Early ischemic lesion on computed tomography: predictor of poor outcome among survivors of aneurysmal subarachnoid hemorrhage

OBJECT: Identifying ischemic lesions after subarachnoid hemorrhage (SAH) is important because the appearance of these lesions on follow-up imaging correlates with a poor outcome. The effect of ischemic lesions seen on computed tomography (CT) scans during the first days of treatment remains unknown, however. METHODS: In 156 patients with SAH, clinical course and outcome, as well as the appearance of ischemic lesions on serial CT scans, were prospectively monitored for 3 months. At 3 months after SAH, magnetic resonance imaging was performed to detect permanent lesions that had not been visible on CT. RESULTS: Of the 53 patients with no lesions on any of the follow-up CT scans, four (8%) had a poor outcome. Of the 52 patients with a new hypodense lesion on the first postoperative day CT, 23 (44%) had a poor outcome. Among the remaining 51 patients with a lesion appearing later than the first postoperative morning, 10 (20%) had a poor outcome (p < 0.001). After adjusting for patient age; clinical condition on admission; amounts of subarachnoid, intracerebral, and intraventricular blood; and plasma glucose and D-dimer levels, a hypodense lesion on CT on the first postoperative morning was an independent predictor of poor outcome after SAH (odds ratio 7.27, 95% confidence interval 1.54-34.37, p < 0.05). CONCLUSIONS: A new hypodense lesion on early postoperative CT seems to be an independent risk factor for poor outcome after SAH, and this early lesion development may be more detrimental to clinical outcome than a later lesion occurrence.     

Bone health and growth in glucocorticoid-treated patients with juvenile idiopathic arthritis

OBJECTIVE: To evaluate bone health and growth and their correlates in glucocorticoid (GC)-treated pediatric patients with juvenile idiopathic arthritis (JIA). METHODS: Consecutive patients with a history of JIA for >or= 2 years and systemic GC treatment for >or= 3 months were assessed for bone health and its determinants. Areal bone mineral density (aBMD) and vertebral body morphology were assessed with DEXA; Z scores were adjusted for calendar and bone age. Values were correlated with biochemistry, disease activity, and medications. RESULTS: Sixty-two patients (43 female; median age 11.8 yrs, median disease duration 5.6 yrs) were included. The median duration of GC treatment was 24 months and the median cumulative dose (as prednisolone) was 2.2 g. Four patients had had fractures. The median bone age-corrected aBMD Z score was -0.4 (range -2.9 to +1.8) for lumbar spine and -0.1 (range -2.1 to +2.4) for femoral neck. Abnormal vertebral morphology was observed in 6 patients (10%). No correlation was found between aBMD and disease characteristics or cumulative GC dose. The median Z score for height was +0.1 (range -2.9 to +1.5) and the median height-adjusted weight +4% (range -17% to +40%). CONCLUSION: Our study showed low prevalence of osteoporosis and normal growth in children with JIA. However, asymptomatic vertebral fractures were observed in 10% of the patients, indicating that DEXA alone may not be sufficient when evaluating bone health in these children. Osteoporosis still remains a concern in children with GC-treated JIA.     

Development of molecular probes for second-site screening and design of protein tyrosine phosphatase inhibitors

We report on the design, synthesis, and evaluation of a series of furanyl-salicyl-nitroxide derivatives as effective chemical probes for second-site screening against phosphotyrosine phosphatases (PTPs) using NMR-based techniques. The compounds have been tested against a panel of PTPs to assess their ability to inhibit a broad spectrum of these phosphatases. The utility of the derived compounds is illustrated with the phosphatase YopH, a bacterial toxin from Yersinia pestis. Novel chemical fragments were identified during an NMR-based screen for compounds that are capable of binding on the surface of YopH in regions adjacent the catalytic site in the presence of the spin-labeled compounds. Our data demonstrate the value of the derived chemical probes for NMR-based second-site screening in PTPs.     

Novel noncatalytic role for caspase-8 in promoting SRC-mediated adhesion and Erk signaling in neuroblastoma cells

Neuroblastomas are extremely aggressive, although heterogeneous, cancers with a poor prognosis upon metastasis. Some evidence has suggested a correlative silencing of caspase-8 with MYCN amplification in neuroblastoma. A prognostic effect of this silencing, however, has been disputed. We report here hitherto undescribed roles for caspase-8 in the modulation of cell adhesion and subsequent activation of the Erk signaling pathway. Re-expression of caspase-8 in neuroblastoma cells lacking endogenous caspase-8 expression was found to promote cell adhesion to extracellular matrix and to activate adhesion-dependent signaling pathways, such as the Erk kinase cascade. This function of caspase-8 occurred irrespective of its proteolytic activity. Additionally, a pool of caspase-8 was shown to co-localize with the Src tyrosine kinase at the cellular periphery. Furthermore, our studies showed that caspase-8 forms a physical protein complex with Src via its death effector domains (DED) and maintains the complex in a detergent-soluble fraction. We also show that the DEDs of caspase-8 alone are necessary and sufficient to recreate the adhesive and biochemical phenotypes observed with the full-length protein, suggesting that caspase-8 may exert these effects via its association with Src. This protein complex association of caspase-8 and Src, and concomitant downstream signaling events, may help reconcile why a potential tumor suppressor such as caspase-8 is rarely absent in cancers.     

Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder, thought to be specific for pregnancy and to spontaneously resolve after delivery. Increased rates of gallstone formation and hepatitis C have previously been associated with ICP. However, there are no longitudinal studies to determine its significance as an indicator of subsequent liver or biliary diseases. In this retrospective cohort study with cases and controls we assessed the risk of liver and biliary diseases in 21,008 women, 10,504 with a history of ICP during the years 1972-2000 (cases) and 10,504 with a normal pregnancy (controls). Cases and controls were matched for age, time of delivery, and place of delivery. The diagnoses of liver and biliary disease were traced from the Finnish Hospital Discharge Register with an almost 100% coverage. Several liver and biliary diseases were found to have a significantly higher incidence in patients with ICP than in controls. The rate ratio for hepatitis C was 3.5 (CI 1.6-7.6; P < .001), for nonalcoholic liver cirrhosis 8.2 (CI 1.9-35.5; P < .05), for gallstones and cholecystitis 3.7 (CI 3.2-4.2; P < .001) and for nonalcoholic pancreatitis 3.2 (CI 1.7-5.7; P < .001). In conclusion, there is an association of ICP with several liver and biliary diseases. Some patients with ICP are at risk of the subsequent development of cirrhosis and other severe chronic diseases. Contrary to what has been previously thought, follow-up may need to be considered for these patients.