Changes in Hyaluronan Metabolism and RHAMM Receptor Expression Accompany Formation of Complicated Carotid Lesions and May be Pro-Angiogenic Mediators of Intimal Neovessel Growth.

Previous studies have shown that changes in expression of the glycosaminoglycan, hyaluronan (HA) were associated with erosion in areas of post-mortem coronary artery liable to rupture. Angiogenesis is an important feature of ulcerating haemorrhagic plaques prone to rupture. HA is a glycosaminoglycan known to possess potent angiogenic properties on metabolism to oligosaccharides of HA (o-HA) in the presence of hyaluronidase (HYAL) enzymes. In this study, we have examined HA receptor and HYAL enzyme expression in a series of carotid artery specimens used as vascular transplants and exhibiting various stages of atherosclerotic lesions as determined by anatomo-pathology. Our results demonstrated dramatically increased expression of HYAL-1 in regions of inflammation associated with complicated plaques. Receptor for HA-mediated motility (RHAMM), which is known to be important in transducing angiogenic signals in vascular endothelium, was strongly expressed on intimal blood vessels from complicated lesions but almost absent from other regions including adventitial vessels. Metabolism of HA, together with up-regulation of RHAMM in complicated plaque lesions might be partly responsible for over-production of leaky neovessels and predisposition to plaque rupture

ElrA binding to the 3′UTR of cyclin E1 mRNA requires polyadenylation elements

The early cell divisions of Xenopus laevis and other metazoan embryos occur in the presence of constitutively high levels of the cell cycle regulator cyclin E1. Upon completion of the 12th cell division, a time at which many maternal proteins are downregulated by deadenylation and destabilization of their encoding mRNAs, maternal cyclin E1 protein is downregulated while its mRNA is polyadenylated and stable. We report here that stable polyadenylation of cyclin E1 mRNA requires three cis-acting elements in the 3′ untranslated region; the nuclear polyadenylation sequence, a contiguous cytoplasmic polyadenylation element and an upstream AU-rich element. ElrA, the Xenopus homolog of HuR and a member of the ELAV gene family binds the cyclin E1 3′UTR with high affinity. Deletion of these elements dramatically reduces the affinity of ElrA for the cyclin E1 3′UTR, abolishes polyadenylation and destabilizes the mRNA. Together, these findings provide compelling evidence that ElrA functions in polyadenylation and stabilization of cyclin E1 mRNA via binding these elements

Cdk5 interacts with Hif-1α in neurons: A new hypoxic signalling mechanism?

The cyclin dependent kinase 5 (Cdk5)/p35 complex is essential for regulation of cell survival during development and in models of neuronal excitotoxicity. Dysregulation of Cdk5, by cleavage of its neuronal specific activators p35 and p39, has been implicated in various neurodegenerative disorders such as Alzheimer's disease, however targets of the complex that regulate neuronal survival physiologically and/or during pathogenesis are largely unknown. Since hypoxia is a key feature in the pathogenesis of several neuronal disorders we investigated a role for Cdk5/p35 in the neuronal hypoxic response. Our data shows that hypoxia modulates the p35/Cdk5 complex in primary cortical neurons at the transcriptional and protein level. Furthermore hypoxic induction of Cdk5 activity correlates with Hif-1α stabilisation, and direct interaction between these proteins can occur. Importantly, we demonstrate that Cdk5-mediated signaling is involved in Hif-1α stabilisation since inhibition of Cdk5 by roscovitine abrogates Hif-1α accumulation and induces cell death. Taken together our results show that the Cdk5/p35 complex may significantly contribute to modulation of Hif-1α stabilisation and impact neuronal survival during oxygen deprivation. Thus this study highlights a new hypoxia-mediated signaling pathway and implicates the cytoskeleton as a potential regulator of Hif-1α. Section: Cellular and Molecular Biology of Nervous Systems

Finite-size scaling from self-consistent theory of localization

Accepting validity of self-consistent theory of localization by Vollhardt and Woelfle, we derive the finite-size scaling procedure used for studies of the critical behavior in d-dimensional case and based on the use of auxiliary quasi-1D systems. The obtained scaling functions for d=2 and d=3 are in good agreement with numerical results: it signifies the absence of essential contradictions with the Vollhardt and Woelfle theory on the level of raw data. The results \nu=1.3-1.6, usually obtained at d=3 for the critical exponent of the correlation length, are explained by the fact that dependence L+L_0 with L_0>0 (L is the transversal size of the system) is interpreted as L^{1/\nu} with \nu>1. For dimensions d\ge 4, the modified scaling relations are derived; it demonstrates incorrectness of the conventional treatment of data for d=4 and d=5, but establishes the constructive procedure for such a treatment. Consequences for other variants of finite-size scaling are discussed.Comment: Latex, 23 pages, figures included; additional Fig.8 is added with high precision data by Kramer et a

Novel poly(L-lactic acid)/hyaluronic acid macroporous hybrid scaffolds : characterization and assessment of cytotoxicity

Poly(L-lactic acid), PLLA, a synthetic biodegradable polyester, is widely accepted in tissue engineering. Hyaluronic acid (HA), a natural polymer, exhibits an excellent biocompatibility, influences cell signaling, proliferation, and differentiation. In this study, HA crosslinking was performed by immersion of the polysaccharide in water-acetone mixtures containing glutaraldehyde (GA). The objective of this work is to produce PLLA scaffolds with the pores coated with HA, that could be beneficial for bone tissue engineering applications. PLLA tridimensional scaffolds were prepared by compression molding followed by salt leaching. After the scaffolds impregnation with soluble HA solutions of distinct concentration, a GA-crosslinking reaction followed by inactivation of the unreacted GA with glycine was carried out. An increase on surface roughness is shown by scanning electron microscopy (SEM) with the addition of HA. Toluidine blue staining indicates the present of stable crosslinked HA. An estimation of the HA original weight in the hybrid scaffolds was performed using thermal gravimetric analyses. FTIR-ATR and XPS confirmed the crosslinking reaction. Preliminary in vitro cell culture studies were carried out using a mouse lung fibroblast cell line (L929). SEM micrographs of L929 showed that cells adhered well, spread actively throughout all scaffolds, and grew favorably. A MTS test indicated that cells were viable when cultured onto the surface of all scaffolds, suggesting that the introduction of crosslinked HA did not increase the cytotoxicity of the hybrid scaffolds.Contract grant sponsor: Portuguese Foundation for Science and Technology (FCT) through POCTIContract grant sponsor: FEDER programs including project ProteoLight; contract grant number: PTDC/FIS/68517/2006Contract grant sponsor: European Union funded STREP Project HIPPOCRATES; contract grant number: NMP3-CT-2003-505758Contract grant sponsor: European NoE EXPERTISSUES; contract grant number: NMP3-CT-2004-500283Contract grant sponsor: Spanish Ministry of Science (The FEDER financial support); contract grant number: MAT2007-66759-C03-01The authors acknowledge the funding for research in the field of Regenerative Medicine through the collaboration agreement from the Conselleria de Sanidad (Generalitat Valenciana) and the Instituto de Salud Carlos III (Ministry of Science and Innovation). The European Union Financing, as part of the SOCRA-TES/Erasmus program is also gratefully acknowledged

Irinotecan, cisplatin and mitomycin in inoperable gastro-oesophageal and pancreatic cancers – a new active regimen

Irinotecan, mitomycin and cisplatin all demonstrate activity in gastro-oesophageal cancers. This novel combination was administered to outpatients with previously untreated inoperable gastro-oesophageal or pancreatic cancer, in a 28-day cycle. A total of 26 out of 31 patients with gastro-oesophageal cancer and 12 out of 14 patients with pancreatic cancer have been treated with this combination, and were evaluable for response. The overall response rates for patients with gastro-oesophageal cancer was 42%, with a median survival of 9.5 months. In patients with pancreatic cancer, the overall response rate was 42% with a median survival of 8 months. There was a statistically significant increase in survival between those patients who achieved a stable disease response and those who achieved either a partial response or complete response. The toxicity profiles for both cancers were virtually identical. There were five treatment-related deaths, and a high admission rate (42%). Thus irinotecan, mitomycin and cisplatin is a new combination with activity in inoperable upper gastro-oesophageal cancers, but with a high toxicity profile. Future developments include reducing the dose of irinotecan and number of cycles of therapy to four

(123)I-FP-CIT SPECT imaging in early diagnosis of dementia in patients with and without a vascular component.

Alzheimer's disease (AD) and vascular dementia (VaD) are the most common cause of dementia. Cerebral ischemia is a major risk factor for development of dementia. (123)I-FP-CIT SPECT (DaTScan) is a complementary tool in the differential diagnoses of patients with incomplete or uncertain Parkinsonism. Additional application of DaTScan enables the categorization of Parkinsonian disease with dementia (PDD), and its differentiation from pure AD, and may further contribute to change the therapeutic decision. The aim of this study was to analyze the vascular contribution towards dementia and mild cognitive impairment (MCI). We evaluated the utility of DaTScan for the early diagnosis of dementia in patients with and without a clinical vascular component, and the association between neuropsychological function, vascular component and dopaminergic function on DaTScan. One-hundred and five patients with MCI or the initial phases of dementia were studied prospectively. We developed an initial assessment using neurologic examination, blood tests, cognitive function tests, structural neuroimaging and DaTScan. The vascular component was later quantified in two ways: clinically, according to the Framingham Risk Score (FRS) and by structural neuroimaging using Wahlund Scale Total Score (WSTS). Early diagnosis of dementia was associated with an abnormal DaTScan. A significant association was found between a high WSTS and an abnormal DaTScan (p < 0.01). Mixed AD was the group with the highest vascular component, followed by the VaD group, while MCI and pure AD showed similar WSTS. No significant associations were found between neuropsychological impairment and DaTScan independently of associated vascular component. DaTScan seems to be a good tool to discriminate, in a first clinical assessment, patients with MCI from those with established dementia. There was bigger general vascular affectation observable in MRI or CT in patients with abnormal dopaminergic uptake seen on DaTScan

Clinical Course and Outcomes of Small Supratentorial Intracerebral Hematomas.

Intracerebral hemorrhage (ICH) volume, particularly if ≥30 mL, is a major determinant of poor outcome. We used a multinational ICH data registry to study the characteristics, course, and outcomes of supratentorial hematomas with volumes <30 mL.Basic characteristics, clinical and radiological course, and 30-day outcomes of these patients were recorded. Outcomes were categorized as early neurological deterioration (END), hematoma expansion, Glasgow Outcome Scale (GOS), and in-hospital death. Poor outcome was defined as composite of in-hospital death and severe disability (GOS ≤ 3). Comparison was conducted based on hemorrhage location. Logistic regression using dichotomized outcome scales was applied to determine predictors of poor outcome.Among 375 cases of supratentorial ICH with volumes <30 mL, expansion and END rates were 19.2% and 7.5%, respectively. Hemorrhage growth was independently associated with END (odds ratio: 28.7, 95% confidence interval [CI]: 8.51-96.5; P < .0001). Expansion rates did not differ according to ICH location. Overall, 13.9% (exact binomial 95% CI: 10.5-17.8) died in the hospital and 29.1% (CI: 24.5-34.0) had severe disability at 30 days; there was a cumulative poor outcome rate of 42.9% (CI: 37.9-48.1). Age, admission Glasgow Coma Scale, intraventricular extension, and END were independently associated with poor outcome. There was no difference in poor outcome rates between lobar and deep locations (40.2% versus 43.8%, P = .56).Patients with supratentorial ICH <30 mL have high rates of poor outcome at 30 days, regardless of location. Nearly 1 in 5 hematomas <30 mL expands, leading to END or death

Beliefs and practices of patients with advanced cancer: implications for communication

The aim of this study was to investigate the beliefs that patients with advanced cancer held about the curability of their cancer, their use of alternatives to conventional medical treatment, and their need to have control over decisions about treatment. Of 149 patients who fulfilled the criteria for participation and completed a self-administered questionnaire, 45 patients (31%) believed their cancer was incurable, 61 (42%) were uncertain and 39 (27%) believed their cancer was curable. The index of need for control over treatment decisions was low in 53 patients (35.6%) and high in only 17 patients (11.4%). Committed users of alternatives to conventional medical treatments were more likely to believe that their cancer was curable (