Characterising cellular and molecular features of human peripheral nerve degeneration

Nerve regeneration is a key biological process in those recovering from neural trauma. From animal models it is known that the regenerative capacity of the peripheral nervous system (PNS) relies heavily on the remarkable ability of Schwann cells to undergo a phenotypic shift from a myelinating phenotype to one that is supportive of neural regeneration. In rodents, a great deal is known about the molecules that control this process, such as the transcription factors c-Jun and early growth response protein 2 (EGR2/KROX20), or mark the cells and cellular changes involved, including SOX10 and P75 neurotrophin receptor (p75NTR). However, ethical and practical challenges associated with studying human nerve injury have meant that little is known about human nerve regeneration. The present study addresses this issue, analysing 34 denervated and five healthy nerve samples from 27 patients retrieved during reconstructive nerve procedures. Using immunohistochemistry and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), the expression of SOX10, c-Jun, p75NTR and EGR2 was assessed in denervated samples and compared to healthy nerve. Nonparametric smoothing linear regression was implemented to better visualise trends in the expression of these markers across denervated samples. It was found, first, that two major genes associated with repair Schwann cells in rodents, c-Jun and p75NTR, are also up-regulated in acutely injured human nerves, while the myelin associated transcription factor EGR2 is down-regulated, observations that encourage the view that rodent models are relevant for learning about human nerve injury. Second, as in rodents, the expression of c-Jun and p75NTR declines during long-term denervation. In rodents, diminishing c-Jun and p75NTR levels mark the general deterioration of repair cells during chronic denervation, a process thought to be a major obstacle to effective nerve repair. The down-regulation of c-Jun and p75NTR reported here provides the first molecular evidence that also in humans, repair cells deteriorate during chronic denervation

Cardiovascular disease in a cohort exposed to the 1940-45 Channel Islands occupation

BACKGROUND To clarify the nature of the relationship between food deprivation/undernutrition during pre- and postnatal development and cardiovascular disease (CVD) in later life, this study examined the relationship between birth weight (as a marker of prenatal nutrition) and the incidence of hospital admissions for CVD from 1997–2005 amongst 873 Guernsey islanders (born in 1923–1937), 225 of whom had been exposed to food deprivation as children, adolescents or young adults (i.e. postnatal undernutrition) during the 1940–45 German occupation of the Channel Islands, and 648 of whom had left or been evacuated from the islands before the occupation began. METHODS Three sets of Cox regression models were used to investigate (A) the relationship between birth weight and CVD, (B) the relationship between postnatal exposure to the occupation and CVD and (C) any interaction between birth weight, postnatal exposure to the occupation and CVD. These models also tested for any interactions between birth weight and sex, and postnatal exposure to the occupation and parish of residence at birth (as a marker of parish residence during the occupation and related variation in the severity of food deprivation). RESULTS The first set of models (A) found no relationship between birth weight and CVD even after adjustment for potential confounders (hazard ratio (HR) per kg increase in birth weight: 1.12; 95% confidence intervals (CI): 0.70 – 1.78), and there was no significant interaction between birth weight and sex (p = 0.60). The second set of models (B) found a significant relationship between postnatal exposure to the occupation and CVD after adjustment for potential confounders (HR for exposed vs. unexposed group: 2.52; 95% CI: 1.54 – 4.13), as well as a significant interaction between postnatal exposure to the occupation and parish of residence at birth (p = 0.01), such that those born in urban parishes (where food deprivation was worst) had a greater HR for CVD than those born in rural parishes. The third model (C) found no interaction between birth weight and exposure to the occupation (p = 0.43). CONCLUSION These findings suggest that the levels of postnatal undernutrition experienced by children, adolescents and young adults exposed to food deprivation during the 1940–45 occupation of the Channel Islands were a more important determinant of CVD in later life than the levels of prenatal undernutrition experienced in utero prior to the occupatio

Test-retest variability of left ventricular 4D flow cardiovascular magnetic resonance measurements in healthy subjects

Background: Quantification and visualisation of left ventricular (LV) blood flow is afforded by three-dimensional, time resolved phase contrast cardiovascular magnetic resonance (CMR 4D flow). However, few data exist upon the repeatability and variability of these parameters in a healthy population. We aimed to assess the repeatability and variability over time of LV 4D CMR flow measurements. Methods: Forty five controls underwent CMR 4D flow data acquisition. Of these, 10 underwent a second scan within the same visit (scan-rescan), 25 returned for a second visit (interval scan; median interval 52 days, IQR 28–57 days). The LV-end diastolic volume (EDV) was divided into four flow components: 1) Direct flow: inflow that passes directly to ejection; 2) Retained inflow: inflow that enters and resides within the LV; 3) Delayed ejection flow: starts within the LV and is ejected and 4) Residual volume: blood that resides within the LV for > 2 cardiac cycles. Each flow components’ volume was related to the EDV (volume-ratio). The kinetic energy at end-diastole (ED) was measured and divided by the components’ volume. Results: The dominant flow component in all 45 controls was the direct flow (volume ratio 38 ± 4%) followed by the residual volume (30 ± 4%), then delayed ejection flow (16 ± 3%) and retained inflow (16 ± 4%). The kinetic energy at ED for each component was direct flow (7.8 ± 3.0 microJ/ml), retained inflow (4.1 ± 2.0 microJ/ml), delayed ejection flow (6.3 ± 2.3 microJ/ml) and the residual volume (1.2 ± 0.5 microJ/ml). The coefficients of variation for the scan-rescan ranged from 2.5%–9.2% for the flow components’ volume ratio and between 13.5%–17.7% for the kinetic energy. The interval scan results showed higher coefficients of variation with values from 6.2–16.1% for the flow components’ volume ratio and 16.9–29.0% for the kinetic energy of the flow components. Conclusion: LV flow components’ volume and their associated kinetic energy values are repeatable and stable within a population over time. However, the variability of these measurements in individuals over time is greater than can be attributed to sources of error in the data acquisition and analysis, suggesting that additional physiological factors may influence LV flow measurements

Plutonium in Soils from Northeast China and Its Potential Application for Evaluation of Soil Erosion

Surface and soil core samples from northeast China were analyzed for Pu isotopes. The measured Pu-240/Pu-239 atomic ratios and Pu239 + 240/Cs-137 activity ratios revealed that the global fallout is the dominant source of Pu and Cs-137 at these sites. Migration behavior of Pu varying with land type and human activities resulted in different distribution of Pu in surface soils. A sub-surface maximum followed by exponential decline of Pu239 + 240 concentrations was observed in an undisturbed soil core, with a total Pu239 + 240 inventory of 86.9 Bq/m(2) and more than 85% accumulated in 0 similar to 20 cm layers. While only half inventory of Pu was obtained in another soil core and no sub-surface maximum value occurred. Erosion of topsoil in the site should be the most possible reason for the significantly lower Pu inventory, which is also supported by the reported Cs-137 profiles. These results demonstrated that Pu could be applied as an ideal substitute of Cs-137 for soil erosion study in the future.</p

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohort

Older People, Sense of Coherence and Community

Population ageing is a global trend and even though years added to life often are lived in good health; it will have an impact on healthcare, housing and facilities, and social security costs. Healthy ageing in place, especially in one’s own home and community, increasingly receives attention from health professionals, researchers, and policymakers. In this chapter, we first discuss the meaning of the concept of healthy ageing, and how Sense of Coherence contributes to this process. Next, we discuss the characteristics of the community in which older people live their lives and how the community can provide resources (GRR and SRR) to strengthen Sense of Coherence and hence perceived well-being and quality of life

Experimental infection in calves with a specific subtype of verocytotoxin-producing Escherichia coli O157:H7 of bovine origin

<p>Abstract</p> <p>Background</p> <p>In Sweden, a particular subtype of verocytotoxin-producing <it>Escherichia coli </it>(VTEC) O157:H7, originally defined as being of phage type 4, and carrying two <it>vtx</it>₂genes, has been found to cause the majority of reported human infections during the past 15 years, including both sporadic cases and outbreaks. One plausible explanation for this could be that this particular subtype is better adapted to colonise cattle, and thereby may be excreted in greater concentrations and for longer periods than other VTEC O157:H7 subtypes.</p> <p>Methods</p> <p>In an experimental study, 4 calves were inoculated with 10⁹colony forming units (cfu) of strain CCUG 53931, representative of the subtype VTEC O157:H7 (PT4;<it>vtx</it>₂;<it>vtx</it>_2c). Two un-inoculated calves were co-housed with the inoculated calves. Initially, the VTEC O157:H7 strain had been isolated from a dairy herd with naturally occurring infection and the farm had previously also been linked to human infection with the same strain. Faecal samples were collected over up to a 2-month period and analysed for VTEC O157 by immuno-magnetic separation (IMS), and IMS positive samples were further analysed by direct plating to elucidate the shedding pattern. Samples were also collected from the pharynx.</p> <p>Results</p> <p>All inoculated calves proved culture-positive in faeces within 24 hours after inoculation and the un-inoculated calves similarly on days 1 and 3 post-inoculation. One calf was persistently culture-positive for 43 days; in the remainder, the VTEC O157:H7 count in faeces decreased over the first 2 weeks. All pharyngeal samples were culture-negative for VTEC O157:H7.</p> <p>Conclusion</p> <p>This study contributes with information concerning the dynamics of a specific subtype of VTEC O157:H7 colonisation in dairy calves. This subtype, VTEC O157:H7 (PT4;<it>vtx</it>_2;<it>vtx</it>_2c), is frequently isolated from Swedish cattle and has also been found to cause the majority of reported human infections in Sweden during the past 15 years. In most calves, inoculated with a representative strain of this specific subtype, the numbers of shed bacteria declined over the first two weeks. One calf could possibly be classified as a high-shedder, excreting high levels of the bacterium for a prolonged period.</p

The prognosis for individuals on disability retirement An 18-year mortality follow-up study of 6887 men and women sampled from the general population

BACKGROUND: Several studies have shown a markedly higher mortality rate among disability pensioners than among non-retired. Since most disability pensions are granted because of non-fatal diseases the reason for the increased mortality therefore remains largely unknown. The aim of this study was to evaluate potential explanatory factors. METHODS: Data from five longitudinal cohort studies in Sweden, including 6,887 men and women less than 65 years old at baseline were linked to disability pension data, hospital admission data, and mortality data from 1971 until 2001. Mortality odds ratios were analyzed with Poisson regression and Cox's proportional hazards regression models. RESULTS: 1,683 (24.4%) subjects had a disability pension at baseline or received one during follow up. 525 (7.6%) subjects died during follow up. The subjects on disability pension had a higher mortality rate than the non-retired, the hazards ratio (HR) being 2.78 (95%CI 2.08–3.71) among women and 3.43 (95%CI 2.61–4.51) among men. HR was highest among individuals granted a disability pension at young ages (HR >7), and declined parallel to age at which the disability pension was granted. The higher mortality rate among the retired subjects was not explained by disability pension cause or underlying disease or differences in age, marital status, educational level, smoking habits or drug abuse. There was no significant association between reason for disability pension and cause of death. CONCLUSION: Subjects with a disability pension had increased mortality rates as compared with non-retired subjects, only modestly affected by adjustments for psycho-socio-economic factors, underlying disease, etcetera. It is unlikely that these factors were the causes of the unfavorable outcome. Other factors must be at work

Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage

Background. Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. Methods. We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients. Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. Results. The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). Conclusion. We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision.