Conradi-Hünermann-Happle syndrome (X-linked dominant chondrodysplasia punctata) confirmed by plasma sterol and mutation analysis

Conradi-Hünermann-Happle syndrome, or X-linked dominant chondrodysplasia punctata, is a rare genetic disorder characterized by skeletal dysplasia, stippled epiphyses, cataracts, transient ichthyosis and atrophic residua in a mosaic pattern. Mutations in the gene encoding the emopamil-binding protein have been identified as an underlying cause. A 5-year-old girl presented for evaluation of ill-defined patches of cicatricial alopecia. In addition, subtle follicular atrophoderma, esotropia, craniofacial asymmetry and short stature were noted. Her history revealed widespread scaly erythema and eye surgery for congenital cataract in the first months of life. Diagnosis of Conradi-Hünermann-Happle syndrome was confirmed by plasma sterol analysis showing markedly elevated levels of 8(9)-cholestenol and 8-dehydrocholesterol and by detection of a missense mutation (c.307G>A; p.E103K) in the emopamil-binding protein gene. We suggest that plasma sterol analysis is a reliable method of establishing the diagnosis of Conradi-Hünermann-Happle syndrome, even in patients with less striking phenotypical changes beyond infancy.     

Antibody and cytokine responses in Dracunculus medinensis patients at distinct states of infection

Dracunculiasis is a promising candidate for eradication, but transmission of Dracunculus medinensis and recrudescence of the disease have been observed repeatedly. In the present investigation, the D. medinensis-specific cellular cytokine response profiles and the parasite-specific antibody subclass reactivity were evaluated in dracunculiasis patients at distinct states of infection. Analysis of the cellular cytokine response in dracunculiasis patients disclosed a D. medinensis antigen-specific depression of IFN-gamma production with patent D. medinensis infection, while the T helper type 2 cytokine IL-10 was similar in patent, post-patent and control individuals, and IL-5 production was always the highest in controls. In parallel, diminished IFN-gamma and IL-12 responses to antigens from Ascaris lumbricoides, Entamoeba histolytica and mycobacteria were observed in patent and post-patent dracunculiasis cases. The parasite-specific IgG(1) and IgG(4) subclass reactivity profiles corresponded with the D. medinensis infection state, and a clear distinction between patent and post-patent patients and controls was found. Overall a depressed cytokine release was observed with patent D. medinensis, which extended beyond the parasite-specific immune responsiveness. The detection of D. medinensis-specific IgG(1) and IgG(4) isotypes may help to distinguish newly exposed, patent and post-patent D. medinensis infections.     

Propranolol selectively blocks the enhanced parietal old/new effect during long-term recollection of unpleasant pictures: A high density ERP study

Evidence from both animal and human research suggests that the formation of emotional memories is triggered by the beta-adrenergic system. To confirm whether modulation of central beta-adrenergic transmission is specifically involved in the neural signature of memory performance, the pre-encoding effect of propranolol (80 mg) on event-related potentials (ERPs) was measured in a placebo-controlled, double-blind, parallel-group study in 46 male healthy subjects using high density EEG and source imaging analysis during encoding and retrieval (after 1 week) of IAPS pictures of unpleasant, neutral and pleasant contents; for recognition 90 old pictures were randomly mixed with 90 new pictures. During retrieval correctly remembered old pictures elicited a significantly larger positive voltage change over the centro-parietal cortex than new pictures. Propranolol significantly reduced this old/new difference of the mean ERP amplitudes (500–800 ms) for unpleasant but not for neutral and pleasant memories. This effect correlated with salivary alpha-amylase activity, a surrogate for central adrenergic stimulation. In conclusion, propranolol selectively blocked the neural signature of unpleasant memories by mechanisms in which the parietal cortex seems to be specifically involved.     

Elasticity-based determination of isovolumetric phases in the human heart

Background/Motivation

To directly determine isovolumetric cardiac time intervals by magnetic resonance elastography (MRE) using the magnitude of the complex signal for deducing morphological information combined with the phase of the complex signal for tension-relaxation measurements.

Methods

Thirty-five healthy volunteers and 11 patients with relaxation abnormalities were subjected to transthoracic wave stimulation using vibrations of approximately 25 Hz. A k-space-segmented, ECG-gated gradient-recalled echo steady-state sequence with a 500-Hz bipolar motion-encoding gradient was used for acquiring a series of 360 complex images of a short-axis view of the heart at a frame rate of less than 5.2 ms. Magnitude images were employed for measuring the cross-sectional area of the left ventricle, while phase images were used for analyzing the amplitudes of the externally induced waves. The delay between the decrease in amplitude and onset of ventricular contraction was determined in all subjects and assigned to the time of isovolumetric tension. Conversely, the delay between the increase in wave amplitude and ventricular dilatation was used for measuring the time of isovolumetric elasticity relaxation.

Results

Wave amplitudes decreased during systole and increased during diastole. The variation in wave amplitude occurred ahead of morphological changes. In healthy volunteers the time of isovolumetric elasticity relaxation was 75 ± 31 ms, which is significantly shorter than the time of isovolumetric tension of 136 ± 36 ms (P < 0.01). In patients with relaxation abnormalities (mild diastolic dysfunction, n = 11) isovolumetric elasticity relaxation was significantly prolonged, with 133 ± 57 ms (P < 0.01), whereas isovolumetric tension time was in the range of healthy controls (161 ± 45 ms; P = 0.053).

Conclusion

The complex MRE signal conveys complementary information on cardiac morphology and elasticity, which can be combined for directly measuring isovolumetric tension and elasticity relaxation in the human heart.     

GRAM: A framework for geodesic registration on anatomical manifolds

Medical image registration is a challenging problem, especially when there is large anatomical variation in the anatomies. Geodesic registration methods have been proposed to solve the large deformation registration problem. However, analytically defined geodesic paths may not coincide with biologically plausible paths of registration, since the manifold of diffeomorphisms is immensely broader than the manifold spanned by diffeomorphisms between real anatomies. In this paper, we propose a novel framework for large deformation registration using the learned manifold of anatomical variation in the data. In this framework, a large deformation between two images is decomposed into a series of small deformations along the shortest path on an empirical manifold that represents anatomical variation. Using a manifold learning technique, the major variation of the data can be visualized by a low-dimensional embedding, and the optimal group template is chosen as the geodesic mean on the manifold. We demonstrate the advantages of the proposed framework over direct registration with both simulated and real databases of brain images.     

Myocardial viability: assessment with three-dimensional MR imaging in pigs and patients

PURPOSE: To prospectively evaluate the correlation between a three-dimensional (3D) delayed enhancement magnetic resonance (MR) imaging sequence and a two-dimensional (2D) delayed enhancement MR imaging sequence for noninvasive assessment of myocardial viability in pigs and patients. MATERIALS AND METHODS: The pig and patient studies were approved by the responsible authorities, and patients gave written informed consent. MR imaging was performed by using a rapid 3D inversion-recovery balanced steady-state free precession sequence and a 2D segmented inversion-recovery fast low-angle shot sequence as the reference standard. Fourteen pigs with reperfused (n=7) or nonreperfused (n=7) myocardial infarction and 17 patients (13 men, four women; mean age, 64.9 years+/-8.6 [standard deviation]) suspected of having myocardial infarction were included. Linear regression analysis and Bland-Altman analysis were used to compare the infarction volumes. RESULTS: In 10 of the 14 pigs the induction of myocardial infarction was successful. In these pigs, altogether 81 segments with myocardial infarction were demonstrated by both MR sequences, and agreement between the two sequences for classification of transmural extent of myocardial infarction was 99.7%. The infarction volume determined by using 3D MR imaging (4.64 cm3+/-2.48) in the pigs highly correlated with that of 2D MR imaging (4.65 cm3+/-2.39, r=0.989, P<.001) and that of staining by using triphenyltetrazolium chloride (4.67 cm3+/-2.44, r=0.996, P<.001). Thirteen of the 17 patients examined showed myocardial infarction in 34 myocardial segments with both sequences, and agreement between the two sequences for classification of transmural extent of myocardial infarction was 98.6%. In the patients, the infarction volume determined with both sequences highly correlated (9.71 cm3+/-7.47 for the 3D sequence vs 10.01 cm3+/-8.04 for the 2D sequence, r=0.982, P<.001). The breath-hold time necessary for the 3D MR imaging (21.0+/-2.3 seconds) was significantly shorter than that for 2D MR imaging (188.3+/-20.2 seconds, P<.001). CONCLUSION: Myocardial infarction volumes obtained with the 3D MR imaging sequence are highly correlated and in good agreement with volumes obtained with the 2D MR imaging standard approach and reduced the acquisition time by a factor of nine.     

Recognition of nucleic acid and nucleic acid analogs by Toll-like receptors 7, 8 and 9

The mammalian immune system senses pathogens through pattern recognition receptors (PRR) and responds with activation. Toll-like receptors (TLRs) that are expressed on immune and non-immune cells play a critical role in this process. As part of the innate immune response, TLRs lead to cellular activation and cytokine production with subsequent initiation of an adaptive immune response. TLR7-9 recognize single-stranded RNA, nucleoside analogs and single-stranded CpG-DNA, respectively, and their activation initiates the immune response against viruses and bacteria. Furthermore, the stimulation of these TLRs may be exploited for adjuvant therapy, vaccination and anti-tumor responses. However, a role in the generation or perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE) has also been suggested.     

Delayed glucose treatment improves cognitive function following fluid-percussion injury

Experimental traumatic brain injury (TBI) results in marked neurochemical and metabolic changes. Research has demonstrated that after the initial insult the brain undergoes an immediate state of hypermetabolism followed by a sustained period of hypometabolism. The altered extra- and intracellular environment can compromise neuronal performance and limit functional recovery. If brain metabolism is depressed chronically after TBI, then interventions that are designed to increase metabolism may be beneficial to outcome. Glucose treatment has been shown to improve cognition in many populations, particularly those with cognitive deficits. The following experiments examined the effects of delayed postinjury glucose supplementation on cognitive function following TBI. Male Sprague-Dawley rats received either sham or lateral fluid-percussion (LFP) injury. Cognitive functioning was assessed with the Morris water maze (MWM) on postinjury days 11-15. In the first experiment, saline or 100mg/kg glucose was administered 10 min before cognition assessment. Injured animals treated with glucose displayed significantly shorter latencies to reach the goal platform compared to injured saline-treated animals. Glucose had no effect on sham-injured rats. In the second experiment, injured rats were given daily injections of saline or 100mg/kg glucose for 10 days beginning 24h after injury. Rats were then tested in the MWM on days 11-15 without glucose or saline treatment. In this experiment, glucose treatment did not affect MWM performance. These data provide evidence that the chronic energy supplementation after TBI improves outcome when administered shortly before cognitive assessment.     

Magnetically enriched bone marrow-derived macrophages loaded in vitro with iron oxide can migrate to inflammation sites in mice

In vitro labelling of cells permits incorporation of large amounts of iron oxide and consequently high detection sensitivity, but it remains controversial whether labelled cells would respond normally to stimuli. This question was addressed by differentiating bone marrow-derived macrophages (BMDMs) in vitro, labelling cells with high concentrations of Endorem in vitro, and eliminating unlabelled cells by magnetic enrichment. To explore their acute inflammatory response, enriched cells were injected into mice with carrageenan-induced inflammation, the 'air pouch model'. Cells recovered from the inflammation site 16 h after intravenous BMDM injection into the tail vein were analysed by in vitro MRI and fluorescent microscopy. With both assays, Endorem-labelled cells were detectable. This indicates that BMDMs, loaded with high concentrations of iron oxide in vitro, can still respond to chemokine gradients and infiltrate inflamed tissue in mice. Furthermore, by using genetically modified mice as BMDM donors, it should be possible to study the role of individual genes in macrophage recruitment.     

Brain activation and defensive response mobilization during sustained exposure to phobia-related and other affective pictures in spider phobia

This study explored defensive response mobilization as well as fMRI responses during sustained exposure to phobia-relevant stimuli. To test the specificity of affective physiology and brain activation, neutral and other affective stimuli were included. Phobia-specific startle potentiation was maintained and autonomic responses even increased during sustained phobic stimulation. Viewing of spider pictures also resulted in increased activation of the amygdala in spider-phobic participants. This effect, however, was not fear specific because other affective materials evoked comparable signal strength in the amygdala. In contrast, insula activation was specifically increased during sustained phobic exposure in phobic volunteers. These data suggest that the activation of the amygdala in fMRI studies primarily indexes the detection of motivationally relevant stimuli whereas the insula might be more specifically linked to defensive response mobilization.