bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction
Authors: Stears Marc
Published: October 2011

The political scenario in Britain and the United States saw much development in the three decades of World War I. However, with the shift in political debate, interest groups and issue-oriented pressure groups were formed and demanded reforms. Intellectuals heavily engaged in politics have also sought opportunities in these movements. Discussions sprang up, including that of the intense and politically controversial debate between the British social pluralists led by Harold Laski, G. D. H. Cole, and R. H. Tawney, and the American national progressives directed by Herbert Croly, Walter Lippmann, and Walter Weyl. They argued on the size, scope, and legitimate role of the central state which was the single most important question facing reformers. This chapter aims to re-establish the centrality of international exchange and provides a unique perspective on the evolution of modern ideological politics in Britain and the United States.
Why do some pains become chronic?
Authors: Jaggar Sian
Published: October 2011

Chronic pain happens for many different reasons and not only as a consequence of tissue injury. There are also many different risk factors. This chapter describes two patients and how pain becomes long term for the second.
Mechanisms of acute pain
Authors: Bromley Lesley
Published: October 2011

Our increasing understanding of how the nervous system detects painful stimuli, and how it deals with the information has improved acute pain management. Since prehistory it has been evident that the nervous system conducted information to the brain. Philosophers such as Descartes thought the nerves ‘opened up pores in the common sense centre’. We know that the old idea of the nerves as a form of wiring is too simplistic and that the nervous system is able to modify the information that arrives at every synapse along the way to the brain. This chapter explains the current science behind the development of pain when tissue damage first occurs.
Pharmacological targets in acute pain
Authors: Newton Mary
Published: October 2011

This chapter employs some of the targets that were discussed in the last chapter. It describes the management of two patients with severe acute pain. The first one has acute musculoskeletal pain, and the second, a combination of musculoskeletal and neuropathic pain. The chapter emphasizes the importance of regular analgesia, co-analgesia and non-pharmacological adjuncts.
Some treatments cause chronic pain: can we reduce the risk?
Authors: Brandner Brigitta
Published: October 2011

For many, the million dollar question is whether chronic pain can be prevented. In the opening chapter of this book some of the determinants of chronic pain were discussed. Many of them relate to psychosocial issues that play a part in the development of pretty much all major Western ailments. They are tied in to a person’s life, work and relationships and become very difficult to unravel without effort at a national level. This chapter looks at the pains that doctors can cause. Surgery and trauma are potent stimulators of pain and sometimes this persists. We will explore possible strategies to prevent chronic pain from developing in a patient undergoing a lower limb amputation, which is a common and distressing experience for amputees.
Prescribing for people with pain originating in the nervous system. Part 2. Anticonvulsants
Authors: Chong Sam
Published: October 2011

This chapter describes the use of anticonvulsants in neuropathic pain. The form of neuropathic pain described here is called central post-stroke pain which can be particularly difficult to treat with a patient driven to distraction by the discomfort. The chapter concludes with a suggested prescribing regimen (Table 9.1) and treatment algorithm (Figure 9.1).
Strong opioids in the treatment of people with non-malignant pain
Authors: Francis Jon
Published: October 2011

Opioids are our most powerful analgesics, but prejudice, ignorance and fear of addiction remain barriers to their use in the treatment of chronic non-cancer pain. Attitudes are changing, as witnessed by an increasingly free use of opioid patches; this has created a new set of issues. Improved understanding is needed widely amongst primary care and hospital physicians about the best use of this group of medicines.
Pain of urological and genital origin
Authors: Baranowski Andrew
Published: October 2011

The following chapter covers pain of urological and genital origin. It serves as an example of how more complex pains may be approached employing a team effort. The chapter also illustrates how pain medicine is developing and how an understanding of anatomy and physiology may help in the understanding of presenting symptoms and signs.
Cancer pain
Authors: de Courcy James
Published: October 2011

Pain is common in cancer but not universal. It affects up to 70% of patients. The good news is that despite these initially discouraging statistics, relatively simple approaches can manage the majority of patients’ pain effectively. These approaches have many features in common with many outlined elsewhere in this volume, and to avoid duplication in this brief overview detailed discussion of the various pain types, drug groups and treatments will not be repeated here.
Psychological aspects of pain
Authors: Mandeville Anna , Ridout Kate
Published: October 2011

Cognitive behavioural therapy (CBT) is increasingly recognised as an intrinsically appropriate aspect of the treatment of many long-term medical problems. There is a strong evidence base for its use in reducing disability and distress in the context of chronic pain. A CBT approach to pain is often delivered via an in- or outpatient group pain management program, usually led by a clinical psychologist and supported by other disciplines. This chapter provides an introduction to the key ways in which CBT can be used in the treatment of someone with pain.
Getting back to work
Authors: Price Cathy
Published: October 2011

There are some key questions to ask when having pain and thinking about going back to work. Why is work such a problem for people with pain, what is the right sort of help for people in pain, and when should this help be provided?
Clinical course of Alzheimer’s disease
Authors: Lleo Alberto , Blesa Rafael
Published: October 2011

• Alzheimer’s disease is an age-related neurodegenerative disorder, with onset usually in late life, characterized by cognitive impairment, a variety of behavioural symptoms, and restrictions in the activities of daily living

• The initial symptom is episodic memory loss, in particular in delayed recall of visual and/or verbal material. Immediate and remote memory is usually preserved in early stages...
Pharmacological treatment of Alzheimer’s disease
Authors: Wilkinson David
Published: October 2011

• Pharmacotherapy of Alzheimer’s disease (AD) has progressed in the last 10 years with the emergence of rational treatments aimed at neuro-transmitter replacement

• All the compounds improve attention and alertness and have global benefits for patient and carer not always reflected in improvements in cognitive scores...
Safety, legal issues and driving
Authors: Jones Roy W.
Published: October 2011

• A person with dementia’s autonomy must be respected as far as possible and recognition given to their remaining abilities and rights

• People with dementia usually reach a point where they cannot manage their own legal and financial affairs

• The capacity needed to make a particular decision depends on the nature and complexity of the decision...
Essential role of the adaptor protein Nck1 in Jurkat T cell activation and function
Authors: Yiemwattana I , Ngoenkam J , Paensuwan P , Kriangkrai R , Chuenjitkuntaworn B , Pongcharoen S
Published: October 2011

The non-catalytic region of tyrosine kinase (Nck) is proposed to play an essential role in T cell activation. However, evidence based on functional and biochemical studies has brought into question the critical function of Nck. Therefore, the aim of the present work was to investigate the role of Nck in T cell activation. To study this, the human Jurkat T cell line was used as a model for human T lymphocytes. The short interfering (si) RNA targeting Nck1 gene was used with electroporation to knock-down Nck1 protein expression in Jurkat T cells. Primary human CD4 T cells were also transfected with the siRNA of Nck1. The results showed that decreased Nck1 protein expression did not affect the apoptosis of the transfected Jurkat T cells compared with control siRNA-transfected cells and non-transfected cells. Upon CD3ε/CD28 stimulation, knock-down of Nck1 in Jurkat T cells caused a decrease in CD69 expression and in interleukin (IL)-2 secretion. Similarly, knock-down of Nck1 in primary CD4 T cells also caused decreased CD69 expression. However, no significant alterations of CD69 and IL-2 expression were found upon phytohaemagglutinin (PHA)/phorbol myristate acetate (PMA) stimulation. Knock-down of Nck1 had no effect on the proliferation of Jurkat T cells stimulated with either PHA or anti-T cell receptor (TCR) monoclonal antibody (C305). The reduced Nck1 expression in Jurkat cells was also associated with a reduced phosphorylation of extracellular regulated kinase (Erk)1 and Erk2 proteins upon CD3ε/CD28 stimulation. In conclusion, the decreased Nck1 protein in Jurkat T cells resulted in an impairment of TCR–CD3-mediated activation involving a defective Erk phosphorylation pathway.
Evaluating the effects of urbanisation on salamander abundances using a before‐after control‐impact design
Authors: PRICE STEVEN J. , BROWNE ROBERT A. , DORCAS MICHAEL E.
Published: October 2011

1. Urbanisation represents a significant threat to semi‐aquatic amphibian populations, especially stream‐dwelling salamanders. Although studies of urbanisation effects on amphibians have been conducted, there is an urgent need to follow populations over longer time periods, account for imperfect detection and determine the response time to urbanisation. Consequently, we used a before‐after control‐impact (BACI) study design to estimate changes in abundances of larval and adult salamanders in streams affected by urbanisation.

2. From 2005 to 2009, we used standard sampling techniques to obtain a count of salamanders in 13 first‐order streams that underwent urbanisation of their catchments after the first year of sampling. Simultaneously, we counted salamanders in 17 streams that experienced no disturbance within stream catchments. Additionally, we measured environmental variables at each stream.

3. We used Royle’s binomial mixture model to estimate annual mean abundances and individual detection probabilities, and Bayesian inference was used to estimate population parameters for each stage and species.

4. Although mean abundance estimates varied among years in control and urbanised streams, we found that urbanisation had a negative effect on larval and adult salamander abundances. Larval salamander abundances at sites 1 year after urbanisation were significantly lower than abundances from control sites. Abundances of adult two‐lined salamanders (Eurycea cirrigera) at urbanised sites were lower than abundances at control sites 2 years post‐urbanisation, and adult dusky salamander (Desmognathus fuscus) abundances at urbanised sites were lower than abundances at control sites 3 years post‐urbanisation. Maximum conductivity, sedimentation level and maximum stream channel width differed between urban and non‐urban streams.

5. Our results suggest that stream‐dwelling salamanders exhibit little resistance to urbanisation. Our study also highlights the use of the BACI design to study how urbanisation affects populations in semi‐aquatic habitats. We emphasise that inferences regarding urbanisation effects on population response may be compromised unless urban populations are compared to populations in control sites, especially for species in which populations fluctuate.
Service source and channel choice in G2C service environments: a model comparison in the anti/counter‐terrorism domain1
Authors: Lee JinKyu , Rao H. Raghav
Published: October 2011

This paper compares the relative advantages of two models (a) a two‐factor (i.e. source and channel) choice model; and (b) a theory of planned behaviour (TPB)–based acceptance model, developed to explain electronic government (e‐government) service adoption. The models were empirically validated in the government‐to‐citizen (G2C) anti/counter‐terrorism (ACT) service domain by a telephone survey administered to a sample of 500 US residents systematically drawn from the mainland USA. The structured telephone survey questionnaire measured respondents' intentions to use Web‐based ACT services and their beliefs and attitudes towards various ACT service providers (e.g. the Federal Bureau of Investigation, Department of Homeland Security, local police, non‐governmental organisations (NGOs) and news companies) and media (e.g. Web, email, telephone, TV, newspapers, postal mail). The results of multiple‐regression analysis of the 500 interview responses show that the source–channel choice model can explain the service usage intentions as well as, or better than, the TPB‐based acceptance model. Both service source and channel exerted consistent and substantive effects on citizens' intention to use ACT services, explaining, on average, more than 43% of variance in the dependent variable. In contrast, subjective norms in the TPB‐based model seemed to have a marginal effect. Privacy protection and integrity of the service source appeared to be key antecedents of source preference, while the influence of channel attributes on channel preference varied widely depending on the type of services. This study provides an empirical basis for the validity and applicability of the source–channel choice model and offers insightful and prescriptive knowledge for e‐government initiatives and service providers.
The role of asynapsis in human spermatocyte failure
Authors: Sciurano R. B. , Rahn M. I. , Rey‐Valzacchi G. , Coco R. , Solari A. J.
Published: October 2011

The basic molecular mechanisms by which chromosomal rearrangements in heterozygous state produce spermatogenic disturbances are poorly understood. Testicular biopsies from five patients – one carrier of a Robertsonian translocation rob t(13;14), two carriers of two different Y‐autosome translocations, a t(Y;6) and a t(Y;11), one carrier of a reciprocal translocation t(3;13) and one carrier of a heterochromatin duplication in chromosome 9 – were processed for histopathological analysis, electron microscopy and fluorescent immunolocalization of meiotic proteins. In all the patients, the asynaptic regions during pachytene are labelled by BRCA1 and retained RAD51 foci. The variant histone γ‐H2AX is located on the chromatin domains of the asynaptic regions and the XY body. In contrast, these meiotic proteins are absent in those chromosomal segments that are non‐homologously synapsed. The present observations on five new cases and a review of recent studies show that the common features shared by all these cases are the abnormal location of some meiotic proteins and the presence of transcriptionally silenced chromatin domains on asynaptic regions. The frequent association of these silenced regions with the XY body and the rescue of spermatocyte viability through non‐homologous synapsis are also shared by all these carriers. A passive, random mechanism of clustering of asynaptic regions with the XY body is suggested.
Patch occupancy and abundance of local populations in landscapes differing in degree of habitat fragmentation: a case study of the colonial black‐headed gull, Chroicocephalus ridibundus
Authors: Kajzer Joanna , Lenda Magdalena , Kośmicki Andrzej , Bobrek Rafał , Kowalczyk Tomasz , Martyka Rafał , Skórka Piotr
Published: October 2011

Aim  This study investigated whether habitat fragmentation at the landscape level influences patch occupancy and abundance of the black‐headed gull, Chroicocephalus ridibundus, and whether the response of the species to environmental factors is consistent across replicated landscape plots.

Location  Water bodies (habitat patches) in southern Poland.

Methods  Surveys were conducted in two landscape types (four plots in each): (1) more‐fragmented landscape, in which habitat patches were small (mean size 2.2–6.2 ha) and far apart (mean distance 2.5–3.1 km); and (2) less‐fragmented landscape, in which habitat patches were large (mean size 9.2–16.5 ha) and separated by short distances (mean 0.9–1.4 km). Observations were performed twice in 284 potential habitat patches during the 2007 breeding season.

Results  Colonies were significantly more frequent and larger in the less‐fragmented landscapes than in the more‐fragmented ones. Probability of patch occupancy and number of breeding birds were positively related with patch size and these relationships were especially strong in the more‐fragmented landscapes. In the less‐fragmented landscapes, the occurrence of black‐headed gulls was negatively related to the distance to the nearest local population, but in the more‐fragmented landscapes such a relationship was not detected. As distance to the nearest habitat patch increased, the probability of the patch occupancy decreased in the more‐fragmented landscapes. Moreover, abundance was negatively influenced by distance to the nearest habitat patch, especially strongly in more‐fragmented landscapes. Proximity of corridors (rivers) positively influenced the occupation of patches regardless of landscape type. The number of islets positively influenced occupancy and abundance of local populations, and this relationship was stronger in the more‐fragmented landscapes.

Main conclusions  Our results are in agreement with predictions from metapopulation theory and are the first evidence that populations of black‐headed gulls may have a metapopulation structure. However, patch occupancy and abundance were differentially affected by explanatory variables in the more‐fragmented landscapes than in the less‐fragmented ones. This implies that it is impossible to derive, a priori, predictions about presence/abundance patterns based on only a single landscape.
Differential regional response of the bushy‐tailed woodrat (Neotoma cinerea) to late Quaternary climate change
Authors: Hornsby Angela D. , Matocq Marjorie D.
Published: October 2011

Aim  To reconstruct the regional biogeographical history of the bushy‐tailed woodrat, Neotoma cinerea (Rodentia: Cricetidae), across its distribution using multiple sources of information, including genetic data, ecological niche models and the palaeorecord.

Location  Western North America.

Methods  We analysed complete cytochrome b gene (1143 bp) sequences from 182 specimens of N. cinerea using Bayesian and coalescent methods to infer phylogenetic relationships, time of major divergences, and recent demographic trends. For comparison, we developed clade‐specific ecological niche models for groups of interest and analysed spatial trends of N. cinerea in the palaeorecord as well as temporal frequency trends across strata of individual palaeomiddens.

Results  We found two largely allopatric clades within N. cinerea, with several regionally distinct subclades showing contrasting recent population dynamics. Niche models showed consistent habitat at the Last Glacial Maximum (LGM) and modern times in the Rocky Mountains and northern United States, while the Great Basin may have been markedly less suitable at the LGM than today. The palaeorecord showed great spatio‐temporal variability in the presence of N. cinerea, but documents broad‐scale patterns of occupancy and regional population trends.

Main conclusions  The Quaternary dynamics and evolutionary history of N. cinerea appear to have been shaped by both vicariant events associated with geographical barriers and the availability of suitable habitat through time. Divergence of the two major clades dates to the Pliocene–Pleistocene transition, with clades separated by the Green and Colorado rivers and northern Rocky Mountain Pleistocene glaciations. We found largely concordant genetic, niche model and palaeorecord patterns suggesting long‐term population stability in the Rocky Mountains, while extant clades in the Great Basin and far north appear to have expanded or re‐expanded into these regions relatively recently. Furthermore, disjunct haplotype distributions, regional demographic history, and historical distribution of suitable habitat suggest that the Great Basin has been a particularly dynamic region.
Prospective study of risk factors for hepatitis C virus acquisition by Caucasian, Hispanic, and Asian American patients
Authors: Ho E. Y. , Ha N. B. , Ahmed A. , Ayoub W. , Daugherty T. , Garcia G. , Cooper A. , Keeffe E. B. , Nguyen M. H.
Published: October 2011

Summary.  Commonly known risk factors for infection with hepatitis C virus (HCV) include blood transfusion, injection drug use, intranasal cocaine use, and body tattoos. We hypothesized that Asian Americans infected with HCV may not identify with these established risk factors present in Caucasians and Hispanics, and our aim was to conduct a survey of risk factors in HCV‐infected patients in these ethnic groups. In this prospective study, 494 patients infected with HCV completed a detailed risk assessment questionnaire at a liver centre in Northern California from 2001 to 2008. Among subjects participating in this study, 55% identified themselves as Caucasian, 20% as Hispanic, and 25% as Asian. Asian Americans were older, less likely to smoke or consume alcohol, and have a family history of cancer compared with Caucasians and Hispanics. The laboratory profiles were similar, and genotype 1 was the most common infection in all groups (74–75%). The great majority of Caucasians (94%) and Hispanics (86%) identified with commonly known risk factors, which was in contrast to 67% of Asians (P < 0.0001). The most common risk factors in Asians were blood transfusions (50%) and acupuncture (50%). Furthermore, 74% of Caucasians and 66% of Hispanics identified more than one major risk factor, while only 20% of Asians reported having more than one risk factor (P < 0.0001). Survey for established risk factors for acquisition of HCV may be more appropriate for risk assessment of Caucasians and Hispanics, but not for Asian Americans. These findings may guide the development of HCV screening in our increasingly diverse population.
Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection
Authors: Yamada I. , Suzuki F. , Kamiya N. , Aoki K. , Sakurai Y. , Kano M. , Matsui H. , Kumada H.
Published: October 2011

Summary.  Background: Telaprevir in combination with peginterferon and ribavirin is a promising advancement in chronic hepatitis C treatment. However, the safety, tolerability, pharmacokinetics and antiviral profiles of telaprevir alone beyond 2 weeks have not been studied. Methods: In a phase 1b study in Japan, 10 treatment‐naïve patients infected with hepatitis C virus genotype 1b with high viral load (>5 log10 IU/mL) received telaprevir 750 mg every 8 h (q8h) for 12 weeks. We examined the safety, tolerability, pharmacokinetics, hepatitis C virus (HCV) RNA levels and resistant variants of telaprevir. Results: Neither serious adverse events nor discontinuations of study drug owing to an adverse event occurred. The most common adverse drug reactions were rash (80%) and anaemia (70%). Telaprevir concentration reached its steady state within 2 days after the first administration without abnormal accumulation. Telaprevir alone provided potent antiviral activity: a median log10 decrease of 2.325 at 16 h and 5.175 on Day 14. During the treatment, HCV RNA levels at the nadir were below the limit of the quantification in seven patients and undetectable in three of 10 patients. Viral breakthrough associated with mainly Ala156‐substituted variants occurred in eight patients, and only one patient showed end‐of‐treatment response. The selected variants reverted to the wild‐type during the 24‐week follow‐up period. Conclusion: Telaprevir alone was well tolerated at 750 mg q8h for up to 12 weeks. The safety profile and emergence of resistant variants of genotype 1b under telaprevir monotherapy for 12 weeks will become increasingly important in evaluating an oral combination of telaprevir with other direct‐acting antiviral agents.
Hepatic expression of MxA and OAS1 in an ex vivo liver slice assay independently predicts treatment outcomes in chronic hepatitis C
Authors: Cheng J.‐C. , Yeh Y.‐J. , Huang Y.‐H. , Liang K.‐H. , Chang M.‐L. , Lin C.‐Y. , Yeh C.‐T.
Published: October 2011

Summary.  Antiviral effect of interferon is mediated by the expression of interferon‐stimulated genes (ISGs). However, because of the difficulty in obtaining paired liver biopsies before and after interferon treatment, the key ISGs expressed in human hepatocytes and responsible for interferon‐based antiviral activities in chronic hepatitis C remain illusive. Prior to a standard course of peginterferon plus ribavirin therapy, 104 patients underwent a liver biopsy. A small piece of the liver biopsy sample from each patient was submitted for ex vivo tissue culture in the presence or absence of interferon. Hepatic expression of 8 ISGs was detected by RT‐PCR. The ISG expression patterns and clinicopathological variables were correlated with subsequent treatment outcomes. Multivariate logistic regression analysis showed that hepatic MxA expression (P = 0.008) and leucocyte count (P = 0.040) independently predicted the end of therapeutic virological response, while hepatic OAS1 expression (P = 0.003), genotype 1 (P = 0.002), HCV‐RNA level (P = 0.007), AST/ALT ratio (P = 0.004) and leucocyte count (P = 0.034) independently predicted the sustained virological response. Immunohistochemistry analysis showed that interferon‐induced OAS1 expression localized to the hepatocytes. In conclusion, hepatic MxA and OAS1 expression predicted, respectively, the end of therapeutic and sustained virological responses in interferon‐based treatment of chronic hepatitis C.
Reply to comment on ‘Insights from the Mw 6.3 2009 L’Aquila earthquake (Central Apennines) – unveiling new seismogenic sources through their surface signatures: the adjacent San Pio Fault’
Authors: Di Bucci Daniela , Vannoli Paola , Burrato Pierfrancesco , Fracassi Umberto , Valensise Gianluca
Published: October 2011

Terra Nova, 23, 421–423, 2011

We reply to a comment by Messina et al., who strongly criticized our article on the San Pio Fault, by showing that in areas of complex geology such as the central Apennines, where the current tectonic setting results from the superposition of different tectonic regimes, the equation: `most visible active fault = major seismogenic fault' can be misleading.
Crustal stress and strain patterns in the Indian plate interior: implications for the deformation behaviour of a stable continent and its seismicity
Authors: Mohanty Saradaprasad
Published: October 2011

Terra Nova, 23, 407–415, 2011

The present analyses indicate that the maximum principal stress axis of the Indian plate interior does not coincide with the plate motion vector. The strain rate curves for the Indian plate indicate interference of two different orders of deformation. The magnitudes of the first‐order maximum strain rates are lower than local extreme strain rates of the second‐order deformation. It has been shown herein that the oblique motion of the Indian plate with respect to a state of dominant strike‐slip deformation in the Indian plate interior is partitioned into a principal deformation zone, synthetic shear and antithetic shear. The strain rates along these regional shear zones show complex association of second‐order high shortening rate coinciding with high extension rate. The earthquakes of the Indian plate interior are interpreted to be results of periodic accumulation of stress/strain due to shortening and release of strain along the same directions during the extension.
What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration
Authors: Ketelaar ME , Hofstra RMW , Hayden MR
Published: October 2011

Ketelaar ME, Hofstra RMW, Hayden MR. What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration.

As monozygotic (MZ) twins are believed to be genetically identical, discordance for disease phenotype between MZ twins has been used in genetic research to understand the contribution of genetic vs environmental factors in disease development. However, recent studies show that MZ twins can differ both genetically and epigenetically. Screening MZ twins for genetic and/or epigenetic differences could be a useful and novel approach to identify modifying factors influencing phenotypic expression of disease. MZ twins that are phenotypically discordant for monogenic diseases are of special interest. Such occurrences have been described for Huntington's disease, spinocerebellar ataxias, as well as for familial forms of Alzheimer's disease. By comparing MZ twins that are phenotypically discordant, crucial factors influencing the phenotypic expression of the disease could be identified, which may be of relevance for understanding disease pathogenesis and variability in disease phenotype. Overall, understanding the crucial factors in development of a neurodegenerative disorder will have relevance for predictive testing, preventive treatment and could help to identify novel therapeutic targets.
Clinical and radiological features of respiratory syncytial virus in solid organ transplant recipients: a single‐center experience
Authors: Ariza‐Heredia E.J. , Fishman J.E. , Cleary T. , Smith L. , Razonable R.R. , Abbo L.
Published: October 2011

Background

Respiratory syncytial virus (RSV) infections range from upper respiratory illness to severe lower respiratory disease. There is no universally accepted treatment for RSV in solid organ transplant (SOT) recipients.

Methods

Retrospective review of adult SOT patients with RSV infections, between January 2007 and December 2009, in a single transplant center was performed.

Results

During the 3‐year period, a total of 24 adults developed RSV infection, including 12 (50%) SOT recipients (5 kidneys, 4 livers, and 3 lungs). Most cases were seen in 2009 during the influenza H1N1 pandemic, likely as a result of increased testing. In 83% of the cases, the diagnosis was based on RSV antigen detection, which was also used to follow subsequent shedding (mean duration: 20.6 days). Most of the cases presented with lower respiratory disease and required hospitalization. All the patients were on at least two classes of immunosuppressive drugs. We observed a lower lymphocyte count in patients with lower respiratory tract infection. Computed tomography was superior to chest x‐ray in demonstrating pulmonary disease, with the most common findings being pulmonary nodules and ground‐glass opacities. Novel radiographic findings were small cavities and pleural effusions. No co‐infections were documented, and no mortality could be attributed to RSV. Inhaled or oral ribavirin was administered in 67% of the cases, with variations in the treatment regimens.

Conclusion

SOT recipients accounted for half of all adult cases of RSV at our institution. Type and length of treatment varied widely, and we cannot conclude that outcomes differed between treatments with oral or inhaled ribavirin. Current therapeutic management of RSV in SOT is empiric, and can be rather expensive and difficult, without clear evidence of effectiveness.
Expression of pERK and pAKT in pediatric high grade astrocytomas: Correlation with YKL40 and prognostic significance
Authors: Antonelli Manila , Massimino Maura , Morra Isabella , Garrè Maria Luisa , Gardiman Marina Paola , Buttarelli Francesca Romana , Arcella Antonietta , Giangaspero Felice
Published: October 2011

The Ras signaling pathway, consisting of mitogen‐activated protein kinase (MAPK) and PI3K/AKT signaling, is a prominent oncogenic pathways in adult diffuse gliomas, but few studies have evaluated such pathways in pediatric malignant gliomas. We investigated by immunohistochemistry MAPK and AKT signaling in a series of 28 pediatric high‐grade gliomas (WHO grade III and IV). We sought a possible association of phospho‐ERK (p‐ERK) and phospho‐AKT (p‐AKT) with expression of other proteins involved in the Ras pathway, that is, YKL40, epidermal growth factor receptor (EGFR), EGFR vIII and c‐Met. Moreover we correlated the expression of p‐ERK and p‐AKT with prognosis. No cases showed expression for c‐Met and EGFR, and only one case was positive for EGFR vIII. YKL‐40 protein was expressed in 43% of cases. We detected expression of p‐ERK and p‐AKT in 61% and 57%, respectively, of pediatric high grade gliomas. Statistical analysis comparing the two groups in term of high and low p‐ERK and p‐AKT expression showed a trend toward worse overall survival in patients with high expression of p‐AKT. The activation of ERK and AKT suggest a possible role of this protein in inducing activation of the Ras signaling pathway in pediatric high‐grade gliomas. Moreover high levels of p‐AKT are associated with worse overall survival.
Essential, but at what risk? A prospective study on central venous access in patients with haematological malignancies
Authors: Dix C. H. K. , Yeung D. T. O. , Rule M. L. , Ma D. D. F.
Published: October 2011

Aims:  Central venous catheters (CVC) are integral to modern haematology practice; however, they are associated with a range of complications. This prospective study aimed to determine the rate of CVC‐related complications and risk factors in haematology patients, who are vulnerable because of their underlying pathology and treatments.

Methods:  All inpatients that had a non‐tunnelled CVC inserted in a 14‐month period in the haematology ward at St Vincent's Hospital were enrolled. Complications (immediate and late), demographics, type of device, insertion technique and duration of dwell, were examined using multivariate analysis.

Results:  One hundred and seventy‐four CVC in 84 patients were recorded, representing 3016 catheter‐days. At least one complication was found in 43 (24.7%) patients. Immediate complications occurred in 13 (7.5%) insertions, with a higher rate in those inserted after ≥2 attempts compared with one (P= 0.02). Catheter‐related bloodstream infection occurred at a rate of 7.6 per 1000 catheter‐days, with acute lymphoblastic leukaemia associated with a higher rate (P= 0.02), and subclavian vein CVC had a lower rate compared with other locations (P < 0.01). Thrombosis was found in seven (4.0%) patients, with subclavian CVC carrying an increased risk (P= 0.02).

Conclusions:  This prospective observational study found almost a quarter of haematology patients experience a CVC‐related complication. An association was found with a number of attempts at insertion and immediate complications; other risk factors included anatomical location, underlying disease and duration of catheterisation. The relatively high complication rate, compared with reports of non‐haematology patients, highlights the need to improve CVC management, a vital part of care for this population.
Characterization of cytokines associated with Th17 cells in the eyes of horses with recurrent uveitis
Authors: Regan Daniel P. , Aarnio Megan C. , Davis Wesley S. , Carmichael K. Paige , Vandenplas Michel L. , Lauderdale James D. , Moore Phillip A.
Published: October 2011

Objective  Equine recurrent uveitis (ERU) is a spontaneous disease that is the most common cause of blindness in horses, affecting up to 15% of the horse population. Th17 cells are a major cell population driving the pathogenesis in several mouse models of autoimmune inflammation, including experimental autoimmune uveitis. The purpose of this study is to investigate the role a Th17 cell‐mediated response plays in the pathogenesis of ERU.

Procedure  Banked, Davidson’s‐fixed equine globes histopathologically diagnosed with ERU (n = 7) were compared immunohistochemically with healthy control globes (n = 7). Immunohistochemical staining was performed using a pan‐Leptospira antibody and antibodies against IL‐6, IL‐17, and IL‐23. Additionally, immunostaining was performed for T‐cell (CD3) and B‐cell (CD79α) markers. Specificity of immunoreactivity was confirmed by western blot analysis.

Results  Immunohistochemical staining was positive for IL‐6, IL‐17, and IL‐23 within the cytoplasm of nonpigmented ciliary epithelial cells and mononuclear inflammatory cells infiltrating the iris, and ciliary body of ERU horses (n = 7) but negative in controls (n = 7). ERU‐affected eyes were CD3 positive (n = 7) and CD79α negative (n = 7). Staining for Leptospira was negative in all ERU and control globes.

Conclusions  Strong immunoreactivity for IL‐6, IL‐17, and IL‐23, in conjunction with the fact that T lymphocytes are the predominating inflammatory cells present in ERU, suggests that IL‐17‐secreting helper T‐cells play a role in the pathogenesis of ERU. These findings suggest that horses with ERU may serve as a naturally occurring animal model for autoimmune uveitis.
A preliminary study of changes in tear film proteins in the feline eye following nictitating membrane removal
Authors: Petznick Andrea , Evans Margaret D. M. , Madigan Michele C. , Garrett Qian , Sweeney Deborah F.
Published: October 2011

Objective  To investigate the influence of nictitating membrane (third eyelid) removal on selected proteins in feline tears.

Animal studied  Domestic short‐haired cats (7–17 months; 2.6–5.2 kg) were used.

Procedures  Eye‐flush tears were collected periodically for up to 18 weeks from both eyes of animals with nictitating membranes removed, but nictitating gland left intact, (n = 4) or with nictitating membranes intact (n = 4). Tear comparisons were based on total protein content (TPC) using micro bicinchoninic acid assay, immunoglobulin A (IgA), and matrix‐metalloproteinase (MMP)‐9 measurements using sandwich enzyme‐linked immunosorbent assay (ELISA) and tear gelatinase activity using gelatin zymography. Expression of MMP‐2 and ‐9 in nictitating membranes removed at baseline (week 0) and eyes collected at 18 weeks were also investigated in histological sections using immunoperoxidase for visualization.

Results  Nictitating membrane removal did not significantly change TPC and MMP‐9 in tears within the first 4 weeks. MMP‐9 was not detected by ELISA in tears from eyes without nictitating membranes from week 5 onwards. IgA (%IgA of TPC) data varied between animals. Gelatin zymography showed increased MMP‐2 and ‐9 activity in tears from eyes without nictitating membranes at week 1 and a decrease following week 2 post‐surgery. MMP‐2 and ‐9 were immunolocalised to conjunctival goblet cells of removed nictitating membranes and to the conjunctival epithelium, respectively. After 18 weeks, the distribution of MMPs in tissue was comparable between eyes with and without nictitating membranes.

Conclusions  Based on this preliminary study, nictitating membrane removal appeared to cause long‐term changes in expression of tear proteins, including reduced MMP‐9 expression.
Genome gender diversity in affected sib‐pairs with familial vesico‐ureteric reflux identified by single nucleotide polymorphism linkage analysis
Authors: Marchini Giovanni S. , Onal Bulent , Guo Chao‐Yu , Rowe Courtney K. , Kunkel Louis , Bauer Stuart B. , Retik Alan B. , Nguyen Hiep T.
Published: October 2011

Study Type – Aetiology (case series)

Level of Evidence 4

What's known on the subject? and What does the study add?

Genetic linkage to distinguish loci for VUR has been previously described in several autosomal chromosomes. Although there are numerous explanations for the dissimilar findings, e.g. multifactorial etiology of VUR and hereditary miscellany among studied populations, clinical diversity between males and females may indicate a central gender‐specific genetic susceptibility.

Early studies suggested the presence of modified VUR gene(s) on the X‐chromosome, accounting for the higher incidence of this disorder among female members in the pedigrees studied. On the other hand male‐to‐male transmission and a higher ratio of females to males argued against X‐linked inheritance. More recently, additional chromosomal regions (i.e. chromosomes 1–7, 10–13, and 18–22) have been identified for VUR by using single nucleotide polymorphism‐genome‐wide linkage analysis.

This is the first study to show that there is autosomal difference in VUR expression in males and females. This genotype variability may be the basis for the clinical differences between genders in children with VUR.

OBJECTIVE

To assess gender‐specific genetic differences in the susceptibility loci for vesico‐ureteric reflux (VUR) in families who have two or more affected children.

PATIENTS AND METHODS

A genome‐wide linkage analysis of VUR with high‐density single nucleotide polymorphisms was conducted in 98 families with two or more affected children.

A total of 221 affected offspring (123 sibling pairs) were included in the analysis.

Genomic DNA was extracted from blood or saliva from all the patients.

Data was stratified and analysed according to clinical presentation and gender of the proband and affected siblings.

RESULTS

Using the affected sib‐pair method, statistically significant peaks were found on chromosomes 1 (logarithm of odds, base10 [LOD] 4.4) and 5 (LOD 3.7) in males and on chromosomes 3 (LOD 3.5), 13 (LOD 4.5), and 15 (LOD 3.4) in females.

CONCLUSION

This genotype variability might be the basis for the clinical differences between genders in children with VUR. Our data might be the first step to understanding the genetic background behind the gender‐specific differences of VUR and more clearly defining the genetically different subgroups of VUR.
High cytoplasmic expression of p27Kip1 is associated with a worse cancer‐specific survival in clear cell renal cell carcinoma
Authors: Kruck Stephan , Merseburger Axel S. , Hennenlotter Joerg , Scharpf Marcus , Eyrich Christian , Amend Bastian , Sievert Karl‐Dietrich , Stenzl Arnulf , Bedke Jens
Published: October 2011

What's known on the subject? and What does the study add?

The loss of p27Kip1 correlates with poor prognosis in various human cancers, and was postulated as a biomarker in RCC. Up to now p27Kip1 analysis in RCC was focused on its nuclear localization.

We confirmed higher p27Kip1 expression in the nucleus and cytoplasm of RCC and correlated high cytoplasmic p27Kip1 with an unfavourable clinic and a reduced survival.

OBJECTIVES

To analyse the cytoplasmic and nuclear differences of p27Kip1 expression and localization in benign and clear cell renal cell carcinoma (ccRCC) with regard to overall survival (OS) and cancer‐specific survival (CSS).

p27Kip1 is considered to contribute to the progression of ccRCC and is targeted by next generation dual‐therapies.

PATIENTS AND METHODS

In 140 patients, ccRCC and corresponding benign kidney tissue were analyzed for nuclear and cytoplasmic staining of p27Kip1 by immunohistochemistry using a tissue microarray technique.

Staining intensity and percentage of positive stained cells are given as expression scores. p27Kip1 expression was categorized as high if ccRCC tissue stained stronger than the respective level of the corresponding benign tissue and categorized as low if ccRCC tissue stained less than or equal to the corresponding benign tissue.

Differences in OS and CSS were analyzed by log‐rank analysis and expression levels were correlated with tumour and patient characteristics using Fisher's exact test.

RESULTS

Cytoplasmatic (mean [sd]: 13.8% [1.2%] vs 10.7% [1.7%]; P= 0.04) and nuclear (mean [sd]: 75.6% [2.7%] vs 13.6% [2.1%]; P < 0.001) staining of p27Kip1 were significantly stronger in ccRCC tissues compared to benign tissue.

High cytoplasmic p27Kip1 expression was significantly associated with a higher T and N stage, Fuhrman grade and the presence of metastatic disease (P < 0.001).

The median follow‐up time was 38.2 months.

There was no difference in OS between the low and high expression groups, although CSS was significantly lower in patients with high cytoplasmic p27Kip1 (P < 0.001) and CSS heavily tended to be lower in the nuclear low expression group (P= 0.069).

CONCLUSIONS

High cytoplasmic p27Kip1 levels in renal cancer tissues are associated with advanced disease and reduced cancer specific survival, whereas low nuclear expression levels appear to be beneficial.

The present study corroborates the consideration of cytoplasmic p27Kip1 for future diagnostic and targeted therapeutic approaches in RCC establishing a potential protective shift of p27Kip1 from the cytoplasm to the nucleus.
Increased plasma levels of total homocysteine but not asymmetric dimethylarginine in Hispanic subjects with ischemic stroke FREC‐VI sub‐study
Authors: Rueda‐Clausen C. F. , Córdoba‐Porras A. , Bedoya G. , Silva F. A. , Zarruk J. G. , López‐Jaramillo P. , Villa L. A.
Published: October 2011

Background and purpose:  Despite sharing some metabolic and pathological mechanisms, the reported association between total homocysteine (tHcy), asymmetric dimethylarginine (ADMA) and stroke remains controversial, particularly in Hispanic populations from developing countries in which genetic, socioeconomic, and nutritional factors are different to those described in developed countries. Our objectives were to determine the relationships of these factors to stroke and to each other independent of other cardiovascular risk factors, and to explore potential sex differences.

Methods:  This national (Colombia) multicenter case–control study included 238 cases and 238 controls to evaluate traditional and emerging risk factors for ischemic stroke including tHcy and ADMA plasma levels.

Results:  The median plasma levels of tHcy were 8.48 μM for controls and 10.01 μM for cases (P < 0.0001). Plasma levels of tHcy between 12 and 50 μM were considered moderate hyperhomocysteinemia (HtHcy). There were no differences in plasma ADMA concentration between groups (P = 0.40). Plasma levels of ADMA and creatinine were not correlated (P = 0.47). After adjusting for confounding factors, the presence of HtHcy was strongly associated with stroke (OR 8.97; P < 0.0001). The adjusted association between HtHcy and stroke in men (OR 9.98) was comparable to that in women (OR 8.98) (P = 0.41).

Conclusions:  In this Hispanic population, with relatively normal renal function, plasma levels of tHcy but not ADMA were associated with stroke independent of other cardiovascular risk factors.
Soluble VEGFR1 (sVEGFR1) as a novel marker of amyotrophic lateral sclerosis (ALS) in the North Indian ALS patients
Authors: Anand A. , Gupta P. K. , Sharma N. K. , Prabhakar S.
Published: October 2011

Background and purpose:  North Indian patients with amyotrophic lateral sclerosis (ALS) exhibit substantially extended survival time after onset of the disease as compared to their Western counterparts. Earlier, we found that vascular endothelial growth factor‐A (VEGF‐A) may be associated with increased survival of these patients. We now measured soluble vascular endothelial growth factor receptor‐1 (sVEGFR1), an inhibitor receptor for VEGF‐A, in these patients with ALS.

Methods:  Patients with sporadic ALS (n = 36) attending the Neurology Outpatient at Post Graduate Institute of Medical Education and Research (PGIMER) at Chandigarh were included on the basis of El Escorial criteria. The sVEGFR1 levels were analyzed in serum of these patients using enzyme‐linked immunosorbent assay (ELISA) and compared with normal controls (n = 36).

Results:  Soluble vascular endothelial growth factor receptor‐1 was found to be decreased significantly in serum of patients with ALS. Serum obtained from definite ALS revealed significantly lower sVEGFR1 as compared to probable ALS. However, there was no difference in serum sVEGFR1 levels between male and female patients with ALS.

Conclusions:  Soluble vascular endothelial growth factor receptor‐1 downregulation may result in increased serum VEGF‐A reported previously in our patients with ALS and may indicate the activation of compensatory mechanism in response to neurodegeneration. The lower serum sVEGFR1 levels may have a possible clinicopathological association, if not causal, to the extended survival of North Indian patients with ALS; however, the result needs further investigations particularly in comparable Caucasian ALS population.