The basophil activation test differentiates between patients with wheat‐dependent exercise‐induced anaphylaxis and control subjects using gluten and isolated gluten protein types

BackgroundOral food challenge using gluten and cofactors is the gold standard to diagnose wheat‐dependent exercise‐induced anaphylaxis (WDEIA), but this procedure puts patients at risk of an anaphylactic reaction. Specific IgE to ω5‐gliadins as major allergens and skin prick tests to wheat may yield negative results. Thus, we designed a proof‐of‐principle study to investigate the utility of the basophil activation test (BAT) for WDEIA diagnosis.MethodsDifferent gluten protein types (GPT; α‐, γ‐, ω1,2‐ and ω5‐gliadins, high‐molecular‐weight glutenin subunits [HMW‐GS] and low‐molecular‐weight glutenin subunits [LMW‐GS]) and gluten were used in different concentrations to measure basophil activation in 12 challenge‐confirmed WDEIA patients and 10 control subjects. The results were compared to routine allergy diagnostics. Parameters analyzed include the percentage of CD63⁺ basophils, the ratio of %CD63⁺ basophils induced by GPT/gluten to %CD63⁺ basophils induced by anti‐FcεRI antibody, area under the dose‐response curve and test sensitivity and specificity.ResultsGPT and gluten induced strong basophil activation for %CD63⁺ basophils and for %CD63⁺/anti‐FcɛRI ratio in a dose‐dependent manner in patients, but not in controls (p < 0.001, respectively). BAT performance differed from acceptable (0.73 for LMW‐GS) to excellent (0.91 for ω5‐gliadins) depending on the specific GPT as evaluated by the area under the receiver operating characteristic curve. Patients showed individual sensitization profiles. After determination of the best cut‐off points, ω5‐gliadins and HMW‐GS showed the best discrimination between patients and controls with a sensitivity/specificity of 100/70 and 75/100, respectively.ConclusionThis study shows the alternative role of BAT in better defining WDEIA and the causative wheat allergens. The best BAT parameters to distinguish WDEIA patients from controls were %CD63⁺ basophil values for ω5‐gliadins and HMW‐GS.     

Functional neuroanatomy of sustained memory encoding performance in healthy aging and in Alzheimer's disease

The aim of our study was to examine brain networks involved with sustaining memory encoding performance in healthy aging and in Alzheimer's disease (AD). Since different brain regions are affected by degradation in these two conditions, it might be conceivable that different compensation mechanisms occur to keep up memory performance in aging and in AD. Using an event-related functional magnetic resonance imaging (FMRI) design and a correlation analysis, 8 patients suffering from AD and 29 elderly control subjects were scanned while they studied a list of words for a subsequent memory test. Individual performance was assessed on the basis of a subsequent recognition test, and brain regions were identified where functional activations during study correlated with memory performance. In both groups, successful memory encoding performance was significantly correlated with the activation of the right frontal cortex. Furthermore, in healthy controls, there was a significant correlation of memory performance and the activation of the left medial and lateral temporal lobe. In contrast, in AD patients, increasing memory performance goes along with increasing activation of the hippocampus and a bilateral brain network including the frontal and temporal cortices. Our data show that in healthy aging and in AD, common and distinct compensatory mechanisms are employed to keep up a certain level of memory performance. Both in healthy aging and in patients with AD, an increased level of monitoring and control processes mediated by the (right) frontal lobe seems to be necessary to maintain a certain level of memory performance. In addition, memory performance in healthy older subjects seems to rely on an increased effort in encoding item-specific semantic and contextual information in lateral areas of the (left) temporal lobe. In AD patients, on the other hand, the maintenance of memory performance is related to an increase of activation of the (left) hippocampus in conjunction with a bilateral network of cortical areas that might be involved with phonological and visual rehearsal of the incoming information.     

Coronary saddle embolism causing myocardial infarction in a patient with mechanical mitral valve prosthesis: treatment with thrombolytic therapy

Coronary embolism is an uncommon cause for myocardial infarction in clinical practice and there is no consensus on the treatment of this subject. Thrombolytic agents and percutaneous intervention are up to date options and yet there are only a few case reports regarding thrombolytic therapy in this special subgroup of patients suffering from myocardial infarction. We reported a 37-year-old woman patient with non-ST elevation myocardial infarction due to coronary embolism who was successfully treated using intravenous thrombolytic therapy with tissue plasminogen activator.     

Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities

Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs--adverse effects attributed to suppression of COX-1-derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2-derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a "balance" between COX-2-derived PGI2 and COX-1-derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.     

Dihydralazine treatment limits liver injury after hemorrhagic shock in rats

OBJECTIVE: Impaired hepatic perfusion after hemorrhagic shock frequently results in hepatocellular dysfunction associated with increased mortality. This study characterizes the effect of the vasodilators dihydralazine and urapidil on hepatocellular perfusion and integrity after hemorrhagic shock and resuscitation. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University experimental laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: To register systemic and regional hepatic hemodynamics, rats (n=6 per group) were instrumented and randomly assigned to the following groups: shock+vehicle; shock+dihydralazine (1.5 mg/kg); or shock+urapidil (3 mg/kg). After 1 hr of hemorrhagic shock, animals were resuscitated for 5 hrs and mean arterial pressure was maintained at 70+/-5 mm Hg by administration of dihydralazine or urapidil. To evaluate hepatic heme oxygenase-1 expression and liver injury (determination of levels of alanine and aspartate aminotransferase [ALT, AST] and histology), an additional series of experiments with six animals per group was performed. At the end of each experiment, animals were killed and blood and liver tissue was obtained for subsequent analyses. MEASUREMENTS AND MAIN RESULTS: Dihydralazine increased cardiac output and portal and hepatic microvascular flow (p<.05) and reduced liver injury after shock (lower ALT and AST levels [p<.05]; improvement of histopathological changes). In contrast, urapidil had no effect on portal flow or liver injury. Hepatic heme oxygenase-1 mRNA expression was upregulated in animals subjected to hemorrhagic shock but did not differ among experimental groups. CONCLUSIONS: Dihydralazine increases nutritive portal and hepatic microvascular flow and limits liver injury after hemorrhagic shock. This protective effect appears to be the result of increased cardiac output and increased portal flow. These findings may offer a new strategy for hepatic protection after hemorrhagic shock.     

Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2

BACKGROUND & AIMS: Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib. METHODS: Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects. RESULTS: Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1 and CYP2C9. CONCLUSIONS: The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications.     

Measuring attachment representation in an FMRI environment: a pilot study

This exploratory study is the first to examine the neural correlates of attachment status in adults. The study examined the feasibility of assessing attachment narratives in the functional magnetic resonance imaging (fMRI) environment by challenging subjects to tell attachment stories to specific attachment pictures from the Adult Attachment Projective (AAP) while being scanned. We investigated theoretically derived hypotheses regarding predicted differences in the brain activation patterns of individuals whose attachment status was organized (resolved) versus disorganized (unresolved) with respect to attachment trauma (e.g., as associated with loss through death, abuse, threat of abandonment). Adult attachment was assessed using the AAP, a new representational attachment measure that we thought might be suitable for use in the fMRI environment. This measure was used to obtain a preliminary picture of the neural processes associated with the activation of attachment in 11 healthy female adults. Results are reported from a second-level analysis (p < 0.001 uncorrected) and confirm that the AAP is a feasible measure for use in a neuroimaging environment. Cerebral activation during continuous speech yielded results consistent with the literature. Brain activation was demonstrated in expected visual and semantic brain regions. Furthermore, we found that the rate of articulation was positively correlated with activation in the right superior temporal gyrus. The results of theoretically derived attachment hypotheses showed no differences at the chosen level of significance when comparing the 'all attachment pictures' effect between both groups (resolved vs. unresolved). More interestingly, we found a significant interaction effect between the sequence of pictures and attachment category. Only the unresolved participants showed increasing activation of medial temporal regions, including the amygdala and the hippocampus, in the course of the AAP task. This pattern was demonstrated especially at the end of the AAP task where the pictures are drawn to portray traumatic situations. We interpret these results as confirming our hypothesis, linking unresolved attachment to emotional dysregulation of the attachment system. These results are discussed in relation to assessing attachment in an fMRI environment and future research in this area.     

A possible brain network for representation of cooperative behavior and its implications for the psychopathology of schizophrenia

It has been shown that social deficits contribute to psychopathology in schizophrenia, such as the bleulerian autism. A possible dysfunction in the mirror neuron system may be the reason for these deficits in the disorder. We wanted to better characterize the neural networks involved in the perception of social behavior. Fifteen healthy participants were presented with video clips of 8 seconds' duration depicting either (1) one actor manipulating an object, (2) two actors with only one manipulating an object or (3) two actors cooperating in manipulating an object and 2 other control conditions. Functional magnetic resonance imaging data were acquired during watching these videos. We found the perception of social cooperation is supported by a neural network comprising the precuneus, the temporoparietal junction (supramarginal gyrus, angular gyrus, BA 39/40), the middle temporal gyrus (including superior temporal sulcus) and frontal regions (medial frontal gyrus, inferior frontal gyrus). These areas form a complex network also being activated during theory of mind and cooperative behavior tasks. Its nodes overlap with those of the mirror neuron system. Consequently, both theory of mind abilities and mirror mechanisms are relevant in the perception and understanding of social cooperative behavior. We outline the consequences of these results for a further understanding of schizophrenic psychopathology with respect to social deficits and ego disturbances.     

Feeling addressed! The neural processing of social communicative cues in patients with major depression

The feeling of being addressed is the first step in a complex processing stream enabling successful social communication. Social impairments are a relevant characteristic of patients with major depressive disorder (MDD). Here, we investigated a mechanism which—if impaired—might contribute to withdrawal or isolation in MDD, namely, the neural processing of social cues such as body orientation and gesture. During funtional magnetic resonance imaging (fMRI) data acquisition, 33 patients with MDD and 43 healthy control subjects watched video clips of a speaking actor: one version with a gesture accompanying the speech and one without gesture. Videos were filmed simultaneously from two different viewpoints: one with the actor facing the viewer head‐on (frontal) and one side‐view (lateral). After every clip, the participants were instructed to evaluate whether they felt addressed or not. Despite overall comparable addressment ratings and a large overlap in activation patterns in MDD and healthy subjects for gesture processing, the anterior cingulate cortex, bilateral superior/middle frontal cortex, and right angular gyrus were more strongly activated in patients than in healthy subjects for the frontal conditions. Our analyses revealed that patients showed specifically higher activation than healthy subjects for the frontal condition without gesture in regions including the posterior cingulate cortex, left prefrontal cortex, and the left hippocampus. We conclude that MDD patients can recognize and interpret social cues such as gesture or body orientation; however, they seem to require more neural resources. This additional effort might affect successful communication and contribute to social isolation in MDD.