Role of endogenous Fas (CD95/Apo-1) ligand in balloon-induced apoptosis, inflammation, and neointima formation

BACKGROUND: Fas (CD95/Apo-1) ligand (FasL)-induced apoptosis in Fas-bearing cells is critically involved in modulating immune reactions and tissue repair. Apoptosis has also been described after mechanical vascular injury such as percutaneous coronary intervention. However, the relevance of cell death in this context of vascular repair remains unknown. METHODS AND RESULTS: To determine whether FasL-induced apoptosis is causally related to neointimal lesion formation, we subjected FasL-deficient (generalized lymphoproliferative disorder [gld], C57BL/6J) and corresponding wild-type (WT) mice to carotid balloon distension injury, which induces marked endothelial denudation and medial cell death. FasL expression in WT mice was induced in injured vessels compared with untreated arteries (P<0.05; n=5). Conversely, absence of functional FasL in gld mice decreased medial and intimal apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling [TUNEL] index) at 1 hour and 7 days after balloon injury (P<0.05; n=6). In addition, peritoneal macrophages isolated from gld mice showed no apoptosis and enhanced migration (P<0.05; n=4). In parallel, we observed increased balloon-induced macrophage infiltrations (anti-CD68) in injured arteries of FasL-deficient animals (P<0.05; n=6). Together with enhanced proliferation (bromodeoxyuridine index; P<0.05), these events resulted in a further increase in medial and neointimal cells (P<0.01; n=8) with thickened neointima in gld mice (intima/media ratio, x3.8 of WT; P<0.01). CONCLUSIONS: Our data identify proapoptotic and antiinflammatory effects of endogenous FasL as important factors in the process of neointimal lesion formation after balloon injury. Moreover, they suggest that activation of FasL may decrease neointimal thickening after percutaneous coronary intervention.

Pontocerebellar hypoplasia type 2: variability in clinical and imaging findings

We report 24 children (14 girls) who presented with the typical neuroimaging findings of pontocerebellar hypoplasia (PCH) to describe the clinical spectrum of type 2. Twenty-one presented with the classical form described by Barth; characteristic features (15/21) were breathing and/or sucking problems during neonatal period and early onset hyperkinetic movement disorder. Eighteen were normocephalic at birth, but all developed microcephaly during infancy. Development was severely affected with none of the children being capable of sitting, walking, or talking. Social contact and visual fixation were persistently poor. Dyskinetic movement disorder was present in all, in some together with mild spasticity. Seizures occurred in 14 (in 7 as neonates). Eight children died (age 1 day-6 years). Neuroimaging showed an absent or severely flattened pons, different degrees of vermian hypoplasia, with cerebellar hemispheres (wing-like structures) being equally or more affected. Three (all girls) were less severely affected clinically and did not develop the dyskinetic movement disorder, motor and cognitive development were somewhat better. Microcephaly was also a prominent sign. Severity of pontocerebellar neuroimaging findings did not differentiate between the typical and atypical clinical group and did not correlate with clinical outcome.

Does diagnostic delay result in decreased survival in paediatric brain tumours?

To study the hypothesis that a delay in the diagnosis of paediatric brain tumours results in decreased survival outcome probability, we compared the prediagnostic period of 315 brain tumour patients (median age 6.7 years, range, 0 to 16 years) with progression-free and overall survival. The median prediagnostic symptomatic interval was 60 days (range, 0 to 3,480 days), with a median parental delay of 14 days (range, 0 to 1,835 days) and a median doctor's delay of 14 days (range, 0 to 3,480 days). The prediagnostic symptomatic interval correlated significantly with the patient age, tumour histology, tumour location and year of diagnosis, but not with gender. We then grouped the patients according to histology (low-grade glioma [n=77], medulloblastoma [n=57], high-grade glioma [n=40], craniopharyngioma [n=27], ependymoma [n=20] and germ cell tumours [n=18]). Contrary to common belief, long prediagnostic symptomatic interval or long doctor's delay did not result in decreased survival outcome probability in any of these groups. The effect of tumour biology on survival seems to be dominant and overwhelms any possible opposing effect on survival of a delay in diagnosis.

Evaluating the potential of IP-10 and MCP-2 as biomarkers for the diagnosis of tuberculosis

The aim of the present study was to evaluate the potential of diagnostic tests based on interferon-gamma inducible protein (IP)-10 and monocyte chemotactic protein (MCP)-2, and compare the performance with the QuantiFERON TB Gold In-Tube (QFT-IT; Cellestis, Carnagie, Australia) test. IP-10 and MCP-2 were determined in supernatants from whole blood stimulated with Mycobacterium tuberculosis-specific antigens. Samples were obtained from 80 patients with culture- and/or PCR-proven tuberculosis (TB), and 124 unexposed healthy controls: 86 high school students and 38 high school staff. IP-10 and MCP-2 test cut-offs were established based on receiver operating characteristic curve analysis. TB patients produced significantly higher levels (median) of IP-10 (2158 pg x mL(-1)) and MCP-2 (379 pg x mL(-1)) compared with interferon (IFN)-gamma (215 pg x mL(-1)). The QFT-IT, IP-10 and MCP-2 tests detected 81, 83 and 71% of the TB patients; 0, 3 and 0% of the high school students and 0, 16 and 3% of the staff, respectively. Agreement between tests was high (>89%). By combining IP-10 and IFN-gamma tests, the detection rate increased among TB patients to 90% without a significant increase in positive responders among the students. In conclusion, interferon-gamma inducible protein-10 and monocyte chemotactic protein-2 responses to Mycobacterium tuberculosis-specific antigens could be used to diagnose infection. Combining interferon-gamma inducible protein-10 and interferon-gamma may be a simple approach to increase the detection rate of the Mycobacterium tuberculosis-specific in vitro tests.

Transesophageal echocardiography for verification of the position of the electrocardiographically-placed central venous catheter

OBJECTIVE: Compare changes in P-wave amplitude of the intra-atrial electrocardiogram (ECG) and its corresponding transesophageal echocardiography (TEE)-controlled position to verify the exact localization of a central venous catheter (CVC) tip. DESIGN: A prospective study. SETTING: University, single-institutional setting. PARTICIPANTS: Two hundred patients undergoing elective cardiac surgery. INTERVENTIONS: CVC placement via the right internal jugular vein with ECG control using the guidewire technique and TEE control in 4 different phases: phase 1: CVC placement with normalized P wave and measurement of distance from the crista terminalis to the CVC tip; phase 2: TEE-controlled placement of the CVC tip; parallel to the superior vena cava (SVC) and measurements of P-wave amplitude; phase 3: influence of head positioning on CVC migration; and phase 4: evaluation of positioning of the CVC postoperatively using a chest x-ray. MEASUREMENTS AND MAIN RESULTS: The CVC tip could only be visualized in 67 patients on TEE with a normalized P wave. In 198 patients with the CVC parallel to the SVC wall controlled by TEE (phase 2), an elevated P wave was observed. Different head movements led to no significant migration of the CVC (phase 3). On a postoperative chest-x-ray, the CVC position was correct in 87.6% (phase 4). CONCLUSION: The study suggests that the position of the CVC tip is located parallel to the SVC and 1.5 cm above the crista terminalis if the P wave starts to decrease during withdrawal of the catheter. The authors recommend that ECG control as per their study should be routinely used for placement of central venous catheters via the right internal jugular vein.