H2 R-deficient mice secreted higher levels of IL-4, IL-5, and GM-CSF. In vivo, αGalCer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment, and cytokine production in H2 R-deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to αGalCer. Removal of iNKT cells in H2 R-deficient (CD1d-/- H2 R-/- ) animals normalized the lung response to HDM. CONCLUSION: The deliberate activation of H2 R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d-mediated presentation of lipid antigens to iNKT cells is contributing to the pathology.

Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk.

BACKGROUND: Common genetic variations in toll-like receptor 2 (TLR2), an innate pathogen recognition receptor, may influence the development of atopic diseases. So far, very little is known about the role of rare TLR2 mutations in these diseases. OBJECTIVE: We investigated the functional properties of six rare amino acid changes in TLR2 (and one amino acid change in a TLR2 pseudogene) and studied their effect on atopic sensitization and disease. METHODS: We identified rare TLR2 mutations leading to amino acid changes from databases. Functional effects of TLR2 variants were analyzed by NF-kappaB-dependent luciferase reporter assay and interleukin-8 enzyme linked immunosorbent assay in vitro. The frequency of these mutations was determined in a random sample of the general population (n = 368). Association with atopic diseases were studied in a cross sectional German study population (n = 3099). RESULTS: Three out of six mutations in the TLR2 gene altered receptor activity in vitro. Out of these, only the minor allele of R753Q occurred reasonably frequent in the German population (minor allele frequency 3%). The risk to develop atopy increased by 50% in carriers of the 753Q allele (P = 0.021) and total (P = 0.040) as well as allergen specific serum IgE levels (P = 0.011) were significantly elevated. CONCLUSION: The rare but functionally relevant mutation R753Q in TLR2 may significantly affect common conditions such as atopic sensitization in the general population.

Exopolysaccharide from Bifidobacterium longum subsp. longum 35624™ modulates murine allergic airway responses.

Interactions between the host and the microbiota are thought to significantly influence immunological tolerance mechanisms at mucosal sites. We recently described that the loss of an exopolysaccharide (EPS) from Bifidobacterium longum 35624™ eliminated its protective effects in colitis and respiratory allergy murine models. Our goal was to investigate the immune response to purified EPS from B. longum 35624, determine if it has protective effects within the lung and identify the protective mechanisms. Isolated EPS from B. longum 35624 cultures was used for in vitro, ex vivo and in vivo studies. Human monocyte-derived dendritic cells (MDDCs) were used to investigate in vitro immunological responses to EPS. Cytokine secretion, expression of surface markers and signalling pathways were examined. The ovalbumin (OVA) respiratory allergy murine model was used to evaluate the in vivo immunomodulatory potential of EPS. In addition, interleukin (IL)-10 knockout (KO) mice and anti-Toll-like receptor (TLR)-2 blocking antibody were used to examine the underlying protective mechanisms of intranasal EPS administration. Stimulation of human MDDCs with EPS resulted in IL-10 secretion, but not proinflammatory cytokines. IL-10 secretion was TLR-2-dependent. Eosinophil recruitment to the lungs was significantly decreased by EPS intranasal exposure, which was associated with decreased expression of the Th2-associated markers C-C motif chemokine 11 (CCL11), C-C chemokine receptor type 3 (CCR3), IL-4 and IL-13. TLR-2-mediated IL-10 secretion was shown to be required for the reduction in eosinophils and Th2 cytokines. EPS-treatment reduced eosinophil recruitment within the lung in a respiratory inflammation mouse model, which is both TLR-2 and IL-10 mediated. EPS can be considered as a novel molecule potentially reducing the severity of chronic eosinophil-related airway disorders.

Central nervous correlates of chemical communication in humans.

The recording of chemosensory event-related potentials (CSERPs) has been established as an objective method in the assessment of central odor processing in humans. In the present study CSERPs were used to investigate whether human body odor is genetically determined by the major histocompatibility complex (MHC), referred to in humans as the human leukocyte antigen (HLA). The immunological function of the MHC is the discrimination of self/nonself within the immune system. In rodents it has been shown that body odor is significantly influenced by the MHC and that it can be discriminated by members of different species. To create a sufficiently large subject pool, 144 subjects were screened for their HLA class I loci A and B. During the electroencephalography (EEG) session the subjects (n = 40/20 women) were confronted with the body odor (axillary hair) of three different donors. Two donors (d1 and d2) were HLA-similar but had a different HLA type than the third donor (d3) and the perceiving subject. The third donor and the perceiver shared a similar HLA type. Half of the perceivers received odors from donors of the same sex, the other half smelt odors from donors of the opposite sex. In the EEG session subjects were presented with 200 trials. The odors were delivered through a constant flow olfactometer non-synchronously to breathing. The odor of d1 appeared frequently (p = 0.6) whereas the odors of d2 and d3 appeared each at a rate of p = 0.2. During half the trials the subjects were instructed to respond to the odor of d2, during the other half to the odor of d3. The EEG was recorded from Fz, Cz, Pz, F3, P3, F4 and P4 in reference to linked mastoids. First results show that male perceivers show enhanced potentials in response to male donors of a similar HLA type (d3). The CSERP results of the other groups as well as valence and attractiveness ratings will be discussed.

Reduced olfactory performance in patients with major depression.

The aim of the present study is to investigate olfactory sensitivity and odor evaluations in a homogeneous sample of unipolar depressive patients using pure olfactory odors. Twenty-four in-patients with major depressive disorder (MDD) were investigated during their acute depressive phase. Eighteen of them participated a second time after successful treatment. A group of healthy subjects, matched by age, sex, and smoking behavior, served as a control. Olfactory sensitivity, as measured by threshold tests, was strongly reduced in patients with severe depression. Additional correlative analyses revealed that the lowered sensitivity could partly be predicted by high depression scores. After successful medical treatment, these sensitivity differences were reduced and did not reach the significance level. The subjective odor evaluations (valence and intensity ratings) were not markedly changed in general. The results reveal that olfactory performance in MDD patients is reduced at an early perceptional level of stimulus processing. It is discussed whether this effect can be attributed to the close functional connection between the main olfactory bulb and the amygdala.

Is the modality-shift effect specific for schizophrenia patients?

Several studies have found that the reaction time of schizophrenia patients is longer when successive imperative stimuli are of different modality (e.g., light followed by sound) than when they are identical (e.g., sound followed by sound). This effect is called the modality-shift effect. In this study, the reaction times of 175 persons were analyzed: 54 schizophrenia patients, 33 patients with mood disorders, 13 alcoholics, 17 patients with rheumatoid arthritis, 13 patients with internal diseases, and 45 normal controls. The results indicated that a shift from light to sound stimuli lengthened the reaction time for schizophrenia patients considerably more than for alcoholics, patients with rheumatoid arthritis, patients with internal diseases, or normal controls. No difference was found between the reaction times of schizophrenia patients and patients with mood disorders.

Olfactory event-related potentials in patients with brain tumors.

OBJECTIVE: The aim of the study was to determine how odor processing is altered in patients with unilateral supratentorial brain tumors. METHODS: Olfactory event-related potentials (OERPs) were evaluated in 10 patients with unilateral brain tumors of the frontal or temporal lobe in response to linalool and allylcaproate. Both odors were presented monorhinally by a constant-flow olfactometer. In addition, 20 healthy subjects were examined. While sniffing, the subjects were asked to discriminate the two odors. EEG was recorded from 7 electrode positions (Fz, Cz, Pz, F3/4, P3/4). Amplitudes and latencies of 3 peaks (N1, P2, P3) were measured. To control for effects of modality-non-specific alterations on the olfactory components acoustic event-related potentials (AERPs) were registered by use of an oddball paradigm. RESULTS: Patients with right-sided lesions showed distinct deficits in the discrimination task after stimulation of the right and left nostril. In contrast, patients with left-sided lesions only had an attenuation of correct reactions after left-sided stimulation. In the OERPs, patients with right-sided lesions showed P2- and P3-components with decreased amplitudes at parietal electrode positions. These alterations appeared after ipsi- and contralateral stimulation. Patients with left-sided lesions showed a significant effect of the side of stimulation. Their OERP-amplitudes were decreased after left-sided stimulation but not after right-sided stimulation. After right-sided olfactory stimulation a correlation between the olfactory and the acoustic ERP was seen in patients with right-sided lesions. CONCLUSIONS: Olfactory performance of the participating patients was markedly reduced. Patients with right-sided lesions showed bilateral impairment, which would support the importance of the right hemisphere in olfaction. The alteration of the topographic distribution of P2- and P3-amplitudes in patients with right-sided lesions might reflect an impairment of early and late olfactory processing steps.

Effects of modality shift and motor response shift on simple reaction time in schizophrenia patients.

The modality shift effect (MSE) shows that the reaction time (RT) of schizophrenia patients is longer when successive imperative stimuli are of different modality (e.g., light followed by sound) than when they are identical (e.g., sound followed by sound). The authors analyzed the RTs of 49 men: 21 had schizophrenia, 13 were alcoholic, and 15 were controls. The results from a standard paradigm to provoke the MSE indicated a considerably more pronounced MSE in schizophrenia patients than in the comparison groups. Another experimental condition was used to test whether the effect is due to the longer activity of neural traces in sensory pathways in schizophrenia patients or to changes in an entire stimulus response cycle. Results suggest that only a shift in modality and not in the required motor response lengthened the RTs of the schizophrenia patients more than of the other groups.

MHC-associated and MHC-independent urinary chemosignals in mice.

The chemosensory identity of mice, rats, and humans is determined partly by polymorphic genes of the major histocompatibility complex (MHC). In inbred strains of mice as well as in seminatural populations MHC-associated mating preferences selectively influence reproductive success. To explore MHC-associated chemosignals in relation to otherwise genetically determined chemosignals a first study was conducted on seven trained rats' responses to the odors of inbred strains of mice. Results of the first study confirmed that neither the MHC nor genes in the genetic background dominate in determining urine odor specificity of mice and that specific olfactory cues associated with either the MHC or the genetic background can be identified by olfaction. In a second study, these specific olfactory cues were analyzed by means of gas chromatography. The results indicate that specific volatile components associated with either the MHC or the genetic background can be found in mouse urine odor, and that profiles of ubiquitous volatile components show some association with either the MHC or the genetic background. Furthermore, results show that a small number of specific compounds as well as a profile of some few ubiquitous volatiles constitute MHC-associated odor cues and that influences of the MHC and genes in the genetic background interact in constituting urine odor specificity in mice.

Sensitivity to androstenone in female subjects is associated with an altered brain response to male body odor.

Androstenone is a boar pheromone. and has also been found within different human body fluids. However, it is still unclear whether it carries pheromonal information in humans and whether it contributes significantly to the complex human body odor at all. Some humans fail to perceive the odor of androstenone, but most of these anosmics can achieve sensitivity by daily sniffing. The following study was designed to investigate whether sensitivity to androstenone influences the perception of body odors. Four females osmic to and four females anosmic to androstenone attended two EEG sessions. Anosmics were successfully sensitized to androstenone between sessions. CSERPs (chemosensory event-related potentials) were obtained while subjects perceived their own body odor and a male body odor within an olfactory oddball paradigm. The CSERPs showed a general decrease in amplitude from the first to the second session except for the sensitized anosmics in response to male body odor. The results indicate that the sensitivity to androstenone in females is associated with a stronger brain response to male body odor.

Fractionation and bioassay of human odor types.

Human urine samples were fractionated to examine the contribution of volatiles to the individual body odor. The samples were obtained from 4 male donors and fractionated using a vacuum technique. The volatiles from the chemical fractions were analyzed using the CLSA technique and gas chromatography. Thereafter, these fractions were tested in a computer-controlled olfactometer by trained rats. Although the rats were able to discriminate the distillation residue, they could not recognize the urine odor in the distilled fraction. The results of gas chromatography indicate a continuous release of volatile constituents in the distillation residue.

Analgesic effect of ceruletide in men is limited to specific pain qualities.

Cholecystokinin (CCK) and related peptides are supposed to be potent analgesic neuropeptides. Studies in rodents suggest a dose-dependent biphasic effect. The present study aimed to examine the pain modulating effect of different doses (0.5 microgram and 5 micrograms) of ceruletide (CRL), infused i.v. for 30 min. Pain thresholds were obtained for ischemic, mechanical, and thermal pain. In addition, pain tolerance was measured for mechanical pain. According to a placebo-controlled double-blind within-subject design 25 healthy men attended three experimental sessions each. Pain perception was measured as a baseline and twice after the infusion. The effect of both doses of CRL to enhance the pain threshold for thermal stimuli is in line with former studies. However, perception of heat stimuli above or below the threshold was not substantially affected by CRL treatment. Algesic properties of CRL are also indicated, because the tolerance for mechanical pain decreased after administration of the high dose of CRL. Perception of ischemic pain was not obviously influenced by any of the treatments. The role of CRL in human pain modulation seems to vary, depending on the type of experimental pain.

Olfactory information processing during the course of the menstrual cycle.

In the present study we examined whether olfactory information processing depends on the phase of the menstrual cycle. Five female subjects were investigated during three phases (follicular, ovulatory, luteal) of their menstrual cycle. In each session chemosensory (olfactory) event-related potentials (CSERP) were recorded and olfactory thresholds and the hedonic tone of the test stimulus (citral) were determined. Threshold values were correlated with the salivary cortisol level. The results show that olfactory perception changes during the menstrual cycle. After the first stimulus presentations in a recording session, odors were perceived as more complex or novel during the ovulatory period (enhanced amplitude of P3-1). With continued stimulation, odor processing became faster (reduced latency of NI, P2 and P3-2) around ovulation and slower during the follicular phase. Moreover, odors were described more differentially during the ovulatory period. Olfactory sensitivity was correlated positively with the peripheral cortisol level.

Is odor processing related to oral breathing?

This paper addresses two questions related to the inherent association between breathing and odor perception: Does central nervous processing of odors change when an artificial breathing technique (velopharyngeal closure) is introduced and secondly, does odor processing vary with the oral breathing phase (inhalation or exhalation)? Chemosensory event-related potentials (CSERP) were obtained from eight female subjects while they were smelling an odor mixture (citral, eugenol, linalool, menthol and isoamylacetate). Each subject was required to perform spontaneous mouth breathing (120 trials) as well as the velopharyngeal closure technique (120 trials). Simultaneously, a thermistor monitored the phase of the respiratory cycle. The results reveal that the central nervous correlates of odor processing change with the breathing technique but not with the oral breathing cycle. The findings that early stimulus processing is faster (N1 latency) and late stimulus processing more pronounced (P3 amplitudes) when the subjects are breathing spontaneously are discussed with regard to attentional effects. The reduction of the N1 amplitude during the spontaneous breathing condition may be caused by larger latency variations and longer stimulus rise-times. Furthermore, it is concluded that the oral breathing cycle is less important than the nasal breathing cycle for olfactory information transmission.

Children's spatial behavior is differentially affected after traumatic brain injury.

Spatial behavior in 20 children with severe traumatic brain injury (TBI) and 20 healthy controls was investigated using the Kiel Locomotor Maze. Children had to remember defined locations in an experimental chamber with completely controlled intra- and extra-maze cues until learning criterion was reached. In a second experiment, spatial orientation strategies were assessed. Children with TBI were shown to be impaired in spatial learning and spatial memory. Spatial orientation was found to be deficient even in cases where spatial learning and memory proved to be unimpaired, especially in tasks that demanded the use of relational place strategies. Children who suffered a TBI at an early age proved to be more severely impaired in spatial learning and orientation than older children.

Development of spatial memory and spatial orientation in preschoolers and primary school children.

The present study addresses the question of what kind of information children use when orientating in new environments, if given proximal and distal landmarks, and how spatial memory develops in the investigated age groups. Ten 5-year-old, ten 7-year-old and ten 10-year-old children were presented with the 'Kiel Locomotor Maze', containing features of the Radial Arm Maze and the Morris Water Maze, in order to assess spatial memory and orientation. Children had to learn to approach baited locations only. Task difficulty was equated with respect to the children's age. Training was given until the children reached criterion. During testing, the maze configuration and response requirements were systematically altered, including response rotation, cue rotation, cue deletion and response rotation with cue deletion in order to assess the spatial strategies used by the children. During training and testing, working-memory errors (WM), reference-memory errors (RM) and working-reference memory errors (WR) were recorded. As expected, no difference between age groups appeared during training, thus confirming comparable task difficulty across age groups. During testing, age groups differed significantly with regard to the orientation strategy used. The 5-year-olds were bound to a cue strategy, orientating towards local, proximal cues. The 10-year-olds mastered all tasks, thus displaying a place strategy, being able to use distal cues for orientation, and were even able to do so after being rotated 180 degrees. The 7-year-olds proved to be at an age of transition: five of them were bound to a cue strategy, five children were able to adopt a place strategy. The differences in the orientation strategies used by children of different age groups was reflected by the sum of errors they made, also by RM. WM were found to be rare, especially in older children. We conclude that preschoolers use a cue strategy, that the development of place strategies occurs during primary school age and seems to be complete by the age of 10 years.

GC profiles of volatile constituents from human urine obtained by closed loop stripping, purge and trap technique and simultaneous stem distillation-extraction.

Different techniques like "closed loop stripping" [CLSA], "purge and trap" [PTI], and continuous steam distillation extraction [SDE] were used to establish GC profiles of major histocompatibility complex-associated volatile constituents of human urine and statistically evaluated for reliability. Of the three methods investigated, PTI appeared to be superior for the detection of very volatile substances, whereas SDE was the most efficient one with respect to yield. A number of short to medium-chain ketones, 4-hydroxy-3-methoxy-styrene, menthol and nicotine were identified in preliminary analyses.

A new procedure for assessment of proprioception.

A new method for the assessment of proprioception was developed and tested with 40 healthy subjects on two facial muscles (i.e., masseter and zygomatic muscles). The experiment was repeated after 3 1/2 months. In our study, proprioception was studied with respect to sensations arising from the muscle spindles and tendon organs. Therefore, myesthesia was investigated, which was assessed by the correspondence between a voluntary muscle contraction and its immediate replication. Good perception was defined by a small integral of differences, standardized by duration and intensity of the contraction, and its replication. Results show that this measure is independent of the characteristics of muscle activation. In concordance with our hypothesis, myesthesia was superior in a muscle richly supplied with muscle spindles and afferent fibers (i.e., masseter muscle), to that for a muscle less prepared for afferent information processing (i.e., zygomatus major).

Grasp effects of the Ebbinghaus illusion are ambiguous.

The assumption that the Ebbinghaus/Titchener illusion deceives perception but not grasping, which would confirm the two-visual-systems hypothesis (TVSH) as proposed by Milner and Goodale (The visual brain in action, 1995), has recently been challenged. Franz et al. (Exp Brain Res 149:470-477, 2003) found that the illusion affects both perception and grasping, and showed that the effect of the illusion on the peak grip aperture (PGA) cannot be accounted for by different sizes of the gap that separates the central target disk from the surrounding flankers. However, it is not yet clear if the presence of flankers per se influences grasping. We therefore compared kinematic parameters of prehension, using the Ebbinghaus illusion, and a neutral control condition where normal subjects grasped a disk without any flankers. In accordance with the well-known effects of the illusion on perceived size, the PGA was smaller when the target disk was surrounded by large flankers, and larger when it was encircled by small flankers. However, the largest PGA values were reached in the neutral control condition. Hence the presence of flankers leads to a general reduction of the PGA, possibly because the flankers are regarded as obstacles. This 'reduction effect' casts doubts on how appropriate it is to directly compare perceptual measures and PGA values when using the Ebbinghaus illusion. Even smaller effects of the illusion on the PGA compared to larger perceptual effects cannot be unequivocally interpreted.