All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

Heated indoor swimming pools, infants, and the pathogenesis of adolescent idiopathic scoliosis: a neurogenic hypothesis

<p>Abstract</p> <p>Background</p> <p>In a case-control study a statistically significant association was recorded between the introduction of infants to heated indoor swimming pools and the development of adolescent idiopathic scoliosis (AIS). In this paper, a neurogenic hypothesis is formulated to explain how toxins produced by chlorine in such pools may act deleteriously on the infant's immature central nervous system, comprising brain and spinal cord, to produce the deformity of AIS.</p> <p>Presentation of the hypothesis</p> <p>Through vulnerability of the developing central nervous system to circulating toxins, and because of delayed epigenetic effects, the trunk deformity of AIS does not become evident until adolescence. In mature healthy swimmers using such pools, the circulating neurotoxins detected are chloroform, bromodichloromethane, dibromochloromethane, and bromoform. Cyanogen chloride and dichloroacetonitrile have also been detected.</p> <p>Testing the hypothesis</p> <p>In infants, the putative portals of entry to the blood could be dermal, oral, or respiratory; and entry of such circulating small molecules to the brain are via the blood-brain barrier, blood-cerebrospinal fluid barrier, and circumventricular organs. Barrier mechanisms of the developing brain differ from those of adult brain and have been linked to brain development. During the first 6 months of life cerebrospinal fluid contains higher concentrations of specific proteins relative to plasma, attributed to mechanisms continued from fetal brain development rather than immaturity.</p> <p>Implications of the hypothesis</p> <p>The hypothesis can be tested. If confirmed, there is potential to prevent some children from developing AIS.</p

FDG–PET. A possible prognostic factor in head and neck cancer

Previous studies have shown that high uptake of 18F-fluoro-2-deoxy-glucose in head and neck cancer, as determined by the standardized uptake value on positron emission tomography scan, was associated with poor survival. The aim of this study was to confirm the association and to establish whether a high standardized uptake value had prognostic significance. Seventy-three consecutive patients with newly diagnosed squamous cell carcinoma of the head and neck underwent a positron emission tomography study before treatment. Age, gender, performance status tumour grade, stage, maximal tumour diameter and standardized uptake value were analyzed for their possible association with survival. The median standardized uptake value for all primary tumours was 7.16 (90% range 2.30 to 18.60). In univariate survival analysis the cumulative survival was decreased as the stage, tumour diameter and standardized uptake value increased. An standardized uptake value of 10 was taken as a cut-off for high and low uptake tumours. When these two groups were compared, an standardized uptake value >10 predicted for significantly worse outcome (P=0.003). Multivariate analysis demonstrated that an standardized uptake value >10 provided prognostic information independent of the tumour stage and diameter (P=0.002). We conclude that high FDG uptake (standardized uptake value>10) on positron emission tomography is an important marker for poor outcome in primary squamous cell carcinoma of the head and neck. Standardized uptake value may be useful in distinguishing those tumours with a more aggressive biological nature and hence identifying patients that require intensive treatment protocols including hyperfractionated radiotherapy and/or chemotherapy

Effects of Aging and Cyclosporin A on Collagen Turnover in Human Gingiva

BACKGROUND: WE AIMED AT CHARACTERIZING THE AGING GINGIVA ANALYZING: i) collagen content and turnover in human gingival tissues and fibroblasts obtained from healthy young and aging subjects. ii) the effect of cyclosporin A administration in human cultured gingival fibroblasts obtained from aging compared to young subjects. METHODS: Morphological analysis was performed on haematoxylin-eosin and Sirius red stained paraffin-embedded gingival biopsies from young and aging healthy subjects. The expression of the main genes and proteins involved in collagen turnover were determined by real time PCR, dot blot and SDS-zymography on cultured young and aging gingival fibroblasts, and after cyclosporin A administration. RESULTS: Our results suggest that in healthy aged people, gingival connective tissue is characterized by a similar collagen content and turnover. Collagen turnover pathways are similarly affected by cyclosporin A treatment in young and aging gingival fibroblasts. CONCLUSIONS: Cyclosporin A administration affects gingival collagen turnover pathways in young and aging fibroblasts at the same extent, suggesting that during aging cyclosporin A administration is not related to relevant collagen turnover modifications

Aerobic fitness is a potential crucial factor in protecting paralympic athletes with locomotor impairments from atherosclerotic cardiovascular risk

PurposeTo test the hypothesis that aerobic fitness is inversely related to the risk of atherosclerotic cardiovascular disease (ACVD) in athletes with locomotor impairments deriving from health conditions, such as spinal cord injury (SCI), lower limb amputation, cerebral palsy, poliomyelitis, and other health conditions different from the previous ones.MethodsA total of 68 male athletes who competed in either summer or winter Paralympic games were divided in two health conditions groups (35 with SCI, mean age 37.28.0 years, and 33 with different health conditions, mean age 37.89.9 years) and in four sport type groups (skill, power, intermittent-mixed metabolism-and endurance). They were evaluated through anthropometric and blood pressure measurements, laboratory blood tests, and graded cardiopulmonary maximal arm cranking exercise test, with oxygen uptake peak (VO2peak) measurement. Cardiovascular risk profile was assessed in each athlete.ResultsThe prevalence of ACVD-risk factors in the overall population was 20.6% for hypertension; 47% and 55.9% for high values of total and LDL cholesterol, respectively; 22.1% for reduce glucose tolerance; and 8.8% for obesity. No difference was found between athletes with and without SCI, while the prevalence of obesity was significantly higher in those practicing skill sports (22.7%, p=0.035), which was the sport type group with Paralympic athletes with the lowest VO2peak (22.5 +/- 5.70 ml kg(-1) min(-1)). VO2peak was lower in athletes with SCI than those with different health conditions (28.6 +/- 10.0 vs 33.6 +/- 8.9 ml kg(-1) min(-1)p=0.03), and in those with 3-4 risk factors (19.09 +/- 5.34 ml kg(-1) min(-1)) than those with 2 risk factors (27.1 +/- 5.50 ml kg(-1) min(-1)), 1 risk factor (31.6 +/- 8.55 ml kg(-1) min(-1)), or none (36.4 +/- 8.76 ml kg(-1) min(-1)) (p<0.001).ConclusionsThe present study suggests that having higher VO2peak seems to offer greater protection against ACVD in individuals with a locomotor impairment. Prescribing physical exercise at an intensity similar to that of endurance and intermittent sports should become a fundamental tool to promote health among people with a locomotor impairment.Open access funding provided by Universita degli Studi dell'Aquila within the CRUI-CARE Agreement

Baseline factors predictive of serious suicidality at follow-up: findings focussing on age and gender from a community-based study

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-244X/10/41Background: Although often providing more reliable and informative findings relative to other study designs, longitudinal investigations of prevalence and predictors of suicidal behaviour remain uncommon. This paper compares 12-month prevalence rates for suicidal ideation and suicide attempt at baseline and follow-up; identifies new cases and remissions; and assesses the capacity of baseline data to predict serious suicidality at follow-up, focusing on age and gender differences. Methods: 6,666 participants aged 20-29, 40-49 and 60-69 years were drawn from the first (1999-2001) and second (2003-2006) waves of a general population survey. Analyses involved multivariate logistic regression. Results: At follow-up, prevalence of suicidal ideation and suicide attempt had decreased (8.2%-6.1%, and 0.8%-0.5%, respectively). However, over one quarter of those reporting serious suicidality at baseline still experienced it four years later. Females aged 20-29 never married or diagnosed with a physical illness at follow-up were at greater risk of serious suicidality (OR = 4.17, 95% CI = 3.11-5.23; OR = 3.18, 95% CI = 2.09-4.26, respectively). Males aged 40-49 not in the labour force had increased odds of serious suicidality (OR = 4.08, 95% CI = 1.6-6.48) compared to their equivalently-aged and employed counterparts. Depressed/anxious females aged 60-69 were nearly 30% more likely to be seriously suicidal. Conclusions: There are age and gender differentials in the risk factors for suicidality. Life-circumstances contribute substantially to the onset of serious suicidality, in addition to symptoms of depression and anxiety. These findings are particularly pertinent to the development of effective population-based suicide prevention strategies.A Kate Fairweather-Schmidt, Kaarin J Anstey, Agus Salim and Bryan Rodger