Cecostomy in Children with Defecation Disorders

Administration of antegrade enemas through a cecostomy is a therapeutic option for children with severe defecation disorders. The purpose of this study is to report our 4-year experience with the cecostomy procedure in 31 children with functional constipation (n = 9), Hirschsprung's disease (n = 2), imperforate anus (n = 5), spinal abnormalities (n = 8), and imperforate anus in combination with tethered spinal cord (n = 7). Data regarding complications, antegrade enemas used, symptoms, and quality of life were retrospectively obtained. Placement of cecostomy tubes was successful in 30 of 31 patients. Soiling episodes decreased significantly in children with functional constipation (P = 0.01), imperforate anus (P < 0.01), and spinal abnormalities (P = 0.04). Quality of life improved in patients with functional constipation and imperforate anus. No difference in complications was found between percutaneous and surgical placement. Use of antegrade enemas via cecostomy improved symptoms and quality of life in children with a variety of defecation disorders. This study was supported in part by the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences.     

Haematopoietic and endothelial progenitor cells are deficient in quiescent systemic lupus erythematosus

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with a high prevalence of cardiovascular disease. Circulating endothelial progenitor cells (EPCs) contribute to vascular regeneration and repair, thereby protecting against atherosclerotic disease. EPCs are derived from CD34+ haematopoietic stem cells (HSCs), which have an increased propensity for apoptosis in the bone marrow of patients with SLE. AIM: To determine whether circulating HSCs and EPCs are reduced in SLE, contributing to an increased cardiovascular risk. METHODS: Progenitor cells were sampled from 15 female patients with SLE in prolonged clinical remission from their disease and 15 matched healthy controls. HSC and CD34+KDR+ EPCs were quantified by flow cytometry. Annexin V staining was used to identify apoptotic cells. RESULTS: Patients with SLE had reduced levels of circulating CD34+ HSCs and CD34+KDR+ EPCs, associated with increased HSC apoptosis. Compared with controls, the fraction of HSCs that could be identified as EPCs was higher in patients with SLE, consistent with a primary defect of HSCs. EPC outgrowth from mononuclear cells, which depends mainly on CD34- cells, was unaffected. CONCLUSIONS: Patients with SLE have lower levels of circulating HSCs and EPCs, even during clinical remission. The data suggest that increased HSC apoptosis is the underlying cause for this depletion. These observations indicate that progenitor cell-mediated endogenous vascular repair is impaired in SLE, which may contribute to the accelerated development of atherosclerosis.     

Immune dysfunction in HIV-seronegative, Cryptococcus gattii meningitis

The pathophysiology of meningitis caused by Cryptococcus gattii in apparently immunocompetent individuals remains unclear. We measured multiple cytokines in CSF from a HIV-seronegative, apparently immunocompetent, Thai patient with C. gattii meningitis, over the first 2 weeks of antifungal therapy. Levels of proinflammatory IFN-gamma, TNF-alpha, and IL-6 were very low compared to patients with HIV-related Cryptococcus neoformans meningitis and of IL-10 very high. While patients with C. gattii meningitis may be a heterogeneous group, these data suggest in this case a maladapted immune response to cryptococcal exposure had allowed progression to clinical cryptococcal disease.     

Dominant arrhythmia vulnerability of the right ventricle in senescent mice

BACKGROUND: Several cardiac disorders affect the right ventricle (RV) and left ventricle (LV) equally, but nevertheless, RV vulnerability to conduction slowing and arrhythmias exceeds that of the LV. OBJECTIVE: This study sought to assess the mechanism of dominant RV arrhythmia vulnerability in senescent mice as a model of general reduced myocardial integrity. METHODS: Epicardial ventricular activation mapping was performed on senescent (22 months) and adult (3 months) Langendorff perfused mouse hearts. Arrhythmia inducibility was tested by programmed stimulation. Conduction velocity longitudinal and transversal (CVT) to fiber orientation, conduction heterogeneity, and effective refractory period were determined. Subsequently, hearts were processed for immunohistochemistry, Western blotting, and Sirius red staining. RESULTS: In senescent RV, but not LV, CVT was reduced and wavelength decreased, whereas anisotropic ratio and conduction heterogeneity increased. Arrhythmias, based on anisotropic reentry, were induced in 55% of senescent hearts only and predominantly in RV. In senescent mice, Connexin 43 (Cx43) and Cardiac Sodium Channel (Nav1.5) were decreased and interstitial fibrosis increased comparably in RV and LV. However, in senescent mice, heterogeneously distributed patches of replacement fibrosis were present throughout the entire RV myocardium, but only in midendocardium and subendocardium of LV. Cx43 expression in these areas was disrupted. CONCLUSION: Widespread presence of replacement fibrosis in senescent RV compared with LV, combined with Cx43 and Nav1.5 disruption, potentiate shorter wavelength, conduction slowing, and conduction heterogeneity in RV, resulting in greater vulnerability of senescent RV to arrhythmias.     

Correlation-Based Discrimination Between Cardiac Tissue and Blood for Segmentation of the Left Ventricle in 3-D Echocardiographic Images

For automated segmentation of 3-D echocardiographic images, incorporation of temporal information may be helpful. In this study, optimal settings for calculation of temporal cross-correlations between subsequent time frames were determined, to obtain the maximum cross-correlation (MCC) values that provided the best contrast between blood and cardiac tissue over the entire cardiac cycle. Both contrast and boundary gradient quality measures were assessed to optimize MCC values with respect to signal choice (radiofrequency or envelope data) and axial window size. Optimal MCC values were incorporated into a deformable model to automatically segment the left ventricular cavity. MCC values were tested against, and combined with, filtered, demodulated radiofrequency data. Results reveal that using envelope data in combination with a relatively small axial window (0.7–1.25 mm) at fine scale results in optimal contrast and boundary gradient between the two tissues over the entire cardiac cycle. Preliminary segmentation results indicate that incorporation of MCC values has additional value for automated segmentation of the left ventricle.     

Segmentation of the heart muscle in 3-D pediatric echocardiographic images

This study aimed to show segmentation of the heart muscle in pediatric echocardiographic images as a preprocessing step for tissue analysis. Transthoracic image sequences (2-D and 3-D volume data, both derived in radiofrequency format, directly after beam forming) were registered in real time from four healthy children over three heart cycles. Three preprocessing methods, based on adaptive filtering, were used to reduce the speckle noise for optimizing the distinction between blood and myocardium, while preserving the sharpness of edges between anatomical structures. The filtering kernel size was linked to the local speckle size and the speckle noise characteristics were considered to define the optimal filter in one of the methods. The filtered 2-D images were thresholded automatically as a first step of segmentation of the endocardial wall. The final segmentation step was achieved by applying a deformable contour algorithm. This segmentation of each 2-D image of the 3-D+time (i.e., 4-D) datasets was related to that of the neighboring images in both time and space. By thus incorporating spatial and temporal information of 3-D ultrasound image sequences, an automated method using image statistics was developed to perform 3-D segmentation of the heart muscle.     

Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice

Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromogenic assay. FVIII-R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4(+) T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A.     

7.0?T MRI detection of cerebral microinfarcts in patients with a symptomatic high-grade carotid artery stenosis

In the current study, the presence of cerebral cortical microinfarcts (CMIs) was evaluated in a series of 21 patients with a symptomatic high-grade >50% stenosis of the carotid artery. A T₂-weighted fluid-attenuated inversion recovery sequence and a T₁-weighted turbo field echo sequence of the brain were obtained at 7.0 Tesla magnetic resonance imaging. Primary study endpoint was the number of CMIs and macroinfarcts. In total, 53 cerebral infarcts (35 macroinfarcts; 18 CMIs) were found ipsilateral to the symptomatic carotid artery, in 14 patients (67%). In four of these patients, both CMIs and macroinfarcts were visible. In the contralateral hemisphere, seven infarcts (five macroinfarcts and two CMIs) were found in five patients (24%). In the ipsilateral hemispheres, the number of CMIs and macroinfarcts were significantly correlated (P=0.02). Unpaired comparison of medians showed that the number of CMIs in the ipsilateral hemisphere was significantly higher than the number of CMIs in the contralateral hemisphere (P=0.04). No significant correlation was found between stenosis grade and the number of any infarct. The current study shows that in symptomatic patients with significant extracranial carotid artery stenosis, CMIs are part of the total cerebrovascular burden and these CMIs prevail with a similar pattern as observed macroinfarcts.     

Multislice 1H MRSI of the human brain at 7 T using dynamic B0 and B1 shimming

Proton MR spectroscopic imaging of the human brain at ultra-high field (≥7 T) is challenging due to increased radio frequency power deposition, increased magnetic field B(0) inhomogeneity, and increased radio frequency magnetic field inhomogeneity. In addition, especially for multislice sequences, these effects directly inhibit the potential gains of higher magnetic field and can even cause a reduction in data quality. However, recent developments in dynamic B(0) magnetic field shimming and dynamic multitransmit radio frequency control allow for new acquisition strategies. Therefore, in this work, slice-by-slice B(0) and B(1) shimming was developed to optimize both B(0) magnetic field homogeneity and nutation angle over a large portion of the brain. Together with a low-power water and lipid suppression sequence and pulse-acquire spectroscopic imaging, a multislice MR spectroscopic imaging sequence is shown to be feasible at 7 T. This now allows for multislice metabolic imaging of the human brain with high sensitivity and high chemical shift resolution at ultra-high field.     

Tract-based magnetic resonance spectroscopy of the cingulum bundles at 7 T

The cingulum bundle is a white matter fiber bundle in the human brain that is believed to be implicated in various neurological and psychiatric diseases. Subtle disease-related differences in metabolite concentrations in the cingulum tracts that may underlie these diseases may be detected using MR spectroscopic information. However, to date, limited signal to noise and lack of spatial resolution have prevented a reliable and reproducible measurement of metabolites in the cingulum bundle in vivo. Here we propose a new method that combines MR spectroscopic imaging at 7 T with fiber tracking to select only those MR spectroscopy voxels that are actually part of the cingulum bundles. The spectra of the selected spectroscopy voxels are processed per voxel and then combined yielding one spectrum at high spectral resolution for each cingulum bundle. In this way sensitivity is increased, as large parts of the cingulum are included while partial volume effects with both gray matter and white matter from other tracts is kept to a minimum. Three healthy volunteers were scanned to assess the feasibility of the method. For all three healthy volunteers spectra for the left and right cingulum tracts were computed, partial volume fractions calculated and metabolite fractions were quantified yielding similar results suggesting that tract-based MR spectroscopy allows us to study metabolic concentrations of individual white matter fiber bundles with high sensitivity and high specificity.