Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue

Background: ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinum-induced neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG and reference tissues were collected for real time quantitative PCR, RT-PCR, immunohistochemistry and Western blot analysis from healthy control adult rats or from animals treated with intraperitoneal oxaliplatin (1.85 mg/kg) or drug vehicle twice weekly for 8 weeks.
Results: In DRG tissue from healthy control animals, ATP7A mRNA was clearly detectable at levels similar to those found in the brain and spinal cord, and intense ATP7A immunoreactivity was localised to the cytoplasm of cell bodies of smaller DRG neurons without staining of satellite cells, nerve fibres or co-localisation with phosphorylated heavy neurofilament subunit (pNF-H). High levels of CTR1 mRNA were detected in all tissues from healthy control animals, and strong CTR1 immunoreactivity was associated with plasma membranes and vesicular cytoplasmic structures of the cell bodies of larger-sized DRG neurons without co-localization with ATP7A. DRG neurons with strong expression of ATP7A or CTR1 had distinct cell body size profiles with minimal overlap between them. Oxaliplatin treatment did not alter the size profile of strongly ATP7A-immunoreactive neurons but significantly reduced the size profile of strongly CTR1-immunoreactive neurons. ATP7B mRNA was barely detectable, and no specific immunoreactivity for ATP7B was found, in DRG tissue from healthy control animals.
Conclusions: In conclusion, adult rat DRG tissue exhibits a specific pattern of expression of copper transporters with distinct subsets of peripheral sensory neurons intensely expressing either ATP7A or CTR1, but not both or ATP7B. The neuron subtype-specific and largely non-overlapping distribution of ATP7A and CTR1 within rat DRG tissue may be required to support the potentially differing cuproenzyme requirements of distinct subsets of sensory neurons, and could influence the transport and neurotoxicity of oxaliplatin.

Influences of spatial practices on pressure ulcer management in the context of spinal cord injury

Nursing practice is significantly influenced by the type and use of space in which nursing is practised. While investigating current patterns of service delivery for the management of pressure ulcers from the perspective of people with spinal cord injuries and their families, the space in which care was delivered was identified as a central determinant of care. Qualitative methods were used to investigate consumer perspectives among patients residing in both metropolitan and rural communities who had been hospitalized for the management of pressure ulcers. Issues related to the spatial practices of the hospital are discussed, demonstrating a link between well-being and the creation of an appropriate caring milieu. It is concluded that service could be improved markedly if health-care professionals placed more consideration on the impact of space on their service delivery.

Genotoxicity assessment of soils from wastewater irrigation areas and bioremediation sites using the Vicia faba root tip micronucleus assay

Genotoxicity potential of soils taken from wastewater irrigation areas and bioremediation sites was assessed using the Vicia faba root tip micronucleus assay. Twenty five soils were tested, of which 8 were uncontaminated soils and taken as the control to examine the influence of soil properties; 6 soils were obtained from paddy rice fields with a history of long-term wastewater irrigation; 6 soils were obtained from bioremediation sites to examine effects of bioremediation; and 5 PAH-contaminated soils were used to examine methodological effects between direct soil exposure and exposure to aqueous soil extracts on micronuclei (MN) frequency () in the V. faba root tips. Results indicate that soil properties had no significant influences on MN frequencies (p > 0.05) when soil pH varied between 3.4 to 7.6 and organic carbon between 0.4% and 18.6%. The MN frequency measured in these control soils ranged from 1.6‰ to 5.8‰. MN frequencies in soils from wastewater irrigation areas showed 2- to 48-fold increase as compared with the control. Soils from bioremediation sites showed a mixed picture: MN frequencies in some soils decreased after bioremediation, possibly due to detoxification; whereas in other cases remediated soils induced higher MN frequencies, suggesting that genotoxic substances might be produced during bioremediation. Exposure to aqueous soil extracts gave a higher MN frequency than direct exposure in 3 soils. However, the opposite was observed in the other two soils, suggesting that both exposure routes should be tested in case of negative results from one route. Data obtained from this study indicate that the MN assay is a sensitive assay suitable for evaluating genotoxicity of soils.

Role of P-glycoprotein in the intestinal absorption of tanshinone IIA, a major active ingredient in the root of Salvia miltiorrhiza Bunge

The extracts from the roots of Salvia miltiorrhiza Bunge (Danshen) are widely and traditionally used in the treatment of angina pectoris, acute myocardial infarct, hyperlipidemia and stroke in China and other Asian countries. In this study, we have investigated the role of P-glycoprotein (P-gp) in the intestinal absorption of tanshinone IIA (TSA), a major active constituent of Danshen, using several in vitro and in vivo models. The oral bioavailability of TSA was about 2.9

Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.

Purpose. Glabridin is a major active constituent of Glycyrrhiza glabra which is commonly used in the treatment of cardiovascular and central nervous system (CNS) diseases. Recently, we have found that glabridin is a substrate of P-glycoprotein (PgP/MDR1). This study aimed to investigate the role of PgP in glabridin penetration across the blood–brain barrier (BBB) using several in vitro and in vivo models.
Materials and Methods. Cultured primary rat brain microvascular endothelial cells (RBMVECs) were used in the uptake, efflux and transcellular transport studies. A rat bilateral in situ brain perfusion model was used to investigate the brain distribution of glabridin. The brain and tissue distribution of glabridin in rats with or without coadministered verapamil or quinidine were examined with correction for the tissue residual blood. In addition, the brain distribution of glabridin in mdr1a(-/-) mice was compared with the wild-type mice. Glabridin in various biological matrices was determined by a validated liquid chromatography mass spectrometric method.
Results. The uptake and efflux of glabridin in cultured RBMVECs were ATP-dependent and significantly altered in the presence of a PgP or multi-drug resistance protein (Mrp1/2) inhibitor (e.g. verapamil or MK-571). A polarized transport of glabridin was found in RBMVEC monolayers with
facilitated efflux from the abluminal (BL) to luminal (AP) side. Addition of a PgP or Mrp1/2 inhibitor in both luminal and abluminal sides attenuated the polarized transport across RBMVECs. In a bilateral in situ brain perfusion model, the uptake of glabridin into the cerebrum increased from 0.42 T 0.09% at 1 min to 9.27 T 1.69% (ml/100 g tissue) at 30 min and was significantly greater than that for sucrose. Coperfusion of a PgP or Mrp1/2 inhibitor significantly increased the brain distribution of glabridin by 33.6j142.9%. The rat brain levels of glabridin were only about 27% of plasma levels when corrected by tissue residual blood and it was increased to up to 44% when verapamil or quinidine was coadministered. The area under the brain concentration-time curve (AUC) of glabridin in mdr1a(-/-) mice was 6.0-fold higher than the wild-type mice.
Conclusions. These findings indicate that PgP limits the brain penetration of glabridin through the BBB and PgP may cause drug resistance to glabridin (licorice) therapy for CNS diseases and potential drugglabridin interactions. However, further studies are needed to explore the role of other drug transporters (e.g. Mrp1-4) in restricting the brain penetration of glabridin.

Role of the ATP-binding cassette drug transporters in the intestinal absorption of tanshinone IIB, one of the major active diterpenoids from the root of Salvia miltiorrhiza

There is an increasing use of herbal medicines worldwide, and the extracts from the root of Salvia miltiorrhiza are widely used in the treatment of angina and stroke. In this study, we investigated the mechanism for the intestinal absorption of tanshinone IIB (TSB), a major constituent of S. miltiorrhiza. The oral bioavailability of TSB was about 3% in rats with less proportional increase in its maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) with increasing dosage. The time to C_max (T_max) was prolonged at higher oral dosage. In a single pass rat intestinal perfusion model, the permeability coefficients (P_app) based on TSB disappearance from the lumen (P_lumen) were 6.2- to 7.2-fold higher (p < 0.01) than those based on drug appearance in mesenteric venous blood (P_blood). The uptake and efflux of TSB in Caco-2 cells were also significantly altered in the presence of an inhibitor for P-glycoprotein (PgP) or for multi-drug resistance associated protein (MRP1/2). TSB transport from the apical (AP) to basolateral (BL) side in Caco-2 monolayers was 3.3- to 5.7-fold lower than that from BL to AP side, but this polarized transport was attenuated by co-incubation of PgP or MRP1/2 inhibitors. The P_app values of TSB in the BL-AP direction were significantly higher in MDCKII cells over-expressing MDR1 or MRP1, but not in cells over-expressing MRP2-5, as compared with the wild-type cells. The plasma AUC_0-24hr in mdr1a and mrp1 gene-deficient mice was 10.2- to 1.7-fold higher than that in the wild-type mice. Furthermore, TSB significantly inhibited the uptake of digoxin and vinblastine in membrane vesicles containing PgP or MRP1. TSB also moderately stimulated PgP ATPase activity. Taken collectively, our findings indicate that TSB is a substrate for PgP and MRP1 and that drug resistance to TSB therapy and drug interactions may occur through PgP and MRP1 modulation.

Are real exchange rates nonlinear with a unit root? Evidence on PPP for Italy : a note

In this article, we apply the recently developed threshold autoregression model to examine both linearity and stationarity of Italy's real exchange rate vis--vis her six trading partner (G6) countries. Our main finding is that Italy's real exchange rate is a nonlinear process that is not characterized by a unit root process for five of six trading partner countries. This provides strong support for purchasing power parity.

Mean reversion in stock prices: new evidence from panel unit root tests

Purpose – There are several studies that investigate evidence for mean reversion in stock prices. However, there is no consensus as to whether stock prices are mean reverting or random walk (unit root) processes. The goal of this paper is to re-examine mean reversion in stock prices.
Design/methodology/approach – The authors use five different panel unit root tests, namely the Im, Pesaran and Shin t-bar test statistic, the Levin and Lin test, the Im, Lee, and Tieslau Lagrangian multiplier test statistic, the seemingly unrelated regression test, and the multivariate augmented Dickey Fuller test advocated by Taylor and Sarno.
Findings – The main finding is that there is no mean reversion of stock prices, consistent with the efficient market hypothesis.
Research limitations/implications – One issue not considered by this study is the role of structural breaks. It may be the case that the efficient market hypothesis is contingent on structural breaks in stock prices. Future studies should model structural breaks.
Practical implications – The findings have implications for econometric modelling, in particular forecasting.
Originality/value – This paper adds to the scarce literature on the mean reverting property of stock prices based on panel data; thus, it should be useful for researchers.

The effect of osteoporotic vertebral fracture of predicted spinal loads in vivo

he aetiology of osteoporotic vertebral fractures is multi-factorial, and cannot be explained solely by low bone mass. After sustaining an initial vertebral fracture, the risk of subsequent fracture increases greatly. Examination of physiologic loads imposed on vertebral bodies may help to explain a mechanism underlying this fracture cascade. This study tested the hypothesis that model-derived segmental vertebral loading is greater in individuals who have sustained an osteoporotic vertebral fracture compared to those with osteoporosis and no history of fracture. Flexion moments, and compression and shear loads were calculated from T2 to L5 in 12 participants with fractures (66.4 ± 6.4 years, 162.2 ± 5.1 cm, 69.1 ± 11.2 kg) and 19 without fractures (62.9 ± 7.9 years, 158.3 ± 4.4 cm, 59.3 ± 8.9 kg) while standing. Static analysis was used to solve gravitational loads while muscle-derived forces were calculated using a detailed trunk muscle model driven by optimization with a cost function set to minimise muscle fatigue. Least squares regression was used to derive polynomial functions to describe normalised load profiles. Regression co-efficients were compared between groups to examine differences in loading profiles. Loading at the fractured level, and at one level above and below, were also compared between groups. The fracture group had significantly greater normalised compression (p = 0.0008) and shear force (p < 0.0001) profiles and a trend for a greater flexion moment profile. At the level of fracture, a significantly greater flexion moment (p = 0.001) and shear force (p < 0.001) was observed in the fracture group. A greater flexion moment (p = 0.003) and compression force (p = 0.007) one level below the fracture, and a greater flexion moment (p = 0.002) and shear force (p = 0.002) one level above the fracture was observed in the fracture group. The differences observed in multi-level spinal loading between the groups may explain a mechanism for increased risk of subsequent vertebral fractures. Interventions aimed at restoring vertebral morphology or reduce thoracic curvature may assist in normalising spine load profiles.

Joint range of motion limitations in children and young adults with spinal muscular atrophy

Objectives
To elicit descriptive data about limited joint range of motion (ROM) in subjects with type II or III spinal muscular atrophy (SMA) and to examine the relation between the number of motions with limited range and both age and functional ability.
Design
Descriptive cross-sectional study.
Setting
Neurologic pediatric outpatient clinic at a hospital in Taiwan.
Participants
Twenty-seven subjects with SMA type II (mean age, 9.8±6.5y) and 17 with SMA type III (mean age, 12.2±8.7y).
Intervention
Measurement with transparent goniometers of joint ROM bilaterally of the shoulder, elbow, wrist, hip, knee, and ankle.
Main outcome measures
The proportion of participants with each ROM limitation compared with all participants with the same SMA type, age distribution of the participants with each ROM limitation, mean range loss of each motion limitation, and the contracture index (risk index of joint contracture).
Results
Eighty-nine percent of the participants with SMA type II experienced knee extension limitation. Approximately 50% of the participants with both types of SMA had ankle dorsiflexion limitation. The motions of knee and hip extension and ankle dorsiflexion also had a relatively high contracture index. The number of motions with limited range positively correlated (P<.001) with age and upper-extremity functional grade (the higher the functional grade, the poorer the functional ability) for SMA type II.
Conclusions
We found varying degrees of joint ROM limitation. Certain motions were noted to be high risks for the development of contractures. This risk was higher mostly in younger children.

Language processing and acquisition in languages of Semitic, root-based, morphology / Joseph Shimron

This book addresses a fundamental question in the morphological analysis and representation of Semitic languages—namely, whether Semitic word morphology is root based or word based. As Shimron suggests, “there are reasons to view the templates, not the roots, as the more influential factor in determining Semitic morphology” (p. 5). Yet, as others would argue, there are reasons not to disregard the root-based hypothesis altogether. In the case of Arabic morphology, for example, verbal forms inherently contain three nonlinear levels: the consonantal root, the vowel pattern, and the templatic prosody. This nonlinear feature provided a perfect illustration of what has become termed in the literature as root-and-patterns morphology (McCarthy & Prince, 1986, 1990).

Revisiting the US money demand function: an application of the Lagrange multiplier structural break unit root test and the bounds test for a long-run relationship

In this article, we examine the issue of a levels relationship and stability of the US money demand function over the period 1959:01 to 2004:02. We use the Lagrange multiplier structural break unit root test and the bounds testing approach to a long-run relationship in levels of the variables, namely real money demand, nominal interest rate and real income. We find greater evidence for a long-run relationship in levels and stability of the US money demand function when we use M2 as a proxy for money demand. However, we find little evidence for a long-run relationship between M1 and M2 with their determinants for the recent period, spanning the last decade or so.

Do shocks to G7 stock prices have a permanent effect? : evidence from panel unit root tests with structural change

There is a plethora of studies that investigate evidence for the behaviour of stock prices using univariate techniques for unit roots. Whether or not stock prices are characterised by a unit root have implications for the efficient market hypothesis, which asserts that returns of a stock market are unpredictable from previous price changes. The extant literature has found mixed evidence on the integrational properties of stock prices. In this paper, for the first time, we provide evidence on the unit root hypothesis for G7 stock price indices using the Lagrangian multiplier panel unit root test that allows for structural breaks. Our main finding is that stock prices are stationary processes, inconsistent with the efficient market hypothesis.

Examining the behaviour of visitor arrivals to Australia from twenty different countries : an application of panel unit root tests

Testing for the behaviour of visitor arrivals has important implications for policy, for if visitor arrivals are stationary processes then it implies that shocks to visitor arrivals are transitory. However, if visitor arrivals are found to be characterised by a unit root then this implies that shocks to visitor arrivals are permanent. In this paper we provide the first evidence on the unit root hypothesis for visitor arrivals to Australia using a suite of recently developed panel unit root tests. Our main finding is that visitor arrivals to Australia from twenty tourist source markets and from the G7 markets are mean reverting. implying that any shocks will have only a transitory effect. However; visitor arrivals from eight Asian countries are characterised by a unit root. implying that shocks will have a permanent effect on this market.

Are bilateral real exchange rates stationary? Evidence from Lagrange multiplier unit root tests for India

The paper examines the stationarity of India’s real exchange rate vis-a` -vis 16 of its major trading partner countries for the period 1960–2000. Application of the conventional ADF unit root test, the Lagrange multiplier (LM) unit root test with one structural break, and the LM unit root test with two structural breaks provides evidence that India’s exchange rate vis-a` -vis 15 out of 16 countries is stationary, implying support for purchasing power parity.