Pediatric onset Crohn's colitis is characterized by genotype-dependent age-related susceptibility

BACKGROUND: Pediatric onset Crohn's disease (CD) is associated with more colitis and less ileitis compared with adult onset CD. Differences in disease site by age may suggest a different genotype, or different host responses such as decreased ileal susceptibility or increased susceptibility of the colon. METHODS: We evaluated 721 pediatric onset CD patients from 3 cohorts with a high allele frequency of NOD2/CARD15 mutations. Children with isolated upper intestinal disease were excluded. The remaining 678 patients were evaluated for interactions between age of onset, NOD2/CARD15, and disease location. RESULTS: We found an age-related tendency for isolated colitis. Among pediatric onset patients without NOD2/CARD15 mutations, colitis without ileal involvement was significantly more common in first-decade onset patients (P = 4.57 x 10(-5), odds ratio [OR] 2.76, 95% confidence interval [CI] 1.72-4.43). This was not true for colonic disease with ileal involvement (P = 0.35), or for isolated colitis in patients with NOD2/CARD15 mutations (P = 0.61). Analysis of 229 patients with ileal or ileocolonic disease and a NOD2/CARD15 mutation disclosed that ileocolitis was more prevalent through age 10, while isolated ileitis was more prevalent above age 10 (P = 0.016). NOD2/CARD15 mutations were not associated with age of onset. CONCLUSIONS: In early-onset pediatric CD, children with NOD2/CARD15 mutations demonstrate more ileocolitis and less isolated ileitis. Young children without NOD2/CARD15 mutations have an isolated colonic disease distribution, suggesting that this phenotype is associated with genes that lead to a specific phenotype of early-onset disease.     

Intrarenal pseudoaneurysm presenting with microscopic hematuria and right flank pain

We report a case of a 19-year-old female who presented with right flank pain and microscopic hematuria. Three years earlier, she sustained a stab wound to the right flank and was managed conservatively. After being diagnosed with an enhancing renal mass using computed tomography (CT) scan, duplex ultrasound and angiography were performed revealing an intrarenal pseudoaneurysm. Endovascular coils were successfully employed to selectively embolize the pseudoaneurysm.     

A life-saving procedure for treatment of massive pulmonary air embolism

We present an unusual case of massive pulmonary air embolism during permanent pacemaker implantation. Head down position, precordial thumb and cardiac massage must be done immediately after the diagnosis of this life threatening condition. If these maneuvers are not successful, air suctioning with a large-lumen guiding catheter may be effective and life saving.     

Heparin chain-length dependence of factor Xa inhibition by antithrombin in plasma

Heparin anticoagulants function by enhancing the inhibition of coagulation proteases by the serpin antithrombin (AT). A direct evaluation of the specific anti-factor Xa (fXa) activity of therapeutic heparins in the physiologically relevant plasma-based clotting assays has not been feasible since thrombin, the final protease of the cascade, is the primary target for inhibition by AT in the presence of heparin. To circumvent this problem, we developed an assay in which the native AT in plasma was replaced with an AT mutant which exhibits identical affinity for heparin and near normal reactivity for fXa, but does not react with thrombin and other coagulation proteases in either the absence or presence of heparin. This assay was used to distinguish the anti-fXa activity of different molecular weight heparins from their anti-thrombin activity in clotting assays which were initiated by the triggers of either the extrinsic or intrinsic coagulation pathway. The results suggest that the acceleration of fXa inhibition by AT exhibits a marked heparin chain-length dependence, with fondaparinux (a pentasaccharide) having the lowest and unfractionated heparin having the highest effect. Interestingly, comparative studies revealed that the fondaparinux-catalyzed acceleration of thrombin inhibition by AT also contributes to the prolongation of the clotting time, possibly suggesting that the anticoagulant function of the therapeutic pentasaccharide is mediated though the inhibition of both fXa and thrombin.     

Transcriptional profiling of whole blood and serum protein analysis of mice exposed to the neurotoxin Pacific Ciguatoxin-1

Ciguatoxins (CTX) are a suite of cyclic polyether toxins produced by the marine dinoflagellate Gambierdiscus sp., are potent activators of voltage-gated sodium channels and a leading cause of human poisoning from food fish. This report characterizes the genomic and proteomic response in whole blood of adult male mice exposed i.p. to 264 ng/kg of the Pacific congener of CTX (P-CTX-1) at 1, 4 and 24h. Whole genome microarray expression data were filtered by tightness of fit between replicates, fold change (1.8) and p-value (10(-5)), resulting in 183 annotated genes used for trending analysis, K-means clustering and ontology classification. Genes involved with cytokine signaling, proteasome complex and ribosomal function were dominant. qPCR performed on 19 genes of interest had a correlation of 0.95 to array results by Pearson's correlation coefficient. Serum protein analysis showed small but significant changes in 6 of 60 proteins assayed: Ccl2, Ccl12, CD40, IL-10, leptin and M-CSF. In large part, the gene expression was consistent with a Th2 immune response with interesting similarities to expression seen in asthmatic models.     

In situ immune response in brain and kidney during early relapsing fever borreliosis

Characterization of the host immune response during initial pathogenesis of relapsing fever neuroborreliosis would be a key to understanding Borrelia persistence and factors driving the inflammatory process. We analyzed immune cells in brain and kidney with the highly invasive B. crocidurae during the first two weeks of murine infection. In both organs, microglia and/or macrophages predominated while T-cell changes were minimal. Compared to kidney, brain neutrophils infiltrated more rapidly and B-cells were essentially absent. Our results indicate that during early neuroborreliosis, brain defense is comprised primarily of innate immune cells while adaptive immunity plays a minor role.     

Depressive-like behavior and high alcohol drinking co-occur in the FH/WJD rat but appear to be under independent genetic control

This review will consider the evidence supporting the view that a specific substrain of Fawn-Hooded rat (FH/Wjd) exhibits co-occurring depressive-like behavior and high alcohol intake independently. First, the FH/Wjd rat is compared with other Fawn-Hooded substrains (FH/Har, FHH/Eur, FHL/Eur) and it is concluded that only the FH/Wjd rat is both highly immobile in the forced swim test and drinks substantial amounts of 5-10% alcohol voluntarily. Next it is demonstrated that the FH/Wjd rat fulfils many of the criteria proposed for an animal model of alcoholism (becomes tolerant, becomes dependent and expresses withdrawal symptoms, bar-presses for alcohol). Other literature in addition to the high swim test immobility suggests that the FH/Wjd rat may also be an animal model of depression (high basal corticosterone levels, blunted hormonal responses to serotonergic agonists). To study the phenotypes more closely an inbred strain (ACI/N) of rat that drank little alcohol voluntarily and exhibited considerable swimming in the forced swim test (i.e., low immobility) was obtained. A systematic intercrossing of the parental strains and the resulting F1 progeny was carried out to generate more than 800 F2s. Swim test immobility, alcohol intake and preference and saccharin intake are four of the 7 variables assessed in each of these rats. Using classical quantitative genetics methods, it was determined that these four phenotypes exhibited modest heritability and were influenced by multiple genes. Correlation coefficients between immobility and the other measures were near zero, whereas alcohol intake and preference were highly correlated (r=0.9) and alcohol and saccharin intakes were modestly correlated (r=0.3). A final study showed that chronic fluoxetine treatment counteracted the high immobility but did not affect alcohol intake, similar to human studies. These findings suggest that although depressive-like behavior and high alcohol intake co-occur in the FH/Wjd rat, they are independently regulated.     

Calcium-binding sites of the thrombin-thrombomodulin-protein C complex: possible implications for the effect of platelet factor 4 on the activation of vitamin K-dependent coagulation factors

The Ca(2+)-dependence of protein C activation by thrombin in complex with thrombomodulin (TM) containing chondroitin sulfate (CS) exhibits saturation at approximately 0.5-1 mM Ca(2+), but with TM lacking CS, it has a distinct optimum at approximately 0.1 mM Ca(2+). Since the substrate protein C has multiple Ca(2+)-binding sites, and the cofactor TM also interacts with Ca(2+), the basis for differences in Ca(2+) effect on protein C activation by thrombin in complex with TM containing or lacking CS is not known. In this study, by using full-length and Gla-domainless mutants of protein C whose activation by thrombin is independent of either Ca(2+) or both Ca(2+) and TM, we demonstrate that i) the Ca(2+) occupancy of a high-affinity binding site in TM is essential for the high-affinity interaction of the cofactor with thrombin, ii) the Ca(2+) occupancy of a binding site (K(D) approximately 50 microM) in the catalytic domain of protein C is required for the substrate recognition by the thrombin-TM complex, however, at this concentration of Ca(2+) the Gla domain of protein C is not folded properly and thus interacts with exosite-2 of thrombin in complex with TM that lacks CS but not with TM that contains CS, and finally iii) platelet factor 4 can nonspecifically interact with the Gla domain of protein C and other coagulation factors to influence their activation only at subphysiological concentrations of Ca(2+).     

Elk with a long incubation prion disease phenotype have a unique PrPd profile

The transmissible spongiform encephalopathies (TSEs) invariably result in fatal neurodegeneration and accumulation of PrP, an abnormal form of the host prion protein PrP, encoded by the PRNP gene. A naturally occurring polymorphism (methionine/valine) at PRNP codon 129 is associated with variation in relative disease susceptibility, incubation time, clinical presentation, neuropathology, and/or PrP biochemical characteristics in a range of human TSEs. A methionine/leucine polymorphism at the corresponding site in the Rocky Mountain elk PRNP gene is associated with variation in relative susceptibility and incubation time in the cervid TSE chronic wasting disease. We now report that elk lacking the predisposing 132-methionine allele develop chronic wasting disease after a long incubation period and display a novel PrP folding pattern.